Phase I trial of cisplatin and topotecan in children with recurrent solid tumors: Children's Cancer Group Study 0942

OBJECTIVES: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cisplatin after a 72-hour continuous infusion of topotecan. PATIENTS AND METHODS: Thirty-six children younger than age 22 years (range 3-21) with recurrent solid tumors were treated with cisplatin 45 to 75 mg/m2 infused over the course of 6 hours, followed by a 72-hour continuous infusion of topotecan 0.75 or 1 mg/m2 per day, followed by granulocyte colony stimulating factor (G-CSF), either immediately after treatment or when neutropenia developed. Patients were stratified by the presence of bone marrow tumor involvement and previous radiation to the bone marrow. RESULTS: The DLT was neutropenia (absolute neutrophil count <500/microL for >7 days). The MTD was cisplatin 60 mg/m2 and topotecan 1 mg/m2 per day followed by G-CSF starting 24 hours after chemotherapy for patients without marrow involvement or previous radiation to the bone marrow. An acceptable MTD was not found for patients with previous radiation to the bone marrow or bone marrow involvement or without the use of G-CSF starting 24 hours after chemotherapy was completed. Topotecan clearance and steady-state levels were determined. Limited evidence for antitumor activity with this combination was found in rhabdomyosarcoma. CONCLUSIONS: The recommended dose for phase II trials is cisplatin 60 mg/m2 followed by a 72-hour infusion of topotecan 1 mg/m2 per day with G-CSF starting 24 hours after the completion of topotecan.     

Phase I study of irinotecan in pediatric patients with malignant solid tumors

PURPOSE: To determine the dose-limiting toxicity, maximum tolerated dose, and potential efficacy of irinotecan in children with refractory malignant solid tumors. PATIENTS AND METHODS: In the present phase I clinical trial, 28 patients received irinotecan 50 to 200 mg/m2 per day by intravenous 2-hour infusion over the course of 3 days, repeated once after an interval of 25 days. Fifty-one treatment courses were administered to these patients. RESULTS: Dose-limiting toxicities were observed at the dose of 200 mg/m2 per day for 3 days. Diarrhea and hematopoietic toxicities were the dose-limiting factors, and the former required support with intravenous fluid administration. The occurrence of vomiting was variable. Decreases in clinical tumor marker levels were observed in the majority of patients who received two cycles of irinotecan 80 mg/m2 per day to 200 mg/m2 per day over the course of 3 days, and partial response was attained in four patients who received irinotecan in two cycles of 140 mg/m2 per day to 200 mg/m2 per day over the course of 3 days. Pharmacokinetic studies showed that the plasma concentration of irinotecan and its active metabolite SN-38 ranged from 93 to 2,820 ng/mL and 5.2 to 34.8 ng/mL, respectively, during 3-day infusions of irinotecan 200 mg/m2 per day. The mean clearance of irinotecan was 14.54 L/h per m2 (range 8.45-20.83 L/h per m2). CONCLUSION: The maximum tolerated dose was determined to be a dose of irinotecan between 160 mg/m2 per day and 180 mg/m2 per day administered over the course of 3 consecutive days on an inpatient basis, repeated once after 25 days off, and our results indicate that irinotecan is a promising anticancer agent that is worthy of phase II trials in pediatric solid tumors.     

Phase I study of a 120-hour continuous intravenous infusion of 5-fluorouracil in pediatric patients with recurrent solid tumors: a Pediatric Oncology Group study

To determine the maximum tolerated dose of 5-fluorouracil administered as a 120-hour continuous intravenous infusion to pediatric patients, we performed a phase I study using a starting dosage of 900 mg/m2/day. The maximum tolerated dosage (MTD) was 1,100 mg/m2/day. At this dosage level 40% of courses were complicated by grade 3 mucositis. Three additional patients were treated at the dosage level of 1,000 mg/m2/day after the MTD was determined. We recommend the dosage level of 1,000 mg/m2/day for phase II studies of 5-fluorouracil administered as a 120-hour continuous intravenous infusion to pediatric patients.     

A phase II trial of thalidomide and cyclophosphamide in patients with recurrent or refractory pediatric malignancies

BACKGROUND: Previous clinical and pre-clinical research has demonstrated synergy between anti-angiogenic agents and cytotoxic chemotherapy. This trial was undertaken to investigate whether the combination of cyclophosphamide and thalidomide would be active against pediatric tumors. PROCEDURE: Patients with pediatric malignancies who had no remaining conventional therapeutic options were recruited from January 1999 to May 2001. They received thalidomide (6-12 mg/kg po every day; maximum daily dose 800 mg) and cyclophosphamide (1,200 mg/m2 IV every 28 days). RESULTS: Twenty-seven patients were enrolled on the study. Seventeen were male and 10 were female. Median age at the time of registration was 15 years (range 1-54 years). The median number of prior treatment regimens was four. Twenty-one patients were evaluable for response; 1 had a partial response (Hodgkin disease), 1 demonstrated stable disease (neuroendocrine tumor), and 19 had progressive disease. The most common toxicities were hematological (leukocytopenia and neutropenia) and gastrointestinal. One patient experienced a grade 3 rash. Fatigue and daytime somnolence were variable. No peripheral neuropathy was observed. CONCLUSION: The combination of thalidomide and cyclophosphamide as described herein has a modest and tolerable toxicity profile but little evidence of efficacy.