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.

Abstract

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.

• Authors: Toshio Shimizu, Kazuya Fukuoka, Masayuki Takeda, Tutomu Iwasa, Takeshi Yoshida, Joanna Horobin, Mitchell Keegan, Lou Vaickus, Ajit Chavan, Mahesh Padval, Kazuhiko Nakagawa
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 77 Issue 5 Pg. 997-1003 (05 2016) ISSN: 1432-0843 [Electronic] Germany
• PMID: 27025608 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• Asian People
• Benzamides (administration & dosage, adverse effects, pharmacokinetics, 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, drug therapy, enzymology, urine)
• Pyrazines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Response Evaluation Criteria in Solid Tumors
• Sulfonamides (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)