A PHASE IB/II STUDY OF COBIMETINIB ADMINISTERED AS SINGLE AGENT AND IN<br>COMBINATION WITH VENETOCLAX, WITH OR WITHOUT ATEZOLIZUMAB, IN PATIENTS WITH RELAPSED AND REFRACTORY MULTIPLE MYELOMA
- Conditions
- multiple myeloma10035227
- Registration Number
- NL-OMON44406
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 5
- Age >= 18 years
- Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2
- Life expectancy of at least 12 weeks
- Documented MM as defined by criteria such as monoclonal plasma cells in the bone marrow >= 10% or presence of a biopsy-proven plasmacytoma and Measurable disease such as Serum M-protein level >= 1.0 g/dL or urine monoclonal protein (M-protein) level >= 200 mg/24 hours or light chain MM as serum Ig free light chain (FLC) >=10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio
- Received 3 to 5 prior lines of therapy for MM, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD)
- Achieved a response to at least one prior regimen
- Documented evidence of progressive disease on or after their last prior therapy, or patients who were intolerant to their last prior therapy
- Toxicities resulting from previous therapy that must be resolved or stabilized to Grade 1
- Laboratory values such as hemoglobin level >= 7.5 g/dL ( >= 5 mmol/L), platelet count >= 50,000/mm3 or >= 30,000 if bone marrow plasma cell >= 50%, absolute neutrophil count >= 1000/mm3, AST and ALT >= 2.5 × the upper limit of normal (ULN), total bilirubin = 40 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft-Gault formula
- For women of childbearing potential: agreement to remain abstinent or use two contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of cobimetinib, 1 month after the last dose of venetoclax, and 5 months after the last dose of atezolizumab
- For men, agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm during the treatment period and for at least 3 months after the last dose of cobimetinib
- Anti-myeloma treatment within 14 days or 5 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, Bcl-2 inhibitors, or immune checkpoint inhibitor therapies including anti*CTLA-4, anti*PD-1 or 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 with the exceptions as patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after Medical Monitor approval has been obtained
- Surgical procedure or significant traumatic injury within 28 days prior to enrollment, or anticipation of need for major surgical procedure during the course of the study and minor surgical procedure within 7 days
- 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, serous retinopathy, Evidence of ongoing serous retinopathy or RVO at baseline
- Left ventricular ejection fraction below institutional lower limit of normal
- History of clinically significant cardiovascular dysfunction
- Any previous venous thromboembolism > Grade 3 within 12 months of study enrollment
- INR > 1.5 and aPTT > 1.5 × ULN within 7 days prior to study enrollment.
- History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding, severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins (for patients in Arm C only), history of other malignancy that could affect compliance with the protocol or interpretation of results and history of malabsorption or other condition that would interfere with absorption of study drugs
- Active or history of autoimmune disease or immune deficiency
- 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
- 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 patients in Arm C only)
- Received strong CYP3A inhibitors, moderate CYP3A inhibitors strong CYP3A inducers, and moderate CYP3A inducers within 7 days prior to the initiation of study treatment
- Foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment in St John*s wort or hyperforin, Grapefruit juice
- Pregnant or lactating, or intending to become pregnant du
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>• Incidence, nature, and severity of adverse events, graded according to NCI<br /><br>CTCAE, v4.0; laboratory data<br /><br>• ORR (sCR, CR, VGPR, PR) as determined by the investigator using the IMWG<br /><br>response criteria (Kumar et al. 2016) in the safety population and<br /><br>biomarker-selected population</p><br>
- Secondary Outcome Measures
Name Time Method <p>• CBR defined as MR or better<br /><br>• PFS defined as the time from randomization to the first occurrence of disease<br /><br>progression or relapse as determined by the investigator using the IMWG<br /><br>criteria or death from any cause during the study, whichever occurs first<br /><br>• DOR applies to patients achieving at least a PR, and is measured from the<br /><br>first observation of PR to the time of disease progression; deaths not due to<br /><br>progression will be censored<br /><br>• OS defined as the time from randomization until death from any cause</p><br>