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

Breast Cancer Clinical Trial

Official title:

A Multistage, Phase II Study Evaluating the Safety and Efficacy of Cobimetinib Plus Paclitaxel, Cobimetinib Plus Atezolizumab Plus Paclitaxel, or Cobimetinib Plus Atezolizumab Plus Nab-Paclitaxel as First-Line Treatment for Patients With Metastatic Triple-Negative Breast Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02322814
• Other study ID #: WO29479
• Secondary ID: 2014-002230-32
• Status: Terminated
• Phase: Phase 2
• Start date: March 12, 2015
• Est. completion date: September 17, 2021

Study information

• Verified date: March 2023
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 169
• Est. completion date: September 17, 2021
• Est. primary completion date: August 10, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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:

Disease-Specific 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

Cobimetinib-Specific Exclusion Criteria

• 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

Atezolizumab-Specific Exclusion Criteria (Cohorts II and III Only)

• 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

Cardiac Exclusion Criteria

• 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

General Exclusion Criteria

• 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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Triple Negative Breast Neoplasms

Intervention

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

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre; Medical Oncology	Melbourne	Victoria
Australia	St John of God Murdoch Hospital; Oncology West	Murdoch	Western Australia
Australia	Mater Adult Hospital	South Brisbane	Queensland
Australia	Calvary Mater Newcastle	Waratah	New South Wales
Belgium	Clinique Edith Cavell	Bruxelles
Belgium	AZ Sint Lucas (Sint Lucas)	Gent
Belgium	Jessa Zkh (Campus Virga Jesse)	Hasselt
Belgium	AZ Groeninge	Kortrijk
Belgium	AZ Sint Augustinus Veurne	Veurne
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Multiscan s.r.o.	Pardubice
France	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
Israel	Chaim Sheba Medical Center	Ramat Gan
Italy	Centro Di Riferimento Oncologico; SOC Oncologia Medica C	Aviano	Friuli-Venezia Giulia
Italy	A.O.U Policlinico S. Orsola Malpighi di Bologna U.O di Medicina Interna Borghi - Pad.2	Bologna	Emilia-Romagna
Italy	Istituto Europeo Di Oncologia	Milano	Lombardia
Italy	Azienda Ospedaliero Universitaria Seconda Università Degli Studi Di Napoli	Napoli	Campania
Italy	Azienda Ospedaliero - Universitaria Pisana U.O. Oncologia Medica 2 Universitaria ? Polo Oncologico	Pisa	Toscana
Italy	Policlinico Universitario Agostino Gemelli	Roma	Lazio
Korea, Republic of	National Cancer Center; Medical Oncology	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Yonsei University Health System/Severance Hospital	Seoul
Latvia	Pauls Stradins Clinical University Hospital	R?ga
Latvia	Riga East Clinical University Hospital Latvian Oncology Centre	Riga
Romania	Prof. Dr. I. Chiricuta Institute of Oncology	Cluj Napoca
Romania	Oncology Center Sf. Nectarie	Craiova
Spain	Hospital Universitario Infanta Cristina; Servicio de Oncologia	Badajoz
Spain	Organización Sanitaria Integrada Bilbao Basurto	Bilbao	Vizcaya
Spain	Fundacion Jimenez Diaz; Servicio de Oncologia	Madrid
Spain	Hospital Clinico San Carlos; Servicio de Nefrologia	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hosp. Regional Univ. de Malaga ? Hospital Materno Infantil; Hospital Materno Infantil de Malaga	Malaga
Spain	Corporacio Sanitaria Parc Tauli; Servicio de Oncologia	Sabadell	Barcelona
Taiwan	Chang Gung Memorial Hospital	Kaohsiung Country
Taiwan	Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology	Taipei City
United Kingdom	Nuffield Health Bournemouth Hospital	Bournemouth
United Kingdom	Mount Vernon Hospital	Middlesex
United Kingdom	Nottingham University Hospitals City Campus	Nottingham
United States	Montefiore Einstein Cancer Center	Bronx	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Ingalls Memorial Hospital	Harvey	Illinois
United States	Cancer Specialists of North Florida	Jacksonville	Florida
United States	Mercy Hospital, a Campus of Plantation General Hospital	Miami	Florida
United States	Cancer Treatment Centers of America	Newnan	Georgia
United States	Florida Hospital Cancer Inst	Orlando	Florida
United States	Magee Womens Hospital	Pittsburgh	Pennsylvania
United States	Florida Cancer Research Institute	Plantation	Florida
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Northwest Medical Specialties	Tacoma	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Czechia,  France,  Israel,  Italy,  Korea, Republic of,  Latvia,  Romania,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cohort I: Progression-Free Survival, as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)	PFS was defined as the time from randomization to the first occurrence of disease progression or relapse, as determined by the investigator, using RECIST v1.1. As per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). The appearance of one or more new lesions is also considered progression.	Randomization up to disease progression or relapse, whichever occurs first (up to approximately 2 years)
Primary	Cohort II, III: Percentage of Participants With Confirmed Overall Response (OR) (Partial Response [PR] or Complete Response [CR]), as Determined by the Investigator Using RECIST v1.1	OR was defined as the rate of a PR or CR occurring after randomization and confirmed >=28 days later as determined by the investigator using RECIST v1.1. As per RECIST v1.1, CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target and new measurable lesions.	Randomization up to disease progression or relapse, whichever occurs first (up to approximately 5.25 years)
Secondary	Cohort I, II, III: Overall Survival (OS)	OS was defined as the time from randomization to death from any cause	Randomization up to death from any cause (up to approximately 6.5 years)
Secondary	Cohort I: Percentage of Participants With Confirmed OR (PR or CR), as Determined by the Investigator Using RECIST v1.1	OR was defined as the rate of a PR or CR occurring after randomization and confirmed >=28 days later as determined by the investigator using RECIST v1.1. As per RECIST v1.1, CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target and new measurable lesions.	Randomization up to disease progression or relapse, whichever occurs first (up to approximately 2 years)
Secondary	Cohort I, II, III: Duration of Response (DOR), as Determined by the Investigator Using RECIST v1.1	DOR was defined as the time from the first occurrence of a documented objective response to the time of relapse, as determined by the investigator using RECIST v1.1 or death from any cause during the study, whichever occurred first.	Time from the first occurrence of documented objective response to time of relapse or death, whichever occurs first (up to approximately 6.5 years)
Secondary	Cohort I, II, III: Percentage of Participants With Unconfirmed Overall Response (OR_uc) (Unconfirmed PR or CR), as Determined by the Investigator Using RECIST v1.1	ORR_uc (ORR confirmation not required) was defined as the rate of a PR or CR occurring after randomization as determined by the investigator using RECIST v1.1, confirmation not required. As per RECIST v1.1, CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target and new measurable lesions.	Randomization up to disease progression or relapse, whichever occurs fist (up to approximately 6.5 years)
Secondary	Cohort II, III: Progression-Free Survival, as Determined by Investigator Using RECIST v1.1	PFS was defined as the time from randomization to the first occurrence of disease progression or relapse, as determined by the investigator, using RECIST v1.1. As per RECIST v1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.	Randomization up to disease progression or relapse, whichever occurs first (up to approximately 6.5 years)
Secondary	Cohort I, II, III: Percentage of Participants With Adverse Events (AEs)		Randomization up to end of study (up to approximately 6.5 years)
Secondary	Cohort I, II, III: Maximum Plasma Concentration (Cmax) of Cobimetinib		Safety Run-In: Predose (Hour [Hr] 0) on Cycle (Cy) 1 Day (D) 8; predose (Hr 0), 0.5, 1, 2, 4, 6 Hr postdose (2, 4 Hr postdose for Cohorts II, III) on Cy1 D15; Expansion: predose (Hr 0), 1-4 Hr postdose on Cy1 D15; predose (Hr 0) on Cy2 D15 (Cy=28 days)
Secondary	Cohort I, II, III: Minimum Plasma Concentration (Cmin) of Cobimetinib		Safety Run-In: Predose (Hr 0) on Cy 1 D8; predose (Hr 0), 0.5, 1, 2, 4, 6 Hr postdose (2, 4 Hr postdose for Cohorts II, III) on Cy1 D15; Expansion: predose (Hr 0), 1-4 Hr postdose on Cy1 D15; predose (Hr 0) on Cy2 D15 (Cy=28 days)
Secondary	Cohort I: Area Under the Concentration-Time Curve From Time Zero to Dosing Interval (AUC0-tau; Total Exposure) of Cobimetinib		Safety Run-In: Predose (Hr 0) on Cy 1 D8; predose (Hr 0), 0.5, 1, 2, 4, 6 Hr postdose on Cy1 D15; Expansion: predose (Hr 0), 1-4 Hr postdose on Cy1 D15 (Cy=28 days)
Secondary	Cohort I, II: Cmax of Paclitaxel		Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 0.5, 1, 2, 4, and 6 Hr postdose (2, 4 Hr postdose for Cohort II) (infusion duration: 1 Hr) on Cy1 D15 (Cy=28 days)
Secondary	Cohort I, II: Cmin of Paclitaxel		Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 0.5, 1, 2, 4, and 6 Hr postdose (2, 4 Hr postdose for Cohort II) (infusion duration: 1 Hr) on Cy1 D15 (Cy=28 days)
Secondary	Cohort I: AUC0-tau of Paclitaxel		Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 0.5, 1, 2, 4, and 6 Hr postdose (infusion duration: 1 Hr) on Cy1 D15 (Cy=28 days)
Secondary	Cohort III: Cmax of Nab-Paclitaxel		Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 2, 4 Hr postdose (infusion duration: 30 minutes) on Cy1 D15 (Cy=28 days)
Secondary	Cohort III: Cmin of Nab-Paclitaxel		Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 2, 4 Hr postdose (infusion duration: 30 minutes) on Cy1 D15 (Cy=28 days)
Secondary	Cohort III: AUC0-tau of Nab-Paclitaxel		Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 2, 4 Hr postdose (infusion duration: 30 minutes) on Cy1 D15 (Cy=28 days)
Secondary	Cohort II, III: Cmax (in Serum) of Atezolizumab		Safety Run-In, Expansion:Predose (Hr0), 0.5Hr postdose (infusion duration:1Hr) on D1 of Cy1, 3; predose (Hr0) on D1 of Cy2, 4, 8, every 8 Cy up to end of treatment (EOT); 120 days after EOT (approximately 5.25 years) (Cy=28 days)
Secondary	Cohort II, III: Cmin (in Serum) of Atezolizumab		Safety Run-In, Expansion: Predose (Hr 0), 0.5 Hr postdose (infusion duration: 1 Hr) on D1 of Cy1, 3; predose (Hr 0) on D1 of Cy2, 4, 8, every 8 Cy up to EOT; 120 days after EOT (approximately 5.5 years) (Cy=28 days)
Secondary	Cohort II, III: AUC0-tau (in Serum) of Atezolizumab		Safety Run-In, Expansion: Predose (Hr 0), 0.5 Hr postdose (infusion duration: 1 Hr) on D1 of Cy1, 3; predose (Hr 0) on D1 of Cy2, 4, 8, every 8 Cy up to EOT (approximately 5.5 years); 120 days after EOT (approximately 5.5 years) (Cy=28 days)