Abstract OT2-01-02: COLET: A multistage, phase 2 study evaluating the safety and efficacy of a doublet regimen of cobimetinib (C) in combination with paclitaxel (P) or triplet regimens of C in combination with atezolizumab (atezo) plus either P or nab-paclitaxel (nab-P) in metastatic triple-negative breast cancer (TNBC)
Authors: Miles D , Kim S-B , McNally V , Simmons B , Wongchenko M , Xu N , Brufsky A 
Published: March 2017

Abstract
Preclinical data suggest that upregulation of the MAPK pathway confers resistance to taxane chemotherapy. Mutations and gene amplifications in the MAPK pathway are present in many TNBC tumors and may contribute to taxane resistance. Preliminary data from an initial safety run-in stage of the COLET study (ClinicalTrials.gov ID, NCT02322814; EudraCT number, 2014-002230-32) suggest improvement of clinical outcomes when MEK inhibition is combined with taxane chemotherapy. Additionally, in preclinical models, MEK inhibition was shown to enhance anti–PD-L1 activity. The monoclonal antibody PD-L1 inhibitor atezo has shown promising activity in combination with nab-P in metastatic TNBC. Accordingly, the COLET protocol was amended to include the evaluation of triplet regimens combining atezo with MEK inhibition and taxane chemotherapy[SL1] . COLET is evaluating the safety and efficacy of various combinations of C as first-line treatment for metastatic or locally advanced TNBC. Key eligibility criteria include measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) and left ventricular ejection fraction &gt; institutional lower limit of normal or &gt;50%. Neoadjuvant or adjuvant therapy is allowed if completed &gt;6 months prior to study entry. COLET has 3 cohorts: I, II, and III. Cohort I has 2 stages: an initial safety run-in stage (n∼12) followed by an expansion stage (n∼90) of 1:1 randomization to C + P or placebo (PBO) + P. Patients received P 80 mg/m2 on days 1, 8, and 15 and C/PBO 60 mg/day on days 3-23 of each 28-day cycle. In the expansion stage of Cohort I, randomization is stratified by prior neoadjuvant/adjuvant taxane therapy and disease-free interval from last chemotherapy dose. Cohorts II and III will evaluate the safety and efficacy of adding atezo to C + P or nab-P, respectively. Each cohort has a safety run-in stage (n∼15) and an expansion stage (additional n∼15); each will receive atezo 840 mg on days 1 and 15 and C 60 mg/day on days 3-23 of every 28-day cycle. Cohort II will receive P 80 mg/m2 and Cohort III will receive intravenous nab-P 100 mg/m2 on days 1, 8, and 15. Patients will receive treatment until disease progression or toxicity. The primary efficacy end point is investigator-assessed progression-free survival (PFS) for the expansion stage (Cohort I), and the primary PFS analysis will be performed when 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. For Cohorts II and III, the primary efficacy end point is overall response rate per RECIST v1.1; secondary end points include duration of response, PFS, and overall survival. Recruitment into the safety run-in stage of Cohort I is complete. Accrual into the randomization stage of Cohort I and the initial safety run-in stage of Cohorts II and III are ongoing. Patients from sites across North America, Europe, and the Asia-Pacific region will be enrolled.
Citation Format: Miles D, Kim S-B, McNally V, Simmons B, Wongchenko M, Xu N, Brufsky A. COLET: A multistage, phase 2 study evaluating the safety and efficacy of a doublet regimen of cobimetinib (C) in combination with paclitaxel (P) or triplet regimens of C in combination with atezolizumab (atezo) plus either P or nab-paclitaxel (nab-P) in metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-02.