A phase I and pharmacokinetics study of 2-chlorodeoxyadenosine in patients with solid tumors

• Published in: Cancer chemotherapy and pharmacology 1995-01, Vol.35 (5), p.397-402
• Main Authors: WEISS, G. R, KUHN, J. G, RIZZO, J, SMITH, L. S, RODRIGUEZ, G. I, ECKARDT, J. R, BURRIS, H. A, FIELDS, S, VANDENBERG, K, VON HOFF, D. D
• Format: Article
• Language: English
• Subjects: Adult; Aged; Agranulocytosis - chemically induced; Anemia - chemically induced; Antineoplastic agents; Biological and medical sciences; Cell Count - drug effects; Chemotherapy; Chromatography, High Pressure Liquid; Cladribine - administration & dosage; Cladribine - adverse effects; Cladribine - pharmacokinetics; Cladribine - therapeutic use; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Lymphopenia - chemically induced; Male; Medical sciences; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Neutrophils - drug effects; Pharmacology. Drug treatments; Thrombocytopenia - chemically induced
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s002800050253

Preclinical studies of 2-chlorodeoxyadenosine (2-CdA) against solid tumors in the human tumor cloning assay and evidence that 2-CdA is active against slow-growing or resting tumor cells have stimulated interest in the clinical activity of this agent against solid tumors. This study sought to estimate the maximum tolerated dose, dose-limiting toxicity, and plasma and urine pharmacokinetics accompanying the intravenous administration of 2-CdA by 120-h continuous infusion in patients with solid tumors. Treated patients were also assessed for other toxicities of therapy and for antitumor response. A total of 23 patients received 35 courses of treatment given at doses of 3.5, 5.3, 6.5 and 8.1 mg/m2 per day by continuous intravenous infusion for 5 days and repeated every 28 days. Blood and urine specimens were collected before, during, and after drug infusion. The dose-limiting toxicity at 8.1 mg/m2 per day manifested as granulocytopenia in 2 of 5 patients (3 of 7 courses of treatment) and as thrombocytopenia in 3 of 5 patients (3 of 7 courses of treatment). At the dose levels of 6.5 and 8.1 mg/m2 per day, recovery from thrombocytopenia was often delayed. Severe lymphocytopenia (< 1,000/microliters) was observed at all dose levels of 2-CdA. Dose-related anemia and leukopenia were observed and were infrequently severe. Non-hematological toxicities were confined to mild-to-moderate nausea, vomiting, fatigue, and anorexia. Fever of 37 degrees-40 degrees C was induced during drug infusion in 19 patients. No antitumor response was observed. Average plasma concentrations at steady-state (Cpss) ranged from 3 ng/ml at the initial dose level to 13 ng/ml at the dose level of 8.1 mg/m2 per day. Both the Cpss and the area under the plasma concentration-time curve (AUC) were proportional to the dose. A relationship was observed between the percentage of change in absolute neutrophil count and the AUC. Renal excretion accounted for only 18% of the elimination of 2-CdA over the 5-day infusion period. The maximum tolerated dose for 2-CdA given by 5-day continuous infusion was 8.1 mg/m2 per day in this study. The recommended dose on this schedule for phase II studies is 6.5 mg/m2 per day. Granulocytopenia and thrombocytopenia were dose-limiting. No antitumor activity was observed during this study. On the basis of the plasma concentrations of 2-CdA observed, it is unlikely that this schedule of drug administration will permit achievement of the concentrations consistent with ant