Randomized, double-blind trial of F14512, a polyamine-vectorized anticancer drug, compared with etoposide phosphate, in dogs with naturally occurring lymphoma

// Pierre Boyé 1 , 2 , 7 , Franck Floch 2 , François Serres 1 , 2 , Zacharie Segaoula 1 , 3 , Juliette Hordeaux 1 , Quentin Pascal 1 , Virginie Coste 1 , Sandy Courapied 1 , Emmanuel Bouchaert 1 , Agata Rybicka 1 , Claire Mazuy 1 , Laurent Marescaux 2 , Kévyn Geeraert 2 , Corinne Fournel-Fleury 4 , Alain Duhamel 5 , François Machuron 5 , Pierre Ferré 6 , Aurélie Pétain 6 , Nicolas Guilbaud 6 , Dominique Tierny 1 , 2 and Bruno Gomes 6 , 8 1 OCR (Oncovet-Clinical-Research), Loos, France 2 Oncovet, Villeneuve d’Ascq, France 3 Université de Lille, JPARC - Centre de Recherche Jean-Pierre Aubert, Neurosciences et Cancer, Lille, France 4 Laboratoire Fleury-Fournel ALVEDIA, Limonest, France 5 Université Lille, Santé Publique: Epidémiologie et Qualité des Soins, Lille, France 6 Institut de Recherche Pierre Fabre, Toulouse, France 7 Current address: Department of Small Animal Teaching Hospital, The Royal (Dick) School of Veterinary Studies and The Roslin Institute, University of Edinburgh, UK 8 Current address: Hoffmann-La Roche, Switzerland Correspondence to: Pierre Boyé, email: pierre_boye@hotmail.fr Keywords: etoposide phosphate; F14512; non-Hodgkin lymphoma; pet dog model; P-glycoprotein Received: November 19, 2019 Accepted: January 13, 2020 Published: February 18, 2020 ABSTRACT Purpose: F14512 is an epipodophyllotoxin derivative from etoposide, combined with a spermine moiety introduced as a cell delivery vector. The objective of this study was to compare the safety and antitumor activity of F14512 and etoposide phosphate in dogs with spontaneous non-Hodgkin lymphoma (NHL) and to investigate the potential benefit of F14512 in P-glycoprotein (Pgp) overexpressing lymphomas. Experimental Design: Forty-eight client-owned dogs with intermediate to high-grade NHL were enrolled into a randomized, double-blind trial of F14512 versus etoposide phosphate. Endpoints included safety and therapeutic efficacy. Results: Twenty-five dogs were randomized to receive F14512 and 23 dogs to receive etoposide phosphate. All adverse events (AEs) were reversible, and no treatment-related death was reported. Hematologic AEs were more severe with F14512 and gastrointestinal AEs were more frequent with etoposide phosphate. F14512 exhibited similar response rate and progression-free survival (PFS) as etoposide phosphate in the global treated population. Subgroup analysis of dogs with Pgp-overexpressing NHL showed a significant improvement in PFS in dogs treated with F14512 compared with etoposide phosphate. Conclusion: F14512 showed strong therapeutic efficacy against spontaneous NHL and exhibited a clinical benefice in Pgp-overexpressing lymphoma superior to etoposide phosphate. The results clearly justify the evaluation of F14512 in human clinical trials.