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.Non-Hodgkin's lymphoma is the fifth leading cause of cancer deaths and the second fastest-growing form of cancer in the United States. In the latest compilation of Surveillance, Epidemiology and End Results reports, the incidence and death rate for non-Hodgkin's lymphoma continue to increase despite an overall decrease in overall cancer incidence (1). Therefore, there is still a major unmet medical need in non-Hodgkin's lymphoma patients for novel agents with improved efficacy compared with existing treatment modalities, especially in patients who have failed frontline therapy.The acyclic nucleotide phosphonate 9-(2-phosphonylmethoxyethyl) guanine (PMEG) forms an active phosphorylated metabolite, PMEG diphosphate, in cells and causes cytotoxicity in dividing cells due to potent inhibition of the nuclear DNA polymerases α, δ, and ε by causing DNA chain termination, resulting in inhibition of DNA synthesis (2). In rodent

Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia

“…2) have been designed to increase permeability and accumulation of PMEGpp intracellularly (Kreider et al, 1990;Compton et al, 1999;Vail et al, 2009;Wolfgang et al, 2009). cPr-PMEDAP is converted to PMEG and can be considered as an intracellular prodrug of PMEG, limiting plasma exposure to the toxic agent PMEG.…”

“…GS-9219 showed substantial in vivo efficacy in five dogs with advanced-stage non-Hodgkin's lymphoma (NHL) after a single intravenous administration, with either no or low-grade adverse events (Reiser et al, 2008). In a Phase I/II trial conducted in pet dogs (n = 38) with naturally occurring NHL using different dose schedules of GS-9219, the compound was generally well tolerated and showed significant activity (Vail et al, 2009). Antitumor responses were observed in 79% of dogs and occurred in previously untreated dogs and dogs with chemotherapy-refractory NHL.…”

Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma

“…These studies have then been used to inform the design of further human clinical trials as well as determining treatment protocols in veterinary medicine. [25][26][27][28][29][30][31][32] Therefore, canine clinical trials are designed like and have the same objectives (e.g., a Phase I trial is intended to determine doses and assess pharmacokinetics) as human clinical trials but with the possibility of more rapid and complete assessments than is often possible in humans.…”

Animals-as-patients: Improving the Practice of Animal Experimentation

“…The recently completed description of the canine genome has provided a facility to include the comparative investigation of gene/ environment interactions in the etiology and treatment of many of the diseases we share with our animal companions (Ostrander 2000). On this basis there are a number of pilot studies and clinical trials being undertaken treating pet canines using drugs that have the potential to benefit human patients with similar types of cancer and malignancies (London et al 2009;Vail et al 2009). …”