Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066

作者：E.L. Kwak, D. Ross Camidge, John L. Clark, Geoffrey Ira Shapiro, Robert G. Maki, Mark J. Ratain, Benjamin J. Solomon, Yung‐Jue Bang, San‐San Ou, Ravi Salgia · 发表于：Journal of Clinical Oncology · 年份：2009 · DOI：10.1200/jco.2009.27.15_suppl.3509 · 被引用次数：207 · 研究领域：Lung Cancer Treatments and Mutations、Cancer, Hypoxia, and Metabolism、Colorectal Cancer Treatments and Studies

3509 Background: PF-02341066 (PF) is a selective, ATP-competitive, small molecule oral inhibitor of the c-Met/HGFR and ALK receptor tyrosine kinases that has not previously been tested in humans. A Phase 1 dose-escalation trial evaluating PF as an oral single agent was conducted to investigate safety, PK and PD in patients (pts) with advanced cancer (excluding leukemias). Methods: PF was administered under fasting conditions QD or BID on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 50 mg QD to 300 mg BID. Pts with advanced cancer were enrolled in the study. Results: Thirty-seven pts were enrolled into the dose escalation part of the study. Tumor types included colorectal, pancreatic, sarcoma, ALCL and NSCLC. The MTD was 250 mg BID. Three DLTs were observed: grade 3 increase in ALT (1 pt at 200 mg QD) and grade 3 fatigue (2 pts at 300 mg BID). The most common AEs were nausea, emesis, fatigue and diarrhea. Nausea and emesis were independent of dose or duration of treatment. Mean AUC (30–57% CV) and Cmax (36–69% CV) increased proportionally with dose from 100 mg QD to 300 mg BID. The median terminal half-life was 46 hours. A 2- to 4-fold increase in the oral midazolam (MDZ) AUC was observed following 28-days of PF dosing at 100 mg QD (n = 3) and 300 mg BID (n = 2), respectively, suggesting PF to be an inhibitor of CYP3A. Ten pts have entered an enriched RP2D cohort of pts with tumors harboring c-Met amplification/gene mutation or ALK f...