Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation

Purpose: In the setting of target-based anticancer drug development, it is critical to establish that the observed preclinical activity can be attribu ted to modulation of the intended target in early phase trials in human sub jects. This paradigm of target modulation allows us to determine a Phase II or III dose (optimal biochemical/ biological modulatory dose) that may not necessarily be the maximum tolerated dose. A major obstacle to target-base d (often cytostatic) drug development has been obtaining relevant tumor tis sue during clinical trials of these novel agents for laboratory analysis of the putative marker of drug effect. Experimental Design. From 1989 to present, we have completed seven clinical trials in which the end point was a biochemical or biological modulatory d ose in human tumor tissues (not surrogate tissue). Eligibility enrollment r equired that patients have a biopsiable lesion either with computerized tom ography (CT) guidance or direct visualization and consent to sequential (pr e and posttreatment) biopsies. Results: A total of 192 biopsies were performed in 107 patients. All but 8 patients had sequential pre and posttreatment biopsies. Seventy-eight (73%) of the 107 patients had liver lesion biopsies. In eight patients, either o ne or both biopsies contained insufficient viable tumor tissue or no tumor tissue at all for analysis. Of a total of 99 patients in,whom we attempted to obtain paired biopsies, a total of 87 (88%) were successful. Reasons for failure included patient refusal for a second biopsy (n = 2), vasovagal re action with first biopsy precluding a second biopsy (n = 1), subcapsular he patic bleeding (n = 1), and most commonly obtaining necrotic tumor, fibrous , or normal tissue in one of the two sequential biopsies (n = 8). Conclusions: This is the first and largest reported series demonstrating th at with adequate precautions and experience, sequential tumor biopsies are feasible and safe during early phase clinical trials.