Abstract OT1-04-08: Phase 3 study of etirinotecan pegol versus treatment of physician's choice in patients with metastatic breast cancer who have stable brain metastases previously treated with an anthracycline, a taxane, and capecitabine
Authors: Tripathy D , Tolaney S , Seidman AD , Anders CK , Ibrahim N , Rugo HS , Twelves CJ , Cortes J 
Published: March 2017

Background: Etirinotecan pegol (EP) is a next-generation topoisomerase I inhibitor-polymer conjugate that provides continuous exposure to SN-38. A mouse model of brain metastases demonstrated high penetration and retention of SN-38 in CNS lesions, resulting in decreased size of CNS lesions and improved survival at concentrations clinically achieved at the recommended dose of EP in patients (pts) (Adkins et al, BMC Cancer 2015). A previous phase 3 trial comparing single-agent EP to treatment of physician's choice (TPC) was conducted in 852 pts with advanced breast cancer (BC) (Perez et al, Lancet Oncol 2015). Although the primary efficacy endpoint of improved survival was not met (HR 0.087; p value = 0.08), a subset of 67 pts who entered the study with stable brain metastases demonstrated improved overall survival (HR 0.51 [95% CI 0304 – 0.858]; p &lt; 0.01). A phase 3 trial has therefore been designed for this population of high unmet medical need. Trial Design: Pts with MBC with stable brain metastases will be randomized 1:1 to receive either single-agent EP or TPC in an open-label, randomized, multicenter Phase 3 study. Key Entry Criteria: Adults, with ECOG PS 0 or 1 with adequate liver, kidney and marrow function. All pts must have received prior therapy with an anthracycline, a taxane, and capecitabine (ATC) (these drugs may have been administered in the neo/adjuvant or locally advanced/metastatic setting); pts must have had 1 prior cytotoxic regimen for MBC (triple negative BC); 2 prior cytotoxic regimens and 1 prior hormone therapy (hormone-receptor+ BC); or 2 prior cytotoxic regimens and 1 prior HER2-targeted therapy (HER2+ BC). Pts are required to have undergone definitive local therapy of brain metastases (either whole brain radiation; stereotactic radiation or surgical resection); signs and symptoms of brain metastases must be stable with steroids either unchanged or decreasing for ≥ 7 days prior to randomization. Prior toxicities must have resolved to ≤ Grade 1 (except sensory neuropathy ≤ Grade 2 and complete resolution of prior diarrhea). Methods: Primary efficacy endpoint is OS. Key secondary endpoints: ORR by RECIST v1.1, clinical benefit rate (ORR+SD ≥ 6 months), PFS by RANO-BM and QoL. EP is given IV at 145 mg/m2 over 90-min every 21 days without premedications. Pts randomized to TPC must receive 1 of the following: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel or nab-paclitaxel (the agent must be available at the treating institution). Pts are stratified by region, ECOG PS and receptor status (TNBC, HER2+ or HR+/HER2-). Target Accrual: ∼350 pts will be randomized to obtain the number of deaths required at 90% power to detect a statistically significant improvement in OS; 1 interim analysis will occur when 50% of the deaths are reported (130 events). PK sampling is performed in a subset of pts; UGT1A1 testing will occur in pts randomized to EP. Plasma ctDNA will be assessed at baseline for potential predictive markers of efficacy. Enrollment is expected to open in 2016.

Citation Format: Tripathy D, Tolaney S, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves CJ, Cortes J. Phase 3 study of etirinotecan pegol versus treatment of physician's choice in patients with metastatic breast cancer who have stable brain metastases previously treated with an anthracycline, a taxane, and capecitabine [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 OT1-04-08.