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

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