Abstract OT1-02-03: Phase I multicenter clinical trial evaluating the combination of trastuzumab emtansine (T-DM1) and non-pegylated liposomal doxorubicin (NPLD) in HER2-positive metastatic breast cancer (MBC) (MEDOPP038 study)
Authors: López-Miranda E , Brain E , Saura C , Gligorov J , Dubot C , Dieras V , Suter TM , Aguirre E , Perez-García JM , Llombart A , Cortés J 
Published: March 2017

Abstract
BACKGROUND:
Clinical efficacy and safety of T-DM1 for the treatment of HER2-positive MBC has been assessed in several phase II and III trials and is now considered the standard of care in taxane-and trastuzumab-progressing patients. However, although T-DM1 has shown encouraging antitumor activity in the advanced setting, several strategies to improve T-DM1 efficacy are currently evaluated, including the combination with non-pegylated liposomal doxorubicin (NPLD), considering that: i) doxorubicin is one of the most active chemotherapeutic agents against HER2-positive breast cancer; ii) the combination of doxorubicin and trastuzumab induces synergistic antitumor activity in HER2-overexpressing preclinical models; and iii) liposomal formulations of doxorubicin have a reduced risk of developing cardiac toxicity.
OBJECTIVES:
The primary objective of this trial is to determine the maximum tolerated dose (MTD) of the combination of T-DM1 and NPLD in patients with HER2-positive MBC naïve of anthracyclines and previously treated with trastuzumab and a taxane. The secondary objectives include 1) safety, with special emphasis on cardiac safety evaluated by left ventricular ejection fraction, high-sensitivity troponin I and B-type natriuretic peptide (BNP) levels, 2) pharmacokinetics, 3) antitumor activity, and the 4) role of single nucleotide polymorphisms of HER2 gene for developing cardiotoxicity.
TRIAL DESIGN:
This is a dose-finding, open-label, non-randomized and multicenter phase I clinical trial of T-DM1 at a fixed dose of 3.6 mg/kg IV in combination with three different dose levels (DL) of NPLD (45, 50, and 60 mg/m2) IV administered on Day 1 every three weeks. The trial follows a modified dose escalation scheme with a 3+3 design.A total of three patients will be included in the first cohort and observed for dose-limiting toxicities (DLTs) during the first two cycles of treatment. If none of these patients experiences a DLT, three other patients will be treated at the next DL. However, in case of at least one patient experiences a DLT, three more patients will be treated at the same DL. The MTD will be defined as the highest DL at which ≤1 of six patients experiences a DLT during the first two cycles of treatment. An expansion cohort of six additional patients at the MTD will be included.
ELIGIBILITY:
Anthracycline-naïve patients with HER2-positive MBC and up to two prior chemotherapy regimens in the advanced setting who previously were treated with trastuzumab and a taxane. ECOG performance status of 0-1. Adequate organ and cardiovascular function with LVEF ≥ 55%. RECIST v1.1 evaluable disease.
ACCRUAL:
A total of 12-24 patients will be enrolled at four sites in Spain and France. Recruitment was opened on September 2015. To date, four patients (three at DL1 and one at DL2) have been recruited.
Citation Format: López-Miranda E, Brain E, Saura C, Gligorov J, Dubot C, Dieras V, Suter TM, Aguirre E, Perez-García JM, Llombart A, Cortés J. Phase I multicenter clinical trial evaluating the combination of trastuzumab emtansine (T-DM1) and non-pegylated liposomal doxorubicin (NPLD) in HER2-positive metastatic breast cancer (MBC) (MEDOPP038 study) [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 OT1-02-03.