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A first-in-human phase 1b study of a novel allosteric extracellular FGFR2 inhibitor alofanib in patients with refractory metastatic gastric cancerстатья
Статья опубликована в высокорейтинговом журнале
Статья опубликована в журнале из списка Web of Science и/или Scopus- Авторы: Tjulandin Sergei, Statsenko Galina, Artamonova Elena, Vladimirova Liubov Yu, Besova Natalia, Mochalova Anastasia, Rykov Ivan, Moiseyenko Vladimir, Utyashev Igor A., Iugai Sergei, Kazey Vasily, Raskin Grigory, Dragun Nadezhda, Reznikov Dmitry, Gavrilova Evgenia, Tsimafeyeu Ilya
- Журнал: Journal of Clinical Oncology
- Том: 40
- Номер: 4_suppl
- Год издания: 2022
- Издательство: American Society of Clinical Oncology
- Местоположение издательства: United States
- Первая страница: 304
- Последняя страница: 304
- DOI: 10.1200/jco.2022.40.4_suppl.304
- Аннотация: Background: FGFR2 promotes gastric cancer progression, suggesting that inhibition of FGFR2 may be an important therapeutic strategy. Alofanib (RPT835) is a small molecule, allosteric inhibitor that binds to the non-active extracellular site of IIIc and IIIb FGFR2 isoforms with IC50 < 10 nM. Methods: RPT835GC1B is a Phase 1b open-label study evaluating the safety and preliminary efficacy of alofanib in patients with metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. The standard dose-escalation part (design 3+3) aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) as a primary endpoint. Secondary endpoints included pharmacokinetic (PK) parameters, rate of adverse events, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Alofanib was administered daily intravenously for 5-days followed by a 2-day interval (rest). There were five dose levels: 50, 100, 165, 250, and 350 mg/m2. All patients received alofanib until disease progression or unacceptable toxicity. Results: As of 20 September 2021, 21 patients have been enrolled in the study. Patients were Caucasian (100%), predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 14% had ECOG PS 2, and were heavily pretreated (86% had previous 3 and more lines of therapy). All enrolled patients have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28-day DLT-assessment window. 17 (81%) patients had at least one treatment-related adverse event (trAE). Grade 3 or higher trAEs (5/23.8%) have included raised ALT/AST at 50 mg/m2, neutropenia at 50 mg/m2, diarrhea at 165 mg/m2, headache at 165 mg/m2, increased serum amylase at 350 mg/m2, and reactions immediately after intravenous injections (facial flushing, dizziness, weakness, sweating, and sinus tachycardia) at 350 mg/m2. Three (14.3%) patients discontinued treatment due to trAEs. Most common Grade 1-2 adverse events included reactions immediately after intravenous injections, diarrhea, thrombocytopenia, arthralgia, and headache. Grade 1 hyperphosphatemia was found in 1 (4.8%) patient. Table summarizes efficacy data. Conclusions: The MTD has not been reached and dose of 350 mg/m2 has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. Clinical trial information: NCT04071184.
- Добавил в систему: Владимирова Любовь Юрьевна