Inclusion Criteria:
1. Age ≥18 years
2. Patients with histologically confirmed diagnosis of metastatic/locally advanced SCLC with any level of DLL3 expression (Cohort 1) or other poorly differentiated NECs whatever the primary or high-grade MTC (Cohort 2) based on the most recent biopsy of a metastatic site. Tumors from Cohort 2 must be DLL3 positive defined as DLL3 ≥1% or H-score ≥1 by IHC
3. For patients with poorly differentiated NECs whatever the primary, the biopsy of the disease diagnosis should be reviewed by an expert pathologist. Large cell, small cell or not otherwise specified are eligible. In addition, the tumor must have a Ki67 \>20% or mitotic rate \>20 per 10 high-power fields. For prostate cancer, the diagnosis of NEPC must be based on phenotype analysis, which may include IHC markers such as neuron-specific enolase (NSE), Chromogranin A or CD56 in the majority of the tumor sample, or molecular alterations such as TP53, Rb1, and PTEN
4. High-grade MTC should be defined according to international medullary cancer grading system (IMCGS)
5. Patients with metastatic/locally advanced SCLC and other poorly differentiated NECs must have been treated with at least 1 line of prior therapy, including a platinum-based regimen (resistant or sensitive to platinum), have experienced progression on standard treatment, as determined by the investigator. Prior treatment with PD-(L) 1 inhibitors is allowed Specific cases: Patients with NEPC must have received at least 1 line of prior therapy, including a platinum containing regimen for de novo NEPC or an androgen signaling inhibitor (eg. abiraterone, enzalutamide, darolutamide and/or apalutamide) if treatment-emergent NEPC. Patients with high-grade MTC (capped at 4 patients) must have been treated with at least 1 prior therapy including a RET selective inhibitor if the presence of a RET mutation
6. Patients with NEPC and without a history of bilateral orchiectomy are required to remain on luteinizing hormone-releasing hormone (LHRH) analogue therapy during the course of protocol therapy
7. Patients must have an ECOG performance status ≤2 at the time of screening
8. Patients must have a minimum life expectancy of 3 months
9. Patients must have at least one radiologically measurable lesion according to response evaluation criteria in solid tumors (RECIST) v1.1 criteria
10. Patients must have a tumor site easily accessible to biopsy, avoiding bone biopsy when possible. Patient must have accepted to perform pre-treatment, on-treatment, and end-of-treatment tumor and blood biopsies
11. Patients must have adequate bone marrow reserve and organ function, based on local laboratory data within 21 days prior to cycle 1, day 1 defined as:
* Platelet count ≥100 000/mm3 or ≥100 × 109/L (platelet transfusions are not allowed up to 14 days prior to cycle 1 Day 1 to meet eligibility)
* Hemoglobin (Hgb) ≥9.0 g/dL (transfusion and/or growth factor support is allowed)
* Absolute neutrophil count (ANC) ≥1500/mm3 or ≥1.5 × 109/L (use of growth factors is not allowed in the 14 days prior cycle 1)
* Creatinine clearance (CrCl): Creatinine clearance (CrCl) ≥30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl; confirmation of CrCl is only required when SCr is \>1.5 × ULN
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and alkaline phosphatase (ALP) \<3 x ULN (or \<5 x ULN for patients with liver metastases)
* Total bilirubin (TBL) \<.5 x ULN (\<3 x ULN in the presence of documented Gilbert's Syndrome \[unconjugated hyperbilirubinemia\]) or \<2 X ULN for patients with liver metastases
* Serum albumin ≥2.5 g/dL
* Prothrombin time (PT) or Prothrombin time- international normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT)≤1.5 × (ULN), except for patients on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator
12. Patients must have baseline oxygen saturation \> 90% on room air
13. Females of reproductive/childbearing potential must have a negative serum pregnancy test at screening and must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 60 days for females after the last dose of study drug.
Note : Methods considered as highly effective methods of contraception include:
1. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
* Oral
* Intravaginal
* Transdermal
2. Progestogen-only hormonal contraception associated with inhibition of ovulation:
* Oral
* Injectable
* Implantable
3. Intrauterine device (IUD)
4. Intrauterine hormone-releasing system (IUS)
5. Bilateral tubal occlusion
6. Vasectomized partner
7. Complete sexual abstinence defined as refraining from heterosexual intercourse during and upon completion of the study and for at least 7 months for females after the last dose of study drug. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception
14. Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 60 days after the final study drug administration
15. Male patients must be surgically sterile or must withhold heterosexual intercourse or must be willing to use a highly effective birth control upon enrollment, during the treatment period, and for at least 60 days following the last dose of study drug
16. Male patients must not freeze or donate sperm starting at screening and throughout the study period, and at least 60 days after the final study drug administration
17. Patients must understand, sign and date the written informed consent from prior to any protocol-specific procedures performed. Patients should be able and willing to comply with study visits and procedures as per protocol
18. Patients must be affiliated to a Social Security System or beneficiary of the same
Exclusion Criteria:
1. Patients unwilling to participate to the biological investigations and to perform blood and tissue sample collection as required in the protocol
2. Patients with SCLC or other poorly differentiated NECs whatever the primary or high-grade MTC amenable for treatment with curative intent
3. Patients with well differentiated neuroendocrine tumors, whatever the grade, pheocromocytoma, paraganglyoma, or low grade MTC
4. Patients with evidence of interstitial lung disease (ILD) (including pulmonary fibrosis or radiation pneumonitis) or is suspected to have such disease by imaging during screening
5. Patients who experienced recurrent pneumonitis (grade 2 or higher) or severe, life-threatening immune-mediated AEs or infusion-related reactions including those that lead to permanent discontinuation while on treatment with immuno-oncology agents
6. Patients with a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients of tarlatamab
7. Inadequate washout period prior to cycle 1 day 1, defined as:
1. Whole brain radiation therapy or stereotactic brain radiation therapy \<14 days
2. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation \<28 days or palliative radiation therapy \<7 days
3. Any investigational agents or other anticancer drug(s) from a previous cancer treatment regimen or clinical study \<30 days or \< 5 half-lives, whichever is longer, prior to first dose of tarlatamab. Conventional chemotherapy eligible if at least 14 days or \< 5 half-lives, whichever is longer, have elapsed and if all treatment-related toxicity has been resolved to grade ≤1
4. Major surgery (excluding placement of vascular access) \< 21 days
5. Live virus and live-attenuated vaccination \<28 days
6. Systemic steroid therapy or other immunosuppressive therapy \< 7 days
8. Prior treatment with tarlatamab or any selective inhibitor of the DLL3 pathway
9. Evidence of spinal cord compression or brain metastases, defined as being clinically active and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Patients with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study. Patients must have a stable neurologic status for at least 2 weeks prior to cycle 1 day 1
10. Patients with evidence of any leptomeningeal disease
11. Patients with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade 1 or baseline according to the NCI-CTCAE v5.0
12. Any evidence of primary malignancy other than metastatic/locally advanced SCLC, poorly differentiated NEC or high-grade MTC within 3 years prior to cycle 1 day 1, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated
13. Any evidence of severe or uncontrolled systemic diseases including active bleeding diatheses, active infection, psychiatric illness/social situations, geographical factors, substance abuse, or other factors which in the Investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required
14. Patients with symptoms and/or clinical signs and/or radiographic signs that indicate an acute and/or uncontrolled active systemic infection within 7 days prior to the first dose of study treatment.
15. Patients with clinically significant pleural effusion will be excluded. Pleural effusion managed with indwelling pleural catheter (eg, PleurX) are allowed
16. Uncontrolled or significant cardiovascular disease prior to cycle 1 day 1, including:
1. Corrected QT interval \>470 ms for females and \>450 ms for males according to Fridericia's formula (QTcF) and assessed based on triplicate ECGs, approximately 1 minute apart
2. LVEF \<50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan
3. Myocardial infarction within 6 months
4. NYHA \> class II within 6 months
5. Clinically significant pericardial effusion as determined by an ECHO or MUGA scan
17. Patient with history of arterial thrombosis (eg, stroke or transient ischemic attack) within 12 months of first dose of tarlatamab
18. Active Hepatitis B and/or Hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of cycle 1, day 1.
Patients with past or resolved Hepatitis B virus (HBV) infection are eligible if:
1. Hepatitis surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) positive; OR
2. HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load is documented to be ≤ 2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with normal transaminases; OR
3. HBsAg positive and HBV DNA viral load is documented to be ≤ 2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with abnormal transaminases AST/ALT \< 3 ULN.
Patients with a history of Hepatitis C infection will be eligible for enrollment only if the viral load according to local standards of detection, is documented to be below the level of detection in the absence of anti-viral therapy during the previous 12 weeks (ie, sustained viral response according to the local product label but no less than 12 weeks, whichever is longer).
19. Patients with history or evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patient is eligible if no acute symptoms of coronavirus disease 2019 (COVID-19) within 14 days prior to first dose of tarlatamab (counted from day of positive test for asymptomatic subjects)
20. Patient with active or prior documented autoimmune or inflammatory disorders, including but not limited to inflammatory bowel disease \[e.g. colitis or Crohn's disease\], diverticulitis with the exception of diverticulosis, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangitis), rheumatoid arthritis, hypophysitis, uveitis within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
1. Patient with auto-immune alopecia
2. Patient with Grave's disease, vitiligo or psoriasis not requiring systemic treatment within the last 2 years
3. Patient with hypothyroidism (e.g. following Hashimoto syndrome) stable on thyroid hormone replacement
21. Patient with diagnosis of human immunodeficiency virus (HIV). Patients with HIV infection on antiviral therapy and undetectable viral load are allowed with a requirement for regular monitoring for reactivation for the duration of treatment on study per local or institutional guidelines
22. Female patients who are pregnant or breastfeeding or intend to become pregnant during the study
23. Patients with any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
24. Patients under guardianship or deprived of his/her liberty by a judicial or administrative decision or incapable of giving his/her consent
25. Prior history of severe or life-threatening events from any immune-mediated therapy
26. Participation in another clinical trial (\<30 days or \< 5 half-lives, whichever is longer) evaluating an experimental drug (except non-interventional research)
→
Inclusion Criteria:
1. Age ≥18 years
2. Patients with histologically confirmed diagnosis of metastatic/locally advanced SCLC with any level of DLL3 expression (Cohort 1) or other poorly differentiated NECs whatever the primary based on the most recent biopsy of a metastatic site. Tumors from Cohort 2 must be DLL3 positive defined as DLL3 ≥1% or H-score ≥1 by IHC
3. For patients with poorly differentiated NECs whatever the primary, the biopsy of the disease diagnosis should be reviewed by an expert pathologist. Large cell, small cell or not otherwise specified are eligible. In addition, the tumor must have a Ki67 \>20% or mitotic rate \>20 per 10 high-power fields. For prostate cancer, the diagnosis of NEPC must be based on phenotype analysis, which may include IHC markers such as neuron-specific enolase (NSE), Chromogranin A or CD56 in the majority of the tumor sample, or molecular alterations such as TP53, Rb1, and PTEN
4. Patients with metastatic/locally advanced SCLC and other poorly differentiated NECs must have been treated with at least 1 line of prior therapy, including a platinum-based regimen (resistant or sensitive to platinum), have experienced progression on standard treatment, as determined by the investigator. Prior treatment with PD-(L) 1 inhibitors is allowed Specific cases: Patients with NEPC must have received at least 1 line of prior therapy, including a platinum containing regimen for de novo NEPC or an androgen signaling inhibitor (eg. abiraterone, enzalutamide, darolutamide and/or apalutamide) if treatment-emergent NEPC.
5. Patients with NEPC and without a history of bilateral orchiectomy are required to remain on luteinizing hormone-releasing hormone (LHRH) analogue therapy during the course of protocol therapy
6. Patients must have an ECOG performance status ≤2 at the time of screening
7. Patients must have a minimum life expectancy of 3 months
8. Patients must have at least one radiologically measurable lesion according to response evaluation criteria in solid tumors (RECIST) v1.1 criteria
9. Patients must have a tumor site easily accessible to biopsy, avoiding bone biopsy when possible. Patient must have accepted to perform pre-treatment, on-treatment, and end-of-treatment tumor and blood biopsies
10. Patients must have adequate bone marrow reserve and organ function, based on local laboratory data within 21 days prior to cycle 1, day 1 defined as:
* Platelet count ≥100 000/mm3 or ≥100 × 109/L (platelet transfusions are not allowed up to 14 days prior to cycle 1 Day 1 to meet eligibility)
* Hemoglobin (Hgb) ≥9.0 g/dL (transfusion and/or growth factor support is allowed)
* Absolute neutrophil count (ANC) ≥1500/mm3 or ≥1.5 × 109/L (use of growth factors is not allowed in the 14 days prior cycle 1)
* Creatinine clearance (CrCl): Creatinine clearance (CrCl) ≥30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl; confirmation of CrCl is only required when SCr is \>1.5 × ULN
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and alkaline phosphatase (ALP) \<3 x ULN (or \<5 x ULN for patients with liver metastases)
* Total bilirubin (TBL) \<1.5 x ULN (\<3 x ULN in the presence of documented Gilbert's Syndrome \[unconjugated hyperbilirubinemia\]) or \<2 X ULN for patients with liver metastases
* Serum albumin ≥2.5 g/dL
* Prothrombin time (PT) or Prothrombin time- international normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT)≤1.5 × (ULN), except for patients on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator
11. Patients must have baseline oxygen saturation \> 90% on room air
12. Females of reproductive/childbearing potential must have a negative serum pregnancy test at screening and must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 60 days for females after the last dose of study drug.
Note : Methods considered as highly effective methods of contraception include:
1. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
* Oral
* Intravaginal
* Transdermal
2. Progestogen-only hormonal contraception associated with inhibition of ovulation:
* Oral
* Injectable
* Implantable
3. Intrauterine device (IUD)
4. Intrauterine hormone-releasing system (IUS)
5. Bilateral tubal occlusion
6. Vasectomized partner
7. Complete sexual abstinence defined as refraining from heterosexual intercourse during and upon completion of the study and for at least 60 days for females after the last dose of study drug. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception
13. Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 60 days after the final study drug administration
14. Male patients must be surgically sterile or must withhold heterosexual intercourse or must be willing to use a highly effective birth control upon enrollment, during the treatment period, and for at least 60 days following the last dose of study drug
15. Male patients must not freeze or donate sperm starting at screening and throughout the study period, and at least 60 days after the final study drug administration
16. Patients must understand, sign and date the written informed consent from prior to any protocol-specific procedures performed. Patients should be able and willing to comply with study visits and procedures as per protocol
17. Patients must be affiliated to a Social Security System or beneficiary of the same
Exclusion Criteria:
1. Patients unwilling to participate to the biological investigations and to perform blood and tissue sample collection as required in the protocol
2. Patients with SCLC or other poorly differentiated NECs whatever the primary amenable for treatment with curative intent
3. Patients with well differentiated neuroendocrine tumors, whatever the grade, pheocromocytoma, paraganglyoma.
4. Patients with evidence of interstitial lung disease (ILD) (including pulmonary fibrosis or radiation pneumonitis) or is suspected to have such disease by imaging during screening
5. Patients who experienced recurrent pneumonitis (grade 2 or higher) or severe, life-threatening immune-mediated AEs or infusion-related reactions including those that lead to permanent discontinuation while on treatment with immuno-oncology agents
6. Patients with a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients of tarlatamab
7. Inadequate washout period prior to cycle 1 day 1, defined as:
1. Whole brain radiation therapy or stereotactic brain radiation therapy \<14 days
2. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation \<28 days or palliative radiation therapy \<7 days
3. Any investigational agents or other anticancer drug(s) from a previous cancer treatment regimen or clinical study \<30 days or \< 5 half-lives, whichever is longer, prior to first dose of tarlatamab. Conventional chemotherapy eligible if at least 14 days or \< 5 half-lives, whichever is longer, have elapsed and if all treatment-related toxicity has been resolved to grade ≤1
4. Major surgery (excluding placement of vascular access) \< 21 days
5. Live virus and live-attenuated vaccination \<28 days
6. Systemic steroid therapy or other immunosuppressive therapy \< 7 days
8. Prior treatment with tarlatamab or any selective inhibitor of the DLL3 pathway
9. Evidence of spinal cord compression or brain metastases, defined as being clinically active and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Patients with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study. Patients must have a stable neurologic status for at least 2 weeks prior to cycle 1 day 1
10. Patients with evidence of any leptomeningeal disease
11. Patients with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade 1 or baseline according to the NCI-CTCAE v5.0
12. Any evidence of primary malignancy other than metastatic/locally advanced SCLC, poorly differentiated NEC within 3 years prior to cycle 1 day 1, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated
13. Any evidence of severe or uncontrolled systemic diseases including active bleeding diatheses, active infection, psychiatric illness/social situations, geographical factors, substance abuse, or other factors which in the Investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required
14. Patients with symptoms and/or clinical signs and/or radiographic signs that indicate an acute and/or uncontrolled active systemic infection within 7 days prior to the first dose of study treatment.
15. Patients with clinically significant pleural effusion will be excluded. Pleural effusion managed with indwelling pleural catheter (eg, PleurX) are allowed
16. Uncontrolled or significant cardiovascular disease prior to cycle 1 day 1, including:
1. Corrected QT interval \>470 ms for females and \>450 ms for males according to Fridericia's formula (QTcF) and assessed based on triplicate ECGs, approximately 1 minute apart
2. LVEF \<50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan
3. Myocardial infarction within 6 months
4. NYHA \> class II within 6 months
5. Clinically significant pericardial effusion as determined by an ECHO or MUGA scan
17. Patient with history of arterial thrombosis (eg, stroke or transient ischemic attack) within 12 months of first dose of tarlatamab
18. Participant with active hepatitis B or HCV (RNA detected by qualitative assay). HCV RNA testing is not required in participants with negative HCV antibody testing.
Note;
* Active hepatitis B infection is defined as the presence of hepatitis B surface antigen \[HBsAg\] and hepatitis B virus \[HBV\] DNA viral load above the limit of quantification \[HBV DNA positive\]).
* Subjects with resolved HBV infection defined as absence of HBsAg and presence of HBV core antibody followed by an HBV DNA viral load below the limit of quantification (HBV DNA negative) are allowed, with a requirement for regular monitoring for reactivation for the duration of treatment on the study and assessing the need for HBV prophylaxis therapy per local or institutional guidelines.
* Subjects with chronic HBV infection, defined as presence of HBsAg and HBV DNA viral load below the limit of quantification \[HBV DNA negative\] are allowed, with a requirement for regular monitoring for reactivation for the duration of treatment on the study and assessing the need for HBV prophylaxis therapy per local or institutional guidelines.
19. Patients with history or evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patient is eligible if no acute symptoms of coronavirus disease 2019 (COVID-19) within 14 days prior to first dose of tarlatamab (counted from day of positive test for asymptomatic subjects)
20. Patient with active or prior documented autoimmune or inflammatory disorders, including but not limited to inflammatory bowel disease \[e.g. colitis or Crohn's disease\], diverticulitis with the exception of diverticulosis, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangitis), rheumatoid arthritis, hypophysitis, uveitis within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
1. Patient with auto-immune alopecia
2. Patient with Grave's disease, vitiligo or psoriasis not requiring systemic treatment within the last 2 years
3. Patient with hypothyroidism (e.g. following Hashimoto syndrome) stable on thyroid hormone replacement
21. Patient with diagnosis of human immunodeficiency virus (HIV). Patients with HIV infection on antiviral therapy and undetectable viral load are allowed with a requirement for regular monitoring for reactivation for the duration of treatment on study per local or institutional guidelines
22. Female patients who are pregnant or breastfeeding or intend to become pregnant during the study
23. Patients with any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
24. Patients under guardianship or deprived of his/her liberty by a judicial or administrative decision or incapable of giving his/her consent
25. Prior history of severe or life-threatening events from any immune-mediated therapy
26. Participation in another clinical trial (\<30 days or \< 5 half-lives, whichever is longer) evaluating an experimental drug (except non-interventional research)
AMGEN, due to a change in priorities within the Tarlatamab programme, has decided to withdraw its support for the study, which means the clinical trial will be terminated early.
Inclusion Criteria:
* Participants has provided informed consent before initiation of any study-specific activities/procedures.
* Newly diagnosed or relapse of granulomatosis with polyangiitis or microscopic polyangiitis, consistent with Chapel-Hill Consensus Conference definitions (Jennette et al, 2013), where induction treatment with cyclophosphamide or rituximab is needed.
* Age \>/= 18 years (or \>/= legal age within the country if it is older than 18 years).
* Positive test for anti-positive antiproteinase 3 or antimyeloperoxidase (current or historic) antibodies.
* At least 1 Birmingham Vasculitis Activity Score (BVAS) major item, or at least 3 BVAS nonmajor items, or at least the 2 renal items of proteinuria and hematuria.
* eGFR \>/= 15 mL/min/1.73 m\^2 (using Chronic Kidney Disease Epidemiology Collaboration equations).
Exclusion Criteria:
* Alveolar hemorrhage requiring invasive pulmonary ventilation support anticipated to last beyond the screening period of the study.
* Any other known multisystem autoimmune disease that may confound study assessments and study conclusions including but not limited to eosinophilic granulomatosis with polyangiitis (GPA \[Churg-Strauss\]), systemic lupus erythematosus, immunoglobulin (Ig) A vasculitis (Henoch-Schönlein), rheumatoid vasculitis, Sjogren's syndrome, anti-glomerular basement membrane disease, or cryoglobulinemic vasculitis.
* Any other medical condition requiring or expected to require continued use of immunosuppressive therapies, including corticosteroids that may cause confoundment with study assessments and study conclusions.
* Received dialysis or plasma exchange within 16 weeks before Day 1 randomization.
* Have had a kidney transplant.
* Malignancy (except curatively treated nonmelanoma skin cancers, curatively treated cervical carcinoma in situ, or breast ductal carcinoma in situ) within the last 5 years before Day 1 randomization.
* Acute or chronic, active hepatitis B virus or hepatitis C virus, or human immunodeficiency virus infection during screening.
* Any known exposure to a case of active tuberculosis (TB) within the last 12 weeks before Day 1 randomization.
* Positive test for active or latent TB during screening.
* White blood cell count \< 3500/µL, neutrophil count \< 1500/µL, or lymphocyte count \< 500/µl. Note: Complete Blood Count can be repeated once in the screening period at the investigator discretion. In such instances, eligibility will be determined based on the repeat complete blood count.
* Evidence of clinically significant hepatic disease including prior diagnosis of cirrhosis.
* Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) \>2.0 times the upper limit of normal (ULN).
* Total bilirubin \> 1.5 times the ULN. Note: A participant with documented Gilbert's syndrome with total bilirubin \< 2 x ULN may be eligible.
* Any of the following within 6 weeks prior to Day 1 randomization: serious infection, infection requiring treatment with intravenous (IV) anti-infective agents, any other infection (including active infection, chronic infection, opportunistic infection, or history of recurrent infection) that in the opinion of the investigator would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion. Oral or vaginal candidiasis and cutaneous or nail fungal infections do not constitute an exclusion.
* Any of the following within 12 weeks prior to Day 1 randomization: myocardial infarction, stroke, unstable angina, symptomatic congestive heart failure requiring prescription medication, any other clinically significant cardiovascular disease that in the opinion of the investigator would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion.
* Received cyclophosphamide (CYC) within 12 weeks before signing the informed consent; if on azathioprine (AZA), mycophenolate, or methotrexate (MTX) at the time of screening, these drugs must be withdrawn before receiving CYC. Note: If induction therapy with CYC was started within 1 week before signing the informed consent for the current episode of newly diagnosed or relapse of GPA or microscopic polyangiitis (MPA), the participant may be eligible, provided no CYC was received within 12 weeks before the start of the current induction therapy and if on AZA, mycophenolate, or MTX, these were withdrawn prior to receiving the current induction therapy with CYC.
* Have been taking an oral daily dose of a glucocorticoid of more than 10 mg prednisone equivalent for more than 6 weeks continuously before signing of the informed consent.
* Received RTX or other B-cell depleting therapies within 26 weeks before signing of the informed consent; if on AZA, mycophenolate, or MTX at the time of screening, these drugs must be withdrawn before receiving rituximab (RTX). Note: If induction therapy with RTX was started within 1 week before signing the informed consent for the current episode of newly diagnosed or relapse of GPA or MPA, the participant may be eligible, provided no RTX was received within 26 weeks before the start of the current induction therapy and if on AZA, mycophenolate, or MTX, these were withdrawn prior to receiving the current induction therapy with RTX.
* Received any of the following within 16 weeks before Day 1 randomization:
* antitumor necrosis factor treatment
* abatacept
* alemtuzumab
* IV Ig
* belimumab
* anti interleukin-6 agent (eg, tocilizumab, sarilumab).
* Taking a strong or moderate inducer of the cytochrome P450 3A4 (CYP3A4) enzyme unless the strong or moderate CYP3A4 inducer can be changed to an alternative medicine at least 1 week before Day 1 randomization.
* Received an investigational drug within 30 days or within 5 half-lives (whichever is longer) before Day 1 randomization.
* Previously received avacopan without clinical benefit per the Investigator's opinion or received avacopan within 60 days before Day 1 randomization.
→
Inclusion Criteria:
* Participants has provided informed consent before initiation of any study-specific activities/procedures.
* Newly diagnosed or relapse of granulomatosis with polyangiitis or microscopic polyangiitis, consistent with Chapel-Hill Consensus Conference definitions (Jennette et al, 2013), where induction treatment with cyclophosphamide or rituximab is needed.
Note: For participants receiving azathioprine, mycophenolate, or methotrexate, these medications must be discontinued prior to initiation of induction treatment. Participants receiving, or planned to receive combined rituximab and cyclophosphamide for remission induction of the current disease episode at the time of enrollment are not eligible.
* Age \>/= 18 years (or \>/= legal age within the country if it is older than 18 years).
* Positive test for anti-positive antiproteinase 3 or antimyeloperoxidase (current or historic) antibodies.
* At least 1 Birmingham Vasculitis Activity Score (BVAS) major item, or at least 3 BVAS nonmajor items, or at least the 2 renal items of proteinuria and hematuria.
* eGFR \>/= 15 mL/min/1.73 m\^2 (using Chronic Kidney Disease Epidemiology Collaboration equations).
Exclusion Criteria:
* Alveolar hemorrhage requiring invasive pulmonary ventilation support anticipated to last beyond the screening period of the study.
* Any other known multisystem autoimmune disease that may confound study assessments and study conclusions including but not limited to eosinophilic granulomatosis with polyangiitis (GPA \[Churg-Strauss\]), systemic lupus erythematosus, immunoglobulin (Ig) A vasculitis (Henoch-Schönlein), rheumatoid vasculitis, Sjogren's syndrome, anti-glomerular basement membrane disease, or cryoglobulinemic vasculitis.
* Any other medical condition requiring or expected to require continued use of immunosuppressive therapies, including corticosteroids that may cause confoundment with study assessments and study conclusions.
* Received dialysis or plasma exchange within 16 weeks before Day 1 randomization.
* Have had a kidney transplant.
* Malignancy (except curatively treated nonmelanoma skin cancers, curatively treated cervical carcinoma in situ, or breast ductal carcinoma in situ) within the last 5 years before Day 1 randomization.
* Acute or chronic, active hepatitis B virus or hepatitis C virus, or human immunodeficiency virus infection during screening.
* Any known exposure to a case of active tuberculosis (TB) within the last 12 weeks before Day 1 randomization.
* Positive test for active or latent TB during screening.
* White blood cell count \< 3500/µL, neutrophil count \< 1500/µL, or lymphocyte count \< 500/µl. Note: Complete Blood Count can be repeated once in the screening period at the investigator discretion. In such instances, eligibility will be determined based on the repeat complete blood count.
* Evidence of clinically significant hepatic disease including prior diagnosis of cirrhosis.
* Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) \>2.0 times the upper limit of normal (ULN).
* Total bilirubin \> 1.5 times the ULN. Note: A participant with documented Gilbert's syndrome with total bilirubin \< 2 x ULN may be eligible.
* Any of the following within 6 weeks prior to Day 1 randomization: serious infection, infection requiring treatment with intravenous (IV) anti-infective agents, any other infection (including active infection, chronic infection, opportunistic infection, or history of recurrent infection) that in the opinion of the investigator would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion. Oral or vaginal candidiasis and cutaneous or nail fungal infections that are not serious do not constitute an exclusion.
* Any of the following within 12 weeks prior to Day 1 randomization: myocardial infarction, stroke, unstable angina, symptomatic congestive heart failure requiring prescription medication, any other clinically significant cardiovascular disease that in the opinion of the investigator would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion.
* Received cyclophosphamide (CYC) within 12 weeks before signing the informed consent; if on azathioprine (AZA), mycophenolate, or methotrexate (MTX) at the time of screening, these drugs must be withdrawn before receiving CYC. Note: If induction therapy with CYC was started within 2 weeks before signing the informed consent for the current episode of newly diagnosed or relapse of GPA or microscopic polyangiitis (MPA), the participant may be eligible, provided no CYC was received within 12 weeks before the start of the current induction therapy and if on AZA, mycophenolate, or MTX, these were withdrawn prior to receiving the current induction therapy with CYC.
* Have been taking an oral daily dose of a glucocorticoid of more than 10 mg prednisone equivalent for more than 6 weeks continuously before signing of the informed consent.
* Received RTX or other B-cell depleting therapies within 26 weeks before signing of the informed consent; if on AZA, mycophenolate, or MTX at the time of screening, these drugs must be withdrawn before receiving rituximab (RTX). Note: If induction therapy with RTX was started within 2 weeks before signing the informed consent for the current episode of newly diagnosed or relapse of GPA or MPA, the participant may be eligible, provided no RTX was received within 26 weeks before the start of the current induction therapy and if on AZA, mycophenolate, or MTX, these were withdrawn prior to receiving the current induction therapy with RTX.
* Received any of the following within 16 weeks before Day 1 randomization:
* antitumor necrosis factor treatment
* abatacept
* alemtuzumab
* IV Ig
* belimumab
* anti interleukin-6 agent (eg, tocilizumab, sarilumab).
* Taking a strong or moderate inducer of the cytochrome P450 3A4 (CYP3A4) enzyme unless the strong or moderate CYP3A4 inducer can be changed to an alternative medicine at least 1 week before Day 1 randomization.
* Received an investigational drug within 30 days or within 5 half-lives (whichever is longer) before Day 1 randomization.
* Previously received avacopan without clinical benefit per the Investigator's opinion or received avacopan within 60 days before Day 1 randomization.
INCLUSION CRITERIA for all subjects:
1. Written informed consent and HIPAA authorization for release of personal health information signed by the subject or his/her legally authorized representative. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
2. Age greater than or equal to 18 years at the time of consent. Because no dosing or adverse event data are currently available on the use of belantamab mafodotin as a single agent or in combination with KRd in subjects less than 18 years of age, children are excluded from this study.
3. ECOG Performance Status of less than or equal to 2
4. Demonstrate adequate organ function
5. Adequate cardiac function as defined by a greater than 40% left ventricular ejection fraction (LVEF) by ECHO, cardiac MRI or MUGA
1. Note for subjects in phase II: if a cycle of pre-study induction therapy containing a PI or anthracycline was administered, assessment of the LVEF must be repeated.
6. For those with symptomatic pulmonary disease with Grade 2 or higher symptoms (e.g. COPD, asthma) or other signs / symptoms of pulmonary disease, adequate pulmonary function as defined by a FEV1 greater than or equal to 50% of predicted and DLCO/VA greater than or equal to 50% of predicted
7. Females of childbearing potential (FCBP) must have two negative serum pregnancy tests during screening: the first within 10-14 days prior to first dose of study treatment and the second within 24 hours prior to first dose of study treatment. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), are amenorrhoeic for less than 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation; or are postmenopausal (at least 12 consecutive months with no menses without an alternative medical cause).
8. FCBP must be willing to use 2 effective contraceptive methods (at least one that is highly effective) or abstinence starting from the time of informed consent, while on belantamab mafodotin and lenalidomide. If either drug is discontinued, 2 effective forms of contraception should be continued until at least 4 weeks after the last dose of lenalidomide, and 1 form of effective contraception should be continued until 4 months post last dose of belantamab mafodotin. FCBP should use effective contraception or abstinence from consent until 30 days after last treatment with carfilzomib, and males with a partner of childbearing potential must use effective contraception or abstinence for at least 90 days post last dose of carfilzomib.
9. Male subjects must agree to the following from the first dose of study treatment until 6 months after the last dose of belantamab mafodotin, to allow for clearance of altered sperm:
1. Refrain from donating sperm
PLUS either:
2. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR
3. Must agree to use effective contraception/barrier as detailed below:
Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner of reproductive potential to use an additional highly effective contraceptive method with a failure rate of less than 1% per year
10. FCBP must agree not to donate eggs (ova, oocytes) for the purpose of reproduction during the intervention period and for at least 4 months after the last dose of study intervention belantamab mafodotin, at least 30 days after the last dose of carfilzomib, and at least 4 weeks after the last dose of lenalidomide.
11. As determined by the enrolling physician, ability of the subject to understand and adhere with study procedures for the entire length of the study
12. Ability to swallow oral medications
13. Willing to refrain from using contact lenses while participating in this study
INCLUSION CRITERIA - Phase I treatment for Relapsed or Relapsed/Refractory MM:
1. Subjects with Relapsed or Relapsed/Refractory MM who have had at least 1 line of prior therapy.
1. Refractory is defined as less than 25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment
2. A line of therapy is defined as one or more cycles of a planned treatment program.
This may consist of one or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. A new line of therapy starts when a planned course of therapy is modified to include other treatment agents (alone or in combination) as a result of disease progression, relapse, or toxicity. A new line of therapy also starts when a planned period of observation off therapy is interrupted by a need for additional treatment for the disease.
2. Subjects must have measurable disease, as defined by at least one of the following:
1. Serum monoclonal protein level greater than or equal to 0.5 g/dL
2. 24-hour urinary M-protein greater than or equal to 200 mg
3. Involved free light chain level greater than or equal to 10 mg/dL, along with an abnormal free light chain ratio (defined as less than 0.26 or greater than 1.65).
3. Subject must have not progressed on full dose lenalidomide previously (25 mg on days 1-21 of a 28-day cycle or its dosing equivalent based on renal function at the time of progression)
4. Prior to enrollment:
a. There should be a washout period of ≥14 days from any prior chemotherapy AND b. The subject must have adequate recovery from toxicity of prior chemotherapy as defined by the following: i. Hematologic lab results within parameters noted in Table 3.2.1 ii. Non-hematologic toxicity resolved to grade 1 or baseline with the following exceptions:
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1. Subjects who have started a course of antibiotic therapy for infection and symptoms have improved to baseline or grade 1, but remain on antibiotic therapy are eligible
2. Subjects with ≤grade 2 fatigue are eligible
3. Subjects with ≤grade 2 hyperglycemia are eligible, even if pharmacologic treatment was required
4. Subjects with ≤grade 2 electrolyte abnormalities are eligible, even if pharmacologic treatment was required
5. Subjects with ≤grade 2 nausea, constipation or diarrhea are eligible, even if pharmacologic treatment was required
6. Subjects with less than grade 2 peripheral neuropathy
INCLUSION CRITERIA - Phase II treatment for high-risk newly diagnosed MM:
1. Active, newly diagnosed multiple myeloma with CRAB features or a myeloma-defining event per the IMWG 2014 criteria. Note: It is acceptable to include subjects who have had one cycle of emergent treatment for multiple myeloma.
2. High-risk disease, as defined by at least one of the following:
i. Del(1p) ii. Gain of 1q21 \[greater than or equal to 3 copies\] iii. Monosomy 13 or del(13q) by conventional karyotype iv. High risk IgH translocation \[t(4;14), t(14;16) or t(14;20)\] v. del(17p)
3. Measurable disease by 1 or more of the following:
a. Serum monoclonal protein level greater than or equal to 0.5 g/dL b. 24-hour urinary M-protein greater than or equal to 200 mg c. Involved free light chain level greater than or equal to 10 mg/dL (100 mg/L), along with an abnormal free light chain ratio (defined as less than 0.26 or greater than 1.65).
d. Note: for subjects who have received a prior cycle of non-protocol therapy, measurable disease will be based on the serum and urine monoclonal protein and serum free light chain levels prior to the cycle of non-protocol therapy
4. No more than one prior cycle of non-protocol therapy will be allowed, recognizing that high-risk multiple myeloma subjects frequently require immediate therapy at initial diagnosis even before risk assessment is complete. For those subjects who receive a cycle of non-protocol induction therapy:
a. There should be a washout period of ≥14 days from the last dose of pre-study therapy AND b. The subject must have adequate recovery from toxicity of pre-study therapy as defined by the following: i. Hematologic lab results within parameters ii. Non-hematologic toxicity resolved to grade 1 or baseline with the following exceptions:
1\. Subjects who have started a course of antibiotic therapy for infection and symptoms have improved to baseline or grade 1, but remain on antibiotic therapy are eligible 2. Subjects with less than or equal to grade 2 fatigue are eligible 3. Subjects with less than or equal to grade 2 hyperglycemia are eligible, even if pharmacologic treatment was required 4. Subjects with less than or equal to grade 2 electrolyte abnormalities are eligible, even if pharmacologic treatment was required 5. Subjects with less than or equal to grade 2 nausea, constipation or diarrhea are eligible, even if pharmacologic treatment was required 6. Subjects with less than grade 2 peripheral neuropathy
EXCLUSION CRITERIA for all subjects:
1. Active infection requiring systemic therapy. NOTE: at the discretion of the treating investigator, subjects who have started antibiotic therapy for subjects who had symptoms present, symptoms must have improved to baseline or grade 1 in severity may start treatment prior to completion of their course of antibiotic therapy.
2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study.)
3. Subjects cannot have other prior or concomitant malignancies except for:
1. Curatively treated non-melanoma skin cancer
2. Other cancer for which the subject has been medically stable for at least 2 years and/or, in the opinion of the Site Principal Investigators, will not affect the evaluation of the effects of clinical trial treatments on the currently targeted malignancy
4. Active central nervous system (CNS) involvement
5. Concomitant AL amyloidosis or POEMS syndrome
6. Plasma cell leukemia
7. Treatment with any investigational drug within 14 days or five half-lives, whichever is shorter, prior to first dose of study treatment.
8. Medical, psychiatric, or other condition/disorder (including lab abnormalities) which, in the opinion of the treating physician, would make this protocol treatment unreasonably hazardous for the subject, or could interfere with obtaining informed consent or compliance to the study procedures
9. Significant cardiac disease, including any of the following:
1. Greater than or equal to Class 3 New York Heart Association (NYHA) congestive heart failure (see Appendix B)
2. ECG evidence of acute ischemia
3. Unstable angina
4. Myocardial infarction, Coronary angioplasty, stenting, or bypass grafting within three months prior to day 1 of treatment
5. Clinically significant uncontrolled and/or untreated arrhythmias or conduction block, including clinically significant ECG abnormalities such as 2nd degree Mobitz Type ll or 3rd degree atrioventricular (AV)block. However, PACs, PVCs, rate controlled atrial fibrillation, sinus arrhythmia, asymptomatic sinus bradycardia or sinus tachycardia and 1st degree heart block are not considered clinically significant.
6. Greater than or equal to Grade 2 QTcF prolongation (i.e. \>480 msec)
10. Uncontrolled hypertension, defined as a systolic blood pressure of greater than or equal to 160 mmHg or a diastolic blood pressure of greater than or equal to 90 mmHg
11. Grade greater than or equal to 2 peripheral neuropathy
12. Psychiatric illness/social situation that would limit compliance with study requirements as determined by the investigator
13. Known immediate or delayed hypersensitivity or allergic reaction to any components of, or related to, protocol therapy (e.g. during exposure to carfilzomib, lenalidomide or dexamethasone as part of a pre-study cycle of therapy).
14. History of erythema multiforme to lenalidomide or other IMID
15. Discontinuation of prior carfilzomib, lenalidomide or dexamethasone due to treatment toxicity
16. Major surgery within 4 weeks prior to day 1 of treatment
17. Radiation within 14 days prior to day 1 of treatment. Note: palliative XRT to less than 5% of the total marrow volume as assessed by the treating investigator is allowed within 14 days prior to day 1 of treatment
18. Current corneal epithelial disease except mild changes in corneal epithelium
19. Positive hepatitis C antibody test result (this test preferable) or positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment
a. NOTE: Subjects with positive Hepatitis C antibody due to prior eradicated disease can be enrolled if a confirmatory negative Hepatitis C RNA test is obtained
20. A known diagnosis of HIV
21. Is seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen \[HBsAg\]). Subjects with resolved infection (i.e. subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen \[anti-HBc\] and/or antibodies to hepatitis B surface antigen \[anti-HBs\]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Subjects who are PCR positive will be excluded. Subjects with Hepatitis B surface antibodies and previous Hepatitis B vaccination will be eligible.
22. Has current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable non-cirrhotic chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if otherwise meets entry criteria
23. Participant must not have presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant's safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfill inclusion criteria
24. Participant must not have had plasmapheresis within 7 days prior to first dose of study treatment
25. Any evidence of active mucosal or internal bleeding
26. Participant must not be simultaneously enrolled in any therapeutic clinical trial
27. Administration of live or live-attenuated vaccines within 30 days prior to the first dose of study treatment
a. Exception: Monkeypox vaccine may be given if there are at least 3 days between the vaccine and initiation of study treatment.
28. Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drug.
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INCLUSION CRITERIA for all subjects:
1. Written informed consent and HIPAA authorization for release of personal health information signed by the subject or his/her legally authorized representative. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
2. Age greater than or equal to 18 years at the time of consent. Because no dosing or adverse event data are currently available on the use of belantamab mafodotin as a single agent or in combination with KRd in subjects less than 18 years of age, children are excluded from this study.
3. ECOG Performance Status of less than or equal to 2
4. Demonstrate adequate organ function
5. Adequate cardiac function as defined by a greater than 40% left ventricular ejection fraction (LVEF) by ECHO, cardiac MRI or MUGA
a. Note for subjects in phase II: if a cycle of pre-study induction therapy containing a PI or anthracycline was administered, assessment of the LVEF must be repeated.
6. For those with symptomatic pulmonary disease with Grade 2 or higher symptoms (e.g. COPD, asthma) or other signs / symptoms of pulmonary disease, adequate pulmonary function as defined by a FEV1 greater than or equal to 50% of predicted and DLCO/VA greater than or equal to 50% of predicted
7. Females of childbearing potential (FCBP) must have two negative serum pregnancy tests during screening: the first within 10-14 days prior to first dose of study treatment and the second within 24 hours prior to first dose of study treatment. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), are amenorrhoeic for less than 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation; or are postmenopausal (at least 12 consecutive months with no menses without an alternative medical cause).
8. FCBP must be willing to use 2 effective contraceptive methods (at least one that is highly effective) or abstinence starting from the time of informed consent, while on belantamab mafodotin and lenalidomide. If either drug is discontinued, 2 effective forms of contraception should be continued until at least 4 weeks after the last dose of lenalidomide, and 1 form of effective contraception should be continued until 4 months post last dose of belantamab mafodotin. FCBP should use effective contraception or abstinence from consent until 30 days after last treatment with carfilzomib, and males with a partner of childbearing potential must use effective contraception or abstinence for at least 90 days post last dose of carfilzomib.
9. Male subjects must agree to the following from the first dose of study treatment until 6 months after the last dose of belantamab mafodotin, to allow for clearance of altered sperm:
1. Refrain from donating sperm
PLUS either:
b. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR c. Must agree to use effective contraception/barrier as detailed below: Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner of reproductive potential to use an additional highly effective contraceptive method with a failure rate of less than 1% per year
10. FCBP must agree not to donate eggs (ova, oocytes) for the purpose of reproduction during the intervention period and for at least 4 months after the last dose of study intervention belantamab mafodotin, at least 30 days after the last dose of carfilzomib, and at least 4 weeks after the last dose of lenalidomide.
11. As determined by the enrolling physician, ability of the subject to understand and adhere with study procedures for the entire length of the study
12. Ability to swallow oral medications
13. Willing to refrain from using contact lenses while participating in this study
INCLUSION CRITERIA - Phase I treatment for Relapsed or Relapsed/Refractory MM:
1. Subjects with Relapsed or Relapsed/Refractory MM who have had at least 1 line of prior therapy.
a. Refractory is defined as less than 25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment b. A line of therapy is defined as one or more cycles of a planned treatment program. This may consist of one or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. A new line of therapy starts when a planned course of therapy is modified to include other treatment agents (alone or in combination) as a result of disease progression, relapse, or toxicity. A new line of therapy also starts when a planned period of observation off therapy is interrupted by a need for additional treatment for the disease.
2. Subjects must have measurable disease, as defined by at least one of the following:
a. Serum monoclonal protein level greater than or equal to 0.5 g/dL b. 24-hour urinary M-protein greater than or equal to 200 mg c. Involved free light chain level greater than or equal to 10 mg/dL, along with an abnormal free light chain ratio (defined as less than 0.26 or greater than 1.65).
3. Subject must have not progressed on full dose lenalidomide previously (25 mg on days 1-21 of a 28-day cycle or its dosing equivalent based on renal function at the time of progression)
4. Prior to enrollment:
1. There should be a washout period of ≥14 days from any prior chemotherapy AND
2. The subject must have adequate recovery from toxicity of prior chemotherapy as defined by the following:
i. Hematologic lab results within parameters noted in Table 3.2.1 ii. Non-hematologic toxicity resolved to grade 1 or baseline with the following exceptions:
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1. Subjects who have started a course of antibiotic therapy for infection and symptoms have improved to baseline or grade 1, but remain on antibiotic therapy are eligible
2. Subjects with ≤grade 2 fatigue are eligible
3. Subjects with ≤grade 2 hyperglycemia are eligible, even if pharmacologic treatment was required
4. Subjects with ≤grade 2 electrolyte abnormalities are eligible, even if pharmacologic treatment was required
5. Subjects with ≤grade 2 nausea, constipation or diarrhea are eligible, even if pharmacologic treatment was required
6. Subjects with less than grade 2 peripheral neuropathy
INCLUSION CRITERIA - Phase II treatment for high-risk newly diagnosed MM:
1. Active, newly diagnosed multiple myeloma with CRAB features or a myeloma-defining event per the IMWG 2014 criteria. Note: It is acceptable to include subjects who have had one cycle of emergent treatment for multiple myeloma.
2. High-risk disease at diagnosis, as defined by at least one of the following:
i. Monoallelic del(1p) along with +1q, or biallelic del(1p) ii. One of those translocations \[t(4;14), t(14;16) or t(14;20)\]- co-occurring with a +1q and/or del(1p) iii. del(17p)\* and/or TP53 mutation iv. High β2M (\>5.5 mg/L) with normal creatinine (Note: Both must be performed no more than +/- 7 days apart.) v. Primary plasma cell leukemia: peripheral blood plasma cell percentage \>5% as assessed by pathology review of the peripheral smear vi. Presence of extramedullary disease
3. Measurable disease by 1 or more of the following:
a. Serum monoclonal protein level greater than or equal to 0.5 g/dL b. 24-hour urinary M-protein greater than or equal to 200 mg c. Involved free light chain level greater than or equal to 10 mg/dL (100 mg/L), along with an abnormal free light chain ratio (defined as less than 0.26 or greater than 1.65).
d. Note: for subjects who have received a prior cycle of non-protocol therapy, measurable disease will be based on the serum and urine monoclonal protein and serum free light chain levels prior to the cycle of non-protocol therapy
4. No more than one prior cycle of non-protocol therapy will be allowed, recognizing that high-risk multiple myeloma subjects frequently require immediate therapy at initial diagnosis even before risk assessment is complete. For those subjects who receive a cycle of non-protocol induction therapy:
1. There should be a washout period of ≥14 days from the last dose of pre-study therapy AND
2. The subject must have adequate recovery from toxicity of pre-study therapy as defined by the following:
i. Hematologic lab results within parameters ii. Non-hematologic toxicity resolved to grade 1 or baseline with the following exceptions:
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1. Subjects who have started a course of antibiotic therapy for infection and symptoms have improved to baseline or grade 1, but remain on antibiotic therapy are eligible
2. Subjects with less than or equal to grade 2 fatigue are eligible
3. Subjects with less than or equal to grade 2 hyperglycemia are eligible, even if pharmacologic treatment was required
4. Subjects with less than or equal to grade 2 electrolyte abnormalities are eligible, even if pharmacologic treatment was required
5. Subjects with less than or equal to grade 2 nausea, constipation or diarrhea are eligible, even if pharmacologic treatment was required
6. Subjects with less than grade 2 peripheral neuropathy
EXCLUSION CRITERIA for all subjects:
1. Active infection requiring systemic therapy. NOTE: at the discretion of the treating investigator, subjects who have started antibiotic therapy for subjects who had symptoms present, symptoms must have improved to baseline or grade 1 in severity may start treatment prior to completion of their course of antibiotic therapy.
2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study.)
3. Subjects cannot have other prior or concomitant malignancies except for:
a. Curatively treated non-melanoma skin cancer b. Other cancer for which the subject has been medically stable for at least 2 years and/or, in the opinion of the Site Principal Investigators, will not affect the evaluation of the effects of clinical trial treatments on the currently targeted malignancy
4. Active central nervous system (CNS) involvement
5. Concomitant AL amyloidosis or POEMS syndrome
6. Treatment with any investigational drug within 14 days or five half-lives, whichever is shorter, prior to first dose of study treatment.
7. Medical, psychiatric, or other condition/disorder (including lab abnormalities) which, in the opinion of the treating physician, would make this protocol treatment unreasonably hazardous for the subject, or could interfere with obtaining informed consent or compliance to the study procedures
8. Significant cardiac disease, including any of the following:
a. Greater than or equal to Class 3 New York Heart Association (NYHA) congestive heart failure (see Appendix B) b. ECG evidence of acute ischemia c. Unstable angina d. Myocardial infarction, Coronary angioplasty, stenting, or bypass grafting within three months prior to day 1 of treatment e. Clinically significant uncontrolled and/or untreated arrhythmias or conduction block, including clinically significant ECG abnormalities such as 2nd degree Mobitz Type ll or 3rd degree atrioventricular (AV)block. However, PACs, PVCs, rate controlled atrial fibrillation, sinus arrhythmia, asymptomatic sinus bradycardia or sinus tachycardia and 1st degree heart block are not considered clinically significant.
f. Greater than or equal to Grade 2 QTcF prolongation (i.e. \>480 msec)
9. Chronic uncontrolled hypertension, defined as a systolic blood pressure of greater than or equal 160 mmHg or a diastolic blood pressure of greater than or equal 90 mmHg based on at least two readings on two or more separate occasions, ideally over 1-4 weeks. Isolated or situational blood pressure elevations may be acceptable at the treating investigator's discretion.
10. Grade greater than or equal to 2 peripheral neuropathy
11. Psychiatric illness/social situation that would limit compliance with study requirements as determined by the investigator
12. Known immediate or delayed hypersensitivity or allergic reaction to any components of, or related to, protocol therapy (e.g. during exposure to carfilzomib, lenalidomide or dexamethasone as part of a pre-study cycle of therapy).
13. History of erythema multiforme to lenalidomide or other IMID
14. Discontinuation of prior carfilzomib, lenalidomide or dexamethasone due to treatment toxicity
15. Major surgery within 4 weeks prior to day 1 of treatment
16. Radiation within 14 days prior to day 1 of treatment. Note: palliative XRT to less than 5% of the total marrow volume as assessed by the treating investigator is allowed within 14 days prior to day 1 of treatment
17. Current corneal epithelial disease except mild changes in corneal epithelium
18. Positive hepatitis C antibody test result (this test preferable) or positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment
a. NOTE: Subjects with positive Hepatitis C antibody due to prior eradicated disease can be enrolled if a confirmatory negative Hepatitis C RNA test is obtained b. Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months before first dose of study treatment unless the participant can meet the following criteria: i. RNA test negative ii. Successful antiviral treatment (usually 8 weeks duration) is required, followed by a negative HCV RNA test after a washout period of at least 4 weeks.
NOTE: Hepatitis RNA testing is optional and participants with a negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing
19. A known diagnosis of HIV
20. Is seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen \[HBsAg\]). Subjects with resolved infection (i.e. subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen \[anti-HBc\] and/or antibodies to hepatitis B surface antigen \[anti-HBs\]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Subjects who are PCR positive will be excluded. Subjects with Hepatitis B surface antibodies and previous Hepatitis B vaccination will be eligible.
21. Has current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable non-cirrhotic chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if otherwise meets entry criteria
22. Participant must not have presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant's safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfill inclusion criteria
23. Participant must not have had plasmapheresis within 7 days prior to first dose of study treatment
24. Any evidence of active mucosal or internal bleeding
25. Participant must not be simultaneously enrolled in any therapeutic clinical trial
26. Administration of live or live-attenuated vaccines within 30 days prior to the first dose of study treatment a. Exception: Monkeypox vaccine may be given if there are at least 3 days between the vaccine and initiation of study treatment.
28\. Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drug.
29\. Transplant ineligible per institutional guidelines (Phase II)
Inclusion Criteria:
* Healthy male or female participants, 18 to 60 years of age.
* First-generation Chinese ancestry (born in China, Hong Kong, Taiwan, or Macau with 2 Chinese parents and 4 Chinese grandparents) or first-generation Japanese ancestry (born in Japan with 2 Japanese parents and 4 Japanese grandparents).
* Body mass index (BMI) 18.0 to 30.0 kg/m\^2 (inclusive) and body weight ≥40 kg.
* In good general health based on medical history, physical examination, vital signs, electrocardiogram (ECG), and clinical laboratory evaluations.
* Female participants must not be pregnant or breastfeeding.
* Participants of reproductive potential must agree to follow protocol-specified contraception requirements.
* Willing to maintain usual diet and physical activity regimen throughout study participation.
Exclusion Criteria:
* Clinically significant medical condition, disease, or abnormal finding that could interfere with study participation or interpretation of results.
* Clinically significant ECG abnormalities
* Clinically significant abnormal blood pressure or pulse rate at screening/check-in.
* History of malignancy (except adequately treated in situ cervical cancer or non-melanoma skin cancer \>5 years before dosing).
* Deep vein thrombosis or pulmonary embolism within 3 months prior to check-in.
* History of hypersensitivity/anaphylaxis to biologic therapies, mammalian-derived products, or AMG 691 excipients.
* Active, chronic, recurrent, or unresolved infection; history of severe infection requiring intravenous (IV) antibiotics within the past 3 years.
* Positive or indeterminate QuantiFERON-TB Gold test.
* Untreated or unresolved helminth parasitic infection.
* History of immunodeficiency.
* Receipt of live or live-attenuated vaccines within 12 weeks before check-in or planned during the study.
* Estimated glomerular filtration rate (eGFR) \<70 mL/min/1.73 m\^2.
* Alanine Aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, or direct bilirubin \>1.5 × Upper Limit Normal (ULN).
* Positive screening tests for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection.
* Use of prohibited prescription, over-the-counter, herbal, vitamin, or dietary supplement products within 30 days (or 5 half-lives) before enrollment, unless approved by the investigator.
* History of illicit drug use within 1 year, positive drug screen, or unwillingness to abstain from illicit drugs/cannabinoids during the study.
* Use of tobacco or nicotine-containing products within 6 months prior to check-in.
* History of alcohol abuse or excessive alcohol consumption.
* History of non-suicidal self-injury within 5 years or unstable major depressive disorder/other severe psychiatric disorder within 2 years.
* Participation in another investigational drug study within 90 days (or 5 half-lives) prior to check-in.
* Previous exposure to AMG 691.
* Recent donation of blood, plasma, or platelets.
* Any participant considered unsuitable by the investigator or unwilling to comply with study restrictions.
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Inclusion Criteria:
* Healthy male or female participants, 18 to 60 years of age.
* First-generation Chinese ancestry (born in China, Hong Kong, Taiwan, or Macau with 2 Chinese parents and 4 Chinese grandparents) or first-generation Japanese ancestry (born in Japan with 2 Japanese parents and 4 Japanese grandparents).
* Body mass index (BMI) 18.0 to 30.0 kg/m\^2 (inclusive) and body weight ≥40 kg.
* In good general health based on medical history, physical examination, vital signs, electrocardiogram (ECG), and clinical laboratory evaluations.
* Female participants must not be pregnant or breastfeeding.
* Participants of reproductive potential must agree to follow protocol-specified contraception requirements.
* Willing to maintain usual diet and physical activity regimen throughout study participation.
Exclusion Criteria:
* Clinically significant medical condition, disease, or abnormal finding that could interfere with study participation or interpretation of results.
* Clinically significant ECG abnormalities
* Clinically significant abnormal blood pressure or pulse rate at screening/check-in.
* History of malignancy (except adequately treated in situ cervical cancer or non-melanoma skin cancer \>5 years before dosing).
* Deep vein thrombosis or pulmonary embolism within 3 months prior to check-in.
* History of hypersensitivity/anaphylaxis to biologic therapies, mammalian-derived products, or AMG 691 excipients.
* Active, chronic, recurrent, or unresolved infection; history of severe infection requiring intravenous (IV) antibiotics within the past 3 years.
* Positive or indeterminate QuantiFERON-TB Gold test.
* Untreated or unresolved helminth parasitic infection.
* History of immunodeficiency.
* Receipt of live or live-attenuated vaccines within 12 weeks before check-in or planned during the study.
* Estimated glomerular filtration rate (eGFR) \<70 mL/min/1.73 m\^2.
* Alanine Aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, or direct bilirubin \>1.5 × Upper Limit Normal (ULN).
* Positive screening tests for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection. Hepatitis B serology consistent with prior vaccination is permitted.
* Use of prohibited prescription, over-the-counter, herbal, vitamin, or dietary supplement products within 30 days (or 5 half-lives) before enrollment, unless approved by the investigator.
* History of illicit drug use within 1 year, positive drug screen, or unwillingness to abstain from illicit drugs/cannabinoids during the study.
* Use of tobacco or nicotine-containing products within 6 months prior to check-in.
* History of alcohol abuse or excessive alcohol consumption.
* History of non-suicidal self-injury within 5 years or unstable major depressive disorder/other severe psychiatric disorder within 2 years.
* Participation in another investigational drug study within 90 days (or 5 half-lives) prior to check-in.
* Previous exposure to AMG 691.
* Recent donation of blood, plasma, or platelets.
* Any participant considered unsuitable by the investigator or unwilling to comply with study restrictions.