Abstract 4517: Plasma and tumor pharmacokinetics of IV LMP744, a novel indenoisoquinoline topoisomerase I inhibitor, in a canine phase I study
Authors: Eiseman Julie L. , Holleran Julianne , McCormick David L. , Muzzio Miguel , Covey Joseph M. , Khanna Chand , Mazcko Christina , Pommier Yves , Paolini Melissa , Leblanc Amy , Burton Jenna H. , Doroshow James H. , Tomaszewski Joseph E. , Beumer Jan H. 
Published: August 2015

Abstract
Introduction: LMP744 (NSC706744) is one of 3 indenoisoquinolines being evaluated in pet dogs with lymphoma to define their safety, pharmacokinetics, and pharmacodynamic modulation (COTC007b). LMP744 forms stable DNA-topoisomerase I (Top1) cleavage complexes and induces unique DNA cleavage sites relative to approved Top1 poisons; LMP744 is not a substrate for ABC transporters and does not have the stability issues inherent to camptothecins. Here we report the plasma and tumor pharmacokinetics of LMP744 administered IV daily x 5 to patient dogs.
Methods: Eligibility included: dogs &gt;15 kg with histologically confirmed non-Hodgkin's lymphoma with nodal presentation (stage 2 or greater) and minimal nodes size for biopsy of 3 cm in the longest dimension, performance status of Grade 0 or 1 and informed owner consent. Dose levels (DL) explored were 25, 50, 75, 100, and 125 mg/m2/day through a 3+3 dose escalation study design. LMP744 was administered over 1 h IV daily x 5, Q28D. LMP744 was quantitated with a validated LC-MS/MS assay, and plasma pharmacokinetic parameters determined non-compartmentally with PK Solutions and plasma and tumor parameters compartmentally with ADAPT5 through iterated two stage (ITS) and maximum likelihood solution with the expectation maximization algorithm (MLEM).
Results: All 18 dogs had useable pharmacokinetic data. Non-compartmental analysis suggested linear relationships between plasma Cmax and tumor C2h vs. dose. LMP744 distributed extensively to tumor tissue and mean tumor concentrations were at least 2 orders of magnitude higher than plasma concentrations at equivalent time points of 2, 6 and 120 h. Compartmental modeling with a 3 compartment linear model resulted in a good fit to the plasma data. The parameters and%CVs respectively for Clt, Vc, Cld1, Vp1, Cld2, Vp2 were 57.5 L/h/m2 (29%), 136 L/m2 (24%), 234 L/h/m2 (24%), 1180 L/m2 (27%), 30.8 L/h/m2 (63%), 5140 L/m2 (67%). Sequential plasma half-lives were 16.5 min, 13 h, and 183 (31%) h, respectively. In line with the long t1/2, plasma accumulation was observed on this daily times-5 schedule.
Conclusion: The plasma pharmacokinetics of LMP744 in dogs display triphasic behavior, a relatively high total body clearance at 57.5 L/h/m2, and a terminal half-life of 183 h. The favorable biodistribution to tumor may be a valuable distinction to consider in the translation of this novel indenoisoquinoline to the clinic.
Support: N01-CM-2011-00015, N01-CM-42202 and P30-CA-47904
Note: This abstract was not presented at the meeting.
Citation Format: Julie L. Eiseman, Julianne Holleran, David L. McCormick, Miguel Muzzio, Joseph M. Covey, Chand Khanna, Christina Mazcko, Yves Pommier, Melissa Paolini, Amy Leblanc, Jenna H. Burton, James H. Doroshow, Joseph E. Tomaszewski, Jan H. Beumer. Plasma and tumor pharmacokinetics of IV LMP744, a novel indenoisoquinoline topoisomerase I inhibitor, in a canine phase I study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4517. doi:10.1158/1538-7445.AM2015-4517