An Open-Label, Multicenter, Phase Ib Trial Evaluating the Safety, Pharmacokinetics, and Activity of Cevostamab as Monotherapy and Cevostamab Plus Pomalidomide and Dexamethasone or Cevostamab Plus Daratumumab and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
Overview
- Phase
- Phase 1
- Intervention
- Cevostamab
- Conditions
- Multiple Myeloma
- Sponsor
- Genentech, Inc.
- Enrollment
- 126
- Locations
- 27
- Primary Endpoint
- Percentage of Dose Interruptions
- Status
- Active, not recruiting
- Last Updated
- 4 months ago
Overview
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.
Investigators
Eligibility Criteria
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
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)
Arms & Interventions
Single-Agent Cevostamab (Arm A)
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.
Intervention: Cevostamab
Single-Agent Cevostamab (Arm A)
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.
Intervention: Tocilizumab
Single-Agent Cevostamab (Arm A)
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.
Intervention: Dexamethasone
Cevostamab plus Pomalidomide and Dexamethasone (Pd) (Arm B)
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.
Intervention: Cevostamab
Cevostamab plus Pomalidomide and Dexamethasone (Pd) (Arm B)
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.
Intervention: Tocilizumab
Cevostamab plus Pomalidomide and Dexamethasone (Pd) (Arm B)
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.
Intervention: Pomalidomide
Cevostamab plus Pomalidomide and Dexamethasone (Pd) (Arm B)
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.
Intervention: Dexamethasone
Cevostamab plus Daratumumab and Dexamethasone (Dd) (Arm C)
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.
Intervention: Cevostamab
Cevostamab plus Daratumumab and Dexamethasone (Dd) (Arm C)
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.
Intervention: Tocilizumab
Cevostamab plus Daratumumab and Dexamethasone (Dd) (Arm C)
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.
Intervention: Daratumumab
Cevostamab plus Daratumumab and Dexamethasone (Dd) (Arm C)
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.
Intervention: Dexamethasone
Outcomes
Primary Outcomes
Percentage of Dose Interruptions
Time Frame: Baseline up to approximately 4 years
Percentage of Treatment Discontinuation
Time Frame: Baseline up to approximately 4 years
Percentage of Dose Intensity
Time Frame: Baseline up to approximately 4 years
Recommended Phase II Dose (RP2D)
Time Frame: Baseline up to approximately 4 years
Percentage of Participants with Adverse Events
Time Frame: Baseline up to approximately 4 years
Percentage of Dose Reductions
Time Frame: Baseline up to approximately 4 years
Secondary Outcomes
- 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)
- 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)
- Time to Best Response (for Participants who Achieve a Response of 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)