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Clinical Trial
. 2015 Oct;33(5):1100-7.
doi: 10.1007/s10637-015-0282-y. Epub 2015 Sep 4.

A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors

Suzanne F Jones  1 , Lillian L Siu  2 , Johanna C Bendell  3 , James M Cleary  4 , Albiruni R A Razak  2 , Jeffrey R Infante  3 , Shuchi S Pandya  5 , Philippe L Bedard  2 , Kristen J Pierce  6 , Brett Houk  7 , W Gregory Roberts  6 , S Martin Shreeve  7 , Geoffrey I Shapiro  8
Affiliations
Clinical Trial

A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors

Suzanne F Jones et al. Invest New Drugs. 2015 Oct.

Abstract

Objective: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies.

Methods: Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state.

Results: Forty-six patients were treated across nine dose levels (12.5-750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d.

Conclusions: VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.

Trial registration: ClinicalTrials.gov NCT00787033.

Keywords: Defactinib; Dose-escalation study; Focal adhesion kinase; Proline-rich tyrosine kinase-2; VS-6063.

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