Clinical trial design supports original accelerated approval of sunitinib for GIST
Faster more reliable clinical trials are needed to enhance the drug development process
- Date : 04 Jun 2012
- Topic : Gastrointestinal cancers
Patients benefited from an important design element in the pivotal phase III clinical trial that led to worldwide regulatory approval of sunitinib for the treatment of gastrointestinal stromal tumours resistant to the only other available therapy, according to a study inClinical Cancer Research,a journal of the American Association for Cancer Research.
According to Dr George Demetri, senior vice president for experimental therapeutics at the Dana-Farber Cancer Institute and director of the Ludwig Center at the Dana-Farber/Harvard Cancer Center in Boston, USA, the study showed that it is possible to do a definitive placebo-controlled trial while protecting the safety of patients.
Results of crossover trial
The double-blind, placebo-controlled, randomised phase III trial was designed as a crossover trial, meaning that patients initially randomised to receive placebo were offered the opportunity to cross over to sunitinib treatment upon disease progression or following unblinding of the trial, whichever came first. The trial was unblinded after an interim analysis that demonstrated the clinical benefit of sunitinib, as assessed by time to tumour progression.
The crossover design of the trial meant that a final analysis using conventional statistical methods indicated no statistically significant effect of sunitinib on overall survival, because the long-term survival interpretation was shifted by the activity of the drug in patients who received sunitinib after crossover. However, the study researchers expected this and also assessed overall survival using a statistical method to model what might have happened in the absence of crossover. They found that sunitinib conferred a clear statistical benefit on overall survival. It shows that is possible to design clinical trials that indicate a drug works and offer that active therapy to patients from the placebo arm of the trial — this protects the interests of patients and yet allows the study to provide rigorous proof of the safety and efficacy of the study drug, in this case sunitinib.
Of the 243 patients enrolled in the study, 118 received placebo. Of these, 103 crossed over to receive sunitinib. Conventional statistical methods analysing the long-term survival data suggested that sunitinib had no statistical effect on overall survival — median survival was 72.7 weeks for those patients in the sunitinib arm and 64.9 weeks for those initially in the placebo arm (the vast majority of whom crossed over to receive sunitinib). Analysis using a method that modelled the absence of crossover (rank-preserving structural failure time) estimated that treatment with sunitinib conferred substantial overall survival benefit — the modelled median survival for placebo would have been 39 weeks.
GIST, disease deeply understood at a molecular level
The majority of gastrointestinal stromal tumours (GIST) are caused by mutations in the KIT proto-oncogene. These mutations result in the KIT protein constantly transmitting activating signals that drive the growth of the tumour. First-line treatment for GIST is the targeted therapy imatinib, a small-molecule inhibitor of KIT.
Sunitinib is another small-molecule inhibitor of KIT. The FDA approved it in 2006 for the treatment of patients with imatinib-resistant or -intolerant GIST, after interim analysis of the phase III trial demonstrated statistically significant increases in time to tumour progression. In that analysis, median time to tumour progression was 27 weeks for patients in the sunitinib arm of the trial and six weeks for those in the placebo arm.
Approval of sunitinib for this indication was extremely rapid. The first GIST patient received sunitinib in 2002, and the interim results led to its approval in 2006. The final analyses published in Clinical Cancer Research shows that this rapid development was appropriate; it did not cut any corners.
Faster more reliable clinical trials are needed to enhance the drug development process, and these goals really are possible to achieve by designing studies around the best science and choosing diseases that are deeply understood at a molecular level, such as GIST.
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