A Study Evaluating the Efficacy and Safety of Cevostamab in Prior B Cell Maturation Antigen (BCMA)-Exposed Participants With Relapsed/Refractory Multiple Myeloma

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, and pharmacokinetics of cevostamab in participants with refractory multiple myeloma (R/R MM) via intravenous (IV) infusion.

Official Title
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A Phase I/II, Open-Label, Multi-Cohort Study to Evaluate the Efficacy and Safety of Cevostamab in Prior B Cell Maturation Antigen-Exposed Patients With Relapsed/Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Cevostamab
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of MM based on standard International Myeloma Working Group (IMWG) criteria Evidence of progressive disease based on investigators determination of response by IMWG criteria on or after their last dosing regimen Prior BCMA ADC or CAR-T Cohort: participants who have received a BCMA-targeted CAR-T or ADC therapy and are triple-class refractory Prior BCMA Bispecific Cohort: participants who have received a BCMA-targeting T-cell-dependent bispecific (TDB) antibody and are triple-class refractory Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Life expectancy is at least 12 weeks Agreement to protocol-specified assessments, including bone marrow biopsy and aspirate samples as detailed in the protocol Resolution of AEs from prior anti-cancer therapy to Grade =< 1 For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for at least 5 months after the final dose of cevostamab and for 3 months after the last dose of tocilizumab was administered For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm during the treatment period and for at least 2 months after the final dose of tocilizumab (if applicable) to avoid exposing the embryo Exclusion Criteria: Inability to comply with protocol-mandated hospitalization Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of cevostamab or tocilizumab or within 3 months after the last dose of tocilizumab (if applicable) Prior treatment with cevostamab or another agent with the same target Prior BCMA ADC or CAR-T Cohort: prior treatment with any T cell dependent bi-specific antibody (TDB) antibody including non BCMA targeting TDB Prior use of any monoclonal antibody (mAb), radioimmunoconjugate, or ADC as anti-cancer therapy within 4 weeks before first study treatment, except for the use of non-myeloma therapy Prior treatment with systemic immunotherapeutic agents Prior treatment with CAR-T cell therapy within 12 weeks before first cevostamab infusion Known treatment-related, immune-mediated adverse events associated with prior checkpoint inhibitors Treatment with radiotherapy, any chemotherapeutic agent, or treatment with any other anti-cancer agent within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to first study treatment Autologous stem cell transplantation (SCT) within 100 days prior to first study treatment Prior allogeneic SCT Circulating plasma cell count exceeding 500/ microliter (µL) or 5% of the peripheral blood white cells Prior solid organ transplantation History of autoimmune disease History of confirmed progressive multifocal leukoencephalopathy History of severe allergic or anaphylactic reactions to mAb therapy Known history of amyloidosis Lesions in proximity of vital organs that may develop sudden decompensation/deterioration in the setting of a tumor flare History of other malignancy within 2 years prior to screening, except those with negligible risk of metastasis or death, such as ductal carcinoma in situ not requiring chemotherapy, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, low-grade, localized prostate cancer not requiring treatment or appropriately treated Stage I uterine cancer Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, neurodegenerative disease, or CNS involvement by MM Significant cardiovascular disease that may limit a potential participant's ability to adequately respond to a cytokine release syndrome (CRS) event Symptomatic active pulmonary disease or requiring supplemental oxygen Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment, or any major episode of infection requiring treatment with IV (intravenous) antimicrobials where the last dose of IV antimicrobial was given within 14 days prior to first study treatment Active symptomatic COVID-19 infection at study enrollment or requiring treatment with IV antiviral where the last dose of IV antiviral treatment was given within 14 days prior to first study treatment. Participants with active COVID-19 infection must have clinical recovery and two negative antigen tests at least 24 hours apart prior to first study treatment Positive and quantifiable Epstein-Barr virus (EBV) polymerase chain reaction (PCR) or cytomegalovirus (CMV) PCR prior to first study treatment Known or suspected chronic active EBV infection Known history of Grade >=3 CRS or immune effector cell-associated neurotoxicity syndrome (ICANS) with prior bispecific therapies Known history of hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) Recent major surgery within 4 weeks prior to first study treatment Positive serologic or PCR test results for acute or chronic hepatitis B virus (HBV) infection Acute or chronic hepatitis C virus (HCV) infection Known history of human immunodeficiency virus (HIV) seropositivity Administration of a live, attenuated vaccine within 4 weeks before first study treatment or anticipation that such a live attenuated vaccine will be required during the study Treatment with systemic immunosuppressive medications, with the exception of corticosteroid treatment <= 10 mg/day prednisone or equivalent, within 2 weeks prior to first study treatment History of illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment Any medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A1: Prior BCMA antibody-drug conjugate (ADC) or chimeric antigen receptor T (CAR-T)<br>Participants in Cohort A1 will be treated at the double step-up split dosing regimen. | Drug: Cevostamab<br>* Cevostamab will be administered by IV infusion in 21-day cycles.<br>Drug: Tocilizumab<br>* Tocilizumab will be administered for the treatment of cytokine release syndrome (CRS) when necessary.<br>|
| Experimental: Cohort A2: Prior BCMA Bispecific<br>Participants enrolled into exploratory Cohort A2 will receive the same dosing regimen as Cohort A1. | Drug: Cevostamab<br>* Cevostamab will be administered by IV infusion in 21-day cycles.<br>Drug: Tocilizumab<br>* Tocilizumab will be administered for the treatment of cytokine release syndrome (CRS) when necessary.<br>|
| Experimental: Cohort B1: Prior BCMA ADC or CAR-T<br>Participants enrolled in expansion Cohort B1, will be given cevostamab at the recommended Phase 2 dose (RP2D). | Drug: Cevostamab<br>* Cevostamab will be administered by IV infusion in 21-day cycles.<br>Drug: Tocilizumab<br>* Tocilizumab will be administered for the treatment of cytokine release syndrome (CRS) when necessary.<br>|
| Experimental: Cohort B2: Prior BCMA Bispecific<br>Expansion Cohort B2 will be opened, after the initial results from Cohort A2, at the same dose as per Cohort B1. | Drug: Cevostamab<br>* Cevostamab will be administered by IV infusion in 21-day cycles.<br>Drug: Tocilizumab<br>* Tocilizumab will be administered for the treatment of cytokine release syndrome (CRS) when necessary.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) |  | Baseline up to approximately 2 years | 
| Percentage of Participants with Adverse Events |  | Baseline up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR |  | Baseline up to approximately 2 years | 
| Duration of Response (DOR) |  | Baseline up to approximately 2 years | 
| Rate of Complete Response (CR) or Better |  | Baseline up to approximately 2 years | 
| Rate of Very Good Partial Response (VGPR) or Better |  | Baseline up to approximately 2 years | 
| Overall Survival (OS) |  | Baseline up until death from any cause (up to approximately 2 years) | 
| Progression-free Survival (PFS) |  | Baseline up to approximately 2 years | 
| Time to First Response (for Participants who Achieve an Objective Response) |  | Baseline up to approximately 2 years | 
| Time to Best Response (for Participants who Achieve an Objective Response) |  | Baseline up to approximately 2 years | 
| Minimal Residual Disease (MRD) Negative Rate |  | Baseline up to approximately 2 years | 
| Percentage of Participants Experiencing a Clinically Meaningful Improvement in the Fatigue Domain of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core-30 Questionnaire (QLQ-C30) and EORTC QLQ-MY20 |  | Baseline up to approximately 2 years | 
| Time to Deterioration in the Fatigue Domain of the EORTC QLQ-C30 and/or Disease Symptoms Domain of the EORTC QLQ-MY20 |  | Baseline up to approximately 2 years | 
| Serum Concentration of Cevostamab at Specified Timepoints |  | At Cycles 1, 2, 3, 4, 6, 8 and every other cycle until the end of treatment up to approximately 2 years. Each cycle is 21-days. | 
| Number of Anti-drug Antibody (ADAs) Against Cevostamab at Baseline |  | Baseline | 
| Percentage of Participants with ADAs Against Cevostamab During the Study |  | Up to approximately 2 years | 
| Cytokine Release Syndrome (CRS) Following Administration of Tocilizumab |  | Baseline up to approximately 2 years | 
| Relationship Between Serum Concentration of Cevostamab and Cytokine Release |  | Baseline up to approximately 2 years | 
| Relationship Between Serum Concentration of Cevostamab and T Cell Number |  | Baseline up to approximately 2 years | 
| Relationship Between Serum Concentration of Cevostamab and T-cell Activation State |  | Baseline up to approximately 2 years |