OVARIAN CANCER
Conditions
Brief summary
The study will include a safety run-in phase (Stage 1) and a randomization phase (Stage 2). The purpose of Stage 1 is to evaluate the safety of cobimetinib when administered in combination with niraparib (Cohort 1) and cobimetinib with niraparib plus atezolizumab (Cohort 2). Stage 1 will enable patient enrollment in the randomized phase of the study (Stage 2) with both regimens at the recommended dose levels from Stage 1. Stage 2 is a randomized, dose-expansion phase, evaluating clinical outcomes in patients with advanced platinum-sensitive ovarian cancer. All patients will continue to receive study treatment until disease progression (according to Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, unacceptable toxicity, death, or patient or investigator decision to withdraw, whichever occurs first.
Interventions
DRUGCobimetinib
Cobimetinib will be administered at a starting dose of 60 mg by mouth (PO) daily (QD) on Days 1-21 of each 28-day cycle (Stage 1) and PO QD on Days 1-21 (21/7 schedule) at the established dose for the doublet regimen in Stage 1 (Stage 2).
DRUGNiraparib
Niraparib will be administered at a starting dose of 200 mg of niraparib PO QD on Days 1-28 of each 28-day cycle (Stage 1) and PO QD on Days 1-28 of each 28-day cycle at the established dose for the doublet regimen in Stage 1 (Stage 2).
DRUGAtezolizumab
Atezolizumab will be administered by IV infusion at the fixed dose of 840 mg on Days 1 and 15 (+/-3 days) of each 28-day cycle (Stages 1 and 2).
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ability to comply with the study protocol, in the investigator's judgment * Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including the completion of patient-reported outcome questionnaires * Histological diagnosis of high-grade serous or Grade 2 or Grade 3 endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer * Previous treatment with a minimum of one and a maximum of two prior platinum based treatment regimens * Platinum-sensitive disease * Availability of tumor biopsy tissue prior to first dose of study treatment with confirmation by the central laboratory that the sample is not only of adequate quality but also assignable to a molecularly defined subgroup based on breast cancer susceptibility gene (BRCA) and loss of heterozygosity (LOH) status * Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) * Adequate hematologic and organ function * Eastern Cooperative Oncology Group Performance Status of 0 or 1 * Life expectancy of at least 12 weeks * Resolved or stabilized toxicities resulting from previous therapy to Grade 1 * Negative HIV test at screening * Negative hepatitis B surface antigen and total hepatitis B core antibody (HBcAb) test, or positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA \< 500 IU/mL test at screening * Negative hepatitis C virus (HCV) antibody test, or positive HCV antibody test followed by a negative HCV RNA test at screening * For women of childbearing potential: Women must 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, 6 months after the last dose of niraparib, and 5 months after the last dose of atezolizumab. Women must refrain from donating eggs during this same period
Exclusion criteria
* Prior treatment with mitogen-activated protein kinase inhibitor, polyadenosine diphosphate-ribose polymerase inhibitor, or immune checkpoint inhibitor therapies * Prior chemotherapy, hormonal therapy, radiotherapy, antibody therapy, or other immunotherapy, gene therapy, vaccine therapy, or treatment with experimental drugs within 14 days prior to first dose of study treatment * Treatment with systemic immunostimulatory agents within 28 days or 5 half-lives of the drug prior to initiation of study treatment * Treatment with systemic immunosuppressive medication 14 days prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the study * History of other malignancy that could affect compliance with the protocol or interpretation of results, or known to have potentially fatal outcome * Symptomatic and/or untreated central nervous system metastases * Surgical procedure, significant traumatic injury within 14 days prior to enrollment, or anticipation of need for major surgical procedure during the study * Minor surgical procedure within 3 days * History or evidence of retinal pathology on ophthalmic examination * Left ventricular ejection fraction below institutional lower limit of normal * History of clinically significant cardiovascular dysfunction * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on the screening chest computed tomography scan * History or evidence of inherited bleeding diathesis or significant coagulopathy at risk for bleeding * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins, or to any component of the atezolizumab formulation * Known allergy or hypersensitivity to any component of the cobimetinib or niraparib formulation * Active or history of autoimmune disease or immune deficiency including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barre syndrome, or multiple sclerosis * Uncontrolled serious medical or psychiatric illness * History of malabsorption or other condition that would interfere with absorption of oral study drugs, including preexisting duodenal stent or ongoing intestinal obstruction * Active tuberculosis * Severe infection within 14 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 7 days prior to initiation of study treatment * Treatment with a live, attenuated influenza vaccine within 28 days prior to study treatment initiation, at any time during the study, and for at least 5 months after the last dose of study drug * Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications * Previous treatment with strong CYP3A inhibitors (such as ketoconazole and clarithromycin), strong CYP3A inducers (such as carbamazepine and phenytoin), and moderate CYP3A inducers (such as efavirenz, modafinil) within 7 days prior to the initiation of study treatment or with ongoing requirements for these medications * Pregnancy or breastfeeding, or intention to become pregnant during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients reporting Adverse Events (AEs) | From baseline up to 48 months | The safety profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumab will be evaluated in terms of number of patients reporting serious and non-serious AEs with severity graded according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v5.0) |
| Change from baseline in targeted clinical laboratory test results | From baseline up to 48 months | The safety profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumabwill be evaluated in terms of number of patients reporting change from baseline in targeted clinical laboratory test results. |
| Investigator-assessed confirmed objective response rate (ORR) | From baseline up to 48 months | The efficacy profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumab will be evaluated in terms of investigator-assessed confirmed ORR, as determined using RECIST v1.1 in the Intention To Treat (ITT) population and in molecularly defined subgroups by loss of heterozygosity (LOH) status. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma concentration of cobimetinib and niraparib | Arm A: Day 15 of Cycle 1 and 2 - Arm B: Day 15 of Cycle 1 | The Pharmacokinetic (PK) profile of cobimetinib plus niraparib is evaluated in terms of Plasma concentration at specified timepoints. |
| Progression-free survival (PFS) | From Baseline up to 48 months | The efficacy profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumab will be evaluated in terms of PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or relapse, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first, in the ITT population and in the molecularly defined subgroups by LOH status. |
| Number of patients with Anti-Drug Antibodies (ADA) | Day 1 of Cycle 1, 2 and 3 and at treatment discontinuation visit, up to 48 months | The immunogenicity profile of Atezolizumab is evaluated in terms of number of patients with ADA at baseline and during the study. |
| Serum concentration of atezolizumab | Day 1 of Cycle 1, 2 and 3 and at treatment discontinuation visit, up to 48 months | The PK profile of cobimetinib plus niraparib plus atezolizumab will be evaluated in terms of Serum concentration of atezolizumab at specified timepoints (Arm B only). |
| Duration of response (DOR) | From baseline up to 48 months | The efficacy profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumab will be evaluated in terms of DOR, defined for patients achieving at least one confirmed Partial Response (PR), which is measured from the first observation of a Complete Response (CR) or a PR to the time of disease progression in the ITT population and in the molecularly defined subgroups by LOH status. |
| Overall survival (OS) | From baseline up to 48 months | The efficacy profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumab will be evaluated in terms of OS after randomization, defined as the time from randomization until death from any cause in the ITT population and in the molecularly defined subgroups by LOH status. |
Countries
Italy, Spain, United States
Outcome results
None listed