A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors.
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.



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.



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).



The results obtained in this study support further evaluation of PF-04449913 in patients with advanced solid tumors.
Dana-Farber Cancer Institute, Boston, Massachusetts. Andrew_Wagner@dfci.harvard.edu.
Andrew J
AJ
Wagner
University of Colorado Cancer Center, Aurora, Colorado.
Wells A
WA
Messersmith
Pfizer Oncology, La Jolla, California.
M Naveed
MN
Shaik
Pfizer China Research and Development Center, Shanghai, China.
Sherry
S
Li
Pfizer Oncology, La Jolla, California.
Xianxian
X
Zheng
Pfizer Oncology, La Jolla, California.
Karen R
KR
McLachlan
Pfizer Oncology, Milan, Italy.
Rossano
R
Cesari
Pfizer Oncology, La Jolla, California.
Rachel
R
Courtney
Pfizer Oncology, La Jolla, California.
Wendy J
WJ
Levin
University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
Anthony B
AB
El-Khoueiry
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D015513:Oncogene Proteins / Q000235:genetics; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D015534:Trans-Activators / Q000235:genetics; D016896:Treatment Outcome; D000071676:Zinc Finger Protein GLI1
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D010671:Phenylurea Compounds; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; C000592580:glasdegib