An Open-Label, Dose-Escalating Phase I Study of Elsamitrucin (SPI 28090) in Treatment of Malignant Solid Tumors in Dogs

Background: Elsamitrucin, the most potent topoisomerase II inhibitor available, is unique in that it does not cause neutropenia or cardiotoxicosis. It has antitumor activity in human patients with relapsed or refractory non‐Hodgkin's lymphoma. Objectives: To determine the maximum tolerated dose...

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Bibliographic Details
Published in:	Journal of veterinary internal medicine Vol. 25; no. 4; pp. 897 - 902
Main Authors:	Fiocchi, S.C., Selting, K.A., Rosenberg, M.P., Kolli, P., Lenaz, G., Henry, C.
Format:	Journal Article
Language:	English
Published:	Malden, USA Blackwell Publishing Inc 01-07-2011
Subjects:	Aminoglycosides - administration & dosage Aminoglycosides - adverse effects Animals Antibiotics, Antineoplastic - administration & dosage Antibiotics, Antineoplastic - adverse effects Antitumor antibiotic Chemotherapy Cohort Studies Dog Diseases - drug therapy Dog Diseases - pathology Dogs Female Infusions, Intravenous - veterinary Male Maximum Tolerated Dose Neoplasms - drug therapy Neoplasms - pathology Neoplasms - veterinary Prospective Studies Topoisomerase II inhibitor Toxicity
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Summary:	Background: Elsamitrucin, the most potent topoisomerase II inhibitor available, is unique in that it does not cause neutropenia or cardiotoxicosis. It has antitumor activity in human patients with relapsed or refractory non‐Hodgkin's lymphoma. Objectives: To determine the maximum tolerated dose (MTD), safety, and toxicity of elsamitrucin when administered to tumor‐bearing dogs and to evaluate the incidence and severity of adverse events. Animals: Twenty client‐owned dogs with spontaneous malignant solid tumors or lymphoma that were refractory to, or for which the owner declined, conventional therapy were enrolled. Methods: Prospective, open‐label, single‐agent study. Escalating doses of elsamitrucin were administered once weekly IV for up to 16 weeks in a modified 3 + 3 Phase I design. The starting dose was 0.06 mg/kg with escalation to 0.08 and 0.09 mg/kg. Dogs that remained on the study were monitored for evidence of toxicoses for at least 4 weeks and for survival every 2 months. Results: Serious adverse events (SAEs) possibly attributable to elsamitrucin include: 1 dog developed heart failure and another developed hepatotoxicosis manifested by increased alanine aminotransferase, alkaline phosphatase, and total bilirubin (0.06 mg/kg dose); 1 dog developed severe anorexia and diarrhea, another developed severe diarrhea alone, and a 3rd dog went into cardiac arrest (0.09 mg/kg dose). A dose of 0.08 mg/kg was well tolerated with no SAEs. Conclusions and Clinical Importance: The MTD and recommended dose for Phase II trials of elsamitrucin is 0.08 mg/kg IV weekly. Elsamitrucin might be considered for combination protocols with myelosuppressive chemotherapy agents.
Bibliography:	ArticleID:JVIM752 ark:/67375/WNG-2PZFRDX2-L istex:4D34B5EE2AD810D01092B8CBD6A44AB1ED8583A8 This work was performed at Veterinary Cancer Group, Tustin, CA 92780; Veterinary Cancer Group, Culver City, CA 90232; University of Missouri, Department of Veterinary Medicine and Surgery, Columbia, MO 65211. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0891-6640 1939-1676
DOI:	10.1111/j.1939-1676.2011.0752.x