Multiple Myeloma
Conditions
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).
Interventions
DRUGCobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
DRUGVenetoclax
Venetoclax will be administered as per the schedule specified in the respective arm.
DRUGAtezolizumab
Atezolizumab will be administered as per the schedule specified in the respective arm.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events (AEs) | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria | 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) | 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 | 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 | 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. |
| Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria | 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. |
| AUClast of Venetoclax | 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 | 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 | 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 | 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) | — |
| Time to Reach Cmax (Tmax) of Cobimetinib | 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. |
| Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria | 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). |
Countries
Czechia, Denmark, France, Germany, Netherlands, Norway, Poland, Spain, Sweden
Participant flow
Recruitment details
The study was conducted at 16 centers in 8 countries.
Pre-assignment details
A total of 62 participants were screened, of which a total of 49 participants were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Safety Run-In: Cobimetinib + Venetoclax Participants received 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. | 6 |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab Participants received 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. | 6 |
| A: Cobimetinib Participants received 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 were 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 continued until disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurred first. | 6 |
| B: Cobimetinib + Venetoclax Participants received 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 continued until disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurred first. | 16 |
| C: Cobimetinib + Venetoclax + Atezolizumab Participants received 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 continued until disease progression, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurred first. | 15 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 5 | 5 | 4 | 10 | 8 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Participant in another sponsor study. | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Participant summarized as 'ongoing' due to missing data entry for Long-term Follow Up period on eCRF | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Study terminated by sponsor | 1 | 0 | 2 | 3 | 7 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Safety Run-In: Cobimetinib + Venetoclax | Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | A: Cobimetinib | B: Cobimetinib + Venetoclax | C: Cobimetinib + Venetoclax + Atezolizumab | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 65.8 Years STANDARD_DEVIATION 7.6 | 66.5 Years STANDARD_DEVIATION 6.1 | 68.0 Years STANDARD_DEVIATION 5.9 | 64.1 Years STANDARD_DEVIATION 6 | 61.5 Years STANDARD_DEVIATION 10.5 | 64.3 Years STANDARD_DEVIATION 7.9 |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 6 Participants | 6 Participants | 6 Participants | 14 Participants | 11 Participants | 43 Participants |
| Race/Ethnicity, Customized Not Stated | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 6 Participants | 6 Participants | 16 Participants | 15 Participants | 49 Participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 2 Participants | 6 Participants | 3 Participants | 18 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 4 Participants | 10 Participants | 12 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 6 | 5 / 6 | 4 / 6 | 11 / 16 | 8 / 15 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 5 / 6 | 15 / 16 | 15 / 15 |
| serious Total, serious adverse events | 2 / 6 | 3 / 6 | 3 / 6 | 12 / 16 | 11 / 15 |
Outcome results
Primary
Percentage of Participants With Adverse Events (AEs)
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.
Time frame: Randomization up to end of study (up to approximately 3 years, 7 months)
Population: The safety evaluable population included all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Percentage of Participants With Adverse Events (AEs) | 100.0 Percentage of Participants |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Percentage of Participants With Adverse Events (AEs) | 100.0 Percentage of Participants |
| A: Cobimetinib | Percentage of Participants With Adverse Events (AEs) | 100.0 Percentage of Participants |
| B: Cobimetinib + Venetoclax | Percentage of Participants With Adverse Events (AEs) | 100.0 Percentage of Participants |
| C: Cobimetinib + Venetoclax + Atezolizumab | Percentage of Participants With Adverse Events (AEs) | 100.0 Percentage of Participants |
Primary
Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria
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.
Time frame: From randomization to the first occurrence of a response as defined above (up to approximately 3 years, 7 months)
Population: The safety evaluable population included all participants who received any amount of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | Safety Population | 16.7 Percentage of Participants |
| Safety Run-In: Cobimetinib + Venetoclax | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | RAS Mutation Population | 0 Percentage of Participants |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | Safety Population | 33.3 Percentage of Participants |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | RAS Mutation Population | 100 Percentage of Participants |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | t(11;14) Population | 100 Percentage of Participants |
| A: Cobimetinib | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | RAS Mutation Population | 0 Percentage of Participants |
| A: Cobimetinib | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | t(11;14) Population | 0 Percentage of Participants |
| A: Cobimetinib | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | Safety Population | 0 Percentage of Participants |
| B: Cobimetinib + Venetoclax | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | t(11;14) Population | 100 Percentage of Participants |
| B: Cobimetinib + Venetoclax | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | Safety Population | 31.3 Percentage of Participants |
| B: Cobimetinib + Venetoclax | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | RAS Mutation Population | 14.3 Percentage of Participants |
| C: Cobimetinib + Venetoclax + Atezolizumab | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | Safety Population | 26.7 Percentage of Participants |
| C: Cobimetinib + Venetoclax + Atezolizumab | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | RAS Mutation Population | 37.5 Percentage of Participants |
| C: Cobimetinib + Venetoclax + Atezolizumab | Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria | t(11;14) Population | 80.0 Percentage of Participants |
Secondary
Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib
AUC0-24hr area under the plasma concentration-time curve from time 0 to 24 hrs
Time frame: Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Population: The PK population included participants from Arms A, B, and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib | 2390 hr*ng/mL | Geometric Coefficient of Variation 53.4 |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib | 3190 hr*ng/mL | Geometric Coefficient of Variation 55.3 |
| B: Cobimetinib + Venetoclax | Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib | 2540 hr*ng/mL | Geometric Coefficient of Variation 78.1 |
| C: Cobimetinib + Venetoclax + Atezolizumab | Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib | 2900 hr*ng/mL | Geometric Coefficient of Variation 54.6 |
Secondary
AUClast of Venetoclax
AUClast=area under the plasma concentration-time curve (samples collected to 8hr postdose on C1D15)
Time frame: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Population: The PK population included participants from Arms B and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | AUClast of Venetoclax | 4.96 hr*ug/mL | Geometric Coefficient of Variation 67.2 |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | AUClast of Venetoclax | 5.13 hr*ug/mL | Geometric Coefficient of Variation 57 |
| A: Cobimetinib | AUClast of Venetoclax | 6.52 hr*ug/mL | Geometric Coefficient of Variation 63.7 |
| B: Cobimetinib + Venetoclax | AUClast of Venetoclax | 6.52 hr*ug/mL | Geometric Coefficient of Variation 51.3 |
Secondary
Cmax of Venetoclax
Cmax is the maximum observed plasma concentration at steady state.
Time frame: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Population: The PK population included participants from Arms B and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Cmax of Venetoclax | 1.25 ug/mL | Geometric Coefficient of Variation 81 |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Cmax of Venetoclax | 1.16 ug/mL | Geometric Coefficient of Variation 48.7 |
| A: Cobimetinib | Cmax of Venetoclax | 1.32 ug/mL | Geometric Coefficient of Variation 55.3 |
| B: Cobimetinib + Venetoclax | Cmax of Venetoclax | 1.35 ug/mL | Geometric Coefficient of Variation 18.2 |
Secondary
Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria
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.
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)
Population: The safety evaluable population included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria | 11.5 Months |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria | 4.9 Months |
| A: Cobimetinib | Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria | 15.2 Months |
| B: Cobimetinib + Venetoclax | Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria | NA Months |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Cobimetinib
Cmax is the maximum observed plasma concentration at steady state.
Time frame: Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Population: The PK population included participants from Arms A, B, and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Maximum Observed Plasma Concentration (Cmax) of Cobimetinib | 157 ng/mL | Geometric Coefficient of Variation 63.5 |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Maximum Observed Plasma Concentration (Cmax) of Cobimetinib | 192 ng/mL | Geometric Coefficient of Variation 61.7 |
| B: Cobimetinib + Venetoclax | Maximum Observed Plasma Concentration (Cmax) of Cobimetinib | 148 ng/mL | Geometric Coefficient of Variation 72.6 |
| C: Cobimetinib + Venetoclax + Atezolizumab | Maximum Observed Plasma Concentration (Cmax) of Cobimetinib | 166 ng/mL | Geometric Coefficient of Variation 61 |
Secondary
Overall Survival (OS)
OS was defined as the time from randomization until death from any cause.
Time frame: From randomization until death from any cause (up to approximately 3 years, 7 months)
Population: The safety evaluable population included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Overall Survival (OS) | 11.4 Months |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Overall Survival (OS) | 14.3 Months |
| A: Cobimetinib | Overall Survival (OS) | 12.9 Months |
| B: Cobimetinib + Venetoclax | Overall Survival (OS) | 13.5 Months |
| C: Cobimetinib + Venetoclax + Atezolizumab | Overall Survival (OS) | 22.0 Months |
Secondary
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)
Population: The immunogenicity analysis population for atezolizumab consisted of all participants from Arm C with any ADA assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab | 3 Participants |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab | 4 Participants |
Secondary
Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria
Clinical benefit rate (CBR) was defined as a minimal response (MR) or better (PR,VGPR, CR, sCR).
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)
Population: The safety evaluable population included all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria | 33.3 Percentage of Participants |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria | 33.3 Percentage of Participants |
| A: Cobimetinib | Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria | 0 Percentage of Participants |
| B: Cobimetinib + Venetoclax | Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria | 43.8 Percentage of Participants |
| C: Cobimetinib + Venetoclax + Atezolizumab | Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria | 33.3 Percentage of Participants |
Secondary
Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria
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.
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)
Population: The safety evaluable population included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria | 1.7 Months |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria | 3.4 Months |
| A: Cobimetinib | Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria | 2.8 Months |
| B: Cobimetinib + Venetoclax | Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria | 4.9 Months |
| C: Cobimetinib + Venetoclax + Atezolizumab | Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria | 3.8 Months |
Secondary
Time to Reach Cmax (Tmax) of Cobimetinib
Tmax is the time to reach Cmax.
Time frame: Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Population: The PK population included participants from Arms A, B, and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Time to Reach Cmax (Tmax) of Cobimetinib | 4.00 hr |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Time to Reach Cmax (Tmax) of Cobimetinib | 4.00 hr |
| B: Cobimetinib + Venetoclax | Time to Reach Cmax (Tmax) of Cobimetinib | 4.00 hr |
| C: Cobimetinib + Venetoclax + Atezolizumab | Time to Reach Cmax (Tmax) of Cobimetinib | 4.00 hr |
Secondary
Tmax of Venetoclax
Tmax is the time to reach Cmax.
Time frame: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Population: The PK population included participants from Arms B and C who received at least one dose of study medication and for whom at least one evaluable PK sample was collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: Cobimetinib + Venetoclax | Tmax of Venetoclax | 5.73 hr |
| Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab | Tmax of Venetoclax | 5.65 hr |
| A: Cobimetinib | Tmax of Venetoclax | 6.00 hr |
| B: Cobimetinib + Venetoclax | Tmax of Venetoclax | 5.92 hr |