453P - Phase 1 study of the PARP inhibitor E7449 as a single agent in patients with advanced solid tumors or B-cell lymphoma

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Clinical research
Basic Scientific Principles
Presenter Ruth Plummer
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors R. Plummer1, D. Dua2, N. Cresti3, A. Suder4, Y. Drew3, V. Prathapan5, P. Stephens3, J. Thornton2, B.D.L. Heras6, B. Ink7, L. Lee6, M. Matijevic8, S. McGrath8, D. Sarker9
  • 1Medical Oncology, Northern Institute for Cancer Research, University of Newcastle upon Tyne, NE2 4HH - Newcastle/GB
  • 2Northern Centre For Cancer Care, Freeman Hospital, Newcastle Upon Tyne/GB
  • 3Medical Oncology, Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle/GB
  • 4Medical Oncology, Guys Hospital, London/GB
  • 5Oncology, Guy's Hospital, London/GB
  • 6Woodcliff Lake, Eisai, Inc,, NJ/US
  • 7Hertfordshire, Eisai, Hatfield,/GB
  • 8Andover, Eisai, Inc,, massachusettes/US
  • 9Department Of Research Oncology, Guy's and St. Thomas' Hospital NHS Trust, GB-SE1 9RT - London/GB



E7449 is an orally bioavailable, brain penetrable, potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and PARP 2 with an IC50 of 1.0 and 1.2 nmol/L respectively. E7449 is a poor P-gp substrate. Preclinically, E7449 potentiates the antitumour activity of chemotherapy and radiotherapy and has activity as a single-agent in BRCA-deficient and other tumours. A Phase 1 study of E7449 as a single agent is underway to determine the MTD, safety, PK, PD, preliminary activity and perform exploratory biomarker analysis.


Patients (pts) with advanced solid tumours or B-cell lymphoma, ECOG PS 0-1, > 18 years (yrs) and adequate organ function are eligible. E7449 is administered orally, once daily (QD), continuously. Blood samples for PK, PD and biomarkers are collected at multiple time points.


28 pts have been treated at 6 dose levels: 50, 100, 200, 400, 800 and 600 mg QD. Tumour types most frequently included were pancreatic (n = 5), ovarian (n = 5) and lung (n = 4). Five DLTs have been observed, four at 800 mg: Gr3 fatigue (n = 1) and Gr2 fatigue requiring more than 7days (d) dose interruption (n = 3) and one at 600 mg, drug interruption for more than 7d and Gr3 allergic reaction. The MTD was achieved at 600 mg QD. Frequently occurring related adverse events (AEs) (any grade) are fatigue: 48% (Gr3: 12%), photosensitive rash (48%), diarrhoea and nausea: 32% each, chromaturia: 28%, depression: 20%, and decreased appetite: 20% (Gr3: 4%). No significant haematological toxicity and no Gr4 related or fatal AEs have been reported. One PR in a high grade serous ovarian (HGSO) cancer pt (BRCA unknown) and 6 SD for >23 weeks have been observed (one in a pancreatic cancer pt with BRCA2 variant of uncertain significance, one in a HGSO cancer pt BRCA mutant). E7449 PK exhibits rapid absorption, tmax ∼1.5 hrs and elimination t1/2 ∼9 hrs, with dose proportional exposures. Sustained PARP inhibition (PARPi) of ∼90% is observed in PMBCs at 600 mg QD. Predictive biomarker analysis is ongoing.


In this study, E7449 was generally well tolerated at the MTD of 600 mg QD, with preliminary evidence of antitumour activity and sustained PARPi in PMBCs. Further evaluation will continue in Phase 1b/2 combination studies.


B.D.L. Heras: I am Director of Clinical Development, Eisai Inc; B. Ink: I am Director of Project Management, Eisai Ltd; M. Matijevic: Associate Director, Eisai Inc.; D. Sarker: I have a consultant/advisory relationship to disclose at Eisai Inc.All other authors have declared no conflicts of interest.