Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors

Lisa McGregor, Sheri L. Spunt, Wayne L. Furman, Clinton F. Stewart, Paula Schaiquevich, Mark D. Krailo, Rose Anne Speights, Percy Ivy, Peter C. Adamson, Susan M. Blaney

Research output: Contribution to journalArticle

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Abstract

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 o→∞) was 5.9 μg· hour/mL (range, 1.87.6 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.

Original languageEnglish (US)
Pages (from-to)1765-1775
Number of pages11
JournalCancer
Volume115
Issue number8
DOIs
StatePublished - Apr 15 2009

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irinotecan
oxaliplatin
Pediatrics
Diarrhea
Neoplasms
Glucuronosyltransferase
Uridine Diphosphate
Maximum Tolerated Dose
Peptides
Hypokalemia
Cephalosporins
Colitis
Amylases
Serum
Lipase

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

McGregor, L., Spunt, S. L., Furman, W. L., Stewart, C. F., Schaiquevich, P., Krailo, M. D., ... Blaney, S. M. (2009). Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors. Cancer, 115(8), 1765-1775. https://doi.org/10.1002/cncr.24175
McGregor, Lisa ; Spunt, Sheri L. ; Furman, Wayne L. ; Stewart, Clinton F. ; Schaiquevich, Paula ; Krailo, Mark D. ; Speights, Rose Anne ; Ivy, Percy ; Adamson, Peter C. ; Blaney, Susan M. / Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors. In: Cancer. 2009 ; Vol. 115, No. 8. pp. 1765-1775.
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title = "Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors",
abstract = "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 o→∞) was 5.9 μg· hour/mL (range, 1.87.6 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.",
author = "Lisa McGregor and Spunt, {Sheri L.} and Furman, {Wayne L.} and Stewart, {Clinton F.} and Paula Schaiquevich and Krailo, {Mark D.} and Speights, {Rose Anne} and Percy Ivy and Adamson, {Peter C.} and Blaney, {Susan M.}",
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McGregor, L, Spunt, SL, Furman, WL, Stewart, CF, Schaiquevich, P, Krailo, MD, Speights, RA, Ivy, P, Adamson, PC & Blaney, SM 2009, 'Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors', Cancer, vol. 115, no. 8, pp. 1765-1775. https://doi.org/10.1002/cncr.24175

Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors. / McGregor, Lisa; Spunt, Sheri L.; Furman, Wayne L.; Stewart, Clinton F.; Schaiquevich, Paula; Krailo, Mark D.; Speights, Rose Anne; Ivy, Percy; Adamson, Peter C.; Blaney, Susan M.

In: Cancer, Vol. 115, No. 8, 15.04.2009, p. 1765-1775.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors

AU - McGregor, Lisa

AU - Spunt, Sheri L.

AU - Furman, Wayne L.

AU - Stewart, Clinton F.

AU - Schaiquevich, Paula

AU - Krailo, Mark D.

AU - Speights, Rose Anne

AU - Ivy, Percy

AU - Adamson, Peter C.

AU - Blaney, Susan M.

PY - 2009/4/15

Y1 - 2009/4/15

N2 - 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 o→∞) was 5.9 μg· hour/mL (range, 1.87.6 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.

AB - 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 o→∞) was 5.9 μg· hour/mL (range, 1.87.6 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.

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McGregor L, Spunt SL, Furman WL, Stewart CF, Schaiquevich P, Krailo MD et al. Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors. Cancer. 2009 Apr 15;115(8):1765-1775. https://doi.org/10.1002/cncr.24175