2596 Background: PF-02341066 (PF) is a selective, ATP-competitive, small molecule orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases being developed for the treatment of cancer. Methods: Preliminary PK data were collected for the first 80 cancer patients enrolled in the ongoing study A8081001, an open-label, multi- center phase I dose-escalation, safety, pharmacokinetic, and exploratory study (J Clin Oncol 27:15s, 2009). PF was administered orally to patients under fasting conditions in continuous 28-day cycles. Doses ranged from 50-200 mg QD and 200-300 mg BID. Serial blood samples were collected on lead-in Day 7, Cycle 1 Day 1, Cycle 1 Day 15, and/or Cycle 2 Day 1; and predose samples were collected on Days 1 and/or 15 of Cycles 2-5. Plasma concentrations of PF were determined using a validated analytical method. Results: Peak concentrations were reached at approximately 4 hours (hrs), followed by a multi-exponential decline with an average terminal half-life of 43 to 51 hrs across doses. PF AUC increased with median accumulation ratios ranging 1.7-3.4 after QD dosing and 4.0-5.9 after BID dosing, respectively. Repeated administration at 250 mg BID (maximum recommended dose for phase 2/3) for ≥15 days produced a median trough plasma concentration of 256 ng/mL (45 nM, free drug), exceeding the target efficacious levels for ALK and MET predicted from preclinical models. Subjects receiving doses ranging from 100-200 mg QD and 200 mg to 300 mg BID generally demonstrated linear PK, as evidenced by proportional increases in mean AUC. PF exposure was similar between Asian (N=13) and non-Asian (N=20) patients at 250 mg BID. Co-administration with a standard high-fat meal appeared not to change the geometric mean of AUC and Cmax of PF following single 250-mg PF doses. A 3.6-fold (90% CI: 2.7-4.9) increase in the single-dose oral midazolam AUC was observed following 28 days of PF dosing at 250 mg BID, suggesting that PF is a moderate CYP3A4 inhibitor. Conclusions: PF AUC generally increased proportionally with doses over the therapeutic dose range studied. PF AUC accumulated by 4.0-5.9-fold after multiple doses with a terminal half-life of 43-51 hrs. A high-fat meal did not appear to change PF PK.