Saturday, November 24, 2012

Clinical Trials: Ibrutinib (PCI 32765), GS1101, ABT199, AVL 292, CAR-T, GA101 and all the Others

At the very engaging, patient education oriented, annual Lymphoma Research Foundation Meeting earlier this month in Manhattan Beach, CLL was among the invited guest, the only leukemia with a place at the table in the three days event, because CLL is at once both a lymphoma and a leukemia. In fact the official name, CLL/SLL or Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, recognizes that dual nature. The clonal fingerprints are identical for both disease. It is just that in SLL none of the cancer has spilled out into the blood stream. Yet. This dual labeling is a good thing as it allows us with CLL/SLL access to more meds (some that are used for leukemias and some that are used for lymphomas) and more importantly, access to more clinical trials.

One of the big pushes at the meeting was to encourage those attending to consider those clinical trials. Pharmacyclics and other pharmaceutical supporters had booths and brochures explaining the trials that they are running.

Speeches from happy patients in deep and durable remissions and from cutting edge researchers told us why clinical should be a dog-eared bookmark on our web browser.

The poster boys for selling the risks and benefits of the trials to all patients with lymphomas were two early studies involving new CLL drugs (Ibrutinib and GS 1101) using the visually powerful waterfall plots that tell you about shrinking tumor burden.

Here is some of the early data on ibrutinib (PCI-32765) similar to what was presented.  I could show similarly impressive data for GS-1101(CAL 101).

Every picture tells a story. It's easy to see at a glance that for the vast majority of the patients their tumor burden shrank dramatically.

For many of the attendees this was their first exposure to both the brave new world of tyrosine kinase inhibitors and to what could a trial do for you. I was approached by a few with questions about what was this magical  medicine and how could they get in on the action.

So here is my take on clinical trials.

Now I am not talking about letting your doctor pull off a few extra tubes of blood at each visit to bank for studies down the line. Everyone should say yes to those research requests. 

I am talking about therapeutic trials.

First and foremost, you must need therapy. No matter how excited you are about a new medication, the guidelines as to when to initiate or resume treatment do not change if the therapy is tried and true, cutting edge, or experimental. Maybe 30% of us will never ever need any treatment and remissions  from standard chemo-immunotherapy such as FCR can be remarkably durable. If we don't need treatment, we don't need treatment.

Let's say we do need therapy and we are doing the research to find our therapy choice. Here is where my advice about picking our team of experts becomes so critical, because without a CLL guru at the helm of our ship, we may never know or have easy access to all our options. Each of the top guns in CLL aspires to be the one who discovers the next big thing, and so expect there to be some bias towards his or her own trials. This is not entirely sinister as it is what they know best, and if we are seeing that doctor already, odds are a trial at his or her facility is going to make a lot more sense than traveling across the country for a similar option with all the risks of infections, and all the expense, stress, and just inconvenience that flying and hotel rooms entails. Ask me, I am an expert with trips from Orange County to Columbus Ohio every 3 and 1/2 weeks (and there are no direct flights). 

Still, there might be a better option at a distance. It is incumbent on us to do our own research on the web and at clinical That was certainly the circumstances in my case where my only option for an ibrutinib trial was across the country. Is it fun? NO. Is it worth it? YOU BETCHA!

When we are considering a trial, understand this is not a DIY therapeutic tour, but a tightly scripted and heavily escorted guided tour. This is important. Our appointments, biopsies, and CT scans are part of a rigid schedule, and if we don't like it, well, we can always leave the trial. We shouldn't enter a trial expecting it to change to meet our particular needs. When change comes though the IRB (Institutional Review Board), it is never quick and is always very conservative. They are watching out for our safety, but are also very sensitive to not corrupt the data by changing the rules midstream.

Understand what our insurance will pay and what it will not. Often the only costs covered by the trial sponsor is the medication and special blood tests that monitor its levels. How they get away with saying that a CT scan every three months is usually and customary care for CLL and that we and/or our insurance are responsible for the costs is beyond me, but somehow they do .

Look at what doors this trial might open, and what it might close. Having had a transplant as I have shuts off a lot of options. Will the treatment in the trial preclude further treatments or trials?

If it is a multiple arm trial, we need to be comfortable with all the possible options. Are they all realistic for our circumstances or is one arm a straw man chosen because it will be easy to best and represents nothing that we would ever consider? Can we live with letting a computer program randomly decide whatever treatment we will get?

Does it offer a cross-over if we don't respond to the arm to which we are randomly assigned? I believe that less CT sans and more cross-overs would go a long way to increasing the dismal rate of enrollment in most cancer trials in the USA. Why these are persistent sore issues will be a topic for a follow-up post.

Remember we are starting with the premise that we need treatment, so we can't compare the trial option to doing nothing. We must compare it to what we would do if we weren't in the trial. And that's the rub.

Honestly, despite these caveats, for many relapsed and most refractory CLL patients and for nearly all those with 17p deletion (like me), a trial is often our very best option. It is what I chose. And I am sure glad that I did. My circumstances would likely be very different if it weren't for Clinical Trial NCT01217749 at OSU and my daily 420 mg of ibrutinib.

Another point. We should not think of trials just as a last resort when we are knocking at heaven's gate. It is sadly so rare that such a miracle save happens. Trials are much more likely to be helpful at earlier stages of the disease.

Let's be honest. If the existing therapies were so great, the pharmaceutical companies, the universities, the NIH and all the researchers would not be trying so hard to come up with new ones and there wouldn't be the 1274 CLL trials listed on For comparison, strep throat is an illness we nailed decades ago with penicillin and there are only 31 trials listed, nearly all dealing with special populations such as HIV. Most of us with CLL need more research to get us better help, but for the vast majority of us with a strep throat, there are already easy cures.

What I am saying here is that is a desperate need to move the therapy ball forward, to improve our story. As Dr. Susan O'Brien succinctly said: "Those who need treatment for CLL will die of CLL."  Maybe not the cold truth we wanted, but if we are ever going to change that reality, it will be through clinical trials. Conventional therapies, as good as they are, will never change that paradigm. New treatments or protocols are our only hope for a cure.

That's why small phase 1 trials, where there has been an encouraging signal from animal and cell line studies, and now we need to know about dosing and toxicities, make more sense in CLL than in CML where options are already pretty good.

Phase 2 trials are great as there is more experience with the new drug, and now the research is looking at efficacy as well as adverse events. Sometimes the new therapies are used on their own or combined with other standard medications and sometimes new dosing schedules or combos of only already approved drug are tried.

The phase 3 trials are usually the ones that compare the new therapy to standard care and often involves hundreds and hundreds of patients from multiple sites. These are the easiest to find and enroll as they are usually big, but there can be very strict inclusion and exclusion criteria.

Truth is that we help with advancing knowledge whether or not the trial brings us any direct clinical benefit. While it's a good feeling to be beneficent, it is a much better feeling to be beneficent and healthy. Choose carefully. Ask for help.

Today, in CLL, they are so many promising choices in trials. The late Dr. Hamblin implored us to think laterally and trials are one of our best way to do that. 

Last point. With the increased understanding of the biology and structure of the cancerous CLL cells, the new targeted therapies that today are only available in clinical trials are often a better bet or at least an equivalent option when compared to the less specific existing chemo-immunotherapies. In other words, while we are lab rats when we enter a trial these days, odds are improving that we will be long lived lab rats.

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Anonymous Anonymous said...

Excellent post. Thank you, TomD

November 24, 2012 at 8:04 AM  
Anonymous Anonymous said...

Thanks Brian! Chaya has always said "risk vs reward" and as you state you have to do due diligence and then jump. Bottom line is we have cancer and most of us have a "new" normal and are traveling into the unknown. I am in the ABT199 trial and doing better thus far than any other treatment I have had. When I was making the decision of what to do you took the time for a phone call, thank you, again for taking the time. Percentage of leukemic cells in my white cells now at .02% and it was at 67%. Adverse side effects are so small they go unnoticed. All your check points are spot on. When these trials hit the phase 2 and 3 stage many patients will by pass the FCR for a dance with these targeted therapies. Based on what we are seeing so far maybe we have finally entered the days of disease stabilization without doing major harm to our bodies. Fingers crossed.

November 25, 2012 at 7:51 AM  
Blogger Randy Shirley said...

Tnaks DR. Koffman, You just about summed it all up in how I feel with the trial I am on. Best to you!
Randy S.

November 25, 2012 at 10:46 AM  
Blogger Randy Shirley said...

Very well said Dr. Koffman, much of this is how I feel with my own trial.
Best wishes!
Randy S.

November 25, 2012 at 10:47 AM  
Anonymous Anonymous said...

mHi Brian!
After my CLL relapsed (FCR-lite treatment and less than 2 year remission)I enrolled into the same ibrutinib trial you are in. I am doing it at Vanderbilt University. So far so good. The lymph nodes are shrinking and the only side effect is extremely good mood and the general feeling of happiness :) Thank you for all the information you share with us! Marina K

November 26, 2012 at 1:18 PM  
Anonymous Misty said...

You have been a routine source of insight and comfort since my diagnosis only two months ago so I am reluctant to say anything negative here, but...I wonder about the validity and benefit of such broad statements by Dr. O'Brien: "Those who need treatment for CLL will die of CLL." What does that mean? Everyone? At any age- from 43 (like me) to in their 70s? Regardless of prognostic indicators? As it happens, I don't need treatment yet, but if I do I'd like to (and have to) believe
that is not an indicator that I will die any time soon. I imagine her statement is based on some scientific evidence but what are the missing variables? Anecdotally, I have already heard of long remissions and older people with CLL losing their lives to other diseases. I don't mean to be Pollyanna here, but that kind of statement (without context) provides little in the way of hope.
Respectfully yours,

November 27, 2012 at 11:15 AM  
Anonymous Anonymous said...

Good read on future for Ibrutinib

November 27, 2012 at 1:11 PM  
Blogger Terry's CLL Journey said...

Thanks for the post; it struck more than a few chords with me. A few of my personal observations about clinical trials. First for those 30%, count your blessings. Secondly, your financial situation, your insurance issues and your residence, in most cases, dictates if you are able to be in a trial. And lastly, your personal CLL history can make or break you. Such things as never being treated, being over treated, not having a transplant, being over 65, being resistant to a certain drug, having a certain genetic marker, etc, and the list goes on and on.
I am fortunate to have been on 2 Clinical Trials. Yes, I say fortunate, because in my personal situation, NORMAL (whatever that is) treatment would not have worked for me. I have been on a Phase 1 trial and some people make the assumption that all Phase 1 trials are the same and you should shy away from them. THIS IS NOT THE CASE. My Phase 1b trial was with ABT-263 + Rituxan + Bendamustine. The only reason why this was a Phase 1, is because they had added 2 drugs to ABT. The dosage and frequency for ABT had already been determined in testing over 18 months before I entered the trial. You are correct in telling people to INVESTIGATE and EDUCATE themselves on the details of the trials. Call or email the coordinator. Believe me, they are more than willing to talk to you because they need you in the trial.
In October I entered the Phase 3 trial for Ibrutinib OR Ofatumumab. It was a roll of the dice. 50/50 chance of getting Ibrutinib. I thought it was worth the risk since it may be the only way you can get Ibrutinib until it is approved. It turns out I got Ofatumumab. Sure I am disappointed, but the good news is that O is working for me, and more importantly I am not burning any bridges for future treatments. This trial (called a Registration Trial) is one of the final steps before FDA approval, but there is no crossover, so for 6 months, I have to get all the CT Scans, blood work, etc to be qualified participant. And I can opt out at any time, but I don’t see that happening. Yes, I will have made over 15 visits to UCSD in 6 months, but I am hoping that O gives me a long enough remission to be first in line to get Ibrutinib. The trial has 17 trial locations in the U.S., but to date only has 50 participants. Although they won’t say how many patients they would like to have, I have heard the number 30 / site mentioned. Do the math; it has about a 10% participation rate. I think that is actually pretty high for most trials, and it is a shame. Yes, there are risks, but that relates to everything in life, not just CLL. For me, it was a no-brainer; I just wish more people had the opportunity to participate in trials.

November 27, 2012 at 8:41 PM  
Anonymous Anonymous said...

Thank you for all you do, Dr. Koffman, to bring the trial information front and center.

Some of the challenges with clinical trial enrollment are geographical. For example, I checked recently and found only 1 open trial for relapsed/non-transplant B-cell NHL/CLL in the Boston area. There are many more options in New York City.

One observation is that the centers will offer what they have, for concern of losing patients or losing control over the cases and outcomes. Why should someone need to consider a SCT at Dana-Farber when a btk inhibitor might be effective and far less toxic?

I understand that in certain states, insurance companies are not yet obligated to cover the associated costs (e.g. CT scan, labs, BMB). Hopefully the Affordable Care Act will change this scenario.

Mike Abrams
Warwick, RI

March 22, 2013 at 5:51 AM  

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