Journal of Clinical Oncology, Vol 11, 554-560, Copyright © 1993 by American Society of Clinical Oncology

ARTICLES

Phase I study of escalating targeted doses of carboplatin combined with ifosfamide and etoposide in children with relapsed solid tumors

NM Marina, J Rodman, SJ Shema, LC Bowman, E Douglass, W Furman, VM Santana, M Hudson, J Wilimas and W Meyer
Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38101-0318.

PURPOSE: The tolerance of escalating targeted doses of carboplatin combined with ifosfamide (IFOS)/etoposide (VP-16) (ICE) was assessed in children with recurrent solid tumors. PATIENTS AND METHODS: To reduce interpatient variability in carboplatin systemic exposure, 45 children were treated with doses individualized to a target area under the serum concentration versus time curve (AUC) based on renal function, using technetium 99-diethyl-enetriamine pentaacetic acid (99mTc-DTPA) clearance to estimate glomerular filtration rate (GFR). Cohorts of at least three patients received carboplatin at an initial target AUC of 2 mg/mL x min, with escalations of 1 mg/mL x min in subsequent cohorts. Courses consisted of carboplatin on day 1 followed by IFOS 2 g/m2 plus VP-16 100 mg/m2 on days 2 and 3. Patients received at least two courses, with a maximum of eight courses possible in the absence of progressive disease. When only moderate toxicity occurred after escalation to 5 mg/mL x min, a third dose of IFOS plus VP-16 was added. After three patients were treated at this level, carboplatin escalation proceeded. RESULTS: Neutropenia and thrombocytopenia were the dominant toxicities in the 43 assessable patients. At the target AUC of 8 mg/mL x min, 13 of 20 cycles were associated with febrile neutropenia. For phase II trials, we recommend a carboplatin target AUC of 6 mg/mL x min with three doses of IFOS and VP-16 for patients with prior craniospinal irradiation or high-dose cisplatin (CDDP)/VP-16, or 7 mg/mL x min for patients without such histories. There were two complete responses (CRs), 13 partial responses (PRs), and 17 objective responses (ORs). CONCLUSION: The ICE regimen shows promising activity in pediatric solid tumors. The clear relationship between hematologic toxicity and carboplatin systemic exposure supports the use of targeted dosing in further trials of ICE chemotherapy.

This article has been cited by other articles:

				M. Chintagumpala, S. M. Blaney, L. R. Bomgaars, A. Aleksic, J. F. Kuttesch, R. A. Klenke, and S. L. Berg Phase I and Pharmacokinetic Study of Thalidomide With Carboplatin in Children With Cancer J. Clin. Oncol., November 1, 2004; 22(21): 4394 - 4400. [Abstract] [Full Text] [PDF]

				U. H. Athale, C. Stewart, J. F. Kuttesch, A. Moghrabi, W. Meyer, C. Pratt, A. Gajjar, and R. L. Heideman Phase I Study of Combination Topotecan and Carboplatin in Pediatric Solid Tumors J. Clin. Oncol., January 1, 2002; 20(1): 88 - 95. [Abstract] [Full Text] [PDF]

				H. Thomas, A. V. Boddy, M. W. English, R. Hobson, J. Imeson, I. Lewis, B. Morland, A. D. J. Pearson, R. Pinkerton, L. Price, et al. Prospective Validation of Renal Function-Based Carboplatin Dosing in Children With Cancer: A United Kingdom Children's Cancer Study Group Trial J. Clin. Oncol., November 1, 2000; 18(21): 3614 - 3621. [Abstract] [Full Text] [PDF]

				B. H. Hayden, T. G. Murray, I. U. Scott, N. Cicciarelli, E. Hernandez, W. Feuer, L. Fulton, and J. M. O'Brien Subconjunctival Carboplatin in Retinoblastoma: Impact of Tumor Burden and Dose Schedule Arch Ophthalmol, November 1, 2000; 118(11): 1549 - 1554. [Abstract] [Full Text] [PDF]

				E. J. Estlin, S. Cotterill, C. B. Pratt, A. D. J. Pearson, and M. Bernstein Phase I Trials in Pediatric Oncology: Perceptions of Pediatricians From the United Kingdom Children's Cancer Study Group and the Pediatric Oncology Group J. Clin. Oncol., May 9, 2000; 18(9): 1900 - 1905. [Abstract] [Full Text] [PDF]

				M. H. Woo, M. V. Relling, D. S. Sonnichsen, G. K. Rivera, C. B. Pratt, C.-H. Pui, W. E. Evans, and A. S. Pappo Phase I Targeted Systemic Exposure Study of Paclitaxel in Children with Refractory Acute Leukemias Clin. Cancer Res., March 1, 1999; 5(3): 543 - 549. [Abstract] [Full Text] [PDF]

				Media Review: Videotapes Journal of Pediatric Oncology Nursing, January 1, 1993; 10(4): 161 - 165. [PDF]