Abstract 1472: Assessment of CTC-based pharmacodynamic biomarkers in NCI clinical trials of targeted anticancer therapeutics.

Abstract

Abstract Circulating tumor cells (CTC) potentially represent a substitute for biopsy in assessing drug effects on targets. We have previously reported development and validation of CTC-based pharmacodynamic (PD) biomarker assays that directly examine drug-induced responses (e.g. a DNA damage marker γH2AX, and a tumor suppressor marker p16/INK4a). Here, we summarize our results to date and assess utility of CTC-based biomarkers in patients undergoing clinical trials of targeted anti-cancer therapeutics. Across eight NCI Phase 1 and 2 trials in a variety of solid tumors, the portion of the population statistically evaluable is approximately 30% for all trials; the CTC biomarker statistical evaluation is limited by the total number of CTCs collected from each tube of blood. From data obtained from multiple trials of topoisomerase1 and PARP inhibitors, the γH2AX-positive CTC baseline level was less than 20% in 34 of 50 patients. The fraction of CTCs expressing γH2AX independent of changes in the total CTC count, increased in patients following treatment with different topoisomerase 1 inhibitors alone or in combination with other drugs. Furthermore, correlations between γH2AX levels and overall responses were demonstrated in patients with refractory cancer in a phase II randomized trial of the combination of Veliparib with metronomic oral cyclophosphamide. Pharmacodynamic studies measuring re-expression of the tumor suppressor p16 in response to the epigenetic therapy regimen of 5-fluoro-2-deoxycytidine plus tetrahydrouridine yielded similar results on the number of patients evaluable using CTCs in the NCI intramural patient population. Given the limitations of surface molecule-based CTC methods, we are developing and evaluating an antibody-independent CTC capture technology to analyze biomarkers, starting in small animals using lower blood volumes and in patients with a variety of advanced epithelial and non-epithelial cancers. Our studies indicate that assessment of CTC-based PD biomarkers has value for rapidly assessing proof of mechanism in the clinical development of molecularly targeted anticancer therapeutics. Funded by NCI contract # HHSN261200800001E Citation Format: Lihua H. Wang, Shivaani Kummar, Thomas D. Pfister, Priya Balasubramanian, Ralph E. Parchment, Joseph E. Tomaszewski, James H. Doroshow, Robert J. Kinders. Assessment of CTC-based pharmacodynamic biomarkers in NCI clinical trials of targeted anticancer therapeutics. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1472. doi:10.1158/1538-7445.AM2013-1472