Abstract OT2-1-08: A phase II open label study of everolimus in combination with anti-estrogen therapy in hormone receptor-positive HER2-negative advanced breast cancer
Authors: Yardley Denise A , Shastry Mythili , DeBusk Laura M , Burris III Howard A , Hainsworth John D 
Published: May 2015

Abstract
Background: Hormone receptor positive (HR+) breast cancer, defined as estrogen receptor and/or progesterone receptor positive, accounts for 70% of invasive breast cancers. While most HR+ tumors initially respond to anti-estrogen therapy, resistance, linked to crosstalk between cell signaling and signal transduction pathways, subsequently develops in almost 100%. Preclinical data has shown that the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway is activated in long-term estrogen-deprived and aromatase inhibitor-resistant breast cancer cells. It is hypothesized that in this group of endocrine-resistant patients (pts), resistance to anti-estrogen therapy is driven by the PI3K/Akt/mTOR pathway and hence the inhibition of this pathway may reverse resistance. This study will evaluate the efficacy of adding everolimus (an inhibitor of mTOR) to anti-estrogen therapy in pts with HR+ metastatic breast cancer (MBC) who have progressed on anti-estrogen therapy.
Study Objectives: This multi-center, open-label Phase II trial is designed to determine the efficacy (primary endpoint is PFS), safety and tolerability of everolimus in combination with anti-estrogen therapy in pts with HR+, HER2-negative MBC with disease progression on prior anti-estrogen therapy. An exploratory objective of this study is to evaluate the prognostic value of the VeriStrat assay in this population. VeriStrat testing has been used to predict treatment efficacy in clinical trials of non small cell lung cancer, head and neck squamous carcinoma, and MBC.
Eligibility: Pts ≥18 years with HR+, HER2-negative breast cancer that is either unresectable, locally recurrent, or metastatic are eligible. Pts must have progressed on anti-estrogen therapy (recurrence while on/within 12 months of treatment for early stage breast cancer, or progressed while on/within 1 month of treatment for advanced/MBC), but anti-estrogen therapy is not required to be the last therapy prior to enrollment. No washout for anti-estrogen therapy is required, and ≤1 previous chemotherapy regimen is allowed. Post menopausal or pre-/ peri-menopausal women on tamoxifen are eligible and ovarian function suppression is permitted. Prior treatment with a mTOR inhibitor is not allowed. Additional eligibility requirements include: measurable or evaluable disease, ECOG ≤2, adequate bone marrow and organ function and an adequate lipid profile (fasting serum cholesterol ≤300 mg/dL or ≤7.75 mmol/L and fasting triglyceride ≤2.5 x ULN).
Trial Design: Everolimus will be administered at a dose of 10 mg PO daily in combination with the FDA prescribed doses of the most recent anti-estrogen therapy on which the pt progressed. Treatment cycles will be 4 weeks, with response evaluations by CT scans every 2 cycles. Pts will be treated until disease progression or unacceptable toxicity occurs. With an alpha=0.5, a sample size of 42 will provide 80% power to detect improvement in median PFS. Blood samples for the VeriStrat assay will be collected at baseline, on Cycle 3 Day 1, at disease progression and at the first follow-up visit post disease progression. Archival tumor tissue samples will be collected for comprehensive genomic profiling. This trial has a total accrual goal of 46 pts.
Citation Format: Denise A Yardley, Mythili Shastry, Laura M DeBusk, Howard A Burris III, John D Hainsworth. A phase II open label study of everolimus in combination with anti-estrogen therapy in hormone receptor-positive HER2-negative advanced breast cancer [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 OT2-1-08.