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

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 10 Pg. 3503-10 (May 15 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19417014 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Dideoxynucleosides
• Purines
• rabacfosadine
• Alanine
• alovudine

Topics

• Alanine (analogs & derivatives, blood, pharmacokinetics, therapeutic use)
• Animals
• Animals, Domestic
• Anorexia (chemically induced)
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• Diarrhea (chemically induced)
• Dideoxynucleosides
• Disease Models, Animal
• Dog Diseases (drug therapy, metabolism, pathology)
• Dogs
• Drug Administration Schedule
• Female
• Humans
• Kaplan-Meier Estimate
• Lymphoma, Non-Hodgkin (metabolism, pathology, veterinary)
• Male
• Metabolic Clearance Rate
• Nausea (chemically induced)
• Positron-Emission Tomography (methods)
• Purines (blood, pharmacokinetics, therapeutic use)
• Tissue Distribution
• Tomography, X-Ray Computed
• Treatment Outcome
• Weight Loss (drug effects)