title: 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: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan. jcog9511@hotmail.co.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Fukuoka
authors.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan.
authors.forename: Tutomu
authors.initials: T
authors.lastname: Iwasa
authors.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Verastem, Inc., Needham, MA, 02494, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Horobin
authors.affiliation: Verastem, Inc., Needham, MA, 02494, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Keegan
authors.affiliation: Verastem, Inc., Needham, MA, 02494, USA.
authors.forename: Lou
authors.initials: L
authors.lastname: Vaickus
authors.affiliation: Verastem, Inc., Needham, MA, 02494, USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Chavan
authors.affiliation: Verastem, Inc., Needham, MA, 02494, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Padval
authors.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama City, Osaka, 5898511, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D044466:Asian People; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors*; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000652:urine; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D066066:Response Evaluation Criteria in Solid Tumors; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D011719:Pyrazines; D013449:Sulfonamides; C584510:defactinib; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2
keywords: Defactinib; First-in-Asian phase 1 study; Focal adhesion kinase; Proline-rich tyrosine kinase-2; VS-6063