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Phase I and Clinical Pharmacological Study of 4-Demethoxydaunorubicin (Idarubicin) in Children with Advanced Cancer¹

Departments of Pediatrics [C. T. C. T., C. H., P. S., D. B., L. S., E. L., N. W., P. M., A. M., E. D.] and Epidemiology and Biostatistics [D. N.] and Clinical Pharmacology Laboratory [Y-W. S.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

We conducted a phase I and pharmacokinetic study of i.v. idarubicin, a new anthracycline analogue, in 42 evaluable children 1–19 years old. Twenty-seven had leukemia and 15 had various solid tumors. The drug was administered in escalating doses of 10 to 40 mg/m²/course in 3 equal fractions over 3 consecutive days at 14- to 21-day intervals. Myelosuppression and mucositis were the limiting toxicities for short-term administration. Nausea, vomiting, and elevation of liver enzymes and bilirubin were the other toxicities encountered. Peak toxicity occurred 2 weeks after drug administration with median recovery by day 24. All but 4 patients with solid tumors had prior anthracyclines. Mild cardiac function changes without clinical symptoms were observed in 17 of 35 patients measured by serial cardiac evaluations. In addition, there were 4 patients with congestive heart failure. On postmortem examination, 4 patients had changes consistent with anthracycline cardiomyopathy at a prior median total anthracycline dose of 175 mg/m². The maximum tolerated dose for patients with solid tumors was 15 mg/m²/course in 3 divided doses. Patients with leukemia tolerated 30 mg/m²/course. Six of 15 evaluable patients with acute lymphoblastic leukemia who received 30 mg/m² idarubicin achieved a remission (M₁ marrow status). The plasma clearance of idarubicin fits a 3-compartment model with a harmonic mean half-life of 2.4 min, 0.6 h, and 11.3 h for , ß, and phases, respectively. Idarubicinol was the only metabolite detected in the plasma and it accumulated during the 3 days of therapy. Idarubicin is similar to daunorubicin in pharmacology and toxicity. While the cardiotoxic dose still must be delineated, the complete remissions achieved in multiple relapsed patients with acute lymphoblastic leukemia indicate promising activity in at least that disease.

¹ Supported in part by NIH Grant CA29564 and by grants from Farmitalia Carlo Erba and Adria Laboratories.

² To whom requests for reprints should be addressed.

³ Present address: American Cyanamid Company, Wayne, NJ.

⁴ Present address: 177 N. Dean Street, Englewood, NJ.

⁵ Present address: University of Texas Health Science Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX.

Received 5/ 5/86. Revised 2/17/87. Accepted 3/ 6/87.

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