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Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma.

ABSTRACT: Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans' solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas.

SUBMITTER: Boye P

PROVIDER: S-EPMC5432161 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma.

Boyé Pierre P Serres François F Marescaux Laurent L Hordeaux Juliette J Bouchaert Emmanuel E Gomes Bruno B Tierny Dominique D

PloS one 20170515 5

Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in v ...[more]

PMID: 28505195

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Project description:BackgroundPimobendan is widely used for the treatment of dogs with heart failure via the oral route. A new injectable form of pimobendan is now available and its potential usefulness via intravenous route has been recently demonstrated in dogs. However, the cardiovascular effects of intramuscular (IM) administration of injectable pimobendan have not been investigated yet.HypothesisIM administration of pimobendan may have the same hemodynamic effect as the IV route.MethodsSix healthy Beagle dogs underwent a placebo-controlled double-blind crossover study. The early cardiovascular effects after a single dose of IM and IV injections of pimobendan (0.2 ml/kg; Pimo IM and Pimo IV, respectively) were compared to the same volume of IM placebo (Saline IM) in anesthetized dogs. Clinical [heart rate (HR) and blood pressure (BP)] and echocardiographic hemodynamic parameters [left ventricular (LV) inflow waveforms of diastolic early wave (eV), atrial systolic wave (aV), diastolic early mitral ring velocity (e'), peak velocity (pV), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR)] were monitored with 15 min intervals for 120 min.ResultsDiastolic BP decreased significantly at 30 min in Pimo IM compared to Saline IM. Mean eV and CO values significantly increased from 75 min, e' from 60 min, pV from 75 min, and SV from 15 to 120 min, whereas SVR significantly decreased at 30-60 min in Pimo IM compared to those of Saline IM (P < 0.05). Compared with the Pimo IV, eV and pV were significantly lower at 30-60 min (P < 0.05) while SV was significantly higher at 90-105 min in Pimo IM (P < 0.05). Other hemodynamic parameters (BP, HR, SVR, CO, e', and E/e') did not significantly change between Pimo IM and IV.ConclusionsThe hemodynamic effect of pimobendan following IM and IV injection was described. Our results suggested that IM administration of pimobendan is equally comparable and possibly interchangeable with IV administration. This warrant further studies to investigate the clinical effectiveness of IM pimobendan in treating dogs with congestive heart failure or in heart failure cases unable to receive IV or oral administration.

Dataset Information

Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma.

Publications

Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma.

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