Phase I study of a continuous infusion of high-dose ara-C in conjunction with a fixed dose of 2′-deoxycytidine (IND 28108) in patients with refractory leukemia: An interim report

A total of 16 patients with refractory leukemia have been entered on a phase I study employing escalating doses of a 96 h continuous infusion of high-dose cytosine arabinoside (ara-C) administered in conjunction with a 120 h infusion of a fixed dose (22 g/m² per day) of 2′-deoxycytidine (IND 28108) as a host-protective agent. Extramedullary toxicities, even at the highest ara-C dose level (e.g. 14 g/m² per day) were mild (e.g. CALGB grade I or II), and consisted of diarrhea, fluid retention, somnolence, hepatic dysfunction, and febrile episodes. Neutropenia and thrombocytopenia were noted in all patients, but no serious infections or bleeding episodes were encountered. Steady state plasma ara-C concentrations of 20-60 μM were observed in patients treated at the 14 g/m² dose, and were associated with plasma ara-U concentrations approaching 1 mM. Although no complete remissions were obtained at the ara-C dose levels tested to date, three partial remissions were noted, and the large majority of patients experienced a clearing of peripheral blood blasts. In addition, several patients who failed to achieve objective responses exhibited atypically benign clinical courses following completion of therapy. These findings demonstrate that 2′-deoxycytidine protects humans from otherwise lethal doses of high-dose ara-C administered by continuous infusion, and substantially ameliorates the hematologic and nonhematologic toxicity of such regimens without completely abrogating antileukemic activity. Determination of the ultimate efficacy of this strategy will require identification of an ara-C maximum tolerated dose and evaluation of the antileukemic potential of this regimen in prospective phase 11 trials.