title: Phase I Clinical Pharmacology Study of F14512, a New Polyamine-Vectorized Anticancer Drug, in Naturally Occurring Canine Lymphoma.
abstract: OBJECTIVE
  F14512 is a new topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells and increases topoisomerase II poisoning. F14512 is currently in a phase I/II clinical trial in patients with acute myeloid leukemia. The aim of this study was to investigate F14512 potential in a new clinical indication. Because of the many similarities between human and dog lymphomas, we sought to determine the tolerance, efficacy, pharmacokinetic/pharmacodynamic (PK/PD) relationship of F14512 in this indication, and potential biomarkers that could be translated into human trials.
  
  
  METHODS
  Twenty-three dogs with stage III-IV naturally occurring lymphomas were enrolled in the phase I dose-escalation trial, which consisted of three cycles of F14512 i.v. injections. Endpoints included safety and therapeutic efficacy. Serial blood samples and tumor biopsies were obtained for PK/PD and biomarker studies.
  
  
  RESULTS
  Five dose levels were evaluated to determine the recommended dose. F14512 was well tolerated, with the expected dose-dependent hematologic toxicity. F14512 induced an early decrease of tumoral lymph node cells, and a high response rate of 91% (21/23) with 10 complete responses, 11 partial responses, 1 stable disease, and 1 progressive disease. Phosphorylation of histone H2AX was studied as a potential PD biomarker of F14512.
  
  
  CONCLUSIONS
  This trial demonstrated that F14512 can be safely administered to dogs with lymphoma resulting in strong therapeutic efficacy. Additional evaluation of F14512 is needed to compare its efficacy with standards of care in dogs, and to translate biomarker and efficacy findings into clinical trials in humans.
authors.affiliation: Oncovet Clinical Research, SIRIC ONCOLille, Avenue Paul Langevin, Villeneuve d'Ascq, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Tierny
authors.affiliation: Oncovet Clinical Research, SIRIC ONCOLille, Avenue Paul Langevin, Villeneuve d'Ascq, France.
authors.forename: François
authors.initials: F
authors.lastname: Serres
authors.affiliation: Oncovet Clinical Research, SIRIC ONCOLille, Avenue Paul Langevin, Villeneuve d'Ascq, France. Inserm, UMR-S1172, Jean Pierre Aubert Research Centre, Lille, France. Université de Lille, Lille, France.
authors.forename: Zacharie
authors.initials: Z
authors.lastname: Segaoula
authors.affiliation: Oncovet Clinical Research, SIRIC ONCOLille, Avenue Paul Langevin, Villeneuve d'Ascq, France.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bemelmans
authors.affiliation: Oncovet Clinical Research, SIRIC ONCOLille, Avenue Paul Langevin, Villeneuve d'Ascq, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bouchaert
authors.affiliation: Institut de Recherche Pierre Fabre, Oncology Pharmacokinetics, Toulouse, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Pétain
authors.affiliation: Institut de Recherche Pierre Fabre, Experimental Oncology Research Center, Toulouse, France.
authors.forename: Viviane
authors.initials: V
authors.lastname: Brel
authors.affiliation: Institut de Recherche Pierre Fabre, Pharmacokinetics, Bel Air de Campans, Castres, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Couffin
authors.affiliation: UPSP 2011-03-101, Interaction Cellules Environnement, Campus Vétérinaire de VetAgro-Sup, Marcy l'Etoile, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Marchal
authors.affiliation: Institut de Recherche Pierre Fabre, Oncology Pharmacokinetics, Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Inserm, UMR-S1172, Jean Pierre Aubert Research Centre, Lille, France. Université de Lille, Lille, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Thuru
authors.affiliation: Institut de Recherche Pierre Fabre, Oncology Pharmacokinetics, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Ferré
authors.affiliation: Institut de Recherche Pierre Fabre, Experimental Oncology Research Center, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guilbaud
authors.affiliation: Institut de Recherche Pierre Fabre, Experimental Oncology Research Center, Toulouse, France. gomesbruno@live.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Gomes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D008223:Lymphoma / Q000662:veterinary*; D008297:Male; D009367:Neoplasm Staging; D011034:Podophyllotoxin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C534191:F14512; D006657:Histones; D059005:Topoisomerase II Inhibitors; D011034:Podophyllotoxin