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
| Autor: | Toshio Shimizu, Mahesh Padval, Masayuki Takeda, Tutomu Iwasa, Joanna Horobin, Takeshi Yoshida, Ajit Chavan, Mitchell Keegan, Kazuhiko Nakagawa, Lou Vaickus, Kazuya Fukuoka |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research VS-6063 Administration Oral Antineoplastic Agents Pharmacology Toxicology Drug Administration Schedule Focal adhesion 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Asian People Defactinib Neoplasms First-in-Asian phase 1 study Medicine Humans Pharmacology (medical) Tyrosine Response Evaluation Criteria in Solid Tumors Advanced Solid Tumor Aged Sulfonamides Proline-rich tyrosine kinase-2 Dose-Response Relationship Drug business.industry Focal adhesion kinase Middle Aged 030104 developmental biology Focal Adhesion Kinase 2 Oncology Tolerability 030220 oncology & carcinogenesis Area Under Curve Focal Adhesion Kinase 1 Pyrazines Benzamides Female Original Article business Half-Life |
| Zdroj: | Cancer Chemotherapy and Pharmacology |
| ISSN: | 1432-0843 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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