A Study Evaluating the Safety, Pharmacokinetics, and Activity of Cevostamab in Participants With Relapsed or Refractory Multiple Myeloma
Phase 1
Active, not recruiting
- Conditions
- Multiple Myeloma
- Interventions
- Registration Number
- NCT04910568
- Lead Sponsor
- Genentech, Inc.
- Brief Summary
This Phase Ib, multicenter, open-label study will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cevostamab monotherapy, cevostamab plus pomalidomide and dexamethasone (Pd) or cevostamab plus daratumumab and dexamethasone (Dd) which will be administered to participants with relapsed or refractory multiple myeloma (R/R MM) via intravenous (IV) infusion.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 126
Inclusion Criteria
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- Life expectancy of at least 12 weeks
- Agreement to provide bone marrow biopsy and aspirate samples
- Resolution of adverse events from prior anti-cancer therapy to Grade <=1
- Measurable disease
- For women of childbearing potential: agreement to remain abstinent or use contraception, during the treatment period (including treatment interruptions) and for at least 5 months after the last dose of cevostamab and at least 3 months after the last dose of tocilizumab was administered
- For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm, during the treatment period, and for at least 2 months after the last dose of tocilizumab was administered to avoid exposing the embryo and sexual partner Additional Arm A-Specific Inclusion Criteria
- Diagnosis of R/R MM for which no established therapy for MM is appropriate and available, or intolerance to those established therapies Additional Arm B-Specific Inclusion Criteria
- For Cohort B1S: Participants with R/R MM who have received at least two prior lines of treatment
- For Cohort B2S and additional cohorts: Participants with R/R MM who have received at least 1 prior line of treatment
- Agreement to comply with all requirements of the pomalidomide pregnancy prevention program
- For women of childbearing potential: agreement to remain abstinent or use two reliable methods of contraception starting at least 4 weeks prior to, during the treatment period, and for at least 4 weeks after the last dose of pomalidomide was administered
- For men: agreement to remain abstinent or use a condom during the treatment period and for at least 4 weeks after the last dose of pomalidomide, (even if he has undergone a successful vasectomy) and agreement to refrain from donating sperm and blood during this same period Additional Arm C-Specific Inclusion Criteria
- For Cohort C1S: Participants with R/R MM who have received at least two prior lines of treatment
- For Cohort C2S and additional cohorts: Participants with R/R MM who have received at least 1 prior line of therapy
- For women of childbearing potential: agreement to remain abstinent or use contraceptive methods during the treatment period and for at least 102 days after the last dose of daratumumab was administered
- For men: agreement to remain abstinent or use a condom during the treatment period and for at least 102 days after the last dose of daratumumab was administered to avoid exposing the embryo, and agreement to refrain from donating sperm during this same period
Exclusion Criteria
- Prior treatment with cevostamab or another agent targeting FcRH5
- Inability to comply with protocol-mandated hospitalization and activities restrictions
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the last dose of cevostamab or within 3 months after the last dose of tocilizumab (if applicable).
- Prior use of any monoclonal antibody, radioimmunoconjugate, or antibody-drugconjugate 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, including, but not limited to, cytokine therapy and anti-CTLA4, anti-PD-1, and antiPD-L1 therapeutic antibodies within 12 weeks or 5 half-lives of the drug, whichever is shorter, before first study treatment
- Prior treatment with chimeric antigen receptor T (CAR T)-cell therapy within 12 weeks before first study treatment
- Treatment with radiotherapy within 4 weeks (systemic radiation) or 14 days (focal radiation) prior to first study treatment
- Treatment with any chemotherapeutic agent or other anti-cancer agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to first study treatment
- Autologous SCT within 100 days prior to first study treatment
- Prior allogeneic stem cell transplant(ation) (SCT)
- Circulating plasma cell count exceeding 500/micro L 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 monoclonal antibody 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
- Known treatment-related, immune-mediated adverse events associated with prior checkpoint inhibitors
- 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
- Symptomatic active pulmonary disease or requiring supplemental oxygen
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
- Known or suspected chronic active Epstein-Barr virus (EBV) infection
- 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 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)
- Active symptomatic coronavirus disease 2019 (COVID-19) infection at study enrollment or requiring treatment with intravenous (IV) antiviral where the last dose of IV antiviral treatment was given within 14 days prior to first study treatment. Patients 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 EBV polymerase chain reaction (PCR) or Cytomegalovirus (CMV) PCR prior to first study treatment
- Known history of 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 Additional Arm B-Specific Exclusion Criteria
- Pregnant or breastfeeding, or intending to become pregnant 4 weeks prior to initiation of study treatment, during the study, (including treatment interruptions) or within 4 weeks after the last dose of pomalidomide
- Significant cardiovascular disease (such as, but not limited to, New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 12 months, uncontrolled arrhythmias, or unstable angina)
- History of erythema multiforme, Grade >=3 rash, blistering, or severe hypersensitivity to prior treatment with immunomodulatory drugs such as thalidomide, lenalidomide, or pomalidomide
- Inability to tolerate thromboprophylaxis, or contraindication to thromboprophylaxis
- GI disease that might significantly alter absorption of oral drugs Additional Arm C-Specific Exclusion Criteria
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 102 days after the last dose of daratumumab
- Known hypersensitivity to biopharmaceuticals produced in CHO cells or any component of daratumumab formulations
- Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal
- Known moderate or severe persistent asthma within the past 2 years, or current uncontrolled asthma of any classification
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Single-Agent Cevostamab (Arm A) Cevostamab Cohort A1S is a safety run-in arm evaluating cevostamab administered in 28-day cycles on a modified weekly schedule. Cohort A1E, an expansion cohort, has been opened and finished enrolling participants. Participants will be treated with single-agent cevostamab administered in 28-day cycles on a modified weekly schedule. Single-Agent Cevostamab (Arm A) Dexamethasone Cohort A1S is a safety run-in arm evaluating cevostamab administered in 28-day cycles on a modified weekly schedule. Cohort A1E, an expansion cohort, has been opened and finished enrolling participants. Participants will be treated with single-agent cevostamab administered in 28-day cycles on a modified weekly schedule. Single-Agent Cevostamab (Arm A) Tocilizumab Cohort A1S is a safety run-in arm evaluating cevostamab administered in 28-day cycles on a modified weekly schedule. Cohort A1E, an expansion cohort, has been opened and finished enrolling participants. Participants will be treated with single-agent cevostamab administered in 28-day cycles on a modified weekly schedule. Cevostamab plus Pomalidomide and Dexamethasone (Pd) (Arm B) Cevostamab Participants will be treated with cevostamab monotherapy during a 14-day period prior to the start of pomalidomide treatment (cevostamab pre-phase). Cohort B1S is a safety run-in arm evaluating cevostamab and Pd administered in 28-day cycles every 2 weeks (Q2W) followed by every 4 weeks (Q4W) schedule. Additional safety run-in cohort(s) with lower target dose levels of cevostamab may be opened prior to opening the expansion cohorts. Two target dose levels of target dose level 1 (DL1) and lower dose level -1 (DL-1) of cevostamab will be selected for randomization in expansion cohorts. Expansion cohorts will follow the same Q2W/Q4W dosing schedule as Cohort B1S. Cevostamab plus Pomalidomide and Dexamethasone (Pd) (Arm B) Tocilizumab Participants will be treated with cevostamab monotherapy during a 14-day period prior to the start of pomalidomide treatment (cevostamab pre-phase). Cohort B1S is a safety run-in arm evaluating cevostamab and Pd administered in 28-day cycles every 2 weeks (Q2W) followed by every 4 weeks (Q4W) schedule. Additional safety run-in cohort(s) with lower target dose levels of cevostamab may be opened prior to opening the expansion cohorts. Two target dose levels of target dose level 1 (DL1) and lower dose level -1 (DL-1) of cevostamab will be selected for randomization in expansion cohorts. Expansion cohorts will follow the same Q2W/Q4W dosing schedule as Cohort B1S. Cevostamab plus Pomalidomide and Dexamethasone (Pd) (Arm B) Dexamethasone Participants will be treated with cevostamab monotherapy during a 14-day period prior to the start of pomalidomide treatment (cevostamab pre-phase). Cohort B1S is a safety run-in arm evaluating cevostamab and Pd administered in 28-day cycles every 2 weeks (Q2W) followed by every 4 weeks (Q4W) schedule. Additional safety run-in cohort(s) with lower target dose levels of cevostamab may be opened prior to opening the expansion cohorts. Two target dose levels of target dose level 1 (DL1) and lower dose level -1 (DL-1) of cevostamab will be selected for randomization in expansion cohorts. Expansion cohorts will follow the same Q2W/Q4W dosing schedule as Cohort B1S. Cevostamab plus Pomalidomide and Dexamethasone (Pd) (Arm B) Pomalidomide Participants will be treated with cevostamab monotherapy during a 14-day period prior to the start of pomalidomide treatment (cevostamab pre-phase). Cohort B1S is a safety run-in arm evaluating cevostamab and Pd administered in 28-day cycles every 2 weeks (Q2W) followed by every 4 weeks (Q4W) schedule. Additional safety run-in cohort(s) with lower target dose levels of cevostamab may be opened prior to opening the expansion cohorts. Two target dose levels of target dose level 1 (DL1) and lower dose level -1 (DL-1) of cevostamab will be selected for randomization in expansion cohorts. Expansion cohorts will follow the same Q2W/Q4W dosing schedule as Cohort B1S. Cevostamab plus Daratumumab and Dexamethasone (Dd) (Arm C) Cevostamab Cohort C1S is a safety run-in arm evaluating cevostamab and Dd administered in 21 day cycles from Cycle(C)1 - C8 every 3 weeks (Q3W) and 28-day cycles from C9 onwards Q4W. Additional safety run-in cohort(s) with lower target dose levels of cevostamab may be opened prior to opening the expansion cohorts. Two target dose levels of DL1 and DL-1 of cevostamab will be selected for randomization in expansion cohorts. Expansion cohorts will follow the same Q3W/Q4W dosing schedule as Cohort C1S. Cevostamab plus Daratumumab and Dexamethasone (Dd) (Arm C) Daratumumab Cohort C1S is a safety run-in arm evaluating cevostamab and Dd administered in 21 day cycles from Cycle(C)1 - C8 every 3 weeks (Q3W) and 28-day cycles from C9 onwards Q4W. Additional safety run-in cohort(s) with lower target dose levels of cevostamab may be opened prior to opening the expansion cohorts. Two target dose levels of DL1 and DL-1 of cevostamab will be selected for randomization in expansion cohorts. Expansion cohorts will follow the same Q3W/Q4W dosing schedule as Cohort C1S. Cevostamab plus Daratumumab and Dexamethasone (Dd) (Arm C) Tocilizumab Cohort C1S is a safety run-in arm evaluating cevostamab and Dd administered in 21 day cycles from Cycle(C)1 - C8 every 3 weeks (Q3W) and 28-day cycles from C9 onwards Q4W. Additional safety run-in cohort(s) with lower target dose levels of cevostamab may be opened prior to opening the expansion cohorts. Two target dose levels of DL1 and DL-1 of cevostamab will be selected for randomization in expansion cohorts. Expansion cohorts will follow the same Q3W/Q4W dosing schedule as Cohort C1S. Cevostamab plus Daratumumab and Dexamethasone (Dd) (Arm C) Dexamethasone Cohort C1S is a safety run-in arm evaluating cevostamab and Dd administered in 21 day cycles from Cycle(C)1 - C8 every 3 weeks (Q3W) and 28-day cycles from C9 onwards Q4W. Additional safety run-in cohort(s) with lower target dose levels of cevostamab may be opened prior to opening the expansion cohorts. Two target dose levels of DL1 and DL-1 of cevostamab will be selected for randomization in expansion cohorts. Expansion cohorts will follow the same Q3W/Q4W dosing schedule as Cohort C1S.
- Primary Outcome Measures
Name Time Method Percentage of Dose Intensity Baseline up to approximately 4 years Percentage of Dose Interruptions Baseline up to approximately 4 years Percentage of Treatment Discontinuation Baseline up to approximately 4 years Recommended Phase II Dose (RP2D) Baseline up to approximately 4 years Percentage of Participants with Adverse Events Baseline up to approximately 4 years Percentage of Dose Reductions Baseline up to approximately 4 years
- Secondary Outcome Measures
Name Time Method Volume of Distribution at Steady State of Cevostamab CPP D1 up to approximately 4 years Serum Concentration of Cevostamab at Specified Timepoints Cevostamab Pre-Phase (CPP) Day (D) 1 up to approximately 3 years Progression-free Survival (PFS) Start of study treatment to first date of disease progression or death from any cause, whichever occurs first (up to approximately 4 years) Maximum Observed Serum Concentration (Cmax) of Cevostamab CPP D1 up to approximately 4 years Time to Best Response (for Participants who Achieve a Response of PR or Better) Baseline up to approximately 4 years Objective Response Rate (ORR) Baseline up to approximately 4 years Total Exposure (Area Under the Concentration-time Curve [AUC]) of Cevostamab CPP D1 up to approximately 4 years Percentage of Participants with ADAs Against Cevostamab During the Study Up to approximately 4 years Serum Concentration of Daratumumab From C1D1 until disease progression or unexpected toxicity. Cycles 1-8 are 21 days and Cycle 9 onward are 28 days. Complete Response/Stringent Complete Response (CR/sCR) Rate Baseline up to approximately 4 years Rate of Very Good Partial Response (VGPR) or Better Baseline up to approximately 4 years Duration of Response (DOR) From first partial response (PR) or better until the first date of disease progression or death from any cause, whichever occurs first (up to approximately 4 years) Time to First Response (for Participants who Achieve a Response of Partial Response (PR) or Better) Baseline up to approximately 4 years Overall Survival (OS) Baseline up until death from any cause (up to approximately 4 years) Minimum Observed Serum Concentration (Cmin) of Cevostamab CPP D1 up to approximately 4 years Clearance of Cevostamab CPP D1 up to approximately 4 years Serum Concentration of Pomalidomide From Cycle 1 Day 1 through Cycle 6 Day 15. Each cycle=28 days Minimal Residual Disease (MRD) Negativity Baseline up to approximately 4 years Number of Anti-drug Antibody (ADAs) Against Cevostamab at Baseline Baseline
Trial Locations
- Locations (30)
City of Hope
🇺🇸Duarte, California, United States
City of Hope - Lennar Foundation Cancer Center
🇺🇸Irvine, California, United States
Colorado Blood Cancer Institute (CBCI) at Presbyterian/ St. Luke's Medical Center
🇺🇸Denver, Colorado, United States
Karmanos Cancer Institute.
🇺🇸Detroit, Michigan, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
The Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Hamilton Health Sciences
🇨🇦Hamilton, Ontario, Canada
University Health Network
🇨🇦Toronto, Ontario, Canada
Fakultni Nemocnice Ostrava
🇨🇿Ostrava, Czechia
Rigshospitalet
🇩🇰København Ø, Denmark
Hôpital Saint-Louis
🇫🇷Paris, France
CHU de Poitiers - La Miletrie
🇫🇷Poitiers, France
CHU Pontchaillou
🇫🇷Rennes, France
Rambam Medical Center
🇮🇱Haifa, Israel
Sourasky Medical Centre
🇮🇱Tel-Aviv, Israel
Asst Papa Giovanni Xxiii
🇮🇹Bergamo, Lombardia, Italy
A.O. Spedali Civili Di Brescia-P.O. Spedali Civili
🇮🇹Brescia, Lombardia, Italy
The Cancer Institute Hospital of JFCR
🇯🇵Tokyo, Japan
Yamagata University Hospital
🇯🇵Yamagata, Japan
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Uniwersyteckie Centrum Kliniczne
🇵🇱Gda?sk, Poland
Pratia Onkologia Katowice
🇵🇱Katowice, Poland
Uniwersytecki Szpital Kliniczny w Poznaniu
🇵🇱Pozna?, Poland
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital General Universitario Gregorio Marañon
🇪🇸Madrid, Spain
University College London Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
Royal Marsden Hospital
🇬🇧Sutton, United Kingdom