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Invest New Drugs. 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.

Author information

1
Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN, 37203, USA. suzanne.jones@scresearch.net.
2
Princess Margaret Cancer Centre, Toronto, ON, Canada.
3
Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN, 37203, USA.
4
Brigham and Women's Hospital, Boston, MA, USA.
5
Beth Israel Deaconess Medical Center, Boston, MA, USA.
6
Pfizer Oncology, Groton, CT, USA.
7
Pfizer Oncology, La Jolla, CA, USA.
8
Dana-Farber Cancer Institute, Boston, MA, USA.

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

PMID:
26334219
DOI:
10.1007/s10637-015-0282-y
[Indexed for MEDLINE]

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