Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase i trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors

Robert J. Morgan, Timothy Synold, Adam Mamelak, Dean Lim, Zaid Al-Kadhimi, Przemyslaw Twardowski, Lucille Leong, Warren Chow, Kim Margolin, Stephen Shibata, George Somlo, Yun Yen, Paul Frankel, James H. Doroshow

Research output: Contribution to journalArticle

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Abstract

Purpose: This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid. Methods: Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m2/d IV, administered as a 72 h continuous infusion on days 1-3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks. Results: Seventeen patients received 39 cycles of treatment: median 2, (range 1-5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60-90%) and age: 52 (range 24-75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m2/d, the median CSF/plasma ratio was 19.4% (range 15.1-59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02-3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2-5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs. Conclusions: The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m2/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.

Original languageEnglish
Pages (from-to)927-933
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number5
DOIs
Publication statusPublished - Oct 1 2010
Externally publishedYes

Fingerprint

Spinal Cord Neoplasms
Topotecan
Cerebrospinal fluid
Pharmacokinetics
Carboplatin
Tamoxifen
Refractory materials
Cerebrospinal Fluid
Tumors
Brain
Plasmas
Lactones
Therapeutics
Area Under Curve
Toxicity
Cells
Karnofsky Performance Status
Ependymoma
Medulloblastoma
Maximum Tolerated Dose

Keywords

  • Brain tumors
  • Carboplatin
  • Chemotherapy
  • Tamoxifen
  • Topotecan

ASJC Scopus subject areas

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

Cite this

Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase i trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors. / Morgan, Robert J.; Synold, Timothy; Mamelak, Adam; Lim, Dean; Al-Kadhimi, Zaid; Twardowski, Przemyslaw; Leong, Lucille; Chow, Warren; Margolin, Kim; Shibata, Stephen; Somlo, George; Yen, Yun; Frankel, Paul; Doroshow, James H.

In: Cancer Chemotherapy and Pharmacology, Vol. 66, No. 5, 01.10.2010, p. 927-933.

Research output: Contribution to journalArticle

Morgan, RJ, Synold, T, Mamelak, A, Lim, D, Al-Kadhimi, Z, Twardowski, P, Leong, L, Chow, W, Margolin, K, Shibata, S, Somlo, G, Yen, Y, Frankel, P & Doroshow, JH 2010, 'Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase i trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors', Cancer Chemotherapy and Pharmacology, vol. 66, no. 5, pp. 927-933. https://doi.org/10.1007/s00280-010-1242-z
Morgan, Robert J. ; Synold, Timothy ; Mamelak, Adam ; Lim, Dean ; Al-Kadhimi, Zaid ; Twardowski, Przemyslaw ; Leong, Lucille ; Chow, Warren ; Margolin, Kim ; Shibata, Stephen ; Somlo, George ; Yen, Yun ; Frankel, Paul ; Doroshow, James H. / Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase i trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors. In: Cancer Chemotherapy and Pharmacology. 2010 ; Vol. 66, No. 5. pp. 927-933.
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abstract = "Purpose: This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid. Methods: Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m2/d IV, administered as a 72 h continuous infusion on days 1-3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks. Results: Seventeen patients received 39 cycles of treatment: median 2, (range 1-5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70{\%} (range 60-90{\%}) and age: 52 (range 24-75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m2/d, the median CSF/plasma ratio was 19.4{\%} (range 15.1-59.1{\%}). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02-3.83). Plasma lactone levels were 33{\%} of the total; CSF penetration was 20{\%} of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2-5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs. Conclusions: The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m2/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.",
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T1 - Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase i trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors

AU - Morgan, Robert J.

AU - Synold, Timothy

AU - Mamelak, Adam

AU - Lim, Dean

AU - Al-Kadhimi, Zaid

AU - Twardowski, Przemyslaw

AU - Leong, Lucille

AU - Chow, Warren

AU - Margolin, Kim

AU - Shibata, Stephen

AU - Somlo, George

AU - Yen, Yun

AU - Frankel, Paul

AU - Doroshow, James H.

PY - 2010/10/1

Y1 - 2010/10/1

N2 - Purpose: This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid. Methods: Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m2/d IV, administered as a 72 h continuous infusion on days 1-3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks. Results: Seventeen patients received 39 cycles of treatment: median 2, (range 1-5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60-90%) and age: 52 (range 24-75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m2/d, the median CSF/plasma ratio was 19.4% (range 15.1-59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02-3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2-5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs. Conclusions: The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m2/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.

AB - Purpose: This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid. Methods: Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m2/d IV, administered as a 72 h continuous infusion on days 1-3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks. Results: Seventeen patients received 39 cycles of treatment: median 2, (range 1-5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60-90%) and age: 52 (range 24-75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m2/d, the median CSF/plasma ratio was 19.4% (range 15.1-59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02-3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2-5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs. Conclusions: The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m2/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.

KW - Brain tumors

KW - Carboplatin

KW - Chemotherapy

KW - Tamoxifen

KW - Topotecan

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