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

NCT ID: NCT03695380

Last Updated: 2023-08-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 77 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-09
• Study Completion Date: 2023-07-12

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.

Conditions

OVARIAN CANCER

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

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).

Niraparib

Intervention Type: DRUG

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).

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.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

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).

Niraparib

Intervention Type: DRUG

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).

Atezolizumab

Intervention Type: DRUG

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).

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.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

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).

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.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

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).

Interventions

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).

Intervention Type: 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).

Intervention Type: 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).

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of Arizona Cancer Center, North

Tucson, Arizona, United States

Moores Cancer Center at UC San Diego Health

La Jolla, California, United States

Mayo Clinic-Jacksonville

Jacksonville, Florida, United States

Florida Hospital Cancer Institute; Clinical Research Department

Orlando, Florida, United States

Medical College of Georgia; Obstetrics & Gynecolog

Augusta, Georgia, United States

Washington University School of Medicine; Dept of Medicine/Div of Medical Oncology

St Louis, Missouri, United States

Stephenson Cancer Center Investigational Pharmacy

Oklahoma City, Oklahoma, United States

Tennessee Oncology; Sarah Cannon Research Institute

Nashville, Tennessee, United States

Medical College of Wisconsin; Department of Obstetrics and Gynecology

Milwaukee, Wisconsin, United States

Istituto Nazionale Tumori Fondazione G. Pascale

Napoli, Campania, Italy

Fondazione Policlinico Universitario "A. Gemelli"; Unità di Fase 1: Unità di Farmacologia Clinica

Rome, Lazio, Italy

Istituto Europeo di Oncologia; Svil. Nuovi Farmaci per Terapie Innovative

Milan, Lombardy, Italy

Centro Oncologico de Galicia COG; Medical Oncology

A Coruña, LA Coruña, Spain

Hospital Universitari Vall dHebron; Oncology

Barcelona, , Spain

ICO Girona

Girona, , Spain

Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia

Jaén, , Spain

Clinica Universidad de Navarra Madrid; Servicio de Oncología

Madrid, , Spain

Hospital Ramon y Cajal; Servicio de Oncologia

Madrid, , Spain

Hospital Clinico San Carlos; Servicio de Oncologia

Madrid, , Spain

Hospital Clínico Universitario de Valencia; Servicio de Oncología

Valencia, , Spain

Countries

United States; Italy; Spain

References

Mutch D, Voulgari A, Chen XM, Bradley WH, Oaknin A, Perez Fidalgo JA, Montosa FG, Herraez AC, Holloway RW, Powell MA, Nowicka M, Schaefer G, Merchant M, Yan Y. Primary results and characterization of patients with exceptional outcomes in a phase 1b study combining PARP and MEK inhibition, with or without anti-PD-L1, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer. Cancer. 2024 Jun 1;130(11):1940-1951. doi: 10.1002/cncr.35222. Epub 2024 Jan 30.

Reference Type: DERIVED

PMID: 38288862 (View on PubMed)

Other Identifiers

2018-000631-27

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

YO40482

Identifier Type: -

Identifier Source: org_study_id