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

Our plain-English summary of 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, by T. Shimizu, K. Fukuoka, M. Takeda, et al (Cancer Chemotherapy and Pharmacology, 2016).

The study

• Authors: T. Shimizu, K. Fukuoka, M. Takeda, T. Iwasa, T. Yoshida, J. Horobin, M. Keegan, L. Vaickus, A. Chavan, M. Padval, K. Nakagawa
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2016;77(5):997-1003
• Cited by: 97 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a phase 1, open-label, dose-escalation study of VS-6063 (defactinib), an experimental oral cancer drug that blocks an enzyme called focal adhesion kinase. It did not study asbestos exposure. Nine Japanese adults with advanced solid cancers, one of whom had mesothelioma, took the drug twice daily at 200, 400 or 600 mg, with three patients at each dose, between September 2013 and June 2014. No dose-limiting toxicities, serious adverse events or adverse events leading to death were reported. The most common drug-related side effect was a rise in unconjugated bilirubin, seen in 7 patients (78 %). One patient at 200 mg had a Grade 3 rise beginning on Day 42 that resolved 6 days after onset, following drug interruption. Fatigue affected 6 patients, decreased appetite 4 and diarrhea 3. Blood levels of the drug did not rise significantly at doses above 400 mg. Exposure at 400 mg was comparable to that reported in non-Japanese patients. No patient had an objective tumor response by standard criteria. Three of 9 patients had stable disease, including the mesothelioma patient (400 mg) for 169 days. The authors concluded the drug had an acceptable safety profile.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase 1, open-label, dose-escalation drug trial (standard 3 + 3 design) at a single site in Japan
• Who was studied: 9 Japanese patients with locally advanced or metastatic solid tumors who had progressed on, were intolerant of, or were not eligible for standard therapy. They were treated from September 2013 to June 2014. Tumor types were colorectal cancer (4) and one each of esophageal cancer, mesothelioma, non-small cell lung cancer, thymic cancer and extramammary Paget's disease. The article does not state the type of mesothelioma.
• Exposure: The drug VS-6063 (defactinib), a focal adhesion kinase inhibitor, taken by mouth twice daily at 200, 400 or 600 mg in continuous 21-day cycles. No asbestos exposure was studied.
• Main results:
  • No dose-limiting toxicities occurred at any dose level (all 9 patients)
  • There were no adverse events leading to death and no serious adverse events. No patient withdrew early because of adverse events.
  • The most common treatment-related side effects across all 9 patients were unconjugated hyperbilirubinemia in 7 (78 %) and fatigue in 6 (67 %). Decreased appetite occurred in 4 (44 %) and diarrhea in 3 (33 %).
  • One patient in the 200 mg cohort had a Grade 3 rise in unconjugated bilirubin starting on Day 42. It resolved 6 days after onset, following interruption of the drug.
  • Drug blood levels rose less than in proportion to the dose. Doses above 400 mg twice daily did not significantly increase exposure.
  • Median half-life ranged from 2.3 to 4.3 hours across all doses and both sampling days
  • Exposure at the recommended phase 2 dose of 400 mg twice daily was comparable to that previously reported in non-Japanese patients
  • The best response was stable disease, in 3 of the 9 patients, one in each dose cohort
  • The patient with mesothelioma (400 mg cohort) had stable disease lasting 169 days (24 weeks). A patient with rectal cancer (600 mg cohort) had stable disease lasting 162 days (23 weeks).
  • No objective radiographic responses were observed
• The authors' conclusion: The authors concluded that VS-6063 has an acceptable safety profile in Japanese patients with advanced solid tumors, with Grade 1 to 2 side effects that were easily managed and reversible. They concluded that the data support giving it to Japanese patients in investigational trials at the recommended dose of 400 mg twice daily.

Topics

Medical terms in this study, explained in our Lexicon: Disease Progression, Malignant Mesothelioma, Clinical Trial.

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