Clinical trial NCT03695380: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: OVARIAN CANCER
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-10-04
Enrollment: 77
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Number of patients reporting Adverse Events (AEs)
timeFrame: From baseline up to 48 months
measure: Change from baseline in targeted clinical laboratory test results
timeFrame: From baseline up to 48 months
measure: Investigator-assessed confirmed objective response rate (ORR)
timeFrame: From baseline up to 48 months
Secondary outcomes:
measure: Progression-free survival (PFS)
timeFrame: From Baseline up to 48 months
measure: Duration of response (DOR)
timeFrame: From baseline up to 48 months
measure: Overall survival (OS)
timeFrame: From baseline up to 48 months
measure: Plasma concentration of cobimetinib and niraparib
timeFrame: Arm A: Day 15 of Cycle 1 and 2 - Arm B: Day 15 of Cycle 1
measure: Serum concentration of atezolizumab
timeFrame: Day 1 of Cycle 1, 2 and 3 and at treatment discontinuation visit, up to 48 months
measure: Number of patients with Anti-Drug Antibodies (ADA)
timeFrame: Day 1 of Cycle 1, 2 and 3 and at treatment discontinuation visit, up to 48 months
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center, North
state: Arizona
city: La Jolla
country: United States
facility: Moores Cancer Center at UC San Diego Health
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic-Jacksonville
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Cancer Institute; Clinical Research Department
state: Florida
city: Augusta
country: United States
facility: Medical College of Georgia; Obstetrics & Gynecolog
state: Georgia
city: Saint Louis
country: United States
facility: Washington University School of Medicine; Dept of Medicine/Div of Medical Oncology
state: Missouri
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center Investigational Pharmacy
state: Oklahoma
city: Nashville
country: United States
facility: Tennessee Oncology; Sarah Cannon Research Institute
state: Tennessee
city: Milwaukee
country: United States
facility: Medical College of Wisconsin; Department of Obstetrics and Gynecology
state: Wisconsin
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione G. Pascale
state: Campania
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario "A. Gemelli"; Unità di Fase 1: Unità di Farmacologia Clinica
state: Lazio
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia; Svil. Nuovi Farmaci per Terapie Innovative
state: Lombardia
city: A Coruna
country: Spain
facility: Centro Oncologico de Galicia COG; Medical Oncology
state: LA Coruña
city: Barcelona
country: Spain
facility: Hospital Universitari Vall dHebron; Oncology
city: Girona
country: Spain
facility: ICO Girona
city: Jaen
country: Spain
facility: Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra Madrid; Servicio de Oncología
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos; Servicio de Oncologia
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia; Servicio de Oncología
Study officials:
References: