Phase 1 Dose Escalation of Single-Agent Mechlorethamine in Dogs With Lymphoma.

Abstract

Mechlorethamine is commonly prescribed to dogs at 3 mg/m. The minimal toxicity observed indicates that higher doses of mechlorethamine are likely tolerable. The primary objective of this study was to determine the maximally tolerated dose (MTD) of mechlorethamine in dogs with lymphoma. The secondary objectives were to describe the toxicity associated with increased mechlorethamine dose and to evaluate the response in treatment-naive dogs treated at the MTD. Dogs with histologically or cytologically confirmed intermediate to large cell lymphoma were enrolled using a 3 + 3 dose escalation model, starting at 3.5 mg/mmechlorethamine IV, with planned dose increments of 10%-15% between cohorts. Adverse events were monitored per VCOG-CTCAE guidelines. Dose-limiting toxicity was defined as any grade 3 or 4 adverse event. Thirty dogs were enrolled across nine cohorts. Two dogs treated at 12.3 mg/mdeveloped asymptomatic grade 4 neutropenia 7 days after mechlorethamine administration, leading to a MTD of 10.7 mg/m. Low-grade vomiting, diarrhoea, and inappetence were recorded amongst dogs at several dose levels and were managed with supportive medications. Six of 10 chemotherapy-naïve dogs treated at the MTD, representing a separate cohort, showed partial responses (PR) 7 days post-administration; however, PR was also observed at dosages ranging from 3.5 to 12.3 mg/min pre-treated patients. A higher dose of mechlorethamine than previously reported can be safely administered as a single agent to dogs. Increasing the dose of mechlorethamine in combination therapies might offer greater therapeutic benefits.