Abstract OT2-6-04: Dovitinib, a receptor tyrosine kinase inhibitor in combination with fulvestrant in postmenopausal endocrine resistant human epidermal growth factor receptor 2 negative (HER2-) / hormone receptor-positive (HR+) breast cancer: A phase II, randomized, double blind, placebo-controlled study
Authors: Andre F , Neven P , Musolino A , Latini L , Campone M , Cortes J , Barrios C , Squires M , Zhang Y , Deudon S , Gogov S , Blackwell K 
Published: August 2014

Abstract
Background: Overcoming endocrine resistance is a critical goal in the treatment of HR+ breast cancer. Emerging in vitro evidence suggests that amplification and overexpression of fibroblast growth factor receptor 1 (FGFR1) is associated with endocrine resistance. Up to 8% of patients with HER2–/HR+ breast cancer have amplification of the FGFR1 gene. Dovitinib, a potent inhibitor of FGFR, as well as vascular endothelial growth factor receptor, and platelet-derived growth factor receptor, demonstrated antitumor activity in heavily pretreated breast cancer patients with FGF-pathway amplification. The objective of this study is to determine if dovitinib in combination with fulvestrant can improve outcomes in postmenopausal patients with endocrine resistant HER2-/HR+ breast cancer.
Trial design: This multicenter, randomized, double-blind, placebo-controlled, phase II trial (NCT01528345) will enroll postmenopausal patients with HER2–/HR+ locally advanced or metastatic breast cancer. Patients are randomized 1:1 (stratified by FGF amplification [FGFR1, FGFR2, or FGF3] and presence of visceral disease) to receive intramuscular fulvestrant (500 mg q4w [with an additional dose 2 weeks after the initial dose]) in combination with oral dovitinib (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.
Eligibility criteria: Postmenopausal women with HER2-/HR+ breast cancer (N = 150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting are eligible. Other key inclusion criteria are: ECOG performance status ≤1; and adequate bone marrow and organ function; measurable disease as per RECIST 1.1 or ≥ 1 nonmeasurable lytic or mixed bone lesions in the absence of measurable disease. Patients with current or past evidence of CNS or leptomeningeal metastases, HER2 overexpression, and those who received previous treatment with fulvestrant or FGFR inhibitors are excluded.
Specific aims: The primary endpoint is progression free survival (central review). Secondary endpoints include overall response rate, duration of response, overall survival, time to deterioration of ECOG performance status, patient-reported outcome scores, safety, and assessment of plasma pharmacokinetic concentrations of fulvestrant and dovitinib. Additionally, the pharmacodynamics of dovitinib on FGFR-associated angiogenic pathways and potential predictive biomarkers of response will be explored.
Statistical methods: Analysis of primary endpoint will be carried out in FGF amplified subpopulation, FGF non-amplified subpopulation and the full population, using Bayesian methodology.
Target accrual: Enrollment is ongoing. Target accrual is 150 patients (90 FGF amplified patients and 60 FGF non-amplified patients).
Contact: For further information about the study please contact Gogov Sven (sven.gogov@novartis.com)/ Stephanie Deudon (stephanie.deudon@novartis.com).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-04.