دورية أكاديمية
PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours
| العنوان: | PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours |
|---|---|
| المؤلفون: | McKeage Mark J, Jameson Michael B, Ramanathan Ramesh K, Rajendran Joseph, Gu Yongchuan, Wilson William R, Melink Teresa J, Tchekmedyian N |
| المصدر: | BMC Cancer, Vol 12, Iss 1, p 496 (2012) |
| بيانات النشر: | BMC |
| سنة النشر: | 2012 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: | Background The purpose of this phase Ib clinical trial was to determine the maximum tolerated dose (MTD) of PR-104 a bioreductive pre-prodrug given in combination with gemcitabine or docetaxel in patients with advanced solid tumours. Methods PR-104 was administered as a one-hour intravenous infusion combined with docetaxel 60 to 75 mg/m 2 on day one given with or without granulocyte colony stimulating factor (G-CSF) on day two or administrated with gemcitabine 800 mg/m 2 on days one and eight, of a 21-day treatment cycle. Patients were assigned to one of ten PR-104 dose-levels ranging from 140 to 1100 mg/m 2 and to one of four combination groups. Pharmacokinetic studies were scheduled for cycle one day one and 18 F fluoromisonidazole (FMISO) positron emission tomography hypoxia imaging at baseline and after two treatment cycles. Results Forty two patients (23 females and 19 males) were enrolled with ages ranging from 27 to 85 years and a wide range of advanced solid tumours. The MTD of PR-104 was 140 mg/m 2 when combined with gemcitabine, 200 mg/m 2 when combined with docetaxel 60 mg/m 2 , 770 mg/m 2 when combined with docetaxel 60 mg/m 2 plus G-CSF and ≥770 mg/m 2 when combined with docetaxel 75 mg/m 2 plus G-CSF. Dose-limiting toxicity (DLT) across all four combination settings included thrombocytopenia, neutropenic fever and fatigue. Other common grade three or four toxicities included neutropenia, anaemia and leukopenia. Four patients had partial tumour response. Eleven of 17 patients undergoing FMISO scans showed tumour hypoxia at baseline. Plasma pharmacokinetics of PR-104, its metabolites (alcohol PR-104A, glucuronide PR-104G, hydroxylamine PR-104H, amine PR-104M and semi-mustard PR-104S1), docetaxel and gemcitabine were similar to that of their single agents. Conclusions Combination of PR-104 with docetaxel or gemcitabine caused dose-limiting and severe myelotoxicity, but prophylactic G-CSF allowed PR-104 dose escalation with docetaxel. Dose-limiting thrombocytopenia prohibited further ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1471-2407 |
| العلاقة: | http://www.biomedcentral.com/1471-2407/12/496Test; https://doaj.org/toc/1471-2407Test; https://doaj.org/article/075b31c154344b5aab6a4555bbaa90f2Test |
| DOI: | 10.1186/1471-2407-12-496 |
| الإتاحة: | https://doi.org/10.1186/1471-2407-12-496Test https://doaj.org/article/075b31c154344b5aab6a4555bbaa90f2Test |
| رقم الانضمام: | edsbas.82A3D1DD |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 14712407 |
|---|---|
| DOI: | 10.1186/1471-2407-12-496 |