A phase Ib study of alofanib, an allosteric FGFR2 inhibitor, in patients with advanced or metastatic gastric cancer.

Abstract

TPS466 Background: Fibroblast growth factor receptor 2 (FGFR2) is amplified or overexpressed in 3% to 61% of patients with gastric cancer and associated with a poor prognosis. Acquired mutations in FGFR2 develop resistance to multikinase inhibitors. Besides, resistance to monoclonal antibodies depends on the type of FGFR2 isoforms IIIc or IIIb expressed by cancer cells. Alofanib (RPT835) is a novel selective allosteric inhibitor of FGFR2. Alofanib could bind to the non-active site of FGFR2 extracellular domain and had an inhibitory effect on FGF2-induced phosphorylation of FRS2α. On preclinical models no severe organ and function test changes were observed. Based on these results, alofanib has advanced into clinical evaluation. Methods: RPT835GC1B is a Phase 1b study, being conducted in at least four sites in Russia, evaluating the safety and preliminary efficacy of alofanib in patients with advanced and metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. This trial consists of two parts. The standard dose-escalation part (design 3+3) aims to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (R2PD) as a primary endpoint. The first part of the study includes a 28-day period when alofanib is administered daily intravenously for 5-days followed by a 2-day interval (rest). There are five dose levels: 50, 100, 165, 250, and 350 mg/m2. The dose-expansion phase accrues additional 20 patients, where comprehensive information to be collected. Secondary endpoints include pharmacokinetic parameters, rate of adverse events, progression-free survival, overall survival, and objective response rate. All patients will receive alofanib until disease progression or unacceptable toxicity. FGFR2 amplification, fusion, and overexpression will be assessed as well. Clinical trial information: NCT04071184.