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

David M. Vail, 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

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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′-18F-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′-18F-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.

Original languageEnglish (US)
Pages (from-to)3503-3510
Number of pages8
JournalClinical Cancer Research
Volume15
Issue number10
DOIs
StatePublished - May 15 2009

Fingerprint Dive into the research topics of 'Assessment of GS-9219 in a pet dog model of non-Hodgkin's lymphoma'. Together they form a unique fingerprint.

Cite this