Premium
Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors
Author(s) -
McGregor Lisa M.,
Spunt Sheri L.,
Furman Wayne L.,
Stewart Clinton F.,
Schaiquevich Paula,
Krailo Mark D.,
Speights RoseAnne,
Ivy Percy,
Adamson Peter C.,
Blaney Susan M.
Publication year - 2009
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.24175
Subject(s) - medicine , irinotecan , oxaliplatin , gastroenterology , pharmacokinetics , diarrhea , refractory (planetary science) , pharmacology , colorectal cancer , cancer , physics , astrobiology
BACKGROUND: For this report, the authors estimated the maximum tolerated dose (MTD) and investigated the toxicities of oxaliplatin combined with irinotecan in children with refractory solid tumors. METHODS: Oxaliplatin was administered on Days 1 and 8 in combination with irinotecan on Days 1 through 5 and Days 8 through 12 of a 21‐day cycle. An oral cephalosporin was administered daily to ameliorate irinotecan‐associated diarrhea. Pharmacokinetic studies of oxaliplatin and uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 ( UGT1A1 ) genotyping were performed. RESULTS: Thirteen patients were enrolled. Dose‐limiting diarrhea (n = 3), serum lipase elevation (n = 3), serum amylase elevation (n = 2), colitis, abdominal pain, and headache (n = 1 each) occurred at the first dose level (oxaliplatin at a dose of 60 mg/m 2 ; irinotecan at a dose of 20 mg/m 2 ). Only 1 of 7 patients who received reduced doses of both agents (40 mg/m 2 /dose oxaliplatin; 15 mg/m 2 /dose irinotecan) experienced a dose‐limiting toxicity (DLT): diarrhea. When the oxaliplatin dose was re‐escalated (60 mg/m 2 ) with irinotecan at a dose of 15 mg/m 2 , 2 of 3 patients had a DLT (1 episode of diarrhea, 1 episode of hypokalemia). Myelosuppression was minimal. One patient had a complete response, and another patient had stable disease for 6 cycles of therapy. The median oxaliplatin area under the concentration versus time curve (AUC 0→∞ ) was 5.9 μg · hour/mL (range, 1.8‐7.6 μg · hour/mL). The frequency of the 6/6, 6/7, and 7/7 UGT1A1 promoter genotypes was 5 of 10, 4 of 10, and 1 of 10, respectively. CONCLUSIONS: The oxaliplatin MTD was 40 mg/m 2 per dose on Days 1 and 8 in combination with irinotecan 15 mg/m 2 per dose on Days 1‐5 and Days 8‐12. There was some evidence of antitumor activity; however, severe toxicity, both expected (diarrhea) and unexpected (elevation in pancreatic enzymes), was observed. Cancer 2009. © 2009 American Cancer Society.