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Cancer Chemotherapy and Pharmacology

, Volume 65, Issue 4, pp 791–801 | Cite as

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

  • Michael B. Jameson
  • Danny Rischin
  • Mark Pegram
  • John Gutheil
  • Adam V. Patterson
  • William A. Denny
  • William R. Wilson
Clinical Trial Report

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/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.

Keywords

PR-104 Hypoxia Prodrug Dinitrobenzamide nitrogen mustard Phase I 

Notes

Acknowledgments

We thank the patients who participated in this trial and the research staff for their assistance in patient care and their dedication to clinical trials. We also thank Kashyap Patel and Prof. Nick Holford for advice on pharmacokinetic analysis, and Terri Melink for assistance with preparation of the manuscript. Financial support for this trial was provided by Proacta, Inc.

Conflicts of interest statement

No financial conflict exists for authors M.B.J., D.R., and M.P. The following authors have indicated a potential conflict of interest: J.G. is employed by Proacta Inc. with stock ownership; A.V.P is a consultant to Proacta Inc.; and W.A.D. and W.R.W. are consultants/played an advisory role to Proacta Inc. and have stock ownership and received research funding.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Michael B. Jameson
    • 1
  • Danny Rischin
    • 2
  • Mark Pegram
    • 3
  • John Gutheil
    • 4
  • Adam V. Patterson
    • 5
  • William A. Denny
    • 5
  • William R. Wilson
    • 5
  1. 1.Regional Cancer CentreWaikato HospitalHamiltonNew Zealand
  2. 2.Peter MacCallum Cancer CentreMelbourneAustralia
  3. 3.University of California, Los AngelesLos AngelesUSA
  4. 4.Proacta Inc.San DiegoUSA
  5. 5.Auckland Cancer Society Research CentreThe University of AucklandAucklandNew Zealand

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