441OIMAGING MASS SPECTROMETRY OF NOVEL DRUG IN HUMAN TUMOR SPECIMENS: DISTRIBUTION OF UNLABELED DRUGS TO SUPPORT EARLY PHASE CLINICAL TRIAL.

ABSTRACT Aim: Assessment of drug pharmacokinetics is an important component of early phase drug development. Imaging Mass Spectrometry (IMS) is an innovative technique in the preclinical study that allows for analysis of the distribution of target molecules in tumor tissues. The advantage of imaging technology is the detection of the molecule of interest in tissues without labeling. We performed tumor biopsies in patients with solid tumors who were participating in a phase I trial (NCT01813474) of olaparib. The aim of this study was to examine drug distribution in the tumor biopsy specimens by IMS, which provides a sensitive and label-free approach to imaging drugs. Methods: Patients with solid tumors received the tablet formulation of olaparib in dose escalation (200mg BID; 300mg BID) and expansion (300mg BID) cohorts. The timing of biopsies in consenting patients was during cycle 2 and/or at the time of progression. IMS was performed using an Imaging Mass Microscope (Shimadzu, Japan). The concentrations of olaparib in tissues were validated by using LC-MS/MS. Results: In total, seven tumor biopsies were performed in six patients with solid tumors; three breast cancer including one BRCA1 mutation positive, one ovarian cancer, one peritoneal cancer, one cervical cancer. One patient had biopsies performed at the time of drug administration and progression. One patient received olaparib 200mg BID; the remaining patients received olaparib 300mg BID. IMS signal levels of olaparib correlated well with the concentration of drug in tumor tissues derived from patients using LC-MS/MS, a conventional method used in pharmacokinetic studies. The distribution of Olaparib was in the tumor region and the signal level in areas of necrosis was higher than that observed in living cell areas. Conclusions: The use of IMS has allowed to follow the distribution of an unlabeled olaparib in target tissues. In addition, this technique can also allow further understanding of PK/PD relationships of olaparib in combination with other compound at clinical trial. Disclosure: All authors have declared no conflicts of interest.