NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma.
Burton JH, Mazcko C, LeBlanc A, Covey JM, Ji J, Kinders RJ, Parchment RE, Khanna C, Paoloni M, Lana S, Weishaar K, London C, Kisseberth W, Krick E, Vail D, Childress M, Bryan JN, Barber L, Ehrhart EJ, Kent M, Fan T, Kow K, Northup N, Wilson-Robles H, Tomaszewski J, Holleran JL, Muzzio M, Eiseman J, Beumer JH, Doroshow JH, Pommier Y
Clin Cancer Res 24 5830-5840 12/01/2018
PURPOSE: Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology, and pharmacokinetics.
EXPERIMENTAL DESIGN: Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics, and target engagement were determined.
RESULTS: The MTDs were 17.5 mg/m
CONCLUSIONS: These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immunocompetent pets with cancers.