Abstract OT1-1-03: Phase Ib dose allocation study of oral administration of lucitanib given in combination with fulvestrant in patients with estrogen receptor-positive and FGFR1-amplified or non-amplified metastatic breast cancer (INES)
Authors: Campone Mario , Bachelot Thomas , André Fabrice , Saba Chadi , Agrapart Valérie , Pierrat Marie-Jeanne , Dubois Frédéric , Chesnel Thibault , Poirot Camille 
Published: May 2015

Abstract
Background: Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors 1-3 (FGFR1-3), vascular endothelial growth factor receptors 1-3 (VEGFR1-3) and platelet-derived growth factor receptors α/β (PDGFRα/β). FGF aberrancy, as defined as FGFR1-or 11q- amplification, is a hallmark genomic alteration in breast cancer, observed at a frequency of up to 25% of patients and is strongly associated with luminal B type. Breast cancer patients with measurable disease and FGF aberrancy treated in the ongoing Phase 1/2 clinical trial of lucitanib monotherapy experienced an overall response rate of 50% (6 out of 12 patients). FGFR1-knock down was shown to decrease cell proliferation and reverse resistance to endocrine therapy in a FGFR1-amplified breast cancer cell line, hence supporting the idea of combining lucitanib with an endocrine agent such as fulvestrant, at the time of resistance. This has led to this Phase Ib study of lucitanib in combination with fulvestrant in metastatic breast cancer.
Trial design: INES is a multicenter, open-label, 2 -part study to assess the tolerability of lucitanib in terms of Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicities (DLTs) when administered with fulvestrant. A Continual Reassessment Method (CRM) will be used for the 1st part. A minimum of 3 patients will be enrolled at the initial dose level of 10 mg daily in combination with fulvestrant. Additional doses of 12.5 mg and 15 mg of lucitanib will be tested with the option of deescalating to 7.5 mg in case of DLTs. A minimum of 9 patients will be included at the MTD. In the 2nd part, 2 cohorts will be opened: fourteen FGF+ patients (FGFR1-or 11q- amplification), and fourteen non-amplified patients. All patients will receive fulvestrant 500 mg monthly and lucitanib at the recommended dose (RD) until unacceptable toxicity according to the investigator, disease progression or patient withdrawal. The main objective is to identify the Phase II RD when lucitanib is combined with fulvestrant. Secondary objectives include determination the Pharmacokinetic (PK) profile of lucitanib and metabolites; Measurement of tumour response; Description of the pharmacodynamic (PD) profile of lucitanib and investigation of any potential exposure dose-response relationships for safety, efficacy and PD.
Eligibility Criteria: Patients with estrogen receptor-positive, HER2 negative, breast cancer after progression or recurrence on prior therapy including fulvestrant. Patients should have ECOG performance status 0 or 1. Patients with uncontrolled hypertension are not eligible. For part 2, the presence of a metastatic site for biopsy to assess the presence of FGFR1- and/or 11q- amplification, which will be analysed centrally using FISH, is required.
Conclusion: INES is a phase Ib trial testing lucitanib in combination with fulvestrant in order to select the RD for phase II and seek preliminary efficacy signal in FGFR1- or 11q- amplified or non- amplified patients. As of June 2014, 3 patients have been enrolled in the 10 mg dose escalation cohort.
Citation Format: Mario Campone, Thomas Bachelot, Fabrice André, Chadi Saba, Valérie Agrapart, Marie-Jeanne Pierrat, Frédéric Dubois, Thibault Chesnel, Camille Poirot. Phase Ib dose allocation study of oral administration of lucitanib given in combination with fulvestrant in patients with estrogen receptor-positive and FGFR1-amplified or non-amplified metastatic breast cancer (INES) [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 OT1-1-03.