Andrew J Wagner 1 , Wells A Messersmith 2 , M Naveed Shaik 3 , Sherry Li 4 , Xianxian Zheng 3 , Karen R McLachlan 3 , Rossano Cesari 5 , Rachel Courtney 3 , Wendy J Levin 3 , Anthony B El-Khoueiry 6 Show Affiliations »
Abstract
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 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 once daily. The recommended phase II dose was not determined. PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. The most common treatment-related adverse events (AE) 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 once daily. No treatment-related grade 4-5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting once-daily dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by >80% downregulation of GLI1 expression in the skin of treated patients. Eight patients (34.8%) 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. ©2014 American Association for Cancer Research.
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 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 once daily. The recommended phase II dose was not determined. PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. The most common treatment-related adverse events (AE) 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 once daily. No treatment-related grade 4-5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting once-daily dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by >80% downregulation of GLI1 expression in the skin of treated patients . Eight patients (34.8%) 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 . ©2014 American Association for Cancer Research.
Entities: Chemical
Disease
Gene
Species
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Year: 2014
PMID： 25388167 DOI： 10.1158/1078-0432.CCR-14-1116
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531