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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
49
Cobimetinib will be administered as per the schedule specified in the respective arm.
Venetoclax will be administered as per the schedule specified in the respective arm.
Atezolizumab will be administered as per the schedule specified in the respective arm.
Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika
Brno, Czechia
Fakultni nemocnice Ostrava; Klinika hematoonkologie
Ostrava, Czechia
Univerzita Karlova v Praze a Vseobecna fakultni nemocnice v Praze - 1; Lekarska Fakulta - I
Prague, Czechia
Rigshospitalet; Hæmatologisk Klinik
København Ø, Denmark
Odense Universitetshospital
Odense C, Denmark
CHU - Hôtel Dieu hematolgie clinique
Nantes, France
Hôpital Saint-Louis
Paris, France
CHU Lyon - Centre Hospitalier Lyon Sud
Pierre-Benite (Lyon), France
IGR
Villejuif, France
UNI-Klinikum Heidelberg Medizinische Klinik Innere Medizin V
Heidelberg, Germany
...and 16 more locations
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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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