A phase I combination study of olaparib (AZD2281; KU-0059436) and cisplatin (C) plus gemcitabine (G) in adults with solid tumors

3027 Background: Poly (ADP-ribose) polymerase (PARP) group of NAD+-dependent enzymes participate in multiple DNA- related functions. Increased PARP activity can lead to drug resistance. Olaparib (O), a potent oral inhibitor of PARP-1 and PARP-2 may partially overcome resistance to C and G when used in combination. Methods: Eligibility: histologically confirmed metastatic or unresectable solid tumors, PS 0–2, normal organ functions. Treatment at dose level 1 (DL1): O 100 mg orally bid on days (D) −2 to 2, G 500 mg/m2/h on D1 and D8, C 60 mg/m2 on D1 after G; q21 days ×6. Doses (same schedule) at DL −1: O 100 mg once daily, G 400 mg/m2/h, C 50 mg/m2. Peripheral blood mononuclear cells (PBMCs) were collected and processed within 2 hours and poly (ADP-ribose) (PAR) concentration determined by immunoassay. Results: From 5/2008 to 11/2009, 23 patients (pts) enrolled; 14 males, median age 52 yrs (25- 88). Tumor types: 8 NSCLC; 3 ovarian; 3 pancreatic; 2 esophageal; 2 thymic ca; 1 mesothelioma; 1 adrenocortical c...