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.MethodsVS-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.ResultsNine 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).ConclusionsVS-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.

Genomic Copy Number Alterations in Serous Ovarian Cancer

“…Finally, the 8q24 region is the most commonly amplified genomic region in SOC, containing MYC and FAK. Inhibitors to FAK, such as defactinib, are already being tested in the clinic [116], and will hopefully provide some positive results in the near future.…”

Novel systemic therapy against malignant pleural mesothelioma

“…Pre-clinical models demonstrated that maintenance therapy with defactinib delayed tumor regrowth in MPM patient derived xenograft models (126). In a phase I study, one patient with MPM was reported to have radiographic stable disease while on defactinib for 24 weeks at a dose of 400 mg (127). Interestingly, another phase I study with a different FAK inhibitor, GSK2256098, reported that MPM patients with documented loss of Merlin had increased median PFS at 23.4 weeks (n=14) compared to MPM patients with preserved Merlin expression who had median PFS at 11.4 weeks (n=9) (128).…”

PIM1 knockdown inhibits cell proliferation and invasion of mesothelioma cells

“…Α recent study has previously reported the high expression and prognostic value of Cd26 in malignant mesothelioma (17,18), humanized anti-Cd26 monoclonal antibody, yS-110, having inhibitory effect on malignant mesothelioma cell growth in vitro and in vivo experiments (19), and one of the promising new developments for the antibody-based treatment of mesothelioma (19,20). Other trials such as pembrolizumab against programmed death 1 (Pd-1) antibody, PF-03446962 against activin receptor-like kinase 1 (ALK-1), defactinib against focal adhesion kinase (FAK) are ongoing (21)(22)(23).…”