First-in-Human Phase 1/1b Study to Evaluate Sitravatinib in Patients With Advanced Solid Tumors

Authors

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

Publication Date

10-1-2022

Journal

Investigational New Drugs

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).

Keywords

Anilides, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Neoplasms, Pyridines, Tumor Microenvironment, Advanced solid tumors, Adverse events, Objective response rate, Pharmacokinetics, Sitravatinib

DOI

10.1007/s10637-022-01274-y

PMID

35767205

PMCID

PMC9395446

PubMedCentral® Posted Date

6-29-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes