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

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.

• Authors: Suzanne F Jones, Lillian L Siu, Johanna C Bendell, James M Cleary, Albiruni R A Razak, Jeffrey R Infante, Shuchi S Pandya, Philippe L Bedard, Kristen J Pierce, Brett Houk, W Gregory Roberts, S Martin Shreeve, Geoffrey I Shapiro
• Journal: Investigational new drugs (Invest New Drugs) Vol. 33 Issue 5 Pg. 1100-7 (10 2015) ISSN: 1573-0646 [Electronic] United States
• PMID: 26334219 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Organic Chemicals
• Pyrazines
• Sulfonamides
• defactinib

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• Benzamides
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Food-Drug Interactions
• Half-Life
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Organic Chemicals (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Pyrazines
• Sulfonamides