Community Magazine

ASH 2013: Dr Jeff Sharman Discusses the Ideal Design of Phase 3 Trials with Novel Agent Versus the Reality in the Community

By Bkoffman
As a patient, it is easy to be critical of study design.

Case in point: The phase 3 trial of rituximab (R) plus idelalisib (I) versus rituximab plus placebo presented at ASH 2013 in New Orleans.

Wait a minute, we patients scream. One arm of this trial is offering us a monotherapy option that is not recommended by most CLL experts because it produces a lousy response rate in the middle single digits. In the trial, lymph node response rate was a meager 4% for the R+ placebo versus 93% for the arm with the two active agents. And the duration of the response for the R alone is less that six months.

In comparison, in the R+I arm, median progression free survival has not been reached, and remarkably, even overall survival was improved, something unheard of in CLL just a few years ago when FCR was shown to be the first drug combination to add years to our lives.

All the data from the late breaking abstract can be accessed here. It is powerful, but one must ask, does idelalisib look so good because it was being compared to a straw man?

Is this an ethical way to conduct a trial?

Dr. Jeff Sharman, a regular on this web site, is both a community based oncologist and the medical director of hematology research for The US Oncology Network.

He points the pros and cons of the controversial trial design.
Watch the video and form your own opinion before I give you my bottom line.
First Dr. Sharman does a good job reminding us the difference between a phase 1, 2 and 3 trial.

So what do you think?
At first,  I was dismayed by the trial, from a patient's perspective, but when we have a trial design where we are pretty much guaranteed that we will get idelalisib if we need it, and in either arm we  can avoid chemotherapy, on further reflection I am more sanguine about this kind of trial.
The science bothers me more than the ethics. In the study, the results with idelalisib are very impressive and would likely have stood up to a much more active comparator arm, but in this case it was a massive mismatch as evidenced by the unheard of gargantuan P number (p = 1.3 x 10-30 ). In other words, the odds of getting this result by chance alone was not one in a million or one in a billion or one in a trillion, but about one in 10 followed by 30 zeros.

So what is my take away message?

First, I am OK with most trials that have a cross-over built in from the get-go, and especially fond of those that offer us a chance to avoid chemotherapy.

Second, idelalisib is clearly going to be a powerful addition to our armamentarium for treating CLL. 

In this study it took on a tough bunch of patients.The median number of prior therapies was three. The test subjects were all considered too unhealthy to get traditional chemotherapy. Nearly half were 17p deleted and 17 out of 20 were unmutated. We are told that all the risk groups responded better to the idelalisib arm, but the abstracts doesn't give us much detail.
So, bottom line, unless my need to get my disease under control was so acute that I could not risk the delay in getting a response if I was randomized to the R+ placebo arm, I wouldn't hesitate to enroll in a similar trial if I needed therapy.
Based on this and other positive studies, I hope and suspect idelalisib will be approved for CLL in the USA before the end of the year. And that will be a good thing for the CLL community.

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