Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors

Shivaani Kummar, Alice Chen, Martin Gutierrez, Thomas D. Pfister, Lihua Wang, Christophe Redon, William M. Bonner, William Yutzy, Yiping Zhang, Robert J. Kinders, Jiuping Ji, Deborah Allen, Joseph M. Covey, Julie L. Eiseman, Julianne L. Holleran, Jan H. Beumer, Larry Rubinstein, Jerry Collins, Joseph Tomaszewski, Ralph ParchmentYves Pommier, James H. Doroshow

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Purpose: 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/m2/day was established for the daily regimen, compared to 90 mg/m2 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.

Original languageEnglish (US)
Pages (from-to)73-81
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume78
Issue number1
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

Keywords

  • DNA damage
  • DNA topoisomerase I
  • H2AX protein
  • Hair follicle
  • Indenoisoquinolines
  • NSC 743400

ASJC Scopus subject areas

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

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