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

NCT03312530 | Completed Phase 1 Results

• 2 other identifiers: BO398132017-000830-68
• Study Type: interventional
• Target: 49
• Locations: 9 countries
• Sites: 26

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

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  From randomization to the first occurrence of a response as defined above (up to approximately 3 years, 7 months)

Secondary Outcomes (11)

• 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)

• 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)

• 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)

• Overall Survival (OS)

  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

  Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)

Study Arms (5)

A: Cobimetinib

EXPERIMENTAL

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; Drug: Atezolizumab

B: Cobimetinib + Venetoclax

EXPERIMENTAL

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; Drug: Venetoclax

C: Cobimetinib + Venetoclax + Atezolizumab

EXPERIMENTAL

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; Drug: Venetoclax; Drug: Atezolizumab

Safety Run-In: Cobimetinib + Venetoclax

EXPERIMENTAL

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; Drug: Venetoclax

Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab

EXPERIMENTAL

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; Drug: Venetoclax; Drug: Atezolizumab

Interventions

Cobimetinib DRUG

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

Also known as: Cotellic®

A: Cobimetinib; B: Cobimetinib + Venetoclax; C: Cobimetinib + Venetoclax + Atezolizumab; Safety Run-In: Cobimetinib + Venetoclax; Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab

Venetoclax DRUG

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

Also known as: GDC-0199, ABT-199

B: Cobimetinib + Venetoclax; C: Cobimetinib + Venetoclax + Atezolizumab; Safety Run-In: Cobimetinib + Venetoclax; Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab

Atezolizumab DRUG

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

A: Cobimetinib; C: Cobimetinib + Venetoclax + Atezolizumab; Safety Run-In: Cobimetinib + Venetoclax + Atezolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (26)

Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika

Brno, 625 00, Czechia

Location

Fakultni nemocnice Ostrava; Klinika hematoonkologie

Ostrava, 708 52, Czechia

Location

Univerzita Karlova v Praze a Vseobecna fakultni nemocnice v Praze - 1; Lekarska Fakulta - I

Prague, 128 08, Czechia

Location

Rigshospitalet; Hæmatologisk Klinik

København Ø, 2100, Denmark

Location

Odense Universitetshospital

Odense C, 5000, Denmark

Location

CHU - Hôtel Dieu hematolgie clinique

Nantes, 44093, France

Location

Hôpital Saint-Louis

Paris, 75475, France

Location

CHU Lyon - Centre Hospitalier Lyon Sud

Pierre-Benite (Lyon), 69495, France

Location

IGR

Villejuif, 94800, France

Location

UNI-Klinikum Heidelberg Medizinische Klinik Innere Medizin V

Heidelberg, 69120, Germany

Location

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

Mainz, 55131, Germany

Location

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

Tübingen, 72076, Germany

Location

Universtitätsklinikum Ulm; Klinik für Innere Medizin III

Ulm, 89081, Germany

Location

Amsterdam UMC Location AMC

Amsterdam, 1105 AZ, Netherlands

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584 CX, Netherlands

Location

Førde sentralsjukehus

Førde, 6800, Norway

Location

Oslo University Hospital HF, Rikshospitalet

Oslo, 0424, Norway

Location

Medical University School; Dept. of Haematology

Lodz, 93-510, Poland

Location

Uniwersytet Medyczny im.Karola Marcinkowskiego w Poznaniu

Późna, 60-569, Poland

Location

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

Warsaw, 02-781, Poland

Location

Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia

Badalona, Barcelona, 08915, Spain

Location

Clínica Universidad de Navarra

Pamplona, Navarre, 31620, Spain

Location

Hospital Clinic de Barcelona

Barcelona, 08036, Spain

Location

Hospital Universitario de la Princesa

Madrid, 28006, Spain

Location

Hospital Univ 12 de Octubre

Madrid, 28041, Spain

Location

Skånes Universitetssjukhus

Lund, 221 85, Sweden

Location

Related Publications (1)

• 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.

  PMID: 36450626 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

cobimetinib; venetoclax; atezolizumab

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Limitations and Caveats

In March 2019, this study was placed on voluntary enrollment hold. In May 2019, after an informal efficacy review, the Sponsor decided not to remove the hold and discontinued further development of the combination.

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 12, 2017
• First Posted: October 17, 2017
• Study Start: November 13, 2017
• Primary Completion: May 18, 2021
• Study Completion: May 18, 2021
• Last Updated: February 28, 2023
• Results First Posted: February 28, 2023

Record last verified: 2023-02

Locations

NO (2); PL (3); ES (5); SE (1); DE (4); NL (2); CZ (3); DK (2); FR (4)