An open-label, dose-escalating phase I study of elsamitrucin (SPI 28090) in treatment of malignant solid tumors in...

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.

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.

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.

Prospective, open-label, single-agent study. Escalating doses of elsamitrucin were administered once weekly i.v. 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.

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.

The MTD and recommended dose for Phase II trials of elsamitrucin is 0.08 mg/kg i.v. weekly. Elsamitrucin might be considered for combination protocols with myelosuppressive chemotherapy agents.