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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03312530
Other study ID # BO39813
Secondary ID 2017-000830-68
Status Completed
Phase Phase 1/Phase 2
First received
Last updated
Start date November 13, 2017
Est. completion date May 18, 2021

Study information

Verified date February 2023
Source Hoffmann-La Roche
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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).


Recruitment information / eligibility

Status Completed
Enrollment 49
Est. completion date May 18, 2021
Est. primary completion date May 18, 2021
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Cobimetinib
Cobimetinib will be administered as per the schedule specified in the respective arm.
Venetoclax
Venetoclax will be administered as per the schedule specified in the respective arm.
Atezolizumab
Atezolizumab will be administered as per the schedule specified in the respective arm.

Locations

Country Name City State
Czechia 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 2
Denmark Rigshospitalet; Hæmatologisk Klinik København Ø
Denmark Odense Universitetshospital Odense C
France CHU - Hôtel Dieu hematolgie clinique Nantes
France Hôpital Saint-Louis Paris
France CHU Lyon - Centre Hospitalier Lyon Sud Pierre-Benite (Lyon)
France IGR Villejuif
Germany 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
Netherlands Amsterdam UMC Location AMC Amsterdam
Netherlands Universitair Medisch Centrum Utrecht Utrecht
Norway Førde sentralsjukehus Førde
Norway Oslo University Hospital HF, Rikshospitalet Oslo
Poland Medical University School; Dept. of Haematology Lodz
Poland Uniwersytet Medyczny im.Karola Marcinkowskiego w Poznaniu Pozna?
Poland Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Oncology Warszawa
Spain Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia Badalona Barcelona
Spain Hospital Clinic de Barcelona Barcelona
Spain Hospital Univ 12 de Octubre Madrid
Spain Hospital Universitario de la Princesa Madrid
Spain Clínica Universidad de Navarra Pamplona Navarra
Sweden Skånes Universitetssjukhus Lund

Sponsors (1)

Lead Sponsor Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

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

Outcome

Type Measure Description Time frame Safety issue
Primary 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)
Primary 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 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). 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)
Secondary 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. 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)
Secondary 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 from the first observation of partial response (PR) or better to the time of disease progression (up to approximately 3 years, 7 months)
Secondary Overall Survival (OS) OS was defined as the time from randomization until death from any cause. From randomization until death from any cause (up to approximately 3 years, 7 months)
Secondary 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 Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary Maximum Observed Plasma Concentration (Cmax) of Cobimetinib Cmax is the maximum observed plasma concentration at steady state. Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary Time to Reach Cmax (Tmax) of Cobimetinib Tmax is the time to reach Cmax. Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary AUClast of Venetoclax AUClast=area under the plasma concentration-time curve (samples collected to 8hr postdose on C1D15) Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary Cmax of Venetoclax Cmax is the maximum observed plasma concentration at steady state. Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary Tmax of Venetoclax Tmax is the time to reach Cmax. Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
Secondary 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 3 years, 7 months)
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