title: Phase I trial of autologous hematopoietic SCT with escalating doses of topotecan combined with CY and carboplatin in patients with relapsed or persistent ovarian or primary peritoneal carcinoma.
abstract: We designed a phase I clinical trial of escalating doses of topotecan with CY and carboplatin in combination with autologous hematopoietic SCT (AHSCT) for the treatment of relapsed or persistent platinum sensitive ovarian or primary peritoneal carcinoma. After stem cell collection, 16 patients received topotecan at 1.5, 2.5, 3.5, 4.5 or 6.0 mg/m(2)/d combined with CY 1.5 g/m(2)/d and carboplatin 200 mg/m(2)/d, all by 4-day continuous infusion. Steady state pharmacokinetics of topotecan and carboplatin were examined. Pre-treatment biopsies were examined for the expression of topoisomerase (topo) I, Ki67 and Bcl-2 family members by immunohistochemistry. One of six patients at a topotecan dose of 4.5 mg/m(2)/d and two of three patients at 6.0 mg/m(2)/d had dose-limiting toxicity of grade 3 stomatitis lasting >2 weeks. There was no treatment-related mortality. As topotecan clearance was constant over the dose range examined, topotecan steady state plasma concentrations increased with dose. Median progression-free survival and overall survival were 6.5 months and 2.7 years, respectively. Shorter progression-free survival was observed in tumors with low topo expression (P=0.04). Topotecan can safely be dose escalated to 4.5 mg/m(2)/d in combination with CY, carboplatin and AHSCT. This trial is registered at ClinicalTrials.gov as NCT00652691.
authors: Division of Hematology, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. litzow.mark@mayo.edu
authors: M R
authors: MR
authors: Litzow
authors: P P
authors: PP
authors: Peethambaram
authors: S L
authors: SL
authors: Safgren
authors: G L
authors: GL
authors: Keeney
authors: S M
authors: SM
authors: Ansell
authors: A
authors: A
authors: Dispenzieri
authors: M A
authors: MA
authors: Elliott
authors: D A
authors: DA
authors: Gastineau
authors: M A
authors: MA
authors: Gertz
authors: D J
authors: DJ
authors: Inwards
authors: M Q
authors: MQ
authors: Lacy
authors: I N M
authors: IN
authors: Micallef
authors: L F
authors: LF
authors: Porrata
authors: W L
authors: WL
authors: Lingle
authors: L C
authors: LC
authors: Hartmann
authors: M H
authors: MH
authors: Frost
authors: B A
authors: BA
authors: Barrette
authors: H J
authors: HJ
authors: Long
authors: V J
authors: VJ
authors: Suman
authors: J M
authors: JM
authors: Reid
authors: M M
authors: MM
authors: Ames
authors: S H
authors: SH
authors: Kaufmann
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy*; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D019772:Topotecan; D003520:Cyclophosphamide; D016190:Carboplatin; D004264:DNA Topoisomerases, Type I