Abstract OT3-1-10: HERmione: A Phase 2, randomized, open label trial comparing MM-302 plus trastuzumab with physician's choice of chemotherapy plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer, previously treated with pe
Authors: Miller Kathy , Cortes Javier , Hurvitz Sara A , Krop Ian E , Tripathy Debu , Verma Sunil , Riahi Kaveh , Yardley Denise A 
Published: May 2015

Abstract
Background: Despite improvements in treatment with newly approved HER2-targeted therapies such as pertuzumab and trastuzumab emtansine (T-DM1), HER2-positive metastatic breast cancer (MBC) remains a serious and life-threatening disease. MM-302 is an antibody drug conjugated liposomal doxorubicin targeted to HER2. The present Phase 2 study was developed based upon data from a recently reported Phase 1 study (SABCS 2013, Munster, et al., #P4-12-29) in 47 heavily pretreated HER2-positive MBC patients treated with MM-302 alone or in combination with trastuzumab, with more benefit being seen in patients without prior anthracycline exposure. In that study, MM-302 appeared to have an acceptable safety profile and, importantly, no clinically significant declines in left ventricular ejection fraction (LVEF) were observed.
Trial design: HERmione is a randomized Phase 2, two-arm, open-label trial designed to evaluate if MM-302 can address an unmet medical need in treating anthracycline naive patients with HER2-positive metastatic breast cancer who have previously received pertuzumab and T-DM1 in the locally advanced or metastatic setting. Patients are randomly assigned 1:1 to MM-302 (30 mg/m2, IV q3w) plus trastuzumab (6 mg/kg, IV q3w) or a chemotherapy of physician’s choice (chosen from vinorelbine, capecitabine, or gemcitabine) plus trastuzumab (6 mg/kg, IV q3w). Patients will be stratified according to geographic region, presence of visceral disease, and ≥ 4 prior chemotherapy-containing regimens for metastatic disease.
Eligibility criteria: HER2-positive locally advanced or MBC (HER2 confirmed by central lab); prior trastuzumab in any setting, prior pertuzumab and T-DM1 exposure in the incurable locally advanced or metastatic setting; unlimited prior lines of therapy; ECOG 0-1, and LVEF ≥ 50%. Patients with prior anthracycline exposure in any setting are excluded. Central nervous system metastases are permitted, if stable and without symptoms or steroids for 4 weeks after treatment. Patients with significant cardiac dysfunction or risk of cardiac dysfunction are excluded.
Specific aims: The primary efficacy endpoint is independently assessed progression free survival (PFS) with tumor response evaluated based on RECIST version 1.1. Secondary endpoints include Investigator Assessed PFS, Overall Survival (OS), 6 and 12 month OS rate, Time to Treatment Failure, Objective Response Rate, Duration of Response, Clinical Benefit Rate, safety and toxicity, Patient Related Outcomes and pharmacokinetic exposure. Safety assessments include all adverse events, abnormal laboratory values, cardiac events, and LVEF decline.
Statistical methods: A total sample size of 250 subjects will be enrolled to observe 191 PFS events for 90% power to detect a Hazard Ratio of 0.625. The MM-302 arm will be compared to the control arm on the primary endpoint of PFS using a stratified log-rank test at a one-sided 0.025 level.
Accrual status: Recruitment is planned to start in July 2014 at approximately 60 sites in the United States and Western Europe.
Citation Format: Kathy Miller, Javier Cortes, Sara A Hurvitz, Ian E Krop, Debu Tripathy, Sunil Verma, Kaveh Riahi, Denise A Yardley. HERmione: A Phase 2, randomized, open label trial comparing MM-302 plus trastuzumab with physician's choice of chemotherapy plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer, previously treated with pe [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-10.