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Comparative Study
. 2016 Jul;78(1):73-81.
doi: 10.1007/s00280-016-2998-6. Epub 2016 May 11.

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

Shivaani Kummar  1 , Alice Chen  1 , Martin Gutierrez  1 , Thomas D Pfister  2 , Lihua Wang  2 , Christophe Redon  3 , William M Bonner  3 , William Yutzy  2 , Yiping Zhang  2 , Robert J Kinders  2 , Jiuping Ji  2 , Deborah Allen  1 , Joseph M Covey  1 , Julie L Eiseman  4 , Julianne L Holleran  4 , Jan H Beumer  4 , Larry Rubinstein  1 , Jerry Collins  1 , Joseph Tomaszewski  1 , Ralph Parchment  2 , Yves Pommier  3 , James H Doroshow  5   6
Affiliations
Comparative Study

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

Shivaani Kummar et al. Cancer Chemother Pharmacol. 2016 Jul.

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/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.

Keywords: DNA damage; DNA topoisomerase I; H2AX protein; Hair follicle; Indenoisoquinolines; NSC 743400.

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Conflict of interest statement

of Potential Conflicts of Interest: none

Figures

Figure 1
Figure 1
Representative concentration versus time profiles of the daily schedule 1-hour infusion (○), and the weekly schedule 3-hour infusion (△), both dosed at 60 mg/m2 (A) over 5 days and (B) an expanded view of the first 24 hours.
Figure 2
Figure 2
Dose normalized Cmax plotted against dose for the daily schedule 1 hour infusion (○), and the weekly schedule 3 hour infusion (△).
Figure 3
Figure 3
Levels of Top1 protein measured in tumor biopsies collected pre-dose (baseline) and 4 hours after the start of indotecan infusion on cycle 1 day 3. Percent changes from the baseline sample are indicated for each patient; DL-D5 and DL-D5a are indicated with black and purple circles, respectively. +No post-dose sample; ^pre-dose or #post-dose sample < LLQ.
Figure 4
Figure 4
Changes in levels of Top1 protein measured in PBMC samples collected pre-dose (baseline) and (A) 4 hours after the start of indotecan infusion on day 1 or (B) day 3. Percent changes from baseline are indicated for each patient; dose levels are indicated by the different colored circles. +No post-dose sample; ^pre-dose or #post-dose sample < LLQ; ‡pre-dose or †post-dose sample failed assay performance quality control criteria.
Figure 5
Figure 5
Changes in (A) total number of CTCs and (B) percent of CTCs positive for γH2AX in 7.5-mL blood samples collected pre-dose (baseline) and 2–4 hours after the start of indotecan infusion on day 3. Percent changes from baseline are indicated for each patient; DLs indicated by the differently colored circles. *The baseline proportion of γH2AX-positive CTCs was too high to assess a ≥ 3-fold response over baseline.
Figure 6
Figure 6
γH2AX formation in plucked hairs from patients receiving indotecan. Hair samples were collected prior to and 4 to 6 hours post-infusion. (A) On the left, individual patient data are plotted as percentage of γH2AX-positive cells (defined as more than 4 γH2AX foci per cell) ± standard errors. On the right, average grouped patient data plotted ± standard deviations indicate a significant change between pre- and post-treatment samples (p=0.027; N=4 individuals). Numbers in parentheses refer to the numbers of hairs analyzed for each patient. (B) Representative images of γH2AX staining in plucked hair bulbs collected prior and after indotecan. The image in the right panel shows the regions of plucked hairs where both image capture and γH2AX quantification were performed. Green, γH2AX; red, DNA stained with propidium iodide; scale bar, 50 μm.
See this image and copyright information in PMC

References

    1. Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006;6:789–802. - PubMed
    1. Kostopoulos I, Karavasilis V, Karina M, et al. Topoisomerase I but not thymidylate synthase is associated with improved outcome in patients with resected colorectal cancer treated with irinotecan containing adjuvant chemotherapy. BMC Cancer. 2009;9:339. - PMC - PubMed
    1. von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. 2014;32:4012–4019. - PubMed
    1. Cinelli MA, Reddy PV, Lv PC, et al. Identification, synthesis, and biological evaluation of metabolites of the experimental cancer treatment drugs indotecan (LMP400) and indimitecan (LMP776) and investigation of isomerically hydroxylated indenoisoquinoline analogues as topoisomerase I poisons. J Med Chem. 2012;55:10844–10862. - PMC - PubMed
    1. Beck DE, Agama K, Marchand C, Chergui A, Pommier Y, Cushman M. Synthesis and biological evaluation of new carbohydrate-substituted indenoisoquinoline topoisomerase I inhibitors and improved syntheses of the experimental anticancer agents indotecan (LMP400) and indimitecan (LMP776) J Med Chem. 2014;57:1495–1512. - PMC - PubMed

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