NCT03312530 · REGISTRY CONDITION SEARCH

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

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE1, PHASE2
Status at capture: COMPLETED
Registry last update: 2023-02-28

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).

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Percentage of Participants With Adverse Events (AEs)

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outcome · POSTED

Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria

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outcome · POSTED

Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria

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outcome · POSTED

Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria

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outcome · POSTED

Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria

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outcome · POSTED

Overall Survival (OS)

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outcome · POSTED

Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib

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outcome · POSTED

Maximum Observed Plasma Concentration (Cmax) of Cobimetinib

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outcome · POSTED

Time to Reach Cmax (Tmax) of Cobimetinib

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outcome · POSTED

AUClast of Venetoclax

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outcome · POSTED

Cmax of Venetoclax

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outcome · POSTED

Tmax of Venetoclax

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outcome · POSTED

Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

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
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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.
intervention Names
Drug: Cobimetinib
Drug: Atezolizumab
label
A: Cobimetinib
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Cobimetinib
Drug: Venetoclax
label
B: Cobimetinib + Venetoclax
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Cobimetinib
Drug: Venetoclax
Drug: Atezolizumab
label
C: Cobimetinib + Venetoclax + Atezolizumab
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Cobimetinib
Drug: Venetoclax
label
Safety Run-In: Cobimetinib + Venetoclax
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Cobimetinib
Drug: Venetoclax
Drug: Atezolizumab
label
Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab
type
EXPERIMENTAL

interventions

arm Group Labels
A: Cobimetinib
B: Cobimetinib + Venetoclax
C: Cobimetinib + Venetoclax + Atezolizumab
Safety Run-In: Cobimetinib + Venetoclax
Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab
description
Cobimetinib will be administered as per the schedule specified in the respective arm.
name
Cobimetinib
other Names
Cotellic®
type
DRUG
arm Group Labels
B: Cobimetinib + Venetoclax
C: Cobimetinib + Venetoclax + Atezolizumab
Safety Run-In: Cobimetinib + Venetoclax
Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab
description
Venetoclax will be administered as per the schedule specified in the respective arm.
name
Venetoclax
other Names
GDC-0199, ABT-199
type
DRUG
arm Group Labels
A: Cobimetinib
C: Cobimetinib + Venetoclax + Atezolizumab
Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab
description
Atezolizumab will be administered as per the schedule specified in the respective arm.
name
Atezolizumab
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 49
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
Percentage of Participants With Adverse Events (AEs)
time Frame
Randomization up to end of study (up to approximately 3 years, 7 months)
description
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.
measure
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)

secondary Outcomes

description
Clinical benefit rate (CBR) was defined as a minimal response (MR) or better (PR,VGPR, CR, sCR).
measure
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)
description
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.
measure
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)
description
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.
measure
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)
description
OS was defined as the time from randomization until death from any cause.
measure
Overall Survival (OS)
time Frame
From randomization until death from any cause (up to approximately 3 years, 7 months)
description
AUC0-24hr area under the plasma concentration-time curve from time 0 to 24 hrs
measure
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)
description
Cmax is the maximum observed plasma concentration at steady state.
measure
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)
description
Tmax is the time to reach Cmax.
measure
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)
description
AUClast=area under the plasma concentration-time curve (samples collected to 8hr postdose on C1D15)
measure
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)
description
Cmax is the maximum observed plasma concentration at steady state.
measure
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)
description
Tmax is the time to reach Cmax.
measure
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)
measure
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)

Full study description

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).

Source references

references

citation
Schjesvold F, Paiva B, Ribrag V, Rodriguez-Otero P, San-Miguel JF, Robak P, Hansson M, Onishi M, Hamidi H, Malhi V, Dail M, Javery A, Ku G, Raab MS. Cobimetinib Alone and Plus Venetoclax With/Without Atezolizumab in Patients With Relapsed/Refractory Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2023 Jan;23(1):e59-e70. doi: 10.1016/j.clml.2022.10.006. Epub 2022 Oct 22.
pmid
36450626
type
DERIVED

Source notices and limitations

Discovery and provenance

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Preserved source evidence · Not medical advice