dc.contributor.author |
Jameson, Michael |
en |
dc.contributor.author |
Rischin, D |
en |
dc.contributor.author |
Pegram, M |
en |
dc.contributor.author |
Gutheil, J |
en |
dc.contributor.author |
Patterson, Adam |
en |
dc.contributor.author |
Denny, William |
en |
dc.contributor.author |
Wilson, William |
en |
dc.date.accessioned |
2011-11-17T17:13:11Z |
en |
dc.date.issued |
2010-03 |
en |
dc.identifier.citation |
Cancer Chemotherapy and Pharmacology 65(4):791-801 2009 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/9212 |
en |
dc.description.abstract |
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/m(2). The MTD of PR-104 as a single-dose infusion every 3 weeks was established as 1,100 mg/m(2). One of six patients treated at 1,100 mg/m(2) experienced DLT of grade 3 fatigue. Above the MTD, the DLTs at 1,400 mg/m(2) 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 > or = 550 mg/m(2). 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/m(2) 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/m(2) and further trials are underway |
en |
dc.relation.ispartofseries |
Cancer Chemother.Pharmacol. |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from
http://www.sherpa.ac.uk/romeo/issn/0344-5704/ |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
administration & dosage |
en |
dc.subject |
Adult |
en |
dc.subject |
adverse effects |
en |
dc.subject |
Aged |
en |
dc.subject |
Anemia |
en |
dc.subject |
Area Under Curve |
en |
dc.subject |
chemically induced |
en |
dc.subject |
chemistry |
en |
dc.subject |
drug therapy |
en |
dc.subject |
Fatigue |
en |
dc.subject |
Female |
en |
dc.subject |
Humans |
en |
dc.subject |
Hypoxia |
en |
dc.subject |
Infusions,Intravenous |
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dc.subject |
Male |
en |
dc.subject |
Metabolic Clearance Rate |
en |
dc.subject |
metabolism |
en |
dc.subject |
methods |
en |
dc.subject |
Middle Aged |
en |
dc.subject |
Molecular Structure |
en |
dc.subject |
Multienzyme Complexes |
en |
dc.subject |
Neoplasms |
en |
dc.subject |
Neutropenia |
en |
dc.subject |
New Zealand |
en |
dc.subject |
Nitrogen Mustard Compounds |
en |
dc.subject |
pathology |
en |
dc.subject |
pharmacokinetics |
en |
dc.subject |
Prodrugs |
en |
dc.subject |
Treatment Outcome |
en |
dc.title |
A phase I trial of PR-104, a nitrogen mustard prodrug activated by both hypoxia and aldo-keto reductase 1C3, in patients with solid tumors |
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dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1007/s00280-009-1188-1 |
en |
pubs.issue |
4 |
en |
pubs.begin-page |
791 |
en |
pubs.volume |
65 |
en |
dc.rights.holder |
Copyright: Springer-Verlag |
en |
dc.identifier.pmid |
20012293 |
en |
pubs.end-page |
801 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
JOUR |
en |
pubs.elements-id |
99272 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
School of Medicine |
en |
pubs.org-id |
Waikato Clinical school |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
pubs.dimensions-id |
20012293 |
en |