A Study of Cobimetinib Administered as Single Agent and in Combination With Venetoclax, With or Without Atezolizumab, in Participants With Relapsed and Refractory Multiple Myeloma

• ClinicalTrials.gov Identifier: NCT03312530
• Recruitment Status: Completed
• First Posted: October 17, 2017
• Last Update Posted: August 6, 2021
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: October 12, 2017
• First Posted Date: October 17, 2017
• Last Update Posted Date: August 6, 2021
• Actual Study Start Date: November 13, 2017
• Actual Primary Completion Date: May 18, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 12, 2017)

• Percentage of Participants With Adverse Events (AEs) [ Time Frame: Randomization up to end of study (up to approximately 24 months) ]
• Percentage of Participants With Overall Response as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria [ Time Frame: From randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 24 months) ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 12, 2017)

• Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria [ Time Frame: From randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 24 months) ]
• Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria [ Time Frame: From randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 24 months) ]
• Duration of Response as Determined by the Investigator Using IMWG Response Criteria [ Time Frame: Time from the first observation of partial response (PR) to the time of disease progression (up to approximately 24 months) ]
• Overall Survival [ Time Frame: From randomization until death from any cause (up to approximately 24 months) ]
• Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib [ Time Frame: Arm A: 2-4 hours(hrs) post-dose on Day 1 of Cycle 1; predose(within 1 hr),2-4 hrs post-dose on Day 15 of Cycle 1; Arm B and C: 2-4 hrs post-dose on Day 1 of Cycle 1; pre-dose(within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1(cycle length: 28 days) ]
• Maximum Observed Plasma Concentration (Cmax) of Cobimetinib [ Time Frame: Arm A: 2-4 hrs post-dose on Day 1 of Cycle 1; predose (within 1 hr), 2-4 hrs post-dose on Day 15 of Cycle 1; Arm B and C: 2-4 hrs post-dose on Day 1 of Cycle 1; pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days) ]
• Time to Reach Cmax (Tmax) of Cobimetinib [ Time Frame: Arm A: 2-4 hrs post-dose on Day 1 of Cycle 1; predose (within 1 hr), 2-4 hrs post-dose on Day 15 of Cycle 1; Arm B and C: 2-4 hrs post-dose on Day 1 of Cycle 1; pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days) ]
• AUC of Venetoclax [ Time Frame: 6 hrs post-dose on Day 1 of Cycle 1; pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1; pre-dose (within 1 hr) on Day 1 of Cycles 2, 3 (cycle length: 28 days) ]
• Cmax of Venetoclax [ Time Frame: 6 hrs post-dose on Day 1 of Cycle 1; pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1; pre-dose (within 1 hr) on Day 1 of Cycles 2, 3 (cycle length: 28 days) ]
• Tmax of Venetoclax [ Time Frame: 6 hrs post-dose on Day 1 of Cycle 1; pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1; pre-dose (within 1 hr) on Day 1 of Cycles 2, 3 (cycle length: 28 days) ]
• Cmax of Atezolizumab [ Time Frame: Pre-infusion (0 hr), 0.5 hr post-infusion (infusion duration: 1 hr) on Day 1 of Cycle 1; pre-infusion (0 hr) on Day 1 of Cycle 2, 3 (cycle length: 28 days); at treatment discontinuation visit (up to approximately 24 months) ]
• Minimum Observed Serum Concentration (Cmin) of Atezolizumab [ Time Frame: Pre-infusion (0 hr), 0.5 hr post-infusion (infusion duration: 1 hr) on Day 1 of Cycle 1; pre-infusion (0 hr) on Day 1 of Cycle 2, 3 (cycle length: 28 days); at treatment discontinuation visit (up to approximately 24 months) ]
• Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab [ Time Frame: Pre-infusion (0 hr) on Day 1 of Cycles 1, 2, 3 (cycle length: 28 days); at treatment discontinuation visit (up to approximately 24 months) ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Cobimetinib Administered as Single Agent and in Combination With Venetoclax, With or Without Atezolizumab, in Participants With Relapsed and Refractory Multiple Myeloma
• Official Title: A Phase Ib/II Study of Cobimetinib Administered as Single Agent and in Combination With Venetoclax, With or Without Atezolizumab, in Patients With Relapsed and Refractory Multiple Myeloma
• Brief Summary: This open-label, randomized, multicenter, triple-arm Phase Ib/II study is designed to assess the efficacy, safety, tolerability, and pharmacokinetics of cobimetinib administered as a single agent (Arm A), cobimetinib plus venetoclax (Arm B), and cobimetinib plus venetoclax plus atezolizumab (Arm C) in participants with relapsed and refractory multiple myeloma. Two successive cohorts will evaluate the safety of cobimetinib plus venetoclax and that of cobimetinib plus venetoclax plus atezolizumab in the selected population during the safety run-in phase of the study. Once the dose levels have demonstrated acceptable safety during this phase, randomization will begin for all treatment arms (Arms A, B, and C).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: Cobimetinib
  Cobimetinib will be administered as per the schedule specified in the respective arm.
  Other Name: Cotellic®
• Drug: Venetoclax
  Venetoclax will be administered as per the schedule specified in the respective arm.
  Other Name: GDC-0199, ABT-199
• Drug: Atezolizumab
  Atezolizumab will be administered as per the schedule specified in the respective arm.

Study Arms

• Experimental: A: Cobimetinib
  Participants will receive the standard single-agent cobimetinib dose of 60 milligrams (mg) (3 tablets of 20 mg each) orally (PO) daily on Days 1-21 of each 28-day cycle until disease progression. Upon progression, participants will be allowed to receive treatment with cobimetinib and atezolizumab at the recommended Phase II dose of cobimetinib 60 mg PO on Days 1-21 plus atezolizumab intravenous (IV) infusion at a fixed dose of 840 mg on Day 1 and Day 15 of each 28-day cycle. Treatment will continue until the participant has disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
  Interventions:

  • Drug: Cobimetinib
  • Drug: Atezolizumab
• Experimental: B: Cobimetinib + Venetoclax
  Participants will receive cobimetinib PO daily on Days 1-21 of each 28-day cycle plus venetoclax PO daily on Days 1-28 of each 28-day cycle, at the dose level identified in the safety run-in phase. Treatment will continue until the participant has disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
  Interventions:

  • Drug: Cobimetinib
  • Drug: Venetoclax
• Experimental: C: Cobimetinib + Venetoclax + Atezolizumab
  Participants will receive cobimetinib PO daily on Days 1-21 of each 28-day cycle plus venetoclax PO daily on Days 1-28 of each 28-day cycle, at the dose level identified in the safety run-in phase plus atezolizumab IV infusion at a fixed dose of 840 mg on Day 1 and Day 15 of each 28-day cycle. Treatment will continue until the participant has disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
  Interventions:

  • Drug: Cobimetinib
  • Drug: Venetoclax
  • Drug: Atezolizumab
• Experimental: Safety Run-In: Cobimetinib + Venetoclax
  Participants will receive cobimetinib (on Day 1-21) plus venetoclax (on Day 1-28) at escalated doses, in 28-day cycles, to identify the dose level with acceptable safety.
  Interventions:

  • Drug: Cobimetinib
  • Drug: Venetoclax
• Experimental: Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab
  Participants will receive cobimetinib (on Day 1-21) plus venetoclax (on Day 1-28) at escalated doses and atezolizumab (on Day 1 and Day 15) at a fixed dose of 840 mg IV, in 28-day cycles, to identify the dose level with acceptable safety.
  Interventions:

  • Drug: Cobimetinib
  • Drug: Venetoclax
  • Drug: Atezolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 14, 2021): 49
• Original Estimated Enrollment (submitted: October 12, 2017): 72
• Actual Study Completion Date: May 18, 2021
• Actual Primary Completion Date: May 18, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Life expectancy of at least 12 weeks
• Documented multiple myeloma
• Received 3 to 5 prior lines of therapy for multiple myeloma, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD)
• Achieved a response (minimal response [MR] or better) to at least one prior regimen
• Documented evidence of progressive disease (as defined by the IMWG criteria) on or after their last prior therapy, or participants who were intolerant to their last prior therapy
• Toxicities resulting from previous therapy (including peripheral neuropathy) that must be resolved or stabilized to Grade 1

Exclusion Criteria:

• Anti-myeloma treatment within 14 days or 5 pharmacokinetic (PK) half-lives of the treatment, whichever is longer, before the date of randomization
• Completion of autologous stem cell transplant within 100 days prior to the date of randomization
• Prior allogeneic stem cell transplant as well as prior solid organ transplant
• Spinal cord compression not definitively treated with surgery and/or radiation
• Prior treatment with MEK inhibitors, B-cell lymphoma-2 (Bcl-2) inhibitors, or immune checkpoint inhibitor therapies including anti-cytotoxic T-lymphocyte associated protein-4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1) or anti-programmed death-ligand 1 (anti-PD-L1)
• Treatment with systemic immunostimulatory agents within 28 days or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
• Treatment with systemic immunosuppressive medication within 14 days prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study
• Prior radiation therapy within 14 days prior to study enrollment and/or persistence of radiation-related adverse effects
• History or evidence of retinal pathology on ophthalmic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration
• Left ventricular ejection fraction (LVEF) below institutional lower limit of normal
• History of clinically significant cardiovascular dysfunction
• Any previous venous thromboembolism greater than (>) Grade 3 within 12 months of study enrollment
• History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins (for participants in Arm C only)
• History of other malignancy that could affect compliance with the protocol or interpretation of results
• Active or history of autoimmune disease or immune deficiency
• History of malabsorption or other condition that would interfere with absorption of study drugs
• Active tuberculosis
• Severe infection within 28 days prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
• Treatment with therapeutic oral or IV antibiotics within 14 days prior to initiation of study treatment
• Positive test results for hepatitis B (hepatitis B surface antigen [HBsAg] and/or total hepatitis B core antibody [HBcAb]) or hepatitis C virus (HCV) antibody
• Known history of human immunodeficiency virus (HIV) seropositivity
• Treatment with a live, attenuated influenza vaccine (e.g., FluMist) within 28 days prior to Cycle 1 Day 1, at any time during the study, and for at least 5 months after the last dose of study drug (for participants in Arm C only)
• Received strong cytochrome P-3A (CYP3A) inhibitors, moderate CYP3A inhibitors, strong CYP3A inducers, and moderate CYP3A inducers within 7 days prior to the initiation of study treatment

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Czechia, Denmark, France, Germany, Netherlands, Norway, Poland, Spain, Sweden

Administrative Information

• NCT Number: NCT03312530
• Other Study ID Numbers: BO39813; 2017-000830-68 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: August 2021