Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: a pediatric oncology group study.

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/m(2). Cohorts of at least three patients each received escalating doses of Doxil starting at 40 mg/m(2) at 4-week intervals. If no dose-limiting toxicity occurred, dosages were escalated by increments of 10 mg/m(2) 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/m(2). 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/m(2) 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/m(2), 0.03 liter/h/m(2), and 36.4 h, respectively. CONCLUSION: The maximum tolerated dose of Doxil administered every 4 weeks to pediatric patients was 60 mg/m(2). The effect of Doxil on pediatric patients with malignancies remains to be determined and should be studied in pediatric Phase II trials.

Liposomal doxorubicin for the treatment of hormone-refractory prostate cancer.

There is a pressing need for new agents to treat hormone-refractory prostate cancer (HRPC). Doxorubicin has shown modest activity in this setting, but its use is limited by its toxicities. Liposomal encapsulation of doxorubicin appears to promote enhanced tumor accumulation in some tumor types, and toxicity appears to be reduced. A phase II trial of liposomal doxorubicin was therefore conducted in patients with HRPC. Fourteen patients with progressive HRPC were treated. For the first dose only, patients were randomized to receive either doxorubicin 50 mg/m2 or liposomal doxorubicin 50 mg/m2 in order to evaluate exploratory pharmacokinetics. For all subsequent cycles, all patients received liposomal doxorubicin 50 mg/m2. Response to therapy was assessed with serial measurements of serum prostate-specific antigen (PSA) and sequential imaging studies. All 14 patients were evaluable for response and toxicity. Two patients (14%) had declines in serum PSA of > or = 50%. The first patient had a baseline PSA of 34.7 ng/mL and a nadir of 17.0 ng/mL. The second patient had a baseline PSA of 5580.0 ng/mL and a nadir of 200.7 ng/mL. The latter of these 2 patients had an unambiguous improvement in bone scan and a reduction in pain. Treatment was well tolerated overall. One patient was removed from treatment after the development of a grade 3 infusion reaction with the first cycle of liposomal doxorubicin. Neutropenia was the most common toxicity; in only 1 case was it grade 3, and no cases of grade 4 were seen. Doxorubicin plasma concentrations were best fit by a linear, two-compartment model. Liposomal doxorubicin plasma concentrations were best fit by a linear, one-compartment model. Treatment with liposomal doxorubicin was well tolerated overall. While monotherapy with liposomal doxorubicin has only modest activity in the treatment of HRPC, it may be of interest to study this agent as part of combination chemotherapy.