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


METHODS
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.
Department of Medical Sciences, School of Veterinary Medicine and the Paul P Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53706, USA. vaild@svm.vetmed.wisc.edu
David M
DM
Vail
Douglas H
DH
Thamm
Hans
H
Reiser
Adrian S
AS
Ray
Grushenka H I
GH
Wolfgang
William J
WJ
Watkins
Darius
D
Babusis
Ilana N
IN
Henne
Michael J
MJ
Hawkins
Ilene D
ID
Kurzman
Robert
R
Jeraj
Matt
M
Vanderhoek
Susan
S
Plaza
Christie
C
Anderson
Mackenzie A
MA
Wessel
Cecilia
C
Robat
Jessica
J
Lawrence
Daniel B
DB
Tumas
D000409:Alanine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000829:Animals, Domestic; D000855:Anorexia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D003967:Diarrhea / Q000139:chemically induced; D015224:Dideoxynucleosides; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000473:pathology / Q000662:veterinary*; D008297:Male; D008657:Metabolic Clearance Rate; D009325:Nausea / Q000139:chemically induced; D049268:Positron-Emission Tomography / Q000379:methods; D011687:Purines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects
D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D011687:Purines; C531423:rabacfosadine; D000409:Alanine; C002854:alovudine