An important design element in a phase III clinical trial for the multikinase inhibitor sunitinib (Sutent) was particularly helpful to patients while winning the drug FDA approval in January 2006 for the treatment of gastrointestinal stromal tumors (GISTs) resistant to the only other available therapy.

“The study…showed that it is possible to do a definitive placebo-controlled trial while protecting the safety of patients,” said George D. Demetri, MD, 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, both in Boston, Massachusetts.

Demetri, who made his remarks in a statement issued by the American Association for Cancer Research (AACR), led a team that analyzed the final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in patients with GIST after imatinib (Gleevec) failed to help them. In the double-blind trial, 243 patients were randomized to receive daily sunitinib and 118 were randomized to placebo on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression or following study unblinding, whichever came first. The trial was unblinded after an interim analysis that demonstrated the clinical benefit of sunitinib, as assessed by tumor progression.

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A total of 103 members of the placebo group crossed over to open-label sunitinib. Conventional statistical methods that were used to analyze the long-term survival data suggested that sunitinib had no statistical effect on overall survival, with median survival being 72.7 weeks for persons given sunitinib compared with 64.9 weeks for those initially in the placebo arm.

“The crossover design of the trial meant that our 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,” Demetri explained.

However, the investigators expected this, and made a point of also assessing overall survival using a statistical method to model what might have happened in the absence of crossover.

That method—known as rank-preserving structural failure time—estimated that treatment with sunitinib conferred substantial overall survival benefit: The modeled median survival for placebo would have been 39 weeks. “This really is key,” pointed out Demetri. “It shows that we can design clinical trials that indicate a drug works and offer that active therapy to patients from the placebo arm of the trial.”

Such a design protects the interests of the patient while allowing the trial to yield proof of the study drug’s safety and efficacy. As Demetri and colleagues noted in the AACR journal Clinical Cancer Research (2012;18[11]:3170-3179), long-term sunitinib treatment was tolerated without new adverse events.