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. 2018 Dec 1;24(23):5830-5840.
doi: 10.1158/1078-0432.CCR-18-1498. Epub 2018 Jul 30.

NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma

Jenna H Burton  1 , Christina Mazcko  2 , Amy LeBlanc  2 , Joseph M Covey  3 , Jiuping Ji  4 , Robert J Kinders  4 , Ralph E Parchment  4 , Chand Khanna  2 , Melissa Paoloni  2 , Sue Lana  5 , Kristen Weishaar  5 , Cheryl London  6 , William Kisseberth  6 , Erika Krick  7 , David Vail  8 , Michael Childress  9 , Jeffrey N Bryan  10 , Lisa Barber  11 , E J Ehrhart  5 , Michael Kent  1 , Timothy Fan  12 , Kelvin Kow  13 , Nicole Northup  14 , Heather Wilson-Robles  15 , Joseph Tomaszewski  3 , Julianne L Holleran  16 , Miguel Muzzio  17 , Julie Eiseman  16 , Jan H Beumer  16 , James H Doroshow  3   17 , Yves Pommier  18
Affiliations

NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma

Jenna H Burton et al. Clin Cancer Res. .

Abstract

Purpose: Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology, and pharmacokinetics.

Experimental design: Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics, and target engagement were determined.

Results: The MTDs were 17.5 mg/m2 for LMP 776 and 100 mg/m2 for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m2 LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744; γH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744. Objective responses were documented for all indenoisoquinolines; efficacy (13/19 dogs) was greatest for LMP744.

Conclusions: These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immunocompetent pets with cancers.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

C. Khanna is an employee of and has ownership interests (including patents) at Animal Clinical Investigation. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1.
Figure 1.
A and B, Chemical structures of the three indenoisoquinolines included in the present study. The structure of camptothecin is shown for comparison, and for demonstrating that the indenoisoquinolines do not bear the alpha-hydroxylactone E-ring of camptothecins. Topotecan and irinotecan are camptothecin derivatives with substitutions at positions 7 and 10 of camptothecin. C and D, Antitumor activity of the three indenoisoquinolines in dog lymphoma. C, Best Response plots with darker colors indicating higher doses (see Supplementary Table S2). D, Tumor response as a function of dose. Individual dogs are shown as data points (see Supplementary Tables S4–S6). PR is partial response; SD is stable disease; PD is progressive disease. Statistical significance (P values) given for relationship of drug dose level to daily dose level.
Figure 2.
Figure 2.
Representative histone γH2AX response in lymphoma biopsies determined by quantitative immunofluorescence assay for three individual dogs as function of time following treatment with the indenoisoquinolines.
Figure 3.
Figure 3.
Tumor accumulation/retention of LMP744 (right) compared with the two other indenoisoquinolines (see Supplementary Tables S4–S6 for detailed data). A, Red dashed lines denote equivalency; points to the right of the line reflect drug accumulation [day 6/day 1 (6 hours)]. Statistical significance determined for relationship between indenoisoquinoline levels 6 hours after the first drug dose and 24 hours after the last drug dose (6 days). B, Plasma (○) and tumor (●) levels of LMP744 in representative animals at four dose levels. Full pharmacokinetic sampling was performed after the first and fifth doses and trough levels were obtained prior to dosing on days 2–5.
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