Assessment of GS-9219 in a pet dog model of non-Hodgkin's lymphoma

  • Clin Cancer Res. 2009 May 15;15(10):3503-10. doi: 10.1158/1078-0432.CCR-08-3113.
David M Vail  1 ,  Douglas H Thamm ,  Hans Reiser ,  Adrian S Ray ,  Grushenka H I Wolfgang ,  William J Watkins ,  Darius Babusis ,  Ilana N Henne ,  Michael J Hawkins ,  Ilene D Kurzman ,  Robert Jeraj ,  Matt Vanderhoek ,  Susan Plaza ,  Christie Anderson ,  Mackenzie A Wessel ,  Cecilia Robat ,  Jessica Lawrence ,  Daniel B Tumas
Affiliations
  • 1. Department of Medical Sciences, School of Veterinary Medicine and the Paul P Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53706, USA. [email protected]
PMID: 19417014 DOI: 10.1158/1078-0432.CCR-08-3113
Abstract

Purpose: To assess, in dogs with naturally occurring non-Hodgkin's lymphoma, pharmacokinetics, safety, and activity of GS-9219, a prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG), which delivers PMEG and its phosphorylated metabolites to lymphoid cells with preferential cytotoxicity in cells with a high proliferation index such as lymphoid malignancies.

Experimental design: To generate proof-of-concept, a phase I/II trial was conducted in pet dogs (n = 38) with naturally occurring non-Hodgkin's lymphoma using different dose schedules of GS-9219. A subset of dogs was further evaluated with 3'-deoxy-3'-(18)F-fluorothymidine positron emission tomography/computed tomography imaging before and after treatment.

Results: The prodrug had a short plasma half-life but yielded high and prolonged intracellular levels of the cytotoxic metabolite PMEG diphosphate in peripheral blood mononuclear cells in the absence of detectable plasma PMEG. Dose-limiting toxicities were generally manageable and reversible and included dermatopathy, neutropenia, and gastrointestinal signs. Antitumor responses were observed in 79% of dogs and occurred in previously untreated dogs and dogs with chemotherapy-refractory non-Hodgkin's lymphoma. The median remission durations observed compare favorably with Other monotherapies in dogs with non-Hodgkin's lymphoma. High 3'-deoxy-3'-(18)F-fluorothymidine uptake noted in lymphoid tissues before treatment decreased significantly after treatment (P = 0.016).

Conclusions: GS-9219 was generally well tolerated and showed significant activity against spontaneous non-Hodgkin's lymphoma as modeled in pet dogs and, as such, supports clinical evaluation in humans.

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