In this continuation of my video interview from ASCO 2014, Dr. Tom Kipps out of UCSD discusses how a new promising therapy using cirmtuzumab, an antibody directed at RORI will work in the real world, converting years and years of research into the first in human clinical trial.
If you haven’t seen the lead up to our discussion on this brand new and very specific mAb (monoclonal antibody) targeting ROR1, then please revisit this prior post to catch the first part of our interview done in collaboration with my friend Andrew Schorr and his Patient Power team.
Remember that Dr. Kipps is a cutting edge researcher in the field of immunology and this is an immune therapy. For many blood and cancers in general, the path to a cure means inviting an immune therapy onto the team and ROR1 is a very promising and specific target in CLL.
For more background on ROR1 by Dr. Kipps, see this, also from ASH 2012. It’s a ton of long and hard bench science to bring these therapies to the bedside. Dr. Kipps has been excited about this for years and it is finally coming to fruition.
I will let Dr. Kipps tell the update of the story.
I love his push for a cure and I love his pneumonia analogy.
Now the trial for relapsed and refractory CLL patients opened recently, not too much later than the hoped for June start date mentioned at ASCO and this new ROR1 antibody, cirmtuzumab is already being used. A few patients have begun the experimental therapy, and though it is way too early to know much of value, so far so good.
What I like about this trial that it is an immune therapy with the promise of very little off target damage. I also like that it is so time limited- you get the 4 infusions over 8 weeks are you are done.
The downside risk. This is a Phase 1 first in human trial. Nuff said!
The dose escalation is also a potential turn off in Phase 1 trials as they are always about safety first. The hope is to find the highest dose that is not toxic called the dose limiting toxicity or DTL.
We know from our experience with the consequences of too rapid a dose escalation with ABT-199 resulting in fatal tumor lysis syndrome (TLS) that slow and easy is the only way to go. Please see this and this and sadly this if you are not familiar with this tragic and instructive story.
The negative consequence of this emphasis on safety is the risk that those in the first few cohorts may get too low or a sub-therapeutic dose.
That’s why I like that this trial design. I quote from the trial site: “There is intra-patient dose escalation in the first 3 cohorts, followed by the standard 3+3 design for the next 5 cohorts.
What that means is those in the first three groups get a low dose and if they experience no problems a higher and higher dose. After that the dose is fixed for each three patient cohort.
The whole topic of Phase 1 trial design to minimize risk and maximize benefit is complicated and I am no expert, so I welcome comments from those more savvy. This is a link to a nice review article that will help if you want to dig a bit deeper.
Safety comes first and only then is drug efficacy studied more formally in later trials, but that doesn’t mean there can be no measurable benefits from this kind of trial. My ibrutinib trial is sort of a phase 1 trial (1b/2) and I see no reason not to expect that this study with reveal positive results and that cirmtuzumab will eventually become an important new weapon in our arsenal to fight CLL.
For relapsed and refractory patients, admission criteria are pretty standard and there is no mention of prior transplant excluding admission to the trial.
ROR1 has been a long, long time in coming.
Is it the future? It looks promising and safe in the lab and animal models, but only the clinical trials will tell us for sure.
As I have said before, the science only advances when one of patients facing a tough therapeutic decision decides that joining a clinical trial makes more sense for a host of potential reasons than standard of care. I did and it turned out to be a good bet.
Dr. Brian Koffman 9/24/2014