Abstract
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).
Highlights
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
Previous single agent phase I clinical trials of PR104 given as a one hour intravenous infusion identified thrombocytopenia, neutropenia, infection and fatigue as its dose-limiting toxicities (DLTs) and a maximum tolerated dose (MTD) of 1100 mg/m2 given once every 21 days [7] or 675 mg/m2 given on days 1, 8 and 15 every 28 days [8]
Study treatment assignment Serial patient cohorts, comprising of three or six subjects in each, were assigned to one of ten different PR-104 dose-levels ranging from 140 to 1100 mg/m2 given as a one hour intravenous infusion on day one of a 21 day treatment cycle (Table 2)
Summary
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. Docetaxel and gemcitabine are approved agents for the treatment of a wide range of human malignancies, including breast, head and neck, non-small cell lung, ovarian, pancreatic and prostate cancer [9,10], but their clinical efficacy may be limited by their inability to effectively treat hypoxic areas of tumours [11,12]. These considerations led us to undertake this phase Ib, multicentre, open label, serial cohort, non-randomized, uncontrolled trial of PR-104 given in combination with docetaxel or gemcitabine in patients with advanced solid tumours. This imaging technique noninvasively demonstrates anatomical regions of high F-MISO uptake and hypoxia [13], whose detection may be predictive of the therapeutic efficacy of hypoxia-activated antitumour therapies
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