PHASE-I CLINICAL AND PHARMACOKINETIC STUDY OF HEXAMETHYLENE BISACETAMIDE (NSC-95580) ADMINISTERED AS A 5-DAY CONTINUOUS INFUSION

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  • 15 January 1987
    • journal article
    • research article
    • Vol. 47  (2) , 617-623
Abstract
Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was tested in patients with refractory, and solid tumors. Twenty patients received 25 evaluable courses. HMBA was given by continuous i.v. infusion for 5 consecutive days with courses repeated every 4 wk, provided there was acceptable, reversible toxicity. The starting dose was 4.8 g/m2/day for 5 days with escalations in subsequent cohorts of patients to 43.2 g/m2/day for 5 days. The patients included 12 female and eight males with median age of 56 yr (range 35 to 75 yr) and a median performance status of 80% (range, 60 to 100%). All except two patients had received prior chemotherapy, radiation therapy, or both. Metabolic acidosis and neurotoxicity, consisting of agitation, hallucinations, confusion, and alteration of consciousness, were dose dependent and dose limiting. The one patient treated with 43.2 m/m2/day became acidotic, agitated, and disoriented but recovered to his previous mental and electrolyte status by 8 days after the end of the HMBA infusion. One patient treated with 33.6 g/m2/day became severely acidotic (pH 7.07) and obtunded and also developed myocardial and cerebral infarctions during the HMBA infusion. The other two patients treated with 33.6 g/m2/day became mildly agitated during drug infusion. Six patients were treated at 24 g/m2/day without neurotoxicity. Transient renal insufficiency was seen in the two patients with severe neurotoxicity and in three other patients. Dose-related, mild to moderate nausea and vomiting were observed in ten patients. Four patients developed cutaneous herpes infections during treatment. White blood cell depression was not dose related, and at 24 g/m2/day, the median white blood cell nadir was 4,500/.mu.l (range, 2,000 to 7,900/.mu.l). Thrombocytopenia was dose related. At 24 g/m2/day, the median platelet count nadir was 207,000/.mu.l (range, 66,000 to 542,000/.mu.l). No objective tumor regression were noted. HMBA pharmacokinetics was studied at all dosages. Plasma and urine samples from 20 patients were analyzed by gas-liquid chromatography for parent compound. HMBA plasma steady-state concentrations (Css) were achieved in all patients by 12 to 24 h into infusion. Once Css was achieved, daily variation was generally .ltoreq. 10% from the mean Css. HMBA plasma Css increased linearly with dose, but there was a variation in the Css achieved in individual patients at each dose. Doses of 24 to 33.76 g/m/day consistently produced plasma HMBA Css of 1 to 2 mM matching concentrations required for differentiation in vitro. After infusion, HMBA disappeared from plasma monoexponentially with t1/2 of 2.88 .+-. 1.24 (SD) h. Urinary excretion of HMBA accounted for 33.6 .+-. 15.0% of the daily dose. HMBA total-body clearance was 116.8 .+-. 38.2 ml/min and was linearly related to creatinine clearance by the equation, total-body clearance = 0.87 creatinine clearance + 59. The pharmacokinetics of HMBA was also related to the reduction in platelet count. This relationship was well described by the equations % of decrease in platelets = 100 (1 - e-0.000652 area under plasma concentration vs. time curve) and % of decrease in platelets .**GRAPHIC**. In this study, the maximum tolerated dose of HMBA administered by 5- day continuous infusion was 33.6 g/m2/day. The recommended dose for Phase II studies was 24 g/m2/day.