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01-07-2016 | Original Article

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

Authors: 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 Parchment, Yves Pommier, James H. Doroshow

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2016

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.

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Title: Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors
Authors: 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 Parchment
Yves Pommier
James H. Doroshow
Publication date: 01-07-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-016-2998-6

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