Phase 1 study of an oxaliplatin and etoposide regimen in pediatric patients with recurrent solid tumors

• Published in: Cancer Vol. 115; no. 3; pp. 655 - 664
• Main Authors: McGregor, Lisa M., Spunt, Sheri L., Santana, Victor M., Stewart, Clinton F., Ward, Deborah A., Watkins, Amy, Laningham, Fred H., Ivy, Percy, Furman, Wayne L., Fouladi, Maryam
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.02.2009; Wiley-Blackwell
• Subjects: Adolescent; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Child; Child, Preschool; clinical trial; Drug Administration Schedule; etoposide; Etoposide - administration & dosage; Etoposide - adverse effects; Female; Humans; Infant; Magnetic Resonance Imaging; Male; Maximum Tolerated Dose; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - pathology; Neutropenia - chemically induced; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - adverse effects; Oxaliplatin; phase 1; Recurrence; Tumors; Antineoplastic agent; Pediatrics; Solid tumor; Relapse; Podophyllotoxin derivatives; Isomerases; Cancerology; Oxaliplatin; Clinical trial; Antimitotic; Child; Platinum II Complexes; Human; DNA topoisomerase (ATP-hydrolysing); Enzyme; Enzyme inhibitor; Etoposide; Topoisomerase II inhibitor; Malignant tumor; Alkylating agent; phase 1; Adolescent; Phase I trial; Therapeutic protocol; Cancer
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.24054

BACKGROUND: The combination of a platinating agent and etoposide has induced responses in various pediatric tumors. The study estimated the maximum tolerated dose (MTD) of an oxaliplatin and etoposide regimen in children with recurrent solid tumors. METHODS: Oxaliplatin was administered on Day 1 and etoposide on Days 1 to 3 of each 21‐day course. Cohorts of 3 to 6 patients were enrolled at 3 dose levels: 1) oxaliplatin at a dose of 130 mg/m2 and etoposide at a dose of 75 mg/m2, 2) oxaliplatin at a dose of 130 mg/m2 and etoposide at a dose of 100 mg/m2, and 3) oxaliplatin at a dose of 145 mg/m2 and etoposide at a dose of 100 mg/m2. Calcium and magnesium infusions were used at dose level 3 in an attempt to escalate the oxaliplatin dose past the single‐agent MTD. RESULTS: The 16 patients received a total of 63 courses. At dose level 1, dose‐limiting epistaxis, neuropathy, and neutropenia occurred in 1 of 6 patients. No dose‐limiting toxicity (DLT) occurred at dose level 2 (n = 6). At dose level 3, 2 of 4 patients experienced dose‐limiting neutropenia; none experienced grade 3 or 4 acute neuropathy. Six patients required prolongation of the oxaliplatin infusion because of acute sensory neuropathy. Responses were observed in patients with medulloblastoma (1 complete response) and pineoblastoma (1 partial response); 3 others with atypical teratoid rhabdoid tumor, ependymoma, and soft tissue sarcoma had prolonged disease stabilization. CONCLUSIONS: The MTD of this regimen was found to be oxaliplatin at a dose of 130 mg/m2 given on Day 1 and etoposide at a dose of 100 mg/m2/d given on Days 1 to 3. Neutropenia was found to be the DLT. Calcium and magnesium infusions did not allow escalation of the oxaliplatin dose. The combination was well‐tolerated and demonstrated antitumor activity. Cancer 2009. © 2008 American Cancer Society. This phase 1, dose‐finding study in children with recurrent solid tumors found that maximum tolerated doses were oxaliplatin at a dose of 130 mg/m2 on Day 1 in combination with etoposide at a dose of 100 mg/m2/d on Days 1 through 3 of a 21‐day course. The dose‐limiting toxicity was neutropenia, and there was evidence of antitumor activity.