PMID- 27025608 OWN - NLM STAT- MEDLINE DCOM- 20170206 LR - 20221207 IS - 1432-0843 (Electronic) IS - 0344-5704 (Print) IS - 0344-5704 (Linking) VI - 77 IP - 5 DP - 2016 May TI - 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. PG - 997-1003 LID - 10.1007/s00280-016-3010-1 [doi] AB - 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. FAU - Shimizu, Toshio AU - Shimizu T AD - Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan. jcog9511@hotmail.co.jp. FAU - Fukuoka, Kazuya AU - Fukuoka K AD - Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan. FAU - Takeda, Masayuki AU - Takeda M AD - Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan. FAU - Iwasa, Tutomu AU - Iwasa T AD - Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan. FAU - Yoshida, Takeshi AU - Yoshida T AD - Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan. FAU - Horobin, Joanna AU - Horobin J AD - Verastem, Inc., Needham, MA, 02494, USA. FAU - Keegan, Mitchell AU - Keegan M AD - Verastem, Inc., Needham, MA, 02494, USA. FAU - Vaickus, Lou AU - Vaickus L AD - Verastem, Inc., Needham, MA, 02494, USA. FAU - Chavan, Ajit AU - Chavan A AD - Verastem, Inc., Needham, MA, 02494, USA. FAU - Padval, Mahesh AU - Padval M AD - Verastem, Inc., Needham, MA, 02494, USA. FAU - Nakagawa, Kazuhiko AU - Nakagawa K AD - Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan. LA - eng SI - ClinicalTrials.gov/NCT01951690 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160330 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Antineoplastic Agents) RN - 0 (Benzamides) RN - 0 (Pyrazines) RN - 0 (Sulfonamides) RN - 53O87HA2QU (defactinib) RN - EC 2.7.10.2 (Focal Adhesion Kinase 1) RN - EC 2.7.10.2 (Focal Adhesion Kinase 2) SB - IM MH - Administration, Oral MH - Adult MH - Aged MH - Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics/therapeutic use MH - Area Under Curve MH - Asian People MH - Benzamides/*administration & dosage/adverse effects/pharmacokinetics/therapeutic use MH - Dose-Response Relationship, Drug MH - Drug Administration Schedule MH - Female MH - Focal Adhesion Kinase 1/*antagonists & inhibitors MH - Focal Adhesion Kinase 2/*antagonists & inhibitors MH - Half-Life MH - Humans MH - Male MH - Middle Aged MH - Neoplasms/blood/*drug therapy/enzymology/urine MH - Pyrazines/*administration & dosage/adverse effects/pharmacokinetics/therapeutic use MH - Response Evaluation Criteria in Solid Tumors MH - Sulfonamides/*administration & dosage/adverse effects/pharmacokinetics/therapeutic use PMC - PMC4844649 OTO - NOTNLM OT - Defactinib OT - First-in-Asian phase 1 study OT - Focal adhesion kinase OT - Proline-rich tyrosine kinase-2 OT - VS-6063 EDAT- 2016/03/31 06:00 MHDA- 2017/02/07 06:00 PMCR- 2016/03/30 CRDT- 2016/03/31 06:00 PHST- 2016/02/23 00:00 [received] PHST- 2016/03/14 00:00 [accepted] PHST- 2016/03/31 06:00 [entrez] PHST- 2016/03/31 06:00 [pubmed] PHST- 2017/02/07 06:00 [medline] PHST- 2016/03/30 00:00 [pmc-release] AID - 10.1007/s00280-016-3010-1 [pii] AID - 3010 [pii] AID - 10.1007/s00280-016-3010-1 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2016 May;77(5):997-1003. doi: 10.1007/s00280-016-3010-1. Epub 2016 Mar 30.