ASCO 2014: Dr. Kipps Discusses ROR1 and Information about a New ROR1 Monoclonal Antibody (cirmtuzumab) Trial in Relapsed and Refractory CLL (chronic lymphocytic leukemia)

Mural Detail by my son Benjamin Koffman

I am just back from a very exciting AACR (American Association for Cancer Research) Hematologic Malignancies Conference that was focused on pre-clinical research pointing the way to better therapies in the future for CLL and all blood cancers.

I will be sharing some of the most promising and clinically relevant research from that meeting in Philadelphia over the next several weeks, but first I wanted to post this timely video from ASCO earlier this year with Dr. Tom Kipps out of UCSD as there is now a chance to see 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. At the AACR meeting in Philadelphia, when I asked the father of FCR, Dr. Michael Keating out of MDACC how I might cure my own CLL, he quickly said ROR1 therapy (both MDACC and UCSD are working on CAR-T directed at ROR1- See this post with Dr. Wierda from back at ASH 2012). 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.

Here's the link at clinical trials.gov and here is a news article on the trial.

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 tragedies with 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 cohort 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.

Forbes says: "With So Many Terrific New Drugs For Chronic Lymphocytic Leukemia (CLL), Why Worry?" I say it's a Tempest in A Teapot

Hydra (mythical monster that grows two heads when you cut off one)

Elaine Schattner wrote a provocative and helpful editorial in Forbes: With So Many Terrific New Drugs for Chronic Lymphocytic Leukemia, Why worry? I recommend we all read it, but that we also read it critically.

It has to do with her concerns about the dangers of unnecessary treatment.

My friend and fellow cancer advocate Andrew Schorr wisely reminds of us a friend with CLL who has done very well without treatment for nearly 18 years.

We know that about three out of every ten of us diagnosed will follow a very indolent (slow) course and never need treatment.

And so the author cautions us to avoid unneeded therapy. Good counsel. Never take a treatment that's not needed. All drugs and I mean all drugs have side effects. 

Her concern and motive for her editorial is that thousands of us will rise up demanding that our hematologists offer us the new expensive therapies just because they are so darn safe and effective when we would be better off doing nothing, just watching and waiting. Hordes of CLL patients will ignore the carefully tuned 2008 iwCLL guidelines on treatment, and demand an immediate prescription NOW before we are in troubled waters.

I believe it's a false concern. 

A powerful and practical reason that Ms. Schattner is worrying over nothing is that these expensive drug are not yet approved frontline  with the notable exception of ibrutinib in 17p deleted patients as detailed in this recent post). It is highly unlikely our medical insurance is going to pay for an off label use of a pricey therapy when there is ZERO data to support it. And of course, there are vanishingly few of us that could afford the out of pocket cost of at least several thousand dollars per month for any of the new star therapies (in order of appearance on the CLL stage): ofatumumab, obinutuzumab, ibrutinib and idelalisib. And of course, even frontline approval is not the same as approval (and insurance coverage) when there is no indication to treat.

That said, I am sure that there will be a few patients among us who will think it is the height of craziness to sit on our hands. We should strike the cancer while is still in its infancy well before it has the time to achieve its typical mature persistence and wily ways, making it such a formidable foe, making a cure still a dream for almost all of us. Kill it before it grows into a multi headed hydra.  

But a quick review of the facts should dissuade us from this tempting but false path. There is absolutely no evidence that early intervention helps. In this oft quoted article from 1988, Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation, and this one from the NEJM in the same year show we learned that there was no survival advantage to early intervention. And there are certainly risks. Studies such as these reinforces the importance of knowing the data and also knowing where there is no data.

Wait you say: Chlorambucil may have been state of the art in 1988, but today we have better therapies. Might not the results be different if we looked again using today's drugs? 

Good question. The same sort of trial was set up with FCR, but died on the vine due to lack of enrollment.

That is why trial such as this closed trial on using lenalidomide or this new one using ofatumumab are so important and need our support.

Although prognostic factors such as FISH and ZAP 70 and mutation status tell us much about a group of individuals and little about the individual members of that group, wouldn't we all want to jump out of the high risk frying pan and get far far away from the heat in the kitchen to a calm and cool place of low risk if we could do so by intervening early?

That's is exactly why we need more studies to answer if it is possible to save more lives by using the new mAbs such as ofatumumab and obinutuzumab and the new TKIs such as ibrutinib and idelalisib and others in the pipeline before we traditionally need treatment. There is good reason to believe it just might be so, but without data…. it's only conjecture.

So what do I recommend?

I believe all these drugs should be moved towards more frontline therapy for all patients with the help of well designed trials,  not just those of us with high risk prognostic factors.

I believe these drugs should be studied in those of us with high risk unstable disease BEFORE we need treatment. 

And maybe I am about to sound like a doctor when I say this: I also believe that outside of a clinical trial, there is absolutely no role for these drugs for patients who don't meet criteria for treatment.

The Forbes editorial ends with some sage advice:

“As with other malignancies, the best way to prevent overtreatment is to assure that doctors are current in their education, knowledgeable of “lesser” treatment approaches, and not motivated by financial incentives to give therapy. And for patients, the best prophylaxis is to know that not all conditions carrying a malignant label warrant treatment. Patients might ask, “What’s the least toxic therapy you can give, so that I’m likely to stay alive with the quality of life I want, with this particular form of cancer?”

That's precisely what we are trying to do here. Educate doctors and patients about low toxicity options.

IF YOU WANT A PERSONAL RESPONSE OR TO JUST STAY IN TOUCH, PLEASE SEND YOUR EMAIL ADDRESS TO BKOFFMANMD@GMAIL.COM AS I OTHERWISE DO NOT RECEIVE THEM.

iwCLL 2013: My Advice to Patients about their Therapy and How to Talk with Your Doctors: Shared Decision Making

It was a delight for me to be asked by Andrew Schorr on behalf of Patient Power to be interviewed in order to share the patient's perspective on how to use all the news from iwCLL 2013 in Cologne, Germany.

I particularly like the way he took the trouble to highlight some of my points with the superimposed text.

Over the next weeks, I will have many more informative interviews to post with Drs. Kipps, Kay, Furman, Hallek and others, but I thought I would first let you hear my counsel on how to best deal with your doctor appointments.

In the meantime, please let me know what you think of my suggestions and please add your own tips and advice to the communal discussion.

This is a tricky time. So many new CLL therapies on the way, but none of them are here today, except of course in clinical trials. The right approach will be different for each and every one of us. I hope this video gives some ideas on how to have the conversations that best inform our decisions.

My recommendations touch on "share decision making" or SDM, a critical and growing part of every patients' and doctors' future. It is even incentivized in the Affordable Care Act. Here one link that has a nice general discussion and video.

iwCLL 2013 Cologne, Germany