Abstract A69: Phase 1/1b study of the FAK inhibitor defactinib (VS-6063) in combination with weekly paclitaxel for advanced ovarian cancer.
Authors: Patel Manish R. , Infante Jeffrey R. , Moore Kathleen N. , Keegan Mitchell , Poli Anne , Padval Mahesh , Jones Suzanne Fields , Horobin Joannna , Burris Howard A. 
Published: August 2014

Abstract
Background: Defactinib (VS-6063) is a potent, reversible, oral inhibitor of focal adhesion kinase (FAK). Blockade of FAK reduces tumor growth and metastasis through inhibition of tumor cell survival, proliferation, invasion and 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). Therefore the combination of an agent like defactinib targeting CSCs with a cytotoxic chemotherapy offers a unique and novel therapeutic approach. This Phase 1/1b open-label, multicenter study was designed to investigate the safety/tolerability and activity of defactinib in combination with weekly paclitaxel and to evaluate its effect on pharmacokinetics of paclitaxel in advanced ovarian cancer.
Methods: Pts with advanced or refractory ovarian cancer (≤ 4 prior regimens) are enrolled. In the Phase 1 portion, defactinib was administered continuously at a starting dose of 200mg BID with paclitaxel 80 mg/m2 on days 1, 8, and 15, every 28 days, and was escalated to 400mg BID. Paclitaxel pharmacokinetic samples were collected on Day 1 and 15. In Phase 1b, an additional 15 pts with biopsiable disease will be enrolled at 400 mg BID. A 10-day run-in with defactinib alone and isolation of paired tumor biopsies will be used to examine the effects on phosphoFAK expression, CSCs, and other biomarkers. Pts will continue treatment until disease progression.
Preliminary Results: Six pts enrolled: median age was 67 years (53-75); ECOG PS was 0 or 1. Pts received a median of 3.5 (3-6) prior regimens of therapy. 100% had prior taxane exposure and all were platinum resistant. Combination therapy was well tolerated with no dose limiting toxicities (DLTs) observed at either dose level. The recommended Phase 2 dose (RP2D) was determined to be defactinib 400 mg BID with weekly paclitaxel 80 mg/m2. All grade toxicities occurring in ≥ 2 of 6 (33%) of pts included: anemia, fatigue, neutropenia, alopecia, nausea, fever, vomiting, and hypomagnesemia. There was no apparent increase in the severity and incidence of paclitaxel related toxicities. The addition of defactinib did not alter paclitaxel exposure. Significant decreases/normalization of CA-125 were reported in 2 of 6 (33%) of patients. One pt in the 200 mg defactinib BID cohort had a confirmed complete response by RECIST.
Conclusions: Defactinib at its recommended dose at 400 mg BID was well tolerated in combination with standard weekly paclitaxel. Enrollment to the Phase 1b remains ongoing. Clinical trial information: NCT01778803.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A69.
Citation Format: Manish R. Patel, Jeffrey R. Infante, Kathleen N. Moore, Mitchell Keegan, Anne Poli, Mahesh Padval, Suzanne Fields Jones, Joannna Horobin, Howard A. Burris. Phase 1/1b study of the FAK inhibitor defactinib (VS-6063) in combination with weekly paclitaxel for advanced ovarian cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A69.