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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

NCT02322814

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: WO29479
  • SECONDARY ID: 2014-002230-32
  • NCT ID: NCT02322814

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
CobimetinibGDC-0973; RO5514041; XL518Cohort I: Cobimetinib, Paclitaxel
PaclitaxelCohort I: Cobimetinib, Paclitaxel
PlaceboCohort I: Placebo, Paclitaxel
AtezolizumabMPDL3280ACohort II:Cobimetinib,Paclitaxel,Atezolizumab
Nab-PaclitaxelCohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort I: Cobimetinib, PaclitaxelExperimentalParticipants 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.
  • Cobimetinib
  • Paclitaxel
Cohort I: Placebo, PaclitaxelPlacebo ComparatorParticipants 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.
  • Paclitaxel
  • Placebo
Cohort II:Cobimetinib,Paclitaxel,AtezolizumabExperimentalParticipants 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.
  • Cobimetinib
  • Paclitaxel
  • Atezolizumab
Cohort III: Cobimetinib, Nab-Paclitaxel, AtezolizumabExperimentalParticipants will receive cobimetinib plus nab-paclitaxel plus atezolizumab until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.
  • Cobimetinib
  • Atezolizumab
  • Nab-Paclitaxel

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cohort I: Progression-Free Survival, as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Time Frame:Randomization up to disease progression or relapse, whichever occurs first (up to approximately 3.5 years)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Cohort I, II, III: Overall Survival (OS)
Time Frame:Randomization up to death from any cause (up to approximately 5.5 years)
Safety Issue:
Description:
Measure:Cohort I: Percentage of Participants With Confirmed OR (PR or CR), as Determined by the Investigator Using RECIST v1.1
Time Frame:Randomization up to disease progression or relapse, whichever occurs first (up to approximately 5.5 years)
Safety Issue:
Description:
Measure:Cohort I, II, III: Duration of Response (DOR), as Determined by the Investigator Using RECIST v1.1
Time Frame:Time from the first occurrence of documented objective response to time of relapse or death, whichever occurs first (up to approximately 5.5 years)
Safety Issue:
Description:
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
Time Frame:Randomization up to disease progression or relapse, whichever occurs fist (up to approximately 5.5 years)
Safety Issue:
Description:
Measure:Cohort II, III: Progression-Free Survival, as Determined by Investigator Using RECIST v1.1
Time Frame:Randomization up to disease progression or relapse, whichever occurs first (up to approximately 5.5 years)
Safety Issue:
Description:
Measure:Cohort I, II, III: Percentage of Participants With Adverse Events (AEs)
Time Frame:Randomization up to end of study (up to approximately 5.5 years)
Safety Issue:
Description:
Measure:Cohort I, II, III: Maximum Plasma Concentration (Cmax) of Cobimetinib
Time Frame: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)
Safety Issue:
Description:
Measure:Cohort I, II, III: Minimum Plasma Concentration (Cmin) of Cobimetinib
Time Frame: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)
Safety Issue:
Description:
Measure:Cohort I, II, III: Area Under the Concentration-Time Curve From Time Zero to Dosing Interval (AUC0-tau; Total Exposure) of Cobimetinib
Time Frame: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)
Safety Issue:
Description:
Measure:Cohort I, II: Cmax of Paclitaxel
Time Frame: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)
Safety Issue:
Description:
Measure:Cohort I, II: Cmin of Paclitaxel
Time Frame: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)
Safety Issue:
Description:
Measure:Cohort I, II: AUC0-tau of Paclitaxel
Time Frame: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)
Safety Issue:
Description:
Measure:Cohort III: Cmax of Nab-Paclitaxel
Time Frame: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)
Safety Issue:
Description:
Measure:Cohort III: Cmin of Nab-Paclitaxel
Time Frame: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)
Safety Issue:
Description:
Measure:Cohort III: AUC0-tau of Nab-Paclitaxel
Time Frame: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)
Safety Issue:
Description:
Measure:Cohort II, III: Cmax (in Serum) of Atezolizumab
Time Frame: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) (approximately 5.5 years); 120 days after EOT (approximately 5.5 years) (Cy=28 days)
Safety Issue:
Description:
Measure:Cohort II, III: Cmin (in Serum) of Atezolizumab
Time Frame: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)
Safety Issue:
Description:
Measure:Cohort II, III: AUC0-tau (in Serum) of Atezolizumab
Time Frame: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)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

August 17, 2021