A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patientsReportar como inadecuado




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BMC Cancer

, 11:432

Clinical oncology

Abstract

BackgroundThe 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 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.

MethodsPatients 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 3 pts, 270 mg-m 6 pts, 540 mg-m 6 pts, 675 mg-m 7 pts and 900 mg-m 4 pts for a median of two treatment cycles range, 1 to 7 cycles and five infusions range, 1 to 18 per patient.

ResultsDose-limiting toxicities DLTs during cycle one included grade four thrombocytopenia at 540 mg-m 1 of 6 pts and grade four thrombocytopenia and neutropenia at 900 mg-m 2 of 4 pts. At an intermediate dose of 675 mg-m, 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 an oxidative semi-mustard metabolite PR-104S1, but no more strongly than with PR-104 dose-level. There was no significant correlation between plasma AUC for the reduced metabolites and myelotoxicity.

ConclusionsThrombocytopenia, and to a lesser extent neutropenia, was the DLT of weekly PR-104. The MTD was 675 mg-m-week. PR-104 given weekly may be a suitable protocol for further clinical evaluation as a short course of treatment with fractionated radiotherapy or haematopoietic stem cell support, as its duration of dosing is restricted by delayed-onset and protracted thrombocytopenia.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-11-432 contains supplementary material, which is available to authorized users.

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Autor: Mark J McKeage - Yongchuan Gu - William R Wilson - Andrew Hill - Karen Amies - Teresa J Melink - Michael B Jameson

Fuente: https://link.springer.com/







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