Abstract 4632: Plasma and tumor pharmacokinetics of IV LMP400, a novel indenoisoquinoline topoisomerase I inhibitor, in a canine phase I study (2014)

Abstract Introduction: LMP400 is one of 3 indenoisoquinolines that are being evaluated in pet dogs with lymphoma to define their safety, pharmacokinetics, and pharmacodynamic modulation (COTC007b). LMP400 forms stable DNA-topoisomerase I (Top1) cleavable complexes and induces unique DNA cleavage sites relative to approved Top1 poisons; LMP400 is not a substrate for ABC transporters and does not have the stability issues that most camptothecin analogs do. Here we report the plasma and uncoupled tumor pharmacokinetics of LMP400 administered IV daily x 5 to patient dogs. Methods: Eligibility included: dogs &amp;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 8, 16, 24, and 40 mg/m2/day through a 3+3 dose escalation study design. LMP400 was administered over 1 h IV daily x 5, Q28D. LMP400 was quantitated with a validated LC-MS/MS assay (PMID: 20236781), 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 fifteen dogs had useable pharmacokinetic data. Non-compartmental analysis suggested linear relationships between plasma Cmax and AUC vs. dose and tumor C2h vs. dose. Plasma terminal half-life was 11.9 ± 5.0 h and the CL was 26.7 L/h/m2. In line with the t1/2, slight plasma accumulation was observed on this daily times 5 schedule. Compartmental modeling with a 2 compartment linear model resulted in a good fit to the data. The parameters and %CVs respectively for Ke, Vc, Kcp, Kpc, Kct and Ktc were 0.181 h-1 (42.6%), 108 L/m2 (32.7%), 0.250 h-1 (30.1%), 0.0602 h-1 (67%), 0.0632 h-1 (3.65%), and 0.649 h-1 (42.2%). Plasma compartmental CL and half-life were 19.5 L/h/m2 and 29.7 h. Conclusion: The plasma pharmacokinetics of LMP400 in dogs display biphasic behavior, a relatively high total body clearance at 19.5 L/h/m2, and a terminal half-life of 29.7 h. LMP400 distributed to the tumors and mean tumor concentrations were at least 10-fold higher than plasma concentrations at equivalent time points of 2, 6 and 120 h. This favorable biodistribution to tumor (lymph node) 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 Citation Format: Julie L. Eiseman, Julianne Holleran, David L. McCormick, Miguel Muzzio, Joseph M. Covey, Chand Khanna, Christina Mazcko, Yves Pommier, Melissa Paoloni, James D. Doroshow, Joseph E. Tomaszewski, Jan H. Beumer. Plasma and tumor pharmacokinetics of IV LMP400, a novel indenoisoquinoline topoisomerase I inhibitor, in a canine phase I study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4632. doi:10.1158/1538-7445.AM2014-4632