Abstract 4643: Phase I pharmacokinetics and pharmacodynamics of a novel indenoisoquinoline topoisomerase 1 (TOP1) inhibitor, LMP400, administered on a daily x 5 schedule
Authors: Beumer Jan H. , Holleran Julianne , Doroshow James , Chen Alice , Allen Deborah , Covey Joseph , Tomaszewski Joseph , Pommier Yves , Kumar Shivaani , Eiseman Julie L. 
Published: May 2015

Abstract
Introduction: Indenoisoquinoline LMP 400: 1) forms stable DNA-TOP1 cleavage complexes; 2) binds to unique DNA cleavage sites relative to approved top1 poisons; 3) is not a substrate for ABC transporters. Here we report the plasma pharmacokinetics, pharmacodynamics and optimal sampling of LMP400 administered IV daily x 5 in a phase I trial (NCI#8273).
Methods: Eligibility included: refractory solid tumors or lymphoma, ≥18 yrs old; KPS &gt; 70%; adequate organ function. Dose levels (DL) explored were 2.5, 5, 10, 20, 40, 60 and 80 mg/m2/day, following an accelerated titration design transitioning to 3+3 design after one DLT or 2 gr 2 toxicities during cycle 1. LMP400 was administered over 1 h iv daily x 5, q28d. LMP400 was quantitated with a validated LC-MS/MS assay (PMID: 20236781), and pharmacokinetic parameters determined non-compartmentally with PK Solutions and compartmentally with ADAPT5 through iterative two-stage (ITS) and maximum likelihood expectation maximization (MLEM). Exposure metrics were correlated with decreases in neutrophil counts. Optimal sampling strategies were explored with D-optimality.
Results: Twenty subjects had useable pharmacokinetic data. Non-compartmental analysis suggested linear relationships between Cmax and AUCobs vs dose. Given the long half-life and daily administration, substantial plasma accumulation was observed. Compartmental modeling with a 2-compartment linear model resulted in a good fit to the data. Population means (population CV%) of CLt, Vc, CLd, and Vp were 1.54 (24.9%) L/h/m2, 29.7 (35.3%) L/m2, 11.4 (35.8%) L/h/m2, and 66.3 (34.7%) L/m2. Distribution and terminal elimination half-lives were 1.17 (25.9%) h and 46.0 (36.3%) h. %decrease in neutrophil counts was correlated with AUC and C24h. C24h was highly correlated with AUC (R2=0.92). Optimal sampling to determine CLt (expected SE 7.96%) required a single sample at 168 h (day 8). To determine all parameters with an expected SE&lt;25%, and limiting samples to within 6 h on the first day, the following 5 time points were optimal: 1) 15 min into day 1 infusion, 2+3) approximately 2.3 h after day 1 infusion [2 samples], 4) day 2 trough before infusion, and 5) 168 h.
Conclusion: LMP400 displays biphasic plasma pharmacokinetic behavior, a relatively low total body clearance at 1.54 L/h/m2, and a long terminal half-life at 46 h. Exposure was correlated with %decrease in neutrophils, the DLT of LMP400. The optimal sampling times will aid the design of future phase II studies aimed at further documenting the exposure response relationships of LMP400. The long half-life and accumulation of LMP400 in plasma led to the initiation of a phase I study where LMP400 is dosed once weekly. These studies should further define which exposure metric best correlates with toxicity and anti-tumor activity.
Support: N01-CM-2011-00015, U01-CA-099168, P30-CA-47904
Citation Format: Jan H. Beumer, Julianne Holleran, James Doroshow, Alice Chen, Deborah Allen, Joseph Covey, Joseph Tomaszewski, Yves Pommier, Shivaani Kumar, Julie L. Eiseman. Phase I pharmacokinetics and pharmacodynamics of a novel indenoisoquinoline topoisomerase 1 (TOP1) inhibitor, LMP400, administered on a daily x 5 schedule. [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 4643. doi:10.1158/1538-7445.AM2014-4643