AACR 2017 | poster 5050/25 – pharmacodynamic and pharmacokinetic relationship of single agent E7449 in patients with relapsed/refractory Non-Hodgkin Lymphoma

At the American Association for Cancer Research (AACR) annual meeting in Washington, DC, USA, on Wednesday 5^th April, a poster session titled “Anticancer Precision Clinical Pharmacology” took place.

One of the poters on display (5050 / 25) was titled “Pharmacodynamic and pharmacokinetic relationship of single agent E7449 in patients with advanced solid tumors or B-cell malignancies” by Pallavi Sachdev from Eisai, Inc., Woodcliff Lake, NJ, and colleagues.

E7449 is a small-molecule inhibitor of Poly (ADP-Ribose) Polymerase (PARP). A multicenter, open-label, phase I study was conducted aiming to identify the Maximum Tolerated Dose (MTD), safety, Pharmacokinetics (PK), Pharmacodynamics (PD), and preliminary anti-tumor activity of single-agent E7449 (NCT01618136). In the poster, the group presented additional PD and PK results from the phase I trial.

Patients (n = 28) were 18 years or older and had measurable, confirmed, advanced solid tumors or B-Cell Lymphoma that had progressed after approved treatment. Those with Lymphoma must have R/R disease that progressed following three previous systemic treatment regimens. Eligible subtypes were MCL, MZL, FL, DLBCL, and CLL. Patients received E7449 at 50, 100, 200, 600, or 800mg/day. An expansion cohort (n = 13) was used to study food. PD assessments included measurement of PARP activity and comet assay to determine the extent of DNA damage.

Key Highlights:

• MTD = 600mg/day (n = 8)
• At this dose level, treatment-emergent AEs resulted in withdrawal of E7449 in 1 pt and dose interruption in 2 pts
• Treatment at the MTD was associated with substantial and sustained dose-dependent PARP inhibition
• ORR = 7.1% (PR = 2); durable SD (≥23 weeks) reported in 21.4% of pts
• Food-effect cohort: PARP inhibition (≤90%) was sustained during treatment at the MTD up to 24 hours post-dose
• Peak E7449 plasma concentrations delayed by 2 hours in fed versus fasted pts
• PK/PD analysis set: peak E7449 plasma concentrations observed at 2 hours after single dose and corresponded with the lowest levels of Poly (ADP-Ribose) (PAR; ≤90% inhibition)
• E7449 exposure was highest at 800mg dose, however the lowest PAR levels occurred at 600mg dose
• At the time of observed responses, the 2 pts with confirmed PR demonstrated >90% PAR inhibition from baseline
• E7449 did not affect the level of DNA damage detected by the comet assay; DNA damage levels remained similar to those in healthy donors

The poster concluded that “these results support E7449 dosing at 600mg/day.”

Reference:

1. Sachdev P. et al. Pharmacodynamic and pharmacokinetic relationship of single agent E7449 in patients with advanced solid tumors or B-cell malignancies [Poster]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; 2017. Poster nr [5050 / 25].