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Phase I Trial Using Adaptive Control Dosing of Hexamethylene Bisacetamide (NSC 95580)¹

Divisions of Developmental Therapeutics [B. A. C., A. F., M. J. E., E. G. Z.] and Medical Oncology [B. A. C., D. A. V. E., V. S.], University of Maryland Cancer Center, and Division of Medical Oncology, Department of Medicine, University of Maryland School of Medicine [B. A. C., A. F., M. J. E., D. A. V. E., V. S.], and Department of Clinical Pharmacy, University of Maryland School of Pharmacy, [A. F.] Baltimore, Maryland 21201

Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was administered to patients with refractory malignant tumors. Thirteen patients received 30 evaluable courses. HMBA was given by continuous i.v. infusion for 5 days. Therapy was repeated every 28 days, if patients had recovered from toxicity. The starting dose was 24 g/m²/day. Because our previous trial had shown wide interpatient variability in HMBA pharmacokinetics and excess toxicity at HMBA plasma concentrations greater than 2 mM (HMBA doses between 24 and 33.6 g/m²/day), we attempted to individualize each patient's dose based on a dosing scheme using an adaptive (feedback) control algorithm, which assumed linear clearance for HMBA. In all courses, a plasma sample was assayed daily and infusion rates were adjusted to achieve an HMBA plasma concentration of 1.5–2.0 mM (300–400 mg/liter). The patients included 12 men and 1 woman with a median age of 56 years (range, 34–76) and median Karnofsky performance status of 90% (range, 60–100). All patients had received prior chemotherapy and 9 patients had also received radiation therapy. The linear adaptive control algorithm was reasonably precise, with a mean absolute error of 0.28 (SE 0.04) mM. However, adjustments in infusion rate systematically overshot the desired change in steady state concentration, probably due to nonlinear clearance of HMBA. For levels within 24 h of a change in infusion rate, this resulted in significant bias, with a mean error of 0.24 (SE 0.09) mM. The mean absolute error was 0.40 (SE 0.06) mM. A second adaptive control algorithm, using a pharmacokinetic model with parallel first-order (renal) clearance and Michaelis-Menten (nonrenal) clearance and using Bayesian parameter estimation with a priori estimates based on our previous phase I trial, proved to be much more precise than the linear method and was unbiased when applied retrospectively to the same observations, with a mean error (within 24 h of a change in infusion rate) of 0.02 (SE 0.06) mM and a mean absolute error of 0.22 (SE 0.03) mM. Toxicity was reversible in all cases. Neurotoxicity, consisting of hallucinations, agitation, somnolence, or confusion, was seen in 2 patients. Four patients complained of insomnia or anxiety. Mild asymptomatic acidosis was seen in 3 patients. Other toxicity included grade 1–2 nausea and vomiting (10 patients), grade 2 diarrhea (2 patients), grade 3 thrombocytopenia (3 patients), grade 1–3 leukopenia (3 patients), and oral herpes simplex infection (4 patients). Mild reversible renal insufficiency (measured by creatinine clearance) was seen in 8 patients. While no objective responses were seen, 1 patient with non-small cell lung cancer had disappearance of a malignant pleural effusion and a stable endobronchial lesion for 8 months, and 1 patient with recurrent squamous cell carcinoma of the base of the tongue had stable disease for 7 months. The relationship, defined in our previous patient population, between exposure to HMBA and the percentage decrease in platelet count predicted the response in 6 of the current patients well but proved unsuitable in 4 of the current patients. In these 4 patients, the percentage decrease in platelet count was consistently overpredicted. Although the method of adaptive control used in this study proved suboptimal, most patients were managed with mild reversible toxicity, and we believe that refined adaptive control strategies will prove useful for individualized dosing of agents, such as HMBA, which have wide interpatient variability in pharmacokinetics and either excess toxicity above a certain plasma concentration or a narrow therapeutic concentration range.

¹ Supported in part by Contract NO1-CM-57734 awarded by the National Cancer Institute, Department of Health and Human Services, and by Clinical Oncology Career Development Award 88–127 to Dr. Conley from the American Cancer Society.

² To whom requests for reprints should be addressed.

Received 9/21/88. Revised 1/27/89. Accepted 3/14/89.