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
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
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).
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