Preclinical toxicology of alofanib, an allosteric inhibitor of fibroblast growth factor receptor 2

Lapina, N. V.; Stosman, K. I.; Melikhova, M. V.; Vakunenkova, O. A.; Батоцыренова, Е. Г.; Kashuro, V. A.; Rozhko, Mikhail

doi:10.18027/2224-5057-2019-9-3-65-70

Cited by 3 publications

References 7 publications

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

Tsimafeyeu¹,

Statsenko

Владимирова

et al. 2023

Invest New Drugs

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Alofanib is a small-molecule allosteric extracellular FGFR2 inhibitor. We report safety and preliminary e cacy from the rst-in-human phase 1b study of alofanib in heavily pretreated patients with advanced gastric cancer. MethodsThe 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 ve dose levels (50-350 mg/m2). All patients received alofanib until disease progression or unacceptable toxicity. Results21 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 de ned. 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. ConclusionsThe 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 identi er: NCT04071184

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

Tsimafeyeu¹,

Statsenko

Владимирова

et al. 2023

Invest New Drugs

View full text Add to dashboard Cite

show abstract

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

Tsimafeyeu¹,

Statsenko

Владимирова³

et al. 2023

Preprint

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Purpose 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. Methods 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. Results 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. Conclusions 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

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Prospects for the use of allosteric drugs in real-world clinical practice

Svechkareva,

Kolbin

2023

MyRWD

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While the clinical validity of the use of allosteric regulation is known, scientists are working on the discovery of new methods for the development of allosteric drugs that can modulate the functions of enzymes, depending on the desired therapeutic effect, and have a broader safety profile compared with alternative drugs. Allosteric modulators are of increasing interest in medicine, some of which are already used in the clinic and some can potentially be used in real-world clinical practice. This article summarizes the current knowledge about allosteric modulation of receptors and their clinical prospects.

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Preclinical toxicology of alofanib, an allosteric inhibitor of fibroblast growth factor receptor 2

Cited by 3 publications

References 7 publications

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

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

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

Prospects for the use of allosteric drugs in real-world clinical practice

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