The Desmoid Tumor Research Foundation

September 2014

A Phase I, Dose-finding Study in Patients With Advanced Solid Malignancies of the Oral Gamma-Secretase Inhibitor PF-03084014.

Author Information

Antonio Jimeno,Arvind Dasari,Bo Huang,Geoffrey I Shapiro,James M Cleary,Jennifer M Reynolds,Karen R McLachlan,Kenneth A Kern,M Naveed Shaik,Patricia A English,Patricia M LoRusso,Rossano Cesari,Wells A Messersmith,Xianxian Zheng

Cancer Center, Division of Medical Oncology, University of Colorado.,Clinical Development, Pfizer Oncology.,Clinical Pharmacology, Pfizer Oncology.,Clinical Statistics, Pfizer Inc.,Department of Medical Oncology, Dana-Farber Cancer Institute.,Medical Oncology, Dana-Farber Cancer Institute.,Medical Oncology, Pfizer Oncology.,Medical Oncology, University of Colorado Cancer Centerwells.messersmith@ucdenver.edu.,Medicine, University of Colorado School of Medicine.,Molecular Medicine, Pfizer.,Oncology, Karmanos Cancer Institute.,Oncology, Pfizer.,Statistics, Oncology Business Unit, Pfizer Oncology.,Translational Research/Oncology Research Unit, Pfizer Global R & D.

Publication

Summary

Purpose: To estimate the maximum tolerated dose (MTD) for continuous oral administration of the gamma-secretase inhibitor PF-03084014, determine the recommended phase 2 dose (RP2D), and evaluate safety and preliminary activity in patients with advanced solid tumors. A total of 64 patients received treatment. The MTD was estimated to be 220 mg BID. The RP2D was determined to be 150 mg BID, based on the better safety profile versus the 220-mg BID dose, given comparable NOTCH-related target inhibition. The most common treatment-related AEs were diarrhea, nausea, fatigue, hypophosphatemia, vomiting, rash, and decreased appetite, which were generally mild to moderate in severity. One patient with advanced thyroid cancer had a complete response and five of seven response-evaluable patients with desmoid tumor achieved a partial response (71.4% objective response rate). Tumor responses were mostly durable, ranging from 1.74+ to 24+ months. PF-03084014 demonstrated a generally dose-dependent pharmacokinetic profile at doses ranging from 20 to 330 mg BID. Consistent down-modulation of NOTCH-related HES4 gene expression was observed in peripheral blood from all evaluable patients. Conclusions: Further development of PF-03084014 for the treatment of patients with advanced solid tumors is warranted and currently under evaluation.

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