title: Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation.
abstract: OBJECTIVE
  In the setting of target-based anticancer drug development, it is critical to establish that the observed preclinical activity can be attributed to modulation of the intended target in early phase trials in human subjects. 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-based (often cytostatic) drug development has been obtaining relevant tumor tissue during clinical trials of these novel agents for laboratory analysis of the putative marker of drug effect.
  
  
  METHODS
  From 1989 to present, we have completed seven clinical trials in which the end point was a biochemical or biological modulatory dose in human tumor tissues (not surrogate tissue). Eligibility enrollment required that patients have a biopsiable lesion either with computerized tomography (CT) guidance or direct visualization and consent to sequential (pre 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 one 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 reaction with first biopsy precluding a second biopsy (n = 1), subcapsular hepatic 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 that with adequate precautions and experience, sequential tumor biopsies are feasible and safe during early phase clinical trials.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Ireland Cancer Center at University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106, USA. axd44@po.cwru.edu
authors.forename: A
authors.initials: A
authors.lastname: Dowlati
authors.forename: J
authors.initials: J
authors.lastname: Haaga
authors.forename: S C
authors.initials: SC
authors.lastname: Remick
authors.forename: T P
authors.initials: TP
authors.lastname: Spiro
authors.forename: S L
authors.initials: SL
authors.lastname: Gerson
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: S J
authors.initials: SJ
authors.lastname: Berger
authors.forename: N A
authors.initials: NA
authors.lastname: Berger
authors.forename: J K
authors.initials: JK
authors.lastname: Willson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001706:Biopsy / Q000379:methods; D002330:Carmustine / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004317:Doxorubicin / Q000627:therapeutic use; D017313:Fenretinide / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C064976:O(6)-benzylguanine; D017313:Fenretinide; D006147:Guanine; C116890:Semaxinib; D004317:Doxorubicin; D019853:O(6)-Methylguanine-DNA Methyltransferase; D017239:Paclitaxel; D002945:Cisplatin; D002330:Carmustine