Clinical trial NCT02322814: 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
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Breast Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-12-23
Enrollment: 169
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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:

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

Primary outcomes:
measure: Cohort I: Progression-Free Survival, as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: Randomization up to disease progression or relapse, whichever occurs first (up to approximately 2 years)
measure: 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
timeFrame: Randomization up to disease progression or relapse, whichever occurs first (up to approximately 5.25 years)
Secondary outcomes:
measure: Cohort I, II, III: Overall Survival (OS)
timeFrame: Randomization up to death from any cause (up to approximately 6.5 years)
measure: Cohort I: Percentage of Participants With Confirmed OR (PR or CR), as Determined by the Investigator Using RECIST v1.1
timeFrame: Randomization up to disease progression or relapse, whichever occurs first (up to approximately 2 years)
measure: Cohort I, II, III: Duration of Response (DOR), as Determined by the Investigator Using RECIST v1.1
timeFrame: Time from the first occurrence of documented objective response to time of relapse or death, whichever occurs first (up to approximately 6.5 years)
measure: 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
timeFrame: Randomization up to disease progression or relapse, whichever occurs fist (up to approximately 6.5 years)
measure: Cohort II, III: Progression-Free Survival, as Determined by Investigator Using RECIST v1.1
timeFrame: Randomization up to disease progression or relapse, whichever occurs first (up to approximately 6.5 years)
measure: Cohort I, II, III: Percentage of Participants With Adverse Events (AEs)
timeFrame: Randomization up to end of study (up to approximately 6.5 years)
measure: Cohort I, II, III: Maximum Plasma Concentration (Cmax) of Cobimetinib
timeFrame: 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)
measure: Cohort I, II, III: Minimum Plasma Concentration (Cmin) of Cobimetinib
timeFrame: 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)
measure: Cohort I: Area Under the Concentration-Time Curve From Time Zero to Dosing Interval (AUC0-tau; Total Exposure) of Cobimetinib
timeFrame: 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)
measure: Cohort I, II: Cmax of Paclitaxel
timeFrame: 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)
measure: Cohort I, II: Cmin of Paclitaxel
timeFrame: 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)
measure: Cohort I: AUC0-tau of Paclitaxel
timeFrame: 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)
measure: Cohort III: Cmax of Nab-Paclitaxel
timeFrame: 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)
measure: Cohort III: Cmin of Nab-Paclitaxel
timeFrame: 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)
measure: Cohort III: AUC0-tau of Nab-Paclitaxel
timeFrame: 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)
measure: Cohort II, III: Cmax (in Serum) of Atezolizumab
timeFrame: 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)
measure: Cohort II, III: Cmin (in Serum) of Atezolizumab
timeFrame: 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)
measure: Cohort II, III: AUC0-tau (in Serum) of Atezolizumab
timeFrame: 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)
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Cancer Specialists of North Florida
state: Florida
city: Miami
country: United States
facility: Mercy Hospital, a Campus of Plantation General Hospital
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Cancer Inst
state: Florida
city: Plantation
country: United States
facility: Florida Cancer Research Institute
state: Florida
city: Newnan
country: United States
facility: Cancer Treatment Centers of America
state: Georgia
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Bronx
country: United States
facility: Montefiore Einstein Cancer Center
state: New York
city: Pittsburgh
country: United States
facility: Magee Womens Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Tacoma
country: United States
facility: Northwest Medical Specialties
state: Washington
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: South Brisbane
country: Australia
facility: Mater Adult Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre; Medical Oncology
state: Victoria
city: Murdoch
country: Australia
facility: St John of God Murdoch Hospital; Oncology West
state: Western Australia
city: Bruxelles
country: Belgium
facility: Clinique Edith Cavell
city: Gent
country: Belgium
facility: AZ Sint Lucas (Sint Lucas)
city: Hasselt
country: Belgium
facility: Jessa Zkh (Campus Virga Jesse)
city: Kortrijk
country: Belgium
facility: AZ Groeninge
city: Veurne
country: Belgium
facility: AZ Sint Augustinus Veurne
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Pardubice
country: Czechia
facility: Multiscan s.r.o.
city: Lille
country: France
facility: Centre Oscar Lambret
city: Montpellier
country: France
facility: Centre Régional de Lutte Contre Le Cancer Val D'aurelle Paul Lamarque
city: Paris
country: France
facility: Hopital Tenon
city: Rennes
country: France
facility: Centre Eugene Marquis Centre Regional de Lutte Contre Le Cancer
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Napoli
country: Italy
facility: Azienda Ospedaliero Universitaria Seconda Università Degli Studi Di Napoli
state: Campania
city: Bologna
country: Italy
facility: A.O.U Policlinico S. Orsola Malpighi di Bologna U.O di Medicina Interna Borghi - Pad.2
state: Emilia-Romagna
city: Aviano
country: Italy
facility: Centro Di Riferimento Oncologico; SOC Oncologia Medica C
state: Friuli-Venezia Giulia
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli
state: Lazio
city: Milano
country: Italy
facility: Istituto Europeo Di Oncologia
state: Lombardia
city: Pisa
country: Italy
facility: Azienda Ospedaliero - Universitaria Pisana U.O. Oncologia Medica 2 Universitaria ? Polo Oncologico
state: Toscana
city: Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center; Medical Oncology
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System/Severance Hospital
city: R?ga
country: Latvia
facility: Pauls Stradins Clinical University Hospital
city: Riga
country: Latvia
facility: Riga East Clinical University Hospital Latvian Oncology Centre
city: Cluj Napoca
country: Romania
facility: Prof. Dr. I. Chiricuta Institute of Oncology
city: Craiova
country: Romania
facility: Oncology Center Sf. Nectarie
city: Sabadell
country: Spain
facility: Corporacio Sanitaria Parc Tauli; Servicio de Oncologia
state: Barcelona
city: Bilbao
country: Spain
facility: Organización Sanitaria Integrada Bilbao Basurto
state: Vizcaya
city: Badajoz
country: Spain
facility: Hospital Universitario Infanta Cristina; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos; Servicio de Nefrologia
city: Malaga
country: Spain
facility: Hosp. Regional Univ. de Malaga ? Hospital Materno Infantil; Hospital Materno Infantil de Malaga
city: Kaohsiung Country
country: Taiwan
facility: Chang Gung Memorial Hospital
city: Taipei City
country: Taiwan
facility: Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology
city: Bournemouth
country: United Kingdom
facility: Nuffield Health Bournemouth Hospital
city: Middlesex
country: United Kingdom
facility: Mount Vernon Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals City Campus
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.