A phase III trial of vemurafenib versus dacarbazine in sufferers with metastatic melanoma harboring a BRAF V600E mutation was initiated in January 2010.4 A year later,on 19 January 2011,the sponsor announced after a planned interim evaluation the trial had met its key end point of showing improved total survival with vemurafenib compared with dacarbazine,five and these outcomes subsequently appeared syk inhibitor in a published report.six The unprecedented activity of vemurafenib in this condition calls into question regardless if a phase III trial was even needed to show superiority to dacarba?zine,a drug which has a response charge while in the variety of five?10%.6 Benefits of your phase I trial with the extension cohort had by now been presented at a serious experienced meeting over six months prior to initiation in the phase III trial and inevitably demonstrated an unconfirmed response charge of 81%,3 a confirmed total response charge of 52% and median response duration of 6.5 months in sufferers with advanced-stage melanoma.seven Subsequently,338 sufferers have been randomly assigned to dacarbazine along with a disproportionate quantity of those patients progressed and/or died just before the interim analysis was carried out and crossover to vemurafenib was endorsed.
The overall trial effects inevitably demonstrated a substantial improvement Telaprevir selleck in overall survival associated with vemu?rafenib remedy.6 An report while in the New York Occasions dated 19 September 2010 described two cousins,a single of whom was randomized to vemurafenib as well as other to dacarbazine.
8 Unfortunately,the patient on dacarba-zine died 1 month right after enrolling while in the trial,while his cousin had been taking vemurafenib with proof of a sustained response for greater than 9 months at the time in the report.The posting raised concern with regards to the neces?sity,feasibility and ethics of undertaking a randomized controlled trial of the novel agent with higher activity in a patient population with few therapy opportunities.The story of vemurafenib raises various interest?ing issues regarding the need for randomized phase III trials in an era of useful targeted therapies for cancer.First,does it ever make sense to consider foregoing a randomized phase III trial prior to drug approval? Second,what exactly are the consequences of foregoing randomized phase III trials for certain medicines? Lastly,what criteria must be used to select drugs that can forego a random?ized phase III trial prior to marketing and advertising approval? In this article,we evaluation the literature since it pertains to every single of these inquiries and try to offer a framework for
potential discussion.