http://repub.eur.nl/res/aut/20610/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39920/ 2013-05-01T00:00:00Z Over the last decade, the focus of anticancer drug development has shifted from empirical cytotoxic chemotherapy to mechanism-defined molecularly targeted agents, for which appropriate patient selection at the earliest possible point in drug development is rational and critical to success. With the recently legislated "breakthrough product" definition in the U.S., it may be possible to plan a single trial for registration purposes to confirm a major clinical effect observed in phase I. However, most phase I trial designs remain excessively conservative and are driven by criteria developed for cytotoxic agents with the goal of identifying a "maximum tolerable dose" with acceptable risks to patients. This focus on empiric "most dose with acceptable risk" may be misguided for mechanism-targeting new agents, and this could lead to unnecessary delays, increased costs and even higher risk of missing important signals of activity and benefit. There is a compelling need to modify phase I trial designs to facilitate enrichment in molecularly selected patients who are the most likely to harbour disease driven by the targeted pathway and to avoid unjustified exclusions based on obsolete criteria so that the right subset of patients can participate. After discussion of the main inconsistencies of current phase I designs, we propose a new strategy to facilitate the inclusion of molecularly selected patients, in order to accelerate and mitigate risks in drug development as well as to increase the chance of benefit among trial participants. http://repub.eur.nl/res/pub/32920/ 2012-06-29T00:00:00Z Aims: Approximately 20% of soft tissue sarcomas (STS) have subtype-specific chromosomal translocations; these generate chimeric oncoproteins which can act as abnormal transcription factors. Since trabectedin can bind to DNA and displace transcription factors, antitumour activity was explored in translocation-related sarcoma (TRS) subtypes. Methods: The current retrospective pooled analysis includes data from 81 patients with TRS treated in 8 phase II trials. Results: TRS subtypes were: synovial sarcoma (SS, n = 45), myxoid-round cell liposarcoma (MRC-L-sarcoma, n = 27), alveolar soft part sarcoma (ASPS, n = 4), endometrial stromal sarcoma (ESS, n = 3) and clear cell sarcoma (CCS, n = 2). All but one patient had received prior chemotherapy (median of 2 lines). Patients received a median of 4 trabectedin cycles (range, 1-48; median dose intensity = 0.40 mg/m2/week). Partial responses according to Response Evaluation Criteria in Solid Tumours (RECIST) occurred in 8 patients (ORR = 10%; 95% CI, 4-19%): four in MRC-L-sarcoma; three in SS and one in ESS. Tumour control rate (ORR plus stable disease) was 59% (95% CI, 48-70%). Median PFS was 4.1 months (6-month PFS rate = 40%). Median overall survival was 17.4 months (survival rate at 12 months = 60%). Trabectedin had a manageable safety profile. Conclusion: Trabectedin demonstrates encouraging disease control in TRS. Since these promising results were generally noted in patients following chemotherapy, a phase III randomised trial in first-line is ongoing to compare trabectedin with doxorubicin-based chemotherapy in patients with TRS. http://repub.eur.nl/res/pub/17119/ 2009-08-01T00:00:00Z The finding of mutations of KIT in gastrointestinal stromal tumors (GISTs) and subsequent development of kinase-directed therapy in metastatic GIST serve as a touchstone for the translation of laboratory research into clinical therapeutics. A variety of novel developments have followed the discovery of clinical activity of kinase-directed therapy against GIST. Radiological assessment of GIST challenges the standard of care for assessing tumor responses, ie, Response Evaluation Criteria in Solid Tumors (RECIST). Furthermore, the determination of the relationship of specific KIT mutations and sensitivity and resistance to kinase-directed agents and the assessment of inhibitor levels and the quality of response to those agents have implications beyond the treatment of sarcomas. These discoveries and the next chapters in this developing story are discussed in this review.