Rabacfosadine for naïve canine intermediate to large cell lymphoma: Efficacy and adverse event profile across three prospective clinical trials

Abstract

While current lymphoma therapies induce remission in most dogs, drug-resistant relapse is common, creating a need for novel agents. Rabacfosadine (RAB), a double prodrug of the acyclic nucleotide phosphonate 9-(2-phosphonylmethoxyethel) guanine (PMEG), preferentially targets lymphoma cells with reduced systemic toxicity compared with PMEG. Previous studies evaluating RAB administered every 21 days have suggested efficacy in both naïve and relapsed subjects; however, no large studies of RAB as a single agent have been reported in previously untreated dogs with intermediate to large cell lymphoma. The purpose of this study was to evaluate the safety and efficacy of RAB in dogs with previously untreated (excluding corticosteroids) lymphoma. Sixty-three dogs received up to five RAB treatments every 21 days (16 at 0.82 mg/kg and 47 at 1.0 mg/kg) as a 30 minutes intravenous infusion, with (n = 23) or without (n = 40) concurrent corticosteroids. Response assessment and adverse event (Ae) evaluation were performed every 21 days via Veterinary Cooperative Oncology Group (VCOG) criteria. The overall response rate was 87% (52% CR, 35% PR). The overall median progression free interval was 122 days (199 for CR, 89 for PR and 153 days for all responders). T-cell immunophenotype and corticosteroid pretreatment were predictive of inferior outcomes on multivariate analysis. AEs were most commonly of gastrointestinal origin (hyporexia/diarrhoea) and generally resolved with supportive treatment and/or dosage adjustment. Three dogs experienced VCOG-CTCAE grade 5 delayed pulmonary fibrosis. In conclusion, RAB administered every 3 weeks is generally well tolerated and demonstrates substantial antitumour activity in dogs with previously untreated intermediate to large cell lymphoma.

Predicting likelihood of in vivo chemotherapy response in canine lymphoma using ex vivo drug sensitivity and immunophenotyping data in a machine learning model

“…Patients treated with rabacfosadine in our study were also more likely to have stage 4 or higher disease (36% vs 19%‐24% in other treatment cohorts; Table 1). This prevalence of high‐stage disease in our rabacfosadine cohort translated to a positive response rate lower than that reported in clinical trials (54% vs 74%‐87%) 6,9 …”

“…We modelled in vivo drug responses to five common chemotherapeutic agents that have direct cytotoxic effects in canine lymphoma cells: doxorubicin, vincristine, cyclophosphamide, lomustine, and rabacfosadine 1,6 . Model performance was evaluated with a variety of measures, including ROC‐AUC, representing a model's ability to discriminate between positive and negative responses; Brier score, a proper scoring function that represents the error between probabilistic predictions and actual outcomes; and Brier skill score, which compares the Brier score for a drug response model to the prevalence of positive responses in our data set.…”

“…Treatment regimens typically combine cyclophosphamide, doxorubicin, vincristine, and prednisone—collectively known as CHOP—which results in a clinical remission rate of 73% to 96% and overall survival time of 275 to 344 days for high‐grade lymphomas 4,5 . Recently, a novel antineoplastic drug called rabacfosadine (TANOVEA‐CA1) has also become available; an overall response rate of 87% and median progression free interval of 122 days were reported for naïve canine multicentric lymphoma treated with single agent rabacfosadine 6 . With the failure of first‐line protocols or relapse, rescue treatments are considered, with lomustine being a key component of many rescue protocols 7,8 .…”

Life-long passion for antiviral research and drug development: 80th birthday of Prof. Dr. Erik De Clercq

“…The efficacy and safety of rabacfosadine have been reported by several clinical studies in dogs [94] , [95] , [96] , [97] . The clinical efficacy of rabacfosadine was often measured by the overall response rate of dogs experiencing either partial responses or complete responses during the post-treatment period [94] , [95] , [96] , [97] . In the treatment of T-cell lymphoma using the 1 mg/kg dose of rabacfosadine, the clinical efficacy was 47% (8/17) and 50% (2/4) in the treatment-naive and treatment-experienced dogs, respectively ( Fig.…”

“… Disease Treatment & Subjects Clinical efficacy* Ref. T-cell lymphoma 1mg/kg Treatment-experienced dogs 50% (2/4) [95] 1mg/kg Treatment-naive dogs 43% (3/7) [95] 1 mg/kg Treatment-naive dogs 50% (5/10) [94] 0.82 mg/kg Treatment-naive dogs 50% (2/4) [94] B-cell lymphoma 1 mg/kg Treatment-experienced dogs 77% (24/31) [96] 0.82 mg/kg Treatment-experienced dogs 69% (11/16) [96] 1 mg/kg Treatment-naive dogs 97% (29/30) [94] 0.82 mg/kg Treatment-naive dogs 100% (11/11) [94] non-Hodgkin's lymphoma 0.66 mg/kg Treatment-naive dogs # 67% (2/3) [97] 0.82 mg/kg Treatment-naive dogs # 50% (2/4) [97] &: A 30-minute intravenous infusion of rabacfosadine was administered once every 3 weeks for 5 doses *: Clinical efficacy was defined by the overall response rate of dogs experiencing either partial responses or complete responses during the post-treatment period. #: Previous treatment was allowable with ≥ three-week washouts from the most recent therapy.…”