Dovitinib plus fulvestrant in postmenopausal endocrine resistant HER2-/ HR+ breast cancer: A phase II, randomized, placebo-controlled study.

Abstract

TPS651 Background: Overcoming endocrine resistance (ER) is a critical goal in the treatment of hormone receptor−positive (HR+) breast cancer (BC). Emerging in vitro evidence suggests that amplification and overexpression of fibroblast growth factor receptor 1 (FGFR1) is associated with ER. Up to 8% pts with HR+/ human epidermal growth factor receptor 2 negative (HER2–) BC have amplification of the FGFR1 gene. Dovitinib (DOV), a potent inhibitor of FGFR, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor demonstrated antitumor activity in heavily pretreated BC pts with FGF-pathway amplification (FGFR1, FGFR2, or FGF3). The objective of this study is to determine if DOV plus fulvestrant (FUL) can improve outcomes in postmenopausal pts with endocrine resistant HER2-/HR+ BC. Methods: This multicenter, randomized, double-blind, placebo-controlled, ph II trial (NCT01528345) will enroll postmenopausal pts with HER2–/HR+ locally advanced or metastatic BC (N=150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting. Pts will be randomized 1:1 (stratified by FGF amplification and presence of visceral disease) to receive intramuscular FUL (500 mg q4w [with an additional dose 2 weeks after the initial dose]) plus oral DOV (500 mg, 5 days on/2 days off) or matching placebo until disease progression, unacceptable toxicity, death, or discontinuation (any reason). Crossover is not permitted. Primary endpoint is progression free survival (investigator’s assessment; RECIST v1.1). Secondary endpoints include overall response rate (investigator’s assessment; RECIST v1.1), duration of response, overall survival, time to deterioration of ECOG performance status, pt-reported outcome scores over time, safety, and assessment of plasma pharmacokinetic concentrations of FUL and DOV. Additionally, the pharmacodynamic effect of DOV on FGFR-associated angiogenic pathways in tumor specimens and potential predictive biomarkers of response to DOV will be explored. As of 21 Jan 2013, 128 pts had molecular screening; 73 pts are enrolled (of these 9 pts are FGF amplified). Clinical trial information: NCT01528345.