Phase I Clinical Pharmacology Study of F14512, a New Polyamine-Vectorized Anticancer Drug, in Naturally Occurring Canine Lymphoma.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Dominique Tierny, François Serres, Zacharie Segaoula, Ingrid Bemelmans, Emmanuel Bouchaert, Aurélie Pétain, Viviane Brel, Stéphane Couffin, Thierry Marchal, Laurent Nguyen, Xavier Thuru, Pierre Ferré, Nicolas Guilbaud, Bruno Gomes
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 23 Pg. 5314-23 (Dec 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 26169968 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Biomarkers
• F14512
• Histones
• Topoisomerase II Inhibitors
• Podophyllotoxin

Topics

• Animals
• Antineoplastic Agents (adverse effects, pharmacokinetics, pharmacology)
• Biomarkers
• Cell Line, Tumor
• Dog Diseases (drug therapy, metabolism, pathology)
• Dogs
• Drug Evaluation, Preclinical
• Female
• Histones (metabolism)
• Humans
• Lymphoma (veterinary)
• Male
• Neoplasm Staging
• Podophyllotoxin (adverse effects, analogs & derivatives, pharmacokinetics, pharmacology)
• Topoisomerase II Inhibitors (adverse effects, pharmacokinetics, pharmacology)
• Treatment Outcome