A Study of Cobimetinib Plus Paclitaxel, Cobimetinib Plus Atezolizumab Plus Paclitaxel, or Cobimetinib Plus Atezolizumab Plus Nab-Paclitaxel as Initial Treatment for Participants With Triple-Negative Breast Cancer That Has Spread

NCT ID: NCT02322814

Last Updated: 2023-04-13

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 169 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-03-12
• Study Completion Date: 2021-09-17

Brief Summary

This three-cohort, multi-stage, randomized, Phase II, multicenter trial will evaluate the safety and tolerability and estimate the efficacy of cobimetinib plus paclitaxel versus placebo plus paclitaxel in Cohort I, of cobimetinib plus atezolizumab plus paclitaxel in Cohort II, and of cobimetinib plus atezolizumab plus nab-paclitaxel in Cohort III in participants with metastatic or locally advanced, triple-negative adenocarcinoma of the breast who have not received prior systemic therapy for metastatic breast cancer (MBC). Participants may continue on study treatment until the development of progressive disease (PD) or the loss of clinical benefit, unacceptable toxicity, and/or consent withdrawal. The Cohort I target sample size is 12 participants for the safety run-in stage and approximately 90 participants in the expansion stage. Each of Cohorts II and III will consist of a safety run-in stage of approximately 15 participants followed by an expansion stage of approximately 15 participants.

Conditions

Breast Cancer

Study Design

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

Study Groups

Cohort I: Cobimetinib, Paclitaxel

Participants will receive a combination of cobimetinib plus paclitaxel in 28-day cycles until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Cobimetinib will be administered orally at a dose of 60 milligrams (mg) per day, once a day, on Day 3 through Day 23 of each 28-day treatment cycle.

Paclitaxel

Intervention Type: DRUG

Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m\^2) by intravenous (IV) infusion on Day 1, Day 8, and Day 15 of each 28-day cycle according to prescribing information.

Cohort I: Placebo, Paclitaxel

Participants will receive a combination of cobimetinib placebo plus paclitaxel in 28-day cycles until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Group Type: PLACEBO_COMPARATOR

Paclitaxel

Intervention Type: DRUG

Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m\^2) by intravenous (IV) infusion on Day 1, Day 8, and Day 15 of each 28-day cycle according to prescribing information.

Placebo

Intervention Type: DRUG

Placebo matching to cobimetinib will be administered orally, once a day, on Day 3 through Day 23 of each 28 day treatment cycle.

Cohort II:Cobimetinib,Paclitaxel,Atezolizumab

Participants will receive cobimetinib plus paclitaxel plus atezolizumab in 28-day cycles until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Cobimetinib will be administered orally at a dose of 60 milligrams (mg) per day, once a day, on Day 3 through Day 23 of each 28-day treatment cycle.

Paclitaxel

Intervention Type: DRUG

Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m\^2) by intravenous (IV) infusion on Day 1, Day 8, and Day 15 of each 28-day cycle according to prescribing information.

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered to Cohorts II and III at a dose of 840 mg IV every 2 weeks on Days 1 and 15 of each 28-day treatment cycle.

Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab

Participants will receive cobimetinib plus nab-paclitaxel plus atezolizumab until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Cobimetinib will be administered orally at a dose of 60 milligrams (mg) per day, once a day, on Day 3 through Day 23 of each 28-day treatment cycle.

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be administered to Cohorts II and III at a dose of 840 mg IV every 2 weeks on Days 1 and 15 of each 28-day treatment cycle.

Nab-Paclitaxel

Intervention Type: DRUG

Nab-Paclitaxel will be administered to Cohort III according to the local prescribing information at a starting dose of 100 mg/m\^2 by IV infusion on Days 1, 8, and 15 of each 28 day cycle.

Interventions

Cobimetinib

Cobimetinib will be administered orally at a dose of 60 milligrams (mg) per day, once a day, on Day 3 through Day 23 of each 28-day treatment cycle.

Intervention Type: DRUG

Paclitaxel

Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m\^2) by intravenous (IV) infusion on Day 1, Day 8, and Day 15 of each 28-day cycle according to prescribing information.

Intervention Type: DRUG

Placebo

Placebo matching to cobimetinib will be administered orally, once a day, on Day 3 through Day 23 of each 28 day treatment cycle.

Intervention Type: DRUG

Atezolizumab

Atezolizumab will be administered to Cohorts II and III at a dose of 840 mg IV every 2 weeks on Days 1 and 15 of each 28-day treatment cycle.

Intervention Type: DRUG

Nab-Paclitaxel

Nab-Paclitaxel will be administered to Cohort III according to the local prescribing information at a starting dose of 100 mg/m\^2 by IV infusion on Days 1, 8, and 15 of each 28 day cycle.

Intervention Type: DRUG

Other Intervention Names

GDC-0973; RO5514041; XL518; MPDL3280A

Eligibility Criteria

Inclusion Criteria

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Histologically confirmed estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor 2 (HER2)-negative adenocarcinoma of the breast with measurable metastatic or locally advanced disease
• Locally advanced disease must not be amenable to resection with curative intent
• Measurable disease, according to RECIST, v1.1
• Adequate hematologic and end organ function
• Agreement to use highly effective contraceptive methods as stated in protocol

Exclusion Criteria

• Known HER2-, ER-positive, or PR-positive breast cancer by local laboratory assessment
• Any prior chemotherapy, hormonal, or targeted therapy, for inoperable locally advanced or metastatic triple-negative breast cancer (mTNBC)
• Any systemic anticancer therapy within 3 weeks prior to Cycle 1, Day 1
• Any radiation treatment to metastatic site within 28 days of Cycle 1, Day 1
• Major surgical procedure, open biopsy, or significant traumatic injury within 30 days prior to Cycle 1, Day 1 or anticipation of need for major surgical procedure during the course of the study
• Prior exposure to experimental treatment targeting rapidly accelerated fibrosarcoma (Raf), MAP kinase/ERK kinase (MEK), or the mitogen-activated protein kinase (MAPK) pathway
• Brain metastases (symptomatic or nonsymptomatic) that have not been treated previously, are progressive, or require any type of therapy (e.g., radiation, surgery, or steroids) to control symptoms from brain metastases within 30 days prior to first study treatment dose

• History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration
• Cobimetinib is metabolized by the hepatic cytochrome P3A4 (CYP3A4) enzyme. Drugs CYP3A4/5 inhibitors and inducers should be avoided

• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
• History of autoimmune disease
• Prior allogenic stem cell or solid organ transplantation
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Positive test for Human Immunodeficiency Virus (HIV)
• Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] or positive hepatitis B virus [HBV] deoxyribonucleic acid [DNA] test at screening) or hepatitis C
• Active tuberculosis
• Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation that such a live, attenuated vaccine will be required during the study
• Prior treatment with cluster of differentiation (CD) 137 (CD137) agonists or immune checkpoint blockade therapies, including anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), or anti-programmed death ligand-1 (anti-PD-L1) therapeutic antibodies
• Treatment with systemic immunostimulatory agents (including but not limited to interferons or Interlukin-2 [IL-2]) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial

• History of clinically significant cardiac dysfunction
• Corrected QT interval at screening greater than (>) 480 milliseconds (ms) (average of triplicate screening measurements)
• Left ventricular ejection fraction (LVEF) below the institutional lower limit of normal or below 50 percent (%), whichever is lower

• No other history of or ongoing malignancy that would potentially interfere with the interpretation of the pharmacodynamic or efficacy assay
• Pregnancy (positive serum pregnancy test) or lactation
• Uncontrolled serious medical or psychiatric illness
• Active infection requiring IV antibiotics on Cycle 1, Day 1
• Participants who have a history of hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil) or to nab-paclitaxel and any of the excipients

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

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Cancer Specialists of North Florida

Jacksonville, Florida, United States

Mercy Hospital, a Campus of Plantation General Hospital

Miami, Florida, United States

Florida Hospital Cancer Inst

Orlando, Florida, United States

Florida Cancer Research Institute

Plantation, Florida, United States

Cancer Treatment Centers of America

Newnan, Georgia, United States

Ingalls Memorial Hospital

Harvey, Illinois, United States

Montefiore Einstein Cancer Center

The Bronx, New York, United States

Magee Womens Hospital

Pittsburgh, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Avera Cancer Institute

Sioux Falls, South Dakota, United States

Northwest Medical Specialties

Tacoma, Washington, United States

Calvary Mater Newcastle

Waratah, New South Wales, Australia

Mater Adult Hospital

South Brisbane, Queensland, Australia

Peter MacCallum Cancer Centre; Medical Oncology

Melbourne, Victoria, Australia

St John of God Murdoch Hospital; Oncology West

Murdoch, Western Australia, Australia

Clinique Edith Cavell

Brussels, , Belgium

AZ Sint Lucas (Sint Lucas)

Ghent, , Belgium

Jessa Zkh (Campus Virga Jesse)

Hasselt, , Belgium

AZ Groeninge

Kortrijk, , Belgium

AZ Sint Augustinus Veurne

Veurne, , Belgium

Fakultni nemocnice Hradec Kralove

Hradec Králové, , Czechia

Multiscan s.r.o.

Pardubice, , Czechia

Centre Oscar Lambret

Lille, , France

Centre Régional de Lutte Contre Le Cancer Val D'aurelle Paul Lamarque

Montpellier, , France

Hopital Tenon

Paris, , France

Centre Eugene Marquis Centre Regional de Lutte Contre Le Cancer

Rennes, , France

Chaim Sheba Medical Center

Ramat Gan, , Israel

Azienda Ospedaliero Universitaria Seconda Università Degli Studi Di Napoli

Napoli, Campania, Italy

A.O.U Policlinico S. Orsola Malpighi di Bologna U.O di Medicina Interna Borghi - Pad.2

Bologna, Emilia-Romagna, Italy

Centro Di Riferimento Oncologico; SOC Oncologia Medica C

Aviano, Friuli Venezia Giulia, Italy

Policlinico Universitario Agostino Gemelli

Rome, Lazio, Italy

Istituto Europeo Di Oncologia

Milan, Lombardy, Italy

Azienda Ospedaliero - Universitaria Pisana U.O. Oncologia Medica 2 Universitaria ? Polo Oncologico

Pisa, Tuscany, Italy

Pauls Stradins Clinical University Hospital

R?ga, , Latvia

Riga East Clinical University Hospital Latvian Oncology Centre

Riga, , Latvia

Prof. Dr. I. Chiricuta Institute of Oncology

Cluj-Napoca, , Romania

Oncology Center Sf. Nectarie

Craiova, , Romania

National Cancer Center; Medical Oncology

Gyeonggi-do, , South Korea

Asan Medical Center

Seoul, , South Korea

Korea University Guro Hospital

Seoul, , South Korea

Yonsei University Health System/Severance Hospital

Seoul, , South Korea

Corporacio Sanitaria Parc Tauli; Servicio de Oncologia

Sabadell, Barcelona, Spain

Organización Sanitaria Integrada Bilbao Basurto

Bilbao, Vizcaya, Spain

Hospital Universitario Infanta Cristina; Servicio de Oncologia

Badajoz, , Spain

Hospital Universitario Ramon y Cajal

Madrid, , Spain

Fundacion Jimenez Diaz; Servicio de Oncologia

Madrid, , Spain

Hospital Clinico San Carlos; Servicio de Nefrologia

Madrid, , Spain

Hosp. Regional Univ. de Malaga ? Hospital Materno Infantil; Hospital Materno Infantil de Malaga

Málaga, , Spain

Chang Gung Memorial Hospital

Kaohsiung Country, , Taiwan

Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology

Taipei, , Taiwan

Nuffield Health Bournemouth Hospital

Bournemouth, , United Kingdom

Mount Vernon Hospital

Middlesex, , United Kingdom

Nottingham University Hospitals City Campus

Nottingham, , United Kingdom

Countries

United States; Australia; Belgium; Czechia; France; Israel; Italy; Latvia; Romania; South Korea; Spain; Taiwan; United Kingdom

References

Barteselli G, Goodman GR, Patel Y, Caro I, Xue C, McCallum S. Characterization of Serous Retinopathy Associated with Cobimetinib: Integrated Safety Analysis of Four Studies. Drug Saf. 2022 Dec;45(12):1491-1499. doi: 10.1007/s40264-022-01248-2. Epub 2022 Oct 30.

Reference Type: DERIVED

PMID: 36310331 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2014-002230-32

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

WO29479

Identifier Type: -

Identifier Source: org_study_id