Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors

The Children's Oncology Group

Suman Malempati, H. Stacy Nicholson, Joel M. Reid, Susan M. Blaney, Ashish M. Ingle, Mark Krailo, Linda Stork, Allen S. Melemed, Renee McGovern, Stephanie Safgren, Matthew M. Ames, Peter C. Adamson

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Purpose: We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children. Patients and Methods: Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment. Results: Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively. Conclusion: Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase 11 studies is 1,910 mg/m 2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.

Original languageEnglish (US)
Pages (from-to)1505-1511
Number of pages7
JournalJournal of Clinical Oncology
Volume25
Issue number12
DOIs
StatePublished - Apr 20 2007

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Pemetrexed
Pharmacokinetics
Maximum Tolerated Dose
Neoplasms
Vitamin B 12
Folic Acid
Dexamethasone
Folic Acid Antagonists
Purine Nucleotides
Exanthema
Neutropenia
Intravenous Infusions
Thymidine
Half-Life

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors : The Children's Oncology Group. / Malempati, Suman; Nicholson, H. Stacy; Reid, Joel M.; Blaney, Susan M.; Ingle, Ashish M.; Krailo, Mark; Stork, Linda; Melemed, Allen S.; McGovern, Renee; Safgren, Stephanie; Ames, Matthew M.; Adamson, Peter C.

In: Journal of Clinical Oncology, Vol. 25, No. 12, 20.04.2007, p. 1505-1511.

Research output: Contribution to journalArticle

Malempati, S, Nicholson, HS, Reid, JM, Blaney, SM, Ingle, AM, Krailo, M, Stork, L, Melemed, AS, McGovern, R, Safgren, S, Ames, MM & Adamson, PC 2007, 'Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors: The Children's Oncology Group', Journal of Clinical Oncology, vol. 25, no. 12, pp. 1505-1511. https://doi.org/10.1200/JCO.2006.09.1694
Malempati, Suman ; Nicholson, H. Stacy ; Reid, Joel M. ; Blaney, Susan M. ; Ingle, Ashish M. ; Krailo, Mark ; Stork, Linda ; Melemed, Allen S. ; McGovern, Renee ; Safgren, Stephanie ; Ames, Matthew M. ; Adamson, Peter C. / Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors : The Children's Oncology Group. In: Journal of Clinical Oncology. 2007 ; Vol. 25, No. 12. pp. 1505-1511.
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abstract = "Purpose: We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children. Patients and Methods: Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment. Results: Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively. Conclusion: Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase 11 studies is 1,910 mg/m 2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.",
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T1 - Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors

T2 - The Children's Oncology Group

AU - Malempati, Suman

AU - Nicholson, H. Stacy

AU - Reid, Joel M.

AU - Blaney, Susan M.

AU - Ingle, Ashish M.

AU - Krailo, Mark

AU - Stork, Linda

AU - Melemed, Allen S.

AU - McGovern, Renee

AU - Safgren, Stephanie

AU - Ames, Matthew M.

AU - Adamson, Peter C.

PY - 2007/4/20

Y1 - 2007/4/20

N2 - Purpose: We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children. Patients and Methods: Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment. Results: Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively. Conclusion: Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase 11 studies is 1,910 mg/m 2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.

AB - Purpose: We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children. Patients and Methods: Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment. Results: Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively. Conclusion: Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase 11 studies is 1,910 mg/m 2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.

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