PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours

BMC Cancer

Research Article

N Simon Tchekmedyian¹  Teresa J Melink²  Yongchuan Gu³  William R Wilson³  Mark J McKeage⁴  Joseph Rajendran⁵  Ramesh K Ramanathan⁶  Michael B Jameson⁷ 

[1] Pacific Shores Medical Group, Long Beach, CA, USA;Proacta Inc, San Diego, CA, USA;The University of Auckland, Auckland, New Zealand;The University of Auckland, Auckland, New Zealand;Department of Pharmacology and Clinical Pharmacology and the Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, 85 Park Road Grafton, 1142, Auckland, New Zealand;University of Washington, Seattle, WA, USA;Virginia G Piper Cancer Center & TGEN, Scottsdale, AZ, USA;Waikato Hospital, Hamilton, Waikato, New Zealand;

关键词: Docetaxel;    Gemcitabine;    Granulocyte Colony Stimulate Factor;    Maximum Tolerate Dose;    Tumour Hypoxia;   

DOI  :  10.1186/1471-2407-12-496

 received in 2012-07-02, accepted in 2012-10-23,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsPR-104 was administered as a one-hour intravenous infusion combined with docetaxel 60 to 75 mg/m2 on day one given with or without granulocyte colony stimulating factor (G-CSF) on day two or administrated with gemcitabine 800 mg/m2 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/m2 and to one of four combination groups. Pharmacokinetic studies were scheduled for cycle one day one and 18F fluoromisonidazole (FMISO) positron emission tomography hypoxia imaging at baseline and after two treatment cycles.ResultsForty 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/m2 when combined with gemcitabine, 200 mg/m2 when combined with docetaxel 60 mg/m2, 770 mg/m2 when combined with docetaxel 60 mg/m2 plus G-CSF and ≥770 mg/m2 when combined with docetaxel 75 mg/m2 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.ConclusionsCombination 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 evaluation of the PR104-gemcitabine combination. A recommended dose was identified for phase II trials of PR-104 of 770 mg/m2 combined with docetaxel 60 to 75 mg/m2 both given on day one of a 21-day treatment cycle supported by prophylactic G-CSF (NCT00459836).

【 授权许可】

CC BY   
© McKeage et al.; licensee BioMed Central Ltd. 2012