Clinical trial NCT03312530: 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
Official title: A Phase Ib/II Study of Cobimetinib Administered as Single Agent and in Combination With Venetoclax, With or Without Atezolizumab, in Patients With Relapsed and Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-10-17
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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

Primary outcomes:
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: Randomization up to end of study (up to approximately 3 years, 7 months)
measure: Percentage of Participants With Overall Response Rate (ORR) as Determined by the Investigator Using International Myeloma Working Group (IMWG) Response Criteria
timeFrame: From randomization to the first occurrence of a response as defined above (up to approximately 3 years, 7 months)
Secondary outcomes:
measure: Percentage of Participants With Clinical Benefit as Determined by the Investigator Using IMWG Response Criteria
timeFrame: 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)
measure: Progression-Free Survival (PFS) as Determined by the Investigator Using IMWG Response Criteria
timeFrame: 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)
measure: Duration of Response (DOR) as Determined by the Investigator Using IMWG Response Criteria
timeFrame: Time from the first observation of partial response (PR) or better to the time of disease progression (up to approximately 3 years, 7 months)
measure: Overall Survival (OS)
timeFrame: From randomization until death from any cause (up to approximately 3 years, 7 months)
measure: Area Under the Plasma Concentration Versus Time Curve (AUC) of Cobimetinib
timeFrame: Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
measure: Maximum Observed Plasma Concentration (Cmax) of Cobimetinib
timeFrame: Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
measure: Time to Reach Cmax (Tmax) of Cobimetinib
timeFrame: Pre-dose (within 1 hr), 2, 4, 6 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
measure: AUClast of Venetoclax
timeFrame: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
measure: Cmax of Venetoclax
timeFrame: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
measure: Tmax of Venetoclax
timeFrame: Pre-dose (within 1 hr), 2, 4, 6, 8 hrs post-dose on Day 15 of Cycle 1 (cycle length: 28 days)
measure: Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab
timeFrame: 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)
Other outcomes:
Locations:
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika
city: Ostrava
country: Czechia
facility: Fakultni nemocnice Ostrava; Klinika hematoonkologie
city: Prague 2
country: Czechia
facility: Univerzita Karlova v Praze a Vseobecna fakultni nemocnice v Praze - 1; Lekarska Fakulta - I
city: København Ø
country: Denmark
facility: Rigshospitalet; Hæmatologisk Klinik
city: Odense C
country: Denmark
facility: Odense Universitetshospital
city: Nantes
country: France
facility: CHU - Hôtel Dieu hematolgie clinique
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Pierre-Benite (Lyon)
country: France
facility: CHU Lyon - Centre Hospitalier Lyon Sud
city: Villejuif
country: France
facility: IGR
city: Heidelberg
country: Germany
facility: UNI-Klinikum Heidelberg Medizinische Klinik Innere Medizin V
city: Mainz
country: Germany
facility: Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen Medizinische UNI-Klinik und Poliklinik Abt. Innere Medizin II
city: Ulm
country: Germany
facility: Universtitätsklinikum Ulm; Klinik für Innere Medizin III
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC Location AMC
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Førde
country: Norway
facility: Førde sentralsjukehus
city: Oslo
country: Norway
facility: Oslo University Hospital HF, Rikshospitalet
city: Lodz
country: Poland
facility: Medical University School; Dept. of Haematology
city: Pozna?
country: Poland
facility: Uniwersytet Medyczny im.Karola Marcinkowskiego w Poznaniu
city: Warszawa
country: Poland
facility: Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Oncology
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia
state: Barcelona
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa
city: Madrid
country: Spain
facility: Hospital Univ 12 de Octubre
city: Lund
country: Sweden
facility: Skånes Universitetssjukhus
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: