Phase I clinical and pharmacokinetic study of N -behenoyl-1-β- d-arabinofuranosylcytosine.

A phase I study of N -behenoyl-1-β- d-arabinofuranosylcytosine (BHAC) was conducted in 66 patients, 41 with solid tumors and 25 with hematological malignancies. The patients received either a 2-h single intravenous (i.v.) drip infusion (Schedule 1) or consecutive daily 2-h i.v. infusions (Schedule 2). In Schedule 1 the daily dose was initiated with 1.5 mg kg which was escalated up to 7 mg kg. Side-effects were mild, and included nausea, vomiting, epilation, and hot flushes. Because of the presence of the solvent vehicle, HCO-60 and in consideration of the mechanism of action of BHAC, the dose escalation was stopped at 7 mg kg. In Schedule 2, the daily dose was started with 1.5 mg kg which was escalated up to 8 mg kg and given for 2-16 days. Myelosuppression was found to be dose-limiting toxicity. The maximum tolerated dose (MTD) in patients with non-hematological solid tumors was assumed to be 5 mg kg daily × 5 days. The plasma disappearance curve of BHAC looked biphasic, and when 4 mg kg of BHAC were administered the half-lives of the initial phase ( t α) and the second phase ( t β) were calculated as 0.798 and 5.76 h respectively. In Schedule 2 complete remission was observed in 5 out of 21 patients with acute leukemia, one partial remission in Hodgkin's disease, and one 1-B response (Karnofsky) in thyroid papillary adenocarcinoma. [ABSTRACT FROM AUTHOR]