Academic Journal
Safety assessment and determination of a maximally tolerated dose of an RAS-GTPase inhibitor (iRAS) in the treatment of gastrointestinal tumors: preliminary results of the phase I trial
| العنوان: | Safety assessment and determination of a maximally tolerated dose of an RAS-GTPase inhibitor (iRAS) in the treatment of gastrointestinal tumors: preliminary results of the phase I trial |
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| المؤلفون: | Vladimir K. Bozhenko, Sergey V. Goncharov, Elena A. Kudinova, Tatiana M. Kulinich, Elena A. Kukoleva, Mikhail S. Filippov, Anna F. Bykova, Oksana B. Knyazeva, Ilya A. Puchkov, Vladimir A. Solodkiy |
| المصدر: | Alʹmanah Kliničeskoj Mediciny, Vol 51, Iss 7, Pp 376-396 (2023) |
| بيانات النشر: | MONIKI, 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Medicine |
| مصطلحات موضوعية: | anti-tumor agent, peritoneal carcinomatosis, ras-gtpase inhibitor, intraperitoneal aerosol chemotherapy (pipac), molecular targets, clinical studies, Medicine |
| الوصف: | Background: Ras oncogene mutations leading to hyperactivation of the MAPK/ERK signaling pathway occur in 25% of all human tumors, and for gastrointestinal tumors, the frequency of Ras mutations amounts to 60%. The introduction of a Ras-GTPase inhibitor into clinical practice would increase the effectiveness of the treatment of socially significant diseases such as stomach and intestinal cancer. Aim: To select the optimal dose with a subsequent assessment of the safety of iRAS when administered to patients with gastrointestinal tract tumors, including those with peritoneal carcinomatosis. Materials and methods: This was a prospective open-label non-randomized phase I study for the assessment of safety and tolerability, with an adaptive design and determination of the maximally tolerated dose of the iRAS. Three dose levels were used (0.45 mg/kg, 0.9 mg/kg, 1.8 mg/kg) according to the "3 + 3" scheme. The study included 11 patients after surgery for stomach or colorectal cancer. The patients were administered PIPAC therapy with iRAS twice with a 7-days interval. The study duration was 28 ± 1 days. During the study, the patient monitoring included physical examination, assessment of vital signs, electrocardiography and echocardiography, laboratory parameters (hematology, clinical chemistry, coagulation tests, and urine analysis). Results: The anti-tumor iRAS agent demonstrated satisfactory tolerability of all doses studied, including the maximal 1.8 mg/kg dose. Vital sign and laboratory abnormalities were clinically non-significant and did not require additional therapeutic interventions. Statistically significant abnormalities were registered for total protein (p = 0.00028), white blood cell counts (p = 0.007), lymphocyte counts (p = 0.0008), and a number of other blood parameters; however, most of these abnormalities were within the physiological normal ranges. Vital signs such as electrocardiography and echocardiography parameters remained stable throughout the entire follow-up period (28 days after administration of the drug). There were short-term rises in body temperature, minor pains in the postoperative scar area. Conclusion: This trial of safety and tolerability of iRAS showed that no cases of dose-limiting toxicity in the studied dose range. The 1.8 mg/kg dose can be recommended for further clinical studies. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | Russian |
| تدمد: | 2072-0505 2587-9294 |
| Relation: | https://almclinmed.ru/jour/article/viewFile/17182/1625; https://doaj.org/toc/2072-0505; https://doaj.org/toc/2587-9294 |
| DOI: | 10.18786/2072-0505-2023-51-045 |
| URL الوصول: | https://doaj.org/article/13cae4f84e954f659bf2b1c7fc510fad |
| رقم الانضمام: | edsdoj.13cae4f84e954f659bf2b1c7fc510fad |
| قاعدة البيانات: | Directory of Open Access Journals |
| تدمد: | 20720505 25879294 |
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| DOI: | 10.18786/2072-0505-2023-51-045 |