A phase 1b study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with pretreated advanced gastric cancer.

Abstract

Alofanib is a small-molecule allosteric extracellular FGFR2 inhibitor. We report safety and preliminary efficacy from the first-in-human phase 1b study of alofanib in heavily pretreated patients with advanced gastric cancer. The standard dose-escalation design 3+3 aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Alofanib was administered daily intravenously 5 days on, 2 days off. There were five dose levels (50-350 mg/m2). All patients received alofanib until disease progression or unacceptable toxicity. 21 patients were enrolled. Patients were predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 19% had ECOG PS 2, and were heavily pretreated (86% had previous 2 and more treatment lines). During dose escalation, no dose-limiting toxicities were observed, and MTD was not defined. 15 (71.4%) patients had at least one adverse event associated with the treatment (TRAE). Grade 3 or higher TRAEs were observed in 6 patients (28.6%). The most common TRAEs included reactions immediately after administration, diarrhea, thrombocytopenia, arthralgia, and headache. The median progression-free survival and overall survival was 3.63 (95% CI 1.58-5.68) and 7.0 (95% CI 3.82-10.18) months, respectively. The 6- and 12-month overall survival rates were 57.1% and 33.3%. Disease control rate was 68% with one durable partial response. The MTD has not been reached and dose of 350 mg/m2, 5 days on, 2 days off has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. (ClinicalTrials.gov identifier: NCT04071184).

• Authors: Ilya Tsimafeyeu, Galina Statsenko, Liubov Vladimirova, Natalia Besova, Elena Artamonova, Grigory Raskin, Ivan Rykov, Anastasia Mochalova, Igor Utyashev, Svetlana Gorbacheva, Vasily Kazey, Evgenia Gavrilova, Nadezhda Dragun, Vladimir Moiseyenko, Sergei Tjulandin
• Journal: Investigational new drugs (Invest New Drugs) Vol. 41 Issue 2 Pg. 324-332 (04 2023) ISSN: 1573-0646 [Electronic] United States
• PMID: 36907947 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• alofanib
• Benzoates
• Sulfonamides
• FGFR2 protein, human
• Receptor, Fibroblast Growth Factor, Type 2

Topics

• Humans
• Male
• Female
• Stomach Neoplasms (drug therapy, pathology)
• Benzoates (pharmacology, therapeutic use)
• Sulfonamides (therapeutic use)
• Receptor, Fibroblast Growth Factor, Type 2