1. Evaluate the mechanism of action of vandetanib in the care of patients with thyroid cancer.2. Analyze the current status of clinical development and early clinical results observed with vandetanib.3. Determine appropriate dose and schedule of administration, safety, and identification of molecular biomarkers predictive of response.This article is available for continuing medical education credit at CME.TheOncologist.com. The Oncologist CME Program is located online at http://cme.theoncologist.com/. CME CME ABSTRACTTo take the CME activity related to this article, you must be a registered user. Clinical PharmacologyThe

The synthesis and cytotoxic evaluation of 3-(alkyl)(alkyl-substituted)spiro[(dihydroimidazo-2,4-dione)-5,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)]derivatives are described. Evaluation of these analogues against the MCF-7 human breast carcinoma and SW 620 human colon carcinoma cell lines uncovered for most of the compounds a cytotoxic potency comparable to or greater than that of doxorubicin. Compound 15 exhibited remarkable cytotoxic activity against several other human solid tumor cell lines. Interestingly, only a partial cross-resistance to compound 15 in selected tumor cell sublines known to be resistant to doxorubicin (MCF-7/Dx and A2780/Dx) was observed, whereas a total absence of cross-resistance in a tumor cell subline selected for resistance to cisplatin was found (A2780/DDP).

AimThe aim of this paper is to describe the time spent to activate oncological non-profit clinical trials promoted in Italy by the National Cancer Institute of Naples, following the implementation of recent European laws.MethodologyData about the process of activation of 5 non-profit multicentre clinical trials were prospectively collected through a web-based system. The impact of European guidelines was assessed by comparing the efficiency of the process between applications started before and after the decree introducing in Italy the Clinical Trial Application form (MD-CTA). Outcomes of the descriptive analyses were the time to EC opinion, the time to administrative agreement signature after a positive EC opinion, and the cumulative percentage of submissions that came to closure (either positive or negative) within four subsequent time cohorts.Principal FindingsFrom March 2007 to October 2009, 202 applications were submitted to 107 centres. Forty-four (59%) applications of those submitted before were successful, compared to 71 (55%) of those submitted after MD-CTA. Most of the failures were due to missing EC response (27% and 22%) or administrative reasons (10% and 16%, before and after, respectively); very few (4% and 7%) were due to EC refusal. The impact of the MD-CTA on time to EC opinion looked positive (median 4.1 vs 2.4 months, before and after, respectively) but a subgroup analysis revealed that the impact was limited to a comparison biased by the selection of EC. After a positive EC opinion, there was no difference before and after MD-CTA in the time to administrative agreement signature (median 3.6 and 3.8 months, respectively). A trend to shortening time to closure of the whole submission process over the time was evident, with 58% of the applications coming to closure within 6 months from submission in the most recent cohort.ConclusionsIn our experience there is reassuring evidence of a trend toward shortening the time spent to activate non-profit clinical trials in Italy, but the whole process still remains inefficient. Efforts should be made to improve the process, also focusing on administrative procedures.

The epidermal growth factor receptor (EGFR) signaling plays a key role in tumorigenesis and it has been considered an attractive target for novel antitumoral agents. Small-molecule tyrosine kinase inhibitors such as gefitinib and erlotinib have been approved for the treatment of advanced non-small-cell lung cancer (NSCLC) patients. However, the positive results obtained in early clinical trials with gefitinib were not confirmed in large phase 3 trials, testing the efficacy of this drug in combination with chemotherapy or as single agent. An advantage in overall survival has been observed with erlotinib as single agent in NSCLC, but not in combination with chemotherapy. Conversely, an additive effect has been observed with the combination of the monoclonal antibody cetuximab and irinotecan in heavily pretreated patients with irinotecan-refractory colorectal cancer. The combination of cetuximab and radiotherapy or chemotherapy has also shown efficacy in patients with squamous cancer cell of head and neck. However, the major limit in the development of these agents is the lack of validated predictive markers of response that might allow appropriate selection of patients. In this review, we will discuss the major issues in clinical development of such agents, focusing on the challenges in designing and conducting clinical trials with EGFR inhibitors.

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