title: 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.
abstract: OBJECTIVE
  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/m(2)/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/m(2)/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/m(2)/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.
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA. rmorgan@coh.org
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morgan
authors.forename: Timothy
authors.initials: T
authors.lastname: Synold
authors.forename: Adam
authors.initials: A
authors.lastname: Mamelak
authors.forename: Dean
authors.initials: D
authors.lastname: Lim
authors.forename: Zaid
authors.initials: Z
authors.lastname: Al-Kadhimi
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Twardowski
authors.forename: Lucille
authors.initials: L
authors.lastname: Leong
authors.forename: Warren
authors.initials: W
authors.lastname: Chow
authors.forename: Kim
authors.initials: K
authors.lastname: Margolin
authors.forename: Stephen
authors.initials: S
authors.lastname: Shibata
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: Paul
authors.initials: P
authors.lastname: Frankel
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D013120:Spinal Cord Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013629:Tamoxifen / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D013629:Tamoxifen; D019772:Topotecan; D016190:Carboplatin