rabacfosadine and Lymphoma

Tanovea® (first named GS-9219, then VDC-1101, generic name: rabacfosadine) is a pro-prodrug or "double" prodrug of PMEG [9-(2-phosphonylmethoxyethyl)guanine], which has been conditionally approved by the US FDA (Food and Drug Administration) for the treatment of lymphoma in dogs. Tanovea has been demonstrated to be effective against non-Hodgkin's lymphoma (NHL) in dogs, as well as canine cutaneous T-cell lymphoma, spontaneous canine multiple myeloma, naïve canine multicentric lymphoma and relapsed canine B-cell lymphoma. As a double prodrug of PMEG, GS-9219 is first converted intracellularly by hydrolysis to cPr-PMEDAP, then deaminated to PMEG, which is then phosphorylated twice to its active metabolite PMEGpp, acting at the level of the cellular DNA polymerases.

Topics: Alanine; Animals; Antineoplastic Agents; Dogs; Lymphoma; Prodrugs; Purines; Treatment Outcome

Rabacfosadine (RAB, Tanovea-CA1) is a novel chemotherapy agent conditionally approved for the treatment of lymphoma in dogs.. To determine the efficacy and safety of RAB in dogs with lymphoma.. One hundred and fifty-eight client-owned dogs with naïve or relapsed multicentric lymphoma were prospectively enrolled from January to October 2019.. Dogs were randomized to receive RAB or placebo at a 3 : 1 ratio. Treatment was given every 21 days for up to 5 treatments. Study endpoints included progression-free survival (PFS), overall response rate (ORR) at a given visit, best overall response rate (BORR), and percent progression free 1 month after treatment completion. Safety data were also collected.. The median PFS was significantly longer in the RAB group compared to placebo (82 vs 21 days; P < .0001, HR 6.265 [95% CI 3.947-9.945]). The BORR for RAB-treated dogs was 73.2% (50.9% complete response [CR], 22.3% partial response [PR]) and 5.6% (0% CR, 5.6% PR) for placebo-treated dogs (P < .0001). One month after the last treatment, 37 RAB-treated dogs (33%) were progression free compared with no placebo-treated dogs (P < .0001). The most common adverse events observed in the RAB group were diarrhea (87.5%), decreased appetite (68.3%), and vomiting (68.3%) and were generally low grade and reversible. Serious adverse events were reported in 24 RAB-treated (20%) and 5 placebo-treated dogs (13%).. Rabacfosadine demonstrated statistically significant antitumor efficacy in dogs with lymphoma when administered every 21 days for up to 5 treatments as compared to placebo.

Topics: Alanine; Animals; Antineoplastic Combined Chemotherapy Protocols; Dog Diseases; Dogs; Lymphoma; Purines; Treatment Outcome

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 pre-treatment 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.

Topics: Alanine; Animals; Dog Diseases; Dogs; Female; Lymphoma; Male; Purines; Treatment Outcome

RABACFOSADINE (TANOVEA CA1®) IST EIN NEUES CHEMOTHERAPEUTIKUM, DAS IN DEN USA ZUR INTRAVENöSEN BEHANDLUNG DES CANINEN LYMPHOMS KONDITIONELL ZUGELASSEN IST. BISHER LIEGEN VERSCHIEDENE KLINISCHE UNTERSUCHUNGEN VOR, DIE DIE WIRKSAMKEIT DIESES NEUEN ZYTOSTATIKUMS ALLEIN ODER IN KOMBINATION MIT BEISPIELSWEISE L-ASPARAGINASE BEIM THERAPIENAIVEN ODER REFRAKTäREN LYMPHOM DES HUNDES EVALUIEREN. DATEN AUS EINER RANDOMISIERT VERGLEICHENDEN STUDIE, DIE DIE WIRKSAMKEIT VON TANOVEA-CA1 IM VERGLEICH ZUM PLAZEBO ODER ANDEREN THERAPIEPROTOKOLLEN BESCHREIBEN LIEGEN BISHER NOCH NICHT VOR. ZIEL DIESER STUDIE WAR ES DAHER DIE EFFEKTIVITäT VON TANOVEA-CA1 BEIM LYMPHOM DES HUNDES RANDOMISIERT IM VERGLEICH ZU EINER PLAZEBOBEHANDLUNG ZU UNTERSUCHEN.

Topics: Alanine; Animals; Dog Diseases; Dogs; Lymphoma; Purines

Rabacfosadine (RAB), a novel antineoplastic agent conditionally licensed for the treatment of lymphoma in dogs, is efficacious in both naïve and previously treated dogs. Its use in combination with L-asparaginase (L-ASP) has not been studied.. To evaluate the safety and efficacy of L-ASP given concurrently with RAB in dogs with relapsed multicentric lymphoma.. Fifty-two dogs with relapse of lymphoma after treatment with at least 1 doxorubicin-based chemotherapy protocol.. Open-label, multicenter, prospective single-arm clinical trial. Dogs were treated with RAB at 1.0 mg/kg IV every 21 days for up to a total of 5 doses. L-asparaginase was administered at 400 IU/kg SQ concurrently with the first 2 treatments of RAB.. The overall response rate (ORR) for all dogs was 67%, with 19 dogs (41%) achieving a complete response (CR). The median progression-free survival time (MPFS) was 63 days (range 5-428 days). Dogs experiencing a CR as their best response had an MPFS of 144 days (range 44-428 days). Adverse events were similar to previous studies evaluating single agent RAB. Failure to achieve a CR and having previously received L-ASP were negative prognostic factors on multivariate analysis.. Concurrent RAB/L-ASP appears to be both efficacious and safe for treating relapsed multicentric lymphoma in dogs. Adverse events were most often mild and no unexpected toxicoses were observed.

Topics: Alanine; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Colorado; Disease-Free Survival; Dog Diseases; Dogs; Female; Lymphoma; Male; Neoplasm Recurrence, Local; Prospective Studies; Purines; Remission Induction; Washington; Wisconsin

Standard of care treatment for multicentric lymphoma in dogs remains doxorubicin (DOX)-based combination chemotherapy, but owners may hesitate to commit the time and financial resources to complete such a protocol, typically requiring 12-16 visits. Rabacfosadine (RAB), a double prodrug of the nucleotide analog 9-(2-phosphonylmethoxyethyl) guanine, has substantial single-agent activity in dogs with lymphoma, and a different mechanism of action than DOX.. Our objective was to evaluate the efficacy and adverse effect (AE) profile of alternating doses of RAB and DOX in dogs with naïve multicentric lymphoma.. Fifty-four dogs with previously untreated lymphoma.. Open-label, multicenter prospective clinical trial. Dogs received alternating RAB (1.0 mg/kg IV weeks 0, 6, 12) and DOX (30 mg/m. The overall response rate was 84% (68%; CR; 16%; partial response [PR)]. The overall median progression-free interval (PFI) was 194 days (216 for CR and 63 for PR). Most AEs were mild and self-limiting: gastrointestinal and hematologic AEs were most common. Thirteen dogs experienced dermatologic AEs, and 2 dogs developed grade 5 pulmonary fibrosis.. Alternating RAB/DOX generally was well tolerated and resulted in PFIs comparable to standard DOX-based multi-agent protocols, with fewer treatment visits. Most adverse events were mild or moderate and self-limiting. Further studies are warranted to explore long-term outcome and other RAB chemotherapy combinations.

Topics: Alanine; Animals; Antineoplastic Agents; Dog Diseases; Dogs; Doxorubicin; Drug Administration Schedule; Female; Lymphoma; Male; Prodrugs; Purines; Treatment Outcome