Abstract 5050: Pharmacodynamic and pharmacokinetic relationship of single agent E7449 in patients with advanced solid tumors or B-cell malignancies
Authors: Pallavi Sachdev, Shannon McGrath, Robert Shumaker, Jagadeesh Aluri, Claudio Savulsky
Journal: Cancer Research (2017)

Abstract E7449 is a small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP). Preclinical studies reported antitumor activity of single-agent E7449 in BRCA-deficient in vivo models. An open-label, multicenter, phase 1 study was completed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of single-agent E7449. The MTD was determined to be 600 mg/day (n = 8). Treatment-emergent adverse events led to drug withdrawal in 1 patient and dose interruption in 2 patients at this dose level. E7449 treatment at the MTD was associated with substantial and sustained dose-dependent PARP inhibition. The overall response rate was 7.1% (2 confirmed partial responses [PR]) and durable stable disease (≥23 weeks) was observed in 21.4% of patients. Here we report additional PD and PK results from this trial. Patients in this study (N=28) were ≥ 18 years and had measurable, confirmed, advanced solid tumors or B-cell lymphoma that had progressed after approved treatment. Patients received E7449 at 50, 100, 200, 600, or 800 mg/day. Food effect was examined in an MTD expansion cohort. PD assessments included measurement of PARP activity and comet assay to determine the extent of DNA damage. In the food-effect cohort (n=13), PARP inhibition (up to 90%) was sustained during treatment with the MTD of E7449 600 mg/day up to 24 hours post-dose. Peak E7449 plasma concentrations were delayed by 2 hours in fed patients compared with fasted patients. In the PK/PD analysis set, peak plasma concentrations of E7449 were observed at 2 hours following a single dose, and coincided with the lowest levels of poly (ADP-ribose) (PAR; up to 90% inhibition). Of note, while E7449 exposure was highest at the 800 mg dose, the lowest PAR levels were observed at the 600 mg dose. At the time of observed responses, the 2 patients with confirmed PR demonstrated greater than 90% PAR inhibition from baseline. E7449 did not cause a change in the level of DNA damage that could be detected by the comet assay. DNA damage levels remained similar to the damage seen in healthy donors. No significant changes in percent DNA in the electrophoresis comet tail by dose or E7449 plasma concentration were observed. In conclusion, continuous E7449 dosing at 600 mg/day was associated with sustained PARP inhibition. Dose-dependent PARP inhibition was observed and the greatest PARP inhibition occurred at the 600 mg dose. Peak E7449 plasma concentration appeared to coincide with maximal PARP inhibition. These results support E7449 dosing at 600 mg/day. Citation Format: Pallavi Sachdev, Shannon McGrath, Robert Shumaker, Jagadeesh Aluri, Claudio Savulsky. Pharmacodynamic and pharmacokinetic relationship of single agent E7449 in patients with advanced solid tumors or B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5050. doi:10.1158/1538-7445.AM2017-5050