Deoxyspergualin: phase I clinical, immunologic and pharmacokinetic study

Deoxyspergualin (DSG) is an analog of the polyamine spergualin with preclinical evidence of activity in murine and human tumor models. This phase I study examined a 120 h continuous infusion schedule in 56 patients with refractory solid tumors at doses ranging from 80 to 2792 mg/m/day. Dose-limiting toxicity was reversible hypotension and appeared to be associated with plasma levels of DSG > 4 μg/ml. Other dose-dependent effects noted were pruritus and circumoral paresthesias. Myelo-suppression and gastrointestinal toxicities were mild and sporadic. Two patients with refractory head and neck cancer had minor responses. The recommended phase II dose on this schedule is 1800 mg/m. Additional monitoring to identify immunologic properties included im-munophenotyping of peripheral lymphocytes and cytotoxic activity by means of standard Cr-release assays. These studies revealed a non-dose-dependent increase in the number of cells expressing T cell antigens predominantly the T suppressor (CD8) phenotype post-treatment. In three patients, a mild increase in LAK activity was noted post-treatment without a consistent relationship to dose or change in cell surface antigens. Pharmacokinetic studies were completed on 26 patients ranging from doses of 80 to 2792 mg/m. The average plasma concentration ranged from 0.07 to 7 μg/ml. DSG was rapidly cleared from the plasma with a mean terminal half-life of 1.9 h. Mean total body clearance was 25.24 l/h/m. Further in vivo immunologic studies should be pursued while the agent is studied in fixed dosage phase II clinical trials.