Abstract
TPS2620 Background: Blockade of FAK reduces tumor growth and metastasis through inhibition of tumor cell survival, proliferation and invasion as well as tumor angiogenesis. Furthermore, treatment with FAK inhibitors reduces the proportion of cancer stem cells (CSCs) in a dose dependent manner while paclitaxel treatment enriches for CSCs. (Kolev VN San Antonio Breast Cancer Symposia 2012 abstr P6-11-09). The ability of CSCs to survive exposure to chemotherapy but remain susceptible to novel drugs suggests a unique therapeutic approach whereby standard of care chemotherapy may be sequentially combined with targeted drugs to kill surviving CSCs and thus prevent tumor recurrence and metastasis. VS-6063 (previously PF-04554878) is a potent oral inhibitor of FAK and proline-rich tyrosine-kinase -2. The phase I first-in-man trial explored doses ranging from 12.5 -750 mg twice daily (BID). (Jones SF J Clin Oncol 2011 29:1 suppl; abstr 3002) Dose-limiting toxicities consisted of headache, fatigue, and unconjugated hyperbilirubinemia at various dose levels. A maximum tolerated dose was not defined, but doses > 100 mg BID consistently yielded concentrations above the preclinically predicted minimal efficacious concentration. Seven pts demonstrated stable disease lasting approximately 6 months or greater, including 3 heavily-pretreated ovarian cancer pts (2 platinum resistant). Methods: Pts with advanced or refractory ovarian cancer (≤ 4 prior regimens) will be enrolled. In the phase I portion, VS-6063 is administered continuously at a starting dose of 200mg BID with paclitaxel 80 mg/m2 on days 1, 8, and 15 every 28 days, and will be escalated to 400mg BID if tolerated. Pharmacokinetics will be analyzed. An additional 15 pts with biopsiable disease will be enrolled at the recommended dose. A 10-day run-in with VS-6063 alone will be used to obtain paired tumor biopsies in order to examine the effects on pFAK expression, CSCs, and other biomarkers. Patients will continue treatment until disease progression. Clinical trial information: NCT01778803.
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