First-in-human phase 1/1b study to evaluate sitravatinib in patients with advanced solid tumors

Todd Bauer, Byong Chul Cho, Rebecca Heist, Lyudmila Bazhenova, Theresa Werner, Sanjay Goel, Dong Wan Kim, Douglas Adkins, Richard D. Carvajal, Ajjai Alva, Keith Eaton, Judy Wang, Yong Liu, Xiaohong Yan, Jamie Christensen, Saskia Neuteboom, Richard Chao, Shubham Pant

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Sitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient selection. In phase 1, 32 patients received 10–200 mg, while phase 1b dose expansion comprised 161 patients (150 mg n = 99, 120 mg n = 62). Maximum tolerated dose was determined as 150 mg daily. Dose-limiting toxicity was reported in 4/28 evaluable phase 1 patients (three at 200 mg, one at 80 mg). In phase 1b, 120 mg was defined as the recommended dose due to tolerability. Treatment-related adverse events (TRAEs) were experienced by 174/193 patients (90.2%); grade ≥ 3 TRAEs in 103 patients (53.4%). Most common TRAEs were diarrhea, fatigue, hypertension and nausea; TRAEs led to treatment discontinuation in 26 patients (13.5%) and death in one patient. Sitravatinib was steadily absorbed and declined from plasma with a terminal elimination half-life of 42.1–51.5 h following oral administration. Overall objective response rate was 11.8% in phase 1b, 13.2% in patients with non-small cell lung cancer (NSCLC) and 4.2% in patients with NSCLC with prior checkpoint inhibitor experience. Sitravatinib demonstrated manageable safety and modest clinical activity in solid tumors. NCT02219711 (first posted August 14, 2014).

Original languageEnglish (US)
Pages (from-to)990-1000
Number of pages11
JournalInvestigational New Drugs
Volume40
Issue number5
DOIs
StatePublished - Oct 2022

Keywords

  • Advanced solid tumors
  • Adverse events
  • Objective response rate
  • Pharmacokinetics
  • Sitravatinib

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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