A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors

Cancer Chemother Pharmacol. 2016 May;77(5):997-1003. doi: 10.1007/s00280-016-3010-1. Epub 2016 Mar 30.


Purpose: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting.

Methods: VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response.

Results: Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer).

Conclusions: VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

Trial registration: ClinicalTrials.gov NCT01951690.

Keywords: Defactinib; First-in-Asian phase 1 study; Focal adhesion kinase; Proline-rich tyrosine kinase-2; VS-6063.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Area Under Curve
  • Asian Continental Ancestry Group
  • Benzamides / administration & dosage*
  • Benzamides / adverse effects
  • Benzamides / pharmacokinetics
  • Benzamides / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Focal Adhesion Kinase 1 / antagonists & inhibitors*
  • Focal Adhesion Kinase 2 / antagonists & inhibitors*
  • Half-Life
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / urine
  • Pyrazines / administration & dosage*
  • Pyrazines / adverse effects
  • Pyrazines / pharmacokinetics
  • Pyrazines / therapeutic use
  • Response Evaluation Criteria in Solid Tumors
  • Sulfonamides / administration & dosage*
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / therapeutic use


  • Antineoplastic Agents
  • Benzamides
  • Pyrazines
  • Sulfonamides
  • defactinib
  • Focal Adhesion Kinase 1
  • Focal Adhesion Kinase 2

Associated data

  • ClinicalTrials.gov/NCT01951690