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Open Access Research article

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

Mark J McKeage17*, Michael B Jameson2, Ramesh K Ramanathan3, Joseph Rajendran4, Yongchuan Gu1, William R Wilson1, Teresa J Melink5 and N Simon Tchekmedyian6

Author Affiliations

1 The University of Auckland, Auckland, New Zealand

2 Waikato Hospital, Hamilton, Waikato, New Zealand

3 Virginia G Piper Cancer Center & TGEN, Scottsdale, AZ, USA

4 University of Washington, Seattle, WA, USA

5 Proacta Inc, San Diego, CA, USA

6 Pacific Shores Medical Group, Long Beach, CA, USA

7 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, Auckland, 1142, New Zealand

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BMC Cancer 2012, 12:496  doi:10.1186/1471-2407-12-496

Published: 25 October 2012

Abstract

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/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.

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/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.

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 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).