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Dose Escalation and Pharmacokinetics of Pegylated Liposomal Doxorubicin (Doxil) in Children with Solid Tumors

A Pediatric Oncology Group Study¹

Department of Pediatrics, Stanford University Medical Center, Stanford, California 94305–5208 [N. M. M., D. C., M. P. L.]; Alza Corporation, Mountain View, California 94039–7210 [E. H., K. Z.]; Texas Children’s Cancer Center at Baylor College of Medicine, Houston, Texas 77030–2399 [S. B.]; University of Texas Southwestern Medical School, Department of Pediatrics, Dallas, Texas 75390 [N. W.]; and Sainte-Justine Hospital (University of Montreal), Montreal, Quebec, H3T 1C5 Canada [M. B.]

Purpose: To determine the maximum tolerated dose and pharmacokinetics of Doxil in children with recurrent or refractory solid tumors. Doxil is pegylated doxorubicin.

Experimental Design: Eligible patients were children with refractory tumors who had received cumulative anthracycline doses <300 mg/m². Cohorts of at least three patients each received escalating doses of Doxil starting at 40 mg/m² at 4-week intervals. If no dose-limiting toxicity occurred, dosages were escalated by increments of 10 mg/m² in subsequent cohorts. Originally, Doxil was administered over 60 min, but significant infusion reactions prompted longer infusion times of 4 h. Patients also received premedication with dexamethasone, ranitidine, and diphenhydramine 24 h before infusion, with ranitidine continued 24 h after infusion. Periodic blood samples were collected and plasma doxorubicin concentrations were quantified to characterize the pharmacokinetics of Doxil.

Results: Between January 1997 and June 2000, 22 children ages 4–21 years with refractory tumors were treated with Doxil. Most patients had received one to five prior chemotherapy regimens, and all but five had prior radiotherapy (two had no prior therapy). Doxil was escalated to a dosage of 70 mg/m². At that level, dose-limiting mucositis was seen during the first cycle in two of six patients, thus defining dose-limiting toxicity, and in one additional patient during a subsequent cycle. Grade 4 neutropenia lasting less than 7 days was documented in two of six patients. The dose-limiting toxicity among two of six patients at 70 mg/m² was grade 3 mucositis during the first cycle of therapy. Painful desquamating dermatitis of the hands and feet, palmar-plantar erythrodysesthesia, occurred in six patients. In two of those patients, palmar-plantar erythrodysesthesia started as grade 1 and progressed to grade 2 during subsequent courses. Mean estimates of central volume of distribution, clearance, and elimination half-life were 1.45 liters/m², 0.03 liter/h/m², and 36.4 h, respectively.

Conclusion: The maximum tolerated dose of Doxil administered every 4 weeks to pediatric patients was 60 mg/m². The effect of Doxil on pediatric patients with malignancies remains to be determined and should be studied in pediatric Phase II trials.

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