| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Multiple myeloma is a cancer formed by malignant plasma cells that starts in the bone marrow (the spongy tissue inside the bones). |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| •To evaluate the preliminary safety and tolerability and the preliminary efficacy of cobimetinib administered as single agent (Arm A), cobimetinib + venetoclax (Arm B), and cobimetinib + venetoclax + atezolizumab (Arm C) |
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| E.2.2 | Secondary objectives of the trial |
•To further evaluate the efficacy of cobimetinib administered as single agent (Arm A), cobimetinib + venetoclax (Arm B), and cobimetinib + venetoclax + atezolizumab (Arm C)
•To characterize the pharmacokinetics (PK) of cobimetinib (Arm A), to characterize the PK of cobimetinib and venetoclax when administered together (Arm B), and to characterize the pharmacokinetics of cobimetinib, venetoclax, and atezolizumab when administered together (Arm C)
•To evaluate the immune response to atezolizumab administered in Arm C
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- 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 (there is no required time period between last prior therapy and documented evidence of PD)
- 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 <= 1.5 × ULN and Adequate renal function as demonstrated by a calculated creatinine clearance of >= 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. Women must refrain from donating eggs during this same period.
- 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
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| E.4 | Principal exclusion criteria |
- 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 during the study
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Incidence, nature, and severity of adverse events, graded as per National Cancer Institute Common Terminology Criteria for Adverse Events, v4.0; laboratory data
2. Overall response rate as defined by the International Myeloma Working Group (2016)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Clinical benefit rate
2. Progression-free survival
3. Duration of response
4. Overall survival
5. Plasma concentration of cobimetinib and venetoclax at specified timepoints
6. Serum concentration of atezolizumab at specified timepoints
7. Incidence of anti-drug antibody during the study relative to the prevalence of anti-drug antibody at baseline
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-4. Up to 24 months
5. Cobimetinib: Day 1 and 15 of Cycle 1; Venetoclax: Day 1 and 15 of Cycle 1, Day 1 of Cycle 2 and 3
6-7. Day 1 of Cycle 1, 2 and 3, at treatment discontinuation visit (30 days after the last dose of study drug)
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| safety run in followed by randomization phase |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of this study is defined as when all patients randomized have been followed until death, withdrawal of consent, lost to follow-up, or the Sponsor decides to end the trial, whichever occurs first. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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