دورية أكاديمية
A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients
| العنوان: | A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients |
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| المؤلفون: | Amies Karen, Hill Andrew, Wilson William R, Gu Yongchuan, McKeage Mark J, Melink Teresa J, Jameson Michael B |
| المصدر: | BMC Cancer, Vol 11, Iss 1, p 432 (2011) |
| بيانات النشر: | BMC |
| سنة النشر: | 2011 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: | Background The phosphate ester PR-104 is rapidly converted in vivo to the alcohol PR-104A, a nitrogen mustard prodrug that is metabolised to hydroxylamine (PR-104H) and amine (PR-104M) DNA crosslinking agents by one-electron reductases in hypoxic cells and by aldo-keto reductase 1C3 independently of oxygen. In a previous phase I study using a q 3 week schedule of PR-104, the maximum tolerated dose (MTD) was 1100 mg/m 2 and fatigue, neutropenic fever and infection were dose-limiting. The primary objective of the current study was to determine the dose-limiting toxicity (DLT) and MTD of weekly PR-104. Methods Patients with advanced solid tumours received PR-104 as a 1-hour intravenous infusion on days 1, 8 and 15 every 28 days with assessment of pharmacokinetics on cycle 1 day 1. Twenty-six patients (pts) were enrolled (16 male/10 female; median age 58 yrs, range 30 to 70 yrs) who had received a median of two prior chemotherapy regimens (range, 0 to 3) for melanoma (8 pts), colorectal or anal cancer (3 pts), NSCLC (3 pts), sarcoma (3 pts), glioblastoma (2 pts), salivary gland tumours (2 pts) or other solid tumours (5 pts). PR-104 was administered at 135 mg/m 2 (3 pts), 270 mg/m 2 (6 pts), 540 mg/m 2 (6 pts), 675 mg/m 2 (7 pts) and 900 mg/m 2 (4 pts) for a median of two treatment cycles (range, 1 to 7 cycles) and five infusions (range, 1 to 18) per patient. Results Dose-limiting toxicities (DLTs) during cycle one included grade four thrombocytopenia at 540 mg/m 2 (1 of 6 pts) and grade four thrombocytopenia and neutropenia at 900 mg/m 2 (2 of 4 pts). At an intermediate dose of 675 mg/m 2 , there were no DLTs among a total of seven patients given 12 treatment cycles but all experienced moderate to severe (grade 2 to 4) haematological toxicity. Thrombocytopenia was delayed in its onset and nadir, and its recovery was protracted and incomplete in many patients. There were no complete or partial tumour responses. PR-104-induced thrombocytopenia and neutropenia correlated with plasma AUC of PR-104, PR-104A and ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1471-2407 |
| العلاقة: | http://www.biomedcentral.com/1471-2407/11/432Test; https://doaj.org/toc/1471-2407Test; https://doaj.org/article/d2c3a3579d074af3a69897eb9abdeb8fTest |
| DOI: | 10.1186/1471-2407-11-432 |
| الإتاحة: | https://doi.org/10.1186/1471-2407-11-432Test https://doaj.org/article/d2c3a3579d074af3a69897eb9abdeb8fTest |
| رقم الانضمام: | edsbas.9425DCC3 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 14712407 |
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| DOI: | 10.1186/1471-2407-11-432 |