Abstract

Non-Hodgkin’s lymphoma (NHL) is the fifth leading cause of cancer deaths and the second fastest growing form of cancer in the United States. While clinical remission can be induced using currently available antineoplastic agents, drug resistant relapse is common. Canine NHL has proven to be a relevant model for preclinical testing of novel therapeutics prior to human trials. GS-9219, a novel double prodrug of the anti-proliferative nucleotide analog 9-(2-phosphonylmethoxyethyl) guanine (PMEG), has been shown to have potent cytotoxic activity in lymphoblasts and leukemia cell lines and was designed to load and functionally target malignant lymphoid cell populations upon intravenous administration. To generate proof-of-concept, activity and safety data in lymphoid malignancies, a dose-finding and activity trial with GS-9219 monotherapy was initiated in pet dogs (N = 38) with naturally occurring chemotherapy naïve or refractory NHL. Dose cohorts of 3 to 6 dogs were treated using several schedules including daily treatments for 5 consecutive days out of every 21 days, once weekly, once biweekly and once every 3 weeks. Adverse events, when observed, were manageable and reversible, dose- and regimen-dependent and included predominantly Grade 1 to 2 transient neutropenia, gastrointestinal signs, lethargy, dermatopathy and proteinuria. Major antitumor responses were noted in 79% of dogs treated with GS-9219 monotherapy (61% complete and 18% partial responses) as measured by tumor size (RECIST criteria). Responses were similar across the different treatment regimens evaluated. Importantly, responses were noted in both previously untreated dogs (N=16) and dogs with chemotherapy-refractory NHL (N=22), implying a role both in induction therapy and in the rescue of drug resistant disease. B and T cell phenotypes were both found to respond to GS-9219 therapy; however, first remission durations were significantly longer in dogs with B cell NHL. The overall median first remission duration of 4.5 months observed compares favorably to other monotherapies reported in dogs with NHL. Furthermore, in dogs retreated with GS-9219 after recrudescence of their NHL, 78% achieved a second remission. A subset of nine dogs were further evaluated with 18F-fluorothymidine (FLT) PET/CT imaging prior to and after their first treatment with GS-9219; 8 of 9 displayed initially high FLT uptake (mean standardized uptake values [SUV] of 81.55) prior to treatment which decreased significantly after GS-9219 monotherapy (SUV of 13.39; p < 0.05). Given these very promising results in this relevant preclinical model, a Phase I study of GS-9219 in humans with NHL has been initiated.

Author notes

Disclosure:Employment: Authors listed from Gilead Sciences, Inc are employees of said company. Ownership Interests:; Authors listed from Gilead Sciences, Inc have ownership interest in Gilead, Inc. Research Funding: The research presented was entirely funded by Gilead Sciences, Inc.