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Patel K.,University of Auckland | Choy S.S.F.,University of Auckland | Hicks K.O.,University of Auckland | Melink T.J.,Proacta Inc. | And 2 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2011

Background: PR-104 is a phosphate ester that is systemically converted to the corresponding alcohol PR-104A. The latter is activated by nitroreduction in tumours to cytotoxic DNA cross-linking metabolites. Here, we report a population pharmacokinetic (PK) model for PR-104 and PR-104A in non-human species and in humans. Methods: A compartmental model was used to fit plasma PR-104 and PR-104A concentration-time data after intravenous (i.v.) dosing of humans, Beagle dogs, Sprague-Dawley rats and CD-1 nude mice. Intraperitoneal (i.p.) PR-104 and i.v. PR-104A dosing of mice was also investigated. Protein binding was measured in plasma from each species. Unbound drug clearances and volumes were scaled allometrically. Results: A two-compartment model described the disposition of PR-104 and PR-104A in all four species. PR-104 was cleared rapidly by first-order (mice, rats, dogs) or mixed-order (humans) metabolism to PR-104A in the central compartment. The estimated unbound human clearance of PR104A was 211 L/h/70 kg, with a steady state unbound volume of 105 L/70 kg. The size equivalent unbound PR-104A clearance was 2.5 times faster in dogs, 0.78 times slower in rats and 0.63 times slower in mice, which may reflect reported species differences in PR-104A O-glucuronidation. Conclusions: The PK model demonstrates faster size equivalent clearance of PR-104A in dogs and humans than rodents. Dose-limiting myelotoxicity restricts the exposure of PR-104A in humans to approximately 25% of that achievable in mice. © 2010 Springer-Verlag. Source


Guise C.P.,University of Auckland | Abbattista M.R.,University of Auckland | Singleton R.S.,University of Auckland | Holford S.D.,University of Auckland | And 9 more authors.
Cancer Research | Year: 2010

PR-104, currently in phase II clinical trials, is a phosphate ester pre-prodrug which is converted in vivo to its cognate alcohol, PR-104A, a prodrug designed to exploit tumor hypoxia. Bioactivation occurs via one-electron reduction to DNA crosslinking metabolites in the absence of oxygen. However, certain tumor cell lines activate PR-104A in the presence of oxygen, suggesting the existence of an aerobic nitroreductase. Microarray analysis identified a cluster of five aldo-keto reductase (AKR) family members whose expressions correlated with aerobic metabolism of PR-104A. Plasmid-based expression of candidate genes identified aldo-keto reductase 1C3 as a novel nitroreductase. AKR1C3 protein was detected by Western blot in 7 of 23 cell lines and correlated with oxic PR-104A metabolism, an activity which could be partially suppressed by Nrf2 RNAi knockdown (or induced by Keap1 RNAi), indicating regulation by the ARE pathway. AKR1C3 was unable to sensitize cells to 10 other bioreductive prodrugs and was associated with single-agent PR-104 activity across a panel of 9 human tumor xenograft models. Overexpression in two AKR1C3-negative tumor xenograft models strongly enhanced PR-104 antitumor activity. A population level survey of AKR1C3 expression in 2,490 individual cases across 19 cancer types using tissue microarrays revealed marked upregulation of AKR1C3 in a subset including hepatocellular, bladder, renal, gastric, and non-small cell lung carcinoma. A survey of normal tissue AKR1C3 expression suggests the potential for tumor-selective PR-104A activation by this mechanism. These findings have significant implications for the clinical development of PR-104. ©2010 AACR. Source


Jameson M.B.,Regional Cancer Center | Rischin D.,Peter MacCallum Cancer Center | Pegram M.,University of California at Los Angeles | Gutheil J.,Proacta Inc. | And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2010

Purpose: PR-104 is a "pre-prodrug" designed to be activated to a dinitrobenzamide nitrogen mustard cytotoxin by nitroreduction in hypoxic regions of tumors. This study was conducted to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetics (PK) of PR-104 in patients with advanced solid tumors. Methods: Patients with solid tumors refractory or not amenable to conventional treatment were evaluated in a dose-escalation trial of PR-104 administered as a 1-h intravenous (IV) infusion every 3 weeks. The plasma PK of PR-104 and its primary metabolite, PR-104A, were evaluated. Results: Twenty-seven patients received a median of two cycles of PR-104 in doses ranging from 135 to 1,400 mg/m2. The MTD of PR-104 as a single-dose infusion every 3 weeks was established as 1,100 mg/m2. One of six patients treated at 1,100 mg/m2 experienced DLT of grade 3 fatigue. Above the MTD, the DLTs at 1,400 mg/m2 were febrile neutropenia and infection with normal absolute neutrophil count. No objective responses were observed, although reductions in tumor size were observed in patients treated at doses ≥550 mg/m2. The plasma PK of PR-104 demonstrated rapid conversion to PR-104A, with approximately dose-linear PK of both species. Conclusions: PR-104 was well tolerated at a dose of 1,100 mg/m2 administered as an IV infusion every 3 weeks. The area under the PR-104A plasma concentration-time curve at this dose exceeded that required for activity in human tumor cell cultures and xenograft models. The recommended dose of PR-104 as a single agent for phase II trials is 1,100 mg/m2 and further trials are underway. © 2009 Springer-Verlag. Source


McKeage M.J.,University of Auckland | Jameson M.B.,Waikato Hospital | Ramanathan R.K.,Virginia per Cancer Center and | Rajendran J.,University of Washington | And 4 more authors.
BMC Cancer | Year: 2012

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). © 2012 McKeage et al.; licensee BioMed Central Ltd. Source


Abou-Alfa G.K.,Sloan Kettering Cancer Center | Chan S.L.,Chinese University of Hong Kong | Lin C.-C.,National Taiwan University Hospital | Chiorean E.G.,Indiana University | And 8 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2011

Purpose: PR-104 is activated by reductases under hypoxia or by aldo-keto reductase 1C3 (AKR1C3) to form cytotoxic nitrogen mustards. Hepatocellular carcinoma (HCC) displays extensive hypoxia and expresses AKR1C3. This study evaluated the safety and efficacy of PR-104 plus sorafenib in HCC. Methods: Patients with advanced-stage HCC, Child-Pugh A cirrhosis, and adequate organ function, were assigned to dose escalating cohorts of monthly PR-104 in combination with twice daily sorafenib. The plasma pharmacokinetics (PK) of PR-104 and its metabolites were evaluated. Results: Fourteen (11 men, 3 women) HCC patients: median age 60 years, ECOG 0-1, received PR-104 at two dose levels plus sorafenib. Six patients were treated at starting cohort of 770 mg/m 2. In view of one DLT of febrile neutropenia and prolonged thrombocytopenia, a lower PR-104 dose cohort (550 mg/m2) was added and accrued 8 patients. One patient had a partial response and three had stable disease of ≥8 weeks in the 770 mg/m2 cohort. Three patients at the 550 mg/m2 had stable disease. There were no differences in PK of PR-104 or its metabolites with or without sorafenib, but the PR-104A AUC was twofold higher (P < 0.003) than in previous phase I studies at equivalent dose. Conclusions: PR-104 plus sorafenib was poorly tolerated in patients with advanced HCC, possibly because of compromised clearance of PR-104A in this patient population. Thrombocytopenia mainly and neutropenia were the most clinically significant toxicities and led to discontinuation of the study. PR-104 plus sorafenib is unlikely to be suitable for development in this setting. © 2011 Springer-Verlag. Source

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