ASCO 2014: Dr. Byrd: What we could only Learn from a CLL Phase 3 Trial about Ibrutinib and Ofatumumab in Relapsed CLL (chronic lymphocytic leukemia)
But first I must apologize for all the popping from my holding the microphone too close to my loud mouth. Without any technical support for my audio recording, I did a lousy job on my own. But I have learned from my mistakes. Fortunately the important speaker in the interview, Dr. Byrd, is much more easily understood. Which is good because he has a lot of revealing thoughts and information to share. So despite the annoying pops, I decided to post this audio interview. There is a second section too on its way.
Dr. Byrd starts by explaining the important data that can only be discovered in a Phase III trial. Phase I is all about slow dose escalation and safety. While a Phase II trial is about watching for adverse events (AE) and sniffing around for efficacy, there is no comparator arm so anything bad that happens is automatically blamed on the trial drug to be extra cautious. But the bad happenstance may be just part of the background noise of the disease process, with or without the drug. There is no way to tell until we get to Phase III trials where we can see what happens and how often it happens to those on and off the novel therapy.
And we learned some surprises about AE with both drug with this trial. Here is a link to the abstract.
It also soon becomes abundantly clear to the trialists that ibrutinib was the far more potent drug for most patients. The difference in the responses with ibrutinib and with ofatumumab were so pronounced that all decent ethical standards forced a midstream redesign of the trial (and possibly all future trials) to allow a cross-over when there is such a wide gap between outcomes. Amazingly, even with the cross-over, ibrutinib still showed a significant survival advantage in the trial. That is good news for those of us on the outside looking in or those in the trial randomized to ibrutinib, but not for everyone: sadly it meant is that some patients on the ofatumumab arm had to die in order to prove the superiority of ibrutinib.
Dr. Byrd bravely and realistically takes on the issue of cross-over in trial design and getting drugs to market and those who need them.
He also discussed prognostic factors (the bad guys are the usual suspects: 17p deletion, complex karyotype, and perhaps three or more prior treatments). ASH 2014 will pick up this theme where it at least one abstract seems to say that complex karyotype is the ringleader of the bad players. I tend to agree. I have wondered aloud if 17p, the guardian of the genome, is just a surrogate marker for genes gone wild. This is personally annoying because I have a complex karyotype.
Later I think you can hear Dr. Byrd's pride in the new predictive tests that he and the team at OSU are developing to tell who is likely to progress on ibrutinib before they actually do.
Enough preamble. Let's listen to Dr. Byrd.
By the way, I wrote this entire blog post over the Atlantic Ocean on my way to Greece to lecture to hematologists on what patients want in their CLL treatment and also to attend and report from the ESH conference on B cell lymphomas.
Part two of my interview with Dr. Byrd to follow soon.