Phase I and pharmacokinetic study of pemetrexed with high-dose folic acid supplementation or multivitamin supplementation in patients with locally advanced or metastatic cancer

Chris H. Takimoto, Lisa A. Hammond-Thelin, Jane E. Latz, Leonardo Forero, Muralidhar Beeram, Bahram Forouzesh, Johann De Bono, Anthony W. Tolcher, Amita Patnaik, Pamela Monroe, Leslie Wood, Karen B. Schneck, Romnee Clark, Eric K. Rowinsky

Research output: Contribution to journalArticle

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Abstract

Purpose: This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability. Patients and Methods: Patients received a 10-min infusion of 600 to 14,00 mg/m2 pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1. Results: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m2 were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation. Conclusions: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m2 in LPT patients and 800 mg/m2 in HPT patients, irrespective of the type of vitamin supplementation.

Original languageEnglish (US)
Pages (from-to)2675-2683
Number of pages9
JournalClinical Cancer Research
Volume13
Issue number9
DOIs
StatePublished - May 1 2007
Externally publishedYes

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Pemetrexed
Folic Acid
Pharmacokinetics
Neoplasms
Vitamins
Febrile Neutropenia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I and pharmacokinetic study of pemetrexed with high-dose folic acid supplementation or multivitamin supplementation in patients with locally advanced or metastatic cancer. / Takimoto, Chris H.; Hammond-Thelin, Lisa A.; Latz, Jane E.; Forero, Leonardo; Beeram, Muralidhar; Forouzesh, Bahram; De Bono, Johann; Tolcher, Anthony W.; Patnaik, Amita; Monroe, Pamela; Wood, Leslie; Schneck, Karen B.; Clark, Romnee; Rowinsky, Eric K.

In: Clinical Cancer Research, Vol. 13, No. 9, 01.05.2007, p. 2675-2683.

Research output: Contribution to journalArticle

Takimoto, CH, Hammond-Thelin, LA, Latz, JE, Forero, L, Beeram, M, Forouzesh, B, De Bono, J, Tolcher, AW, Patnaik, A, Monroe, P, Wood, L, Schneck, KB, Clark, R & Rowinsky, EK 2007, 'Phase I and pharmacokinetic study of pemetrexed with high-dose folic acid supplementation or multivitamin supplementation in patients with locally advanced or metastatic cancer', Clinical Cancer Research, vol. 13, no. 9, pp. 2675-2683. https://doi.org/10.1158/1078-0432.CCR-06-2393
Takimoto, Chris H. ; Hammond-Thelin, Lisa A. ; Latz, Jane E. ; Forero, Leonardo ; Beeram, Muralidhar ; Forouzesh, Bahram ; De Bono, Johann ; Tolcher, Anthony W. ; Patnaik, Amita ; Monroe, Pamela ; Wood, Leslie ; Schneck, Karen B. ; Clark, Romnee ; Rowinsky, Eric K. / Phase I and pharmacokinetic study of pemetrexed with high-dose folic acid supplementation or multivitamin supplementation in patients with locally advanced or metastatic cancer. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 9. pp. 2675-2683.
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abstract = "Purpose: This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability. Patients and Methods: Patients received a 10-min infusion of 600 to 14,00 mg/m2 pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1. Results: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m2 were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation. Conclusions: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m2 in LPT patients and 800 mg/m2 in HPT patients, irrespective of the type of vitamin supplementation.",
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T1 - Phase I and pharmacokinetic study of pemetrexed with high-dose folic acid supplementation or multivitamin supplementation in patients with locally advanced or metastatic cancer

AU - Takimoto, Chris H.

AU - Hammond-Thelin, Lisa A.

AU - Latz, Jane E.

AU - Forero, Leonardo

AU - Beeram, Muralidhar

AU - Forouzesh, Bahram

AU - De Bono, Johann

AU - Tolcher, Anthony W.

AU - Patnaik, Amita

AU - Monroe, Pamela

AU - Wood, Leslie

AU - Schneck, Karen B.

AU - Clark, Romnee

AU - Rowinsky, Eric K.

PY - 2007/5/1

Y1 - 2007/5/1

N2 - Purpose: This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability. Patients and Methods: Patients received a 10-min infusion of 600 to 14,00 mg/m2 pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1. Results: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m2 were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation. Conclusions: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m2 in LPT patients and 800 mg/m2 in HPT patients, irrespective of the type of vitamin supplementation.

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