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
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| ClinicalTrials.gov Identifier: NCT03312530 |
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Recruitment Status :
Completed
First Posted : October 17, 2017
Results First Posted : February 28, 2023
Last Update Posted : February 28, 2023
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Sponsor:
Hoffmann-La Roche
Information provided by (Responsible Party):
Hoffmann-La Roche
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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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Multiple Myeloma | Drug: Cobimetinib Drug: Venetoclax Drug: Atezolizumab | Phase 1 Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 49 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | November 13, 2017 |
| Actual Primary Completion Date : | May 18, 2021 |
| Actual Study Completion Date : | May 18, 2021 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Multiple myeloma
MedlinePlus related topics:
Multiple Myeloma
| Arm | Intervention/treatment |
|---|---|
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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.
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Drug: Cobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
Other Name: Cotellic® Drug: Atezolizumab Atezolizumab will be administered as per the schedule specified in the respective arm. |
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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.
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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 |
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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.
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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. |
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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.
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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 |
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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.
|
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. |
Primary Outcome Measures :
- Percentage of Participants With Adverse Events (AEs) [ Time Frame: Randomization up to end of study (up to approximately 3 years, 7 months) ]An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with the treatment. An AE was therefore any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. New or pre-existing conditions which worsened during the study were also considered AEs.
- Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria [ Time Frame: From randomization to the first occurrence of a response as defined above (up to approximately 3 years, 7 months) ]ORR was defined as a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) and was analyzed in the safety evaluable population and in the biomarker-selected sub-populations of t(11;14) and RAS mutations.
Secondary Outcome Measures :
- 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 3 years, 7 months) ]Clinical benefit rate (CBR) was defined as a minimal response (MR) or better (PR,VGPR, CR, sCR).
- Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria [ Time Frame: From enrollment or first treatment date to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 3 years, 7 months) ]PFS was defined as the time from randomization (for randomized participants) or first treatment date (for non-ranomized participants) to the first occurrence of disease progression or relapse as determined by the investigator using the IMWG criteria or death from any cause during the study, whichever occurred first.
- Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria [ Time Frame: Time from the first observation of partial response (PR) or better to the time of disease progression (up to approximately 3 years, 7 months) ]DOR was applicable to participants who achieved at least a PR, and was measured from the first observation of PR or better to the time of disease progression.
- Overall Survival (OS) [ Time Frame: From randomization until death from any cause (up to approximately 3 years, 7 months) ]OS was defined as the time from randomization until death from any cause.
- Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib [ Time Frame: Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days) ]AUC0-24hr area under the plasma concentration-time curve from time 0 to 24 hrs
- Maximum Observed Plasma Concentration (Cmax) of Cobimetinib [ Time Frame: Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days) ]Cmax is the maximum observed plasma concentration at steady state.
- Time to Reach Cmax (Tmax) of Cobimetinib [ Time Frame: Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days) ]Tmax is the time to reach Cmax.
- AUClast of Venetoclax [ Time Frame: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days) ]AUClast=area under the plasma concentration-time curve (samples collected to 8hr postdose on C1D15)
- Cmax of Venetoclax [ Time Frame: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days) ]Cmax is the maximum observed plasma concentration at steady state.
- Tmax of Venetoclax [ Time Frame: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days) ]Tmax is the time to reach Cmax.
- 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 3 years, 7 months) ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03312530
Locations
Show 26 study locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
| Study Director: | Clinical Trials | Hoffmann-La Roche |
Study Documents (Full-Text)
Documents provided by Hoffmann-La Roche:
Documents provided by Hoffmann-La Roche:
Study Protocol and Statistical Analysis Plan [PDF] February 18, 2021
| Responsible Party: | Hoffmann-La Roche |
| ClinicalTrials.gov Identifier: | NCT03312530 |
| Other Study ID Numbers: |
BO39813 2017-000830-68 ( EudraCT Number ) |
| First Posted: | October 17, 2017 Key Record Dates |
| Results First Posted: | February 28, 2023 |
| Last Update Posted: | February 28, 2023 |
| Last Verified: | February 2023 |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Multiple Myeloma Neoplasms, Plasma Cell Neoplasms by Histologic Type Neoplasms Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders |
Hematologic Diseases Hemorrhagic Disorders Lymphoproliferative Disorders Immunoproliferative Disorders Immune System Diseases Atezolizumab Venetoclax Antineoplastic Agents |