A phase I study to assess the safety, tolerability, and PK of dovitinib (D) in combination with gemcitabine (G) and capecitabine (C) in patients with advanced solid tumors.

Abstract

2603 Background: Fibroblast growth factor receptor (FGFR) signaling is implicated in many cancer types. D is a potent multikinase inhibitor of FGFRs, VEGFRs and PDGFR. D’s preclinical anti-cancer effect was most pronounced in pancreatic cancer (PC) with enhanced FGFR signaling. The trial aimed to determine the MTD, toxicity and PK profile of D plus G/C. Methods: Patients (pts) with advanced solid tumors in whom G/C was appropriate and ECOG PS 0-1 were eligible. Dose escalation was conducted per a 3+3 design (Part A) with an expansion cohort (Part B; n=20) at the MTD with advanced PC and biliary cancers. Dose levels were D 300/400/500 mg oral daily on a ‘5-days-on/2-days-off’ schedule with G 1000 mg/m2 i.v. weekly x 2 and C 650 mg/m2twice-daily x 14 days (1 cycle = 21 days). Adverse events (AEs) were graded using CTCAE 4.0 while tumor response by RECIST 1.1. Plasma samples were collected up to 48 hr post-dose. D, G, and C concentrations were determined using LC/MS/MS, and PK analysis was performed. Results: 18 pts were enrolled in total. 6 of 9 pts enrolled to Part A were evaluable for DLT. One of 6 pts treated at D 300 mg level experienced dose-limiting Gr3 colitis; 2 pts experienced non dose-limiting Gr2 neuropathy (reversible) after multiple cycles requiring D dose reduction. Dose escalation was halted and D 300 mg level used for Part B, which enrolled 9 pts so far. D 300 mg level was tolerable when dosed over multiple cycles. Preliminary efficacy included PFS > 12 months in 2 PC pts (1st line and post-FOLFIRINOX respectively). Common (>15%) ≥Gr 2 AEs included asthenia, elevated LFTs, N/V, hypertension, neutropenia and thrombocytopenia. Median Cmax and AUC24 for D were similar after 3 weeks of dosing; 181 (Day 1) vs. 221 ng/ml (Day 19) and 3419 vs. 3854 ng*hr/mL, indicating no presence of autoinduction of D metabolism. Median T1/2 of D was 13.1 hr. G and C PK were similar to literature. Conclusions: D 300 mg level was determined to be the recommended phase II dose and tolerable when dosed over multiple cycles. The PK analysis showed no drug-drug interaction. A clinical trial of D/G/nab-paclitaxel in PC is currently underway. Full toxicity and PK profile will be presented at the conference. Clinical trial information: NCT01497392.