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

NCT ID: NCT03312530

Last Updated: 2023-02-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 49 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-13
• Study Completion Date: 2021-05-18

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).

Conditions

Multiple Myeloma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Cobimetinib will be administered as per the schedule specified in the respective arm.

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered as per the schedule specified in the respective arm.

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.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Cobimetinib will be administered as per the schedule specified in the respective arm.

Venetoclax

Intervention Type: DRUG

Venetoclax will be administered as per the schedule specified in the respective arm.

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.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Cobimetinib will be administered as per the schedule specified in the respective arm.

Venetoclax

Intervention Type: DRUG

Venetoclax will be administered as per the schedule specified in the respective arm.

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered as per the schedule specified in the respective arm.

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.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Cobimetinib will be administered as per the schedule specified in the respective arm.

Venetoclax

Intervention Type: DRUG

Venetoclax will be administered as per the schedule specified in the respective arm.

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.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Cobimetinib will be administered as per the schedule specified in the respective arm.

Venetoclax

Intervention Type: DRUG

Venetoclax will be administered as per the schedule specified in the respective arm.

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered as per the schedule specified in the respective arm.

Interventions

Cobimetinib

Cobimetinib will be administered as per the schedule specified in the respective arm.

Intervention Type: DRUG

Venetoclax

Venetoclax will be administered as per the schedule specified in the respective arm.

Intervention Type: DRUG

Atezolizumab

Atezolizumab will be administered as per the schedule specified in the respective arm.

Intervention Type: DRUG

Other Intervention Names

Cotellic®; GDC-0199, ABT-199

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

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

Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik

Mainz, , Germany

Universitätsklinikum Tübingen Medizinische UNI-Klinik und Poliklinik Abt. Innere Medizin II

Tübingen, , Germany

Universtitätsklinikum Ulm; Klinik für Innere Medizin III

Ulm, , Germany

Amsterdam UMC Location AMC

Amsterdam, , Netherlands

Universitair Medisch Centrum Utrecht

Utrecht, , Netherlands

Førde sentralsjukehus

Førde, , Norway

Oslo University Hospital HF, Rikshospitalet

Oslo, , Norway

Medical University School; Dept. of Haematology

Lodz, , Poland

Uniwersytet Medyczny im.Karola Marcinkowskiego w Poznaniu

Późna, , Poland

Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Oncology

Warsaw, , Poland

Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia

Badalona, Barcelona, Spain

Clínica Universidad de Navarra

Pamplona, Navarre, Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

Hospital Universitario de la Princesa

Madrid, , Spain

Hospital Univ 12 de Octubre

Madrid, , Spain

Skånes Universitetssjukhus

Lund, , Sweden

Countries

Czechia; Denmark; France; Germany; Netherlands; Norway; Poland; Spain; Sweden

References

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.

Reference Type: DERIVED

PMID: 36450626 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2017-000830-68

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

BO39813

Identifier Type: -

Identifier Source: org_study_id