Inclusion Criteria:
1. Has a confirmed diagnosis of UC established at least 3 months prior to screening, by clinical and endoscopic evidence and corroborated by a histopathology report.
2. Has moderately to severely active UC as determined by a complete Mayo score \[including physician's global assessment (PGA)\] of 6 to 12 with a rectal bleeding subscore ≥1 and a centrally assessed endoscopic subscore ≥2 at screening.
3. Has evidence of UC extending proximally to the rectum \[≥15 centimeter (cm) of involved colon\].
4. Participants with extensive colitis or pancolitis of \>8 years duration or left sided colitis \>12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial screening visit.
5. Participants with a family history of colorectal cancer, personal history of increased colorectal cancer risk, age \>50 years, or other known risk factors must be up to date on colorectal cancer surveillance.
6. Has demonstrated an inadequate response to, loss of response to, or intolerance to at least 1, but no more than 2 TNFα antagonists. Participants without prior failure or intolerance to biologics are not eligible. Participants who discontinued TNFα antagonist therapy for reasons other than failure or intolerance (eg, pregnancy) may be eligible after discussion with the medical monitor.
Note: After the interim analysis, participants with inadequate response, loss of response, or intolerance to conventional UC therapy without prior exposure to biologics may be enrolled if deemed appropriate. Participants who discontinued biologics for reasons other than failure or intolerance (eg, pregnancy) may be eligible after discussion with the Medical Monitor.
7. If using corticosteroids must be on a stable dose of oral corticosteroids up to a maximum of 40 mg daily of prednisone or 9 mg daily of budesonide, or equivalent for at least 2 weeks prior to screening endoscopy and must be willing to follow a mandatory taper of corticosteroids from enrollment.
Exclusion Criteria:
Gastrointestinal Exclusion criteria:
1. Has any of the following UC-related complications:
1. Acute severe UC.
2. The participant has had extensive colonic resection, subtotal or total colectomy.
3. The participant has clinical evidence of abdominal abscess or toxic megacolon.
4. The participant has an ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.
5. Short bowel syndrome.
2. Has Crohn's colitis, indeterminate colitis, ischemic colitis, nonsteroidal anti-inflammatory drug (NSAID) induced colitis, idiopathic colitis (i.e, colitis not consistent with UC), radiation colitis, microscopic colitis, colonic mucosal dysplasia, or untreated bile acid malabsorption. Participants with a history of colonic mucosal dysplasia are also excluded.
3. Has uncontrolled primary sclerosing cholangitis.
Infectious Disease Exclusion Criteria:
1. Has any evidence of an active systemic infection during screening. Participants with nonsystemic infections (eg, active fungal infection of nail beds) may be eligible, if in the opinion of the investigator, inclusion of the participant will not interfere with the collection or interpretation of study results and poses no risk to the participant.
2. Has active or latent tuberculosis (TB), regardless of treatment history, as evidenced by any of the following:
1. History of TB.
2. A diagnostic TB test performed during screening that is positive, as defined by:
i. A positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests or ii. A tuberculin skin test reaction ≥10 mm (≥5 mm in subjects receiving the equivalent of \>15 mg daily prednisone).
3. A positive test for hepatitis B virus (HBV).
4. A positive test for hepatitis C virus (HCV).
5. Evidence of, or treatment for, Clostridium difficile infection or other intestinal pathogen within 28 days prior to first dose of study treatment. Participants who test positive for C. difficile or other intestinal pathogens at screening and receive treatment may be enrolled or rescreened (if required) following confirmation of infection resolution.
6. Evidence of active Cytomegalovirus (CMV) infection at screening.
Medication exclusion criteria:
1. Has received immunomodulators (eg, 6-mercaptopurine, azathioprine, and methotrexate) within 4 weeks prior to first dose or immunosuppressants (eg, cyclosporine, tacrolimus) within 8 weeks prior to first dose.
2. Any medicinal product, herbal medication, or natural health product which might interfere with cytochrome P450 genotype 3A4 (CYP3A4) within 2 weeks prior to enrollment, except for any CYP3A4 modulator used to treat a C. difficile or an intestinal pathogen infection at screening.
3. Has received any of the following medical therapies for UC:
1. IV antibiotics within 8 weeks prior to enrollment.
2. Any rectal therapy for treatment of UC within 2 weeks prior to screening endoscopy.
3. Chronic NSAID use defined as daily use for \>2 consecutive weeks (Note: occasional use \[\<2 consecutive weeks\] of NSAIDs and acetaminophen \[\<100 mg daily\] for headache, arthritis, myalgias, or menstrual cramps and chronic low dose aspirin use \[81-162.5 mg daily\] for cardiovascular prophylaxis are permitted).
4. Has received a live virus or live bacterial vaccine within 4 weeks prior to enrollment or planned vaccination during the study and for 12 weeks after last dose.
General Exclusion Criteria:
1. Has any of the following cardiovascular or thrombotic conditions:
1. Recent (within past 6 months) cerebrovascular accident, myocardial infarction, or coronary stenting.
2. Recent (within past 6 months) moderate to severe congestive heart failure (New York Heart Association class III or IV).
3. Prior history of thrombotic events, including deep vein thrombosis and pulmonary embolism.
4. Known inherited conditions that predispose to hypercoagulability.
2. History of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.
3. A surgical procedure requiring general anesthesia within 3 months prior to screening or is planning to undergo major surgery during the study period.
4. Any investigational procedure ≤4 weeks prior to screening that, in the investigator's opinion, may interfere with interpretation of study results.
→
Inclusion Criteria:
1. Has a confirmed diagnosis of UC established at least 3 months prior to screening, by clinical and endoscopic evidence and corroborated by a histopathology report.
2. Has moderately to severely active UC as determined by a complete Mayo score \[including PGA\] of 6 to 12 with a rectal bleeding subscore ≥1 and a centrally assessed endoscopic subscore ≥2 at screening.
3. Has evidence of UC extending proximally to the rectum \[≥15 centimeter (cm) of involved colon\].
4. Participants with extensive colitis or pancolitis of \>8 years duration or left sided colitis \>12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial screening visit.
5. Participants with a family history of colorectal cancer, personal history of increased colorectal cancer risk, age \>50 years, or other known risk factors must be up to date on colorectal cancer surveillance.
6. Has demonstrated an inadequate response to, loss of response to, or intolerance to at least 1, but no more than 2 TNFα antagonists. Determination of inadequate response, loss of response, or intolerance is based upon investigator's clinical judgment. Participants who discontinued TNFα antagonist therapy for reasons other than failure or intolerance (eg, pregnancy) may be eligible after discussion with the medical monitor.
Note: After the interim analysis, participants with inadequate response, loss of response, or intolerance to conventional UC therapy per standard of care treatment without prior exposure to biologics may be enrolled if deemed appropriate. Determination of inadequate response, loss of response, or intolerance is based upon investigator's clinical judgment. Participants who discontinued biologics for reasons other than failure or intolerance (eg, pregnancy) may be eligible after discussion with the Medical Monitor. If using corticosteroids must be on a stable dose of oral corticosteroids up to a maximum of 40 mg daily of prednisone or 9 mg daily of budesonide, or equivalent for at least 2 weeks prior to screening endoscopy and must be willing to follow a mandatory taper of corticosteroids.
Exclusion Criteria:
Gastrointestinal Exclusion criteria:
1. Has any of the following UC-related complications:
1. Acute severe UC.
2. The participant has had extensive colonic resection, subtotal or total colectomy.
3. The participant has clinical evidence of abdominal abscess or toxic megacolon.
4. The participant has an ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.
5. Short bowel syndrome.
2. Has Crohn's colitis, indeterminate colitis, ischemic colitis, nonsteroidal anti-inflammatory drug (NSAID) induced colitis, idiopathic colitis (i.e, colitis not consistent with UC), radiation colitis, microscopic colitis, colonic mucosal dysplasia, or untreated bile acid malabsorption. Participants with a history of colonic mucosal dysplasia are also excluded.
3. Has uncontrolled primary sclerosing cholangitis.
Infectious Disease Exclusion Criteria:
1. Has any evidence of an active systemic infection during screening. Participants with nonsystemic infections (eg, active fungal infection of nail beds) may be eligible, if in the opinion of the investigator, inclusion of the participant will not interfere with the collection or interpretation of study results and poses no risk to the participant.
2. Has active or latent tuberculosis (TB), regardless of treatment history, as evidenced by any of the following:
1. History of TB.
2. A diagnostic TB test performed during screening that is positive, as defined by:
i. A positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests or ii. A tuberculin skin test reaction ≥10 mm (≥5 mm in participants receiving the equivalent of \>15 mg daily prednisone).
3. A positive test for hepatitis B virus (HBV).
4. A positive test for hepatitis C virus (HCV).
5. Evidence of, or treatment for, Clostridium difficile infection or other intestinal pathogen during screening. Participants who test positive for C. difficile or other intestinal pathogens at screening and receive treatment may be enrolled or rescreened (if required) following confirmation of infection resolution.
6. Evidence of active Cytomegalovirus (CMV) infection at screening.
Medication exclusion criteria:
1. Has received immunomodulators (eg, 6-mercaptopurine, azathioprine, and methotrexate) within 4 weeks prior to first dose or immunosuppressants (eg, cyclosporine, tacrolimus) within 8 weeks prior to first dose.
2. Any medicinal product, herbal medication, or natural health product which might interfere with cytochrome P450 genotype 3A4 (CYP3A4) within 2 weeks prior to enrollment, except for any CYP3A4 modulator used to treat a C. difficile or an intestinal pathogen infection at screening.
3. Has received any of the following medical therapies for UC:
1. IV antibiotics within 8 weeks prior to enrollment.
2. Any rectal therapy for treatment of UC within 2 weeks prior to screening endoscopy.
3. Chronic NSAID use defined as daily use for \>2 consecutive weeks (Note: occasional use \[\<2 consecutive weeks\] of NSAIDs and acetaminophen \[\<100 mg daily\] for headache, arthritis, myalgias, or menstrual cramps and chronic low dose aspirin use \[81-162.5 mg daily\] for cardiovascular prophylaxis are permitted).
4. Has received a live vaccine within 4 weeks prior to first dose.
General Exclusion Criteria:
1. Has any of the following cardiovascular or thrombotic conditions:
1. Recent (within past 6 months) cerebrovascular accident, myocardial infarction, or coronary stenting.
2. Recent (within past 6 months) moderate to severe congestive heart failure (New York Heart Association class III or IV).
3. Prior history of thrombotic events, including deep vein thrombosis and pulmonary embolism.
4. Known inherited conditions that predispose to hypercoagulability.
2. History of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.
3. A surgical procedure requiring general anesthesia within 3 months prior to screening or is planning to undergo major surgery during the study period.
4. Any investigational procedure ≤4 weeks prior to screening that, in the investigator's opinion, may interfere with interpretation of study results.
Key Inclusion Criteria:
* Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
* Ability to provide informed consent and documentation of informed consent before initiation of any study-related tests or procedures that are not part of standard of care for the participant's disease. Participants must also be willing and able to comply with study procedures, including the acquisition of specified research specimens.
* Life expectancy ≥ 12 weeks
* Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria and documented by Computed tomography (CT) and/or magnetic resonance imaging (MRI). The definitions for measurable lesions are the same whether conventional and modified RECIST criteria are applied. Cutaneous or subcutaneous lesions must be measurable by calipers. Lesions to be used as measurable disease for the purpose of response assessment must either a) not reside in a field that has been subjected to prior radiotherapy, or b) have demonstrated clear evidence of radiographic progression since the completion of prior radiotherapy and before study enrollment or c) have been radiated at least 6 months before study enrollment.
* Tumor Histology Types:
* Participants with pathologically proven, unresectable, locally advanced or metastatic solid tumors that based on literature reports are considered to express EGFR. During cohort expansion, participants with locally advanced or metastatic solid tumors expressing EGFR including advanced or metastatic NSCLC, CRC, and HNSCC are eligible for enrollment.
\* Tumors During Cohort Expansion:
* Participants with pathologically proven, unresectable, locally advanced or metastatic solid tumors that based on literature reports are considered to express EGFR are eligible for enrollment:
* NSCLC: locally advanced or metastatic NSCLC that has progressed during or following treatment with platinum-based chemotherapy, a checkpoint inhibitor (unless known to be PD-L1 negative), or targeted therapy (for participants with a known actionable mutation).
* CRC: locally advanced or metastatic CRC that has progressed after systemic therapies, including irinotecan, oxaliplatin, an anti-EGFR inhibitor (if K-RAS or N-RAS is WT), a checkpoint inhibitor (if MSI-H), and a VEGF inhibitor (if locally approved and accessible as a standard-of-care).
* HNSCC: HNSCC that has progressed during or following treatment with a checkpoint inhibitor (unless ineligible, e.g, PD-L1 negative) and platinum-based chemotherapy (unless ineligible for or intolerant to platinum-based chemotherapy) with or without cetuximab for metastatic or recurrent disease.
1. Participants with salivary gland tumors will not be considered as having HNSCC.
2. Participants who refuse surgery for potentially curable disease where the surgery or radiotherapy could result in severe morbidity are eligible. The reason for the refusal will be captured in the electronic case report form (eCRFs).
* Archival Tissue:
* Participants must allow acquisition of existing formalin-fixed paraffin-embedded (FFPE) archival tumor sample, either a block or unstained slides. Participants who provide fresh pretreatment biopsy samples will not be required to submit archival tumor samples.
* Tumor Biopsy:
• Participants must be willing to consent to mandatory pretreatment (during screening) and on-treatment fresh tumor biopsies for cohort expansion phase and backfill in dose escalation. Once the target number of biopsies have been collected, additional paired pretreatment and on-treatment biopsies will not be required; sample collection will be optional after this time point. For fresh tumor biopsies, the lesion must be accessible (those occurring outside the brain or those that are accessible by an interventional or endoscopic procedure) for a low-risk biopsy procedure that does not place the participant at an unjustifiable risk in the opinion of the investigator. Participants who have an archived biopsy specimen available that was obtained up to 90 days prior to treatment initiation and have received no other treatment from the time of biopsy until the start of treatment with TAK-186, may submit that archived specimen in lieu of a pretreatment biopsy upon agreement from the sponsor.
* Laboratory Features:
* Acceptable laboratory parameters as follows:
1. Albumin ≥ 3.0 g/dL
2. Platelet count ≥ 75 × 103/μL
3. Hemoglobin ≥ 9.0 g/dL
4. Absolute neutrophil count ≥ 1.0 × 103/μL
5. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3.0 × upper limit of normal (ULN); for participants with hepatic metastases, ALT/AST ≤ 5 × ULN
6. Total bilirubin ≤ 1.5 × ULN, except participants with Gilbert's syndrome, who may enroll if the conjugated bilirubin is within normal limits.
7. Creatinine clearance of ≥ 30 mL/minute using Cockcroft-Gault equation.
* Reproductive Features:
* WOCBP must have a negative serum pregnancy test performed within 72 hours before the initiation of study drug administration. WOCBP must use 1 form of highly effective method and 1 additional effective (barrier) method of contraception at the same time throughout the study, starting at screening through 90 days after the last dose of TAK-186. Contraception methods may be considered highly effective if they can achieve a failure rate of less than 1% per year when used consistently and correctly.
* Male participants with partners of childbearing potential must use barrier contraception during the entire study treatment period through 120 days after the last dose of study drug and must not donate sperm during this period. In addition, male participants should also have their partners use contraception (as documented for female participants) for the same period of time.
\* Previous Checkpoint Inhibitor Therapy:
* Participants who have previously received an immune checkpoint before enrollment must have checkpoint inhibitor immune-related toxicity resolved to either Grade ≤ 1 or baseline
* Symptomatic central nervous system (CNS) metastases must have been treated, be asymptomatic for ≥ 14 days, and meet the following criteria at the time of enrollment:
1. No concurrent treatment for CNS disease (e.g., surgery, radiation, corticosteroids ≥ 10 mg prednisone per day or equivalent).
2. No concurrent leptomeningeal disease or spinal cord compression.
Key Exclusion Criteria:
* Participants with a history of known autoimmune disease with the exceptions of:
1. Vitiligo.
2. Psoriasis not requiring systemic treatment for \> 1 year before receiving TAK-186.
3. History of Graves' disease in participants now euthyroid for \> 4 weeks.
4. Hypothyroidism managed by thyroid replacement.
5. Alopecia.
6. Well-controlled diabetes type 1.
* Major surgery or traumatic injury within 8 weeks before first dose of TAK-186.
* Unhealed wounds from surgery or injury.
* Radiation therapy \< 2 weeks before initiation of TAK-186.
* Treatment with \> 10 mg per day of prednisone (or equivalent) or other immune-suppressive drugs within the 7 days before the initiation of study drug. Steroids for topical, ophthalmic, inhaled, or nasal administration are allowed.
* Prior therapy within the following timeframe before the planned start of TAK-186 as follows:
1. Cytotoxic chemotherapy, small molecule inhibitors, radiation, interventional radiology procedure, or similar investigational therapies: ≤ 2 weeks or 5 half-lives, whichever is shorter.
2. Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or similar investigational therapies: ≤ 4 weeks.
3. Concurrent use of hormones either to maintain castrate levels of testosterone in participants with castration-sensitive prostate cancer or for non-cancer-related conditions (e.g., insulin for diabetes, hormone replacement therapy) is acceptable. Bisphosphonates are permitted for supportive care of bone metastases (e.g., breast or prostate cancer) or osteoporosis.
* Clinically significant cardiovascular or vascular disease including:
1. Myocardial infarction or unstable angina \< 6 months before the initiation of study drug.
2. Clinically significant cardiac arrhythmia (e.g., with potential for hemodynamic instability).
3. Uncontrolled hypertension: systolic blood pressure \> 180 mmHg; diastolic blood pressure \> 100 mmHg.
4. Pulmonary embolism, stroke, or transient ischemic attack \< 6 months before initiation of TAK-186.
5. QTcF (QT interval by Fridericia correction) prolongation \> 480 msec.
6. Congestive heart failure (New York Heart Association Class III or IV).
7. Pericarditis or clinically significant pericardial effusion.
8. Myocarditis.
9. Vasculitis not resolved \< 6 months before TAK-186 initiation.
* Clinically significant gastrointestinal disorders including:
1. Gastrointestinal perforation \< 6 months before study drug administration. Participants must have documented evidence (e.g., upper endoscopy, colonoscopy) of completely healed area of prior perforation.
2. Gastrointestinal bleeding \< 2 months before study drug administration. Participants must have documented evidence (e.g., upper endoscopy, colonoscopy) of completely healed area of prior bleeding.
3. Pancreatitis \< 6 months before the initiation of study drug. Participants must have a CT scan negative for evidence of remaining disease or normal pancreatic enzyme levels for \> 4 weeks before the initiation of TAK-186.
4. Diverticulitis flare \< 2 months before study drug administration. Participants must have a CT scan negative for evidence of remaining disease before the initiation of TAK-186.
5. History of Crohn's disease or ulcerative colitis.
* Inflammatory process that has not resolved for ≥ 4 weeks from the date of first study dose. Participants with chronic low-grade inflammatory processes such as radiation-induced pneumonitis are excluded regardless of duration.
* Clinically significant pulmonary compromise (e.g., requirement for supplemental oxygen on a continuous basis).
* Active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days before the initiation of study drug. Systemic antiviral, antifungal, or antibacterial therapy must be completed \> 1 week before the initiation of study drug. Antimicrobial prophylaxis (e.g., for Pneumocystis carinii infection) may continue the antimicrobial for that purpose.
* Vaccination with any live virus vaccine within 4 weeks before the initiation of study drug administration or vaccination with other vaccines 2 weeks before the initiation of study drug administration. Inactivated annual influenza vaccination is allowed.
* Participants who are known to be human immunodeficiency virus positive or who are known to be hepatitis B or C positive. Participants treated for hepatitis C must have viral titers of 0 for ≥ 2 years to be eligible. Participants with hepatitis B having undetectable or ≤ 500 IU hepatitis B viral titers are eligible. Participants with hepatocellular carcinoma (HCC) known history of hepatitis B are excluded, regardless of hepatitis B viral titers.
* Second primary invasive malignancy not in remission for ≥ 3 years. Exceptions include non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer (Gleason score ≤ 7), resected melanoma in situ, or any malignancy considered to be indolent and never having required therapy, excluding indolent lymphoid malignancies.
* Any serious underlying medical or psychiatric condition that would preclude understanding and rendering of informed consent or impair the ability of the participant to receive or tolerate the planned treatment.
* Known hypersensitivity to TAK-186 (or any excipient \[trehalose, histidine, arginine, or polysorbate-80\] contained in the drug or diluent formulation) known hypersensitivity to tocilizumab.
* Investigative site personnel or sponsor personnel directly affiliated with this study or known hypersensitivity to tocilizumab.
* Prisoners or other individuals who are involuntarily detained.
* Any medical or non-medical issue that would contraindicate the participant's participation in the study or confound the results of the study.
* Female participants who are breastfeeding.
→
Key Inclusion Criteria:
* Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
* Ability to provide informed consent and documentation of informed consent before initiation of any study-related tests or procedures that are not part of standard of care for the participant's disease. Participants must also be willing and able to comply with study procedures, including the acquisition of specified research specimens.
* Life expectancy ≥ 12 weeks
* Measurable disease as per RECIST v1.1 criteria and documented by Computed tomography (CT) and/or magnetic resonance imaging (MRI). The definitions for measurable lesions are the same whether conventional and modified RECIST criteria are applied. Cutaneous or subcutaneous lesions must be measurable by calipers. Lesions to be used as measurable disease for the purpose of response assessment must either a) not reside in a field that has been subjected to prior radiotherapy, or b) have demonstrated clear evidence of radiographic progression since the completion of prior radiotherapy and before study enrollment or c) have been radiated at least 6 months before study enrollment.
* Tumor Histology Types:
* Participants with pathologically proven, unresectable, locally advanced or metastatic solid tumors that based on literature reports are considered to express EGFR. During cohort expansion, participants with locally advanced or metastatic solid tumors expressing EGFR including advanced or metastatic NSCLC, CRC, and HNSCC are eligible for enrollment.
\* Archival Tissue:
* Participants must allow acquisition of existing formalin-fixed paraffin-embedded (FFPE) archival tumor sample, either a block or unstained slides. Participants who provide fresh pretreatment biopsy samples will not be required to submit archival tumor samples.
* Tumor Biopsy:
• Participants must be willing to consent to mandatory pretreatment (during screening) and on-treatment fresh tumor biopsies for cohort expansion phase and backfill in dose escalation. Once the target number of biopsies have been collected, additional paired pretreatment and on-treatment biopsies will not be required; sample collection will be optional after this time point. For fresh tumor biopsies, the lesion must be accessible (those occurring outside the brain or those that are accessible by an interventional or endoscopic procedure) for a low-risk biopsy procedure that does not place the participant at an unjustifiable risk in the opinion of the investigator. Participants who have an archived biopsy specimen available that was obtained up to 90 days prior to treatment initiation and have received no other treatment from the time of biopsy until the start of treatment with TAK-186, may submit that archived specimen in lieu of a pretreatment biopsy upon agreement from the sponsor.
* Laboratory Features:
* Acceptable laboratory parameters as follows:
1. Albumin ≥ 3.0 g/dL
2. Platelet count ≥ 75 × 103/μL
3. Hemoglobin ≥ 9.0 g/dL
4. Absolute neutrophil count ≥ 1.0 × 103/μL
5. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3.0 × upper limit of normal (ULN); for participants with hepatic metastases, ALT/AST ≤ 5 × ULN
6. Total bilirubin ≤ 1.5 × ULN, except participants with Gilbert's syndrome, who may enroll if the conjugated bilirubin is within normal limits.
7. Creatinine clearance of ≥ 30 mL/minute using Cockcroft-Gault equation.
* Reproductive Features:
* WOCBP must have a negative serum pregnancy test performed within 72 hours before the initiation of study drug administration. WOCBP must use 1 form of highly effective method and 1 additional effective (barrier) method of contraception at the same time throughout the study, starting at screening through 90 days after the last dose of TAK-186. Contraception methods may be considered highly effective if they can achieve a failure rate of less than 1% per year when used consistently and correctly.
* Male participants with partners of childbearing potential must use barrier contraception during the entire study treatment period through 120 days after the last dose of study drug and must not donate sperm during this period. In addition, male participants should also have their partners use contraception (as documented for female participants) for the same period of time.
\* Previous Checkpoint Inhibitor Therapy:
* Participants who have previously received an immune checkpoint before enrollment must have checkpoint inhibitor immune-related toxicity resolved to either Grade ≤ 1 or baseline
* Central nervous system (CNS) metastases must have been treated and meet the following criteria at the time of enrollment:
1. Definitive therapy was completed at least 2 weeks prior to the first dose of TAK-186.
2. No evidence of radiographic CNS progression following definitive therapy and by the time of study screening.
3. Any CNS disease is asymptomatic for at least 7 days (unless symptoms are deemed irreversible by the investigator), the patient is off steroids for at least 7 days, and the patient is either off or on stable doses of anti-epileptic drugs for malignant CNS disease for at least 7 days.
4. No concurrent leptomeningeal disease or spinal cord compression.
Key Exclusion Criteria:
* Participants with a history of known autoimmune disease with the exceptions of:
1. Vitiligo.
2. Psoriasis not requiring systemic treatment for \> 1 year before receiving TAK-186.
3. History of Graves' disease in participants now euthyroid for \> 4 weeks.
4. Hypothyroidism managed by thyroid replacement.
5. Alopecia.
6. Well-controlled diabetes type 1.
* Major surgery or traumatic injury within 8 weeks before first dose of TAK-186.
* Unhealed wounds from surgery or injury.
* Radiation therapy \< 2 weeks before initiation of TAK-186.
* Treatment with \> 10 mg per day of prednisone (or equivalent) or other immune-suppressive drugs within the 7 days before the initiation of study drug. Steroids for topical, ophthalmic, inhaled, or nasal administration are allowed.
* Prior therapy within the following timeframe before the planned start of TAK-186 as follows:
1. Cytotoxic chemotherapy, small molecule inhibitors, radiation, interventional radiology procedure, or similar investigational therapies: ≤ 2 weeks or 5 half-lives, whichever is shorter.
2. Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or similar investigational therapies: ≤ 4 weeks.
3. Concurrent use of hormones either to maintain castrate levels of testosterone in participants with castration-sensitive prostate cancer or for non-cancer-related conditions (e.g., insulin for diabetes, hormone replacement therapy) is acceptable. Bisphosphonates are permitted for supportive care of bone metastases (e.g., breast or prostate cancer) or osteoporosis.
* Clinically significant cardiovascular or vascular disease including:
1. Myocardial infarction or unstable angina \< 6 months before the initiation of study drug.
2. Clinically significant cardiac arrhythmia (e.g., with potential for hemodynamic instability).
3. Uncontrolled hypertension: systolic blood pressure \> 180 mmHg; diastolic blood pressure \> 100 mmHg.
4. Pulmonary embolism, requiring treatment occurring \< 3 months before initiation of TAK-186.
5. QTcF (QT interval by Fridericia correction) prolongation \> 480 msec.
6. Congestive heart failure (New York Heart Association Class III or IV).
7. Pericarditis or clinically significant pericardial effusion.
8. Myocarditis. I) Hypotension Grade ≥2.
j) Vasculitis not resolved \< 6 months before TAK-186 initiation.
* Clinically significant gastrointestinal disorders including:
1. Gastrointestinal perforation \< 6 months before study drug administration. Participants must have documented evidence (e.g., upper endoscopy, colonoscopy) of completely healed area of prior perforation.
2. Gastrointestinal bleeding \< 2 months before study drug administration. Participants must have documented evidence (e.g., upper endoscopy, colonoscopy) of completely healed area of prior bleeding.
3. Pancreatitis \< 6 months before the initiation of study drug. Participants must have a CT scan negative for evidence of remaining disease or normal pancreatic enzyme levels for \> 4 weeks before the initiation of TAK-186.
4. Diverticulitis flare \< 2 months before study drug administration. Participants must have a CT scan negative for evidence of remaining disease before the initiation of TAK-186.
5. History of Crohn's disease or ulcerative colitis.
* Inflammatory process that has not resolved for ≥ 4 weeks from the date of first study dose. Participants with any history of Grade 2 or higher noninfectious pneumonitis will be excluded. (Participants with a radiation induced pneumonitis or Grade 1 noninfectious pneumonitis that has resolved may be eligible for enrollment).
* Clinically significant pulmonary compromise (oxygen saturation ≤92% on room air and requirement for any supplemental oxygen at the time of enrollment).
* Active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days before the initiation of study drug. Systemic antiviral, antifungal, or antibacterial therapy must be completed \> 1 week before the initiation of study drug. Antimicrobial prophylaxis (e.g., for Pneumocystis carinii infection) may continue the antimicrobial for that purpose.
* Vaccination with any live virus vaccine within 4 weeks before the initiation of study drug administration or vaccination with other vaccines 2 weeks before the initiation of study drug administration. Inactivated annual influenza vaccination is allowed.
* Participants who are known to be human immunodeficiency virus positive or who are known to be hepatitis B or C positive. Participants treated for hepatitis C must have viral titers of 0 for ≥ 2 years to be eligible. Participants with hepatitis B having undetectable or ≤ 500 IU hepatitis B viral titers are eligible. Participants with hepatocellular carcinoma (HCC) known history of hepatitis B are excluded, regardless of hepatitis B viral titers.
* Second primary invasive malignancy not in remission for ≥ 3 years. Exceptions include non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer (Gleason score ≤ 7), resected melanoma in situ, or any malignancy considered to be indolent and never having required therapy, excluding indolent lymphoid malignancies.
* Any serious underlying medical or psychiatric condition that would preclude understanding and rendering of informed consent or impair the ability of the participant to receive or tolerate the planned treatment.
* Known hypersensitivity to TAK-186 (or any excipient \[trehalose, histidine, arginine, or polysorbate-80\] contained in the drug or diluent formulation) known hypersensitivity to tocilizumab.
* Investigative site personnel or sponsor personnel directly affiliated with this study or known hypersensitivity to tocilizumab.
* Prisoners or other individuals who are involuntarily detained.
* Any medical or non-medical issue that would contraindicate the participant's participation in the study or confound the results of the study.
* Female participants who are breastfeeding.
Inclusion Criteria:
* Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information and/or protected personal data in accordance with national and local study participant data protections and privacy regulations.
* Male or female greater than or equal to (≥)18 years of age at the time of signing informed consent.
* Diagnosis of MDS with or without RS (as determined in an evaluable bone marrow aspirate, read by an independent central reader to confirm diagnosis at Screening) according to the World Health Organization 2016 classification that meets the International Prognostic Scoring System-Revised (IPSS-R) classification of very low, low, or intermediate risk disease.
* Transfusion dependence assessed in the 16 weeks immediately preceding randomization in two 8-week blocks, classified as either:
a. Low-transfusion burden (LTB), defined as 4 to 7 red blood cells (RBC) units per 16 weeks; or b. High-transfusion burden (HTB), defined as ≥8 RBC units per 16 weeks; and c. For all participants: i. Only transfusion events for a pretransfusion hemoglobin (Hgb) lesser than (\<)10 grams per deciliter (g/dL) are counted toward eligibility; ii. At least 1 transfusion event in each 8-week period and a minimum of 2 transfusion events separated by ≥7 days within the 16-week period immediately preceding randomization; and iii. No consecutive 56-day period can be RBC transfusion-free during the 16-week period immediately preceding randomization.
* Refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) treatment (discontinued ≥4 weeks before randomization), or unlikely to respond to ESA treatment, defined as follows:
a. Refractory to prior ESA treatment: documentation of nonresponse or a response that was no longer maintained with a prior ESA-containing regimen, either as a single agent or combination (e.g., with granulocyte colony-stimulating factor \[G-CSF\]); ESA regimen must have been either: i. Recombinant human erythropoietin (EPO) ≥40,000 international units per week (IU/week) for ≥8 doses or equivalent; or ii. Darbepoetin alpha ≥500 micrograms (μg) every 3 weeks for ≥4 doses or equivalent.
b. Intolerant to prior ESA treatment: documentation of discontinuation of a prior ESA-containing regimen, either as a single agent or combination (e.g., with G-CSF), at any time after introduction due to intolerance or an AE.
c. Unlikely to respond to ESA treatment: low chance of response to ESA based on an endogenous serum EPO level greater than (\>)200 units per liter (U/L).
* Less than 5% blasts in an evaluable bone marrow aspirate collected at Screening, read by an independent central reader.
* Eastern Cooperative Oncology Group performance status of 0 to 2.
* Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception.
* In the opinion of the Investigator, the participant is able and willing to comply with the requirements of the protocol (e.g., all study procedures, return for follow-up visits).
Exclusion Criteria:
* Del(5q) MDS or therapy-related (secondary) MDS.
* Anemia due to any other known cause (e.g., thalassemia, hemolytic anemia, bleeding events, or deficiency of iron, B12, and/or folate).
* Receipt of RBC transfusion for any reason(s) other than underlying MDS within 16 weeks before randomization.
* Clinically significant cardiovascular disease defined as:
1. New York Heart Association heart disease class III or IV;
2. Fridericia corrected QT (QTcF) interval \>500 milliseconds during Screening;
3. Presence of uncontrolled hypertension defined as mean systolic blood pressure ≥160 millimeters of mercury (mm Hg) or diastolic blood pressure ≥100 mm Hg during Screening; or
4. Uncontrolled arrhythmia, myocardial infarction, or unstable angina within 6 months before Screening.
* Known ejection fraction \<35%, confirmed by a local echocardiogram performed during Screening, or a previously performed echocardiogram if collected within 6 months before Screening.
* Child-Pugh class C hepatic impairment.
* Stroke, deep vein thrombosis, or pulmonary embolism within 6 months before Screening.
* Any known history of acute myeloid leukemia (AML).
* Prior history of malignancies, other than MDS, unless participant has been free of the disease (including completion of any treatment, including maintenance, for prior malignancy) for ≥ 5 years. However, participants with a history or concurrent diagnosis of the following conditions are allowed if not requiring systemic therapy:
1. Basal or squamous cell carcinoma of the skin;
2. Carcinoma in situ of the cervix;
3. Carcinoma in situ of the breast; and/or
4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis \[TNM\] clinical staging system).
* History of solid organ or bone marrow transplantation.
* Active infection requiring intravenous treatment (e.g., antibiotics, antifungals, or antivirals) within 28 days, or oral treatment within 14 days before randomization.
* History of or known active chronic infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
* Body mass index ≥ 40 kilograms per meter square (kg/m\^2).
* Major surgery within 28 days before randomization.
* History of allergy/anaphylaxis to investigational medicinal product (IMP) excipients (refer to the current elritercept IB for a list of excipients) or recombinant proteins.
* Prior use of elritercept, luspatercept, or sotatercept.
* Prior use of hypomethylating agents (HMAs), isocitrate dehydrogenase inhibitor, lenalidomide, imetelstat, or immunosuppressive therapy given for treatment of MDS.
* Iron chelation therapy initiated within 8 weeks before randomization. Participants on stable doses of iron chelation therapy for ≥ 8 weeks are allowed.
* Vitamin B12 or folate therapy initiated within 4 weeks before randomization. Participants on stable replacement doses for ≥ 4 weeks and without ongoing concurrent vitamin B12 or folate deficiency are allowed.
* Androgen use within 8 weeks before randomization. Participants on stable androgen dosing for hypogonadism for ≥ 8 weeks are allowed.
* High-dose corticosteroid use within 4 weeks before randomization. Participants on stable chronic steroid doses of prednisone lesser than or equal to (≤) 10 mg/day or corticosteroid equivalent for ≥ 4 weeks are allowed.10 mg/day or corticosteroid equivalent for ≥ 4 weeks are allowed.
* Treatment with any investigational drug within 28 days before Screening or, if the half-life of the product is known, within 5 times the half-life before Screening, whichever is longer.
* Ongoing participation in another interventional clinical study.
* Serum EPO level \>500 U/L.
* Platelet count ≥450 × 10\^9/L or ≤25 × 10\^9/L.
* Absolute neutrophil count ≤ 500/µL.
* Serum aspartate aminotransferase or alanine aminotransferase ≥3 × the upper limit of normal (ULN).
* Total bilirubin ≥2 × ULN unless attributable to Gilbert's syndrome.
* Ferritin ≤ 50 micrograms per litre (μg/L).
* Folate ≤2.0 nanograms per milliliter (ng/mL).
* Vitamin B12 ≤200 picograms per milliliter (pg/mL).
* Estimated glomerular filtration rate \<30 milliliters per minute per 1.73 meter square (mL/min/1.73m\^2) as determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Collaboration equation.
* Pregnant or lactating female.
* Any other condition not specifically noted above that, in the opinion of the Investigator, would preclude the participant from participating in the study or could confound interpretation of data from the study.
* Investigational site staff members directly involved in the conduct of the study and site staff members otherwise supervised by the Investigator, employees of the Sponsor or contract research organization (CRO) directly involved in the conduct of the study, or immediate family members (defined as a spouse, parent, child, or sibling, whether biological or legally adopted).
* For Participants in France: Persons under court protection, persons not affiliated with a social security system, and protected adults (per applicable French law \[Art. L. 1121-6, Art. L. 1121-8, Art. L. 1121-8-1\]).
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Inclusion Criteria:
* Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information and/or protected personal data in accordance with national and local study participant data protections and privacy regulations.
* Male or female greater than or equal to (≥)18 years of age at the time of signing informed consent.
* Diagnosis of MDS with or without RS (as determined in an evaluable bone marrow sample, read by an independent central reader to confirm diagnosis at Screening) according to the World Health Organization 2016 classification that meets the International Prognostic Scoring System-Revised (IPSS-R) classification of very low, low, or intermediate risk disease. In cases where a local bone marrow (BM) assessment establishing an MDS diagnosis was conducted within 12 weeks prior to informed consent form (ICF) signature, the associated local BM samples and/or reports may be permitted.
* Transfusion dependence assessed in the 16 weeks immediately preceding randomization in two 8-week blocks, classified as either:
a. LTB, defined as 4 to 7 RBC units per 16 weeks; or b. HTB, defined as ≥8 RBC units per 16 weeks; and c. For all participants: i. Only transfusion events for a pretransfusion hemoglobin (Hgb) lesser than (\<)10 grams per deciliter (g/dL) are counted toward eligibility; ii. At least 1 transfusion event in each 8-week period and a minimum of 2 transfusion events separated by ≥7 days within the 16-week period immediately preceding randomization; and iii. No consecutive 56-day period can be RBC transfusion-free during the 16-week period immediately preceding randomization.
* Refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) treatment (discontinued ≥4 weeks before randomization), or unlikely to respond to ESA treatment, defined as follows:
a. Refractory to prior ESA treatment: documentation of nonresponse or a response that was no longer maintained with a prior ESA-containing regimen, either as a single agent or combination (e.g., with granulocyte colony-stimulating factor \[G-CSF\]); ESA regimen must have been either: i. Recombinant human erythropoietin (EPO) ≥30,000 international units per week (IU/week) for ≥8 doses or equivalent; or ii. Darbepoetin alpha ≥500 micrograms (μg) every 3 weeks for ≥3 doses or ≥ 120 μg every week for ≥ 8 doses or equivalent.
b. Intolerant to prior ESA treatment: documentation of discontinuation of a prior ESA-containing regimen, either as a single agent or combination (e.g., with G-CSF), at any time after introduction due to intolerance or an AE.
c. Unlikely to respond to ESA treatment: low chance of response to ESA based on an endogenous serum EPO level greater than (\>)200 units per liter (U/L).
* Less than 5 percent (%) blasts in an evaluable bone marrow sample collected at Screening.
* Eastern Cooperative Oncology Group performance status of 0 to 2.
* Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception.
* In the opinion of the Investigator, the participant is able and willing to comply with the requirements of the protocol (e.g., all study procedures, return for follow-up visits).
Exclusion Criteria:
* Del(5q) MDS, secondary MDS (MDS with a documented history of prior exposure to chemotherapy, radiotherapy, or other leukemogenic agents that is considered causally related to the development of MDS).
* Anemia due to any other known cause (e.g., thalassemia, hemolytic anemia, bleeding events, or deficiency of iron, B12, and/or folate).
* Receipt of RBC transfusion for any reason(s) other than underlying MDS within 16 weeks before randomization.
* Clinically significant cardiovascular disease defined as:
1. New York Heart Association heart disease class III or IV;
2. Fridericia corrected QT (QTcF) interval \>500 milliseconds during Screening;
3. Presence of uncontrolled hypertension defined as mean systolic blood pressure ≥160 millimeters of mercury (mm Hg) or diastolic blood pressure ≥100 mm Hg during Screening; or
4. Uncontrolled arrhythmia, myocardial infarction, or unstable angina within 6 months before Screening.
* Known ejection fraction \<35%, confirmed by a local echocardiogram performed during Screening, or a previously performed echocardiogram if collected within 6 months before Screening.
* Child-Pugh class C hepatic impairment.
* Stroke, deep vein thrombosis, or pulmonary embolism within 6 months before Screening.
* Any known history of acute myeloid leukemia (AML).
* Prior history of malignancies, other than MDS, unless participant has been free of the disease (including completion of any treatment, including maintenance, for prior malignancy) for ≥ 2 years. However, participants with a history or concurrent diagnosis of the following conditions are allowed if not requiring systemic therapy:
1. Basal or squamous cell carcinoma of the skin;
2. Carcinoma in situ of the cervix;
3. Carcinoma in situ of the breast; and/or
4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis \[TNM\] clinical staging system).
5. Early papillary thyroid cancer (stage I \[T1-T2, N0, M0\]).
* History of solid organ or bone marrow transplantation.
* Active infection requiring intravenous treatment (e.g., antibiotics, antifungals, or antivirals) within 28 days, or oral treatment within 14 days before randomization.
* Active infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV). Participants with a history of HIV infection may be enrolled if they are receiving antiretroviral therapy and have a documented CD4+ T cell count \> 200 cells per microliter (cells/μL) at screening. Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
* Body mass index ≥ 40 kilograms per meter square (kg/m\^2).
* Major surgery within 28 days before randomization.
* History of allergy/anaphylaxis to investigational medicinal product (IMP) excipients (refer to the current elritercept IB for a list of excipients) or recombinant proteins.
* Prior use of elritercept, luspatercept, or sotatercept.
* Prior use of hypomethylating agents (HMAs), isocitrate dehydrogenase inhibitor, lenalidomide, imetelstat, or immunosuppressive therapy given for treatment of MDS.
* Iron chelation therapy initiated within 8 weeks before randomization. Participants on stable or decreasing doses of iron chelation therapy for ≥ 8 weeks are allowed.
* Vitamin B12 or folate therapy initiated within 4 weeks before randomization. Participants on stable replacement doses for ≥ 4 weeks and without ongoing concurrent vitamin B12 or folate deficiency are allowed.
* Androgen use within 8 weeks before randomization. Participants on stable androgen dosing for hypogonadism for ≥ 8 weeks are allowed.
* High-dose systemic corticosteroid use within 4 weeks before randomization. Participants on stable chronic steroid doses of prednisone lesser than or equal to (≤) 10 milligrams per day (mg/day) or corticosteroid equivalent for ≥ 4 weeks are allowed.10 mg/day or corticosteroid equivalent for ≥ 4 weeks are allowed.
* Treatment with any investigational drug within 28 days before Screening or, if the half-life of the product is known, within 5 times the half-life before Screening, whichever is longer.
* Ongoing participation in another interventional clinical study.
* Serum EPO level \>500 U/L.
* Platelet count ≥800 × 10\^9 per liter (/L) or ≤25 × 10\^9/L.
* Absolute neutrophil count ≤ 500 per microliter (/µL).
* Serum aspartate aminotransferase or alanine aminotransferase ≥3 × the upper limit of normal (ULN).
* Total bilirubin ≥2 × ULN unless attributable to Gilbert's syndrome. Participants with known history of Gilbert syndrome with unconjugated bilirubin \< 3 × ULN are allowed. Higher levels, if attributed to active RBC precursor destruction within the bone marrow (ineffective erythropoiesis), may be allowed upon medical monitor review.
* Ferritin ≤ 50 micrograms per litre (μg/L).
* Folate ≤2.0 nanograms per milliliter (ng/mL).
* Vitamin B12 ≤200 picograms per milliliter (pg/mL).
* Estimated glomerular filtration rate \<30 milliliters per minute per 1.73 meter square (mL/min/1.73m\^2) as determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Collaboration equation.
* Pregnant or lactating female.
* Any other condition not specifically noted above that, in the opinion of the Investigator, would preclude the participant from participating in the study or could confound interpretation of data from the study.
* Investigational site staff members directly involved in the conduct of the study and site staff members otherwise supervised by the Investigator, employees of the Sponsor or CRO directly involved in the conduct of the study, or immediate family members (defined as a spouse, parent, child, or sibling, whether biological or legally adopted).
* For Participants in France: Persons under court protection, persons not affiliated with a social security system, and protected adults (per applicable French law \[Art. L. 1121-6, Art. L. 1121-8, Art. L. 1121-8-1\]).
Inclusion Criteria:
1. Participants or their legally authorized representative must be willing and able to sign the ICF and to adhere to the protocol requirements.
2. Japanese adult male or female participant \>=18 years of age at the time of signing informed consent.
3. Diagnosis of MDS with or without ring sideroblasts (RS) (as determined in an evaluable bone marrow aspirate collected at Screening to confirm diagnosis) according to WHO 2016 classification that meets the International Prognostic Scoring System-Revised (IPSS-R) classification of very low-, low-, or intermediate-risk MDS.
Note: Due to expected impacts of transfusion, hemoglobin (Hgb) values from blood samples collected within 14 days following a RBC transfusion and platelet count obtained within 7 days following a platelet transfusion cannot be used to evaluate IPSS-R for eligibility.
4. TD\[YY1.1\] cohort: Transfusion dependence assessed in the 16 weeks immediately preceding enrollment in two 8-week blocks classified as either:
1. Low-transfusion burden (LTB), defined as 4 to 7 RBC units per 16 weeks; or
2. HTB\[YY2.1\], defined as \>=8 RBC units per 16 weeks; and
3. For all participants: i. Only transfusion events for a pretransfusion Hgb \<10 g/dL are counted toward eligibility; ii. At least 1 transfusion event in each 8-week block and a minimum of 2 transfusion events separated by \>=7 days within the 16-week period immediately preceding enrollment; and iii. No consecutive 56-day period can be RBC transfusion-free during the 16 week period immediately preceding enrollment.
Note: Only transfusions for the disease under study will be counted towards classification for LTB or HTB participants. Transfusions for intercurrent diseases (bleeding, surgical procedure, infection, etc.) are not considered.
NTD\[YY3.1\] cohort: NTD, defined as 0 to 1 RBC units per 8 weeks immediately preceding enrollment.
Note: RBC transfusions administered when Hgb levels were \<9.0 g/dL are counted for eligibility. RBC transfusions administered for other than MDS-related anemia (bleeding, surgical procedure, infection, etc.) will not be counted as a required transfusion for the purpose of meeting eligibility criteria.
5. TD cohort: Refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) treatment (discontinued \>=4 weeks before enrollment), or unlikely to respond to ESA treatment, defined as follows:
a. Refractory to prior ESA treatment: documentation of nonresponse or a response that was no longer maintained with a prior ESA-containing regimen, either as a single agent or combination (eg, with granulocyte colony-stimulating factor \[G-CSF\]); ESA regimen must have been either: i. Recombinant human erythropoietin (EPO) \>=40,000 IU/week for \>=8 doses or equivalent; or ii. Darbepoetin alpha \>=500 mcrg every 3 weeks for \>=4 doses or equivalent. b. Intolerant to prior ESA treatment: documentation of discontinuation of a prior ESA containing regimen, either as a single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an AE.
c. Unlikely to respond to ESA treatment: low chance of response to ESA based on an endogenous serum EPO level \>200 U/L.
Note: Due to expected impacts of transfusion on EPO levels, blood samples collected within the 14 days following an RBC transfusion or within 7 days following a platelet transfusion cannot be used to evaluate serum EPO level for eligibility.
NTD cohort: Hgb \<10 g/dL and exhibiting anemia-related clinical symptoms (eg, fatigue, shortness of breath, or others) during screening.
6. Less than 5% blasts in an evaluable bone marrow aspirate collected at Screening.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
8. Women of childbearing potential (WOCBP), defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 consecutive months must
1. Agree to use 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 60 days after the last dose of study drug; or
2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
9. Male participants must, even if he is surgically sterilized (ie, status postvasectomy),
1. Agree to practice effective barrier contraception the time of signing the informed consent through 60 days after the last dose of study drug; or
2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
Exclusion Criteria:
Medical History
1. Del(5q) MDS or therapy-related (secondary) MDS.
2. Anemia due to any other known cause (eg, thalassemia, hemolytic anemia, bleeding events, or deficiency of iron, B12, and/or folate).
3. Receipt of RBC transfusion for any reason(s) other than underlying MDS within 16 weeks in TD cohort or 8 weeks in NTD cohort before enrollment.
4. Clinically significant cardiovascular disease defined as:
1. New York Heart Association heart disease class III or IV;
2. Fridericia corrected QT (QTcF) interval \>500 milliseconds during Screening;
3. Presence of uncontrolled hypertension defined as mean systolic blood pressure \>=160 mm Hg or diastolic blood pressure \>=100 mm Hg during Screening; or
4. Uncontrolled arrhythmia, myocardial infarction, or unstable angina within 6 months before Screening.
5. Known ejection fraction \<35%, confirmed by a local echocardiogram performed during Screening, or a previously performed echocardiogram if collected within 6 months before Screening.
6. Stroke, deep vein thrombosis, or pulmonary embolism within 6 months before Screening.
7. Any known history of acute myeloid leukemia (AML).
8. Prior history of malignancies, other than MDS, unless the participant has been free of the disease (including completion of any treatment, including maintenance, for prior malignancy) for \>=5 years. However, participants with a history or concurrent diagnosis of the following conditions are allowed if not requiring systemic therapy:
1. Basal or squamous cell carcinoma of the skin;
2. Carcinoma in situ of the cervix;
3. Carcinoma in situ of the breast; and/or
4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis \[TNM\] clinical staging system).
9. History of solid organ or bone marrow transplantation.
10. Active infection requiring intravenous antibiotics within 28 days or oral antibiotics within 14 days before enrollment.
11. History of or known active or chronic infection with HIV, active infectious hepatitis B virus (HBV), or active infectious hepatitis C virus (HCV). Participants who are positive for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis B surface antibody (HBsAb) may be eligible for enrollment if their hepatitis B viral load is below the limit of detection. Participants who are positive for hepatitis C virus antibodies (HCVAb) may be enrolled if their hepatitis C viral load is below the limit of detection.
12. Body mass index \>=40 kg/m\^2.
13. Major surgery within 28 days before enrollment.
14. History of allergy/anaphylaxis to investigational medicinal product (IMP) excipients (refer to the current elritercept \[TAK 226\] IB for a list of excipients) or recombinant proteins.
Treatment History
15. TD cohort: Prior use of TAK 226, luspatercept, imetelstat, or sotatercept. \[YY4.1\] NTD cohort: Prior use of TAK 226, luspatercept, imetelstat, sotatercept, or ESAs.
Note for NTD cohort: At the investigator's discretion in consultation with the medical monitor, may be allowed if received no more than 2 doses of ESAs \>=8 weeks prior to enrollment.
16. Prior use of hypomethylating agents (HMAs), isocitrate dehydrogenase inhibitor, lenalidomide, or immunosuppressive therapy given for treatment of MDS.
17. Iron chelation therapy initiated within 8 weeks before enrollment. Participants on stable doses of iron chelation therapy for \>=8 weeks are allowed.
18. Vitamin B12 or folate therapy initiated within 4 weeks before enrollment. Participants on stable replacement doses for \>=4 weeks and without ongoing concurrent vitamin B12 or folate deficiency are allowed.
19. Androgen use within 8 weeks before enrollment. Participants on stable androgen dosing for hypogonadism for \>=8 weeks are allowed.
20. High-dose corticosteroid use within 4 weeks before enrollment. Participants on stable chronic steroid doses of prednisone/prednisolone \<=10 mg/day or corticosteroid equivalent for \>=4 weeks are allowed.
21. Treatment with any investigational drug within 28 days before Screening or, if the half-life of the product is known, within 5 times the half-life before Screening, whichever is longer.
22. Ongoing participation in another interventional clinical study. Laboratory Exclusions (during Screening)
23. Serum EPO level \>500 U/L. Note: Due to expected impacts of transfusion on EPO levels, laboratory results from blood samples collected within the 14 days following an RBC transfusion cannot be used to evaluate serum EPO level for eligibility.
24. Platelet count \>=450\*10\^3/mcrL or \<=25\*10\^3/mcrL. Note: Due to expected impacts of transfusion, laboratory results from blood samples collected within the 7 days following a platelet transfusion cannot be used to evaluate platelet count for eligibility.
25. Absolute neutrophil count \<=500/mcrL
26. Serum AST or ALT \>=3\*the upper limit of normal (ULN).
27. Total bilirubin \>=2\*ULN unless attributable to Gilbert syndrome.
28. Ferritin \<=50 mcrg/L.
29. Folate \<=2.0 ng/mL.
30. Vitamin B12 \<=200 pg/mL.
31. Estimated glomerular filtration rate \<30 mL/min/1.73m\^2 as determined by Japanese Society of Nephrology. Calculated by the correction formula for Japanese. a)
a) eGFR=194\* (serum creatinine value)\^-1.094\* (age)\^-0.287\* (sex correction factor), Sex correction factor: 0.739 in female.
Miscellaneous
32. Pregnant or lactating female\[YY5.1\]. Note: Participants who may be in the very early stage of pregnancy based on the doctor's interview with a negative pregnancy test are excluded from the study. Participants who are lactating will be eligible if they discontinue breastfeeding from before the first dose of study drug until 60 days after the last dose of study drug.
33. Any other condition not specifically noted above that, in the opinion of the investigator, would preclude the participant from participating in the study or could confound interpretation of data from the study.
34. Investigational site staff members directly involved in the conduct of the study and site staff members otherwise supervised by the investigator, employees of the Sponsor or contract research organization (CRO) directly involved in the conduct of the study, or immediate family members (defined as a spouse, parent, child, or sibling, whether biological or legally adopted).
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Inclusion Criteria:
1. Participants or their legally authorized representative must be willing and able to sign the ICF and to adhere to the protocol requirements.
2. Japanese adult male or female participant greater than or equal to (\>=) 18 years of age at the time of signing informed consent.
3. Diagnosis of MDS with or without ring sideroblasts (RS) (as determined in an evaluable bone marrow sample collected at screening to confirm diagnosis) according to WHO 2016 classification that meets the International Prognostic Scoring System-Revised (IPSS-R) classification of very low-, low-, or intermediate-risk MDS.
Note: Due to expected impacts of transfusion, hemoglobin (Hgb) values from blood samples collected within 14 days following a red blood cell (RBC) transfusion and platelet count obtained within 7 days following a platelet transfusion cannot be used for IPSS-R eligibility, unless considered pretransfusion values.
4. Transfusion dependent (TD) cohort: Transfusion dependence assessed in the 16 weeks immediately preceding enrollment in two 8-week blocks classified as either:
1. Low-transfusion burden (LTB), defined as 4 to 7 RBC units per 16 weeks; or
2. High-transfusion burden (HTB), defined as \>=8 RBC units per 16 weeks; and
3. For all participants:
i. Only transfusion events for a pretransfusion Hgb \<10 grams per deciliter (g/dL) are counted toward eligibility; ii. At least 1 transfusion event in each 8-week block and a minimum of 2 transfusion events separated by \>=7 days within the 16-week period immediately preceding enrollment; and iii. No consecutive 56-day period can be RBC transfusion-free during the 16 week period immediately preceding enrollment.
Note: Only transfusions for the disease under study will be counted towards classification for LTB or HTB participants. Transfusions for intercurrent diseases (bleeding, surgical procedure, infection, etc.) are not considered.
Non-transfusion dependent (NTD) cohort: NTD, defined as 0 to 1 RBC units per 8 weeks immediately preceding enrollment.
Note: RBC transfusions administered when Hgb levels were \<9.0 g/dL are counted for eligibility. RBC transfusions administered for other than MDS-related anemia (bleeding, surgical procedure, infection, etc.) will not be counted as a required transfusion for the purpose of meeting eligibility criteria.
5. TD cohort: Refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) treatment (discontinued \>=4 weeks before enrollment), or unlikely to respond to ESA treatment, defined as follows:
a. Refractory to prior ESA treatment: documentation of nonresponse or a response that was no longer maintained with a prior ESA-containing regimen, either as a single agent or combination (eg, with granulocyte colony-stimulating factor \[G-CSF\]); ESA regimen must have been either: i. Recombinant human erythropoietin (EPO) \>=30,000 IU/week for \>=8 doses or equivalent; or ii. Darbepoetin alpha \>=500 mcrg every 3 weeks for \>=3 doses, \>=120 mcrg every week for \>=8 doses or equivalent.
b. Intolerant to prior ESA treatment: documentation of discontinuation of a prior ESA containing regimen, either as a single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an AE.
c. Unlikely to respond to ESA treatment: low chance of response to ESA based on an endogenous serum EPO level \>200 U/L.
Note: Due to expected impacts of transfusion on EPO levels, blood samples collected within the 14 days following an RBC transfusion or within 7 days following a platelet transfusion cannot be used to evaluate serum EPO level for eligibility, unless considered pretransfusion values.
NTD cohort: Hgb \<10 g/dL and exhibiting anemia-related clinical symptoms (eg, fatigue, shortness of breath, or others) during screening.
6. Less than 5% blasts in an evaluable bone marrow sample collected at screening.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
8. Women of childbearing potential (WOCBP), defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 consecutive months must
1. Agree to use 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 60 days after the last dose of study drug; or
2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
9. Male participants must, even if he is surgically sterilized (ie, status postvasectomy), a. Agree to practice effective barrier contraception the time of signing the informed consent through 60 days after the last dose of study drug; or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
Exclusion Criteria:
Medical History
1. Del(5q) MDS or secondary MDS.
2. Anemia due to any other known cause (eg, thalassemia, hemolytic anemia, bleeding events, or deficiency of iron, B12, and/or folate).
3. Receipt of RBC transfusion for any reason(s) other than underlying MDS within 16 weeks in TD cohort or 8 weeks in NTD cohort before enrollment.
4. Clinically significant cardiovascular disease defined as:
1. New York Heart Association heart disease class III or IV;
2. Fridericia corrected QT (QTcF) interval \>500 milliseconds during screening;
3. Presence of uncontrolled hypertension defined as mean systolic blood pressure \>=160 mm Hg or diastolic blood pressure \>=100 mm Hg during screening; or
4. Uncontrolled arrhythmia, myocardial infarction, or unstable angina within 6 months before screening.
5. Known ejection fraction \<35%, confirmed by a local echocardiogram performed during screening, or a previously performed echocardiogram if collected within 6 months before screening.
6. Stroke, deep vein thrombosis, or pulmonary embolism within 6 months before screening.
7. Any known history of acute myeloid leukemia (AML).
8. Prior history of malignancies, other than MDS, unless the participant has been free of the disease (including completion of any treatment, including maintenance, for prior malignancy) for \>=2 years. However, participants with a history or concurrent diagnosis of the following conditions are allowed if not requiring systemic therapy:
1. Basal or squamous cell carcinoma of the skin;
2. Carcinoma in situ of the cervix;
3. Carcinoma in situ of the breast; and/or
4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis \[TNM\] clinical staging system).
5. Early papillary thyroid cancer (stage I \[T1-T2, N0, M0\]).
9. History of solid organ or bone marrow transplantation.
10. Active infection requiring intravenous antibiotics within 28 days or oral antibiotics within 14 days before enrollment.
11. Active infection with HIV, active infectious hepatitis B virus (HBV), or active infectious hepatitis C virus (HCV). Participants who are positive for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis B surface antibody (HBsAb) may be eligible for enrollment if their hepatitis B viral load is below the limit of detection. Participants who are positive for hepatitis C virus antibodies (HCVAb) may be enrolled if their hepatitis C viral load is below the limit of detection.
12. Body mass index \>=40 kg/m\^2.
13. Major surgery within 28 days before enrollment.
14. History of allergy/anaphylaxis to investigational medicinal product (IMP) excipients (refer to the current elritercept \[TAK 226\] IB for a list of excipients) or recombinant proteins.
Treatment History
15. TD cohort: Prior use of TAK 226, luspatercept, imetelstat, or sotatercept. NTD cohort: Prior use of TAK 226, luspatercept, imetelstat, sotatercept, or ESAs.
Note for NTD cohort: At the investigator's discretion in consultation with the medical monitor, may be allowed if received no more than 2 doses of ESAs \>=8 weeks prior to enrollment.
16. Prior use of hypomethylating agents (HMAs), isocitrate dehydrogenase inhibitor, lenalidomide, or immunosuppressive therapy given for treatment of MDS.
17. Iron chelation therapy initiated within 8 weeks before enrollment. Participants on stable or decreasing doses of iron chelation therapy for \>=8 weeks are allowed.
18. Vitamin B12 or folate therapy initiated within 4 weeks before enrollment. Participants on stable replacement doses for \>=4 weeks and without ongoing concurrent vitamin B12 or folate deficiency are allowed.
19. Androgen use within 8 weeks before enrollment. Participants on stable androgen dosing for hypogonadism for \>=8 weeks are allowed.
20. High-dose systemic corticosteroid use within 4 weeks before enrollment. Participants on stable chronic steroid doses of prednisone/prednisolone \<=10 mg/day or corticosteroid equivalent for \>=4 weeks are allowed.
21. Treatment with any investigational drug within 28 days before screening or, if the half-life of the product is known, within 5 times the half-life before screening, whichever is longer.
22. Ongoing participation in another interventional clinical study.
Laboratory Exclusions (during Screening)
23. Serum EPO level \>500 U/L. Note: Due to expected impacts of transfusion on EPO levels, laboratory results from blood samples collected within the 14 days following an RBC transfusion cannot be used to evaluate serum EPO level for eligibility, unless considered pretransfusion values.
24. Platelet count \>=800\*10\^3/mcrL or \<=25\*10\^3/mcrL. Note: Due to expected impacts of transfusion, laboratory results from blood samples collected within the 7 days following a platelet transfusion cannot be used to evaluate platelet count for eligibility, unless they are considered pretransfusion values.
25. Absolute neutrophil count \<=500/mcrL
26. Serum AST or ALT \>=3\*the upper limit of normal (ULN).
27. Total bilirubin \>=2\*ULN. Participants with known history of Gilbert syndrome with unconjugated bilirubin \<3\*ULN are allowed.
28. Ferritin \<=50 mcrg/L.
29. Folate \<=2.0 ng/mL.
30. Vitamin B12 \<=200 pg/mL.
31. Estimated glomerular filtration rate \<30 mL/min/1.73 m\^2 as determined by Japanese Society of Nephrology. Calculated by the correction formula for Japanese. a)
a) eGFR=194\* (serum creatinine value)\^-1.094\* (age)\^-0.287\* (sex correction factor), Sex correction factor: 0.739 in female.
Miscellaneous
32. Pregnant or lactating female. Note: Participants who may be in the very early stage of pregnancy based on the doctor's interview with a negative pregnancy test are excluded from the study. Participants who are lactating will be eligible if they discontinue breastfeeding from before the first dose of study drug until 60 days after the last dose of study drug.
33. Any other condition not specifically noted above that, in the opinion of the investigator, would preclude the participant from participating in the study or could confound interpretation of data from the study.
Investigational site staff members directly involved in the conduct of the study and site staff members otherwise supervised by the investigator, employees of the Sponsor or contract research organization (CRO) directly involved in the conduct of the study, or immediate family members (defined as a spouse, parent, child, or sibling, whether biological or legally adopted).
Inclusion Criteria:
* Pregnant women aged 18 to 44 years with constipation.
* Maternal coverage by health care and prescriptions insurance during eligibility period:
a) To study pregnancy outcomes (live births, spontaneous abortions, terminations, or stillbirths): 90 days prior to the LMP until end of pregnancy; and b) to study malformations, perinatal and infant outcomes: 90 days to LMP until 30 days post-delivery.
* For infant outcomes, the cohort will be restricted to pregnancies with linked offspring.
* For major malformations, only pregnancies with livebirths will be included, since information regarding the pathological results from a pregnancy loss or the indication for termination is rarely recorded. In addition, infants are required to have full insurance coverage from delivery to at least 90 days after the delivery, unless the infant died prior to the end of the 90 days, in which case a shorter eligibility period until death is permitted.
* For the analyses of pregnancy losses, the cohort also includes pregnancies ending in spontaneous abortion, terminations, stillbirth and any livebirth (linked or unlinked to a delivery).
Exclusion Criteria:
* Women with opioids dispensed in the 3 months prior to LMP or during the first trimester (to exclude potential opioid-induced constipation) and women with inflammatory bowel diseases (IBD) (because IBD is a contraindication)
* For major malformations, the cohort excludes pregnancies with a chromosomal abnormality based on at least one inpatient or outpatient ICD-9 code for 758.xx,759.81-759.83, or 655.1x within 90 days after delivery in the infant and/or maternal claims.
* For major malformations, pregnancies with outpatient exposure to definite teratogens including warfarin, valproate, antineoplastic agents, colchicine, testosterone, radioiodine, isotretinoin, misoprostol, and thalidomide from LMP through LMP plus 90 days.
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Inclusion Criteria:
* Pregnant women aged 18 to 44 years with constipation.
* Maternal coverage by health care and prescriptions insurance during eligibility period:
a) To study pregnancy outcomes (live births, spontaneous abortions, terminations, or stillbirths): 90 days prior to the LMP until end of pregnancy; and b) to study malformations, perinatal, and infant outcomes: 90 days to LMP until 30 days post-delivery.
* For infant outcomes, the cohort will be restricted to pregnancies with linked offspring.
* For major malformations, only pregnancies with livebirths will be included, since information regarding the pathology results from a pregnancy loss or the indication for termination is rarely recorded. In addition, infants are required to have full insurance coverage from delivery to at least 90 days after the delivery, unless the infant died prior to the end of the 90 days, in which case a shorter eligibility period until death is permitted.
* For the analyses of pregnancy losses, the cohort also includes pregnancies ending in spontaneous abortion, terminations, stillbirth and any livebirth (linked or unlinked to a delivery).
Exclusion Criteria:
* Women with opioids dispensed in the 90 days prior to LMP or during the first trimester (to exclude potential opioid-induced constipation).
* Women with inflammatory bowel diseases (IBDs) identified based on ICD codes recorded in the 90 days prior to LMP or during the first trimester (because it is a contraindication).
* For major malformations, pregnancies with outpatient exposure to definite teratogens including warfarin, valproate, antineoplastic agents, colchicine, testosterone, radioiodine, isotretinoin, misoprostol, and thalidomide from LMP through LMP plus 90 days.
Inclusion Criteria:
1. Participants ≥18 years or ≥ the local legal age of majority, as applicable, at the time of signing the ICF.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Participants must provide biopsy samples (core needle or other surgical procedure) collected within 28 days prior to C1D1 and also on treatment unless procedure is determined to be unsafe following discussion with sponsor. Participants with an archival biopsy specimen collected within 90 days prior to C1D1 of TAK-188 who have not received any other cancer-specific treatment (with the exception of adjuvant endocrine therapy for a history of breast cancer) at least 14 days prior to the biopsy and throughout the period leading up to C1D1 may use that archival specimen in lieu of a new pretreatment biopsy. Archival biopsy from the same tumor must be provided, if available.
4. Adequate bone marrow, renal, and hepatic functions, as determined by the following laboratory parameters:
1. Absolute neutrophil count (ANC) ≥1500 per microliter (μL), platelet count ≥75,000/μL, and hemoglobin (Hgb) ≥8.0 g/dL without growth factor support for ANC or transfusion support for platelets within 14 days before the first trial treatment dose. Transfusion of packed red blood cells is allowed, post infusion Hgb must be greater than 8.0 g/dL.
2. Total bilirubin ≤1.5 times the institutional upper limit of the normal range (ULN). For participants with Gilbert's disease, ≤3 milligrams per deciliter (mg/dL).
3. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × ULN or baseline or ≤5.0 × ULN or baseline with liver metastases.
4. Albumin ≥3.0 grams per deciliter (g/dL).
5. Calculated creatinine clearance CLCR (using the Cockcroft-Gault formula) ≥60 mL/minute.
6. Left Ventricular Ejection Fraction (LVEF) \>50%, as measured by echocardiogram or multiple-gated acquisition scan (MUGA) within 4 weeks before receiving the first dose of TAK-188.
5. Clinically significant toxic effects of previous therapy have recovered to Grade 1 (per NCI CTCAE v5.0) or baseline, except for alopecia, Grade 2 peripheral neuropathy, and/or autoimmune endocrinopathies with stable endocrine replacement therapy.
6. Female participants must be:
1. Postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before the screening visit, or
2. Surgically sterile, or
3. If they are of childbearing potential, agree to practice 2 effective methods of contraception at the same time, from the time of signing the informed consent through 180 days after the last dose of TAK-188, or
4. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant.
5. Periodic abstinence (for example, calendar ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
7. Male participants, even if surgically sterilized (that is, status postvasectomy), must:
1. Agree to practice effective barrier contraception (that is, a condom) during the entire trial treatment period and through 180 days after the last dose of TAK-188, or
2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant.
3. Periodic abstinence (for example, calendar ovulation, symptothermal, postovulation methods), withdrawal, and spermicides only are not acceptable methods of contraception.
8. Voluntary written consent must be given before performance of any trial-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
9. Participants with controlled Human Immunodeficiency Virus (HIV) are allowed:
1. Cluster of differentiation 4 (CD4) cell count greater than 350 cell per cubic millimeters (cell/mm\^3).
2. Viral load undetectable for at least a year.
10. The following solid tumor participants will be allowed:
a. Participants with the following pathologically confirmed (cytological diagnosis is adequate) locally advanced or metastatic solid tumors, who have progressed on all standard, curative, or life-prolonging treatments (or are intolerant to all available standard therapies): i. Gastroesophageal (esophageal, gastroesophageal junction, and gastric) adenocarcinoma and squamous cell carcinoma.
ii. PDAC. iii. Nonsquamous and squamous NSCLC (participants with actionable genomic alteration \[AGAs\] are allowed in dose escalation only).
iv. squamous cell carcinoma of head and neck (SCCHN). v. Colorectal cancer.
11. Participants with metastatic or advanced solid tumors must have radiographically measurable disease per RECIST Version 1.1. Lesions to be used as measurable disease for the purpose of response assessment must either a) not reside in a field that has been subjected to prior radiotherapy or b) have demonstrated clear evidence of radiographic progression since the completion of prior radiotherapy and before trial enrollment or c) have been radiated at least 6 months before trial enrollment or d) should not be the same lesion selected for mandatory biopsy at screening.
12. For expansion in NSCLC (post programmed cell death-ligand 1 \[PD-L1\] treatment):
1. Participants with pathologically confirmed (cytological diagnosis is adequate) locally advanced or metastatic NSCLC.
2. Participants must have tested negative for a known AGA (for example, estimated glomerular filtration rate (EGFR), anaplastic lymphoma kinase (ALK), mesenchymal epithelial transition \[MET\], c-ros oncogene 1 \[ROS1\], BRAF).
3. Must have had disease progression in the advanced or metastatic setting. No more than 1 line of therapy in advanced or metastatic setting is permitted.
4. Participants must have received at least 6 weeks of 1 prior anti-PD-(L)1 therapy, and this must have been given during the immediately preceding line of therapy. Anti-PD-(L)1 therapy may have been given in the metastatic or neoadjuvant setting.
5. Participants are eligible regardless of PD-L1 status but this information must be provided.
6. NOTE: Prior anti-PD-(L)1 therapy may have been given with or without an anti-CTLA-4 antibody and/or chemotherapy (for example, carboplatin and pemetrexed).
13. For Phase 1 backfill and possible expansion, in SCCHN (post PD-(L)1 treatment):
1. Participants with histologically confirmed (cytological diagnosis is acceptable) metastatic or unresectable, recurrent SCCHN that is considered incurable by local therapies. Participants should have PD-(L)1 monotherapy or in combination with chemotherapy administered in the recurrent or metastatic setting or neo-adjuvant/adjuvant. Anti-PD-(L)1 therapy must have been given during the immediately preceding line of therapy. No more than 1 line of therapy in advanced or metastatic setting is permitted.
2. Anatomic subsites to be included are oral cavity, oropharynx, hypopharynx, larynx, nasal cavity, and paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal). The exception to this is nasopharyngeal cancer and salivary gland tumors, which will not be included.
3. Participants with oropharyngeal cancer or tumors arising in the paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal) must agree to provide archival tissue for human papillomavirus (HPV) testing or if known, HPV testing results using CINtec p16 histology assay and a 70% cutoff point must be provided. If HPV status was previously tested using this method, no additional testing is required. Otherwise, if another validated HPV assay was performed, tissue will be required for central confirmation.
4. Tumors must have a PD-L1 CPS ≥1.
14. For dose expansion in gastroesophageal adenocarcinoma (GEA) (post PD-(L)1 treatment):
1. Participants with pathologically confirmed (cytological diagnosis is adequate) locally advanced or metastatic gastroesophageal (esophageal, gastroesophageal junction, and gastric) adenocarcinoma.
2. Must have had disease progression while on or following 1 prior line of therapy:
3. Disease progression while on or following at least 6 weeks of 1 prior anti-PD-(L)1 therapy in the recurrent locally advanced or metastatic setting. Prior anti-PD-(L)1 therapy may have been given with or without chemotherapy (for example, mFOLFOX or CAPOX); CAPOX); HER-2 positive participants must have received trastuzumab. Anti-PD-(L)-1 therapy must have been given during the immediately preceding line of therapy. No more than 1 line of therapy in advanced or metastatic setting is permitted.
4. Tumors must have a PD-L1 CPS ≥1.
Exclusion Criteria:
1. History of any of the following cardiac illnesses within 6 months before first dose of TAK-188:
1. Congestive heart failure New York Heart Association Grade III or IV.
2. Unstable angina, myocardial infarction.
3. Persistent hypertension ≥160/100 mm mercury (Hg) despite optimal medical therapy.
4. Ongoing cardiac arrhythmias of Grade \>2 (including atrial flutter/fibrillation or intermittent ventricular tachycardia).
5. Other ongoing serious cardiac conditions (for example, Grade 3 pericardial effusion or Grade 3 restrictive cardiomyopathy).
6. Symptomatic cerebrovascular events.
7. Chronic, stable atrial fibrillation on stable anticoagulation therapy, including low molecular-weight heparin, is allowed.
2. Baseline prolongation of Fridericia-corrected QT interval (QTcF) (for example, repeated demonstration of QTc \>480 milliseconds, history of congenital long QT syndrome, or torsades de pointes) on a 12-lead ECG during the screening period. If participants are taking medications known to prolong QTc at screening, participants may continue to take these medications as long as their baseline QTcF is \<480 milliseconds. Participants may not start using such medications on or after C1D1.
3. Oxygen saturation of \<90% of room air at screening.
4. Participants treated with other chemokine (C-C motif) receptor 8 (CCR8) targeting agents within the past 6 months.
5. Active diagnosis of lung conditions including:
1. Pneumonitis.
2. Interstitial lung disease.
3. Severe chronic obstructive pulmonary disease.
4. Idiopathic pulmonary fibrosis.
5. Other restrictive lung diseases.
6. Acute symptomatic pulmonary embolism.
7. Grade ≥2 pleural effusion not controlled by tap or requiring indwelling catheters.
6. History of known brain metastasis or leptomeningeal disease unless:
1. Brain metastases are stable on cranial imaging (that is, ≥4 weeks) following prior surgery, whole-brain radiation OR
2. Stereotactic radiosurgery and off corticosteroids for brain metastases
3. Must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs.
7. Grade ≥2 fever of malignant origin.
8. Systemic infection requiring IV antibiotic therapy or other serious infection within 14 days before the first dose of TAK-188 or severe infections on continued treatment.
9. Participants with uncontrolled, known or suspected, autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to an autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
10. Participants with a diagnosis of an identified congenital or acquired immunodeficiency (for example, common variable immunodeficiency, uncontrolled HIV infections, organ transplantation).
11. Chronic, active hepatitis (for example, participants with known hepatitis B surface antigen seropositive and/or detectable HCV RNA). Note:
1. Participants who have positive hepatitis B core antibody can be enrolled but must have an undetectable serum hepatitis B virus-DNA.
2. Participants who have positive HCV antibody must have an undetectable HCV-RNA serum level.
12. Prior or current clinically significant ascites, as measured by physical examination, that requires active paracentesis for control.
13. Any pre-existing medical or psychiatric condition or illness, metabolic dysfunction, physical examination finding, or clinical laboratory finding that gives reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug or that would limit compliance with trial requirements or compromise ability to provide written informed consent. Participants with a history of PE on anti-coagulation are permitted unless symptomatic requiring oxygen supplementation.
14. Recent major surgery where the participant has not fully recovered based on physician assessment.
15. Recent major bleeding event that has not resolved, and the underlying reason for bleeding has not been corrected.
16. Participant with concurrent malignancy requiring active treatment, with the exception of participants on chronic hormonal therapy.
17. Treatment with fully human/humanized antineoplastic monoclonal antibodies less than 4 weeks or the time period equal to the dosing interval, whichever is shorter. No washout period is required for prior treatment with anti-PD-(L)1 antibodies.
18. Treatment with any investigational products or other anticancer therapy (including chemotherapy, targeted agents, and immunotherapy), within 14 days or 5 half-lives, whichever is shorter, before C1D1 of TAK-188.
19. Concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy (with the exception of adjuvant endocrine therapy for a history of breast cancer). Concurrent use of hormones for noncancer-related conditions is acceptable (except for corticosteroid hormones).
20. Radiation therapy within 14 days (42 days for radiation to the lungs) and/or systemic treatment with radionuclides within 42 days before C1D1 of TAK-188. Participants with clinically relevant ongoing pulmonary complications from prior radiation therapy are not eligible.
21. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 7 days of C1D1 of TAK-188, with the following exceptions:
1. Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic corticosteroids.
2. Physiological doses of replacement steroid therapy (for example, for adrenal insufficiency).
3. Single doses of steroids (for example, for imaging premedication) within the 7-day timeframe may be allowed after clarification with sponsor.
22. Receipt of live attenuated vaccine (for example, tuberculosis Bacillus Calmette-Guerin vaccine, oral polio vaccine, measles, rotavirus, yellow fever) within 28 days of C1D1 of TAK-188. Non-live, approved vaccines are allowed (for example, COVID-19 vaccine).
a. Note: COVID-19 vaccination should not be given within ±3 days of systemic trial treatments.
23. Recipients of stem cell transplantation or organ transplantation.
24. Female participants who are lactating or have a positive serum/urine pregnancy test during the screening period or a positive serum/urine pregnancy test on Day 1 before first dose of TAK-188.
a. Note: Female participants who are lactating will be eligible if they choose to discontinue breastfeeding before the first dose of TAK-188.
25. Participant is a trial site employee, a site employee's immediate family member (for example, spouse, parent, child, sibling), or is in a dependent relationship with a site employee who is involved in conduct of this trial or may consent under duress.
26. Participant is considered to be vulnerable, as defined per local regulations and if exclusion is required by local regulations. Examples are persons under safeguard of justice, persons deprived of liberty by judicial or administrative decision, persons receiving psychiatric care without their consent, persons admitted to a health or social establishment for purposes other than research, persons of full age who are subject to a legal protection measure (guardianship or curatorship), and persons unable to express their consent.
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Inclusion Criteria:
1. Participants greater than or equal to (≥)18 years or ≥ the local legal age of majority, as applicable, at the time of signing the informed consent form.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Participants must provide biopsy samples (core needle or other surgical procedure) collected within 21 days prior to Cycle 1 Day 1 (C1D1) and also on treatment unless procedure is determined to be unsafe following discussion with sponsor. Participants with an archival biopsy specimen collected within 90 days prior to C1D1 of TAK-188 who have not received any other cancer-specific treatment (with the exception of adjuvant endocrine therapy for a history of breast cancer) at least 14 days prior to the biopsy and throughout the period leading up to C1D1 may use that archival specimen in lieu of a new pretreatment biopsy. Archival biopsy from the same tumor must be provided, if available. On-treatment tumor biopsies will be optional in mainland China, but are highly desired.
4. Adequate bone marrow, renal, and hepatic functions, as determined by the following laboratory parameters:
1. Absolute neutrophil count (ANC) ≥1500 per microliter (μL), platelet count ≥75,000/μL, and hemoglobin (Hgb) ≥8.0 g/dL without growth factor support for ANC or transfusion support for platelets within 14 days before the first trial treatment dose. Transfusion of packed red blood cells is allowed, post infusion Hgb must be greater than 8.0 g/dL.
2. Total bilirubin ≤1.5 times the institutional upper limit of the normal range (ULN). For participants with Gilbert's disease, ≤3 milligrams per deciliter (mg/dL).
3. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × ULN or baseline; or, for participants with liver metastases, ≤5.0 × ULN or baseline with liver metastases.
4. Albumin ≥3.0 grams per deciliter (g/dL).
5. Adequate renal function, as determined by both of the following:
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1. Calculated creatinine clearance CLCR (using the Cockcroft-Gault formula) ≥60 mL/minute, and
2. Urine protein-creatinine ratio (UPCR) of ≤0.5. (For participants with a UPCR \>0.5 to \<1, participant may be considered for enrollment only after discussion with the sponsor medical monitor or its designee).
f. Left Ventricular Ejection Fraction (LVEF) \>50%, as measured by echocardiogram or multiple-gated acquisition scan (MUGA) within 4 weeks before receiving the first dose of TAK-188.
5. Clinically significant toxic effects of previous therapy have recovered to Grade 1 (per National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] v5.0) or baseline, except for alopecia, Grade 2 peripheral neuropathy, and/or autoimmune endocrinopathies with stable endocrine replacement therapy.
6. Female participants must be:
1. Postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before the screening visit, or
2. Surgically sterile, or
3. If they are of childbearing potential, agree to practice 2 effective methods of contraception at the same time, from the time of signing the informed consent through 180 days after the last dose of TAK-188, or
4. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant.
5. Periodic abstinence (for example, calendar ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
7. Male participants, even if surgically sterilized (that is, status postvasectomy), must:
1. Agree to practice effective barrier contraception (that is, a condom) during the entire trial treatment period and through 180 days after the last dose of TAK-188, or
2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant.
3. Periodic abstinence (for example, calendar ovulation, symptothermal, postovulation methods), withdrawal, and spermicides only are not acceptable methods of contraception.
8. Voluntary written consent must be given before performance of any trial-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
9. Participants with controlled Human Immunodeficiency Virus (HIV) are allowed:
1. Cluster of differentiation 4 (CD4) cell count greater than 350 cell per cubic millimeters (cell/mm\^3).
2. Viral load undetectable for at least a year.
10. The following solid tumor participants will be allowed:
a. Participants with the following pathologically confirmed (cytological diagnosis is adequate) locally advanced or metastatic solid tumors, who have progressed on all standard, curative, or life-prolonging treatments (or are intolerant to all available standard therapies): i. Gastroesophageal (esophageal, gastroesophageal junction, and gastric) adenocarcinoma and squamous cell carcinoma.
ii. pancreatic ductal adenocarcinoma (PDAC). iii. Nonsquamous and squamous nonsmall cell lung cancer (NSCLC) (participants with actionable genomic alteration \[AGAs\] are allowed in dose escalation only).
iv. squamous cell carcinoma of head and neck (SCCHN). v. Colorectal cancer.
11. Participants with metastatic or advanced solid tumors must have radiographically measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Lesions to be used as measurable disease for the purpose of response assessment must either a) not reside in a field that has been subjected to prior radiotherapy or b) have demonstrated clear evidence of radiographic progression since the completion of prior radiotherapy and before trial enrollment or c) have been radiated at least 6 months before trial enrollment or d) should not be the same lesion selected for mandatory biopsy at screening.
12. For expansion in NSCLC (post programmed cell death-ligand 1 \[PD-L1\] treatment):
1. Participants with pathologically confirmed (cytological diagnosis is adequate) locally advanced or metastatic NSCLC.
2. Participants must have tested negative for a known AGA (for example, estimated glomerular filtration rate (EGFR), anaplastic lymphoma kinase (ALK), mesenchymal epithelial transition \[MET\], c-ros oncogene 1 \[ROS1\], BRAF).
3. Must have had disease progression in the advanced or metastatic setting. No more than 1 line of therapy in advanced or metastatic setting is permitted.
4. Participants must have received at least 6 weeks of 1 prior anti-PD-(L)1 therapy, and this must have been given during the immediately preceding line of therapy. Anti-PD-(L)1 therapy may have been given in the metastatic or neoadjuvant setting.
5. Participants are eligible regardless of PD-L1 status but this information must be provided.
6. NOTE: Prior anti-PD-(L)1 therapy may have been given with or without an anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody and/or chemotherapy (for example, carboplatin and pemetrexed).
13. For phase 1 backfill and possible expansion, in SCCHN (post PD-(L)1 treatment):
1. Participants with histologically confirmed (cytological diagnosis is acceptable) metastatic or unresectable, recurrent SCCHN that is considered incurable by local therapies. Participants should have PD-(L)1 monotherapy or in combination with chemotherapy administered in the recurrent or metastatic setting or neo-adjuvant/adjuvant. Anti-PD-(L)1 therapy must have been given during the immediately preceding line of therapy. No more than 1 line of therapy in advanced or metastatic setting is permitted.
2. Anatomic subsites to be included are oral cavity, oropharynx, hypopharynx, larynx, nasal cavity, and paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal). The exception to this is nasopharyngeal cancer and salivary gland tumors, which will not be included.
3. Participants with oropharyngeal cancer or tumors arising in the paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal) must agree to provide archival tissue for human papillomavirus (HPV) testing or if known, HPV testing results using CINtec p16 histology assay and a 70% cutoff point must be provided. If HPV status was previously tested using this method, no additional testing is required. Otherwise, if another validated HPV assay was performed, tissue will be required for central confirmation.
4. Tumors must have a PD-L1 combined Positive Score (CPS) ≥1.
14. For dose expansion in gastroesophageal adenocarcinoma (GEA) (post PD-(L)1 treatment):
1. Participants with pathologically confirmed (cytological diagnosis is adequate) locally advanced or metastatic gastroesophageal (esophageal, gastroesophageal junction, and gastric) adenocarcinoma.
2. Must have had disease progression while on or following 1 prior line of therapy:
3. Disease progression while on or following at least 6 weeks of 1 prior anti-PD-(L)1 therapy in the recurrent locally advanced or metastatic setting. Prior anti-PD-(L)1 therapy may have been given with or without chemotherapy (for example, mFOLFOX or CAPOX); CAPOX); HER-2 positive participants must have received trastuzumab. Anti-PD-(L)-1 therapy must have been given during the immediately preceding line of therapy. No more than 1 line of therapy in advanced or metastatic setting is permitted.
4. Tumors must have a PD-L1 CPS ≥1.
15. For phase 1b backfill and possible expansion in PDAC:
1. Participants with pathologically confirmed (cytological diagnosis is adequate) locally advanced or metastatic PDAC.
2. Must have had disease progression in the advanced or metastatic setting. Participants must have had at least 1, and no more than 2, lines of therapy in the advanced or metastatic setting. This may have included standard of care chemotherapies and may include a RAS inhibitor or a combination of the two.
Exclusion Criteria:
1. History of any of the following cardiac illnesses within 6 months before first dose of TAK-188:
1. Congestive heart failure New York Heart Association Grade III or IV.
2. Unstable angina, myocardial infarction.
3. Persistent hypertension ≥160/100 mm mercury (Hg) despite optimal medical therapy.
4. Ongoing cardiac arrhythmias of Grade \>2 (including atrial flutter/fibrillation or intermittent ventricular tachycardia).
5. Other ongoing serious cardiac conditions (for example, Grade 3 pericardial effusion or Grade 3 restrictive cardiomyopathy).
6. Symptomatic cerebrovascular events.
7. Chronic, stable atrial fibrillation on stable anticoagulation therapy, including low molecular-weight heparin, is allowed.
2. Baseline prolongation of Fridericia-corrected QT interval (QTcF) (for example, repeated demonstration of QTc \>480 milliseconds, history of congenital long QT syndrome, or torsades de pointes) on a 12-lead ECG during the screening period. If participants are taking medications known to prolong QTc at screening, participants may continue to take these medications as long as their baseline QTcF is \<480 milliseconds. Participants may not start using such medications on or after C1D1.
3. Oxygen saturation of \<90% of room air at screening.
4. Participants treated with other chemokine (C-C motif) receptor 8 (CCR8) targeting agents within the past 6 months.
5. Active diagnosis of lung conditions including:
1. Pneumonitis.
2. Interstitial lung disease.
3. Severe chronic obstructive pulmonary disease.
4. Idiopathic pulmonary fibrosis.
5. Other restrictive lung diseases.
6. Acute symptomatic pulmonary embolism.
7. Grade ≥2 pleural effusion not controlled by tap or requiring indwelling catheters.
6. History of known brain metastasis or leptomeningeal disease unless:
1. Brain metastases are stable on cranial imaging (that is, ≥4 weeks) following prior surgery, whole-brain radiation OR
2. Stereotactic radiosurgery and off corticosteroids for brain metastases
3. Must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs.
7. Grade ≥2 fever of malignant origin.
8. Systemic infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before the first dose of TAK-188 or severe infections on continued treatment.
9. Participants with autoimmune diseases which currently require ongoing systemic therapy or have required systemic therapy within the preceding 3 months (for example, traditional disease-modifying antirheumatic drugs, biologics, and so forth). Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to an autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
10. Participants with a diagnosis of an identified congenital or acquired immunodeficiency (for example, common variable immunodeficiency, uncontrolled HIV infections, organ transplantation).
11. Chronic, active hepatitis (for example, participants with known hepatitis B surface antigen seropositive and/or detectable HCV RNA). Note:
1. Participants who have positive hepatitis B core antibody can be enrolled but must have an undetectable serum hepatitis B virus-DNA.
2. Participants who have positive HCV antibody must have an undetectable HCV-RNA serum level.
12. Prior or current clinically significant ascites, as measured by physical examination, that requires regularly scheduled paracentesis for control.
13. Any pre-existing medical or psychiatric condition or illness, metabolic dysfunction, physical examination finding, or clinical laboratory finding that gives reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug or that would limit compliance with trial requirements or compromise ability to provide written informed consent. Participants with a history of pulmonary embolism on anti-coagulation are permitted unless symptomatic requiring oxygen supplementation.
14. Recent major surgery where the participant has not fully recovered based on physician assessment.
15. Recent major bleeding event that has not resolved, and the underlying reason for bleeding has not been corrected.
16. Participant with concurrent malignancy requiring active treatment, with the exception of participants on chronic hormonal therapy.
17. Treatment with fully human/humanized antineoplastic monoclonal antibodies less than 4 weeks or the time period equal to the dosing interval, whichever is shorter. No washout period is required for prior treatment with anti-PD-(L)1 antibodies.
18. Treatment with any investigational products or other anticancer therapy (including chemotherapy, targeted agents, and immunotherapy), within 14 days or 5 half-lives, whichever is shorter, before C1D1 of TAK-188.
19. Concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy (with the exception of adjuvant endocrine therapy for a history of breast cancer). Concurrent use of hormones for noncancer-related conditions is acceptable (except for corticosteroid hormones).
20. Radiation therapy within 14 days (42 days for radiation to the lungs) and/or systemic treatment with radionuclides within 42 days before C1D1 of TAK-188. Participants with clinically relevant ongoing pulmonary complications from prior radiation therapy are not eligible.
21. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 7 days of C1D1 of TAK-188, with the following exceptions:
1. Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic corticosteroids.
2. Physiological doses of replacement steroid therapy (for example, for adrenal insufficiency).
3. Single doses of steroids (for example, for imaging premedication) within the 7-day timeframe may be allowed after clarification with sponsor.
22. Receipt of live attenuated vaccine (for example, tuberculosis Bacillus Calmette-Guerin vaccine, oral polio vaccine, measles, rotavirus, yellow fever) within 28 days of C1D1 of TAK-188. Non-live, approved vaccines are allowed (for example, COVID-19 vaccine).
a. Note: COVID-19 vaccination should not be given within ±3 days of systemic trial treatments.
23. Recipients of stem cell transplantation or organ transplantation.
24. Female participants who are lactating or have a positive serum/urine pregnancy test during the screening period or a positive serum/urine pregnancy test on Day 1 before first dose of TAK-188.
a. Note: Female participants who are lactating will be eligible if they choose to discontinue breastfeeding before the first dose of TAK-188.
25. Participant is a trial site employee, a site employee's immediate family member (for example, spouse, parent, child, sibling), or is in a dependent relationship with a site employee who is involved in conduct of this trial or may consent under duress.
26. Participant is considered to be vulnerable, as defined per local regulations and if exclusion is required by local regulations. Examples are persons under safeguard of justice, persons deprived of liberty by judicial or administrative decision, persons receiving psychiatric care without their consent, persons admitted to a health or social establishment for purposes other than research, persons of full age who are subject to a legal protection measure (guardianship or curatorship), and persons unable to express their consent.
Inclusion Criteria:
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local study participant privacy regulations.
2. Male or female ≥ 18 years of age, at the time of signing informed consent.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (if related to anemia).
4. Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception.
5. In the opinion of the Investigator, the participant is able and willing to comply with the requirements of the protocol (e.g., all study procedures, return for follow-up visits).
Part 1 Inclusion Criteria
Participants are eligible to be included in Part 1 of the study only if all the following criteria apply:
1. Diagnosis of MDS according to WHO classification that meets International Prognostic Scoring System-Revised (IPSS-R) classification of very low, low, or intermediate risk disease.
2. Less than (\<)5percent (%) blasts in bone marrow during the Pretreatment Period.
3. Peripheral blood white blood cell (WBC) count \<13,000/microliter (μL) during the Pretreatment Period.
4. Anemia defined as:
1. In non-transfused participants, having received no RBC transfusions within 8 weeks, Hgb concentration ≤ 10.0 g/dL during the Pretreatment Period OR
2. In LTB participants, having received 1 to 3 units of RBCs for Hgb ≤ 9.0 g/dL within 8 weeks of the Pretreatment Period.
OR
3. In HTB participants, having received ≥ 4 units of RBCs for Hgb ≤ 9.0 g/dL within 8 weeks of the Pretreatment Period.
Part 1 Extension - Abbreviated Inclusion Criteria
Participants from Part 1 are eligible to be included in Part 1 Extension of the study only if all the following criteria apply:
1. Previously completed 4 cycles of elritercept in Part 1 with no dose-limiting toxicities (DLTs).
2. Participant has the potential to benefit from administration of elritercept, in the opinion of the Investigator.
3. \< 5% blasts in bone marrow.
4. Peripheral WBC count \< 13,000/μL during the 28 days prior to cycle 5 day 1 (C5D1).
Part 2 Inclusion Criteria
Participants are eligible to be included in Part 2 of the study only if all the following criteria apply:
1. Cohort A:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* ring sideroblast (RS)-positive as defined by WHO 2016 criteria.
* Requiring at least 2 units of RBC transfusions in the preceding 8 weeks before cycle 1 day 1 (C1D1).
2. Cohort B:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Non-RS as defined by WHO 2016 criteria.
* Requiring at least 2 units of RBC transfusions in the 8 weeks before C1D1.
3. Cohort C:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Has anemia, defined by Hgb ≤ 10 g/dL during the Pretreatment Period, and received no RBC transfusion in the 8 weeks before C1D1.
4. Cohort D:
* Diagnosis of CMML according to WHO classification.
* Has anemia, defined by Hgb ≤ 10 g/dL during the Pretreatment Period, and received no RBC transfusion in the 8 weeks before C1D1.
* OR
* Received at least 2 units of RBC transfusions for anemia in the 8 weeks before C1D1.
5. Cohort E:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Requiring ≥ 2 units of RBC transfusions in the preceding 8 weeks before C1D1.
* Receipt of ≥ 20 units of RBC in transfusion over the participant's lifetime.
* Serum ferritin \> 1000 nanograms per milliliter (ng/mL) on ≥ 2 assessments in the preceding 8 weeks before C1D1.
* Treated with stable dose of iron chelation therapy for ≥ 8 weeks prior to C1D1.
6. Cohort F:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Requiring ≥ 2 units of RBC transfusions in the preceding 8 weeks before C1D1.
* Receipt of ≥ 20 units of RBC in transfusion over the participant's lifetime.
* Serum ferritin \> 1000 ng/mL on ≥ 2 assessments in the preceding 8 weeks before C1D1.
* Not treated with iron chelation therapy in the preceding 8 weeks before C1D1 and not eligible to initiate iron chelation therapy in the opinion of the Investigator and in accordance with local treatment guidelines for initiation of iron chelation therapy.
7. Cohort G:
* Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* RS-positive as defined by WHO 2016 criteria OR non-RS as defined by WHO 2016 criteria.
* Relapsed, refractory, or intolerant to frontline luspatercept treatment and have not received an interceding therapy (for example, erythropoiesis-stimulating agent \[ESA\])
* Relapsed is defined as documentation of response to luspatercept therapy and subsequent development of a need for transfusion(s).
* Refractory is defined as documentation of no response with luspatercept ≥ 1 mg/kg administered for ≥ 12 weeks duration.
* Intolerant is defined as documentation of discontinuation of luspatercept therapy due to intolerance or an AE at any time after introduction.
* Requiring ≥ 2 units of RBC transfusions over 8 weeks prior to C1D1.
* Erythropoietin (EPO) \< 500 international units per liter (U/L) at Baseline.
* Last dose of luspatercept is ≥ 3 weeks and \< 12 months from C1D1.
8. \< 5% blasts in bone marrow assessed by bone marrow aspirate during the Pretreatment Period.
Part 1 Exclusion Criteria
Participants are excluded from Part 1 of the study if any of the following criteria apply.
Medical History
1. Diagnosis of MDS with deletion of chromosome 5q (Del5q).
2. Active infection requiring parenteral antibiotic therapy within 28 days prior to C1D1 or oral antibiotics within 14 days of C1D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
3. Presence of uncontrolled heart disease or New York Heart Association (NYHA) Class III or IV heart failure.
4. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
5. History of stroke, deep venous thrombosis (DVT), or arterial embolism within 6 months prior to C1D1.
6. Major surgery within 28 days prior to C1D1. Participants must be completely recovered from any previous surgery prior to C1D1.
7. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B virus (HBV), or active infectious hepatitis C virus (HCV). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
8. Any malignancy other than MDS that has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy, or surgery, within 1 year prior to C1D1. Diagnosis of secondary MDS (i.e., MDS known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases).
9. History of solid organ or hematological transplantation.
10. Presence of uncontrolled hypertension, defined as systolic blood pressure (BP) ≥ 150 mmHg or diastolic BP ≥ 100 mmHg despite adequate treatment.
11. Body mass index (BMI) ≥ 40 kilograms per meter square (kg/m\^2) during the Pretreatment Period.
12. History of severe allergic or anaphylactic reaction(s) or hypersensitivity to recombinant proteins or excipients in the investigational medicinal product (IMP).
Treatment History
1. Prior treatment with azacitidine, decitabine, lenalidomide, luspatercept, or sotatercept.
2. Treatment with ESA within 56 days prior to C1D1.
3. Prior or concurrent chronic treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF).
4. Iron chelation therapy if initiated within 8 weeks prior to C1D1.
5. Vitamin B12 therapy initiated within 8 weeks prior to C1D1. Participants on stable replacement doses for ≥ 8 weeks and without concurrent vitamin B12 or folate deficiency are allowed.
6. Treatment with another investigational drug or device or approved therapy for investigational use ≤ 28 days prior to C1D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer.
Laboratory Exclusions (during Pretreatment Period)
1. Platelet count \> 450 ✕ 10\^9/L or \< 30 ✕ 10\^9/L.
2. Transferrin saturation \< 15%.
3. Ferritin \< 50 nanograms per milliliter (ng/mL).
4. Folate \< 4.5 nanomoles per liter (nmol/L) (\< 2.0 ng/mL).
5. Vitamin B12 \< 148 picomoles per liter (pmol/L) (\< 200 picograms per milliliter \[pg/mL\]).
6. Estimated glomerular filtration rate (GFR) \< 30 milliliter per minute per 1.73 meter square (mL/min/1.73 m\^2), as determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
7. Positive for HIV.
Miscellaneous
1. Pregnant or lactating females.
2. Any other condition not specifically noted above which, in the opinion of the Investigator, would preclude the participant from participating in the study.
3. Participants who are investigational site staff members directly involved in the conduct of the trial and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Sponsor or contract research organization (CRO) employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
Part 1 Extension - Exclusion Criteria
Participants from Part 1 are excluded from Part 1 Extension of the study if any of the following criteria apply.
Medical History
1. Discontinuation of IMP in Part 1 for any reason.
2. Has not completed a study visit in the past 12 months.
3. Active infection requiring parenteral antibiotic therapy within 28 days prior to C5D1 or oral antibiotics within 14 days of C5D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
4. Presence of uncontrolled heart disease or NYHA Class III or IV heart failure.
5. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
6. History of stroke, DVT, or arterial embolism within 6 months prior to C5D1.
7. Major surgery within 28 days prior to C5D1. Participants must be completely recovered from any previous surgery prior to C5D1.
8. Known positive for HIV, active infectious HBV, or active infectious HCV. Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
9. Any malignancy other than MDS that has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy, or surgery, within 1 year prior to C5D1.
10. History of solid organ or hematological transplantation.
11. Presence of uncontrolled hypertension, defined as systolic BP ≥ 150 mmHg or diastolic BP ≥ 100 mmHg despite adequate treatment.
12. BMI ≥ 40 kg/m\^2 during the 28 days prior to C5D1.
Treatment History
1. Prior treatment with azacitidine, decitabine, lenalidomide, luspatercept, or sotatercept.
2. Treatment with ESA within 56 days prior to C5D1.
3. Prior or concurrent chronic treatment with G-CSF or GM-CSF.
4. Iron chelation therapy if initiated within 8 weeks prior to C5D1.
5. Vitamin B12 with treatment initiated within 8 weeks prior to C5D1. Participants on stable replacement doses for ≥ 8 weeks and without concurrent vitamin B12 or folate deficiency are allowed.
6. Treatment with another investigational drug or device or approved therapy for investigational use ≤ 28 days prior to C5D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C5D1, whichever is longer. Previous treatment with elritercept is acceptable.
Laboratory Exclusions (during Abbreviated Pretreatment Period)
1. Platelet count \> 450 × 10\^9/L or \< 30 × 10\^9/L.
2. Transferrin saturation \< 15%.
3. Ferritin \< 50 ng/mL.
4. Folate \< 4.5 nmol/L (\< 2.0 ng/mL).
5. Vitamin B12 \< 148 pmol/L (\< 200 pg/mL).
6. Estimated GFR \< 30 mL/min/1.73 m\^2, as determined by the CKD-EPI equation.
Miscellaneous
1. Pregnant or lactating females.
2. Any other condition not specifically noted above which, in the opinion of the Investigator, would preclude the participant from participating in the study.
3. Participants who are investigational site staff members directly involved in the conduct of the trial and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Sponsor or CRO employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
Part 2 Exclusion Criteria
Participants are excluded from Part 2 of the study if any of the following criteria apply.
Medical History
1. Diagnosis of MDS with Del5q.
2. Diagnosis of secondary MDS (i.e., MDS known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases).
3. Active infection requiring parenteral antibiotic therapy within 28 days prior to C1D1 or oral antibiotics within 14 days of C1D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
4. Presence of the following cardiac conditions:
1. Presence of uncontrolled heart disease or NYHA Class III or IV heart failure.
2. QTcF (QT interval corrected by Fridericia's formula) \> 500 msec on the screening or C1D1 electrocardiogram (ECG; mean of 3 measurements).
3. Uncontrolled clinically significant arrhythmia (participants with rate-controlled atrial fibrillation are not excluded).
4. Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to C1D1.
5. Presence of uncontrolled hypertension, defined as systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite adequate treatment.
6. History of stroke, DVT, or arterial embolism within 6 months prior to C1D1.
7. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
8. Major surgery within 28 days prior to C1D1. Participants must be completely recovered from any previous surgery prior to C1D1.
9. Any malignancy other than MDS or CMML that has not been in remission and/or has required major surgery or systemic therapy including radiation, chemotherapy, targeted therapy, or hormonal therapy within 1 year prior to C1D1.
10. History of solid organ or hematological transplantation.
11. Diagnosis of hemolytic anemia, active bleeding, hemoglobinopathies, or congenital disorders as a cause of the participant's anemia.
12. NCI-CTCAE Grade ≥ 2 bleeding events within the 3 months prior to C1D1.
13. Receipt of an RBC or platelet transfusion for any reason(s) or combination of reasons other than underlying MDS within the 16 weeks prior to C1D1. If a participant requires a transfusion for an unanticipated reason during the Pretreatment Period, a prolonged screening period may be considered after discussion with the Medical Monitor.
14. Known positive for HIV, active infectious HBV with positive viral load (HBV DNA), or active infectious HCV with positive viral load (HCV RNA). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
15. BMI ≥ 40 kg/m\^2.
16. History of severe allergic or anaphylactic reaction(s) or hypersensitivity to recombinant proteins or excipients in the IMP.
17. Diagnosis of cirrhosis, non-alcoholic steatohepatitis, alcoholic liver disease, hepatitis, or other liver disease (acute or chronic) meeting Child-Pugh C criteria for hepatic impairment. Participants with elevated liver enzymes are allowed if the liver enzyme elevation is suspected to be due to iron-overload or iron chelation, and other hepatic causes have been ruled out, in the opinion of the Investigator.
Treatment History
1. Prior treatment with azacitidine, decitabine, lenalidomide, or sotatercept.
2. Prior treatment with luspatercept (Cohorts A, B, C, D, E, and F only).
3. Treatment with ESA within 8 weeks prior to C1D1.
4. Prior or concurrent chronic treatment with G-CSF or GM-CSF, for reasons other than for treatment of MDS.
a. Note: Previous treatment with G-CSF or GM-CSF for MDS, which has been discontinued ≥ 8 weeks prior to C1D1 is allowed.
5. Iron chelation therapy if initiated within 8 weeks prior to C1D1. Participants on stable doses of iron chelation therapy for ≥ 8 weeks are allowed.
6. Vitamin B12 and/or folate therapy initiated within 8 weeks prior to C1D1. Participants on stable replacement doses for ≥ 8 weeks and without concurrent vitamin B12 or folate deficiency are allowed.
7. Any need to receive a prohibited medication.
8. Treatment with another investigational drug or device or approved therapy for investigational use within 8 weeks prior to C1D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer.
Laboratory Exclusions (during Pretreatment Period)
1. Peripheral WBC count ≥ 13,000/μL.
2. Platelet count \> 450 × 10\^9/L or \< 25 × 10\^9/L.
3. Transferrin saturation \< 15%.
4. Ferritin \< 50 ng/mL.
5. Folate \< 4.5 nmol/L (\< 2.0 ng/mL).
6. Vitamin B12 \< 148 pmol/L (\< 200 pg/mL).
7. Estimated GFR \< 30 mL/min/1.73 m\^2 as determined by the CKD-EPI equation.
Miscellaneous
1. Pregnant or lactating females.
2. Any other condition not specifically noted above which, in the opinion of the Investigator, would preclude the participant from participating in the study.
3. Participants who are investigational site staff members directly involved in the conduct of the trial and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Sponsor or CRO employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
For Cohort G ONLY:
1. Any luspatercept related AE Grade ≥ 3 that has not resolved to baseline or Grade ≤ 1.
2. No history of allergy/anaphylaxis/hypersensitivity to luspatercept.
3. No prior treatment with imetelstat.
→
Inclusion Criteria:
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local study participant privacy regulations.
2. Male or female ≥ 18 years of age, at the time of signing informed consent.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (if related to anemia).
4. Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception.
5. In the opinion of the Investigator, the participant is able and willing to comply with the requirements of the protocol (e.g., all study procedures, return for follow-up visits).
Part 1 Inclusion Criteria
Participants are eligible to be included in Part 1 of the study only if all the following criteria apply:
1. Diagnosis of MDS according to WHO classification that meets International Prognostic Scoring System-Revised (IPSS-R) classification of very low, low, or intermediate risk disease.
2. Less than (\<)5 percent (%) blasts in bone marrow during the Pretreatment Period.
3. Peripheral blood white blood cell (WBC) count \<13,000/microliter (μL) during the Pretreatment Period.
4. Anemia defined as:
1. In non-transfused participants, having received no RBC transfusions within 8 weeks, Hgb concentration ≤ 10.0 g/dL during the Pretreatment Period. OR
2. In LTB participants, having received 1 to 3 units of RBCs for Hgb ≤ 9.0 g/dL within 8 weeks of the Pretreatment Period. OR
3. In HTB participants, having received ≥ 4 units of RBCs for Hgb ≤ 9.0 g/dL within 8 weeks of the Pretreatment Period.
Part 1 Extension - Abbreviated Inclusion Criteria
Participants from Part 1 are eligible to be included in Part 1 Extension of the study only if all the following criteria apply:
1. Previously completed 4 cycles of elritercept in Part 1 with no dose-limiting toxicities (DLTs).
2. Participant has the potential to benefit from administration of elritercept, in the opinion of the Investigator.
3. \< 5% blasts in bone marrow.
4. Peripheral WBC count \< 13,000/μL during the 28 days prior to cycle 5 day 1 (C5D1).
Part 2 Inclusion Criteria
Participants are eligible to be included in Part 2 of the study only if all the following criteria apply:
1. Cohort A:
* Diagnosis of MDS according to WHO 2016 classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* ring sideroblast (RS)-positive as defined by WHO 2016 criteria.
* Requiring at least 2 units of RBC transfusions in the preceding 8 weeks before cycle 1 day 1 (C1D1).
2. Cohort B:
* Diagnosis of MDS according to WHO 2016 classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Non-RS as defined by WHO 2016 criteria.
* Requiring at least 2 units of RBC transfusions in the 8 weeks before C1D1.
3. Cohort C:
* Diagnosis of MDS according to WHO 2016 classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Has anemia, defined by Hgb ≤ 10 g/dL during the Pretreatment Period, and received no RBC transfusion in the 8 weeks before C1D1.
4. Cohort D:
* Diagnosis of CMML according to WHO 2016 classification.
* Has anemia, defined by Hgb ≤ 10 g/dL during the Pretreatment Period, and received no RBC transfusion in the 8 weeks before C1D1. OR
* Received at least 2 units of RBC transfusions for anemia in the 8 weeks before C1D1.
5. Cohort E:
* Diagnosis of MDS according to WHO 2016 classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Requiring ≥ 2 units of RBC transfusions in the preceding 8 weeks before C1D1.
* Receipt of ≥ 20 units of RBC in transfusion over the participant's lifetime.
* Serum ferritin \> 1000 nanograms per milliliter (ng/mL) on ≥ 2 assessments in the preceding 8 weeks before C1D1.
* Treated with stable dose of iron chelation therapy for ≥ 8 weeks prior to C1D1.
6. Cohort F:
* Diagnosis of MDS according to WHO 2016 classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* Requiring ≥ 2 units of RBC transfusions in the preceding 8 weeks before C1D1.
* Receipt of ≥ 20 units of RBC in transfusion over the participant's lifetime.
* Serum ferritin \> 1000 ng/mL on ≥ 2 assessments in the preceding 8 weeks before C1D1.
* Not treated with iron chelation therapy in the preceding 8 weeks before C1D1 and not eligible to initiate iron chelation therapy in the opinion of the Investigator and in accordance with local treatment guidelines for initiation of iron chelation therapy.
7. Cohort G:
* Diagnosis of MDS according to WHO 2016 classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
* RS-positive as defined by WHO 2016 criteria OR non-RS as defined by WHO 2016 criteria.
* Relapsed, refractory, or intolerant to luspatercept treatment
* Relapsed is defined as documentation of response to luspatercept therapy followed by subsequent development of a need for transfusion(s), whether the transfusion need develops during luspatercept treatment or after luspatercept has been discontinued.
* Refractory is defined as documentation of no response with luspatercept ≥ 1 mg/kg administered for ≥ 12 weeks duration.
* Intolerant is defined as documentation of discontinuation of luspatercept therapy due to intolerance including, discontinuation because of any adverse event (serious or nonserious) at any time after treatment initiation.
* Has anemia, defined as either of the following:
* Has received at least 1 unit of RBC transfusions for anemia in the 8 weeks before C1D1; OR
* Hgb ≤ 10 g/dL, and received no RBC transfusion in the 8 weeks before C1D1
* Erythropoietin (EPO) \< 500 international units per liter (U/L) at Baseline.
* Last dose of luspatercept is ≥ 3 weeks from C1D1.
8. \< 5% blasts in bone marrow assessed by bone marrow aspirate during the Pretreatment Period.
Part 1 Exclusion Criteria
Participants are excluded from Part 1 of the study if any of the following criteria apply.
Medical History
1. Diagnosis of MDS with deletion of chromosome 5q (Del5q).
2. Active infection requiring parenteral antibiotic therapy within 28 days prior to C1D1 or oral antibiotics within 14 days of C1D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
3. Presence of uncontrolled heart disease or New York Heart Association (NYHA) Class III or IV heart failure.
4. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
5. History of stroke, deep venous thrombosis (DVT), or arterial embolism within 6 months prior to C1D1.
6. Major surgery within 28 days prior to C1D1. Participants must be completely recovered from any previous surgery prior to C1D1.
7. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B virus (HBV), or active infectious hepatitis C virus (HCV). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
8. Any malignancy other than MDS that has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy, or surgery, within 1 year prior to C1D1. Diagnosis of secondary MDS (i.e., MDS known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases).
9. History of solid organ or hematological transplantation.
10. Presence of uncontrolled hypertension, defined as systolic blood pressure (BP) ≥ 150 mmHg or diastolic BP ≥ 100 mmHg despite adequate treatment.
11. Body mass index (BMI) ≥ 40 kilograms per meter square (kg/m\^2) during the Pretreatment Period.
12. History of severe allergic or anaphylactic reaction(s) or hypersensitivity to recombinant proteins or excipients in the investigational medicinal product (IMP).
Treatment History
1. Prior treatment with azacitidine, decitabine, lenalidomide, luspatercept, or sotatercept.
2. Treatment with ESA within 56 days prior to C1D1.
3. Prior or concurrent chronic treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF).
4. Iron chelation therapy if initiated within 8 weeks prior to C1D1.
5. Vitamin B12 therapy initiated within 8 weeks prior to C1D1. Participants on stable replacement doses for ≥ 8 weeks and without concurrent vitamin B12 or folate deficiency are allowed.
6. Treatment with another investigational drug or device or approved therapy for investigational use ≤ 28 days prior to C1D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer.
Laboratory Exclusions (during Pretreatment Period)
1. Platelet count \> 450 ✕ 10\^9/L or \< 30 ✕ 10\^9/L.
2. Transferrin saturation \< 15%.
3. Ferritin \< 50 nanograms per milliliter (ng/mL).
4. Folate \< 4.5 nanomoles per liter (nmol/L) (\< 2.0 ng/mL).
5. Vitamin B12 \< 148 picomoles per liter (pmol/L) (\< 200 picograms per milliliter \[pg/mL\]).
6. Estimated glomerular filtration rate (GFR) \< 30 milliliter per minute per 1.73 meter square (mL/min/1.73 m\^2), as determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
7. Positive for HIV.
Miscellaneous
1. Pregnant or lactating females.
2. Any other condition not specifically noted above which, in the opinion of the Investigator, would preclude the participant from participating in the study.
3. Participants who are investigational site staff members directly involved in the conduct of the trial and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Sponsor or contract research organization (CRO) employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
Part 1 Extension - Exclusion Criteria
Participants from Part 1 are excluded from Part 1 Extension of the study if any of the following criteria apply.
Medical History
1. Discontinuation of IMP in Part 1 for any reason.
2. Has not completed a study visit in the past 12 months.
3. Active infection requiring parenteral antibiotic therapy within 28 days prior to C5D1 or oral antibiotics within 14 days of C5D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
4. Presence of uncontrolled heart disease or NYHA Class III or IV heart failure.
5. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
6. History of stroke, DVT, or arterial embolism within 6 months prior to C5D1.
7. Major surgery within 28 days prior to C5D1. Participants must be completely recovered from any previous surgery prior to C5D1.
8. Known positive for HIV, active infectious HBV, or active infectious HCV. Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
9. Any malignancy other than MDS that has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy, or surgery, within 1 year prior to C5D1.
10. History of solid organ or hematological transplantation.
11. Presence of uncontrolled hypertension, defined as systolic BP ≥ 150 mmHg or diastolic BP ≥ 100 mmHg despite adequate treatment.
12. BMI ≥ 40 kg/m\^2 during the 28 days prior to C5D1.
Treatment History
1. Prior treatment with azacitidine, decitabine, lenalidomide, luspatercept, or sotatercept.
2. Treatment with ESA within 56 days prior to C5D1.
3. Prior or concurrent chronic treatment with G-CSF or GM-CSF.
4. Iron chelation therapy if initiated within 8 weeks prior to C5D1.
5. Vitamin B12 with treatment initiated within 8 weeks prior to C5D1. Participants on stable replacement doses for ≥ 8 weeks and without concurrent vitamin B12 or folate deficiency are allowed.
6. Treatment with another investigational drug or device or approved therapy for investigational use ≤ 28 days prior to C5D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C5D1, whichever is longer. Previous treatment with elritercept is acceptable.
Laboratory Exclusions (during Abbreviated Pretreatment Period)
1. Platelet count \> 450 × 10\^9/L or \< 30 × 10\^9/L.
2. Transferrin saturation \< 15%.
3. Ferritin \< 50 ng/mL.
4. Folate \< 4.5 nmol/L (\< 2.0 ng/mL).
5. Vitamin B12 \< 148 pmol/L (\< 200 pg/mL).
6. Estimated GFR \< 30 mL/min/1.73 m\^2, as determined by the CKD-EPI equation.
Miscellaneous
1. Pregnant or lactating females.
2. Any other condition not specifically noted above which, in the opinion of the Investigator, would preclude the participant from participating in the study.
3. Participants who are investigational site staff members directly involved in the conduct of the trial and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Sponsor or CRO employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
Part 2 Exclusion Criteria
Participants are excluded from Part 2 of the study if any of the following criteria apply.
Medical History
1. Diagnosis of MDS with Del5q.
2. Diagnosis of secondary MDS (i.e., MDS known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases).
3. Active infection requiring parenteral antibiotic therapy within 28 days prior to C1D1 or oral antibiotics within 14 days of C1D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
4. Presence of the following cardiac conditions:
1. Presence of uncontrolled heart disease or NYHA Class III or IV heart failure.
2. QTcF (QT interval corrected by Fridericia's formula) \> 500 msec on the screening or C1D1 electrocardiogram (ECG; mean of 3 measurements).
3. Uncontrolled clinically significant arrhythmia (participants with rate-controlled atrial fibrillation are not excluded).
4. Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to C1D1.
5. Presence of uncontrolled hypertension, defined as systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite adequate treatment.
6. History of stroke, DVT, or arterial embolism within 6 months prior to C1D1.
7. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
8. Major surgery within 28 days prior to C1D1. Participants must be completely recovered from any previous surgery prior to C1D1.
9. Any malignancy other than MDS or CMML that has not been in remission and/or has required major surgery or systemic therapy including radiation, chemotherapy, targeted therapy, or hormonal therapy within 1 year prior to C1D1.
10. History of solid organ or hematological transplantation.
11. Diagnosis of hemolytic anemia, active bleeding, hemoglobinopathies, or congenital disorders as a cause of the participant's anemia.
12. NCI-CTCAE Grade ≥ 2 bleeding events within the 3 months prior to C1D1.
13. Receipt of an RBC or platelet transfusion for any reason(s) or combination of reasons other than underlying MDS within the 16 weeks prior to C1D1. If a participant requires a transfusion for an unanticipated reason during the Pretreatment Period, a prolonged screening period may be considered after discussion with the Medical Monitor.
14. Known positive for HIV, active infectious HBV with positive viral load (HBV DNA), or active infectious HCV with positive viral load (HCV RNA). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
15. BMI ≥ 40 kg/m\^2.
16. History of severe allergic or anaphylactic reaction(s) or hypersensitivity to recombinant proteins or excipients in the IMP.
17. Diagnosis of cirrhosis, non-alcoholic steatohepatitis, alcoholic liver disease, hepatitis, or other liver disease (acute or chronic) meeting Child-Pugh C criteria for hepatic impairment. Participants with elevated liver enzymes are allowed if the liver enzyme elevation is suspected to be due to iron-overload or iron chelation, and other hepatic causes have been ruled out, in the opinion of the Investigator.
Treatment History
1. Prior treatment with azacitidine, decitabine, lenalidomide, or sotatercept.
2. Prior treatment with luspatercept (Cohorts A, B, C, D, E, and F only).
3. Treatment with ESA within 8 weeks prior to C1D1.
4. Iron chelation therapy if initiated within 8 weeks prior to C1D1. Participants on stable doses of iron chelation therapy for ≥ 8 weeks are allowed.
5. Vitamin B12 and/or folate therapy initiated within 8 weeks prior to C1D1. Participants on stable replacement doses for ≥ 8 weeks and without concurrent vitamin B12 or folate deficiency are allowed.
6. Any need to receive a prohibited medication.
7. Treatment with another investigational drug or device or approved therapy for investigational use within 8 weeks prior to C1D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer.
Laboratory Exclusions (during Pretreatment Period)
1. Platelet count \> 800 × 10\^9/L or \< 25 × 10\^9/L.
2. Ferritin \< 50 ng/mL.
3. Folate \< 4.5 nmol/L (\< 2.0 ng/mL).
4. Vitamin B12 \< 148 pmol/L (\< 200 pg/mL).
5. Estimated GFR \< 30 mL/min/1.73 m\^2 as determined by the CKD-EPI equation.
Miscellaneous
1. Pregnant or lactating females.
2. Any other condition not specifically noted above which, in the opinion of the Investigator, would preclude the participant from participating in the study.
3. Participants who are investigational site staff members directly involved in the conduct of the trial and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Sponsor or CRO employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
For Cohort G ONLY:
1. Any luspatercept related AE Grade ≥ 3 that has not resolved to baseline or Grade ≤ 1.
2. History of allergy/anaphylaxis/hypersensitivity to luspatercept.
3. Prior treatment with imetelstat.
Inclusion Criteria
1. Male or female participants aged ≥ 18 years or older at time of signing the informed consent form (ICF).
2. Able to understand the purpose and risks of the trial and voluntarily sign an ICF prior to any trial-related procedures being conducted and authorization to use protected health information and personal data in accordance to national and local privacy regulations.
3. Documented diagnosis of myelodysplastic syndrome(s) (MDS) according to WHO 2016 classification that meets International Prognostic Scoring System - Revised (IPSS-R) classification of very low-, low-, or intermediate-risk disease, confirmed by central laboratory independent reviewer prior to randomization. Hemoglobin (Hgb), platelet, and absolute neutrophil count (ANC) values should be collected greater than (\>) 14 days after red blood cell (RBC) transfusion or greater than (\>) 7 days after platelet transfusion, unless otherwise considered to be pretransfusion values.
4. Bone marrow less than (\<) 5% blasts in an evaluable bone marrow collected at screening and confirmed by central pathology independent reviewer.
5. Endogenous serum erythropoietin s (EPO) level of \<500 U/L. Should be results from blood samples collected \>14 days following an RBC transfusion to evaluate for eligibility unless considered pretransfusion values.
6. Participant requires RBC transfusion, as documented by the following criteria. A transfusion requirement of 2 to 6 pRBCs units/8 weeks confirmed for a minimum of 8 weeks immediately preceding randomization.
• Hgb levels at the time of or within 3 days prior to administration of a RBC transfusion must have been less than or equal to (≤) 9.0 grams per deciliter (g/dL) (5.6 millimoles per liter (mmol/L)) with symptoms of anemia (or ≤7 g/dL \[4.3 mmol/L\] in the absence of symptoms) in order for the transfusion to be counted towards meeting eligibility criteria.
• RBC transfusions administered when hemoglobin (Hgb) levels were \>9.0 g/dL (or \>7 g/dL in the absence of symptoms) and/or RBC transfusions administered for elective surgery, infections or bleeding events will not qualify as a required transfusion for the purpose of meeting eligibility criteria or stratification.
7. Hgb \<11.0 g/dL (6.8 mmol/L) after last RBC transfusion preceding randomization. Local laboratory is acceptable to facilitate randomization.
8. Eastern Cooperative Oncology Group score of 0, 1, or 2. Exclusion Criteria
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1. Prior therapy with any of the following:
1. Epoetin alfa
• At the investigator's discretion in consultation with the medical monitor, may be allowed if received no more than 2 doses of only epoetin alfa ≥8 weeks prior to randomization. No other erythropoiesis-stimulating agent (ESA) agent is allowed.
2. Darbepoetin
3. Granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor administered ≤8 weeks (56 days) prior to randomization unless given for treatment of febrile neutropenia.
4. Immunomodulatory drug (IMiDs) including lenalidomide
• At the investigator's discretion in consultation with the medical monitor may be allowed if received ≤1 week of an IMiD ≥8 weeks prior to randomization.
5. Hypomethylating agent
• At the investigator's discretion, in consultation with the medical monitor may be allowed if received no more than 2 doses ≥8 weeks prior to randomization.
6. Luspatercept, sotatercept, imetelstat, or elritercept
7. Immunosuppressive therapy
8. Hematopoeitic cell transplant
9. Iron chelation if administered ≤8 weeks prior to randomization. Participants on stable doses of iron chelation therapy for ≥8 weeks are allowed Vitamin B12 or folate therapy initiated within 4 weeks prior to randomization. Participants on stable replacement doses for ≥4 weeks and without ongoing concurrent vitamin B12 or folate deficiency are allowed.
10. Androgen use within 8 weeks before randomization. Participants on stable androgen dosing for hypogonadism for ≥8 weeks are allowed
11. High-dose corticosteroid use within 4 weeks before randomization. Participants on stable chronic steroid doses of prednisone ≤10 mg/day or corticosteroid equivalent for ≥ 4 weeks are allowed. Other disease modifying treatments for autoimmune diseases may be allowed upon medical monitor review.
12. Investigational agent or any other agent intended for treatment MDS treatment
2. Diagnosed to have MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable according to WHO 2016 classification or secondary MDS.
3. Known history of diagnosis of acute myeloid leukemia (AML).
4. Anemia due to any other known cause including but not limited to thalassemia; hypothyroidism; due to iron, vitamin B12, vitamin B6, zinc, or folate deficiencies; autoimmune or hereditary hemolytic anemia; any type of known clinically significant bleeding or sequestration or drug induced anemia, hemolytic anemia, or bleeding events.
5. Clinically significant cardiovascular disease defined as:
1. New York Heart Association heart disease class III or IV
2. Fridericia corrected QT (QTcF) interval \>500 milliseconds during screening
3. Uncontrolled arrhythmia, myocardial infarction, or unstable angina within 6 months before screening
6. Known ejection fraction \<35%, confirmed by a local echocardiogram performed during screening, or a previously performed echocardiogram if collected within 6 months before screening.
7. Medical history of thromboembolic events within 6 months before screening, including history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (DVT; including proximal and distal), pulmonary or arterial embolism, arterial thrombosis or other venous thrombosis. Participants with prior superficial thrombophlebitis are allowed.
8. Uncontrolled hypertension, defined as repeated elevations of systolic blood pressure of ≥160 millimeters of mercury (mmHg) and/or diastolic blood pressure ≥100 mmHg despite adequate treatment.
9. Prior history of malignancies, other than MDS. Participants who are free of other malignant disease for ≥3 years and have completed treatment, including maintenance are allowed. Participants with a history or concurrent diagnosis of the following conditions are allowed if not requiring systemic therapy:
1. Basal or squamous cell carcinoma of the skin;
2. Carcinoma in situ of the cervix;
3. Carcinoma in situ of the breast;
4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis \[TNM\] clinical staging system).
10. History of solid organ or bone marrow transplantation.
11. Active infection requiring intravenous antibiotics within 28 days or oral antibiotics within 14 days before randomization.
12. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B virus (HBV), or active infectious hepatitis C virus (HCV). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
13. Body mass index ≥ 40 kilograms per square meter (kg/m\^2).
14. Major surgery within 28 days before randomization.
15. New-onset seizures or poorly controlled seizures within 12 weeks prior to randomization are excluded from trial participation.
16. History of allergy/anaphylaxis to investigational product (including epoetin alfa) excipients (refer to the current elritercept investigator's brochure for a list of excipients) or recombination proteins.
17. History of pure red cell aplasia and/or antibody against erythropoietin (EPO).
18. Any of the following laboratory abnormalities:
1. ANC \<500/microliter (μL) (0.5×109/L).
2. Platelet count \<50,000/μL (50×109/L) or ≥450,000/μL (450×109/L).
3. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3× upper limit of the normal (ULN).
4. Total bilirubin ≥2×ULN. Participants with known history of Gilbert syndrome with unconjugated bilirubin \<3×ULN are allowed. Higher levels if attributed to active RBC precursor destruction within the bone marrow (ineffective erythropoiesis) may be allowed upon medical monitor review.
5. Estimated glomerular filtration rate \<30 mL/min/1.73 m\^2 as determined by the Chronic Kidney Disease Epidemiology (CKD-EPI) collaboration equation.
6. Ferritin ≤50 micrograms per liter (μg/L).
7. Folate ≤2.0 nanograms per milliliter (ng/mL).
8. Vitamin B12 ≤200 picograms per milliliter (pg/mL).
19. Ongoing participation in another interventional clinical trial.
20. Participant is unwilling or in the opinion of the investigator the participant is unable to comply with the requirements of the protocol.
21. Is a participant of childbearing potential (POCBP) but does not agree to use at least 1 form of highly effective contraception from the time of signing the ICF until at least 60 days after the last dose of trial intervention.
22. Participants of male birth who are fertile and who have partners of childbearing potential, who do not agree to use acceptable barrier contraception, that is, a male condom during the entire trial intervention period until at least 60 days after the last dose of trial intervention.
23. If applicable, participant with a positive serum pregnancy test during the screening period or known to be pregnant or a lactating participant who does not agree to forego breastfeeding during the entire trial intervention period until at least 60 days after the last dose of trial intervention.
24. For Participants in France: Persons under court protection, persons not affiliated with a social security system, and protected adults.
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Inclusion Criteria
1. Male or female participants aged ≥ 18 years or older at time of signing the informed consent form (ICF).
2. Able to understand the purpose and risks of the trial and voluntarily sign an ICF prior to any trial-related procedures being conducted and authorization to use protected health information and personal data in accordance to national and local privacy regulations.
3. Documented diagnosis of myelodysplastic syndrome(s) (MDS) according to WHO 2016 classification that meets International Prognostic Scoring System - Revised (IPSS-R) classification of very low-, low-, or intermediate-risk disease, confirmed by central laboratory independent reviewer prior to randomization. Hemoglobin (HgB), platelet, and absolute neutrophil count (ANC) values should be collected greater than (\>) 14 days after red blood cell (RBC) transfusion or \> 7 days after platelet transfusion, unless otherwise considered to be pretransfusion values.
4. Bone marrow less than (\<) 5% blasts in an evaluable bone marrow collected at screening and confirmed by central pathology independent reviewer.
5. Endogenous serum erythropoietin (EPO) level of \<500 units per liter (U/L). Should be results from blood samples collected \>14 days following an RBC transfusion to evaluate for eligibility unless considered pretransfusion values.
6. Participant requires RBC transfusion, as documented by the following criteria. A transfusion requirement of 2 to 6 pRBCs units/8 weeks confirmed for a minimum of 8 weeks immediately preceding randomization.
* Hgb levels at the time of or within 3 days prior to administration of a RBC transfusion must have been less than or equal to (≤) 9.0 grams per deciliter (g/dL) (5.6 millimoles per liter (mmol/L)) with symptoms of anemia (or ≤7 g/dL \[4.3 mmol/L\] in the absence of symptoms) in order for the transfusion to be counted towards meeting eligibility criteria.
* RBC transfusions administered when hemoglobin (Hgb) levels were \>9.0 g/dL (or \>7 g/dL in the absence of symptoms) and/or RBC transfusions administered for elective surgery, infections or bleeding events will not qualify as a required transfusion for the purpose of meeting eligibility criteria or stratification.
7. Hgb \<11.0 g/dL (6.8 mmol/L) before randomization. Local laboratory is acceptable to facilitate randomization.
8. Eastern Cooperative Oncology Group score of 0, 1, or 2.
Exclusion Criteria
1. Prior therapy with any of the following:
1. Epoetin alfa
• At the investigator's discretion in consultation with the medical monitor, may be allowed if received no more than 2 doses of only epoetin alfa ≥8 weeks prior to randomization.
2. Darbepoetin
• At the investigator's discretion in consultation with the medical monitor, may be allowed if received no more than 1 dose of only darbepoetin ≥8 weeks prior to randomization.
3. Granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor administered ≤8 weeks (56 days) prior to randomization unless given for treatment of febrile neutropenia.
4. Immunomodulatory drug (IMiDs) including lenalidomide
• At the investigator's discretion in consultation with the medical monitor may be allowed if received ≤1 week of an IMiD ≥8 weeks prior to randomization.
5. Hypomethylating agent
• At the investigator's discretion, in consultation with the medical monitor may be allowed if received no more than 2 doses ≥8 weeks prior to randomization.
6. Luspatercept, sotatercept, imetelstat, or elritercept
7. Immunosuppressive therapy for the disease under study.
8. Hematopoeitic cell transplant
9. Iron chelation if initiated ≤8 weeks prior to randomization. Participants on stable or decreasing doses of iron chelation therapy for ≥8 weeks are allowed.
10. Vitamin B12 or folate therapy initiated within 4 weeks prior to randomization. Participants on stable or decreasing replacement doses for ≥4 weeks and without ongoing concurrent vitamin B12 or folate deficiency are allowed.
11. Androgen use within 8 weeks before randomization. Participants on stable androgen dosing for hypogonadism for ≥8 weeks are allowed
12. High-dose systemic corticosteroid use within 4 weeks before randomization. Participants on stable chronic steroid doses of prednisone ≤10 millligrams per day (mg/day) or corticosteroid equivalent for ≥4 weeks are allowed. Other disease modifying treatments for autoimmune diseases may be allowed upon medical monitor review.
13. Investigational agent or any other agent intended for MDS treatment
2. Diagnosed to have MDS with presence of del(5q) cytogenetic abnormality or MDS unclassifiable according to WHO 2016 classification or secondary MDS.
3. Known history of diagnosis of acute myeloid leukemia (AML).
4. Anemia due to any other known cause including but not limited to thalassemia; hypothyroidism, autoimmune or hereditary hemolytic anemia, any type of known clinically significant bleeding or sequestration or drug induced anemia, hemolytic anemia, bleeding events, or other deficiencies (that is, iron, folate, or vitamin B12).
5. Clinically significant cardiovascular disease defined as:
1. New York Heart Association heart disease class III or IV
2. Fridericia corrected QT (QTcF) interval \>500 milliseconds during screening
3. Uncontrolled arrhythmia, myocardial infarction, or unstable angina within 6 months before screening
6. Known ejection fraction \<35%, confirmed by a local echocardiogram performed during screening, or a previously performed echocardiogram if collected within 6 months before screening.
7. Medical history of thromboembolic events within 6 months before screening, including history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (DVT; including proximal and distal), pulmonary or arterial embolism, arterial thrombosis or other venous thrombosis. Participants with prior superficial thrombophlebitis are allowed.
8. Uncontrolled hypertension, defined as repeated elevations of systolic blood pressure of ≥160 millimeters of mercury (mmHg) and/or diastolic blood pressure ≥100 mmHg despite adequate treatment.
9. Prior history of malignancies, other than MDS. Participants who are free of other malignant disease for ≥3 years and have completed treatment, including maintenance are allowed. Participants with a history or concurrent diagnosis of the following conditions are allowed if not requiring systemic therapy:
1. Basal or squamous cell carcinoma of the skin;
2. Carcinoma in situ of the cervix;
3. Carcinoma in situ of the breast;
4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis \[TNM\] or early papillary thyroid cancer (Stage I \[T1-T2, N0, M0\]) clinical staging system).
10. History of solid organ or bone marrow transplantation.
11. Active infection requiring intravenous antibiotics within 28 days or oral antibiotics within 14 days before randomization.
12. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B virus (HBV), or active infectious hepatitis C virus (HCV). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
13. Body mass index ≥ 40 kilograms per square meter (kg/m\^2).
14. Major surgery within 28 days before randomization.
15. New-onset seizures or poorly controlled seizures within 12 weeks prior to randomization are excluded from trial participation.
16. History of allergy/anaphylaxis to investigational product (including epoetin alfa) excipients (refer to the current elritercept investigator's brochure for a list of excipients) or recombination proteins.
17. History of pure red cell aplasia and/or antibody against erythropoietin (EPO).
18. Any of the following laboratory abnormalities:
1. ANC \<500/microliter (μL) (0.5×10\^9/liter \[L\]).
2. Platelet count \<50,000/μL (50×10\^9/L) or ≥800,000/μL (800×10\^9/L).
3. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3× upper limit of the normal (ULN).
4. Total bilirubin ≥2×ULN. Participants with known history of Gilbert syndrome with unconjugated bilirubin \<3×ULN are allowed. Higher levels if attributed to active RBC precursor destruction within the bone marrow (ineffective erythropoiesis) may be allowed upon medical monitor review.
5. Estimated glomerular filtration rate \<30 milliliters per minute per 1.73 square meters (mL/min/1.73 m\^2) as determined by the Chronic Kidney Disease Epidemiology (CKD-EPI) collaboration equation.
6. Ferritin ≤50 micrograms per liter (μg/L).
7. Folate ≤2.0 nanograms per milliliter (ng/mL).
8. Vitamin B12 ≤200 picograms per milliliter (pg/mL).
19. Ongoing participation in another interventional clinical trial or use of any other investigational medicinal product within 5 times the half-life.
20. Participant is unwilling or in the opinion of the investigator the participant is unable to comply with the requirements of the protocol.
21. Is a participant of childbearing potential (POCBP) but does not agree to use at least 1 form of highly effective contraception from the time of signing the ICF until at least 60 days after the last dose of trial intervention.
22. Participants of male birth who are fertile and who have partners of childbearing potential, who do not agree to use acceptable barrier contraception, that is, a male condom during the entire trial intervention period until at least 60 days after the last dose of trial intervention.
23. If applicable, participant with a positive serum pregnancy test during the screening period or known to be pregnant or a lactating participant who does not agree to forego breastfeeding during the entire trial intervention period until at least 60 days after the last dose of trial intervention.
24. For Participants in France: Persons under court protection, persons not affiliated with a social security system, and protected adults.
Inclusion Criteria:
1. The Japanese participant is a male or female, aged 12 to 17 years at the time of informed consent (patients who turn 18 years during the trial will be allowed to continue in the trial).
2. The participant is capable of communicating with the site personnel.
3. The participant is able to understand the informed assent form or the ICF and parent(s)/legal guardian(s) are able to read and understand the ICF. The participant is able and willing to accept video recording at the assessment by the trial site and evaluation by third party evaluators (Central Evaluating Committee).
4. The participant has provided the written informed assent as much as possible to participation and parent(s)/legal guardian(s) signed the ICF.
5. The participant and parent(s)/legal guardian(s) are willing and able to attend trial appointments within the specified time windows.
6. The participant is an outpatient consulting a clinician.
7. The participant has a primary diagnosis of MDD or persistent depressive disorder and fully meet the criteria for major depressive episodes according to DSM-5-TR without psychotic features although co-morbid anxiety disorders will be permitted. The diagnoses will be confirmed using the MINI-KID.
8. The participant has a CDRS-R total score greater than or equal to 45 at the Screening Visit and at the Baseline A Visit (Week 0).
9. The participant has a CGI-S score greater than or equal to4 at the Screening Visit and at the Baseline A Visit (Week 0).
10. The participant has a PHQ-A score of greater than or equal to10 at the Baseline A Visit (Week 0).
11. The participant, if a female and is capable of producing viable ova, agrees to the following, for the period from the signing of ICF until 30 days after the last dose of trial intervention.
* To use a highly effective or acceptable contraceptive method
* To avoid donating ova
12. The participant, if a female, must have a confirmed negative urine pregnancy test at the Screening Visit
Exclusion Criteria:
1. The participant has previously been entered and moved to Phase A in this trial.
2. The participant has participated in a clinical trial less than 30 days before the Screening Visit.
3. The participant is a member of the trial personnel or of their immediate families or is a subordinate (or immediate family member of a subordinate) to any of the trial personnel.
4. The participant has been previously treated with vortioxetine.
5. The participant has the current or previous major depressive episode which was considered by the investigators to have been resistant to 2 or more adequate antidepressants treatments of at least 6-weeks duration each at sufficient doses.
6. The participant is under forced treatment.
7. The participant has experienced any environmental change (eg, hospitalization, change of residence) considered by the investigator to have the potential impact on the participant's disease situation or plans such environmental changes during the trial.
8. The participant is pregnant or breast-feeding.
9. The participant receives on-going psychotherapy (except for a supportive psychotherapy) that is started less than 3 months before the Baseline A Visit (Week 0) and/or that is planned to be intensified during the trial.
10. The participant has a history of severe drug allergy or hypersensitivity or known hypersensitivity to any of the IMPs or their excipients.
11. The participant has hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltose insufficiency.
12. The participant has any current psychiatric disorder (DSM-5-TR criteria), including posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) established as the primary diagnosis, as assessed using the MINI-KID.
13. The participant has a medical history of substance use disorder (excluding nicotine, and caffeine) or alcohol use disorder (DSM-5-TR criteria) less than 6 months before the Screening Visit.
14. The participant has reported current use of or has tested positive for drugs of abuse (opiates, methadone, cocaine, amphetamines \[including ecstasy\], barbiturates, benzodiazepines, and cannabinoids, etc).
15. The participant suffers from medical, organic or drug cause mental disorders (DSM-5-TR criteria).
16. The participant has a known intellectual disability; or clinical evidence or known social or school history indicative of intellectual disability.
17. The participant has any other disorder for which the treatment takes priority over treatment of MDD or is likely to interfere with trial treatment or impair treatment compliance.
18. The participant has a history of moderate or severe head trauma; or other neurological disorders or systemic medical diseases that are, in the investigator's opinion, likely to affect central nervous system functioning.
19. The participant has a known first degree relative with a history of bipolar disorder.
20. The participant is unable to swallow tablets.
21. The participant has a history of cancer that has not been in remission for more than 5 years before the first dose of trial intervention.
22. The participant has or has had 1 or more of the following conditions that is/are considered clinically relevant in the context of the trial: neurological disorder, other psychiatric disorder, cardiovascular disease, seizure disorder or encephalopathy, congestive heart failure, cardiac hypertrophy, arrhythmia, bradycardia (pulse less than 50 bpm), respiratory disease, hepatic impairment or renal insufficiency, metabolic disorder, endocrinological disorder, gastrointestinal disorder, hematological disorder, infectious disorder, any clinically significant immunological condition, dermatological disorder, venereal disease, congenital or juvenile glaucoma or is at risk of acute narrow-angle glaucoma
23. The participant takes or has taken disallowed recent or concomitant medication, or it is anticipated that the participant will require treatment with at least one of the disallowed concomitant medications/procedures or treatment during the trial.
24. The participant has clinically significant abnormal vital signs at the Screening Visit.
25. The participant has 1 or more clinical laboratory test values outside the reference range, based on the blood and urine samples taken at the Screening Visit, which are of potential risk to the participant's safety; or the participant has, at the Screening Visit:
* a serum creatinine value more than 1.5 times the upper limit of the reference range
* a serum total bilirubin value more than 1.5 times the upper limit of the reference range
* a serum ALT or AST value more than 2 times the upper limit of the reference range
26. The participant has an abnormal TSH level. Participant with thyroid disease may be enrolled in the trial provided they are stable and euthyroid at the discretion of the investigator.
27. The participant has, at the Screening Visit:
* an abnormal ECG that is, in the investigator's opinion, clinically significant
* a QTcF interval more than 450 ms (based on the Fridericia correction where QTcF = QT/RR0.33)
28. The participant has a disease or takes medication that could, in the investigator's opinion, interfere with the assessments of safety, tolerability, or efficacy, or interfere with the conduct or interpretation of the trial.
29. The participant is, in the investigator's opinion, unlikely to comply with the protocol or is unsuitable for any reason.
30. The participant has attempted suicide within the last 12 months or is at significant risk of suicide (either in the opinion of the investigator or defined as a 'yes' to suicidal ideation questions 4 or 5 or answering 'yes' to suicidal behavior questions on the C-SSRS within the last 12 months).
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Inclusion Criteria:
1. The Japanese participant is a male or female, aged 12 to 17 years at the time of informed consent (patients who turn 18 years during the trial will be allowed to continue in the trial).
2. The participant is capable of communicating with the site personnel.
3. The participant is able to understand the informed assent form or the ICF and parent(s)/legal guardian(s) are able to read and understand the ICF. The participant is able and willing to accept video recording at the assessment by the trial site and evaluation by third party evaluators (Central Evaluating Committee).
4. The participant has provided the written informed assent as much as possible to participation and parent(s)/legal guardian(s) signed the ICF.
5. The participant and parent(s)/legal guardian(s) are willing and able to attend trial appointments within the specified time windows.
6. The participant is an outpatient consulting a clinician.
7. The participant has a primary diagnosis of MDD or persistent depressive disorder and fully meet the criteria for major depressive episodes according to DSM-5-TR without psychotic features although co-morbid anxiety disorders will be permitted. The diagnoses will be confirmed using the MINI-KID.
8. The participant has a CDRS-R total score greater than or equal to 45 at the Screening Visit and at the Baseline A Visit (Week 0).
9. The participant has a CGI-S score greater than or equal to4 at the Screening Visit and at the Baseline A Visit (Week 0).
10. The participant has a PHQ-A score of greater than or equal to10 at the Baseline A Visit (Week 0).
11. The participant, if a female and is capable of producing viable ova, agrees to the following, for the period from the signing of ICF until 30 days after the last dose of trial intervention.
* To use a highly effective or acceptable contraceptive method
* To avoid donating ova
12. The participant, if a female, must have a confirmed negative urine pregnancy test at the Screening Visit
Exclusion Criteria:
1. The participant has previously been entered and moved to Phase A in this trial.
2. The participant has participated in a clinical trial less than 30 days before the Screening Visit.
3. The participant is a member of the trial personnel or of their immediate families or is a subordinate (or immediate family member of a subordinate) to any of the trial personnel.
4. The participant has been previously treated with vortioxetine.
5. The participant has the current or previous major depressive episode which was considered by the investigators to have been resistant to 2 or more adequate antidepressants treatments of at least 6-weeks duration each at sufficient doses.
6. The participant is under forced treatment.
7. The participant has experienced any environmental change (eg, hospitalization, change of residence) considered by the investigator to have the potential impact on the participant's disease situation or plans such environmental changes during the trial.
8. The participant is pregnant or breast-feeding.
9. The participant receives on-going psychotherapy (except for a supportive psychotherapy) that is started less than 3 months before the Baseline A Visit (Week 0) and/or that is planned to be intensified during the trial.
10. The participant has a history of severe drug allergy or hypersensitivity or known hypersensitivity to any of the IMPs or their excipients.
11. The participant has hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltose insufficiency.
12. The participant has any current psychiatric disorder, including posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) as assessed using the MINI-KID. If the MINI-KID screening assessment suggests the presence of any current psychiatric disorders other than permitted co-morbid anxiety disorders, the participant may be enrolled only if an additional evaluation confirms that the participant does not meet DSM-5-TR criteria for that disorder at Screening, as determined by the investigator.
13. The participant has a medical history of substance use disorder (excluding nicotine, and caffeine) or alcohol use disorder (DSM-5-TR criteria) less than 6 months before the Screening Visit.
14. The participant has reported current use of or has tested positive for drugs of abuse (opiates, methadone, cocaine, amphetamines \[including ecstasy\], barbiturates, benzodiazepines, and cannabinoids, etc).
15. The participant suffers from medical, organic or drug cause mental disorders (DSM-5-TR criteria).
16. The participant has a known intellectual disability; or clinical evidence or known social or school history indicative of intellectual disability.
17. The participant has any other disorder for which the treatment takes priority over treatment of MDD or is likely to interfere with trial treatment or impair treatment compliance.
18. The participant has a history of moderate or severe head trauma; or other neurological disorders or systemic medical diseases that are, in the investigator's opinion, likely to affect central nervous system functioning.
19. The participant has a known first degree relative with a history of bipolar disorder.
20. The participant is unable to swallow tablets.
21. The participant has a history of cancer that has not been in remission for more than 5 years before the first dose of trial intervention.
22. The participant has or has had 1 or more of the following conditions that is/are considered clinically relevant in the context of the trial: neurological disorder, other psychiatric disorder, cardiovascular disease, seizure disorder or encephalopathy, congestive heart failure, cardiac hypertrophy, arrhythmia, bradycardia (pulse less than 50 bpm), respiratory disease, hepatic impairment or renal insufficiency, metabolic disorder, endocrinological disorder, gastrointestinal disorder, hematological disorder, infectious disorder, any clinically significant immunological condition, dermatological disorder, venereal disease, congenital or juvenile glaucoma or is at risk of acute narrow-angle glaucoma
23. The participant takes or has taken disallowed recent or concomitant medication, or it is anticipated that the participant will require treatment with at least one of the disallowed concomitant medications/procedures or treatment during the trial.
24. The participant has clinically significant abnormal vital signs at the Screening Visit.
25. The participant has 1 or more clinical laboratory test values outside the reference range, based on the blood and urine samples taken at the Screening Visit, which are of potential risk to the participant's safety; or the participant has, at the Screening Visit:
* a serum creatinine value more than 1.5 times the upper limit of the reference range
* a serum total bilirubin value more than 1.5 times the upper limit of the reference range
* a serum ALT or AST value more than 2 times the upper limit of the reference range
26. The participant has an abnormal TSH level. Participant with thyroid disease may be enrolled in the trial provided they are stable and euthyroid at the discretion of the investigator.
27. The participant has, at the Screening Visit:
* an abnormal ECG that is, in the investigator's opinion, clinically significant
* a QTcF interval more than 450 ms (based on the Fridericia correction where QTcF = QT/RR0.33)
28. The participant has a disease or takes medication that could, in the investigator's opinion, interfere with the assessments of safety, tolerability, or efficacy, or interfere with the conduct or interpretation of the trial.
29. The participant is, in the investigator's opinion, unlikely to comply with the protocol or is unsuitable for any reason.
30. The participant has attempted suicide within the last 12 months or is at significant risk of suicide (either in the opinion of the investigator or defined as a 'yes' to suicidal ideation questions 4 or 5 or answering 'yes' to suicidal behavior questions on the C-SSRS within the last 12 months).
Inclusion Criteria:
1. Must be able to understand and willing to sign the written informed consent form (ICF), be able to comply with the visit schedule and related procedures specified in the protocol.
2. Male or female participants must be at least 18 years old or the legal age of majority in their country, whichever is greater. For Japan-specific safety run-in (SRI) part of the trial, participants must be Japanese residing in Japan.
3. Have locally unresectable advanced or metastatic histologically or cytologically confirmed squamous NSCLC. Mixed small cell carcinoma, or other pathological components are excluded.
Note: For Japan-specific SRI only: Participants' histology is not restricted to squamous NSCLC and may include all metastatic or unresectable solid tumor participants.
4. Have had disease progression on or after prior treatment with anti-PD-1/PD-L1 therapy and platinum-based doublet chemotherapy (for example, carboplatin and paclitaxel), given either concurrently or sequentially. Eligible participants include those that have:
\- Received platinum-based chemotherapy in combination with anti-PD-1/PD-L1 therapy as the only prior line of therapy.
OR
\- Received platinum-based chemotherapy and anti-PD-1/PD-L1 therapy sequentially (in either order) as the only 2 prior lines of therapy.
Note: For Japan-specific SRI only: Participants must be refractory OR intolerant to standard of care (SOC) treatment.
5. Participants that have received prior anti-PD-1/PD-L1 therapy with curative intent for locally advanced disease are eligible if they meet either of the following criteria:
\- Received prior platinum-based chemotherapy with or without radiotherapy with maintenance anti-PD-1/PD-L1 therapy for Stage III disease and relapsed/progressed within 6 months from the last dose of platinum-based chemotherapy.
OR
\- Received prior peri-operative platinum-based chemotherapy with maintenance anti-PD-1/PD-L1 therapy for resectable Stage II/III and have relapsed within 6 months from the last dose of platinum-based chemotherapy.
Note: For Japan-specific SRI only: This criterion is not applicable for Japanese participants enrolled in the SRI part of the trial.
6. Provide formalin-fixed tumor tissue specimen. Fresh biopsies are preferred but archival specimens collected within 2 years before signing the informed consent form are acceptable (blocks or 10-15 unstained slides sectioned 4-5 microns in thickness, if tissue slides, they must be sectioned from blocks less than or equal to (\<=) 2 months from date of consent). Formalin-fixed paraffin-embedded (FFPE) blocks are preferred for submission; slides should be sent only if there is a local regulation preventing submission of the FFPE block. Ideally, the archival specimen should be collected subsequent to the most recent systemic therapy.
Note: For Japan-specific SRI only: Collection of tumor tissue specimen is not required for Japanese participants enrolled in the SRI part of the trial.
7. Have at least 1 measurable lesion (target lesion) by computed tomography (CT) or magnetic resonance imaging (MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST) V1.1. Lesions that have previously received radiotherapy or intratumoral injection can only be used as measurable lesions if they show progression after treatment (either pathologically confirmed or with observation of radiographic progression more than 3 months after treatment) as per RECIST V1.1.
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.
9. Expected survival time greater than or equal to (\>=) 3 months.
10. Women of childbearing potential (WOCBP) must take a urine or serum pregnancy test, highly sensitive tests are required where available based on region, and must test negative for trial inclusion. WOCBP must agree to use at least 1 form of highly effective contraception and 1 barrier method of contraception during the entire course of treatment and for 6 months after the last dose of trial treatment. Fertile men must agree to use a condom, preferably combined with at least 1 form of acceptable contraception for any WOCBP partner(s) during the entire course of treatment and for 6 months after the last dose of trial intervention.
11. Lactating women must agree to strictly abstain from breastfeeding during the entire Treatment Period and for 6 months after the treatment.
Exclusion Criteria:
1. Women who are pregnant or breastfeeding, or intending to become pregnant before, during, or within 6 months after the last dose of any trial intervention. WOCBP not using and/or not willing to use at least 1 form of highly effective method of contraception and 1 barrier method of contraception or fertile men with WOCBP partner(s) not using and/or not willing to use at least 1 form of acceptable contraception. Note: If in the investigator's judgment, the participant may be pregnant based on the physician's medical interview or other information, the participant will be excluded from the trial irrespective of a negative pregnancy test.
2. Known actionable genomic alteration, including any of the following driver gene mutations:
* Epidermal growth factor receptor (EGFR): including exon 19 deletion, exon 21 L858R, exon 20 T790M, exon 20 S768I, exon 21 L861Q, exon 18 G719X, and exon 20 insertion mutations.
* Kirsten rat sarcoma virus (KRAS) G12C mutation.
* Anaplastic lymphoma kinase (ALK) rearrangement.
* ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) rearrangement.
* B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation.
* Neurotrophic tyrosine receptor kinase (NTRK) 1/2/3 fusion.
* MET proto-oncogene, receptor tyrosine kinase (MET) exon 14 skipping mutation.
* RET proto-oncogene (RET) rearrangement.
* V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2, also known as HER2) mutation.
Note: (a) It is not mandatory to have undergone driver gene testing. (b) For Japan-specific SRI only: This criterion is not applicable for Japanese participants enrolled in the SRI part of the trial.
3. Participants with enlarging or symptomatic brain metastases are excluded from the trial. Participants who are neurologically, clinically and radiologically stable \>=4 weeks after definitive treatment for brain metastases and participants with small, asymptomatic, incidental, untreated brain metastases that remain radiographically stable \>=4 weeks after initial identification may participate in this trial as long as they meet all of the following criteria:
* No metastases to meninges, midbrain, pons, medulla oblongata (leptomeningeal metastases), or cerebellar metastases.
* No compression of the aqueduct of Sylvius, no compression of the third or fourth ventricle.
* No participant with epidural spinal cord compression or spinal cord metastases.
* Participants must be off steroids for at least 7 days for CNS disease. Systemic steroids of \<=10 milligrams per day (mg/day) of prednisone or equivalent are acceptable if needed for other indications.
* CNS-related symptoms must be stable \>=14 days prior to randomization
* Brain metastases should not be included as RECIST V1.1 target lesions
4. Presence of any of the following hematologic abnormalities at baseline\*:
* Hemoglobin \<9 grams per deciliter (g/dL).
* Absolute neutrophil count (ANC) \<1,500 per cubic millimeters (mm\^3).
* Platelet (PLT) count \<100 x 10\^3/mm\^3. \*"Baseline" is defined as the last available observation prior to the first dose of investigational product. Note: Participants must not receive supportive treatments such as blood products (including RBC suspension, apheresis platelets, cryoprecipitation, and so on.) within 7 days of confirming eligibility. Erythropoietin or colony-stimulating factors must not be administered within 28 days of confirming eligibility.
5. Presence of any of the following serum chemistry abnormalities at baseline:
* Total bilirubin greater than (\>) 1.5×upper limit of normal (ULN) except for participants with Gilbert's syndrome with serum bilirubin \<=3×ULN or if concurrent conjugated bilirubin \<=ULN.
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>3×ULN; for liver metastasis, AST or ALT \>5×ULN.
* Creatinine clearance (CrCl) \<30 milliters per minute (mL/min); the Cockcroft-Gault formula is used to calculate CrCl (using ideal body weight for obese participants and actual body weight for non-obese participants).
* Albumin \<30 grams per liter (g/L).
6. Presence of any of the following coagulation parameter abnormalities at baseline:
* International normalized ratio (INR) \>1.5×ULN (\>3×ULN if on stable dose anticoagulation).
* Partial thromboplastin time (PTT; or activated partial thromboplastin time \[aPTT\]) \>1.5×ULN (\>3×ULN if on stable-dose anticoagulation).
7. History of deep venous thrombosis, pulmonary embolism, or any other serious thromboembolic events within 30 days prior to enrollment (implantable port or catheter-related thrombosis, or superficial venous thrombosis are not considered "serious" thromboembolisms). Participants with a history of serious thromboembolic event must be asymptomatic and on stable anticoagulation therapy (if such therapy is deemed necessary by the treating physician).
8. Active uncontrolled bleeding, known bleeding diathesis, or significant concern for risk of acute life-threatening bleeding (for example, radiographic evidence that tumor invades large blood vessels or has unclear boundaries with a major vessel \[including aorta, left pulmonary artery, right pulmonary artery, pulmonary vein, superior vena cava, inferior vena cava, and so on\], or the investigator judges that the tumor is very likely to invade major vessels with the potential to cause fatal bleeding during the duration of the trial).
9. Presence of clinically significant cardiovascular or cerebrovascular diseases, including:
* Symptomatic, clinically unstable arrhythmia or arrhythmia requiring clinical intervention.
* Severe conduction disorders (such as third-degree atrioventricular block and bundle branch block).
* QT interval corrected for heart rate (QTc interval, calculated using Fridericia's formula) \>=480 milliseconds (msec).
* Uncontrolled hypertension (systolic blood pressure \>=160 millimeters of mercury (mmHg) or diastolic blood pressure \>=100 mmHg) despite standard treatment.
* History of myocarditis.
* Left ventricular ejection fraction \<50 percent (%).
* Congestive heart failure requiring treatment.
* Class II to IV cardiac insufficiency according to the New York Heart Association functional classification.
* History of acute coronary syndrome (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to the first dose of investigational product.
* Cerebrovascular accident or transient ischemic attack within 6 months before the first dose of the investigational product.
* History of seizures unless controlled on stable dose of antiseizure medications.
10. Cardiac enzymes \>=levels consistent with acute myocardial infarction as defined by laboratory-specific criteria. Participants with isolated Grade 1 elevated cardiac enzymes require cardiology clearance and consultation with the sponsor's medical monitor to confirm absence of ongoing myocardial/ischemic disease.
11. History of or current interstitial lung disease (ILD), pulmonary fibrosis, and drug-related, immune-related and radiation pneumonitis; current active pulmonary infection requiring anti-infective therapy; active pulmonary tuberculosis (TB) within 1 year prior to enrollment; severely impaired pulmonary function, including but not limited to the following: pulmonary embolism, severe asthma or chronic obstructive pulmonary disease within 3 months prior to randomization; autoimmune, connective tissue, or inflammatory diseases involving the lungs (such as rheumatoid arthritis, Sjögren's disease, and sarcoidosis); previous unilateral pneumonectomy.
Note: Participants with a positive interferon-gamma release assay (IGRA) and negative chest imaging for active pulmonary TB (that is, participants with a history of latent TB) may enroll if they have completed appropriate definitive treatment for latent TB prior to enrollment in the trial (C1D1). Participants with a history of active TB may enroll if they have completed appropriate definitive treatment for active TB more than 1 year before enrollment in the trial (C1D1) and chest imaging at the time of screening is negative for active disease.
12. History of severe, poorly controlled allergies, asthma or atopic dermatitis (except for atopic dermatitis caused by immunotherapy).
Note: remote history of childhood asthma is not exclusionary.
13. Uncontrolled third space effusion requiring repeated drainage, such as pleural effusion, abdominal effusion, pericardial effusion, so on.
Note: Participants with the following conditions may be enrolled:
* Not requiring active drainage.
* No significant increase in effusion after stopping drainage determined using at least 2 ultrasound examinations at least 7 days apart.
14. Current or recent significant gastrointestinal disease or condition, including:
* Flare of inflammatory bowel disease (within 6 months prior to the first dose of the investigational product).
* Grade \>=2 diarrhea Common Terminology Criteria for Adverse Events (CTCAE V5.0) within 2 weeks prior to the first dose of the investigational product.
15. Active autoimmune disease requiring systemic treatment (for example, use of disease-modifying drugs, corticosteroids, biologics or immunosuppressants) within 2 years before the first dose.
Note: Replacement therapies (for example, thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) are not considered systemic treatments and exclusionary.
16. Known history of allogeneic organ transplantation and/or allogeneic hematopoietic stem cell transplantation.
17. Known or suspected allergy to the investigational product and any excipients. Known or suspected severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80.
18. Prior history of significant toxicity related to immune checkpoint inhibitor (ICI) administration that required permanent discontinuation of this therapy.
19. Unresolved Grade \>1 toxicity related to any previous antitumor therapy (excluding alopecia, asthenia, hypothyroidism requiring only thyroid hormone replacement therapy (HRT), hyperglycemia requiring only insulin replacement therapy, adrenal insufficiency requiring physiological steroid replacement, electrolyte abnormalities requiring only symptomatic treatment, and other conditions not affecting the investigational product treatment as assessed by the investigator).
20. Have not adequately recovered from previous surgery or have undergone any major surgery, within 4 weeks before the first dose of investigational product.
21. Uncontrolled tumor-related pain or symptomatic hypercalcemia.
22. Uncontrolled human immunodeficiency virus (HIV), active syphilis, active hepatitis B virus (HBV), or hepatitis C virus (HCV).
* Participants who are HIV-positive must have CD4 \>=350 cells per microliter (cells/µL) and must be on established highly active antiretroviral therapy (ensure no expected drug-drug interactions) for at least 4 weeks with an HIV viral load \<400 copies per milliliter (copies/mL).
* Participants with positive results consistent with an untreated syphilis infection cannot enroll.
Note: Testing with either a treponemal \[for example, Treponema Pallidum hemagglutination TPHA or Treponema Pallidum particle agglutination TPPA test\] or nontreponemal \[for example, rapid plasma reagin (RPR) or Venereal Disease Research Laboratory test\] assay is acceptable. An initial positive test should be confirmed with an assay using the alternate testing approach (for example, treponemal followed by nontreponemal or vice versa). If the second test is negative, the participant may enroll in the trial.
* Participants with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) should undergo HBV DNA testing. If the HBV DNA copy number is \<=2.5×10\^3 copies/mL or \<=500 international units per milliliter (IU/mL) or below the lower limit of detection, the participant can be enrolled. Participants who are HBsAg (+) should receive anti-HBV treatment throughout the treatment period to avoid viral activation. For participants with anti-hepatitis B core antibody (anti-HBcAb) (+), HBsAg (-), anti-HBs (-), and HBV viral load (-), prophylactic anti-HBV treatment can be considered but is not required; however, close monitoring for viral reactivation is required.
* Participants with positive HCV serology results must have an HCV RNA viral load that is negative or below the lower limit of detection.
* Participants who have received definitive HCV treatment and have undetectable viral load results are allowed.
23. Serious/active/uncontrolled infection, infection requiring systemic intravenous antibiotics, or fever of unknown origin (\>=38 degree celsius \[°C\]) within 2 weeks before the first dose of investigational product.
24. History or current evidence of any disease, treatment, or laboratory abnormality that, in the judgment of the investigator, could compromise the safety of the participant, interfere with obtaining informed consent, affect participant compliance, or affect safety evaluations of the investigational product.
25. Psychiatric illness, altered mental status, or drug abuse that prevents understanding of the informed consent process and/or completion of required trial-related evaluations.
26. Unable to meet protocol requirements for known or foreseeable reasons per investigator judgement.
27. Diagnosed with other pathologically confirmed malignancies within 5 years prior to informed consent, with the exception of radically treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ, localized prostate cancer, papillary thyroid cancer, and other radically treated malignancies with no known active disease for at least 2 years prior to enrollment and with a very low risk of recurrence.
28. Received any of the following excluded medications or treatments:
* Docetaxel.
* Received more than 1 anti-PD-1/PD-L1 therapy in the metastatic or recurrent unresectable locally advanced setting. Prior anti-PD-1/PD-L1 therapy in the curative locally advanced setting followed by anti-PD-1/PD-L1 therapy in the metastatic or recurrent unresectable locally advanced setting is allowed, not to exceed 2 prior lines of anti-PD-1/PD-L1 therapy in total.
* Systemic antitumor therapy except anti-PD-1/PD-L1 therapy and platinum-based doublet chemotherapy including but not limited to bispecific antibodies, targeted therapy, antibody drug conjugate, cell therapies, and other ICIs.
Note: For Japan-specific SRI only: The above listed 3 limitations regarding prior systemic antitumor therapy do not apply to participants enrolled in the Japan-specific SRI cohorts.
* Interleukin (IL)-2 or IL-15 cytokines or related therapies.
* Chemotherapy within 2 weeks or 5 half-lives (whichever is longer) before the first dose of investigational product without delayed toxicity.
* Antitumor antibody therapy (excluding antibody drugs such as denosumab for the treatment of bone metastases) within 4 weeks before the first dose of the investigational product.
* Palliative radiotherapy within 2 weeks prior to the first dose of investigational product.
* Live vaccine within 28 days prior to the first dose of investigational product.
* Immunosuppressive or systemic steroid therapy (\>10 mg/day of prednisone or equivalent) within 2 weeks prior to the first dose of investigational product.
* Received traditional Chinese medicine with potential antitumor activity or known antitumor indications within 1 week before the first dose of the investigational product.
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Inclusion Criteria:
1. Must be able to understand and willing to sign the written ICF and be able to comply with the visit schedule and related procedures specified in the protocol.
2. Male or female participants must be at least 18 years old or the legal age of majority in their country, whichever is greater. Note: For the Japan-specific SRI part, participants must be Japanese residing in Japan.
3. (a) Squamous NSCLC: Have locally unresectable advanced or metastatic histologically or cytologically confirmed squamous NSCLC. Mixed small cell carcinoma, or other pathological components are excluded.
(b) Nonsquamous NLSCLC: Have locally unresectable advanced or metastatic histologically or cytologically confirmed nonsquamous NSCLC. Mixed small cell carcinoma, or other pathological components are excluded.
(c) For Japan-specific SRI part: Have metastatic or unresectable solid tumors.
4. Have had radiographic disease progression on or after prior treatment with anti-PD-1/PD-L1 therapy and platinum-based doublet chemotherapy (for example, carboplatin and paclitaxel), given either concurrently or sequentially. A total exposure of \>=6 weeks of prior anti-PD-1/PD-L1 therapy is required. Eligible participants include those that have:
* Received platinum-based chemotherapy in combination with anti-PD-1/PD-L1 therapy as only prior line of therapy. OR
* Received platinum-based chemotherapy and anti-PD-1/PD-L1 therapy sequentially (in either order) as the only 2 prior lines of therapy.
Note: (1) Participants that are ineligible to receive platinum-based doublet chemotherapy may still be eligible for trial enrollment, assuming all other criteria are met. (2) For the Japan-specific SRI part only: participants' disease must be refractory OR participants must be intolerant to indication-specific SOC treatment.
5. Participants who have received prior anti-PD-1/PD-L1 therapy with curative intent for locally advanced disease are eligible if they meet either of the following criteria:
* Received prior platinum-based chemotherapy with or without radiotherapy with maintenance anti-PD-1/PD-L1 therapy for Stage III disease and radiographic recurrence/progression within 6 months from the last dose of platinum-based chemotherapy. OR
* Received prior peri-operative platinum-based chemotherapy with maintenance anti-PD-1/PD-L1 therapy for resectable Stage II/III and have radiographic recurrence within 6 months from the last dose of platinum-based chemotherapy.
Note: 1) Participants that are ineligible to receive platinum-based doublet chemotherapy may still be eligible for trial enrollment, assuming all other criteria are met.
(2) For the Japan-specific SRI part only: This criterion is not applicable for Japanese participants enrolled in the SRI part of the trial.
6\. Provide formalin-fixed tumor tissue specimen. Fresh biopsies are preferred but archival specimens collected within 2 years before signing the informed consent form are acceptable (blocks or 10-15 unstained slides sectioned 4-5 microns in thickness, if tissue slides, they must be sectioned from blocks \<= 2 months from date of consent). FFPE blocks are preferred for submission; slides should be sent only if there is a local regulation preventing submission of the FFPE block. Ideally, the archival specimen should be collected subsequent to the most recent systemic therapy.
Note: For the Japan-specific SRI part only: Collection of tumor tissue specimen is not required for Japanese participants enrolled in the SRI part of the trial.
7\. Have at least 1 measurable lesion (target lesion) by CT or MRI according to RECIST V1.1. Lesions that have previously received radiotherapy or intratumoral injection can only be used as measurable lesions if they show progression after treatment (either pathologically confirmed or with observation of radiographic progression more than 3 months after treatment) as per RECIST V1.1. Lesions chosen for a screening biopsy should not be designated as target lesions, unless pretreatment baseline imaging is performed at least 2 weeks after the biopsy to allow for adequate healing.
8\. ECOG performance status (PS) score of 0 or 1. 9. Expected survival time \>=3 months. 10. WOCBP must take a urine or serum pregnancy test, highly sensitive tests are required where available based on region and must test negative for trial inclusion. WOCBP must agree to use at least 1 form of highly effective contraception and 1 barrier method of contraception during the entire course of treatment and for 6 months after the last dose of trial treatment. Fertile men must agree to use a condom, preferably combined with at least 1 form of acceptable contraception for any WOCBP partner(s) during the entire course of treatment and for 6 months after the last dose of trial intervention.
11\. Lactating women must agree to strictly abstain from breastfeeding during the entire Treatment Period and for 6 months after the treatment.
Exclusion Criteria:
1. Women who are pregnant or breastfeeding, or intending to become pregnant before, during, or within 6 months after the last dose of any trial intervention. WOCBP not using and/or not willing to use at least 1 form of highly effective method of contraception and 1 barrier method of contraception or fertile men with WOCBP partner(s) not using and/or not willing to use at least 1 form of acceptable contraception.
2. (a) Squamous NSCLC: Known actionable genomic alteration, including any of the following driver gene mutations:
* EGFR: including exon 19 deletion, exon 21 L858R, exon 20 T790M, exon 20 S768I, exon 21 L861Q, exon 18 G719X, and exon 20 insertion mutations.
* ALK rearrangement.
* ROS proto-oncogene 1, ROS1 rearrangement.
* B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation.
* NTRK 1/2/3 fusion.
* MET proto-oncogene, MET exon 14 skipping mutation.
* RET proto-oncogene (RET) rearrangement.
* V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2, also known as HER2) mutation.
Note: (1) It is not mandatory to have undergone driver gene testing for participants with squamous NSCLC. (2) KRAS mutations are not exclusionary.
(b) Nonsquamous NSCLC: Must have documentation of prior testing demonstrating negative AGA status for any of the following driver gene mutations:
* EGFR: including exon 19 deletion, exon 21 L858R, exon 20 T790M, exon 20 S768I, exon 21 L861Q, exon 18 G719X, and exon 20 insertion mutations.
* ALK rearrangement.
* ROS1 rearrangement.
* Any other driver gene mutations listed here are excluded if known to be present, but routine testing for these or other known actionable genomic alterations is not required: BRAF V600E mutation; NTRK 1/2/3 fusion; MET exon 14 skipping mutation; RET rearrangement; and ERBB2, also known as HER2 mutation.
Note: KRAS mutations are not exclusionary.
(c) For Japan-specific SRI part: This criterion is not applicable for Japanese participants enrolled in the SRI part.
3. Participants with enlarging or symptomatic brain metastases are excluded from the trial. Participants who are neurologically, clinically and radiologically stable \>=2 weeks after definitive treatment for brain metastases and/or participants with small (sum of all brain lesions: ≤3 cm), asymptomatic, incidental, untreated brain metastases may participate in this trial as long as they meet certain criteria as defined in the protocol.
4. Presence of any of the following hematologic abnormalities at baseline\*:
* Hemoglobin \<9 g/dL.
* Absolute neutrophil count (ANC) \<1,500 mm\^3.
* PLT count \<100 x 10\^3/mm\^3. \*"Baseline" is defined as the last available observation prior to the first dose of investigational product.
5. Presence of any of the following serum chemistry abnormalities at baseline:
* Total bilirubin greater than (\>) 1.0×ULN except for participants with Gilbert's syndrome with serum bilirubin \<=3×ULN or if concurrent conjugated bilirubin \<=ULN.
* AST or ALT \>2.5×ULN without concomitant alkaline phosphatase \>2.5×ULN or AST or ALT \>1.5×ULN with concomitant alkaline phosphatase \>2.5×ULN. For participants with liver metastases, AST or ALT \>5×ULN (alkaline phosphatase must be \<=2.5×ULN).
* Creatinine clearance (CrCl) \<30 milliliters per minute (mL/min); the Cockcroft-Gault formula is used to calculate CrCl (using ideal body weight for obese participants and actual body weight for non-obese participants).
* Albumin \<30 grams per liter (g/L).
6. Presence of any of the following coagulation parameter abnormalities at baseline:
* International normalized ratio (INR) \>1.5×ULN (\>3×ULN if on stable dose anticoagulation).
* Partial thromboplastin time (PTT; or activated partial thromboplastin time \[aPTT\]) \>1.5×ULN (\>3×ULN if on stable-dose anticoagulation).
7. History of deep venous thrombosis, pulmonary embolism, or any other serious thromboembolic events within 30 days prior to enrollment (implantable port or catheter-related thrombosis, or superficial venous thrombosis are not considered "serious" thromboembolisms). Participants with a history of a serious thromboembolic event must be asymptomatic and on stable anticoagulation therapy (if such therapy is deemed necessary by the treating physician).
8. Active uncontrolled bleeding, known bleeding diathesis, or significant concern for risk of acute life-threatening bleeding (for example, radiographic evidence that tumor invades large blood vessels or the investigator judges that the tumor is very likely to invade major vessels with the potential to cause fatal bleeding during the duration of the trial).
9. Presence of clinically significant cardiovascular or cerebrovascular diseases, including:
* Symptomatic, clinically unstable arrhythmia or arrhythmia requiring clinical intervention.
* Severe conduction disorders (such as third-degree atrioventricular block and bundle branch block).
* QT interval corrected for heart rate (QTc interval, calculated using Fridericia's formula) \>=480 msec.
* Uncontrolled hypertension despite standard treatment.
* History of myocarditis.
* Left ventricular ejection fraction \<50%.
* Congestive heart failure requiring treatment.
* Class II to IV cardiac insufficiency according to the New York Heart Association functional classification.
* History of acute coronary syndrome (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to the first dose of investigational product.
* Cerebrovascular accident or transient ischemic attack within 6 months before the first dose of the investigational product.
* History of seizures unless controlled on stable dose of antiseizure medications.
10. Cardiac enzymes \>=levels consistent with acute myocardial infarction as defined by laboratory-specific criteria. Participants with isolated Grade 1 elevated cardiac enzymes require cardiology clearance and consultation with the sponsor's medical monitor to confirm absence of ongoing myocardial/ischemic disease.
11. History of or current ILD; history or current presence of the following lung diseases requiring corticosteroid therapy: pulmonary fibrosis, and drug-related, immune-related or radiation pneumonitis; current active pulmonary infection requiring anti-infective therapy; active pulmonary TB within 1 year prior to enrollment; severely impaired pulmonary function, including but not limited to the following:, severe asthma or severe chronic obstructive pulmonary disease within 3 months prior to randomization; autoimmune, connective tissue, or inflammatory diseases involving the lungs (such as rheumatoid arthritis, Sjögren's disease, and sarcoidosis); previous unilateral pneumonectomy.
Note: Participants with a positive IGRA and negative chest imaging for active pulmonary TB (that is, participants with a history of latent TB) may enroll if they have completed appropriate definitive treatment for latent TB prior to enrollment in the trial (C1D1). Participants with a history of active TB may enroll if they have completed appropriate definitive treatment for active TB more than 1 year before enrollment in the trial (C1D1) and chest imaging at the time of screening is negative for active disease.
12. History of severe, poorly controlled allergies, asthma or atopic dermatitis (except for atopic dermatitis caused by immunotherapy).
Note: remote history of childhood asthma is not exclusionary.
13. Uncontrolled third space effusion requiring repeated drainage, such as pleural effusion, abdominal effusion, or pericardial effusion.
14. Current or recent significant gastrointestinal disease or condition, including:
* Flare of inflammatory bowel disease (within 6 months prior to the first dose of the investigational product).
* Grade \>=2 diarrhea CTCAE V5.0 within 2 weeks prior to the first dose of the investigational product.
15. Active autoimmune disease requiring systemic treatment (for example, use of disease modifying drugs, corticosteroids \>10 milligrams (mg) daily equivalent of prednisone, biologics or immunosuppressants) within 2 years before the first dose.
Note: Replacement therapies (for example, thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) are not considered systemic treatments and are not exclusionary.
16. Known history of allogeneic organ transplantation and/or allogeneic hematopoietic stem cell transplantation.
17. Known or suspected allergy to the investigational product and any excipients. Known or suspected severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80.
18. Prior history of significant toxicity related to ICI administration that required permanent discontinuation of this therapy.
19. Unresolved Grade \>1 toxicity related to any previous antitumor therapy (excluding alopecia, asthenia, hypothyroidism requiring only thyroid hormone replacement therapy (HRT), hyperglycemia requiring only insulin replacement therapy, adrenal insufficiency requiring physiological corticosteroid replacement, electrolyte abnormalities requiring only symptomatic treatment, and other conditions not affecting the investigational product treatment as assessed by the investigator).
20. Have not adequately recovered from previous surgery or have undergone any major surgery, within 4 weeks before the first dose of investigational product.
21. Uncontrolled tumor-related pain or symptomatic hypercalcemia.
22. Uncontrolled human immunodeficiency virus (HIV), active syphilis, active hepatitis B virus (HBV), or hepatitis C virus (HCV).
* Participants who are HIV-positive must have CD4 \>=350 cells per microliter (cells/µL) and must be on established highly active antiretroviral therapy (ensure no expected drug-drug interactions) for at least 4 weeks with an HIV viral load \<400 copies/mL).
* Participants with positive results consistent with an untreated syphilis infection cannot enroll.
Note: Testing with either a treponemal (for example, Treponema Pallidum hemagglutination \[TPHA\] or Treponema Pallidum particle agglutination \[TPPA\] test) or nontreponemal (for example, rapid plasma reagin \[RPR\] or Venereal Disease Research Laboratory test) assay is acceptable. An initial positive test should be confirmed with an assay using the alternate testing approach (for example, treponemal followed by nontreponemal or vice versa). If the second test is negative, the participant may enroll in the trial.
* Participants with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) should undergo HBV DNA testing. If the HBV DNA copy number is \<=2.5×10\^3 copies/mL or \<=500 IU/mL) or below the lower limit of detection, the participant can be enrolled.
* Participants with positive HCV serology results must have an HCV RNA viral load that is negative or below the lower limit of detection.
* Participants who have received definitive HCV treatment and have undetectable viral load results are allowed.
23. Serious/active/uncontrolled infection, infection requiring systemic intravenous antibiotics, or fever of unknown origin (\>=38°C) within 2 weeks before the first dose of investigational product.
24. History or current evidence of any disease, treatment, or laboratory abnormality that, in the judgment of the investigator, could compromise the safety of the participant, interfere with obtaining informed consent, affect participant compliance, or affect safety evaluations of the investigational product.
25. Psychiatric illness altered mental status, or drug abuse that prevents understanding of the informed consent process and/or completion of required trial-related evaluations.
26. Unable to meet protocol requirements for known or foreseeable reasons per investigator judgement.
27. Diagnosed with other pathologically confirmed malignancies within 5 years prior to informed consent, with exception of radically treated basal cell carcinoma of skin, squamous cell carcinoma of skin, carcinoma in situ, localized prostate cancer, papillary thyroid cancer, and other radically treated malignancies with no known active disease for at least 2 years prior to enrollment and with very low risk of recurrence.
28. Received any of following excluded medications or treatments:
* Docetaxel.
* Received more than 1 anti-PD-1/PD-L1 therapy in metastatic or recurrent unresectable locally advanced setting. Prior anti-PD-1/PD-L1 therapy in the curative locally advanced setting followed by anti-PD-1/PD-L1 therapy in the metastatic or recurrent unresectable locally advanced setting is allowed, not to exceed 2 prior lines of anti-PD-1/PD-L1 therapy in total.
* Systemic antitumor therapy except anti-PD-1/PD-L1 therapy and platinum-based doublet chemotherapy including but not limited to targeted therapy, antibody drug conjugates, cell therapies, and other ICIs.
* One prior line of anti-VEGF antibody administered in combination with 1L ICI and chemotherapy is allowed.
* For participants with KRAS mutations, 1 prior line of RAS-targeted therapy is allowed.
Note: For Japan-specific SRI part only: The above listed 3 limitations regarding prior systemic antitumor therapy do not apply to participants enrolled in the Japan-specific SRI part.
* Interleukin (IL)-2 or IL-15 cytokines or related therapies.
* Chemotherapy within 2 weeks or 5 half-lives (whichever is longer) before the first dose of investigational product without delayed toxicity.
* Antitumor antibody therapy (excluding antibody drugs such as denosumab for the treatment of bone metastases) within 4 weeks before first dose of the investigational product.
* Palliative radiotherapy within 2 weeks prior to the first dose of investigational product.
* Live vaccine within 28 days prior to first dose of investigational product.
* Immunosuppressive or systemic corticosteroid therapy (\>10 mg/day of prednisone or equivalent) within 2 weeks prior to the first dose of investigational product.
* Received traditional Chinese medicine with potential antitumor activity or known antitumor indications within 1 week before the first dose of the investigational product.