A Phase I Study of PF-04449913, an Oral Hedgehog Inhibitor, in Patients with Advanced Solid Tumors

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 3þ3 design was used in this openlabel, 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.

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

“…Lower incidences of grade 3/4 AEs, SAEs and AEs leading to discontinuation were observed with 200 mg vs. 800 mg. The majority of the most common AEs were generally grade 1 or 2 and were similar to those reported with other HPIs10, 11, 12, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39; muscle‐related AEs and the increase in CK that can accompany these AEs are thought to be a class effect of HPIs 11, 12, 30, 31, 35, 39. Muscle‐related AEs were effectively managed with dose adjustments or interruptions.…”

Targeting the Hedgehog Signaling Pathway by Glasdegib Limits the Self- Renewal of MDS-Derived Induced Potent Stem Cells (iPSC)

“…Glasdegib is a potent and selective hedgehog pathway inhibitor that acts by binding SMO and blocking signal transduction [9]. The phase I study shows that glasdegib is safe and tolerable, with on-target adverse events, doseproportional pharmacokinetics, and early suggestions of clinical activity in patients with hematological malignancies [11,12]. 5-azacytidine is a hypomethylating agent that is used as first-line therapy in MDS.…”

“…In xenograft models of human colorectal and pancreatic cancer, treatment with glasdegib in combination with other anticancer agents reduced the tumor growth [10]. Furthermore, glasdegib demonstrated preliminary antitumor activity in a phase I trial, when given as monotherapy in patients with several hematopoietic malignancies [11,12]. In the present study, we investigated the molecular mechanisms by which glasdegib regulate the self-renewal of MDS-derived iPS cells (iPSCs) in vivo.…”

Phase I trial of the oral smoothened inhibitor sonidegib in combination with paclitaxel in patients with advanced solid tumors

“…Several other SMO inhibitors have been developed and tested in clinical trials [18][19][20]. As with vismodegib and sonidegib, single-agent activity was limited to BCC and medulloblastoma, two tumor types with known mutations (mainly PATCH1 and SMO) leading to ligand-independent Hh pathway activation.…”