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

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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

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Keywords

  • Brain tumors
  • Carboplatin
  • Chemotherapy
  • Tamoxifen
  • Topotecan

ASJC Scopus subject areas

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

Cite this

Morgan, R. J., 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, J. H. (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, 66(5), 927-933. https://doi.org/10.1007/s00280-010-1242-z