Multi-Arm, Nonrandomized, Open-Label Phase Ib Study to Evaluate Fp1039/Gsk3052230 with Chemotherapy in Nsclc and Mpm with Deregulated Fgf Pathway Signaling

Abstract

ABSTRACT Background: FP1039/GSK3052230 (GSK230) is a soluble fusion protein that acts as a ligand trap by sequestering fibroblast growth factors (FGFs) involved in tumor growth. FGF ligand-dependent signaling plays an important role in cancer development and growth through autocrine production of FGFs from cancer cells, or paracrine production of FGFs from local stroma, or by tumor overexpression of FGF receptors (FGFRs) or amplification of FGFR genes. FGFR1 amplification has been identified in ∼15-20% of squamous non-small cell lung cancers (NSCLC) and is associated with shorter disease-free and overall survival. Efficacy was observed with GSK230 + chemotherapy in FGFR1 amplified in NSCLC xenograft models and in xenograft models of malignant pleural mesothelioma (MPM) where FGF2 mRNA levels were overexpressed. In a phase I study, no maximum tolerated dose (MTD) was identified and 20 mg/kg weekly was the maximum feasible dose (MFD) achieving the desired target concentration. Toxicities associated with small-molecule FGFR inhibition, namely hyperphosphatemia and retinal, nail, and skin changes, were not observed. Trial design: This is a multi-arm, nonrandomized, open-label phase IB study designed to evaluate the safety and preliminary efficacy of GSK230 in combination with paclitaxel + carboplatin in previously untreated FGFR1 amplified metastatic squamous NSCLC (Arm A), in combination with docetaxel in FGFR1 amplified metastatic squamous NSCLC that has progressed after 1 line of chemotherapy (Arm B), or in combination with pemetrexed + cisplatin in patients with untreated and unresectable MPM (Arm C). Approximately 70 patients will be enrolled. Each arm involves a dose escalation phase utilizing the 3 + 3 design, followed by a cohort expansion phase of at least 12 patients treated at either MTD or MFD. GSK230 will be administered as a 30-minute intravenous infusion once a week in a 21-day cycle. The starting dose is 5 mg/kg and will be dose escalated until MTD or MFD in combination with chemotherapy is reached. Endpoints include the combination dose of GSK230 with chemotherapy, safety, response rates and their duration, and translational objectives (NCT01868022). Disclosure: P. Garrido: I don't have any specific conflict interest related to this trial except from being part the clinical trial; E. Felip: Advisory boards for BI, Novartis, Roche, BMS and Lilly; F. Barlesi: Honorarium from GSK; P.K. Paik: Research funding provided by GlaxoSmithKline, BristolMyersSquibb; D. Morgensztern: Member of Advisory Board – Celgene Speaker – Boehringer Ingelheim; K. Reckamp: GSK provided research funding to institution. All other authors have declared no conflicts of interest.