Inclusion Criteria: Healthy Participants
Healthy participants between the ages of 18 and 55 years.
* Have body weight of at least 50 kilograms (kg) and body mass index (BMI) between 18 and 32 kilogram per square meter (kg/m²), inclusive.
Participants with Systemic Lupus Erythematosus (SLE)
* Are 18 to 75 years of age, inclusive.
* Have body weight between 45 and 145 kg, inclusive, and BMI between 18 and 35 kg/m², inclusive.
* Have a clinical diagnosis of SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria at least 6 months prior to screening.
Participants with Rheumatoid Arthritis (RA)
* Are 18 to 75 years of age, inclusive.
* Have body weight between 45 and 145 kg, inclusive, and BMI between 18 and 35 kg/m², inclusive.
* Have a diagnosis of adult-onset RA for at least 6 months prior to screening, as defined by the 2010 ACR/EULAR classification criteria
* Have Disease Activity Score in 28 joints (DAS28)-high-sensitivity C-reactive protein (hsCRP) greater than or equal to 4.4.
* Have positive test results for rheumatoid factor or anti-citrullinated peptide antibodies
* Have had a history of failure (an inadequate response, intolerance, or loss of response) to at least 2 advanced therapies (biological disease-modifying antirheumatic drug \[bDMARD\] or targeted synthetic DMARD \[tsDMARD\]) after failing a conventional synthetic DMARD (csDMARD).
Exclusion Criteria:
* Have known allergies to LY4298445, related compounds, or any components of the formulation
* Are individuals assigned female at birth (AFAB) who are lactating or have a positive pregnancy test at screening or Day -1.
* Have severe active lupus-associated renal disease (lupus nephritis) defined clinically and/or by
* urine protein/creatinine ratio greater than 200 milligrams per millimole (mg/mmol) (as an estimate of approximate proteinuria greater than 2 reams (g) per day) or
* an estimated glomerular filtration rate (eGFR) less than 40 milliliters per minute (mL/min)/1.73 m² at screening, as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) 2021.
* requiring hemodialysis within 6 months prior to screening
* Have active central nervous system lupus as defined by ACR nomenclature for neuropsychiatric lupus syndromes and as captured by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K); seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, and cerebrovascular accident, within 2 months prior to screening
* Have a Class 4 RA according to the ACR revised criteria
→
Inclusion Criteria: Healthy Participants
Healthy participants between the ages of 18 and 55 years.
* Have body weight of at least 50 kilograms (kg) and body mass index (BMI) between 18 and 32 kilogram per square meter (kg/m²), inclusive.
Participants with Systemic Lupus Erythematosus (SLE)
* Are 18 to 75 years of age, inclusive.
* Have body weight between 45 and 145 kg, inclusive, and BMI between 18 and 35 kg/m², inclusive.
* Have a clinical diagnosis of SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria at least 6 months prior to screening.
Participants with Rheumatoid Arthritis (RA)
* Are 18 to 75 years of age, inclusive.
* Have body weight between 45 and 145 kg, inclusive, and BMI between 18 and 35 kg/m², inclusive.
* Have a diagnosis of adult-onset RA for at least 6 months prior to screening, as defined by the 2010 ACR/EULAR classification criteria
* Have Disease Activity Score in 28 joints (DAS28)-high-sensitivity C-reactive protein (hsCRP) greater than or equal to 3.2.
* Have positive test results for rheumatoid factor or anti-citrullinated peptide antibodies
* Have had a history of failure (an inadequate response, intolerance, or loss of response) to at least 2 advanced therapies (biological disease-modifying antirheumatic drug \[bDMARD\] or targeted synthetic DMARD \[tsDMARD\]) after failing a conventional synthetic DMARD (csDMARD).
Exclusion Criteria:
* Have known allergies to LY4298445, related compounds, or any components of the formulation
* Are individuals assigned female at birth (AFAB) who are lactating or have a positive pregnancy test at screening or Day -1.
* Have severe active lupus-associated renal disease (lupus nephritis) defined clinically and/or by
* urine protein/creatinine ratio greater than 200 milligrams per millimole (mg/mmol) (as an estimate of approximate proteinuria greater than 2 reams (g) per day) or
* an estimated glomerular filtration rate (eGFR) less than 40 milliliters per minute (mL/min)/1.73 m² at screening, as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) 2021.
* requiring hemodialysis within 6 months prior to screening
* Have active central nervous system lupus as defined by ACR nomenclature for neuropsychiatric lupus syndromes and as captured by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K); seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, and cerebrovascular accident, within 2 months prior to screening
* Have a Class 4 RA according to the ACR revised criteria
Inclusion Criteria:
* Have a body mass index (BMI) ≥27.0 kilogram/square meter (kg/m²).
* Have a history of at least 1 self-reported unsuccessful dietary effort to lose body weight.
* Have a diagnosis of Type 2 Diabetes (T2D), with HbA1c ≥7% (≥53 mmol/mol) to ≤10% (86 mmol/mol) and are on stable treatment for T2D for at least 90 days prior to screening, consisting of:
* either diet/exercise alone or
* up to 3 oral antihyperglycemic medications (excluding dipeptidyl peptidase IV inhibitors (DPP-4i) or glucagon-like peptide-1 (GLP-1) receptor agonists (RA).
Exclusion Criteria:
* Have Type 1 Diabetes (T1D), history of ketoacidosis or hyperosmolar state/coma, or any other types of diabetes except T2D.
* Have a self-reported change in body weight \>5 kg (11 pounds) within 90 days prior to screening.
* Are currently receiving or planning to receive treatment for diabetic retinopathy and/or macular edema (for example, laster photocoagulation or intravitreal injections of anti-vascular endothelial growth factor inhibitors).
* Have family (first-degree relative) or personal history of medullary thyroid cancer (MTC) or multiple endocrine neoplasia 2 (MEN2) syndrome.
* Have had a history of chronic or acute pancreatitis.
→
Inclusion Criteria:
* Have a body mass index (BMI) ≥27.0 kilogram/square meter (kg/m²).
* Have a history of at least 1 self-reported unsuccessful dietary effort to lose body weight.
* Have a diagnosis of Type 2 Diabetes (T2D), with HbA1c ≥7% (≥53 mmol/mol) to ≤10% (86 mmol/mol) and are on stable treatment for T2D for at least 90 days prior to screening, consisting of:
* either diet/exercise alone or
* up to 3 oral antihyperglycemic medications (excluding dipeptidyl peptidase IV inhibitors (DPP-4i) or glucagon-like peptide-1 (GLP-1) receptor agonists (RA).
Exclusion Criteria:
* Have Type 1 Diabetes (T1D), history of ketoacidosis or hyperosmolar state/coma, or any other types of diabetes except T2D.
* Have a self-reported change in body weight \>5 kg (11 pounds) within 90 days prior to screening.
* Are currently receiving or planning to receive treatment for diabetic retinopathy and/or macular edema (for example, laser photocoagulation or intravitreal injections of anti-vascular endothelial growth factor inhibitors).
* Have family (first-degree relative) or personal history of medullary thyroid cancer (MTC) or multiple endocrine neoplasia 2 (MEN2) syndrome.
* Have had a history of chronic or acute pancreatitis.
Inclusion Criteria:
* Have one of the following solid tumor cancers:
* Dose Escalation: Ovarian (epithelial ovarian, primary peritoneal, and fallopian tube) cancer, endometrial cancer, cervical cancer, non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), pancreatic cancer, or colorectal cancer (CRC)
* Dose Optimization: Ovarian (epithelial ovarian, primary peritoneal, and fallopian tube) and endometrial cancer
* Dose Expansion: Low grade serous ovarian cancer, cervical cancer, NSCLC, and TNBC
Exclusion Criteria:
* Individual with known or suspected uncontrolled central nervous system (CNS) metastases
* Individual with history of carcinomatous meningitis
* Individual with active uncontrolled systemic bacterial, viral, fungal, or parasitic infection
* Individual with evidence of corneal keratopathy or history of corneal transplant
* Any serious unresolved toxicities from prior therapy
* Significant cardiovascular disease
* Prolongation of QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 milliseconds (ms)
* History of pneumonitis/interstitial lung disease
* Individuals who are pregnant, breastfeeding or plan to breastfeed during study or within 30 days of last dose of study intervention
→
Inclusion Criteria:
* Have one of the following solid tumor cancers:
* Dose Escalation: Ovarian (epithelial ovarian, primary peritoneal, and fallopian tube) cancer, endometrial cancer, cervical cancer, non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), pancreatic cancer, or colorectal cancer (CRC)
* Dose Optimization: Ovarian (epithelial ovarian, primary peritoneal, and fallopian tube) and endometrial cancer
* Dose Expansion: Low grade serous ovarian cancer, cervical cancer, NSCLC, TNBC, and high grade endometrioid cancer
Exclusion Criteria:
* Individual with known or suspected uncontrolled central nervous system (CNS) metastases
* Individual with history of carcinomatous meningitis
* Individual with active uncontrolled systemic bacterial, viral, fungal, or parasitic infection
* Individual with evidence of corneal keratopathy or history of corneal transplant
* Any serious unresolved toxicities from prior therapy
* Significant cardiovascular disease
* Prolongation of QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 milliseconds (ms)
* History of pneumonitis/interstitial lung disease
* Individuals who are pregnant, breastfeeding or plan to breastfeed during study or within 30 days of last dose of study intervention
Inclusion Criteria:
* Must have met all entry criteria for, and have completed, an acute, placebo-controlled clinical trial of LY2140023 (such as Study H8Y-MC-HBBM, or other acute, placebo-controlled LY2140023 studies if allowed by the protocols for those studies).
* Female patients of childbearing potential must agree to use a single, effective, medically acceptable method of birth control.
* Patients must be considered reliable and have a level of understanding sufficient to perform all tests and examinations required by the protocol.
* Patients must be able to understand the nature of the study and have given their own informed consent.
Exclusion Criteria:
* Are currently enrolled in, or discontinued within the last 30 days from a clinical trial involving an investigational product or nonapproved use of a drug or device (other than LY2140023), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
* Patients for whom treatment with olanzapine, risperidone, aripiprazole, quetiapine, or LY2140023, as specified in this protocol, is relatively or absolutely clinically contraindicated.
* Patients who have received treatment with clozapine at doses greater than 200 mg daily within 12 months prior to study enrollment, or who have received any clozapine at all during the month before study enrollment.
* Patients who require concomitant treatment with any other medication with primary central nervous system activity, other than those allowed in study protocol.
* Patients have risk of suicide.
* Patients diagnosed with substance dependence or substance abuse within the 6 months prior to study enrollment.
* Patients diagnosed with substance-induced psychosis within 7 days of study enrollment or at any time during the study.
* Female patients who are pregnant, nursing, lactating or who intend to become pregnant within 30 days of completing the study.
* Have known glaucoma.
* Have a history of some types of seizures.
* Have seizure liability inconsistent with the exclusion criteria of the completed acute feeder study.
* Patients who have had electroconvulsive therapy (ECT) within 3 months of study enrollment or who will have ECT at any time during the study.
* Patients with known Human Immunodeficiency Virus positive (HIV+) status.
* Patients have a serious disease, such as recent stroke, heart, liver, kidney, lung or blood diseases
* Patients with Parkinson's disease
* Are incapable of participating in the study or are unwilling to engage in a meaningful way as study participants.
→
Inclusion Criteria:
* Must have met all entry criteria for, and have completed, an acute, placebo-controlled clinical trial of LY2140023 (such as Study H8Y-MC-HBBM, or other acute, placebo-controlled LY2140023 studies if allowed by the protocols for those studies).
* Female participants of childbearing potential must agree to use a single, effective, medically acceptable method of birth control.
* Participants must be considered reliable and have a level of understanding sufficient to perform all tests and examinations required by the protocol.
* Participants must be able to understand the nature of the study and have given their own informed consent.
Exclusion Criteria:
* Are currently enrolled in, or discontinued within the last 30 days from a clinical trial involving an investigational product or nonapproved use of a drug or device (other than LY2140023), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
* Participants for whom treatment with olanzapine, risperidone, aripiprazole, quetiapine, or LY2140023, as specified in this protocol, is relatively or absolutely clinically contraindicated.
* Participants who have received treatment with clozapine at doses greater than 200 mg daily within 12 months prior to study enrollment, or who have received any clozapine at all during the month before study enrollment.
* Participants who require concomitant treatment with any other medication with primary central nervous system activity, other than those allowed in study protocol.
* Participants have risk of suicide.
* Participants diagnosed with substance dependence or substance abuse within the 6 months prior to study enrollment.
* Participants diagnosed with substance-induced psychosis within 7 days of study enrollment or at any time during the study.
* Female participants who are pregnant, nursing, lactating or who intend to become pregnant within 30 days of completing the study.
* Have known glaucoma.
* Have a history of some types of seizures.
* Have seizure liability inconsistent with the exclusion criteria of the completed acute feeder study.
* Participants who have had electroconvulsive therapy (ECT) within 3 months of study enrollment or who will have ECT at any time during the study.
* Participants with known Human Immunodeficiency Virus positive (HIV+) status.
* Participants have a serious disease, such as recent stroke, heart, liver, kidney, lung or blood diseases
* Participants with Parkinson's disease
* Are incapable of participating in the study or are unwilling to engage in a meaningful way as study participants.
Inclusion Criteria:
* Participants are clinically diagnosed with schizophrenia
* Female participants of childbearing potential must test negative for pregnancy at study entry and agree to use a single, effective, medically acceptable method of birth control
* New participants must require initiation of or modification to current antipsychotic treatment, as indicated by their present clinical psychiatric status and/or treatment tolerability as outpatients. Criterion does not apply to participants rolling over from a feeder study (NCT01328093 and NCT01452919)
* Participants must be considered reliable and have a level of understanding sufficient to perform all tests and examinations required by the protocol, and be willing to perform all study procedures
* Participants must be able to understand the nature of the study and have given their own informed consent
Exclusion Criteria:
* Are currently enrolled in, or discontinued within the last 60 days from, a clinical trial involving an investigational product (IP) or nonapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study, except for participants who are rolling over from a feeder study (NCT01328093 and NCT01452919) who will have completed a clinical trial of pomaglumetad methionil
* Have any other current psychiatric diagnoses in addition to schizophrenia
* Have previously completed or withdrawn from this study, or any other study investigating pomaglumetad methionil or any predecessor molecules with glutamatergic activity, except for participants who are rolling over from a feeder study (NCT01328093 and NCT01452919) who will have completed a clinical trial of pomaglumetad methionil
* Participants who have received an adequate treatment trial, in the opinion of the investigator, with clozapine at doses greater than 200 mg daily within 12 months prior to study entry, or who have received any clozapine at all during the month before study entry
* Participants who have a history of an inadequate clinical response to antipsychotic treatment for schizophrenia
* Participants who, for any reason, are considered to be a danger to themselves, or who are actively exhibiting suicidal behaviors
* Female participants who are pregnant, nursing, or who intend to become pregnant within 30 days of completing the study
* Have known, uncorrected, narrow-angle glaucoma
* Participants with current or a history of seizure disorder, leucopenia, uncontrolled diabetes, certain diseases of the liver, renal insufficiency, uncontrolled thyroid condition or other serious or unstable illnesses
* Participants who have had electroconvulsive therapy (ECT) within 3 months of study entry or who will have ECT at any time during the study
* Participants with known medical history of Human Immunodeficiency Virus (HIV) positive status
* Participants who test positive for (1) Hepatitis C virus antibody or (2) Hepatitis B surface antigen (HBsAg) with or without positive Hepatitis B core total antibody
* Participants with a corrected QT interval (Bazett's; QTcB) \>450 msec (male) or \>470 msec (female) at study entry
→
Inclusion Criteria:
* Participants are clinically diagnosed with schizophrenia
* Female participants of childbearing potential must test negative for pregnancy at study entry and agree to use a single, effective, medically acceptable method of birth control
* New participants must require initiation of or modification to current antipsychotic treatment, as indicated by their present clinical psychiatric status and/or treatment tolerability as outpatients. Criterion does not apply to participants rolling over from a feeder study (NCT01328093 and NCT01452919)
* Participants must be considered reliable and have a level of understanding sufficient to perform all tests and examinations required by the protocol, and be willing to perform all study procedures
* Participants must be able to understand the nature of the study and have given their own informed consent
Exclusion Criteria:
* Are currently enrolled in, or discontinued within the last 60 days from, a clinical trial involving an investigational product (IP) or nonapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study, except for participants who are rolling over from a feeder study (NCT01328093 and NCT01452919) who will have completed a clinical trial of pomaglumetad methionil
* Have any other current psychiatric diagnoses in addition to schizophrenia
* Have previously completed or withdrawn from this study, or any other study investigating pomaglumetad methionil or any predecessor molecules with glutamatergic activity, except for participants who are rolling over from a feeder study (NCT01328093 and NCT01452919) who will have completed a clinical trial of pomaglumetad methionil
* Participants who have received an adequate treatment trial, in the opinion of the investigator, with clozapine at doses greater than 200 mg daily within 12 months prior to study entry, or who have received any clozapine at all during the month before study entry
* Participants who have a history of an inadequate clinical response to antipsychotic treatment for schizophrenia
* Participants who, for any reason, are considered to be a danger to themselves, or who are actively exhibiting suicidal behaviors
* Female participants who are pregnant, nursing, or who intend to become pregnant within 30 days of completing the study
* Have known, uncorrected, narrow-angle glaucoma
* Participants with current or a history of seizure disorder, leucopenia, uncontrolled diabetes, certain diseases of the liver, renal insufficiency, uncontrolled thyroid condition or other serious or unstable illnesses
* Participants who have had electroconvulsive therapy (ECT) within 3 months of study entry or who will have ECT at any time during the study
* Participants with known medical history of Human Immunodeficiency Virus (HIV) positive status
* Participants who test positive for (1) Hepatitis C virus antibody or (2) Hepatitis B surface antigen (HBsAg) with or without positive Hepatitis B core total antibody
* Participants with a corrected QT interval (Bazett's; QTcB) \>450 milliseconds (msec) (male) or \>470 msec (female) at study entry
Inclusion Criteria:
* Diagnosis of schizophrenia as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR; APA 2000) (Disorganized, 295.10; Catatonic, 295.20; Paranoid 295.30; or Undifferentiated, 295.90) and confirmed by the Structured Clinical Interview for DSM-IV-TR (SCID).
* Non pregnant female patients who agree to use acceptable birth control
* At entry to the study must be considered moderately ill in the opinion of the investigator
* Willing to participate in a minimum of 3 weeks of inpatient hospitalization and this must be appropriate for the patient in the clinical judgment of the investigator.
* 1 year history of Schizophrenia prior to entering the study
* At study entry patients with a history of antipsychotic treatment must have a lifetime history of at least one hospitalization for the treatment of schizophrenia, not including the hospitalization required for study. Patients who have never taken antipsychotic treatment may enter the study even without a history of hospitalization.
* At study entry patients with a history of antipsychotic treatment must have a history of at least one episode of illness exacerbation requiring an intensification of treatment intervention or care in the last 2 years, not including the present episode of illness. Patients who have never taken antipsychotic treatment may enter the study without a past history of illness exacerbation and intensification of treatment in the last 2 years.
* At study entry patients must have experienced an exacerbation of illness within the 2 weeks prior to entering the study, leading to an intensification of psychiatric care in the opinion of the investigator. If exacerbation occurs in patients who are presently hospitalized, the patient must not have been hospitalized longer than 60 days at entry of the study
Exclusion Criteria:
* Participated in any clinical trial with any pharmacological treatment intervention for which they received a study-related medication in the 6 months prior to visit 1
* Previously completed or withdrawn from this study, or any other study investigating LY2140023 or any predecessor molecules with glutamatergic activity.
* Treatment with clozapine at doses greater than 200 mg daily within 12 months prior to entering the study, or who have received any clozapine at all during the month before entering the study
* Patients currently receiving treatment (within 1 dosing interval, minimum of 4 weeks, prior entering the study) with a depot formulation of an antipsychotic medication.
* Patients who are currently suicidal.
* Females who are pregnant, nursing, or who intend to become pregnant within 30 days of completing the study.
* Patients with uncorrected narrow-angle glaucoma, uncontrolled diabetes, certain diseases of the liver, renal insufficiency, uncontrolled thyroid condition or other serious or unstable illnesses
* Have a history of one or more seizures, except for those who experienced a single simple febrile seizure between ages 6 months and 5 years
* Patients are excluded if their, biological father, mother, brother, sister, or child has a history of idiopathic epilepsy.
* Within 1 year of study enrollment, patients have a history of central nervous system infection, uncontrolled migraine, transient ischemic attack (TIA), or head trauma with loss of consciousness or a post-concussive
* Patients are excluded if they have a lifetime history of any of the following:
* head trauma, stroke, or CNS infection with persistent neurological deficit (focal or diffuse);
* brain surgery;
* an electroencephalogram with paroxysmal (epileptiform) activity, or
* brain structural lesion, including developmental abnormalities, as determined by examination or previous neuroimaging studies that are consistent with a diagnosable neurological disease or syndrome.
* Electroconvulsive therapy (ECT) within 3 months of entering the study or who will have ECT at any time during the study.
* Leukopenia
* Medical history of Human Immunodeficiency Virus positive (HIV+) status.
* Higher than normal blood prolactin levels
* Certain electrocardiogram results
→
Inclusion Criteria:
* Diagnosis of schizophrenia as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR; APA 2000) (Disorganized, 295.10; Catatonic, 295.20; Paranoid 295.30; or Undifferentiated, 295.90) and confirmed by the Structured Clinical Interview for DSM-IV-TR (SCID).
* Non-pregnant female patients who agree to use acceptable birth control.
* At entry to the study, must be considered at least moderately ill in the opinion of the investigator.
* Willing to participate in a minimum of 3 weeks of inpatient hospitalization and this must be appropriate for the patient in the clinical judgment of the investigator.
* 1 year history of schizophrenia prior to entering the study.
* At study entry, patients with a history of antipsychotic treatment must have a lifetime history of at least one hospitalization for the treatment of schizophrenia, not including the hospitalization required for study. Patients who have never taken antipsychotic treatment may enter the study even without a history of hospitalization.
* At study entry, patients with a history of antipsychotic treatment must have a history of at least one episode of illness exacerbation requiring an intensification of treatment intervention or care in the last 2 years, not including the present episode of illness. Patients who have never taken antipsychotic treatment may enter the study without a past history of illness exacerbation and intensification of treatment in the last 2 years.
* At study entry, patients must have experienced an exacerbation of illness within the 2 weeks prior to entering the study, leading to an intensification of psychiatric care in the opinion of the investigator. If exacerbation occurs in patients who are presently hospitalized, the patient must not have been hospitalized longer than 60 days at entry of the study.
Exclusion Criteria:
* Participated in any clinical trial with any pharmacological treatment intervention for which they received a study-related medication in the 6 months prior to visit 1.
* Previously completed or withdrawn from this study, or any other study investigating LY2140023 or any predecessor molecules with glutamatergic activity.
* Treatment with clozapine at doses greater than 200 mg daily within 12 months prior to entering the study, or who have received any clozapine at all during the month before entering the study.
* Patients currently receiving treatment (within 1 dosing interval, minimum of 4 weeks, prior entering the study) with a depot formulation of an antipsychotic medication.
* Patients who are currently suicidal.
* Females who are pregnant, nursing, or who intend to become pregnant within 30 days of completing the study.
* Patients with uncorrected narrow-angle glaucoma, uncontrolled diabetes, certain diseases of the liver, renal insufficiency, uncontrolled thyroid condition or other serious or unstable illnesses.
* Have a history of one or more seizures, except for those who experienced a single simple febrile seizure between ages 6 months and 5 years.
* Patients are excluded if their biological father, mother, brother, sister, or child has a history of idiopathic epilepsy.
* Within 1 year of study enrollment, patients have a history of central nervous system infection, uncontrolled migraine, transient ischemic attack (TIA), or head trauma with loss of consciousness or a post-concussive.
* Patients are excluded if they have a lifetime history of any of the following:
* head trauma, stroke, or central nervous system (CNS) infection with persistent neurological deficit (focal or diffuse);
* brain surgery;
* an electroencephalogram with paroxysmal (epileptiform) activity, or
* brain structural lesion, including developmental abnormalities, as determined by examination or previous neuroimaging studies that are consistent with a diagnosable neurological disease or syndrome.
* Electroconvulsive therapy (ECT) within 3 months of entering the study or who will have ECT at any time during the study.
* Leukopenia.
* Medical history of human immunodeficiency virus positive (HIV+) status.
* Higher than normal blood prolactin levels.
* Certain electrocardiogram results.
Some Inclusion Criteria:
* Patients must have a diagnosis of Schizophrenia as defined in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (Disorganized, 295.10; Catatonic, 295.20; Paranoid, 295.30; Residual, 295.60; or Undifferentiated, 295.90) and confirmed by the Structured Clinical Interview for DSM-IV (SCID).
* Patients must meet the following psychopathologic severity criteria at Visit 1: Brief Psychiatric Rating Scale (BPRS) total score, extracted from the Positive and Negative Syndrome Scale (PANSS), of at least 45 (18-item version, in which 1 indicates "absent" and 7 indicates "severe"). In addition, item scores of at least 4 (moderate) will be required on 2 of the following BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and/or unusual thought content.
* Patients must receive a rating of 4 (moderately ill) or greater on the Clinical Global Impression-Severity (CGI-S) scale at Visit 1.
* Patients in whom, in the opinion of the investigator, a switch to another antipsychotic medication or initiation of an antipsychotic medication is acutely indicated.
Some Exclusion Criteria:
* Patients in whom treatment with olanzapine or placebo is relatively or absolutely clinically contraindicated.
* Patients who have a history of inadequate response to an adequate treatment trial with olanzapine, in the opinion of the investigator.
* Patients who have received treatment with olanzapine within 6 weeks prior to Visit 1.
* Patients who have received treatment with clozapine at doses greater than 200 mg daily within 12 months prior to Visit 1, or who have received any clozapine at all during the month before Visit 1.
* Patients who have a history of an inadequate response, in the opinion of the investigator, to 2 or more adequate antipsychotic medication trials of at least 8 weeks duration in the past 12 months prior to Visit 1.
* Patients with acute, serious, or unstable medical conditions, including (but not limited to) inadequately controlled diabetes (hemoglobin A1c (HbA1c) 8%), severe hypertriglyceridemia (fasting triglycerides 5.6 mmol/L, recent cerebrovascular accidents, serious acute systemic infection or immunologic disease, unstable cardiovascular disorders (including ischemic heart disease), malnutrition, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic, or hematologic diseases.
→
Some Inclusion Criteria:
* Participants must have a diagnosis of Schizophrenia as defined in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (Disorganized, 295.10; Catatonic, 295.20; Paranoid, 295.30; Residual, 295.60; or Undifferentiated, 295.90) and confirmed by the Structured Clinical Interview for DSM-IV (SCID).
* Participants must meet the following psychopathologic severity criteria at Visit 1: Brief Psychiatric Rating Scale (BPRS) total score, extracted from the Positive and Negative Syndrome Scale (PANSS), of at least 45 (18-item version, in which 1 indicates "absent" and 7 indicates "severe"). In addition, item scores of at least 4 (moderate) will be required on 2 of the following BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and/or unusual thought content.
* Participants must receive a rating of 4 (moderately ill) or greater on the Clinical Global Impression-Severity (CGI-S) scale at Visit 1.
* Participants in whom, in the opinion of the investigator, a switch to another antipsychotic medication or initiation of an antipsychotic medication is acutely indicated.
Some Exclusion Criteria:
* Participants in whom treatment with olanzapine or placebo is relatively or absolutely clinically contraindicated.
* Participants who have a history of inadequate response to an adequate treatment trial with olanzapine, in the opinion of the investigator.
* Participants who have received treatment with olanzapine within 6 weeks prior to Visit 1.
* Participants who have received treatment with clozapine at doses greater than 200 mg daily within 12 months prior to Visit 1, or who have received any clozapine at all during the month before Visit 1.
* Participants who have a history of an inadequate response, in the opinion of the investigator, to 2 or more adequate antipsychotic medication trials of at least 8 weeks duration in the past 12 months prior to Visit 1.
* Participants with acute, serious, or unstable medical conditions, including (but not limited to) inadequately controlled diabetes (hemoglobin A1c (HbA1c) 8%), severe hypertriglyceridemia (fasting triglycerides 5.6 millimoles per litre (mmol/L), recent cerebrovascular accidents, serious acute systemic infection or immunologic disease, unstable cardiovascular disorders (including ischemic heart disease), malnutrition, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic, or hematologic diseases.
Inclusion Criteria:
* are overtly healthy males or females, as determined by medical history and physical examination
* female subjects of childbearing potential, who test negative for pregnancy at screening. Male subjects/female subjects of childbearing potential/female subjects who have been sterilized by tubal ligation and their partners will be required to use a condom (male condom or female condom) used in conjunction with spermicidal gel, foam, cream, film, or suppository from the time of screening (female subjects) or dosing (male subjects) until 3 months after the last dose of investigational product. Male subjects with female partners of childbearing potential and female subjects of childbearing potential will be requested to use an additional highly effective form of contraception from the first dosing occasion until 3 months after the last dose of investigational product. The additional method of contraception can be any of the following: diaphragm or cervical vault cap used in conjunction with spermicidal gel, foam, cream, film, or suppository; male sterilization, with the appropriate post vasectomy documentation of the absence of sperm in the ejaculate, or for female subjects the vasectomized male partner should be the sole partner for that subject; true abstinence (this must be due to subject's lifestyle choice; placement of an effective hormonal intrauterine device (IUD) (i.e. Mirena Coil) (steel or copper IUDs are not acceptable); or established use of oral, injected, or implanted hormonal methods of contraception
* female subjects who are of non childbearing potential i.e. post menopausal or permanently sterile following hysterectomy, bilateral salpingectomy or confirmed tubal occlusion (not tubal ligation). Postmenopausal is defined as at least 1 year post cessation of menses (without an alternative medical cause) with follicle stimulating hormone (FSH) ≥40 mIU/mL
* have a body mass index (BMI) of 19 to 32 kg/m\^2, inclusive, at the time of screening
* have clinical laboratory test results within normal reference range for the population or investigator site, or results with acceptable deviations that are judged to be not clinically significant by the investigator
* have venous access sufficient to allow for blood sampling
* are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures
* have given written informed consent approved by Lilly and the chosen ethical review board (ERB)
* are willing to adhere to dietary requirements
Exclusion Criteria:
* are currently enrolled in, have completed or discontinued within the last 90 days from, a clinical trial involving an investigational product; or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
* have known allergies to LY2140023, LY404039, ammonium chloride, sodium bicarbonate, related compounds, or any components of the formulation
* are persons who have previously received the investigational product in this study, withdrawn from this study or any other study investigating LY2140023 or LY404039
* have an abnormality in the 12-lead electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study
* have an abnormality in the serum chemistry of calcium, sodium, magnesium, or potassium, that, in the opinion of the investigator, increases the risks associated with participating in the study
* have an abnormal supine and standing blood pressure or pulse rate, as determined by the investigator
* have a history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a risk when taking the study medication; or of interfering with the interpretation of data
* have evidence of significant active neuropsychiatric disease (for example, manic depressive illness, schizophrenia, depression)
* have increased risk of seizures based on a history of:
* one or more seizures (except for a single simple febrile seizure \[lacking focality and lasting less than 15 minutes, not associated with a central nervous system (CNS) infection or severe metabolic disturbance\] as a child between ages 6 months to 5 years)
* head trauma with loss of consciousness or a post concussive syndrome within 1 year or lifetime history of head trauma with persistent neurological deficit (focal or diffuse)
* CNS infection, uncontrolled migraine or transient ischemic attack (TIA) within 1 year; stroke with persistent neurological deficit (focal or diffuse), uncontrolled migraine is defined as migraine attacks that produce headache lasting up to 72 hours and are often accompanied by associated symptoms (nausea, photophobia, and phonophobia) that impair well-being and disrupt social functioning. TIA is defined as "mini-stroke" caused by temporary disturbance of blood supply to an area of the brain, which results in a sudden, brief decrease in brain function
* CNS infection with persistent neurological deficit (focal or diffuse)
* brain surgery
* electroencephalogram (EEG) with paroxysmal (epileptiform) activity (isolated spikes waves, repetitive bursts of sharp waves, paroxysmal activity, frank seizures, spike-wave complexes, or sharp-slow wave complexes, or as locally defined)
* brain structural lesion, including developmental abnormalities, as determined by examination or imaging studies (does not include hydrocephalus unless treated by shunt or resulting in neurological deficits)
* show evidence of known substance dependence or abuse within 6 months prior to the study (according to Diagnostic and Statistical Manual of Mental Disorders \[DSM IV\] diagnosis), or regularly use known drugs of abuse and/or show positive findings on urinary drug screening
* show evidence of human immunodeficiency virus (HIV) infection and/or positive human HIV antibodies
* show evidence of hepatitis C and/or positive hepatitis C antibody
* show evidence of hepatitis B and/or positive hepatitis B surface antigen
* are women with a positive pregnancy test or women who are lactating
* intend to use over the counter (excluding most vitamin/mineral supplements but including herbal remedies/health supplements or prescription medication (excluding paracetamol, oral contraceptives and hormone replacement therapy) within 14 days prior to dosing of LY2140023. If this situation arises, inclusion of an otherwise suitable subject may be at the discretion of the investigator in consultation with the Lilly Clinical Pharmacologist (CP) or designee
* have donated blood of more than 500 mL within 3 months prior to screening
* have an average weekly alcohol intake that exceeds 28 units per week (males up to age 65) and 21 units per week (females), or are unwilling to stop alcohol consumption for the duration of the study (1 unit equals 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits)
* have a clinical significant abnormality in the neurological examination
* subjects judged prior to randomization to be at suicidal risk by the investigator
* subjects who are unwilling to refrain from tobacco or nicotine containing products while in the Clinical Research Unit (CRU) or are unable to abide by the CRU restrictions
* history of, in the opinion of the investigator, excessive methylxanthine use within previous 6 months, such as \>6 cups of coffee (or equivalent) per day
* show evidence of active renal disease (for example, diabetic renal disease, polycystic kidney disease) or creatinine clearance (CrCL) less than 80 mL/min (as calculated by the Cockcroft Gault equation) Men: \[(140 - age) \* (weight in kg) \* 1.23\] / (serum creatinine in µmol/L). Women: \[(140 - age) \* (weight in kg) \* 1.04\] / (serum creatinine in µmol/L)
* show evidence of pruritus or skin exfoliation
* have an eosinophil count \>1.5 x 109/L
* have creatine kinase (CK) \>5 x upper limit of normal (ULN)
→
Inclusion Criteria:
* are overtly healthy males or females, as determined by medical history and physical examination
* female subjects of childbearing potential, who test negative for pregnancy at screening. Male subjects/female subjects of childbearing potential/female subjects who have been sterilized by tubal ligation and their partners will be required to use a condom (male condom or female condom) used in conjunction with spermicidal gel, foam, cream, film, or suppository from the time of screening (female subjects) or dosing (male subjects) until 3 months after the last dose of investigational product. Male subjects with female partners of childbearing potential and female subjects of childbearing potential will be requested to use an additional highly effective form of contraception from the first dosing occasion until 3 months after the last dose of investigational product. The additional method of contraception can be any of the following: diaphragm or cervical vault cap used in conjunction with spermicidal gel, foam, cream, film, or suppository; male sterilization, with the appropriate post vasectomy documentation of the absence of sperm in the ejaculate, or for female subjects the vasectomized male partner should be the sole partner for that subject; true abstinence (this must be due to subject's lifestyle choice; placement of an effective hormonal intrauterine device (IUD) (that is, Mirena Coil) (steel or copper IUDs are not acceptable); or established use of oral, injected, or implanted hormonal methods of contraception
* female subjects who are of non childbearing potential, that is post menopausal or permanently sterile following hysterectomy, bilateral salpingectomy or confirmed tubal occlusion (not tubal ligation). Postmenopausal is defined as at least 1 year post cessation of menses (without an alternative medical cause) with follicle stimulating hormone (FSH) ≥40 milli-international units per milliliter (mIU/mL)
* have a body mass index (BMI) of 19 to 32 kilogram per square meter (kg/m²), inclusive, at the time of screening
* have clinical laboratory test results within normal reference range for the population or investigator site, or results with acceptable deviations that are judged to be not clinically significant by the investigator
* have venous access sufficient to allow for blood sampling
* are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures
* have given written informed consent approved by Lilly and the chosen ethical review board (ERB)
* are willing to adhere to dietary requirements
Exclusion Criteria:
* are currently enrolled in, have completed or discontinued within the last 90 days from, a clinical trial involving an investigational product; or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
* have known allergies to LY2140023, LY404039, ammonium chloride, sodium bicarbonate, related compounds, or any components of the formulation
* are persons who have previously received the investigational product in this study, withdrawn from this study or any other study investigating LY2140023 or LY404039
* have an abnormality in the 12-lead electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study
* have an abnormality in the serum chemistry of calcium, sodium, magnesium, or potassium, that, in the opinion of the investigator, increases the risks associated with participating in the study
* have an abnormal supine and standing blood pressure or pulse rate, as determined by the investigator
* have a history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a risk when taking the study medication; or of interfering with the interpretation of data
* have evidence of significant active neuropsychiatric disease (for example, manic depressive illness, schizophrenia, depression)
* have increased risk of seizures based on a history of:
* one or more seizures (except for a single simple febrile seizure \[lacking focality and lasting less than 15 minutes, not associated with a central nervous system (CNS) infection or severe metabolic disturbance\] as a child between ages 6 months to 5 years)
* head trauma with loss of consciousness or a post concussive syndrome within 1 year or lifetime history of head trauma with persistent neurological deficit (focal or diffuse)
* CNS infection, uncontrolled migraine or transient ischemic attack (TIA) within 1 year; stroke with persistent neurological deficit (focal or diffuse), uncontrolled migraine is defined as migraine attacks that produce headache lasting up to 72 hours and are often accompanied by associated symptoms (nausea, photophobia, and phonophobia) that impair well-being and disrupt social functioning. TIA is defined as "mini-stroke" caused by temporary disturbance of blood supply to an area of the brain, which results in a sudden, brief decrease in brain function
* CNS infection with persistent neurological deficit (focal or diffuse)
* brain surgery
* electroencephalogram (EEG) with paroxysmal (epileptiform) activity (isolated spikes waves, repetitive bursts of sharp waves, paroxysmal activity, frank seizures, spike-wave complexes, or sharp-slow wave complexes, or as locally defined)
* brain structural lesion, including developmental abnormalities, as determined by examination or imaging studies (does not include hydrocephalus unless treated by shunt or resulting in neurological deficits)
* show evidence of known substance dependence or abuse within 6 months prior to the study (according to Diagnostic and Statistical Manual of Mental Disorders \[DSM IV\] diagnosis), or regularly use known drugs of abuse and/or show positive findings on urinary drug screening
* show evidence of human immunodeficiency virus (HIV) infection and/or positive human HIV antibodies
* show evidence of hepatitis C and/or positive hepatitis C antibody
* show evidence of hepatitis B and/or positive hepatitis B surface antigen
* are women with a positive pregnancy test or women who are lactating
* intend to use over the counter (excluding most vitamin/mineral supplements but including herbal remedies/health supplements or prescription medication (excluding paracetamol, oral contraceptives and hormone replacement therapy) within 14 days prior to dosing of LY2140023. If this situation arises, inclusion of an otherwise suitable subject may be at the discretion of the investigator in consultation with the Lilly Clinical Pharmacologist (CP) or designee
* have donated blood of more than 500 milliliter (mL) within 3 months prior to screening
* have an average weekly alcohol intake that exceeds 28 units per week (males up to age 65) and 21 units per week (females), or are unwilling to stop alcohol consumption for the duration of the study (1 unit equals 12 \[ounce\] oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits)
* have a clinical significant abnormality in the neurological examination
* subjects judged prior to randomization to be at suicidal risk by the investigator
* subjects who are unwilling to refrain from tobacco or nicotine containing products while in the Clinical Research Unit (CRU) or are unable to abide by the CRU restrictions
* history of, in the opinion of the investigator, excessive methylxanthine use within previous 6 months, such as \>6 cups of coffee (or equivalent) per day
* show evidence of active renal disease (for example, diabetic renal disease, polycystic kidney disease) or creatinine clearance (CrCL) less than 80 milliliter per minute (mL/min) (as calculated by the Cockcroft Gault equation) Men: \[(140 - age) \* (weight in kg) \* 1.23\] / (serum creatinine in micromoles per liter \[µmol/L\]). Women: \[(140 - age) \* (weight in kg) \* 1.04\] / (serum creatinine in µmol/L)
* show evidence of pruritus or skin exfoliation
* have an eosinophil count \>1.5 x 10\^9/liter (L)
* have creatine kinase (CK) \>5 x upper limit of normal (ULN)
Inclusion Criteria:
* have a visual analog scale (VAS) pain value \>40 and \<95 at screening and prerandomization screening.
* have a history of daily pain for at least 12 weeks based on participant report or medical history
* have a value of ≤30 on the pain catastrophizing scale
* have a body mass index \<40 kilogram/square meter (kg/m²) (inclusive)
* are willing to maintain a consistent regimen of any ongoing nonpharmacologic pain-relieving therapies (for example, physical therapy) and will not start any new nonpharmacologic pain-relieving therapies during study participation.
* are willing to discontinue all medications taken for chronic pain conditions, except rescue medication for the duration of the study
Exclusion Criteria:
* have second- or third-degree atrioventricular (AV) heart block or AV dissociation or history of ventricular tachycardia
* have had a procedure within the past 6 months intended to produce permanent sensory loss in the target area of interest (for example, ablation techniques)
* have surgery planned during the study for any reason, related or not to the disease state under evaluation.
* have, in the judgment of the investigator, an acute, serious, or unstable medical condition or a history or presence of any other medical illness that would preclude study participation.
* have had cancer within 2 years of baseline, except for cutaneous basal cell or squamous cell carcinoma resolved by excision.
* have fibromyalgia
* have substance use disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders (5th edition; DSM-5; American Psychiatric Association)
* have any clinically important abnormality at screening, as determined by investigator, in physical or neurological examination, vital signs, electrocardiogram (ECG), or clinical laboratory test results that could be detrimental to the participant or could compromise the study.
* have a positive human immunodeficiency virus (HIV) test result at screening
* have a history of alcohol, illicit drug, analgesic or narcotic use disorder within 2 years prior to screening.
→
Inclusion Criteria:
* have a visual analog scale (VAS) pain value ≥40 and \<95 at screening and prerandomization screening.
* have a history of daily pain for at least 12 weeks based on participant report or medical history
* have a value of ≤30 on the pain catastrophizing scale
* are willing to maintain a consistent regimen of any ongoing nonpharmacologic pain-relieving therapies (for example, physical therapy) and/or nutritional supplements and will not start any new nonpharmacologic pain-relieving therapies and/or nutritional supplements during study participation
* are willing to discontinue all medications taken for chronic pain conditions, except rescue medication for the duration of the study
Exclusion Criteria:
* have second- or third-degree atrioventricular (AV) heart block or AV dissociation or history of ventricular tachycardia
* have had a procedure within the past 6 months intended to produce permanent sensory loss in the target area of interest (for example, ablation techniques)
* have surgery planned during the study for any reason, related or not to the disease state under evaluation.
* have, in the judgment of the investigator, an acute, serious, or unstable medical condition or a history or presence of any other medical illness that would preclude study participation.
* have had cancer within 2 years of baseline, except for cutaneous basal cell or squamous cell carcinoma resolved by excision.
* have fibromyalgia
* have any clinically important abnormality at screening, as determined by investigator, in physical or neurological examination, vital signs, electrocardiogram (ECG), or clinical laboratory test results that could be detrimental to the participant or could compromise the study.
* have a positive human immunodeficiency virus (HIV) test result at screening
* have a history of alcohol, illicit drug, analgesic or narcotic use disorder within 2 years prior to screening.
Inclusion Criteria:
* Subjects aged ≥ 18 years with documented diagnosis of WM with the definition of measurable disease
* Subjects who are able to comply with the study protocol.
* Subjects with relapsed or refractory WM who have received at least one prior line of therapy.
* Must have received prior treatment with covalent BTK inhibitor or have declined such treatment.
* Prior autologous stem cell transplant is permitted if completed ≥ 100 days prior to treatment.
* Prior allogeneic transplants are not permitted.
* Subjects must have an indication for treatment per 2nd International Workshop on WM35
* ECOG Performance Status ≤ 2
* Adequate organ function as defined as:
* Hematologic:
* Absolute neutrophil count ≥ 1000/mm3 independent of G-CSF support, unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case ANC of 750 cells/mm3 (0.75 x 10\^9/L) is permissible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
* Platelet count ≥75,000 cells/mm3 (≥75 x 10\^9/L) independent of transfusion support unless there is documented bone marrow involvement in which case platelet count of 50,000 cells/mm3 (50 x 10\^9/L) is permissible. Patients must be responsive to transfusion support if given for thrombocytopenia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
* Hemoglobin of ≥ 8.5 g/dL (≥ 85 g/L) independent of transfusion support unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case hemoglobin of 7 g/dL (70 g/L) is permissible. Patients must be responsive to transfusion support if given for anemia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
* Coagulation: Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN.
* Hepatic:
* Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN) or ≤3 x ULN with document liver involvement and/ or Gilbert's disease
* AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
* Participants with liver metastases will be allowed to enroll with AST and ALT levels ≤ 5 x ULN.
* Renal:
* Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula.
* Participants must adhere to the following sex and contraceptive/barrier requirements:
* If participant is of childbearing potential, they must have a negative pregnancy test
* For participants of non-childbearing potential: The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
* \< 50 years of age:
* Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
* Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
--≥ 50 years of age:
* Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
* Had radiation-induced menopause with last menses \>1 year ago; or
* Had chemotherapy-induced menopause with last menses \>1 year ago
* Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
* Participants of childbearing potential and participants with a sexual partner of childbearing potential must agree to use a highly effective method of contraception and lactation requirements as described in Sections 5.4.1 and 5.4.2.
* Able to swallow oral tablets.
* Clinically significant adverse effects from any prior oncologic treatment (e.g. prior surgery, radiotherapy, or other antineoplastic therapy) must have recovered to grade 1 or have been determined to be clinically stable per the Investigator.
* Subject or their legal representative is able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
Exclusion Criteria:
* History of transformation of indolent disease to DLBCL
* Active or history of CNS lymphoma or leptomeningeal infiltration
* Prior treatment with a non-covalent BTK inhibitor
* Prior treatment with CD20-directed bispecific antibody therapy
* Receiving other investigational agents.
* Receipt of a live, attenuated vaccine within 4 weeks before first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study
* Patients must not receive live, attenuated vaccines (e.g., FluMistâ) while receiving study treatment or after the last dose until B-cell recovery to the normal ranges.
* Inactivated influenza vaccination should be given during the influenza season only.
* An approved coronavirus disease 2019 (COVID-19) vaccine (messenger RNA \[mRNA\], inactivated virus, and replication deficient viral vector vaccines) is allowed, as these are not considered live vaccines.
* Receipt of systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) with the exception of corticosteroid treatment £ 10 mg/day prednisone or equivalent within 2 weeks prior to the first dose of mosunetuzumab
* Patients who received acute, low-dose, systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea or B-symptoms) may be enrolled in the study if deemed appropriate by the investigator.
* The use of inhaled corticosteroids is permitted.
* The use of mineralocorticoids for management of orthostatic hypotension is permitted.
* The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted.
* History of solid organ transplantation
* History of severe allergic or anaphylactic reaction to humanized, chimeric or murine monoclonal antibodies (MAbs) or known sensitivity or allergy to murine products
* Known active bacterial, viral (including SARS-CoV-2), fungal, or other infection, or any major episode of infection requiring treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1
* Known or suspected chronic active Epstein-Barr virus (EBV) infection
* Known or suspected history of macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH)
* History of confirmed progressive multifocal leukoencephalopathy (PML)
* Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
* Patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 1 year and have no significant residual neurologic deficits as judged by the investigator are allowed.
* Patients with a history of epilepsy who have had no seizures in the past 1 year while not receiving any anti-epileptic medications are allowed.
* Clinically significant active malabsorption syndrome or other conditions likely to affect gastrointestinal absorption of the study drug
* History of bleeding diathesis
* Major surgery 4 weeks prior to starting study therapy or participant has not fully recovered from major surgery.
* The diagnosis of another malignancy which, in the opinion of the Investigator, is likely to negatively impact the participant's safety or ability to participate in the study.
* Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
* Cardiovascular disorders:
* Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias.
* Unstable angina or acute coronary syndrome within 6 months prior to first dose of study therapy.
* History of myocardial infarction within 6 months prior to first dose of study therapy
* QTc prolongation defined as a QTcF \> 470 ms.
* Correction of suspected drug induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
* Correction for underlying bundle branch block (BBB) allowed.
* Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
---Left ventricular ejection fraction \< 40% within 12 months prior to first dose of study therapy.
* Any other condition that would, in the Investigator's judgment, contraindicate the participant's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, social/ psychological issues, etc.)
* Evidence of other clinically significant uncontrolled condition(s) or other clinically significant active disease process which, in the opinion of the investigator, is likely to pose a risk for patient participation.
* Known HIV infection.
* Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis
--Note: Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Participants with positive anti-HBc and negative HBV DNA should be on prophylactic nucleo(t)side analogue therapy to prevent reactivation with serial HBV DNA PCR monitoring Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
* Known active cytomegalovirus (CMV) infection.
* History of autoimmune disease, including, but not limited to myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
* Patients with a remote history of, or well-controlled, autoimmune disease with a treatment-free interval from immunosuppressive therapy for 12 months may be eligible to enroll if judged to be safe by the investigator.
* Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone are eligible.
* Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
* Patients with a history of disease-related immune thrombocytopenic purpura, or autoimmune hemolytic anemia may be eligible.
* Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
* Rash must cover 10% of body surface area
* Disease is well controlled at baseline and requires only low-potency topical corticosteroids
* No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency oral corticosteroids within the previous 12 months.
* Positive SARS-CoV-2 test within 7 days prior to enrollment
* Substance abuse within 12 months prior to screening
* Medical, psychiatric, cognitive, or other conditions that may compromise the participant's ability to understand the participant information, give informed consent, comply with the study protocol or complete the study.
* Known prior severe hypersensitivity to investigational product or any component in its formulations (CTCAE v 6.0 Grade ≥ 3).
* Participants taking prohibited medications as described in Section 7.4.10.
* Subject has received prior standard or investigational anti cancer therapy as specified below:
* Chimeric antigen receptor T-cell therapy within 60 days prior to Day 1 of Cycle 1.
* Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1.
* Prior treatment with monoclonal antibodies, chemotherapy, or antibody-drug conjugates within 4 weeks before first mosunetuzumab administration.
* Treatment with any anticancer agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to first dose of study treatment.
* Radiotherapy
* 14 days for local site radiation therapy
* 6 weeks for prior radioisotope therapy
* 12 weeks for 50% pelvic or total body irradiation
→
Inclusion Criteria:
* Subjects aged ≥ 18 years with documented diagnosis of WM with the definition of measurable disease
* Subjects who are able to comply with the study protocol.
* Subjects with relapsed or refractory WM who have received at least one prior line of therapy.
* Must have received prior treatment with covalent BTK inhibitor or have declined such treatment.
* Prior autologous stem cell transplant is permitted if completed ≥ 100 days prior to treatment.
* Prior allogeneic transplants are not permitted.
* Subjects must have an indication for treatment per IWWM
* ECOG Performance Status ≤ 2
* Adequate organ function as defined as:
* Hematologic:
* Absolute neutrophil count ≥ 1000/mm3 independent of G-CSF support, unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case ANC of 750 cells/mm3 (0.75 x 10\^9/L) is permissible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
* Platelet count ≥75,000 cells/mm3 (≥75 x 10\^9/L) independent of transfusion support unless there is documented bone marrow involvement in which case platelet count of 50,000 cells/mm3 (50 x 10\^9/L) is permissible. Patients must be responsive to transfusion support if given for thrombocytopenia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
* Hemoglobin of ≥ 8.5 g/dL (≥ 85 g/L) independent of transfusion support unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case hemoglobin of 7 g/dL (70 g/L) is permissible. Patients must be responsive to transfusion support if given for anemia and patients refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
* Coagulation: Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN.
* Hepatic:
* Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN) or ≤3 x ULN with document liver involvement and/ or Gilbert's disease
* AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
* Participants with liver metastases will be allowed to enroll with AST and ALT levels ≤ 5 x ULN.
* Renal:
* Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula.
* Participants must adhere to the following sex and contraceptive/barrier requirements:
* If participant is of childbearing potential, they must have a negative pregnancy test
* For participants of non-childbearing potential: The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause (or having undergone surgical sterilization (bilateral oophorectomy of hysterectomy). The following age-specific requirements apply:
* \< 50 years of age:
* Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
* Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
--≥ 50 years of age:
* Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
* Had radiation-induced menopause with last menses \>1 year ago; or
* Had chemotherapy-induced menopause with last menses \>1 year ago
* Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
* Participants of childbearing potential and participants with a sexual partner of childbearing potential must agree to use a highly effective method of contraception and lactation requirements as described in Sections 5.4.1 and 5.4.2.
* Able to swallow oral tablets.
* Clinically significant adverse effects from any prior oncologic treatment (e.g. prior surgery, radiotherapy, or other antineoplastic therapy) must have recovered to grade 1 or have been determined to be clinically stable per the Investigator.
* Subject or their legal representative is able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
Exclusion Criteria:
* History of transformation of indolent disease to DLBCL
* Active or history of CNS lymphoma or leptomeningeal infiltration
* Prior treatment with a non-covalent BTK inhibitor
* Prior treatment with CD20-directed bispecific antibody therapy
* Receiving other investigational agents.
* Receipt of a live, attenuated vaccine within 4 weeks before first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study
* Patients must not receive live, attenuated vaccines (e.g., FluMistâ) while receiving study treatment or after the last dose until B-cell recovery to the normal ranges.
* Inactivated influenza vaccination should be given during the influenza season only.
* An approved coronavirus disease 2019 (COVID-19) vaccine (messenger RNA \[mRNA\], inactivated virus, and replication deficient viral vector vaccines) is allowed, as these are not considered live vaccines.
* Receipt of systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) with the exception of corticosteroid treatment £ 10 mg/day prednisone or equivalent within 2 weeks prior to the first dose of mosunetuzumab
* Patients who received acute, low-dose, systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea or B-symptoms) may be enrolled in the study if deemed appropriate by the investigator.
* The use of inhaled corticosteroids is permitted.
* The use of mineralocorticoids for management of orthostatic hypotension is permitted.
* The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted.
* History of solid organ transplantation
* History of severe allergic or anaphylactic reaction to humanized, chimeric or murine monoclonal antibodies (MAbs) or known sensitivity or allergy to murine products
* Known active bacterial, viral (including SARS-CoV-2), fungal, or other infection, or any major episode of infection requiring treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1
* Known or suspected chronic active Epstein-Barr virus (EBV) infection
* Known or suspected history of macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH)
* History of confirmed progressive multifocal leukoencephalopathy (PML)
* Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
* Patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 1 year and have no significant residual neurologic deficits as judged by the investigator are allowed.
* Patients with a history of epilepsy who have had no seizures in the past 1 year while not receiving any anti-epileptic medications are allowed.
* Clinically significant active malabsorption syndrome or other conditions likely to affect gastrointestinal absorption of the study drug
* History of bleeding diathesis
* Major surgery 4 weeks prior to starting study therapy or participant has not fully recovered from major surgery.
* The diagnosis of another malignancy which, in the opinion of the Investigator, is likely to negatively impact the participant's safety or ability to participate in the study.
* Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
* Cardiovascular disorders:
* Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias.
* Unstable angina or acute coronary syndrome within 6 months prior to first dose of study therapy.
* History of myocardial infarction within 6 months prior to first dose of study therapy
* QTc prolongation defined as a QTcF \> 470 ms.
* Correction of suspected drug induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
* Correction for underlying bundle branch block (BBB) allowed.
* Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
---Left ventricular ejection fraction \< 40% within 12 months prior to first dose of study therapy.
* Any other condition that would, in the Investigator's judgment, contraindicate the participant's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, social/ psychological issues, etc.)
* Evidence of other clinically significant uncontrolled condition(s) or other clinically significant active disease process which, in the opinion of the investigator, is likely to pose a risk for patient participation.
* Known HIV infection.
* Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis
--Note: Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Participants with positive anti-HBc and negative HBV DNA should be on prophylactic nucleo(t)side analogue therapy to prevent reactivation with serial HBV DNA PCR monitoring Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
* Known active cytomegalovirus (CMV) infection.
* History of autoimmune disease, including, but not limited to myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
* Patients with a remote history of, or well-controlled, autoimmune disease with a treatment-free interval from immunosuppressive therapy for 12 months may be eligible to enroll if judged to be safe by the investigator.
* Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone are eligible.
* Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
* Patients with a history of disease-related immune thrombocytopenic purpura, or autoimmune hemolytic anemia may be eligible.
* Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
* Rash must cover 10% of body surface area
* Disease is well controlled at baseline and requires only low-potency topical corticosteroids
* No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency oral corticosteroids within the previous 12 months.
* Positive SARS-CoV-2 test within 7 days prior to enrollment
* Substance abuse within 12 months prior to screening
* Medical, psychiatric, cognitive, or other conditions that may compromise the participant's ability to understand the participant information, give informed consent, comply with the study protocol or complete the study.
* Known prior severe hypersensitivity to investigational product or any component in its formulations (CTCAE v 6.0 Grade ≥ 3).
* Participants taking prohibited medications as described in Section 7.5.10.
* Subject has received prior standard or investigational anti cancer therapy as specified below:
* Chimeric antigen receptor T-cell therapy within 60 days prior to Day 1 of Cycle 1.
* Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1.
* Prior treatment with monoclonal antibodies, chemotherapy, or antibody-drug conjugates within 4 weeks before first mosunetuzumab administration.
* Treatment with any anticancer agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to first dose of study treatment.
* Radiotherapy
* 14 days for local site radiation therapy
* 6 weeks for prior radioisotope therapy
* 12 weeks for 50% pelvic or total body irradiation
Criteria for Inclusion:
1. Participants may be of any age, based on Cohort Criteria
2. At least two mutations in the otoferlin gene
3. Clinical presentation of Profound bilateral sensorineural hearing loss as assessed by ABR
4. Preserved distortion product otoacoustic emissions (DPOAEs)
5. Able and willing to comply with all study requirements, including willingness to participate in a separate long term follow-up study after completion of this trial
Criteria for Exclusion:
1. Persistent ear infections, anatomic or other abnormalities of the ear, and/or medical conditions that would contraindicate undergoing surgery, anesthesia, and/or administration of investigational gene therapy
2. Cochlear Implant(s) in the ear(s) to receive AAVAnc80-hOTOF
3. Prior participation in a clinical trial with an investigational drug, within six months prior to administration, or any prior participation in a gene therapy clinical trial
→
Criteria for Inclusion:
1. Participants may be of any age, based on Cohort Criteria
2. At least two mutations in the otoferlin gene
3. Clinical presentation of Profound (Part A) or Severe to Profound (Parts B, C, and D) bilateral sensorineural hearing loss as assessed by ABR
4. Preserved distortion product otoacoustic emissions (DPOAEs)
5. Able and willing to comply with all study requirements, including willingness to participate in a separate long term follow-up study after completion of this trial
Criteria for Exclusion:
1. Persistent ear infections, anatomic or other abnormalities of the ear, and/or medical conditions that would contraindicate undergoing surgery, anesthesia, and/or administration of investigational gene therapy
2. Cochlear Implant(s) in the ear(s) to receive AAVAnc80-hOTOF
3. Prior participation in a clinical trial with an investigational drug, within six months prior to administration, or any prior participation in a gene therapy clinical trial (with the exception of AK-OTOF-101 for Part D participants)
Inclusion Criteria:
* Age greater than or equal to 18 years
* Histologically confirmed treatment naive WM/LPL
* Patients must have measurable disease as defined by at least one lymph node ≥1.5 cm and/ or IgM levels \> 0.5gm/dl quantified by using densitometry on serum protein electrophoresis (SPEP) or quantitative nephelometry.
* Participants must have at least one of the established criteria to require therapy for WM, including anemia, thrombocytopenia, neuropathy related to WM, symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises, WM-associated glomerulonephritis or renal disease, bulky disease, or constitutional symptoms
* ECOG performance status ≤2
* Platelet count ≥ 50,000 cells/mm3, independent of transfusions within 7 days of screening assessment
* Hemoglobin ≥ 8 g/dL, unless due to disease involvement in which case ≥ 7 g/dL, independent of transfusions within 7 days of screening assessment
* Absolute neutrophil count \>1000 cells/mcL, independent of growth factor support within 7 days of screening assessment
* Total bilirubin \< 1.5 x upper normal institutional limits. In patients with Gilbert's disease total bilirubin up to 3x ULN will be allowed
* AST(SGOT)/ALT(SGPT) \< 3 x institutional upper limit of normal unless elevation is caused by liver involvement with WM in which case AST and ALT may be ≤ 5 x ULN
* Creatinine within normal institutional limits OR Creatinine clearance \>40 mL/min for patients with creatinine levels above institutional normal (by Cockcroft-Gault estimate or 12-24h creatinine clearance measurements)
* Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN
* Ability to understand and the willingness to sign a written informed consent document.
* Patient must be able to swallow pills
* Patients with Hepatitis B surface antibody serum positivity due to prior immunization, as well as those with Hepatitis B core antibody positivity with negative PCR on antiviral therapy will be eligible.
* Willingness of participants of reproductive potential and their partners to observe highly effective birth control methods for the duration of treatment and for 1 year following the last dose of study treatment
Exclusion Criteria:
* Prior/Concomitant Therapy: Participants must not have had prior systemic therapy.
* Medical Conditions
* Major surgery within 4 weeks prior to start of treatment
* History of bleeding diathesis
* Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor.
* NOTE: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)
* History of stroke or intracranial hemorrhage within 6 months of start of treatment
* History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T-cell (CAR-T) therapy within 60 days of start of treatment or presence of any of the following, regardless of prior SCT and/or CAR-T therapy timing:
* active graft versus host disease (GVHD);
* cytopenia from incomplete blood cell count recovery post-transplant;
* need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity \> Grade 1 from CAR-T therapy;
* ongoing immunosuppressive therapy (\> 20 mg prednisone or equivalent daily).
* Significant cardiovascular disease defined as:
* unstable angina or acute coronary syndrome within the past 2 months prior to start of treatment
* history of myocardial infarction within 3 months prior to start of treatment or
* documented LVEF by any method of ≤ 40% in the 12 months prior to start of treatment
* ≥ Grade 3 NYHA functional classification system of heart failure
* Uncontrolled or symptomatic arrhythmias
* Prolongation of the QT interval corrected for heart rate (QTcF) \> 470 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33).
* Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
* Correction for underlying bundle branch block (BBB) allowed. Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
* Patients who have tested positive for Human Immunodeficiency Virus (HIV) are excluded due to risk of opportunistic infections with both HIV and BTK- inhibitors. For patients with unknown HIV status, HIV testing will be performed at Screening and result must be negative for enrollment.
* Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
* Hepatitis B virus (HBV):
* Patients with positive hepatitis B surface antigen (HBsAg) are excluded.
* Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require a negative hepatitis B polymerase chain reaction (PCR) evaluation before start of treatment.
* Patients who are HBV DNA PCR positive will be excluded.
* Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before start of treatment. Patients who are hepatitis C RNA positive will be excluded.
* Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.
* Pregnancy or plan to become pregnant during the study or within 1 month of the last dose of study treatment.
* Lactation or plan to breastfeed during the study or within 1 week of the last dose of study treatment.
* Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug.
* Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator and medical monitor may pose a risk for patient participation. Screening for chronic conditions is not required.
* Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts.
* Active second malignancy unless in remission and with life expectancy \> 2 years.
* Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
* Vaccination with live vaccine within 28 days prior to start of treatment
* Other Exclusions
* Have a known hypersensitivity to any of the excipients of Pirtobrutinib or to any intended study medications.
* Participants who require ongoing use or received a moderate or strong CYP3A inducer, moderate or strong CYP3A inhibitor, P-gp inhibitor within 7 days prior to the first dose of study drug
→
Inclusion Criteria:
* Age greater than or equal to 18 years
* Histologically confirmed treatment naive WM/LPL (participants with non-IgM LPL are NOT eligible for the study)
* Patients must have measurable disease as defined by at least one lymph node ≥1.5 cm and/ or IgM levels \> 0.5gm/dl quantified by using densitometry on serum protein electrophoresis (SPEP) or quantitative nephelometry.
* Participants must have at least one of the established criteria to require therapy for WM, including anemia, thrombocytopenia, neuropathy related to WM, symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises, WM-associated glomerulonephritis or renal disease, bulky disease, or constitutional symptoms
* ECOG performance status ≤2
* Platelet count ≥ 50,000 cells/mm3, independent of transfusions within 7 days of screening assessment
* Hemoglobin ≥ 8 g/dL, unless due to disease involvement in which case ≥ 7 g/dL, independent of transfusions within 7 days of screening assessment
* Absolute neutrophil count \>1000 cells/mcL, independent of growth factor support within 7 days of screening assessment
* Total bilirubin \< 1.5 x upper normal institutional limits. In patients with Gilbert's disease total bilirubin up to 3x ULN will be allowed
* AST(SGOT)/ALT(SGPT) \< 3 x institutional upper limit of normal unless elevation is caused by liver involvement with WM in which case AST and ALT may be ≤ 5 x ULN. In the event of AST or ALT unable to result due to interference of the serum IgM with the liver function tests assay, patient can still be eligible per MSK PI discretion, dependent on other liver enzymes tests being within protocol parameters.
* Creatinine within normal institutional limits OR Creatinine clearance \>40 mL/min for patients with creatinine levels above institutional normal (by Cockcroft-Gault estimate or 12-24h creatinine clearance measurements)
* Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN
* Ability to understand and the willingness to sign a written informed consent document.
* Patient must be able to swallow pills
* Patients with Hepatitis B surface antibody serum positivity due to prior immunization, as well as those with Hepatitis B core antibody positivity with negative PCR on antiviral therapy will be eligible.
* Willingness of participants of reproductive potential and their partners to observe highly effective birth control methods for the duration of treatment and for 1 year following the last dose of study treatment
Exclusion Criteria:
* Prior/Concomitant Therapy: Participants must not have had prior systemic therapy.
* Medical Conditions
* Major surgery within 4 weeks prior to start of treatment
* History of bleeding diathesis
* Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor.
* NOTE: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)
* History of stroke or intracranial hemorrhage within 6 months of start of treatment
* History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T-cell (CAR-T) therapy within 60 days of start of treatment or presence of any of the following, regardless of prior SCT and/or CAR-T therapy timing:
* active graft versus host disease (GVHD);
* cytopenia from incomplete blood cell count recovery post-transplant;
* need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity \> Grade 1 from CAR-T therapy;
* ongoing immunosuppressive therapy (\> 20 mg prednisone or equivalent daily).
* Significant cardiovascular disease defined as:
* unstable angina or acute coronary syndrome within the past 2 months prior to start of treatment
* history of myocardial infarction within 3 months prior to start of treatment or
* documented LVEF by any method of ≤ 40% in the 12 months prior to start of treatment
* ≥ Grade 3 NYHA functional classification system of heart failure
* Uncontrolled or symptomatic arrhythmias
* Prolongation of the QT interval corrected for heart rate (QTcF) \> 470 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33).
* Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
* Correction for underlying bundle branch block (BBB) allowed. Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
* Patients who have tested positive for Human Immunodeficiency Virus (HIV) are excluded due to risk of opportunistic infections with both HIV and BTK- inhibitors. For patients with unknown HIV status, HIV testing will be performed at Screening and result must be negative for enrollment.
* Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
* Hepatitis B virus (HBV):
* Patients with positive hepatitis B surface antigen (HBsAg) are excluded.
* Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require a negative hepatitis B polymerase chain reaction (PCR) evaluation before start of treatment.
* Patients who are HBV DNA PCR positive will be excluded.
* Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before start of treatment. Patients who are hepatitis C RNA positive will be excluded.
* Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.
* Pregnancy or plan to become pregnant during the study or within 1 month of the last dose of study treatment.
* Lactation or plan to breastfeed during the study or within 1 week of the last dose of study treatment.
* Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug.
* Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator and medical monitor may pose a risk for patient participation. Screening for chronic conditions is not required.
* Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts.
* Active second malignancy unless in remission and with life expectancy \> 2 years.
* Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
* Vaccination with live vaccine within 28 days prior to start of treatment
* Other Exclusions
* Have a known hypersensitivity to any of the excipients of Pirtobrutinib or to any intended study medications.
* Participants who require ongoing use or received a moderate or strong CYP3A inducer, moderate or strong CYP3A inhibitor, P-gp inhibitor within 7 days prior to the first dose of study drug
Inclusion Criteria:
* hsCRP ≥2 mg/L and ≤15 mg/L at screening
* At least one of the following chronic conditions:
* Established atherosclerotic cardiovascular disease (ASCVD)
* Obesity (body mass index (BMI) ≥30 kg/m2)
* Type 2 diabetes
* Hypertension
* Chronic kidney disease Grade 3 or 4
Exclusion Criteria:
* Acute cardiovascular event within 60 days prior to screening
* Acute decompensated heart failure hospitalization within 60 days prior to screening
* Planned coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or major surgery at the time of randomization
* New York Heart Association Class III or IV heart failure
* Uncontrolled hypertension at screening (systolic blood pressure (BP) ≥160 mmHg or diastolic BP ≥100 mmHg)
* Type 1 diabetes
* Type 2 diabetes with Hemoglobin A1c ≥9.0% (86 mmol/mol) at screening
* Nephrotic syndrome, estimated glomerular filtration rate (eGFR) \<15 mL/min/1.73 m², or history of kidney transplant
* Dialysis or acute kidney injury within 60 days prior to screening
* Congenital/hereditary kidney disease, polycystic kidney disease, lupus nephritis, or antineutrophil cytoplasmic antibody-associated vasculitis
* Active tuberculosis, untreated latent tuberculosis, or known hepatitis B or hepatitis C infection
* Serious, opportunistic, chronic, or recurrent infection requiring treatment within 12 weeks prior to screening
* Significant active autoimmune disease
* Suspected or confirmed immunocompromised state (e.g., HIV infection)
* History of peptic ulcer disease or gastrointestinal ulceration within 12 months prior to screening
* History of diverticular disease, gastrointestinal perforation, or major gastrointestinal surgery
* Mechanical heart valve prosthesis requiring chronic vitamin K antagonist anticoagulation
* Use of colchicine within 14 days prior to screening or anticipated need during the study
* Use of immunosuppressive or immunomodulatory agents, including other biologic anti-IL-6 therapies, within specified windows prior to screening
* Use of systemic corticosteroids within 14 days prior to screening
* Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs)
→
Inclusion Criteria:
* hsCRP ≥2 mg/L and ≤15 mg/L at screening
* At least one of the following chronic conditions:
* Established atherosclerotic cardiovascular disease (ASCVD)
* Obesity (body mass index (BMI) ≥30 kg/m2)
* Type 2 diabetes
* Hypertension
* Chronic kidney disease Grade 3 or 4
Exclusion Criteria:
* Acute cardiovascular event within 60 days prior to screening
* Acute decompensated heart failure hospitalization within 60 days prior to screening
* Planned coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or major surgery at the time of randomization
* New York Heart Association Class III or IV heart failure
* Uncontrolled hypertension at screening (systolic blood pressure (BP) ≥160 mmHg or diastolic BP ≥100 mmHg)
* Type 1 diabetes
* Type 2 diabetes with Hemoglobin A1c ≥9.0% (86 mmol/mol) at screening
* Nephrotic syndrome, estimated glomerular filtration rate (eGFR) \<15 mL/min/1.73 m², or history of kidney transplant
* Dialysis or acute kidney injury within 60 days prior to screening
* Congenital/hereditary kidney disease, polycystic kidney disease, lupus nephritis, or antineutrophil cytoplasmic antibody-associated vasculitis
* Active tuberculosis, untreated latent tuberculosis, or known hepatitis B or hepatitis C infection
* Serious, opportunistic, chronic, or recurrent infection requiring treatment within 12 weeks prior to screening
* Significant active autoimmune disease
* Suspected or confirmed immunocompromised state (e.g., HIV infection)
* History of peptic ulcer disease or gastrointestinal ulceration within 12 months prior to screening
* History of symptomatic diverticular disease (diverticulitis), gastrointestinal perforation, or major gastrointestinal surgery
* Mechanical heart valve prosthesis requiring chronic vitamin K antagonist anticoagulation
* Use of colchicine within 14 days prior to screening or anticipated need during the study
* Use of immunosuppressive or immunomodulatory agents, including other biologic anti-IL-6 therapies, within specified windows prior to screening
* Use of systemic corticosteroids within 14 days prior to screening
* Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs)
Inclusion Criteria:
* Have severe Alopecia Areata (AA) that meets all of the following criteria:
* Hair loss encompassing ≥50% and ≤90% of the scalp, as measured by Severity of Alopecia Tool (SALT) score
* The duration of the current episode of severe AA is at least 6 months and does not exceed 4 years
* No significant spontaneous hair regrowth in the investigator's opinion for at least 6 months
* Agree not to use any AA treatments during the study
Exclusion Criteria:
* Primarily "diffuse" type of AA (characterized by diffuse hair shedding)
* Are currently experiencing other forms of alopecia
* Participants who, in the opinion of the investigator, are currently experiencing or have a history of unstable concomitant disease that requires frequent hospitalizations, and/or frequent use of systemic immunosuppressants that may interfere with participation in the study
* Have received oral JAK Inhibitors in the past
* Have had any major surgery within 8 weeks prior to screening or will require major surgery during the study
* Have a history or presence of cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric disorders or any other serious and/or unstable illness
→
Inclusion Criteria:
* Have severe Alopecia Areata (AA) that meets all of the following criteria:
* Hair loss encompassing ≥50% and ≤90% of the scalp, as measured by Severity of Alopecia Tool (SALT) score
* The duration of the current episode of severe AA is at least 6 months and does not exceed 4 years
* No significant spontaneous hair regrowth in the investigator's opinion for at least 6 months
* Agree not to use any AA treatments during the study
Exclusion Criteria:
* Primarily "diffuse" type of AA (characterized by diffuse hair shedding)
* Are currently experiencing other forms of alopecia
* Participants who, in the opinion of the investigator, are currently experiencing or have a history of unstable concomitant disease that requires frequent hospitalizations, and/or frequent use of systemic immunosuppressants that may interfere with participation in the study
* Have had any major surgery within 8 weeks prior to screening or will require major surgery during the study
* Have a history or presence of cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric disorders or any other serious and/or unstable illness
Inclusion Criteria:
* Healthy participants (Parts A and B):
* Are male or female not of childbearing potential
* inclusion of healthy Japanese participants, the participant must be first-generation Japanese, defined as the participant's biological parents and all of the participant's biological grandparents must be of exclusive Japanese descent, and must have been born in Japan.
* inclusion of healthy Chinse participants, the participant must be at a minimum, third-generation Chinese, defined as all 4 of the participants' biological grandparents must be of exclusive Chinese descent and born in China.
* Must have a body mass index of 18.0 to 32.0 kilograms per meter squared (kg/m²), inclusive. For healthy Japanese participants, have a body mass index of 18.0 to 28.0 kg/m², inclusive, and a body weight of 50 kg to 85 kg, inclusive.
* Atopic dermatitis participants (Part C):
* Must have a body mass index of 18.0 to 45.0 kg/m², inclusive
* Are male or female participants including those of child bearing potential
* Must have a diagnosis of AD for at least 12 months with either poor response to topical treatments or inability to use topical treatments
* Must agree to use moisturizer daily throughout the treatment period
Exclusion Criteria:
* All participants:
* Have or used to have health problems or laboratory test results or electrocardiogram (ECG) readings that, in the opinion of the doctor, could make it unsafe to participate, or could interfere with understanding the results of the study
* Have active or latent tuberculosis
* Have had any cancer within the past 5 years. Exceptions: successfully treated basal cell skin carcinoma or squamous cell skin carcinoma, with no evidence of recurrence or metastatic disease within the 3 years prior to baseline
* Have one of the following viral infections: hepatitis B virus, hepatitis C virus or human immunodeficiency virus.
* Have received treatment with biologic agents (such as monoclonal antibodies, including marketed drugs) within 30 days or 5 half-lives (whichever is longer) prior to dosing
* Must not have previously completed a clinical trial with a molecule targeting interleukin-33 and/or the interleukin-33 receptor (ST2)
* Are currently participating in or completed a clinical trial within the last 30 days
* Have received a vaccine containing a live (attenuated) virus within 28 days of screening or intend to receive during the course of the study
* Atopic dermatitis participants:
* Must not have received certain topical medications for AD within 2 weeks prior to randomization
* Must not have received certain oral medications for AD or received phototherapy within 4 weeks prior to randomization
* Must not have received any antibody-based biologic agents (marketed or investigational) within 5 half lives (t1/2) of the drug prior to randomization
* Must not have received intravenous, intramuscular, or intra-articular steroids in the past 6 weeks prior to randomization
→
Inclusion Criteria:
* Healthy participants (Parts A and B):
* Are male or female not of childbearing potential
* Inclusion of healthy Japanese participants, the participant must be first-generation Japanese, defined as the participant's biological parents and all of the participant's biological grandparents must be of exclusive Japanese descent, and must have been born in Japan.
* Inclusion of healthy Chinese participants, the participant must be at a minimum, third-generation Chinese, defined as all 4 of the participants' biological grandparents must be of exclusive Chinese descent and born in China.
* Must have a body mass index of 18.0 to 32.0 kilograms per meter squared (kg/m²), inclusive. For healthy Japanese participants, have a body mass index of 18.0 to 28.0 kg/m², inclusive, and a body weight of 50 kg to 85 kg, inclusive.
* Atopic dermatitis participants (Part C):
* Must have a body mass index of 18.0 to 45.0 kg/m², inclusive
* Are male or female participants including those of child bearing potential
* Must have a diagnosis of AtD for at least 12 months with either poor response to topical treatments or inability to use topical treatments
* Must agree to use moisturizer daily throughout the treatment period
Exclusion Criteria:
* All participants:
* Have or used to have health problems or laboratory test results or electrocardiogram (ECG) readings that, in the opinion of the doctor, could make it unsafe to participate, or could interfere with understanding the results of the study
* Have active or latent tuberculosis
* Have had any cancer within the past 5 years. Exceptions: successfully treated basal cell skin carcinoma or squamous cell skin carcinoma, with no evidence of recurrence or metastatic disease within the 3 years prior to baseline
* Have one of the following viral infections: hepatitis B virus, hepatitis C virus or human immunodeficiency virus.
* Have received treatment with biologic agents (such as monoclonal antibodies, including marketed drugs) within 30 days or 5 half-lives (whichever is longer) prior to dosing
* Must not have previously completed a clinical trial with a molecule targeting interleukin-33 and/or the interleukin-33 receptor (ST2)
* Are currently participating in or completed a clinical trial within the last 30 days
* Have received a vaccine containing a live (attenuated) virus within 28 days of screening or intend to receive during the course of the study
* Atopic dermatitis participants:
* Must not have received certain topical medications for AtD within 2 weeks prior to randomization
* Must not have received certain oral medications for AtD or received phototherapy within 4 weeks prior to randomization
* Must not have received any antibody-based biologic agents (marketed or investigational) within 5 half lives (t1/2) of the drug prior to randomization
* Must not have received intravenous, intramuscular, or intra-articular steroids in the past 6 weeks prior to randomization
Inclusion Criteria:
Part A Single Ascending Dose (SAD) and B Multiple Ascending Dose (MAD)
* Have a body mass index within the range of 18 to 34 kilogram/square meter (kg/m²) (inclusive).
* For Japanese participants: To qualify as a participant of first-generation Japanese origin, the participant, the participant's biological parents, and all of the participant's biological grandparents must be of exclusive Japanese descent and born in Japan.
* Have venous access sufficient to allow for blood sampling or administration of study intervention for IV administration, or both.
Part A (SAD) Only
* Participant must be 30 to 85 years of age (inclusive), at the time of signing the informed consent
* Are overtly healthy
* For Chinese participants: To qualify as Chinese for this study, all 4 of the participant's biological grandparents must be exclusive Chinese descent and born in China.
Part B (MAD) Only
* Participant must be 40 to 85 years of age (inclusive), at the time of signing the informed consent
* Diagnosis of Parkinson's disease per United Kingdom (UK) Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria.
* If presently untreated for Parkinson's disease, clinical status is not expected to require changes in symptomatic treatment within 52 weeks from baseline.
* If presently being treated for Parkinson's disease, receiving a stable dose of symptomatic dopaminergic therapy, including monoamine oxidase-B inhibitor, levodopa/carbidopa or dopamine agonist for at least 90 days prior to baseline and not expected to change within 52 weeks.
* Have a Montreal Cognitive Assessment (MoCA) score of greater than or equal to (≥) 24.
Exclusion Criteria:
Part A (SAD) and B (MAD)
* Have significant neurological disease affecting the central nervous system (CNS) (other than Parkinson's disease in Part B cohorts) that may affect the participant's ability to complete the study.
* Have a history or presence of serious or unstable illnesses or conditions that, in the investigator's opinion, could interfere with the analyses in this study, or increase risk for study intervention administration, or result in a participant's life expectancy of less than 24 months.
* Have known allergies to LY4006896, related compounds, or any components of the formulation, or history of allergic reactions to any transferrin receptor antibodies.
* Have significant allergies to humanize monoclonal antibodies.
* Have clinically significant multiple or severe drug allergies (including, but not limited to, erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis); or intolerance to topical corticosteroids, or severe posttreatment hypersensitivity reactions.
* Have history or presence of uncontrolled asthma, significant autoimmune disease, hereditary angioedema, or known history of common variable immune deficiency.
* Evidence of clinically significant anemia.
Part A (SAD) Only
* Have an abnormal blood pressure or pulse rate, or both, as determined by the investigator, or a preexisting history of hypertension.
Part B (MAD) Only
* Have an abnormal blood pressure or pulse rate, or both, as determined by the investigator, or have uncontrolled hypertension, defined as a systolic blood pressure \>150 mm Hg or a diastolic blood pressure \>95 mm Hg at Screening or Treatment Visits.
* Have an implanted deep brain stimulation (DBS) system or any other implanted neurostimulation device (including but not limited to spinal cord stimulation, vagus nerve stimulation or investigational neuromodulation devices)
* Are receiving continuous infusion therapy with anti-parkinsonian medications, including but not limited to subcutaneous foslevodopa-foscarbidopa, subcutaneous apomorphine, or intraduodenal/intestinal levodopa formulations
→
Inclusion Criteria:
Part A Single Ascending Dose (SAD) and B Multiple Dose (MD)
* Have a body mass index within the range of 18 to 34 kilogram per square meter (kg/m²) (inclusive).
* For Japanese participants: To qualify as a participant of first-generation Japanese origin, the participant, the participant's biological parents, and all of the participant's biological grandparents must be of exclusive Japanese descent and born in Japan.
* Have venous access sufficient to allow for blood sampling or administration of study intervention for IV administration, or both.
Part A (SAD) Only
* Participant must be 30 to 85 years of age (inclusive), at the time of signing the informed consent
* Are overtly healthy
* For Chinese participants: To qualify as Chinese for this study, all 4 of the participant's biological grandparents must be exclusive Chinese descent and born in China.
Part B (MD) Only
* Participant must be 40 to 85 years of age (inclusive), at the time of signing the informed consent
* Diagnosis of Parkinson's disease per United Kingdom (UK) Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria.
* If presently untreated for Parkinson's disease, clinical status is not expected to require changes in symptomatic treatment within 52 weeks from baseline.
* If presently being treated for Parkinson's disease, receiving a stable dose of symptomatic dopaminergic therapy, including monoamine oxidase-B inhibitor, levodopa/carbidopa or dopamine agonist for at least 90 days prior to baseline and not expected to change within 52 weeks.
* Have a Montreal Cognitive Assessment (MoCA) score of greater than or equal to (≥) 24.
Exclusion Criteria:
Part A (SAD) and B (MD)
* Have significant neurological disease affecting the central nervous system (CNS) (other than Parkinson's disease in Part B cohorts) that may affect the participant's ability to complete the study.
* Have a history or presence of serious or unstable illnesses or conditions that, in the investigator's opinion, could interfere with the analyses in this study, or increase risk for study intervention administration, or result in a participant's life expectancy of less than 24 months.
* Have known allergies to LY4006896, related compounds, or any components of the formulation, or history of allergic reactions to any transferrin receptor antibodies.
* Have significant allergies to humanize monoclonal antibodies.
* Have clinically significant multiple or severe drug allergies (including, but not limited to, erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis); or intolerance to topical corticosteroids, or severe posttreatment hypersensitivity reactions.
* Have history or presence of uncontrolled asthma, significant autoimmune disease, hereditary angioedema, or known history of common variable immune deficiency.
* Evidence of clinically significant anemia.
Part A (SAD) Only
* Have an abnormal blood pressure or pulse rate, or both, as determined by the investigator, or a preexisting history of hypertension.
Part B (MD) Only
* Have an abnormal blood pressure or pulse rate, or both, as determined by the investigator, or have uncontrolled hypertension, defined as a systolic blood pressure greater than (\>) 150 mmHg or a diastolic blood pressure \>95 mmHg at Screening or Treatment Visits.
* Have an implanted deep brain stimulation (DBS) system or any other implanted neurostimulation device (including but not limited to spinal cord stimulation, vagus nerve stimulation or investigational neuromodulation devices)
* Are receiving continuous infusion therapy with anti-parkinsonian medications, including but not limited to subcutaneous foslevodopa-foscarbidopa, subcutaneous apomorphine, or intraduodenal/intestinal levodopa formulations
Diagnostic assessments
* Hemoglobin A1c 6.5 percent (%) or higher
The trial was intended to be Phase 1/2 but did not move forward to Phase 2 since the company providing drug and funding (Lilly) withdrew support for the trial based on data relating to abemaciclib in advanced prostate cancer.
Inclusion Criteria:
* Have one of the following solid tumor cancers:
* Cohort A1: urothelial carcinoma, triple negative breast cancer, non-small cell lung cancer, esophageal cancer, pancreatic cancer, ovarian cancer, cervical cancer (squamous cell carcinoma), head and neck squamous cell carcinoma or prostate cancer
* Cohort A2/B1/B2: urothelial carcinoma
* Cohort C: triple negative breast cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, HNSCC (head and neck squamous cell carcinoma), esophageal cancer, pancreatic cancer, or prostate cancer
* Prior Systemic Therapy Criteria:
* Cohort A1/C: Individual has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating investigator; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies
* Cohort A2/B1/B2: Individual must have received at least one prior regimen in the advanced or metastatic setting. There is no restriction on number of prior therapies.
* Prior enfortumab vedotin specific requirements:
* Cohorts A1/A2/C: prior treatment with enfortumab vedotin is allowed, but not required
* Cohort B1: individual must be enfortumab vedotin naive in the advanced/metastatic setting
* Cohort B2: individual must have received enfortumab vedotin in the metastatic/advanced setting.
* Measurability of disease
* Cohort A1: measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST 1.1)
* Measurable disease is required as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) for all Cohorts. Cohort A1 may permit non-measurable disease as defined by RECIST v1.1
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Have adequate archival tumor tissue sample available or undergo a screening biopsy if allowed per country specific regulations
Exclusion Criteria:
* Individual with known or suspected uncontrolled CNS metastases
* Individual with uncontrolled hypercalcemia
* Individual with uncontrolled diabetes
* Individual with evidence of corneal keratopathy or keratitis, and history of corneal transplant
* Any serious unresolved toxicities from prior therapy
* Significant cardiovascular disease
* Recent thromboembolic event and/or clinically significant bleeding disorder
* Prolongation of QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms
* History of pneumonitis/interstitial lung disease
* History of Grade ≥3 skin toxicity when receiving enfortumab vedotin
* Individuals who are pregnant, breastfeeding or plan to breastfeed during study or within 30 days of last dose of study intervention
→
Inclusion Criteria:
* Have one of the following solid tumor cancers:
* Cohort A1: urothelial carcinoma, triple negative breast cancer, non-small cell lung cancer, esophageal cancer, pancreatic cancer, ovarian cancer, cervical cancer (squamous cell carcinoma), head and neck squamous cell carcinoma or prostate cancer
* Cohort A2/B/D: urothelial carcinoma
* Cohort C: triple negative breast cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, HNSCC (head and neck squamous cell carcinoma), esophageal cancer, pancreatic cancer, or prostate cancer
* Prior Systemic Therapy Criteria:
* Cohort A1/C: Individual has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating investigator; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies
* Cohort A2/B1/B2: Individual must have received at least one prior regimen in the advanced or metastatic setting. There is no restriction on number of prior therapies.
* Cohort D: Treatment-naive for locally advanced or metastatic urothelial cancer.
* Prior enfortumab vedotin specific requirements:
* Cohorts A1/A2/C/D: prior treatment with enfortumab vedotin is allowed, but not required
* Cohort B1: individual must be enfortumab vedotin naive in the advanced/metastatic setting
* Cohort B2: individual must have received enfortumab vedotin in the metastatic/advanced setting.
* Measurability of disease
* Cohort A1: measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST 1.1)
* Measurable disease is required as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) for all Cohorts. Cohort A1 may permit non-measurable disease as defined by RECIST v1.1
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Have adequate archival tumor tissue sample available or undergo a screening biopsy if allowed per country specific regulations
Exclusion Criteria:
* Individual with known or suspected uncontrolled CNS metastases
* Individual with uncontrolled hypercalcemia
* Individual with uncontrolled diabetes
* Individual with evidence of corneal keratopathy or keratitis, and history of corneal transplant
* Any serious unresolved toxicities from prior therapy
* Significant cardiovascular disease
* Recent thromboembolic event and/or clinically significant bleeding disorder
* Prolongation of QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms
* History of pneumonitis/interstitial lung disease
* History of Grade ≥3 skin toxicity associated with enfortumab vedotin that required treatment discontinuation
* Individuals who are pregnant, breastfeeding or plan to breastfeed during study or within 30 days of last dose of study intervention
Inclusion Criteria:
* All Parts:
* Individuals not of childbearing potential may participate in this trial.
* Individuals assigned male at birth may participate in this trial.
* Healthy as defined by
* the absence of clinically significant illness and surgery within 35 days prior to first dosing, and
* the absence of clinically significant history of neurological, endocrine, cardiovascular, respiratory, hematological, immunological, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.
* Part A:
\-- Have an estimated glomerular filtration rate (eGFR), using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation 2021, of greater than or equal to (≥)90 milliliters per minute per 1.73 square meters (mL/min/1.73 m²) at screening.
* Parts B, C, D, and E:
\-- Have an eGFR, using the CKD-EPI creatinine equation 2021, of ≥60 mL/minute/1.73 m²
* Parts A, B, D, and E:
\-- Have a body mass index ≥18.5 and less than (\<)32.0 kilograms per square meter (kg/m²)
* Part C:
* hsCRP ≥2 mg/L and ≤15 mg/L at screening and Day -1.
* Have a body mass index ≥18.5 and \<40.0 m2.
* Part D:
\-- To qualify as a participant of the first-generation Japanese origin, the participant, the participant's biological parents, and all of the participants' biological grandparents must be of exclusive Japanese descent and born in Japan.
* Part E:
* To qualify as Chinese for the purpose of this study, all the participants' biological grandparents must be of exclusive Chinese descent and born in China.
Exclusion Criteria:
* All Parts:
* Individuals of childbearing potential are excluded from the trial
* Any clinically significant abnormal finding at physical examination at screening and/or Day -1.
* Any clinically significant physical findings in the mouth or tongue (for example, difficulty swallowing) that would be likely to interfere with oral administration of study intervention.
* History of significant allergic reactions (for example, anaphylactic reaction, hypersensitivity, or angioedema) to any medication or known allergic reactions to drugs related to LY5625575, or to any excipient in the formulation.
* History of active tuberculosis or presence of active or latent tuberculosis.
* History or evidence of clinically significant opportunistic infection (for example, invasive candidiasis or pneumocystis pneumonia).
* History of serious local infection (for example, cellulitis or abscess) or systemic infection (for example, septicemia) within 90 days prior to screening.
* History of nonserious but active infections
* History of more than one episode of herpes zoster infection or history of disseminated herpes zoster infection.
* Presence or history of any abnormality or illness, which in the opinion of the investigator may affect absorption, distribution, metabolism, or elimination of the study intervention.
* Are currently enrolled in a clinical study involving an investigational medicinal product (IMP) or any other type of medical research judged not to be scientifically or medically compatible with this study.
* Are currently enrolled in or past participation within the 30 days prior to screening, in a clinical study involving a study intervention for which at least 5 half-lives or 30 days (whichever is longer) have not passed.
* Have a 12-lead echocardiogram (ECG) abnormality that, in the opinion of the investigator,
* increases the risks associated with participating in the study
* may confound ECG data analysis
* Have blood pressure and/or pulse rate constituting a risk when taking the investigational medicinal product, as determined by the investigator.
* Clinically significant abnormal laboratory test results at screening, or positive serology test results for hepatitis B surface antigen, hepatitis B core total antibody, hepatitis C virus antibody, or human immunodeficiency virus antigen and antibody, or QuantiFERON®-TB test at screening
* Positive pregnancy test or lactating participants assigned female at birth at screening and/or Day -1.
* Positive drug screen, cotinine test, or alcohol test at screening and/or Day -1.
* Any screening laboratory evaluation outside the laboratory reference range that is judged by the investigator to be clinically significant, with the exception of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and/or total bilirubin (TBL) greater than (\>)upper limit of normal (ULN) for these laboratory parameters.
* Presence of fever (body temperature \>37.6°C) (for example, a fever associated with a symptomatic viral or bacterial infection) within 2 weeks prior to first dosing.
* Use of medications for the timeframes specified below, with the exception of medications exempted by the investigator on a case-by-case basis because they are judged unlikely to affect the pharmacokinetic (PK) profile of the study intervention or participant safety (for example, topical drug products without significant systemic exposure):
* depot injection or implant for 90 days prior to dosing
* biologics for 90 days (or 5 half-lives, whichever is longer) prior to first dosing
* live attenuated vaccines for 30 days prior to dosing
* prescription medications or over-the-counter (OTC) medications and natural health products (including herbal remedies such as St. John's wort, homeopathic and traditional medicines, probiotics, food supplements such as amino acids, essential fatty acids, and protein supplements used in sports, with the exception of vitamins and minerals) for 14 days (or 5 half-lives, whichever is longer) prior to dosing (acetaminophen ≤3 grams/day will be permitted), or
* any vaccine, including coronavirus disease 2019 (COVID-19) vaccine, for 14 days prior to dosing.
* History of drug abuse within 1 year prior to screening or recreational use of soft drugs (such as marijuana) within 1 month or hard drugs (such as cocaine, phencyclidine, crack, opioid derivatives including heroin, and amphetamine derivatives) within 90 days prior to screening.
* Any use of tobacco and/or nicotine product within 90 days prior to screening.
* Have alcohol intake that exceeds recommended average weekly alcohol consumption limits per local regulation, or an amount deemed significant by the investigator.
* Have donated blood of more than 500 mL within the previous 90 days of screening or intend to donate blood during the course of the study.
* Parts B, C, D, and E:
* Are, in the judgment of the investigator, actively suicidal and therefore deemed to be at significant risk for suicide.
* Have answered "yes" to either Question 4 or Question 5 on the "Suicidal Ideation" portion of the Columbia Suicide Severity Rating Scale (C-SSRS) and the ideation occurred within the past 90 days (at screening and/or Day -1) OR
* Have answered "yes" to any of the suicide-related behaviors on the "Suicidal Behavior" portion of the C-SSRS and the behavior occurred within the past 90 days (at screening and/or Day -1). NOTE: Non-suicidal self-injurious behavior is not considered a suicide-related behavior.
* Have a baseline Patient Health Questionnaire-9 (PHQ-9) score of 15 or greater, and/or a score of 2 or greater for either
→
Inclusion Criteria:
* All Parts:
* Individuals not of childbearing potential may participate in this trial.
* Individuals assigned male at birth may participate in this trial.
* Healthy as defined by
* the absence of clinically significant illness and surgery within 35 days prior to first dosing, and
* the absence of clinically significant history of neurological, endocrine, cardiovascular, respiratory, hematological, immunological, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.
* Part A:
\-- Have an estimated glomerular filtration rate (eGFR), using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation 2021, of greater than or equal to (≥)90 milliliters per minute per 1.73 square meters (mL/min/1.73 m²) at screening.
* Parts B, C, D, and E:
\-- Have an eGFR, using the CKD-EPI creatinine equation 2021, of ≥60 mL/minute/1.73 m²
* Parts A, B, D, and E:
\-- Have a body mass index ≥18.5 and less than (\<)32.0 kilograms per square meter (kg/m²)
* Part C:
* hsCRP ≥2 mg/L and ≤15 mg/L at screening and Day -1.
* Have a body mass index ≥18.5 and \<40.0 m².
* Part D:
\-- To qualify as a participant of the first-generation Japanese origin, the participant, the participant's biological parents, and all of the participants' biological grandparents must be of exclusive Japanese descent and born in Japan.
* Part E:
* To qualify as Chinese for the purpose of this study, all the participants' biological grandparents must be of exclusive Chinese descent and born in China.
Exclusion Criteria:
* All Parts:
* Individuals of childbearing potential are excluded from the trial
* Any clinically significant abnormal finding at physical examination at screening and/or Day -1.
* Any clinically significant physical findings in the mouth or tongue (for example, difficulty swallowing) that would be likely to interfere with oral administration of study intervention.
* History of significant allergic reactions (for example, anaphylactic reaction, hypersensitivity, or angioedema) to any medication or known allergic reactions to drugs related to LY5625575, or to any excipient in the formulation.
* History of active tuberculosis or presence of active or latent tuberculosis.
* History or evidence of clinically significant opportunistic infection (for example, invasive candidiasis or pneumocystis pneumonia).
* History of serious local infection (for example, cellulitis or abscess) or systemic infection (for example, septicemia) within 90 days prior to screening.
* History of nonserious but active infections
* History of more than one episode of herpes zoster infection or history of disseminated herpes zoster infection.
* Presence or history of any abnormality or illness, which in the opinion of the investigator may affect absorption, distribution, metabolism, or elimination of the study intervention.
* Are currently enrolled in a clinical study involving an investigational medicinal product (IMP) or any other type of medical research judged not to be scientifically or medically compatible with this study.
* Are currently enrolled in or past participation in a clinical study involving a study intervention for which at least 5 half-lives or 30 days (whichever is longer) have not passed prior to screening.
* Participation in a clinical study involving an investigational medicinal product (IMP) with an unknown half-life within the 12 months prior to screening.
* Have a 12-lead echocardiogram (ECG) abnormality that, in the opinion of the investigator,
* increases the risks associated with participating in the study
* may confound ECG data analysis
* Have blood pressure and/or pulse rate constituting a risk when taking the investigational medicinal product, as determined by the investigator.
* Clinically significant abnormal laboratory test results at screening, or positive serology test results for hepatitis B surface antigen, hepatitis B core total antibody, hepatitis C virus antibody, or human immunodeficiency virus antigen and antibody, or QuantiFERON®-TB test at screening
* Positive pregnancy test or lactating participants assigned female at birth at screening and/or Day -1.
* Positive drug screen, cotinine test, or alcohol test at screening and/or Day -1.
* Any screening laboratory evaluation outside the laboratory reference range that is judged by the investigator to be clinically significant, with the exception of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and/or total bilirubin (TBL) greater than (\>) upper limit of normal (ULN) for these laboratory parameters.
* Presence of fever (body temperature \>37.6°C) (for example, a fever associated with a symptomatic viral or bacterial infection) within 2 weeks prior to first dosing.
* Use of medications for the timeframes specified below, with the exception of medications exempted by the investigator on a case-by-case basis because they are judged unlikely to affect the pharmacokinetic (PK) profile of the study intervention or participant safety (for example, topical drug products without significant systemic exposure):
* depot injection or implant for 90 days prior to dosing
* biologics for 90 days (or 5 half-lives, whichever is longer) prior to first dosing
* live attenuated vaccines for 30 days prior to dosing
* prescription medications or over-the-counter (OTC) medications and natural health products (including herbal remedies such as St. John's wort, homeopathic and traditional medicines, probiotics, food supplements such as amino acids, essential fatty acids, and protein supplements used in sports, with the exception of vitamins and minerals) for 14 days (or 5 half-lives, whichever is longer) prior to dosing (acetaminophen ≤3 grams/day will be permitted), or
* any vaccine, including coronavirus disease 2019 (COVID-19) vaccine, for 14 days prior to dosing.
* History of drug abuse within 1 year prior to screening or recreational use of soft drugs (such as marijuana) within 1 month or hard drugs (such as cocaine, phencyclidine, crack, opioid derivatives including heroin, and amphetamine derivatives) within 90 days prior to screening.
* Any use of tobacco and/or nicotine product within 90 days prior to screening.
* Have alcohol intake that exceeds recommended average weekly alcohol consumption limits per local regulation, or an amount deemed significant by the investigator.
* Have donated blood of more than 500 mL within the previous 90 days of screening or intend to donate blood during the course of the study.
* Parts B, C, D, and E:
* Are, in the judgment of the investigator, actively suicidal and therefore deemed to be at significant risk for suicide.
* Have answered "yes" to either Question 4 or Question 5 on the "Suicidal Ideation" portion of the Columbia Suicide Severity Rating Scale (C-SSRS) and the ideation occurred within the past 90 days (at screening and/or Day -1) OR
* Have answered "yes" to any of the suicide-related behaviors on the "Suicidal Behavior" portion of the C-SSRS and the behavior occurred within the past 90 days (at screening and/or Day -1). NOTE: Non-suicidal self-injurious behavior is not considered a suicide-related behavior.
* Have a baseline Patient Health Questionnaire-9 (PHQ-9) score of 15 or greater, and/or a score of 2 or greater for either
Inclusion Criteria:
* Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as per IW-CLL 2018 criteria with biopsy proven transformation to diffuse large B-cell lymphoma (DLBCL), consistent with Richter's Transformation. The diagnostic sample must be reviewed by the treating institution. Tumor sample may be obtained by core needle or excisional surgical biopsy. A fresh biopsy is encouraged, but an archival sample is acceptable if the following provisions are met: 1) availability of a tumor-containing formalin-fixed, paraffin-embedded (FFPE) tissue block, 2) if the tumor containing FFPE tissue block cannot be provided in total, sections from this block should be provided. Biopsy can be obtained up to 3 months prior to first day of treatment.
* Cohort-specific eligibility criteria:
* Glofitamab monotherapy cohort: Patients with either relapsed/refractory or previously untreated Richter's Transformation.
* Glofitamab + polatuzumab vedotin cohort: Patients with previously untreated RT. After the first 10 patients are enrolled in this cohort irrespective of prior BTKi exposure status, the remainder of the patients enrolled to this cohort must have previously untreated RT and no prior BTK inhibitor. Patients cannot have prior polatuzumab vedotin exposure.
* Glofitamab + pirtobrutinib cohort: Patients with previously untreated RT and prior BTK inhibitor exposure (with enrollment to begin only after the first 10 patients are accrued to the polatuzumab combination cohort). Patients cannot have prior pirtobrutinib exposure.
* Glofitamab + atezolizumab cohort: Patients with relapsed/refractory RT. Patients are required to have received ≥ 1 prior line of therapy. Patients cannot have prior atezolizumab exposure.
* Age ≥18 years.
* ECOG performance status of 0-2 (Appendix A).
* For patients receiving glofitamab monotherapy, glofitamab in combination with polatuzumab vedotin, or glofitamab in combination with atezolizumab, participants must meet the following organ and marrow function as defined below:
* Absolute neutrophil count must be \> 1.0 x10\^9/L (growth factor allowed to achieve), unless patients have significant bone marrow involvement of their malignancy confirmed on biopsy.
* Platelets must be \> 30 x10\^9/L, independent of transfusion within 7 days of screening, unless patients have bone marrow involvement of their malignancy confirmed on biopsy
* Creatinine \< 2.0 x ULN (upper limit of normal) or estimated CrCl \> 50 ml/min
* Total bilirubin \< 1.5 X ULN
* Subjects with Gilbert's Syndrome or resolving autoimmune hemolytic anemia may have a bilirubin up to 3.0 X ULN
* AST/ALT \< 3.0 X ULN, unless documented liver involvement by lymphoma
* For patients receiving glofitamab in combination with pirtobrutinib, participants must meet the following:
* Absolute neutrophil count must be \> 1.0 x109/L (growth factor \>7 days prior allowed to achieve), unless patients have significant bone marrow involvement of their malignancy confirmed on biopsy.
* Hemoglobin \> 8 g/dL, independent of transfusion within 7 days of screening, unless patients have bone marrow involvement of their malignancy confirmed on biopsy
* Platelets must be \> 50 x109/L, independent of transfusion within 7 days of screening
* Estimated CrCl \> 50 ml/min according to Cockcroft/Gault formula
* AST/ALT \< 3.0 X ULN, or \< 5.0 X ULN with documented liver involvement by lymphoma
* Total bilirubin \< 1.5 X ULN or \< 3.0 x ULN with documented liver involvement by lymphoma and/or Gilbert's Disease
* Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN.
* The patient is able to take oral medications
* Patients who have undergone prior allogeneic transplantation are potentially eligible if their transplant day 0 is \> 6 months from their first dose of treatment and as follows:
* For patients receiving glofitamab monotherapy or glofitamab in combination with polatuzumab vedotin, all of the following must additionally be true:
* No current or prior Grade 3/4 graft versus host disease (GVHD)
* Stable off of immunosuppression for at least 2 months prior to receiving their first dose of treatment on study
* For patients receiving glofitamab in combination with pirtobrutinib, all of the following must additionally be true:
* No active/current GVHD
* No prior history of Grade 3/4 GVHD
* Stable off of immunosuppression for at least 2 months prior to receiving their first dose of treatment on study
* For patients receiving atezolizumab, no prior allogeneic hematopoietic cell transplantation is allowed.
* Willingness to remain abstinent (refrain from heterosexual intercourse) or to use effective contraceptive methods that result in a failure rate of \<1% per year during the treatment period and for at least the following durations listed below:
* Female patients: at least 18 months after pre-treatment with obinutuzumab, or 2 months after the last dose of glofitamab, or 5 months after the last dose of atezolizumab, or 9 months after the last dose of polatuzumab vedotin, 3 months after the last dose of tocilizumab (if applicable), or 1 month after the last dose of pirtobrutinib, whichever whichever is longest.
* Male patients: at least 3 months after pre-treatment with obinutuzumab, or 2 months after the last dose of glofitamab, or 5 months after the last dose of polatuzumab vedotin, or 2 months after the last dose of tocilizumab (if applicable), whichever is longest.
* Examples of highly effective contraceptive methods with a failure rate of \<1% per year include: Tubal ligation, male sterilization, hormonal implants, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of \<1% per year. Barrier methods must always be supplemented with the use of a spermicide.
* For female patients, willingness to refrain from donating ova during the same periods described in section 3.1.6 for female patients. For male patients, willingness to refrain from donating sperm during the same periods described in section 3.1.6 for male patients.
* Ability to understand and the willingness to sign a written informed consent document. (Providing consents in as many languages as possible is encouraged)
Exclusion Criteria:
* Patients with the Hodgkin variant transformation of CLL will be excluded.
* No prior anti-CD20 bispecific antibody is allowed. No prior, polatuzumab vedotin is allowed for patients in the polatuzumab vedotin-containing combination arm. No prior, or atezolizumab therapy is allowed for patients in the atezolizumab-containing combination arm. No prior pirtobrutinib is allowed for patients in the pirtobrutinib-containing arm.
* Subject has received any of the following within 14 days or 5 drug half-lives (whichever is shortest) prior to the first dose of treatment: investigational agents, targeted therapies, e.g. tyrosine kinase inhibitors, systemic immunotherapeutic/immunostimulating agents, including, but not limited to, CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, radio-immunoconjugates, antibody-drug conjugates (patients in the pirtobrutinib combination arm may not have received an antibody-drug conjugate within 28 days prior to the first dose of study treatment), immune/cytokines and monoclonal antibodies. Patients who are currently receiving treatment with a Bruton's tyrosine kinase inhibitor may continue this agent until the day prior to starting treatment, to reduce the risk of tumor flare on treatment cessation.
* Prior treatment with CAR T-cell therapy within 30 days before first study treatment administration.
* Subject has not recovered to less than Grade 1 clinically significant adverse effect(s)/toxicity from prior anti-cancer therapy including immunotherapy, with the exception of alopecia, endocrinopathy managed with replacement therapy, and stable vitiligo.
* Patients with bulky cervical adenopathy that is compressing the upper airway and could result in significant further airway compression during a tumor flare event.
* History of other malignancies, except:
* CLL/SLL
* Malignancy treated with curative intent and with no known active disease present before the first dose of study drug and felt to be at low risk for recurrence by treating physician
* Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
* Adequately treated carcinoma in situ without evidence of disease
* Low-risk prostate cancer on active surveillance
* For patients receiving polatuzumab vedotin: Current \> Grade 1 peripheral neuropathy.
* Any history of immune-related ≥ Grade 3 AE with the exception of endocrinopathy managed with replacement therapy.
* Patient with history of confirmed progressive multifocal leukoencephalopathy (PML).
* Current or past history of central nervous system (CNS) disease involvement or history of leptomeningeal disease.
* Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis or neurodegenerative disease (Note: patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits, as judged by the investigator, are permitted).
* History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
* Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).
* Prior solid organ transplantation.
* History of known or suspected hemophagocytic lymphohistiocytosis (HLH).
* Active or history of autoimmune disease, including but not limited to myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
* Patients with a remote history of, or well controlled, autoimmune disease may be eligible to enroll after consultation with the study PI.
* Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone and patients with controlled Type 1 diabetes mellitus who are on an insulin regimen can be included.
* Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided that the disease is well controlled (Rash \<10% of BSA, and no acute exacerbations requiring methotrexate, retinoids, biologics, or high potency oral corticosteroids) at baseline and requires only low-potency topical corticosteroids.
* For patients enrolling to the pirtobrutinib combination arm, patients with the following should be discussed with the Sponsor-Investigator prior to enrollment: active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts.
* Patients who require systemic immunosuppressive therapy for an ongoing medical condition will be excluded with the exception of corticosteroid use for disease-related symptom control. Treatment for autoimmune disease with systemic immunosuppressive medications including, but not limited to, prednisone, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents are not allowed within 2 weeks prior to Day 1 of Cycle 1.
* Note the following are permitted: use of inhaled corticosteroids, use of mineralocorticoids for management of orthostatic hypotension.
* Corticosteroids for lymphoma symptom control is allowed provided patients are on a stable dose as per discretion of the treating investigator and in discussion with the Sponsor-Investigator.
* History of severe allergic or anaphylactic reactions to monoclonal antibody therapy unless in consultation with an allergy specialist they are deemed eligible for retreatment with desensitization.
* Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia).
* History of Human Immunodeficiency Virus (HIV):
* For patients receiving glofitamab in combination with pirtobrutinib, patients who have tested positive for HIV are excluded due to risk of opportunistic infections with both HIV and BTK inhibitors. For patients with unknown HIV status, HIV testing will be performed at screening and result must be negative for enrollment.
* For patients in all other cohorts, only those without controlled disease (controlled disease defined as CD4 count greater than or equal to 200 per microliter, undetectable viral load, and stable anti-retroviral therapy) will be excluded.
* History of Human T-Cell Leukemia Virus 1 (HTLV-1) infection.
* Known active cytomegalovirus (CMV) infection.
* Clinically significant liver disease, including cirrhosis and active viral or non-viral hepatitis. Patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative viral load (by PCR testing), be willing to undergo regular testing, and be able to be treated with a prophylactic agent (e.g. entecavir). Patients with hepatitis C seropositivity are eligible only if they have a negative viral load (by PCR testing).
* Patients with a known active infection or any major episode of infection requiring hospitalization or treatment with IV antimicrobial within 4 weeks prior to first study drug. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation), antivirals, or antifungals may participate.
* Patients should not have received immunization with live vaccines within 28 days prior to start of study treatment. In addition, patients must not receive live, attenuated vaccines (e.g., FluMist®) while receiving study treatment or after the last dose until B-cell recovery to the normal ranges. Inactivated influenza vaccination is permitted during influenza season.
* Patients with any one of the following currently or in the previous 6 months will be excluded: myocardial infarction, congenital long QT syndrome, torsade de pointes, unstable angina, or coronary/peripheral artery bypass graft.
* Patients with New York Heart Association Class III or IV heart failure or with Objective Assessment Class C or D cardiac disease.
* For patients receiving pirtobrutinib:
* Significant cardiovascular disease defined as:
* unstable angina or acute coronary syndrome within the past 2 months prior to randomization
* history of myocardial infarction within 3 months prior to randomization or
* documented LVEF by any method of ≤ 40% in the 12 months prior to randomization
* Uncontrolled or symptomatic arrhythmias
* Note: patients with atrial fibrillation are allowed as long as they are adequately rate-controlled.)
* Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
* Prolongation of the QT interval corrected for heart rate (QTcF) \> 470 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33).
* Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
* Correction for underlying bundle branch block (BBB) allowed.
* Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug.
* Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts.
* Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
* Have a known hypersensitivity to any of the excipients of Pirtobrutinib or to any intended study medications.
* Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor. Note: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)
* History of bleeding disorders (e.g. von Willebrand's disease, hemophilia).
* History of stroke or intracranial hemorrhage within 6 months of starting study therapy.
* Inability to comply with protocol mandated hospitalizations and restrictions.
* Patients who are pregnant, breast-feeding, or intending to become pregnant during the study.
* Any other diseases, metabolic dysfunction, physical examination finding, mental status or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug.
→
Inclusion Criteria:
Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as per IW-CLL 2018 criteria with biopsy proven transformation to large B-cell lymphoma (LBCL), consistent with Richter's Transformation. The diagnostic sample must be reviewed by the treating institution.
* Tumor sample may be obtained by core needle or excisional surgical biopsy.
* A fresh biopsy is encouraged, but an archival sample is acceptable if the following provisions are met: 1) availability of a tumor-containing formalin-fixed, paraffin-embedded (FFPE) tissue block, 2) if the tumor containing FFPE tissue block cannot be provided in total, sections from this block should be provided.
* Biopsy can be obtained up to 3 months prior to first day of treatment.
Measurable disease, defined as ≥1 measurable nodal lesion (long axis \>1.5 cm or short axis \>1.0 cm) or ≥1 measurable extra-nodal lesion (long axis \>1.0 cm) on PET, CT, or magnetic resonance imaging (MRI). Disease should be FDG-avid based on PET.
Cohort-specific eligibility criteria:
* Glofitamab monotherapy cohort: Patients with either relapsed/refractory or previously untreated Richter's Transformation.
* Glofitamab + polatuzumab vedotin cohort: Patients with previously untreated RT. After the first 10 patients are enrolled in this cohort irrespective of prior BTKi exposure status, the remainder of the patients enrolled to this cohort must have previously untreated RT and no prior BTK inhibitor. Patients cannot have prior polatuzumab vedotin exposure.
* Glofitamab + pirtobrutinib cohort: Patients with previously untreated RT and prior BTK inhibitor exposure (with enrollment to begin only after the first 10 patients are accrued to the polatuzumab combination cohort). Patients cannot have prior pirtobrutinib exposure.
* Glofitamab + atezolizumab cohort: Patients with relapsed/refractory RT. Patients are required to have received ≥ 1 prior line of therapy. Patients cannot have prior atezolizumab exposure.
Age ≥18 years.
ECOG performance status of 0-2 (Appendix A).
For patients receiving glofitamab monotherapy, glofitamab in combination with polatuzumab vedotin, or glofitamab in combination with atezolizumab, participants must meet the following organ and marrow function as defined below:
* Absolute neutrophil count must be \> 1.0 x109/L (growth factor allowed to achieve), unless patients have significant bone marrow involvement of their malignancy confirmed on biopsy.
* Platelets must be \> 30 x109/L, independent of transfusion within 7 days of screening, unless patients have bone marrow involvement of their malignancy confirmed on biopsy
* Creatinine \< 2.0 x ULN (upper limit of normal) or estimated CrCl \> 50 ml/min according to Cockcroft/Gault formula
* Total bilirubin \< 1.5 X ULN
o Subjects with Gilbert's Syndrome or resolving autoimmune hemolytic anemia may have a bilirubin up to 3.0 X ULN
* AST/ALT \< 3.0 X ULN, unless documented liver involvement by lymphoma
For patients receiving glofitamab in combination with pirtobrutinib, participants must meet the following:
* Absolute neutrophil count must be \> 1.0 x109/L (growth factor \>7 days prior allowed to achieve), unless patients have significant bone marrow involvement of their malignancy confirmed on biopsy.
* Hemoglobin \> 8 g/dL, independent of transfusion within 7 days of screening, unless patients have bone marrow involvement of their malignancy confirmed on biopsy
* Platelets must be \> 50 x109/L, independent of transfusion within 7 days of screening
* Estimated CrCl \> 50 ml/min according to Cockcroft/Gault formula
* AST/ALT \< 3.0 X ULN, or \< 5.0 X ULN with documented liver involvement by lymphoma
* Total bilirubin \< 1.5 X ULN or \< 3.0 x ULN with documented liver involvement by lymphoma and/or Gilbert's Disease
* Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN.
* The patient is able to take oral medications
Patients who have undergone prior allogeneic transplantation are potentially eligible if their transplant day 0 is \> 6 months from their first dose of treatment and as follows:
For patients receiving glofitamab monotherapy or glofitamab in combination with polatuzumab vedotin, all of the following must additionally be true:
* No current or prior Grade 3/4 graft versus host disease (GVHD)
* Stable off of immunosuppression for at least 2 months prior to receiving their first dose of treatment on study
For patients receiving glofitamab in combination with pirtobrutinib, all of the following must additionally be true:
* No active/current GVHD
* No prior history of Grade 3/4 GVHD
* Stable off of immunosuppression for at least 2 months prior to receiving their first dose of treatment on study
For patients receiving atezolizumab, no prior allogeneic hematopoietic cell transplantation is allowed.
Willingness to remain abstinent (refrain from heterosexual intercourse) or to use highly effective contraceptive methods that result in a failure rate of \<1% per year during the treatment period and for at least the following durations listed below:
* Female patients: at least 18 months after pre-treatment with obinutuzumab, or 2 months after the last dose of glofitamab, or 5 months after the last dose of atezolizumab, or 9 months after the last dose of polatuzumab vedotin, or 3 months after the last dose of tocilizumab (if applicable), or 1 month after the last dose of pirtobrutinib, whichever is longest.
* Male patients: at least 6 months after pre-treatment with obinutuzumab, or 2 months after the last dose of glofitamab, or 6 months after the last dose of polatuzumab vedotin, or 2 months after the last dose of tocilizumab (if applicable), whichever is longest.
* Examples of highly effective contraceptive methods with a failure rate of \<1% per year include: Tubal ligation, male sterilization, hormonal implants, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of \<1% per year. Barrier methods must always be supplemented with the use of a spermicide.
For female patients, willingness to refrain from donating ova during the same periods described in section 3.1.6 for female patients. For male patients, willingness to refrain from donating sperm during the same periods described in section 3.1.6 for male patients.
Ability to understand and the willingness to sign a written informed consent document. (Providing consents in as many languages as possible is encouraged)
Exclusion Criteria:
Patients with the Hodgkin variant transformation of CLL will be excluded.
No prior anti-CD20 bispecific antibody is allowed. No prior polatuzumab vedotin is allowed for patients in the polatuzumab vedotin-containing combination arm. No prior atezolizumab therapy is allowed for patients in the atezolizumab-containing combination arm. No prior pirtobrutinib is allowed for patients in the pirtobrutinib-containing arm.
Subject has received any of the following within 14 days or 5 drug half-lives (whichever is shortest) prior to the first dose of treatment: investigational agents, targeted therapies, e.g. tyrosine kinase inhibitors, systemic immunotherapeutic/immunostimulating agents, including, but not limited to, CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, radio-immunoconjugates, antibody-drug conjugates1, immune/cytokines and monoclonal antibodies. Patients who are currently receiving treatment with an agent targeting Bruton's tyrosine kinase may continue this agent until the day prior to starting treatment, to reduce the risk of tumor flare on treatment cessation (patients in the pirtobrutinib combination arm may not have received an antibody-drug conjugate within 28 days prior to the first dose of study treatment).
Prior treatment with CAR T-cell therapy within 30 days before first study treatment administration.
Subject has not recovered to less than Grade 1 clinically significant adverse effect(s)/toxicity from prior anti-cancer therapy including immunotherapy, with the exception of alopecia, endocrinopathy managed with replacement therapy, and stable vitiligo.
Patients with bulky cervical adenopathy that is compressing the upper airway and could result in significant further airway compression during a tumor flare event.
History of other malignancies, except:
* CLL/SLL
* Malignancy treated with curative intent and with no known active disease present before the first dose of study drug and felt to be at low risk for recurrence by treating physician
* Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
* Adequately treated carcinoma in situ without evidence of disease
* Low-risk prostate cancer on active surveillance
For patients receiving polatuzumab vedotin: Current \> Grade 2 peripheral neuropathy.
Any history of immune-related ≥ Grade 3 AE with the exception of endocrinopathy managed with replacement therapy.
Patient with history of confirmed progressive multifocal leukoencephalopathy (PML).
Current or past history of central nervous system (CNS) disease involvement or history of leptomeningeal disease.
Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis or neurodegenerative disease (Note: patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 6 months and have no residual neurologic deficits, as judged by the investigator, are permitted).
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).
Prior solid organ transplantation.
History of known or suspected hemophagocytic lymphohistiocytosis (HLH).
Active or history of autoimmune disease, including but not limited to myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
* Patients with a remote history of, or well controlled, autoimmune disease may be eligible to enroll after consultation with the study PI.
* Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone and patients with controlled Type 1 diabetes mellitus who are on an insulin regimen can be included.
* Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided that the disease is well controlled (Rash \<10% of BSA, and no acute exacerbations requiring methotrexate, retinoids, biologics, or high potency oral corticosteroids) at baseline and requires only low-potency topical corticosteroids.
* For patients enrolling to the pirtobrutinib combination arm, patients with the following will be excluded: active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts.
Patients who require systemic immunosuppressive therapy for an ongoing medical condition will be excluded with the exception of corticosteroid use for disease-related symptom control. Treatment for autoimmune disease with systemic immunosuppressive medications including, but not limited to, prednisone, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents are not allowed within 2 weeks prior to Day 1 of Cycle 1.
* Note the following are permitted: use of inhaled corticosteroids, use of mineralocorticoids for management of orthostatic hypotension.
* Corticosteroids for lymphoma symptom control is allowed provided patients are on a stable dose as per discretion of the treating investigator and in discussion with the Sponsor-Investigator.
History of severe allergic or anaphylactic reactions to monoclonal antibody therapy unless in consultation with an allergy specialist they are deemed eligible for retreatment with desensitization.
Patients who have had a major surgery or significant traumatic injury within 2 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia).
History of Human Immunodeficiency Virus (HIV):
* For patients receiving glofitamab in combination with pirtobrutinib, patients who have tested positive for HIV are excluded due to risk of opportunistic infections with both HIV and BTK inhibitors. For patients with unknown HIV status, HIV testing will be performed at screening and result must be negative for enrollment.
* For patients in all other cohorts, only those without controlled disease (controlled disease defined as CD4 count ≥ 200/uL, undetectable viral load, and stable anti-retroviral therapy) will be excluded.
History of Human T-Cell Leukemia Virus 1 (HTLV-1) infection.
Known active cytomegalovirus (CMV) infection.
Clinically significant liver disease, including cirrhosis and active viral or non-viral hepatitis. Patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative viral load (by PCR testing), be willing to undergo regular testing, and be able to be treated with a prophylactic agent (e.g. entecavir) if indicated (see Section 5.5). Patients with hepatitis C seropositivity are eligible only if they have a negative viral load (by PCR testing).
Patients with a known active infection.
Patients with any major episode of infection requiring hospitalization within 2 weeks prior to first study drug or treatment-directed antimicrobials within 1 week prior to first study drug. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation), antivirals, or antifungals may participate.
Patients should not have received immunization with live vaccines within 28 days prior to start of study treatment. In addition, patients must not receive live, attenuated vaccines (e.g., FluMist®) while receiving study treatment or after the last dose until B-cell recovery to the normal ranges. Inactivated influenza vaccination is permitted during influenza season.
Patients with any one of the following currently or in the previous 6 months will be excluded: myocardial infarction, congenital long QT syndrome, torsade de pointes, unstable angina, or coronary/peripheral artery bypass graft.
Patients with New York Heart Association Class III or IV heart failure or with Objective Assessment Class C or D cardiac disease.
For patients receiving pirtobrutinib:
* Significant cardiovascular disease defined as:
* unstable angina or acute coronary syndrome within the past 2 months prior to randomization
* history of myocardial infarction within 3 months prior to randomization or
* documented LVEF by any method of ≤ 40% in the 12 months prior to randomization
* Uncontrolled or symptomatic arrhythmias
* Note: patients with atrial fibrillation are allowed as long as they are adequately rate-controlled.)
* Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
* Prolongation of the QT interval corrected for heart rate (QTcF) \> 470 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33).
* Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
* Correction for underlying bundle branch block (BBB) allowed.
* Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug.
* Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts.
* Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
* Have a known hypersensitivity to any of the excipients of Pirtobrutinib or to any intended study medications.
* Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor. Note: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)
* History of bleeding disorders (e.g. von Willebrand's disease, hemophilia).
* History of stroke or intracranial hemorrhage within 6 months of starting study therapy.
Inability to comply with protocol mandated hospitalizations and restrictions.
Patients who are pregnant, breast-feeding, or intending to become pregnant during the study.
Any other diseases, metabolic dysfunction, physical examination finding, mental status or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug.
Inclusion Criteria:
* Must have an established diagnosis of Ulcerative Colitis (UC) or Crohn's Disease (CD) for at least 3 month duration, which includes clinical and endoscopic evidence of UC or CD and a histopathology report that supports a diagnosis of UC or CD.
* For UC:
* Have moderately to severely active UC as defined by a modified Mayo score (mMS) of 5-9 points and Endoscopic Subscore (ES) greater than or equal to (≥) 2, confirmed by the central reader and rectal bleeding (RB)≥1, with endoscopy performed within 21 days prior to Visit 2.
* For CD:
* Have moderately to severely active CD as defined by a Crohn's disease activity index (CDAI) score ≥ 220 and less than or equal to (≤) 450. Have a centrally read Simple Endoscopic Score for Crohn's Disease (SES-CD) score ≥6 for participants with ileal-colonic or ≥4 for participants with isolated ileal disease within 21 days before the randomization
* Must have demonstrated an inadequate response, loss of response, or intolerance to at least one of the following: corticosteroids, immunomodulators, or an advanced therapy for UC or CD
* Have screening laboratory test results within the protocol specified parameters.
Exclusion Criteria:
* Must not have a current diagnosis of inflammatory bowel disease (IBD)-unclassified or primary sclerosing cholangitis
* For UC - must not have a current diagnosis of CD
* For CD - must not have a current diagnosis of UC
* Must not have had or will need bowel resection or intestinal or intra-abdominal surgery as specified in the protocol
* Must not have complications of UC or CD, including but not limited to stricture or stenosis (some exceptions allowed for CD) or short bowel syndrome
* Must not have a significant uncontrolled illness that in the opinion of the investigator may compromise the participant's safety or interfere with interpretation of data
* Must not have failed more than 5 approved advanced treatments for UC or CD with different mechanisms of action
* Must not have failed an anti-interleukin-23p19 (anti-IL-23p19) antibody treatment
* Must not have received or will need any prohibited medications for UC or CD as specified in the protocol
→
Inclusion Criteria:
* Must have an established diagnosis of Ulcerative Colitis (UC) or Crohn's Disease (CD) for at least 3 month duration, which includes clinical and endoscopic evidence of UC or CD and a histopathology report that supports a diagnosis of UC or CD.
* For UC:
* Have moderately to severely active UC as defined by a modified Mayo score (mMS) of 5-9 points and Endoscopic Subscore (ES) greater than or equal to (≥) 2, confirmed by the central reader and rectal bleeding (RB)≥1.
* For CD:
* Have moderately to severely active CD as defined by a Crohn's disease activity index (CDAI) score ≥ 220 and less than or equal to (≤) 450. Have a centrally read Simple Endoscopic Score for Crohn's Disease (SES-CD) score ≥6 for participants with ileal-colonic or ≥4 for participants with isolated ileal disease.
* Must have demonstrated an inadequate response, loss of response, or intolerance to at least one of the following: corticosteroids, immunomodulators, or an advanced therapy for UC or CD
* Have screening laboratory test results within the protocol specified parameters.
Exclusion Criteria:
* Must not have a current diagnosis of inflammatory bowel disease (IBD)-unclassified or primary sclerosing cholangitis
* For UC - must not have a current diagnosis of CD
* For CD - must not have a current diagnosis of UC
* Must not have had or will need bowel resection or intestinal or intra-abdominal surgery as specified in the protocol
* Must not have complications of UC or CD, including but not limited to stricture or stenosis (some exceptions allowed for CD) or short bowel syndrome
* Must not have a significant uncontrolled illness that in the opinion of the investigator may compromise the participant's safety or interfere with interpretation of data
* Must not have failed more than 5 approved advanced treatments for UC or CD with different mechanisms of action
* Must not have failed an anti-interleukin-23p19 (anti-IL-23p19) antibody treatment
* Must not have received or will need any prohibited medications for UC or CD as specified in the protocol
Inclusion Criteria:
* Must have clinical or imaging evidence of fibroblast activation protein (FAP) expression per local assessment
* Must have histologically or cytologically confirmed diagnosis of one of the following:
* Adenocarcinoma of the pancreas
* Hormone receptor (HR)-positive human epidermal growth factor 2 (HER2)-negative breast cancer
* HER2-positive breast cancer
* Triple negative breast cancer (TNBC)
* Platinum-resistant or refractory ovarian cancer (including ovarian carcinosarcoma)
* Other solid tumors
* Gastric cancer (adenocarcinoma)
* Colorectal cancer (CRC)
* Esophageal cancer (squamous cell carcinoma or adenocarcinoma)
* Cholangiocarcinoma
* Must have received prior treatments as indicated below:
* Phase 1a
* Adenocarcinoma of the pancreas: Participants must have received at least 1, but no more than 2 prior regimens for locally advanced unresectable or metastatic disease.
* HR-positive HER2-negative breast cancer: Participants must have received less than or equal to (≤)5 prior lines of treatment for advanced or metastatic disease, which must include a cyclin-dependent kinase 4/6 inhibitor.
* HER2-positive breast cancer: Participants must have received at least 2 lines of HER2-targeted therapy, which should include at least 1 antibody-drug conjugate (ADC) for metastatic disease (if locally available).
* TNBC: Participants must have received at least 2 lines of therapy for metastatic disease.
* Platinum-resistant or refractory ovarian cancer: Participants must have received or after at least 1 platinum-based therapy.
* Other solid tumors (gastric cancer, CRC, esophageal and cholangiocarcinoma): Participants must have received greater than or equal to (≥)1 prior line of systemic therapy for advanced or metastatic disease; including prior line(s) in combination with immunotherapy or vascular endothelial growth factor inhibitor.
* Phase 1b:
* Participants must have advanced or metastatic solid tumors and have received ≥1 prior line of therapy.
* Must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1.
* Measured creatinine clearance ≥60 milliliters per minute (mL/min)
Exclusion Criteria:
* Have known active central nervous system (CNS) metastases or carcinomatous meningitis.
* Have significant cardiovascular disease
* Have prolongation of the corrected QTcF \>470 milliseconds (msec) during screening. QTcF is calculated using Fridericia's Formula: QTcF = QT/(RR0.33)
* Have evidence of ongoing and untreated urinary tract obstruction
* Had previous hemi- or total-body radiation.
* Had previous adoptive T-cell therapy (e.g., chimeric antigen receptor T-cell \[CAR-T therapy, T-cell receptor \[TCR\] therapy, etc.)
* Unable to lie flat during, or otherwise tolerate, single photon emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT) or magnetic resonance imaging (MRI).
→
Inclusion Criteria:
* Must have clinical or imaging evidence of fibroblast activation protein (FAP) expression per local assessment
* Must have histologically or cytologically confirmed diagnosis of one of the following:
* Adenocarcinoma of the pancreas
* Hormone receptor (HR)-positive human epidermal growth factor 2 (HER2)-negative breast cancer
* HER2-positive breast cancer
* Triple negative breast cancer (TNBC)
* Platinum-resistant or refractory ovarian cancer (including ovarian carcinosarcoma)
* Gastric cancer (adenocarcinoma)
* Colorectal cancer (CRC)
* Esophageal cancer (squamous cell carcinoma or adenocarcinoma)
* Cholangiocarcinoma
* Other non- central nervous system (CNS) solid tumors, which have demonstrated FAP uptake via positron emission tomography (PET),
* Must have received prior treatments as indicated below:
* Phase 1a
* Adenocarcinoma of the pancreas: Participants must have received at least 1, but no more than 2 prior regimens for locally advanced unresectable or metastatic disease.
* HR-positive HER2-negative breast cancer: Participants must have received less than or equal to (≤)5 prior lines of treatment for advanced or metastatic disease, which must include a cyclin-dependent kinase 4/6 inhibitor.
* HER2-positive breast cancer: Participants must have received at least 2 lines of HER2-targeted therapy, which should include at least 1 antibody-drug conjugate (ADC) for metastatic disease (if locally available).
* TNBC: Participants must have received at least 1 prior line of therapy for metastatic disease, and must have received an ADC unless unavailable, ineligible, or refused.
* Platinum-resistant or refractory ovarian cancer: Participants must have received or after at least 1 platinum-based therapy.
* Gastric cancer, CRC, esophageal cancer (squamous cell carcinoma or adenocarcinoma), and cholangiocarcinoma: Participants must have received greater than or equal to (≥)1 prior line of systemic therapy for advanced or metastatic disease; this may include, but does not require, prior line(s) in combination with immunotherapy or vascular endothelial growth factor inhibitor.
* Other non-CNS solid tumors: Participants must have exhausted, be ineligible for, or refused all standard-of-care therapy appropriate for their disease.
* Phase 1b:
* Participants must have advanced or metastatic solid tumors and have received ≥1 prior line of therapy.
* Must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1.
* Measured creatinine clearance ≥60 milliliters per minute (mL/min)
Exclusion Criteria:
* Have known active central nervous system (CNS) metastases or carcinomatous meningitis.
* Have significant cardiovascular disease
* Have prolongation of the corrected QTcF \>470 milliseconds (msec) during screening. QTcF is calculated using Fridericia's Formula: QTcF = QT/(RR0.33)
* Have evidence of ongoing and untreated urinary tract obstruction
* Had previous hemi- or total-body radiation.
* Had previous adoptive T-cell therapy (e.g., chimeric antigen receptor T-cell \[CAR-T therapy, T-cell receptor \[TCR\] therapy, etc.)
* Unable to lie flat during, or otherwise tolerate, single photon emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT) or magnetic resonance imaging (MRI).
Inclusion Criteria:
* Age ≥21 years at the time of enrollment
* Confirmed diagnosis of ulcerative colitis (UC) or Crohn's disease (CD)
* Eligible for treatment with biologic therapy for IBD, defined as failure of prior conventional therapy and/or prior biologic therapy (excluding IL-23p19 antagonists)
* No prior exposure to mirikizumab and no contraindications to mirikizumab
* Ability to provide informed consent
* Willingness to comply with study procedures and follow-up requirements
Exclusion Criteria:
* Prior exposure to IL-23p19 antagonists (e.g., mirikizumab, risankizumab, guselkumab)
* Prior exposure to small molecule targeted therapies for IBD (e.g., JAK inhibitors or S1P receptor modulators)
* Participation in an interventional clinical trial within 90 days prior to enrollment
* History of extensive colorectal resection, including:
* Total proctocolectomy (for UC), or
* Surgical removal of two or more intestinal segments (for CD)
* Any condition that, in the investigator's judgment, may compromise patient safety, data integrity, or ability to participate in the study
→
Inclusion Criteria:
* Age ≥21 years at the time of enrollment
* Confirmed diagnosis of ulcerative colitis (UC) or Crohn's disease (CD)
* Eligible for treatment with biologic therapy for IBD, as per the IBD Clinical Care Pathway
* No prior exposure to mirikizumab and no contraindications to mirikizumab
* Ability to provide informed consent
* Willingness to comply with study procedures and follow-up requirements
Exclusion Criteria:
* Prior exposure to IL-23p19 antagonists (e.g., mirikizumab, risankizumab, guselkumab)
* Prior exposure to small molecule targeted therapies for IBD (e.g., JAK inhibitors or S1P receptor modulators)
* Participation in an interventional clinical trial within 90 days prior to enrollment
* History of extensive colorectal resection, including:
* Total proctocolectomy (for UC), or
* Surgical removal of two or more intestinal segments (for CD)
* Any condition that, in the investigator's judgment, may compromise patient safety, data integrity, or ability to participate in the study