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A Clinical Study of Cobimetinib Administered in Combination With Niraparib, With or Without Atezolizumab to Patients With Advanced Platinum-sensitive Ovarian Cancer

NCT03695380

Description:

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.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Clinical Study of Cobimetinib Administered in Combination With Niraparib, With or Without Atezolizumab to Patients With Advanced Platinum-sensitive Ovarian Cancer
  • Official Title: A Phase Ib Study of Cobimetinib Administered in Combination With Niraparib, With or Without Atezolizumab, To Patients With Advanced Platinum-sensitive Ovarian Cancer

Clinical Trial IDs

  • ORG STUDY ID: YO40482
  • SECONDARY ID: 2018-000631-27
  • NCT ID: NCT03695380

Conditions

  • OVARIAN CANCER

Interventions

DrugSynonymsArms
CobimetinibArm A: Cobimetinib - Niraparib
NiraparibArm A: Cobimetinib - Niraparib
AtezolizumabArm B: Cobimetinib - Niraparib - Atezolizumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Arm A: Cobimetinib - NiraparibExperimentalStage 2 - Patients will receive cobimetinib PO QD on Days 1-21 (21/7 schedule) in combination with niraparib PO QD on Days 1-28 of each 28-day cycle at the established dose for the doublet regimen in Stage 1, Cohort 1.
  • Cobimetinib
  • Niraparib
Arm B: Cobimetinib - Niraparib - AtezolizumabExperimentalStage 2 - Patients will receive cobimetinib PO QD on Days 1-21 (21/7 schedule) in combination with niraparib QD on Days 1-28 at the established doses for the triplet regimen in Stage 1,Cohort 2 plus atezolizumab by IV infusion at the fixed dose of 840 mg on Days 1 and 15 (+/-3 days) of each 28-day cycle.
  • Cobimetinib
  • Niraparib
  • Atezolizumab
Cohort 1 - Cobimetinib - NiraparibExperimentalStage 1 - Patients in Cohort 1 will be treated with cobimetinib plus niraparib. Cobimetinib: Patients will receive a starting dose of 60 mg by mouth (PO) daily (QD) on Days 1-21 of each 28-day cycle. Niraparib: Patients will receive a starting dose of 200 mg of niraparib PO QD on Days 1-28 of each 28-day cycle.
  • Cobimetinib
Cohort 2 - Cobimetinib - Niraparib - AtezolizumabExperimentalStage 1 - Patients in Cohort 2 will be treated with cobimetinib plus niraparib and atezolizumab. Cobimetinib: Patients will receive a starting dose of 60 mg by mouth (PO) daily (QD) on Days 1-21 of each 28-day cycle. Niraparib: Patients will receive a starting dose of 200 mg of niraparib PO QD on Days 1-28 of each 28-day cycle. Atezolizumab: Patients will also receive atezolizumab administered as an IV infusion at a fixed dose of 840 mg on Days 1 and 15 (+/-3 days) of each 28-day cycle.
  • Cobimetinib

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients reporting Adverse Events (AEs)
Time Frame:From baseline up to 48 months
Safety Issue:
Description:The safety profile of Cobimetinib plus Niraparib compared to 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)

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From Baseline up to 48 months
Safety Issue:
Description:The efficacy profile of Cobimetinib plus Niraparib compared to 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 two molecularly defined subgroups: BRCAwt/LOHhigh and BRCAwt/LOHlow in each study arm.
Measure:Duration of response (DOR)
Time Frame:From baseline up to 48 months
Safety Issue:
Description:The efficacy profile of Cobimetinib plus Niraparib compared to 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 two molecularly defined subgroups: BRCAwt/LOHhigh and BRCAwt/LOHlowin each study arm.
Measure:Overall survival (OS)
Time Frame:From baseline up to 48 months
Safety Issue:
Description:The efficacy profile of Cobimetinib plus Niraparib compared to 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 two molecularly defined subgroups: BRCAwt/LOHhigh and BRCAwt/LOHlow in each study arm.
Measure:Plasma concentration of cobimetinib and niraparib
Time Frame:Arm A: Day 15 of Cycle 1 and 2 - Arm B: Day 15 of Cycle 1
Safety Issue:
Description:The Pharmacokinetic (PK) profile of cobimetinib plus niraparib is evaluated in terms of Plasma concentration at specified timepoints.
Measure:Serum concentration of atezolizumab
Time Frame:Day 1 of Cycle 1, 2 and 3 and at treatment discontinuation visit, up to 48 months
Safety Issue:
Description: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).
Measure:Number of patients with Anti-Drug Antibodies (ADA)
Time Frame:Day 1 of Cycle 1, 2 and 3 and at treatment discontinuation visit, up to 48 months
Safety Issue:
Description:The immunogenicity profile of Atezolizumab is evaluated in terms of number of patients with ADA at baseline and during the study.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

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