Purpose: To estimate the maximum tolerated dose (MTD) of single-agent PF-04449913, and to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with advanced tumors. Experimental Design: A 3+3 design was used in this open-label, multicenter, phase I study and dose escalation/de-escalation applied until identification of the MTD. PF-04449913 was orally administered once daily (QD) in continuous 28-day treatment cycles. The starting dose was 80 mg. Results: A total of 23 patients were enrolled; 19 were evaluable for first-cycle dose-limiting toxicity (DLT). The first-cycle DLT rate at the 640-mg dose level was 33.3% and the MTD was estimated to be 320 mg QD. The recommended phase 2 dose was not determined. PF-04449913 was generally well tolerated at doses of 80-320 mg QD. The most common treatment-related adverse events (AEs) were grade 1-2 dysgeusia, fatigue, decreased appetite, nausea, dizziness, dehydration, and diarrhea. Treatment-related grade 3 AEs only occurred in patients receiving PF-04449913 640 mg QD. No treatment-related grade 4-5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting QD dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by >80% down-regulation of GLI1 expression in the skin of treated patients. Eight (34.8%) patients achieved stable disease; none had complete or partial response. Three patients with disease progression at enrollment had prolonged disease stabilization (≥6 months). Conclusions: The results obtained in this study support further evaluation of PF-04449913 in patients with advanced solid tumors.
- Received May 2, 2014.
- Revision received September 24, 2014.
- Accepted October 26, 2014.
- Copyright © 2014, American Association for Cancer Research.