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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Cobimetinib
* Drug: Paclitaxel
* Drug: Placebo
* Drug: Atezolizumab
* Drug: Nab-Paclitaxel


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort I: Cobimetinib, Paclitaxel<br>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. | Drug: Cobimetinib<br>* 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.<br>* Other names: GDC-0973; RO5514041; XL518;Drug: Paclitaxel<br>* 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.<br>|
| Placebo Comparator: Cohort I: Placebo, Paclitaxel<br>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. | Drug: Paclitaxel<br>* 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.<br>Drug: Placebo<br>* Placebo matching to cobimetinib will be administered orally, once a day, on Day 3 through Day 23 of each 28 day treatment cycle.<br>|
| Experimental: Cohort II:Cobimetinib,Paclitaxel,Atezolizumab<br>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. | Drug: Cobimetinib<br>* 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.<br>* Other names: GDC-0973; RO5514041; XL518;Drug: Paclitaxel<br>* 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.<br>Drug: Atezolizumab<br>* 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.<br>* Other names: MPDL3280A;|
| Experimental: Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab<br>Participants will receive cobimetinib plus nab-paclitaxel plus atezolizumab until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study. | Drug: Cobimetinib<br>* 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.<br>* Other names: GDC-0973; RO5514041; XL518;Drug: Atezolizumab<br>* 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.<br>* Other names: MPDL3280A;Drug: Nab-Paclitaxel<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| Cohort I, II, III: Percentage of Participants With Adverse Events (AEs) |  | Randomization up to end of study (up to approximately 6.5 years) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) |