Abstract OT1-03-18: COLET: A multistage, phase 2 study evaluating the safety and efficacy of cobimetinib in combination with paclitaxel as first-line treatment for patients with metastatic triple-negative breast cancer
Authors: Kim S-B , Miles D , Rhee J , Yan Y , Hsu J , Brufsky A 
Published: May 2016

Abstract
Background: Cobimetinib (cobi) is a potent, highly selective inhibitor of MEK that has shown benefit when administered in combination with the BRAF inhibitor vemurafenib in BRAFV600-mutated metastatic melanoma. Preclinical data suggest that up-regulation of the MAPK pathway is a potential resistance mechanism against taxane chemotherapy. Clinically, the combination of MEK inhibition and taxane chemotherapy in non–small cell lung cancer patients (pts) has improved response rate (RR) and progression-free survival (PFS). Because most triple-negative breast cancer (TNBC) pts develop resistance to taxane chemotherapy and because genetic alterations (including mutations and gene amplifications) in the MAPK pathway are present in many TNBC tumors, the combination of taxane chemotherapy and MEK inhibition could be an effective treatment option.
Study design: COLET (WO29497) is a multistage study designed to evaluate the safety of and to estimate the efficacy of cobi  paclitaxel in pts with metastatic or locally advanced TNBC who have not previously received systemic therapy for metastatic disease. The study will be conducted in 2 stages: an initial safety run-in stage of approximately 12 pts, followed by a randomized stage in which approximately 100 pts will be randomly assigned in a 1:1 ratio to receive either cobi + paclitaxel or placebo + paclitaxel. Pts will receive paclitaxel 80 mg/m2 on Days 1, 8, and 15 of each 28-day cycle and cobi/placebo 60 mg/day on Days 3-23 of each 28-day cycle until progression of disease or toxicity occurs.
Key eligibility criteria:
• Metastatic or locally advanced (not amenable to curative resection) TNBC
• No prior systemic therapy for metastatic or unresectable locally advanced TNBC
• Neoadjuvant or adjuvant chemotherapy or radiation therapy is allowed if completed &gt;6 months before the start of study treatment
• Measureable disease using Response Evaluation Criteria In Solid Tumors, version 1.1 (RECIST v1.1)
• History of or active untreated or unstable brain metastases or requiring corticosteroids for brain metastases precludes eligibility
• Left ventricular ejection fraction (LVEF) greater than the institutional lower limit of normal or above 50%
Specific aims of the safety run-in stage: Determine the safety and tolerability of cobi when administered in combination with paclitaxel.
Specific aims of the randomized stage: Investigator-assessed PFS (primary end point); safety; pharmacokinetics; the effect of intrinsic subtypes and genetic alterations in PFS; mechanisms of resistance; and health-related quality of life.
Accrual: Approximately 112 pts from sites across Europe, North America, and the Asia-Pacific region.
Statistical methods: In the randomized stage, pts will be followed up until a total of 60 PFS events occur across the 2 arms. This provides 77% power to detect a hazard ratio of 0.5 at a two-sided significance level of 0.05.
Contact information: Registered with ClinicalTrials.gov, identifier NCT02322814. For more information, please contact Roche/Genentech trials, 888-662-6728 (US only) or reference study ID WO29479 at www.roche.com/about_roche/roche_worldwide.htm.
Citation Format: Kim S-B, Miles D, Rhee J, Yan Y, Hsu J, Brufsky A. COLET: A multistage, phase 2 study evaluating the safety and efficacy of cobimetinib in combination with paclitaxel as first-line treatment for patients with metastatic triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-18.