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
Study Details
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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. |
Drug: Cobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
Other Names:
Drug: Atezolizumab
Atezolizumab will be administered as per the schedule specified in the respective arm.
|
| 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. |
Drug: Cobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
Other Names:
Drug: Venetoclax
Venetoclax will be administered as per the schedule specified in the respective arm.
Other Names:
|
| 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. |
Drug: Cobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
Other Names:
Drug: Venetoclax
Venetoclax will be administered as per the schedule specified in the respective arm.
Other Names:
Drug: Atezolizumab
Atezolizumab will be administered as per the schedule specified in the respective arm.
|
| 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. |
Drug: Cobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
Other Names:
Drug: Venetoclax
Venetoclax will be administered as per the schedule specified in the respective arm.
Other Names:
|
| 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 Names:
Drug: Venetoclax
Venetoclax will be administered as per the schedule specified in the respective arm.
Other Names:
Drug: Atezolizumab
Atezolizumab will be administered as per the schedule specified in the respective arm.
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants With Adverse Events (AEs) [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 [From randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first (up to approximately 24 months)]
Secondary Outcome Measures
- 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 24 months)]
- Progression-Free Survival (PFS) 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 24 months)]
- Duration of Response as Determined by the Investigator Using IMWG Response Criteria [Time from the first observation of partial response (PR) to the time of disease progression (up to approximately 24 months)]
- Overall Survival [From randomization until death from any cause (up to approximately 24 months)]
- Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib [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 [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 [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 [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 [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 [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 [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 [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 [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)]
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika | Brno | Czechia | 625 00 | |
| 2 | Fakultni nemocnice Ostrava; Klinika hematoonkologie | Ostrava | Czechia | 708 52 | |
| 3 | Univerzita Karlova v Praze a Vseobecna fakultni nemocnice v Praze - 1; Lekarska Fakulta - I | Prague 2 | Czechia | 128 08 | |
| 4 | Rigshospitalet; Hæmatologisk Klinik | København Ø | Denmark | 2100 | |
| 5 | Odense Universitetshospital | Odense C | Denmark | 5000 | |
| 6 | CHU - Hôtel Dieu hematolgie clinique | Nantes | France | 44093 | |
| 7 | Hôpital Saint-Louis | Paris | France | 75475 | |
| 8 | CHU Lyon - Centre Hospitalier Lyon Sud | Pierre-Benite (Lyon) | France | 69495 | |
| 9 | IGR | Villejuif | France | 94800 | |
| 10 | UNI-Klinikum Heidelberg Medizinische Klinik Innere Medizin V | Heidelberg | Germany | 69120 | |
| 11 | Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik | Mainz | Germany | 55131 | |
| 12 | Universitätsklinikum Tübingen Medizinische UNI-Klinik und Poliklinik Abt. Innere Medizin II | Tübingen | Germany | 72076 | |
| 13 | Universtitätsklinikum Ulm; Klinik für Innere Medizin III | Ulm | Germany | 89081 | |
| 14 | Amsterdam UMC Location AMC | Amsterdam | Netherlands | 1105 AZ | |
| 15 | Universitair Medisch Centrum Utrecht | Utrecht | Netherlands | 3584 CX | |
| 16 | Førde sentralsjukehus | Førde | Norway | 6800 | |
| 17 | Oslo University Hospital HF, Rikshospitalet | Oslo | Norway | 0424 | |
| 18 | Medical University School; Dept. of Haematology | Lodz | Poland | 93-510 | |
| 19 | Uniwersytet Medyczny im.Karola Marcinkowskiego w Poznaniu | Poznań | Poland | 60-569 | |
| 20 | Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Oncology | Warszawa | Poland | 02-781 | |
| 21 | Gornoslaskie Centrum Medyczne | Wrocław | Poland | 50-367 | |
| 22 | Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia | Badalona | Barcelona | Spain | 08915 |
| 23 | Clínica Universidad de Navarra | Pamplona | Navarra | Spain | 31620 |
| 24 | Hospital Clinic de Barcelona | Barcelona | Spain | 08036 | |
| 25 | Hospital Universitario de la Princesa | Madrid | Spain | 28006 | |
| 26 | Hospital Univ 12 de Octubre | Madrid | Spain | 28041 | |
| 27 | Sahlgrenska University Hospital | Göteborg | Sweden | 413 45 | |
| 28 | Skånes Universitetssjukhus | Lund | Sweden | 221 85 |
Sponsors and Collaborators
- Hoffmann-La Roche
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- BO39813
- 2017-000830-68