Internal medicine

Lymphoma

Polymerase

Biology

Oncology

Poly ADP ribose polymerase

PARP inhibitor

Cancer research

Genetics

Medicine

Journal of Clinical Oncology

e19531^ Background: E7449 is an orally bioavailable, likely 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 antitumor activity of chemotherapy and radiotherapy and has activity as a single-agent in BRCA-deficient and other tumors. 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. Methods: Patients (pts) with advanced solid tumors 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. Results: 25 pts (median age: 66 yrs; M/F: 14/ 11) have been treated at 6 dose levels: 50, 100, 200, 400, 800 and 600 mg QD. Tumor types included: pancreatic (n=5), lung (n=4), ovarian (n=4), mesothelioma (n=3), breast (n=2) and others (n=7). Four DLTs have been observed at 800 mg: Gr3 fatigue (n=1) and Gr2 fatigue requiring more than 7days dose interruption (n=3). The MTD is expected to be 600 mg QD. Frequently occurring related adverse events (AEs) (any grade) are fatigue: 48% (Gr3: 12%), photosensitive rash (48%), diarrhea and nausea: 32% each, chromaturia: 28%, depression: 20%, and decreased appetite: 20% (Gr3: 4%). No significant hematological toxicity and no Gr4 related or fatal AEs have been reported. One partial response in a high grade serous ovarian cancer pt (BRCA unknown) and 5 stable diseases for >23 weeks have been observed, including one in a pancreatic cancer pt with BRCA2 variant of uncertain significance. 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. Conclusions: In this study, E7449 was generally well tolerated at the potential MTD of 600 mg QD, with preliminary evidence of antitumor activity and sustained PARPi in PMBCs. Further evaluation will continue in Phase 1b/2 combination studies. Clinical trial information: NCT01618136.

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