Phase 1 clinical pharmacology study of F14512, a new polyamine-vectorized anti-cancer drug, in naturally occurring canine lymphoma
Mené en France sur 23 chiens atteints d'un lymphome de stade III/IV, cet essai de phase I évalue l'efficacité et la toxicité d'un composé appelé F14512, un inhibiteur de la topoisomérase II actuellement en essai clinique chez des patients atteints d'une leucémie myéloïde aiguë
Résumé en anglais
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 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, 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 1 dose-escalation trial which consisted of three cycles of F14512 intravenous 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 in order to determine the recommended dose. F14512 was well tolerated, with the expected dose-dependent hematological 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 pharmacodynamic 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.
