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
Condition: Breast Cancer
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Intervention: Cobimetinib; Paclitaxel; Placebo; Atezolizumab; Nab-Paclitaxel
Intervention description: 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 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 matching to cobimetinib will be administered orally, once a day, on Day 3 through Day 23 of each 28 day treatment cycle.; 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 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 MeSH terms: Paclitaxel; Albumin-Bound Paclitaxel; Atezolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 169.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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