Abstract OT2-01-21: Phase 2 study of investigational TORC1/2 inhibitor TAK-228 with fulvestrant in women with ER-positive/HER2-negative advanced or metastatic breast cancer that has progressed during or after aromatase inhibitor therapy
Authors: García-Sáenz JA , Carrasco E , Kneissl ML , Zohren F , Martin M 
Published: March 2017

Abstract
Standard therapy for ER-positive tumors in the adjuvant and metastatic settings is antiestrogen therapy, including aromatase inhibitors (AI); however, resistance is common. These tumors may respond to alternative second-line anti-estrogen therapies such as fulvestrant but response durations are often short. Preclinical and clinical studies suggest that simultaneous inhibition of ER and PI3K/mTOR could prevent/delay the emergence of hormone-independent cancer cells thereby improving patient (pt) outcomes. This study will test whether fulvestrant plus TAK-228, a dual TORC1/2 inhibitor, can overcome endocrine therapy resistance in ER-positive breast cancer. This is an open-label, randomized, 3-arm, phase 2 study of continuous once-daily TAK-228 (oral, 4 mg) or once-weekly TAK-228 (oral, 30 mg) plus fulvestrant (500 mg intramuscularly on d1 and d15 of cycle 1 [loading regimen] then d1 of each subsequent 28-d cycle), compared with fulvestrant alone, in pts with advanced or metastatic ER-positive/HER2-negative breast cancer that has progressed during/after AI therapy. Pts will be randomized 1:1:1 to the 3 arms and stratified at randomization via presence or absence of visceral metastasis, prior hormonal therapy sensitivity, and prior exposure to CDK 4/6 inhibitors. Pts will receive study drug(s) until progressive disease (PD), unacceptable toxicity, or consent withdrawal. Postmenopausal women ≥18 yrs old with local histological confirmation of ER-positive/HER2-negative metastatic or advanced breast cancer; with measureable disease; ECOG status 0–1; PD during/after prior AI therapy (defined as progression ≤12 mos after discontinuing adjuvant therapy or ≤1 mo after discontinuation in the metastatic setting) and adequate organ function are eligible. Exclusion criteria include prior therapy with mTOR inhibitors, PI3K inhibitors, dual PI3K-mTOR inhibitors, AKT inhibitors, or fulvestrant; prior treatment with &gt;1 line of chemotherapy for metastatic breast cancer; experienced recurrent or progressive disease on &gt;2 endocrine therapies for metastatic breast cancer; or significant previous/existing cardiac conditions. This study aims to determine the efficacy (primary endpoint: PFS; secondary endpoints: OS, TTP, ORR), safety and tolerability of daily and weekly TAK-228 plus fulvestrant compared with fulvestrant alone. The distribution of PFS will be analyzed via the Kaplan-Meier method. The primary hypothesis (TAK-228 plus fulvestrant can improve median PFS to 8 mos [hazard ratio, HR 0.5] vs fulvestrant-alone median PFS of 4 mos) is to be tested at the 0.10 significance level (2-sided; dropout rate 10%). A total of 72 PFS events are needed for each pair-wise comparison; p-values from a stratified log-rank test and HRs will be presented. The safety profile and clinical laboratory parameters (and/or change from baseline) for all scheduled measurements over time will be summarized by descriptive statistics. Approximately 153 pts (51 pts per arm) will be enrolled from approximately 55 study centers in North America and Spain; to date, no pts have been enrolled. For more information, please contact Michelle Kneissl at michelle.kneissl@takeda.com.
Citation Format: García-Sáenz JA, Carrasco E, Kneissl ML, Zohren F, Martin M. Phase 2 study of investigational TORC1/2 inhibitor TAK-228 with fulvestrant in women with ER-positive/HER2-negative advanced or metastatic breast cancer that has progressed during or after aromatase inhibitor therapy [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 OT2-01-21.