Phase i and pharmacokinetic study of cisplatin and troxacitabine administered intravenously every 28 days in patients with advanced solid malignancies

Chia Chi Lin, Muralidhar Beeram, Eric K. Rowinsky, Chris H. Takimoto, Chee M. Ng, Charles E. Geyer, Louis J. Denis, Johann S. De Bono, Desiree Hao, Anthony W. Tolcher, SunYoung Rha, Jacques Jolivet, Amita Patnaik

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Abstract

Purpose : To assess the feasibility of administering troxacitabine, an l-nucleoside analog that is not a substrate for deoxycytidine deaminase, in combination with cisplatin, to identify pharmacokinetic interactions, and to seek preliminary evidence of antitumor activity. Methods: Patients with advanced solid malignancies were treated with cisplatin intravenously over an hour followed by troxacitabine intravenously over 30 min on day 1 every 28 days at the following cisplatin/troxacitabine (mg/m2) dose levels 50/4.8, 75/4.8, 50/6.4, 75/6.4, and 75/8.0. Plasma and urine sampling were performed to characterize the pharmacokinetic parameters of troxacitabine in combination with cisplatin. Results: Thirty-one patients received 77 courses of cisplatin/troxacitabine at five dose levels. Grade 4 neutropenia lasting more than 5 days and/or grade 4 thrombocytopenia were consistently experienced by minimally pretreated (MP) and heavily pretreated (HP) patients at doses exceeding 75/6.4 and 50/4.8 mg/m2, respectively. Mean values for the volume of distribution at steady state and clearance of troxacitabine were 196-396 L and 7.2-9.8 L/h, respectively. A patient with metastatic non-small cell lung cancer experienced a 42% reduction in extent of disease for 6 months. Conclusions: The combination of cisplatin and troxacitabine produces dose-limiting myelosuppression at lower doses of troxacitabine than single agent doses. The recommended phase II doses of cisplatin/troxacitabine are 75/6.4 and 50/4.8 mg/m2, every 4 weeks, for MP and HP patients, respectively. The addition of cisplatin did not substantially alter the pharmacokinetic behavior of troxacitabine.

Original languageEnglish
Pages (from-to)167-175
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume65
Issue number1
DOIs
Publication statusPublished - 2009 May 18

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Pharmacokinetics
Cisplatin
Neoplasms
deoxycytidine deaminase
troxacitabine
Neutropenia
Nucleosides
Non-Small Cell Lung Carcinoma
Cells
Urine
Sampling
Plasmas

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Lin, Chia Chi ; Beeram, Muralidhar ; Rowinsky, Eric K. ; Takimoto, Chris H. ; Ng, Chee M. ; Geyer, Charles E. ; Denis, Louis J. ; De Bono, Johann S. ; Hao, Desiree ; Tolcher, Anthony W. ; Rha, SunYoung ; Jolivet, Jacques ; Patnaik, Amita. / Phase i and pharmacokinetic study of cisplatin and troxacitabine administered intravenously every 28 days in patients with advanced solid malignancies. In: Cancer Chemotherapy and Pharmacology. 2009 ; Vol. 65, No. 1. pp. 167-175.
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title = "Phase i and pharmacokinetic study of cisplatin and troxacitabine administered intravenously every 28 days in patients with advanced solid malignancies",
abstract = "Purpose : To assess the feasibility of administering troxacitabine, an l-nucleoside analog that is not a substrate for deoxycytidine deaminase, in combination with cisplatin, to identify pharmacokinetic interactions, and to seek preliminary evidence of antitumor activity. Methods: Patients with advanced solid malignancies were treated with cisplatin intravenously over an hour followed by troxacitabine intravenously over 30 min on day 1 every 28 days at the following cisplatin/troxacitabine (mg/m2) dose levels 50/4.8, 75/4.8, 50/6.4, 75/6.4, and 75/8.0. Plasma and urine sampling were performed to characterize the pharmacokinetic parameters of troxacitabine in combination with cisplatin. Results: Thirty-one patients received 77 courses of cisplatin/troxacitabine at five dose levels. Grade 4 neutropenia lasting more than 5 days and/or grade 4 thrombocytopenia were consistently experienced by minimally pretreated (MP) and heavily pretreated (HP) patients at doses exceeding 75/6.4 and 50/4.8 mg/m2, respectively. Mean values for the volume of distribution at steady state and clearance of troxacitabine were 196-396 L and 7.2-9.8 L/h, respectively. A patient with metastatic non-small cell lung cancer experienced a 42{\%} reduction in extent of disease for 6 months. Conclusions: The combination of cisplatin and troxacitabine produces dose-limiting myelosuppression at lower doses of troxacitabine than single agent doses. The recommended phase II doses of cisplatin/troxacitabine are 75/6.4 and 50/4.8 mg/m2, every 4 weeks, for MP and HP patients, respectively. The addition of cisplatin did not substantially alter the pharmacokinetic behavior of troxacitabine.",
author = "Lin, {Chia Chi} and Muralidhar Beeram and Rowinsky, {Eric K.} and Takimoto, {Chris H.} and Ng, {Chee M.} and Geyer, {Charles E.} and Denis, {Louis J.} and {De Bono}, {Johann S.} and Desiree Hao and Tolcher, {Anthony W.} and SunYoung Rha and Jacques Jolivet and Amita Patnaik",
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doi = "10.1007/s00280-009-1020-y",
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Lin, CC, Beeram, M, Rowinsky, EK, Takimoto, CH, Ng, CM, Geyer, CE, Denis, LJ, De Bono, JS, Hao, D, Tolcher, AW, Rha, S, Jolivet, J & Patnaik, A 2009, 'Phase i and pharmacokinetic study of cisplatin and troxacitabine administered intravenously every 28 days in patients with advanced solid malignancies', Cancer Chemotherapy and Pharmacology, vol. 65, no. 1, pp. 167-175. https://doi.org/10.1007/s00280-009-1020-y

Phase i and pharmacokinetic study of cisplatin and troxacitabine administered intravenously every 28 days in patients with advanced solid malignancies. / Lin, Chia Chi; Beeram, Muralidhar; Rowinsky, Eric K.; Takimoto, Chris H.; Ng, Chee M.; Geyer, Charles E.; Denis, Louis J.; De Bono, Johann S.; Hao, Desiree; Tolcher, Anthony W.; Rha, SunYoung; Jolivet, Jacques; Patnaik, Amita.

In: Cancer Chemotherapy and Pharmacology, Vol. 65, No. 1, 18.05.2009, p. 167-175.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase i and pharmacokinetic study of cisplatin and troxacitabine administered intravenously every 28 days in patients with advanced solid malignancies

AU - Lin, Chia Chi

AU - Beeram, Muralidhar

AU - Rowinsky, Eric K.

AU - Takimoto, Chris H.

AU - Ng, Chee M.

AU - Geyer, Charles E.

AU - Denis, Louis J.

AU - De Bono, Johann S.

AU - Hao, Desiree

AU - Tolcher, Anthony W.

AU - Rha, SunYoung

AU - Jolivet, Jacques

AU - Patnaik, Amita

PY - 2009/5/18

Y1 - 2009/5/18

N2 - Purpose : To assess the feasibility of administering troxacitabine, an l-nucleoside analog that is not a substrate for deoxycytidine deaminase, in combination with cisplatin, to identify pharmacokinetic interactions, and to seek preliminary evidence of antitumor activity. Methods: Patients with advanced solid malignancies were treated with cisplatin intravenously over an hour followed by troxacitabine intravenously over 30 min on day 1 every 28 days at the following cisplatin/troxacitabine (mg/m2) dose levels 50/4.8, 75/4.8, 50/6.4, 75/6.4, and 75/8.0. Plasma and urine sampling were performed to characterize the pharmacokinetic parameters of troxacitabine in combination with cisplatin. Results: Thirty-one patients received 77 courses of cisplatin/troxacitabine at five dose levels. Grade 4 neutropenia lasting more than 5 days and/or grade 4 thrombocytopenia were consistently experienced by minimally pretreated (MP) and heavily pretreated (HP) patients at doses exceeding 75/6.4 and 50/4.8 mg/m2, respectively. Mean values for the volume of distribution at steady state and clearance of troxacitabine were 196-396 L and 7.2-9.8 L/h, respectively. A patient with metastatic non-small cell lung cancer experienced a 42% reduction in extent of disease for 6 months. Conclusions: The combination of cisplatin and troxacitabine produces dose-limiting myelosuppression at lower doses of troxacitabine than single agent doses. The recommended phase II doses of cisplatin/troxacitabine are 75/6.4 and 50/4.8 mg/m2, every 4 weeks, for MP and HP patients, respectively. The addition of cisplatin did not substantially alter the pharmacokinetic behavior of troxacitabine.

AB - Purpose : To assess the feasibility of administering troxacitabine, an l-nucleoside analog that is not a substrate for deoxycytidine deaminase, in combination with cisplatin, to identify pharmacokinetic interactions, and to seek preliminary evidence of antitumor activity. Methods: Patients with advanced solid malignancies were treated with cisplatin intravenously over an hour followed by troxacitabine intravenously over 30 min on day 1 every 28 days at the following cisplatin/troxacitabine (mg/m2) dose levels 50/4.8, 75/4.8, 50/6.4, 75/6.4, and 75/8.0. Plasma and urine sampling were performed to characterize the pharmacokinetic parameters of troxacitabine in combination with cisplatin. Results: Thirty-one patients received 77 courses of cisplatin/troxacitabine at five dose levels. Grade 4 neutropenia lasting more than 5 days and/or grade 4 thrombocytopenia were consistently experienced by minimally pretreated (MP) and heavily pretreated (HP) patients at doses exceeding 75/6.4 and 50/4.8 mg/m2, respectively. Mean values for the volume of distribution at steady state and clearance of troxacitabine were 196-396 L and 7.2-9.8 L/h, respectively. A patient with metastatic non-small cell lung cancer experienced a 42% reduction in extent of disease for 6 months. Conclusions: The combination of cisplatin and troxacitabine produces dose-limiting myelosuppression at lower doses of troxacitabine than single agent doses. The recommended phase II doses of cisplatin/troxacitabine are 75/6.4 and 50/4.8 mg/m2, every 4 weeks, for MP and HP patients, respectively. The addition of cisplatin did not substantially alter the pharmacokinetic behavior of troxacitabine.

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U2 - 10.1007/s00280-009-1020-y

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