Phase I Study of PF-04554878, a Second-Generation Focal Adhesion Kinase (FAK) Inhibitor, in Patients with Advanced Solid Tumors.

3002 Background: FAK is a non-receptor tyrosine kinase that transduces signaling from integrins and growth factor receptors to modulate cell invasion, migration, metastasis and survival. PF-04554878 is a potent ATP-competitive inhibitor of FAK that also inhibits the related protein proline-rich tyrosine kinase (Pyk2). METHODS This is an ongoing phase 1 dose escalation study of PF-04554878 given as continuous oral dosing in 21-day cycles in patients (pts) with solid tumors. Endpoints include safety, pharmacokinetics (PK), and response by RECIST. RESULTS 36 patients (data cut-off 09 Dec 2010) received doses ranging from 12.5 mg to 750 mg BID on a fasting schedule. Demographics: M:F 16:20, and mean age: 56 yrs (range 31-84). Primary tumor types: colorectal (CRC) 15, pancreatic 4, ovarian 3, bile duct 3, breast 2, other 9. 72% of pts had ≥3 prior systemic treatments. Adverse events (AEs) possibly related to PF-04554878 in >10% pts: nausea (33%), vomiting (31%), unconjugated hyperbilirubinemia (28%), fatigue (25%), headache (19%), diarrhea (19%), and decreased appetite (17%). All AEs (including unconjugated hyperbilirubinemia) were typically CTCAE grades 1-2, easily managed and reversible even with continued dosing. There have been three dose limiting toxicities (DLTs): a grade 3 headache (at 200 mg BID), and two grade 3 unconjugated hyperbilirubinemias (at 300 mg BID and 425 mg BID). All DLTs were reversed on stopping drug. PK analysis supports the BID dosing regimen and shows that doses above 100 mg BID lead to exposures above the minimal efficacious concentration predicted preclinically. Increasing the dose beyond 425 mg BID did not increase drug exposure. Stable disease (SD) was observed at the end of 2 cycles in 12 (33%) pts once the dose reached ≥100 mg BID. Two of these pts (ovarian, CRC) had SD observed at the end of 6 cycles and a further two pts (bile duct, lung mucoepidermoid) had SD observed for ≥9 cycles. The recommended Phase 2 dose, on a fasting schedule, is 425 mg BID. CONCLUSIONS Clinical safety, tolerability, PK, and the sustained disease control seen in some pts, all support further development.