Abstract OT1-03-19: Design of a phase 1b/2 study to evaluate the efficacy and safety of eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer
Authors: Berrak E , Atkan G , Song J , Almonte A , Karantza V , Yuan R 
Published: May 2016

Abstract
Eribulin mesylate, a microtubule inhibitor, is indicated for treatment of patients (pts) with metastatic breast cancer (MBC) with ≥2 prior chemotherapies for metastatic disease, including an anthracycline or taxane. Pembrolizumab is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for treatment of pts with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAFV600-mutation positive, a BRAF inhibitor. Pembrolizumab is also being evaluated for treatment of metastatic triple-negative breast cancer (mTNBC) and multiple tumor types. We report the design of an open-label, single-arm, multicenter, phase 1b/2 study to evaluate safety and efficacy of the eribulin and pembrolizumab combination in pts with mTNBC previously treated with 0 to 2 lines of therapy in the metastatic setting.
From August 2015 to February 2017, approximately 95 pts (aged ≥18 yrs) will be enrolled (n=12 phase 1b; n=83 phase 2) to reach 80 evaluable pts. Accrual has not yet commenced. Pts with measurable disease of ≥1 lesion &gt;10 mm in long-axis diameter (nonlymph nodes) or &gt;15 mm in short-axis diameter (lymph nodes) and an ECOG status of 0 or 1 will be included. Exclusion criteria include pts who received adjuvant chemotherapy within the past 6 months, chemotherapy/biological therapy within the past 3 wks, or radiation or small molecule targeted therapy within the past 2 wks. Pts will also be excluded if they have an autoimmune disease requiring immunosuppression or were previously treated with eribulin or any anti-PD-1, PD-ligand (L) 1, or PD-L2 agent.
Phase 1b includes a safety run-in cohort in which ≥6 pts will receive intravenous (IV) eribulin 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) on day (d) 1 and d8 and IV pembrolizumab 200 mg on d1 of a 21d cycle. Dose-limiting toxicity (DLT) will be assessed in the first cycle. This dose will be selected as the recommended phase 2 dose (RP2D) if ≤1 pt has a DLT or, if necessary, alternative doses may be explored. Pts will be stratified by prior chemotherapy for MBC (0, ∼70%; 1–2, ∼30%) and will receive RP2D combination treatment. Pts can remain on 1 or both study drugs with clinical benefit until intercurrent illness, unacceptable toxicity, or disease progression. Bayesian predictive probability of response rate, based on the goal of claiming combination superiority at study end, will be used to monitor response rate after postbaseline tumor assessments for ≥38 pts. The study can be stopped early for efficacy or futility.
Primary objectives include determination of safety and tolerability (phase 1b) and evaluation of objective response rate of the drug combination; secondary endpoints include evaluation of progression-free survival (PFS), overall survival (OS), and duration of response (DOR). PFS, OS, and DOR will be analyzed using Kaplan–Meier product-limit estimates. Median PFS, OS, and cumulative probability of PFS, OS, and DOR at 6 and 12 months will be presented with 2-sided 95% confidence intervals. Relationship between PD-L1 tumor status and efficacy endpoints will also be evaluated.
For further information please contact Erhan Berrak (erhan_berrak@eisai.com).
Citation Format: Berrak E, Atkan G, Song J, Almonte A, Karantza V, Yuan R. Design of a phase 1b/2 study to evaluate the efficacy and safety of eribulin mesylate in combination with pembrolizumab in 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 OT1-03-19.