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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03695380
Recruitment Status : Recruiting
First Posted : October 4, 2018
Last Update Posted : March 19, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE September 30, 2018
First Posted Date  ICMJE October 4, 2018
Last Update Posted Date March 19, 2020
Actual Study Start Date  ICMJE January 9, 2019
Estimated Primary Completion Date May 15, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 2, 2018)
  • Number of patients reporting Adverse Events (AEs) [ Time Frame: From baseline up to 48 months ]
    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)
  • Change from baseline in targeted clinical laboratory test results [ Time Frame: From baseline up to 48 months ]
    The safety profile of Cobimetinib plus Niraparib compared to 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) [ Time Frame: From baseline up to 48 months ]
    The efficacy profile of Cobimetinib plus Niraparib compared to 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 the two molecularly defined subgroups: breast cancer susceptibility gene wild type (BRCAwt) /LOHhigh and BRCAwt/LOHlow in each study arm.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 2, 2018)
  • Progression-free survival (PFS) [ Time Frame: From Baseline up to 48 months ]
    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.
  • Duration of response (DOR) [ Time Frame: From baseline up to 48 months ]
    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.
  • Overall survival (OS) [ Time Frame: From baseline up to 48 months ]
    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.
  • Plasma concentration of cobimetinib and niraparib [ Time Frame: 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.
  • Serum concentration of atezolizumab [ Time Frame: 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).
  • 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 ]
    The immunogenicity profile of Atezolizumab is evaluated in terms of number of patients with ADA at baseline and during the study.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Clinical Study of Cobimetinib Administered in Combination With Niraparib, With or Without Atezolizumab to Patients With Advanced Platinum-sensitive Ovarian Cancer
Official Title  ICMJE A Phase Ib Study of Cobimetinib Administered in Combination With Niraparib, With or Without Atezolizumab, To Patients With Advanced Platinum-sensitive Ovarian Cancer
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE OVARIAN CANCER
Intervention  ICMJE
  • Drug: Cobimetinib
    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).
  • Drug: Niraparib
    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).
  • Drug: Atezolizumab
    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).
Study Arms  ICMJE
  • Experimental: Arm A: Cobimetinib - Niraparib
    Stage 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.
    Interventions:
    • Drug: Cobimetinib
    • Drug: Niraparib
  • Experimental: Arm B: Cobimetinib - Niraparib - Atezolizumab
    Stage 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.
    Interventions:
    • Drug: Cobimetinib
    • Drug: Niraparib
    • Drug: Atezolizumab
  • Experimental: Cohort 1 - Cobimetinib - Niraparib

    Stage 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.

    Intervention: Drug: Cobimetinib
  • Experimental: Cohort 2 - Cobimetinib - Niraparib - Atezolizumab

    Stage 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.

    Intervention: Drug: Cobimetinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 2, 2018)
70
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 15, 2022
Estimated Primary Completion Date May 15, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reference Study ID Number: YO40482 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com
Listed Location Countries  ICMJE France,   Italy,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03695380
Other Study ID Numbers  ICMJE YO40482
2018-000631-27 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Hoffmann-La Roche
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP