title: Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors.
abstract: OBJECTIVE
  Indenoisoquinolines are non-camptothecin topoisomerase I (TopI) inhibitors that overcome the limitations of camptothecins: chemical instability and camptothecin resistance. Two dosing schedules of the novel indenoisoquinoline, indotecan (LMP400), were evaluated in patients with advanced solid tumors.
  
  
  METHODS
  The maximum tolerated dose (MTD), toxicities, and pharmacokinetics of two indotecan drug administration schedules (daily for 5 days or weekly) were investigated. Modulation of TopI and the phosphorylation of histone H2AX (γH2AX) were assayed in tumor biopsies; γH2AX levels were also evaluated in circulating tumor cells (CTCs) and hair follicles to assess DNA damage response.
  
  
  RESULTS
  An MTD of 60 mg/m(2)/day was established for the daily regimen, compared to 90 mg/m(2) for the weekly regimen. The TopI response to drug showed target engagement in a subset of tumor biopsies. Pharmacokinetics profiles demonstrated a prolonged terminal half-life and tissue accumulation compared to topotecan. Dose-dependent decreases in total CTCs were measured in seven patients. Formation of γH2AX-positive foci in CTCs (day 3) and hair follicles (4-6 h) was observed following treatment.
  
  
  CONCLUSIONS
  We established the MTD of two dosing schedules for a novel TopI inhibitor, indotecan. Target engagement was demonstrated as Top1 downregulation and γH2AX response. No objective responses were observed on either schedule in this small patient cohort. The principal toxicity of both schedules was myelosuppression; no significant gastrointestinal problems were observed. Increased DNA damage response was observed in CTCs, hair follicles, and a subset of tumor biopsies.
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Gutierrez
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Pfister
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Redon
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Bonner
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: William
authors.initials: W
authors.lastname: Yutzy
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kinders
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ji
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Allen
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Covey
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Eiseman
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Julianne L
authors.initials: JL
authors.lastname: Holleran
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Rubinstein
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Collins
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tomaszewski
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Parchment
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20814, USA. doroshoj@mail.nih.gov.|Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. doroshoj@mail.nih.gov.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000328:Adult; D000368:Aged; D052117:Benzodioxoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004249:DNA Damage / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004334:Drug Administration Schedule; D005260:Female; D018859:Hair Follicle / Q000378:metabolism; D006207:Half-Life; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D014018:Tissue Distribution; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019772:Topotecan / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D052117:Benzodioxoles; C468783:H2AX protein, human; D006657:Histones; D007546:Isoquinolines; C553898:NSC 724998; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human
keywords: DNA damage; DNA topoisomerase I; H2AX protein; Hair follicle; Indenoisoquinolines; NSC 743400