Phase I study of vandetinib in combination with gemcitabine and oxaliplatin in advanced solid malignancies.

Abstract

3037 Background: Vandentinib (VAN) is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor-2 (VEGFR-2) and 3 (VEGFR-3) as well as epidermal growth factor receptor (EGFR) and RET (‘rearranged during transfection’). Combinations of VEGFR kinase inhibitors and cytotoxic agents have been studied with interest, but have been associated with increased toxicity. This phase I trial evaluated the safety, tolerability and maximum tolerated dose of VAN in combination with gemcitabine (GEM) and oxaliplatin (OX). Methods: Subjects with advanced solid malignancy, ≤ 2 prior regimens with adequate hematologic, hepatic and renal function were eligible. GEM and OX were administered intravenously at 1000 mg/m2 and 85 mg/m2 respectively every 14 days. VAN was administered orally at two dose levels: level 1 (200 mg) and level 2 (300 mg) once daily continuously. After a maximum of 6 cycles of GEMOX, non-progressing patients were allowed to continue VAN until progression or intolerance. A dose level was determined to be tolerable if <2 DLTs out of 6 evaluable subjects were observed. Response was assessed by restaging scan after every 2 cycles. Results: A total of 20 subjects were enrolled in the study; 15 male, 5 female. Median age 62 years (47-68). Nine subjects were enrolled on dose level 1 and 11 subjects on dose level 2. One subject in dose level 1 experienced a deep venous thrombosis in cycle 1 deemed a DLT. Thrombocytopenia (worst-grade 3) as well as diarrhea and rash (worst-grade 2) were observed in several patients, without dose-limiting toxicity in cycle 1. Reversible posterior leukoencephalopathy was observed in 1 subject following abrupt self-discontinuation of an antihypertensive mediation. The recommended phase 2 dose was established as GEM (1000mg/m2) OX (85mg/m2) and VAN (300mg). One subject with refractory small cell lung cancer had a confirmed partial response, and 10 subjects (pancreas-7, bladder-2 and biliary-1) achieved stable disease ≥12 weeks. Conclusions: VAN in combination with GEM/OX was well tolerated at full doses of each of the 3 agents. Preliminary anti-tumor activity seen in refractory solid tumors supports further evaluation of this regimen.