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

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Summary

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).

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank all investigators (Vyacheslav Kurakin, Natalia Trenina, Kristina Novoselova, Nikita Volkov, Natalia Abramova, Tatyana Titova, Ilya Agranov, Sergei Iugai, Ekaterina Obarevich, Alina Khashanova, Margarita Suetina, Aiyyna Nikiforova, Maria Mukhina, and Dmitry Reznikov) participating in the study and Kristina Zakurdaeva for her support in the development of the study protocol.

Funding

This work was supported by grant from Skolkovo Foundation (no grant number).

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Authors and Affiliations

  1. Bureau of Cancer Research, Moscow office, Mayakovskogo pereulok 2, Moscow, Russia, 109147, Russian Federation

    Ilya Tsimafeyeu

  2. Omsk Regional Cancer Center, Omsk, Russian Federation

    Galina Statsenko

  3. National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation

    Liubov Vladimirova

  4. N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russian Federation

    Natalia Besova, Elena Artamonova & Sergei Tjulandin

  5. Dr. Berezin Medical Institute, St. Petersburg, Russian Federation

    Grigory Raskin

  6. St. Petersburg Clinical Hospital of the Russian Academy of Sciences, St. Petersburg, Russian Federation

    Ivan Rykov

  7. Clinical hospital #1, Medsi Otradnoe, Moscow, Russian Federation

    Anastasia Mochalova

  8. Hadassah Medical Moscow, Moscow, Russian Federation

    Igor Utyashev

  9. Exacte Labs, Moscow, Russian Federation

    Svetlana Gorbacheva & Vasily Kazey

  10. Ruspharmtech LLC, St. Petersburg, Russian Federation

    Evgenia Gavrilova & Nadezhda Dragun

  11. Clinical and Research Center of Specialized Types of Medical Care (Oncological), Saint-Petersburg, Russian Federation

    Vladimir Moiseyenko

Authors
  1. Ilya Tsimafeyeu
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  2. Galina Statsenko
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  3. Liubov Vladimirova
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  4. Natalia Besova
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  5. Elena Artamonova
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  6. Grigory Raskin
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  7. Ivan Rykov
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  8. Anastasia Mochalova
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  9. Igor Utyashev
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  10. Svetlana Gorbacheva
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  11. Vasily Kazey
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  12. Evgenia Gavrilova
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  13. Nadezhda Dragun
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  14. Vladimir Moiseyenko
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  15. Sergei Tjulandin
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Contributions

Ilya Tsimafeyeu and Sergei Tjulandin conceived and designed the study and analysis. Ilya Tsimafeyeu wrote the first draft of the manuscript. Galina Statsenko, Liubov Vladimirova, Natalia Besova, Elena Artamonova, Ivan Rykov, Anastasia Mochalova, Igor Utyashev, and Vladimir Moiseyenko enrolled patients and collected data. Grigory Raskin performed pathological studies. Svetlana Gorbacheva and Vasily Kazey performed PK studies.Evgenia Gavrilova and Nadezhda Dragun monitored the study and conducted an internal audit. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Ilya Tsimafeyeu.

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Competing interests

Evgenia Gavrilova and Nadezhda Dragun are employees of Ruspharmtech LLC.

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Tsimafeyeu, I., Statsenko, G., Vladimirova, L. et al. A phase 1b study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with pretreated advanced gastric cancer. Invest New Drugs 41, 324–332 (2023). https://doi.org/10.1007/s10637-023-01340-z

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