Kinase inhibitor trials
Mind you, I am just as enthusiastic as the rest of you in hoping these new drugs will prove to be important addition to our arsenal against CLL. But just in case I was too subtle and you did not read between the lines of my previous couple of reviews of kinase inhibitor trials (CAL-101, PCI-32765), I have been a little frustrated by the design and conduct of these trials thus far. I prefer clinical trials that are (1) more transparent (2) do good science while they are about it (3) let the chips fall where they may when discussing clinical trial results and especially adverse efefcts (4) last but by no means least in my opinion, be more concerned about patient safety – and not so much about rocking the boat of the drug company sponsors.
So, it is with considerable relief and enthusiasm I bring to your attention a hot-off-the-presses new clinical trial of PCI-32765. It is so new that it has not yet been announced on www.clinicaltrials.gov . I am not kidding when I designate this trial as this year’s timely Christmas (substitute the holiday of your preference, if you do not like Christmas) present for our patient community.
If you are even the tiniest bit interested in participating in a well designed kinase inhibitor trial, or heck, you just want to learn about a family of drugs that may be the greatest thing since the age of monoclonals, I suggest you sit up, pay attention, and read the details below. And I suggest you log-in to follow the member discussion that follows my review as well. We have some very smart and well informed members on this site, if I say so myself. You can learn a lot from their comments.
If you wish to learn how these new family of drugs work, I recommend an earlier article where we discussed a cartoon version of their biochemistry.
A well designed trial
What do I like about this trial? Let me count the ways, in brief. But since it is next to impossible for me to be brief about anything for too long, the bullet point summary below will be followed by a longer (much longer) exposition of the details. Who ever said patient advocates have to be succinct? And since this review is a bit of a scoop, details ahead of the formal announcement and so forth, I want to make sure you guys have a real head start. The more you know about the details of this study, the better you will be able to make an informed decision about participating in the trial.
What I like about this trial:
- Very sensible inclusion criteria open this trial to a large section of our patient community.
- I cannot find fault with their plans to do detailed science while they are about it. I will have more to say about what you can do to facilitate this, in the editorial section.
- The trial design is very detailed in how they plan to protect patients from adverse effects. I like that.
- This research group has a track record of patient friendliness, world class expertise and quality of care that few institutions can better.
- Icing on the cake: the trial is going to be conducted at the NIH (National Institute of Health), Bethesda, MD. If you are not familiar with the NIH/NCI clinical trial programs, shame on you. I urge you to read an earlier article – and even more important, our member comment section that follow it – to get a feel for what you can expect. Nothing like prior satisfied customers to spread the word.
- Pharmacyclics, the drug company that owns PCI-32765, does not pay for this trial. Your tax dollars do that – a good way of spending the money, in my humble opinion.
- Worried about the status of your medical insurance? Perhaps you are unlucky enough to be winging it without adequate medical insurance? Let me give you helpful hint. They do not (repeat, not) ask for medical insurance card when enrolling patients for this clinical trial. Some of our members who participated in other NIH / NCI clinical trials can tell you a lot more about how the financial stuff works out. Speak up, you guys. You know more about this aspect of it than I do. Your prior experience can guide the new volunteers better than I can.
Nothing in life is totally perfect
- This trial does not include all CLL patients, there will be some that will not fit the inclusion criteria. Left out in the cold are those young and feisty CLL patients younger than 65, unless they have been ‘blessed’ with 17p deletion. Pity. (I suggest you read the section on inclusion criteria below carefully – and be sure to confirm the details with the folks at the NIH. I do my best to be accurate, but the last word is not mine, it is theirs.)
- This is a single agent trial. We need to learn to walk before we can run. I have every expectation that down the road PCI-32765 and others like it will be combined with other drug regimens. But for now, we need to know what this drug can do, on its own; what it can achieve in all three major compartments where CLL cells hide: in the blood, in the lymph nodes, and in the bone marrow.
- This trial is only offered at Bethesda, MD. That may pose an accessibility problem for people who don’t live on the East Coast. But as you will read later, it may be possible to have much of the blood monitoring done by your local physician and fax the results in. The study drug PCI-32765 is an oral pill, so no need to come to the NIH for lengthy drug infusions etc.
- Actual recruitment will begin after January 1, 2012. Please don’t make a pest of yourself and tie up their phone lines with requests before then. Use the time between now and then to get your thoughts together, discuss it with your family, make sure you are truly interested in participating in the trial; get your medical information in one place so that you can answer questions etc. Do your due diligence!
- I will publish contact information and any other updated information regarding this trial after January 1, 2012. Keep an eye out for it.
- The number of people they plan to recruit is unfortunately limited – but I suppose that is to be expected. First come, first served, folks. Word to the wise, I am pretty sure this trial will be sold out quite soon.
Clinical Trial Design
Dr. Mohammed Farooqui is the Principal Investigator of this trial. I do not personally know Dr. Farooqui. But I do know Dr. Adrian Wiestner, who is medically responsible investigator for this trial. Dr. Wiestner is on my very short list of good guys. I remember giving him a very hard time when we got into an argument at an ASH conference. I am glad he did not hold it against me, and we have since become good friends.
- This is a Phase-II trial, single agent (PCI-32765) clinical trial. Two cohorts of patients will be recruited. First cohort is any CLL/SLL patient who is over 65, either chemo naive or previously treated, so long as they are presently in need of treatment (based on standard IWGCLL guidelines). The logic here is to see if this drug will give decent responses in ‘senior citizens’ who may be contra-indicated for aggressive chemoimmunotherapy combinations such as FCR or bendamustine containing regimens. This is particularly of importance in people who have already been through therapy and relapsed, the so-called “salvage” cases. Uggh. I hate that word.
- The second cohort is anyone with 17p deletion or dysfunction – irrespective of their age or the level of progression of their disease (yeah, they can’t be minors, they have to be older than 18. Crying out loud, do you know any CLL patients younger than 18? I don’t.). Logic of inclusion of this group is to see if early intervention in this very high risk group will improve otherwise bleak overall survival statistics.
- Left out in the cold are CLL patients younger than 65, unless they have been ‘blessed’ with 17p deletion. Pity.
- PCI-32765 will be given at a dose of 420 mg/day without interruption. It is an oral pill, you can take it with meals or all by itself. This dose was identified as appropriate in the earlier trial.
- After 6 months (6 cycles, each cycle is 28 days long), patients will be re-assessed using CT scan and physical examination, as well as blood tests.
- If they have done well on therapy for the fist 6 months, after a 3 month drug holiday (if necessary), drug treatment can be continued for a total of 12 months at the NIH. It may be possible for patients to continue therapy beyond 12 months under the supervision of their primary care physician – if the drug is still working well for them and there are no intolerable side effects.
- There is a ceiling of 64 on the total number of patients to be recruited.
- None of the researchers or staff involved in this trial have any financial conflicts of interest with this drug or its manufacturer. Pharmacyclics supplies the drug to the NIH for the purposes of this study, but does not in any way compensate any of the researchers or staff.
Inclusion Criteria Details
Please read this laundry list carefully. Most of it is quite familiar. You have seen these inclusion criteria before. But as always, devil is in the details and you need to know if there is anything in here that becomes a red flag for you. All the same, if you are not sure that you fit the bill, you should check with the PI yourself – rather than taking my word for it.
- I have already described the two cohorts they will be recruiting. Those over 65 (treated or naive) who need treatment now, and those with 17p deletions or dysfunction – irrespective of age.
- You must have confirmed CLL. That means ALC higher than 5K, or confirmed case of SLL where all the cancer cells are hiding out in the lymph nodes and very few of them are in the blood. You must have immunophenotype of CD5, CD19, CD20 and CD23 – this is the confirmatory fingerprint of CLL that we have discussed many times.
- Need for treatment is defined by the usual guidelines set forth by IWGCLL
- Neutrophil counts need to be higher than 0.5K and platelet counts above 25K.
- You must not have had pretty much any CLL therapy in the past 4 weeks prior to start of this therapy. Frankly, I think it will take longer than 4 weeks for all the paperwork to be sorted out – so you would be past the washout period in any case.
- People whose CLL has transformed to more aggressive lymphoma (“Richter’s transformation) are excluded.
- If you have AIHA or ITP that requires you to be on steroid therapy, you cannot be in this trial.
- Your liver function cannot be totally shot. Bilirubin cannot be more than 1.5 times upper limit of normal range. ALT / AST cannot be more than 2.5 times upper limit of normal. (Folks with Gilbert’s syndrome are exempt – these guys have unusually high creatinine).
- As for kidney function, creatinine cannot be more than 2 times upper normal limit. GFR (glomular filtration rate) must be at least 50 ml/min.
- No active or latent Hepatitis B infection, no HIV infection.
- You must be sane enough to sign the consent form, older than 18 years of age, chronologically speaking. Young-at-heart does not disqualify.
- You must promise to use contraceptives, so that you don’t make babies while on the trial, even if you don’t think you will be feeling frisky enough to do so.
I think I got the lot of them. Phew.
Monitoring, Evaluation, Science
It is important for all of us to remember these are clinical trials. We don’t have all the answers, and that is the point of doing these trials – to find the answers. It kind of makes sense to use the opportunity to learn as much as we can, don’t you think? What is the point of going to all the fuss and expense, not to mention risk to our patient volunteers, if we then pull our punches when it comes to doing good science?
- You will be given a full physical examination and your medical history taken during the eligibility assessment. Various blood tests will be done for establishing liver, kidney function, hepatitis, HIV infection etc.
- A CT scan (neck to pelvis) will be done to evaluate the level of lymphadenopathy (size of swollen nodes). There will be a repeat CT scan after six months on the drug, to assess effectiveness of the drug in shrinking swollen lymph nodes.
- EKG will be done to check out your heart.
- Pregnancy test to make sure you are not.
- You must be evaluated at the NIH at certain time points in order to make sure stuff does not fall between the cracks. But interim weekly blood tests can be done at the NIH or through your local healthcare provider, with the results faxed to the NIH. This flexibility may be a huge relief to patients who are far away from Bethesda MD.
- You will stay on the drug for 6 months (six cycles, 28 days each), as long as you are benefiting from it and the adverse effects are not excessive. Then following a 3 month “holiday” (if needed), you can continue on the drug for another 6 months at the NIH. Of course, if the drug company goes belly up in the middle and stops supplying the drug, everything comes to a screeching halt. And you always have the right to quit the trial – that is your prerogative as a volunteer in any clinical trial.
- With your kind permission, they want to do a bone marrow biopsy before start of therapy. Same for a lymph node biopsy. And they would like to repeat these two again after 6 months on the drug. I have a lot more to say about this in the editorial section.
- You may be asked to participate in a cool experiment where you swallow a small amount of “heavy water” (this has an isotope of hydrogen other than the garden variety isotope coming out of the tap). By following this “tagged” water in your blood samples etc, researchers will be able to understand better how this drug works, its mechanism of action in clearing CLL cells out of their protective microenvironments.
- You will have full access to all (and I mean ALL) of your medical data gathered during the trial. Just ask for it, if you want it.
Supportive Care
We do not know enough about the possible adverse effects of these new drugs. That is the whole point of dong these clinical trials, so that we can find out what may be lurking in the bushes. Do kinase inhibitors cause more than normal drop in immunoglobulins? Is there an increased risk of pneumonia? Is this due to infectious agents (bacterial, viral, fungal) or is the pneumonia more akin to drug induced lung inflammation? How long can patients stay on the drug and benefit? Enquiring minds want to know.
- We do not know how PCI-32765 interacts with other drugs that the patient may be taking for other medical issues. It is important that the patient discuss all medication, herbal or otherwise, with the Principal Investigator (PI) ahead of start of therapy.
- Allopurinol (protection against risk of tumor lysis syndrome) will be given prior to start of therapy, at the discretion of the PI. I suppose it depends on the assessment of the patient’s overall tumor burden.
- If the patient is seen to be at increased risk of opportunistic infections, TMP/SMX (“Bactrim”) prophylaxis will be provided; or alternate antibiotic if the patient is allergic to sulfa drugs.
- Anti-viral protection for HSV will not be used routinely, but will be given at the discretion of the PI. (While we are on the subject of Herpes virus, be sure to tell the PI if you have had prior episodes of shingles and concerned about a repeat attack.)
- If the patient develops neutropenia, Neupogen or Neulasta prophylaxis will be used.
- Epoietin growth factors such as Epogen, Procrit will NOT be used in case of anemia. Good! CLL Topics was way out front in warning of the risks associated with use of Epo drugs in cancer patients (“The dark side of Epo“). Instead, this clinical trial will use good old fashioned packed red blood cell transfusions. All required blood products will be irradiated prior to use, to further protect against infections. And if you need to get blood transfusions while you are at home, they ask to talk to your local guy to make sure you will get irradiated blood products only.
Editorial
As promised, this has become a very long review. I hope you will read it carefully, as well as participate in the discussion that follows. Lots of details to get at first reading – but I thought it was important to give you as much information as I had. Once the clinicaltrials.gov citation is up, you can verify most of these details there as well.
I have been a researcher and scientist all my adult life. While I am not a professional oncologist or hematologist, I do know a little something about how to design an experiment such that it has a chance of yielding credible information. My pet peeve with the design of the recent kinase inhibitor trials is the lack of adequate science in their clinical trial protocols – not to mention detailed scrutiny of potential adverse effects and what may be causing them (one in four chance of grade-3 pneumonia, anyone?)
Previous investigators of PCI-32765 said the only reason to do before and after bone marrow biopsies is to confirm MRD negative remission status, and since BMBs are not needed for staging patients, no point in doing them. I humbly beg to differ. Bone marrow biopsies are needed to judge whether or not this drug (and others like it) can clear the bone marrow compartment. Telling us that we can infer this critical bit of information based on improving blood counts is specious and disingenuous at best. Since the claim to fame of kinase inhibitors is that they interfere with CLL cell microenvironment, surely we need to confirm this happens both in the lymph nodes and the bone marrow?
One of the researchers was quoted as saying they did not do BMBs because patients don’t like them. Well, while we are on the subject of what we do not like, we do not like having CLL either. And we do not like being condescended to. When was the last time you felt research protocols were being written with your liking or disliking being taken into account? You want me to sell you a bridge in Brooklyn?
I do not expect any of you to volunteer for a clinical trial solely for the benefit of humanity. You would not be signing on the dotted line of the consent form unless you thought this particular drug would do you some good, that it has a reasonable chance of being better than the alternatives you have available to you.
That said, there is a level of idealism in all of us. We are not quite willing to donate our bodies to science while we are still alive, but if there is anything we can do to help our fellow CLL brother/sister, without going too far out of our way, I hope I can count on each and every one of you to step up to the plate. If you tell me I am crazy to expect that, no one really cares about anyone else, then I might as well shut down this website. Why bother, if each of you does not feel a similar sense of camaraderie for the rest of our little community? We can hope for success, pulling together. Or we can each fight this disease alone, all by our lonesome selves. Which is it going to be?
And then there is this little thing called familial CLL. This “good cancer” will not look even a little bit “good” if someday one of your kids or grand-kids inherits it from you. Kinase inhibitor drugs may be in early stages for us old geezers now. But they may make all the difference to the next generation of patients – if we help make possible well conducted clinical trials looking for results based on solid science.
So. Here is the proposition. You get accepted into this clinical trial. You are not crazy, you are not particularly into S/M lifestyle, you do not enjoy the prospect of a bone marrow biopsy before and after completion of therapy. Same goes for a lymph node biopsy. But pretty please, do say “yes” to both procedures if you are asked. One not-so-bad pinch on the rear-end for you, one giant leap of scientific understanding for our patient community. We will be cheering your courage and bravery from the sidelines, I promise you. We hope the researchers will thank you, but you can be sure we will.
As for the heavy water experiment, that is a slam dunk. It has been done before (at Long Island Jewish Hospital, under the supervision of Dr. Kanti Rai, if I remember correctly) and it is zero hassle, you just drink this little vial of “heavy” water (no, you will not glow in the dark and your urine will not turn blue either). There is very little risk of toxicity of any kind. Do say yes, if you are asked. Just think, how cool it will sound when you describe it to your buddies – or better still, your grand-kids.
See what I mean about this triala being a Christmas present? Not just a Christmas present for you, but one that you can give the rest of the patient community – by participating in this clinical trial and supporting the necessary science. This new family of drugs are too important to leave all the testing to drug company sponsored clinical trials. Here is your chance to make sure that does not happen.
44 comments on "A Well Designed PCI-32765 Clinical Trial – just about to open"
Darn! I don’t make the team! Still hoping for a more inclusive Phase III this year. By the way, I did the heavy water trial through MDA a few years ago and it was very easy. There was just a rush of dizziness after drinking the water. It reminded me of my college days ;) Enough said…
How about being a 11q and 62 years old. Just finished Revlimid trial at Roswell Clinic (got only a pr). Any chance for me.
Dave
I understand the kinase inhibitor is helpful to people whose CLL cells accumulate in the lymph nodes, as opposed to staying in the blood. But I thought that the kinase inhibitor was merely an aid to the cell killing chemotherapy. So, the question is whether the kinase inhibitor is of any value without the chemo?
Dansby:
Just getting the CLL cells out of lymph nodes and into open blood circulation seems to be enough to kill a lot of the little buggers. That is why other single agent trials that we have reviewed did see partial responses, even in late stage patients.
Down the road, I have no doubt they will pair kinase inhibitors with one or more other drugs which excel at picking off the CLL cells as they float around in the blood.
Dweisler: I don’t think so. Not this trial I am afraid. But you are welcome to ask the PI, there is no harm in asking.
Dansby-
My husband is on the PCI trial at MD Anderson and once the lymph nodes are forced to release the CLL cells that accumulate in the lymph glands into the blood stream, they are easy targets to be killed without another chemo. As I understand it, the future trials will use another drug to “synergize” along with PCI, but taken alone, it has been proving to greatly reduce the CLL in the bloodstream also. The bone marrow is another story.
Chaya–the list for drugs that cannot be taken while on PCI is quite a few pages long. Local Doctor’s have to check with the participating clinic when prescribing any kind of medication and over the counter herbs, etc., also have to be checked with the head of the PCI trial. I am forwarding you the list on your email for you to look over.
Jenny Lou
Figures…finally a trial that I would LOVE to be a part of…And, I qualify in every respect… EXCEPT I’m still relatively CLL free since my 2007 treatments!
Now I almost wish that the CLL had returned by now. Well, as CM said above, maybe the phase III trial…
Harley
Chaya-
First let me mention that I took your advice and entered the NIH clinical study on the history of cll. Then, when treatment was needed, I entered the clinical trial at NIH for FCO-after reading your review and receiving your advice. And, I did get the “coveted MRD status”. Treatment was not easy for me, but where I stand now, it was so-o-o-o worth it. I’m in remission:D
So, when I read who was going to be the PI for the PCI-32765 clinical trial, I knew it would have to be a well designed trial. I cannot say enough good about Dr. Farooqui. He is one heck of a doctor that made himself available 24/7. There were times during treatment that I really did not know if I would make it through. Dr. Farooqui is caring, so patient, a gentleman and so knowledgable.
As for all the others at NIH-Dr. Weistner, Dr. Aue, Janet Valdez, Susan Soto, infusion nurses, hospital nurses-everybody is a class act. Working with the team created a very organized and caring environment. The BMBs have been painless. For lymph node biopsy, I was put to sleep. I have been able to trust all involved which has been important.
Unfortunately, I had the 17p before my remission. However, reading your review makes me want to say “fortunately”. The reasons I entered the FCO trial was because I do have children and grandchildren and because I wanted to help get us closer to finding a cure. I will discuss this new trial with Dr. Farooqui at my next visit in Jan.
Chaya, thank you again for all you do for us. You are a gem.
Sounds like the CLL trial of the year for those that qualify. Currently participating in the “FO” trial at the NIH, I can tell you that Dr. Farooqui is a brilliant young doctor just finishing his 4th year fellowship. And yes, I agree that Dr. Wiestner is one of the good guys. I have deep respect and admiration for both of them. I interface more often with Dr. Farooqui. He has a gift for making you feel like you are his only patient.
The heavy water was a breeze during the early part of the “FO” trial. I tasted nothing more than water and never got dizzy-just had to remember to drink it as per schedule.
The very best to those who do participate in this trial. We applaud you and will be closely following your progress. And thank you, Chaya, for so beautifully presenting and outlining this trial.
June
As only 64 will be admitted into this trial, my guesss is that it will fill up rather quickly.
I’m far too young for this trial but I’d certainly like to join the chorus in thanking those volunteers who step up to the plate to participate.
And thanks to the folks at NIH for conducting the trial. The participants are going to receive great care from a fantastic group of professionals at NIH. Perhaps as the trial goes through the paces, we’ll all get the answers with some good news we’re hoping to receive.
Thanks for sneak peek of the coming attraction of 2012, Chaya. Looks like it might be a very promising year for some needed answers.
Hooray !! So glad to see this article.
First, I love Dr. Farooqui. He is extremely attentive, communicative, caring and a gifted “hands on” doc. I’m sure those who have done the FCO/FO trial at NIH, and those in the Natural History Study of Untreated CLL Patients will second my emotion. He also did my totally pain free BMB. And, I am told there is also a PA at NIH who alternatively does the BMB who is extremely good. My understanding is that if you do the heavy water experiment, then you get a “two-fer” in that they will sedate you for the node extraction and then do the BMB while you are in that state.
I am thrilled that they are looking at ways for more remote patients to participate .. as in across the continent !! As I’ve seen in the description for another PCI single agent trial, the first month to six weeks might require closer monitoring than after one slides into a monthly pattern. After my October visit to NIH, when this trial was first presented to me as a possibility, my husband and I have been ruminating on how I can easily participate without monthly flights to Bethesda .. we’ve even considered renting a place for six months. And Chaya is so right ..the standard of care is phenomenal at NIH.
As to cost .. everything they do to you is free. Everything. I’m not sure what the procedure is if you have a side effect and are not near the NIH campus .. that my be when your insurance kicks in. I can talk about what was covered in the Natural History Study:
1) After you are “enrolled”, you plane fare is covered. You can make your own reservations or use the NIH approved travel agent. I found that agency only booked on United from SFO and, after being very rudely bumped by United, I will never fly them again. we are now big fans of Virgin America.
2) If you are coming for a visit that requires someone to accompany you, as in you had sedation, than the fare for that person is covered.
3) You get a stipend of $60 per day toward room and board. By Bethesda standards, this isn’t much so room and board will be your big expense. There are NIH rates at various hotels, but they vary incredibly from $99 (very difficult to get at the Marriott Residence Inn) to $189 (This is a discount rate? LOL .. at the Bethesda Doubletree.) I’ve seen comments on other forums about a patient guest house .. not my cup of tea as I “treat” myself while visiting NIH .. stressful enough to be there and to be so focused on my disease, sigh.
4) NIH has many shuttles toodling between hotels, the campus and Dulles airport. They don’t cover taxi fares even if you arrive after the last NIH airport shuttle. Another potential expense .. about $60 between Dulles and Bethesda. We’ve never needed nor rented a car for my Study visits .. but we tend to only stay three nights and some patients just fly in and fly out. Not my style; I’m into stress-free at this point in my life.
Wow .. this is such good news to see this trial move forward.
Thank you Chaya for this article and for all you do for us. It’s because of you that I found and joined the Natural History Study. Mahalo nui.
Lynn
Well done again! After all these years of reading and trying to understand (much time without much luck with the jargon), I think I understood every word of your last 5 posts. Good timing too because I my CBCs have been on a downhill march since Oct. ’09 (when coincidentally I ran out of the good green tea) and Dr. J says I will be needing treatment SOON!, so why not a trial? I am a relatively healthy, active and untreated 69-year-old. Trips to D.C. will be a cost burden, but perhaps we can find a reasonable place to stay, if chosen. Thanks for the Christmas present, Chaya. We wish a fabulous holiday and new year to you and your family!
Fran
Dr. Mohammed Farooqui:
I saw him on my last visit to NIH in August(Natural History Study). He was then in discussions with drug company re the upcoming PCI study and also deciding whether to stay at NIH as he was finishing up his fellowship. Young,highly intelligent and warm, we had a lengthy discussion on why patients are never thanked in trials (I guess we will get to see if he lives up to what he said, if and when this study is published!) amongst other subjects. I liked his approach and intellectual curiosity…no big ego(yet?)on this doctor. Good person to have running things…hungry for the truth, like many of his colleagues at NIH.
If you get in the study you will be in good hands with a great team.
I have personally thanked Chaya but will do so again here publicly. What an incredible gift she is to us.
She mentioned considering donating your body to science. I have already specified this but there is no way to be sure that my body will be used for any CLL research. It’s also a little hard to evaluate the company or university you choose. It’s not as if the Better Business Bureau evaluates these places.
As I have read many of the responses of the CLL community here on CLL topics the last 18 months, I still feel like a novice. I quess I should of stayed awake during my biology and chemistry classes. However, like Justice Potter Steward who when trying to define pornography said he may not have a fixed definition but “I know it when I see it”.
I can confirm Lynn’s experiances, at NIH. Mine too have been stellar. I may not be able to define what is the best way for me to help others while I help myself but “I know it when I see it”.
When I joined CLL topics one of the first articles I read was: A clinical trial perfect for our times. I was accepted into the trial and have been overwhelmed by the standard of care and responsiveness of the team. I am scheduled back in January for my third visit.
Dr. Adrian Wiestner did not even seem to mind me continuing quoting Chaya, as I asked a dozen questions and quoted “bucket list” and “prognostic indicators” ad nauseam. He, Dr. Farooqui, and other attending physcicians and nurses leave one with the feeling that the individual is as important as the science. Like all good symbiotic relationships, this is a win/win proposition, the person in the trials recieves first class medical care and the scientist recieves information that we hope may one day lead to a cure or most certainly a better quality of life.
Chaya,
I knew about this trial. DrWiestner was one of the doctors I interviewed at ASH. What a wise and caring person!
I had the chutzpah to ask him to amend the trial to include 11q del like me. Not now is what he said.
I am hoping my insurance will cover Byrd’s trial at OSU as it is probitively expensive otherwise. If not I may be out of options to get the best treatment for my massive nodes.
Be well
Brian
Merry Xmas Chaya and the larger CLL family. What an exciting hopeful trial it sounds. Thanks for this gift, maybe not for me, but for my children and grand children to be, I can rest a little easier.
Chaya-
Thanks for the news about this trial. While I unfortunately do not meet the criteria for inclusion (I am only 56 yo) I found the information and your your summary to be extremely interesting…and it brings hope that soon we will have more ways to truly manage CLL. Adding to your words and the words of others, I thank and applaud all those that are able and willing to participate in the trial.
Merry Christmas indeed!
Bob
I have been jerked around by Dr. Byrd for over a year trying to get on his PCI & O study. After he mentions this study, he keeps saying that I don’t need treatment. Then, several more waits when I did need treatment because other people needed it more than me. Then, in August, I finally say I need treatment–no more wait. The next cohort doesn’t start for another month. He says I can wait until then. Long story short, I ended up in the hospital (the week after my appointment where he says I can wait a month) because they suspected Richters. Ended up that they found CLL cells in my liver (rare, but it happens). He says that I could still get on this study, but I’m sure that he’s just saying that because he knows I’m furious. If you want volunteers, don’t jerk them around and let them keep getting sicker.
Just a quick note on bone marrow biopsy. I was asked by a researcher to donate some marrow because of some quirky marker I have. I agreed because I owe it to not only my biological family but also the larger family of CLL/SLL folks. Frankly, I am also up for any test within reason to advance knowledge of my disease and that of others. Science is our best ally. The great irony was that while my counts were just fine for watch and wait, it turned out my BM was heavily laden with nasty buggers. I was put in/let in a trial about two weeks following the test results – that opening was plain luck. (Revlimid and Rituxan with decent results so far.) Two important lessons: 1) if I had not made the donation, the doctor, who is topnotch, would have had no way of knowing what my actual status was, and 2) the people who perform these BM aspirations are highly trained and very careful to reduce the pain as much as possible. It is a low cost to pay for more information and the procedure is only 30 minutes at most. Sure, it may hurt a bit to a lot and you will be sore for a few days but people face far worse protocols.
Thanks for the information, Chaya, and even though I do not qualify, I thank those who do and who sign up for this trial.
JS
Thank you, Chaya, for this series of articles on the kinase inhibitors, and thanks as well to the others who have offered comments. This upcoming NIH trial is excellent news. I’ve been participating in the PCI 32765/Ofatumumab trial at OSU since May, with good results and no major adverse events. In addition to the questions you raise that the NIH trial may clarify, I would include the matter of seemingly spontaneous bruising which has bothered me and apparently others as well (the ASH abstract refers to “ecchymosis”). While this may not be life-threatening – for those not on blood thinners – it is at the least a quality of life issue. So far it is not well understood. I’ve had low platelets for years, but the bruising has been significantly worse since I started the trial. Overall, though, I’ve had a dramatically positive response in terms of WBC and spleen size. Bulky nodes have not been a major problem in my case, but they too (mostly internal) have reduced considerably. The drug sure seems worthy of more study.
Chaya,
This certainly is a great Christmas present for the CLL community. While I do not need tx now, my fish results are such that I will most likely need tx sometime in the future and I have been following the kinase inhibitors closely and am excited about what they may hold for us. Thanks for all the work you do for us.
Chris R
I love you!
Alan
As if Dr. Farooqui needed more praise to swell his head – well, here it is. I am yet another of the FO trial patients; and it would be hard to exaggerate his good points; and I can tell you I know this from my contact with him both as a patient under his care and as a doc who has seen the gamut of docs. Can’t wait to see the results of the BTK trial. Sounds great. Kudos to Dr Farooqui and all who participate.
Some points have come up in this discussion that I feel like I should comment on.
Regarding my own treatment by Dr. Byrd and the James staff, my experience has been the best possible. These early trials are necessarily small, and not everyone who can benefit from or who meet the criteria of any protocol can get in, and they are concerned about that.
The present Pharmacyclics study are preliminary, and many positive and negative observations for this hertofore untested drug have been made and publicly shared. These will have to be attacked in continuing research for resolution. More or less unanticipated potential AEs which have been identified for followup are bruising, lung infection, dizziness and possible vision issues. Essentially all of us with CLL are aging and also impacted by the cancer and previous treatments, so the effect of PCI on all of this is presently unclear. But directions for the next phase have been set. If the results warrant it, maybe FDA approval for general use will follow.
It dosen’t get any better than this. I am 6months out from starting PCI-32765 420mg monotherapy with Dr. Byrd at OSU. While I have had some issues develop during the time of taking PCI I believe they have origin with my previous treatment with R & F. This does not mean adverse events (AEs) will not come up for some patients but my particular ones being, heart tachycardia (high heart rate) A-Fib (irregular heart rhythm) and dry eye that I link to severe sinus reaction from Rituxan in March are A-typical to most patients’ experiences. (review my previous remarks in last article).
I appreciate your detailed analysis of the NIH – NCI Trial and can vouch for the character of Dr. Adrian Wiestner who was my prime Natural History of CLL Trial Doc in 2009.
In clinical trials outside of NIH, like the one I am in at OSU, we lab rats are CT scanned at 3month intervals so the 6th month CT scheduling at NIH is a plus and more than ample to judge efficacy in my humble uncredentialed opinion. The heavy water tracking is interesting as it is safe. To be honest, I appreciate the argument for BMB and I can only hope the “stocking stuffer” along with the X-mas “present” of the Trial itself is a highly gifted BMB technician. Lynn expressed the need for multiple BMBs and had a prior good experience unlike the one and only BMB I had which would temper one’s enthusiasm for the need. Having said that, I will willingly submit to a BMB at my Trial’s end even though it is not stipulated in the Consent agreement.
An interesting feature of this Trial is the 3 month hiatus after 6 months “if needed”. I am wondering what defines “if needed” to the point of declaring a rigid hiatus of 3months? Byrd and I discussed a hiatus of two weeks to evaluate effects on my eye condition but we decided on a drug reduction to 280mg per day instead. My drug reduction will be ongoing for 2 cycles and may yield interesting information as to whether the BTK remains 100% blocked which had been established at the 420mg dose. In the case of most drug trials, one of the primary goals is to establish the Maximum Tolerated Dose which usually means “stuffing” the lab rat with increasing amounts of study drug until toxicity appears with the idea that a maximum amount of drug is “good” and necessary to kill the cancer and defining efficacy. With the kinase inhibitors the paradigm is the opposite in that once the inhibition or blocking purpose of the drug is achieved, will more be better? PCI trials already in progress have been using doses ranging from 420mg to 800mg and in combo with usually Ofatumumab. The problem with a combo at this early stage is whether AEs are the result of PCI, Ofatumumab or the synergy of the two. This trial, which is essentially what I am on, is a superior design for which you did a great job of articulating its merits.
The NIH campus is culturally enriching with much art work in the main building (I think #10) where patients will go and do not pass up visiting the separate library housed at the other end of the campus but within walking distance. My prediction is that folks, on this Trial and in short order after taking PCI, will feel better than they have felt in a long time. If you have nodes – they will melt! LongTerm – Who knows? We are crossing a dangerous river and PCI is a pretty safe rock to stand on for the time being and more rocks to jump to will be appearing in the future. I am dancing – the CLL Bear is hibernating, may he sleep long!
WWW
Chaya – another home run! Thank you again & again for all that you do to keep the CLL community informed and armed w/valuable information.
Thank you for this information about the upcoming NIH/NCI clinical trial w/PCI-32765. I am currently w/w – not yet in need of treatment. However I think we are all grateful for these trials – which will help increase our CLL knowlege & hopefully improve our treatment options.
Since the trial design & conduct of these NIH trials are superior to the drug company sponsored trials (as you point out) – why aren’t the pharma sponsored trials required to have the same design?
I am especially struck Chaya’s comment that the NIH trial design is very detailed in how they plan to protect patients from adverse effects. Again why don’t pharma sponsered trials have to have the same design & conduct features as the NIH trials?
I happened to see my local hem/onc yesterday – I gave him a copy of this article. He agreed that overall the NIH trials are better designed than pharma trials.
Thank you again Chaya for all your labors in the CLL vineyard. You are an absolute treasure! And thank you to all of the CLL folks who post here and elsewhere – I am grateful to all of you for your thoughtful sharing and caring.
Warm regards – Patti
I am not old enough (sounds like when i was 19 and wanted to go to bars) to participate in this trial at 52 but I wnat to thank those of you who can participate. This trial sounds ground breaking and you are leading pioneers in hopefully finding a way to beat this disease for us and others to come.
Happy Holidays-!
Wayne-
that CT Scanning for PCI? After 3 CTScans in 9 months, Tom told Dr. Keating that he didn’t want to have them every 3 months as he felt it was way too invasive and not that necessary. Tom figured that Dr. Keating would say that to stay on trial he HAD to get the scans every 3 months as stated. But, he stepped in and now Tom is on a 6 month CTScan for PCI. So, ask your doc to side-step that every 3 month scanning if possible.
As far as BMB’s go for PCI rats? MD Anderson does one at the one year mark on PCI if all other counts and Flow show remission. No minimal disease can show via Flow. Tom does have MRD so his BMB was cancelled. If the blood isn’t cleared, then they know that the marrow isn’t cleared.
I also wonder about the “rest” period in the PCI trial starting soon. Tom had to stop PCI treatment for 3 days after being on it for 6 months and his lymph nodes swelled back at such a rapid pace that we could watch them grow visually—-it was so scary. Tom went back on PCI and the glands melted away again. I have not heard of anyone who stayed in any kind of remission after stopping PCI. Perhaps someone else has.
CClaver, if I understand the eligibility, ANY age (over 18) can participate if you have 17p deletion or bad tp53 function. Of course, if you are over 65, then you can have any FISH result.
Lynn
I am sure that all “kinase” treatments have different merits and dangers. Chaya is not big on anecdotal information and for good reasons. But with all the stories and comments on Kinase process limiting treatments, I will nevertheless mention a form of such a drug I am taking that is not part of a “controlled trial”. Rather, I am a lab rat in an experiment of one using an approved drug off-label. The drug is Rapamycin. Recently Celebrex has been added to the mix. My nodes are shrinking significantly with this treatment and similar to the reports on PCI and CAL-101, my WBC is increasing…perhaps at least partially caused from the dump of CLL cells from the nodes into the blood.
I had been on Rapamycin previously and had about 70% node shrinkage over about a 1 year time. But I reduced the dose a lot 4 months ago–after taking a mono-Campath treatment for 2 weeks. The Campath reduced a very elevated WBC to near zero, but as discussed in many places, including this site, it left my still significantly enlarged nodes in place. These reseeded the blood with CLL and WBC is above normal range again after 3 months. But it is still low enough that the crowding out stopped and my RBC are recovering well after being dangerously low before the Campath.
Starting up again with the Rapamycin/Celebrex, my nodes are again shrinking fairly quickly. The present plan is to take Campath again after my nodes are very diminished…unless the WBC gets limited from the present treatment after the dump from the nodes is nearly complete (please, may the present node shrinkage rate continue).
The only adverse affects I have seen between the Rapamycin and Campath was a few days of what I consider to be intense diarrhea. I won the lottery by not getting any infections during about 3 weeks with very low WBC. Immuno-globulins are still low, but also were before Campath.
In deference to Chaya’s desire to keep this site free of discussion about treatments that are not meeting the standard of controlled trials, I will stop here and will not respond to questions at this site. But if someone wants to hear more offline, my FaceBook name is: TSvi Howard Epstein. Write me a note please, rather than Friend me.
I am allowing Mr. Epstein’s comment to stand (rather than exercising my editorial rights and deleting it summarily) in order to highlight ground rules of this website that we have discussed many times before.
1. As Mr. Epstein correctly points out, I do not subscribe to one-of-a-kind therapy protocols or give weight to the results obtained from them. CLL comes in so many different flavors that it is impossible to draw valid conclusions based on such stories – in my opinion. Frankly I think they can be downright dangerous in the hands of needy cancer patients looking for any port in a storm.
2. For your information: Sirolimus (aka Rapamycin) is an immune suppressant drug given to patients undergoing organ transplants. It can lead to serious lung toxicity. Here is a Wikipedia link to sirolimus: http://en.wikipedia.org/wiki/Sirolimus . I am by no means an expert on the combination of sirolimus and Campath, but the two drugs do seem to have one thing in common: both drugs are famous for suppressing the immune system, especially T-cells and B-cells. People taking rapamycin are more susceptible to dangerous infections, according to the Wiki article. We already know that is the case with Campath, patients are at increased risk of opportunistic infections and viral reactivations. As for the combination of both drugs – buyer beware. I would not do this without strong clinical trial data to back up the logic.
3. In order not to have this discussion thread hijacked away from the PCI-32765 trial we are talking about here, no further posts on the subject of rapamycin + Campath, please. As the editor and owner of this website, I have both the responsibility and the right to control the kind of information presented here. For the “free-spirits” among you, there are plenty of chat rooms and websites out there with more lax editorial scrutiny.
Yeah, yeah. I know. I am a dictator worse than Kim Jong Il, how do I face myself in the mirror each morning, yada yada. I get it.
Thank you again Chaya. This is excellent news.
We are lucky to have an excellent resercher and scientist who worries and does not forget us, and is always in front with the news and discoveries.
A Happy Christmas for Chaya and all CLL community.
Thank you for your editorial policy, Chaya, and for exercising it as needed – it is part of what makes this site so useful (the low signal-to-noise ratio).
[My comment is not to deny that tsvieps likely had good intentions and was trying to be helpful.]
I am 64 and have CLL (dx 7/2010). I am “lucky enough” () to be 17p deleted (and also unmutated for IgVh). However, I have been fortunate so far that my disease has progressed not overly rapidly, despite the genetics, and I am still on W&W. My principal negative symptom seems to be fatigue and exhaustion (even though my RBC and Hb are still quite high).
I am excited about this trial, but should I be?
Speaking just selfishly for a moment, I can see that the trial might “turn the clock back” a bit on my disease, but, once the trial is over, wouldn’t my lymph nodes (and enlarged spleen) be likely to just fill up with CLL lymphocytes again? Or, might I actually be buying a bit of time?
Speaking more altruistically, I certainly would welcome whatever tests were needed to help with the trial (e.g., BMB’s, scans, heavy water, etc.) in order to make my “experience” as useful as possible for the CLL fraternity.
So, I am very interested in the trial, but wonder about the trade-offs. If I am correct, this is one treatment that would likely present little risk to expose my W&W status to (as compared to FCR, etc.) – would that be a correct assumption?
I did like Waynewells’ “We are crossing a dangerous river and PCI is a pretty safe rock to stand on for the time being and more rocks to jump to will be appearing in the future.” – I am hoping Wayne is correct…
Jlou,
My thoughts on the Trial criteria regarding an “if needed” hiatus from PCI and the stated time period of 3 months was done in mind with Tom’s experience that you had reported on.
Thanks for your sharing the CT issue and what Tom’s success has been in influencing what many of us view as over-use of that tool.
The MD Anderson use of BMB seems rational to me from your explanation. If kinase inhibitors were responsible for total removal of cancer from marrow, nodes and the blood was cleared it would be reasonable to discontinue treatment. Suspension of PCI before the blood is cleared raises the likelihood that the migration and adhesion factors, that the inhibition of the kinase disrupts, will cause rapid repopulation of nodes and most likely the marrow which are the centers of the mayhem and where CLL does its damage. BMB is a most important tool but must be employed judiciously to get meaningful data that is more than observations out of curiosity. Speed of CLL/SLL return after total clearance would probably refocus efforts on an origin of disease from HSCs (Hematopoeitic Stem Cells) or escaped LSCs (Leukemic Stem Cells) which may have unique characteristics of resistance.
Patti,
The design of any trial can vary but having a good doctor in charge of a trial may be more important regarding patient safety and success. Specifically regarding CLL/SLL my comment is probably more correct when pharma Trials are conducted at CLL consortium facilities like the one I go to at the James OSU in Ohio. My care under wing of Byrd has been excellent. :=)
WWW
My understanding is that if there is a good response to the drug, then the drug will be available after the six month trial. Details .. not sure.
Oops .. meant to say “after the 12 month trial” you would be able to continue on the drug.
fwcetus:
You ask good questions – hopefully this clinical trial will help answer some of them.
Based on what I have heard so far from patients who have participated in other kinase inhibitor trials (CAL-101 and PCI-32765), I get the sense that these drugs do a good job of driving CLL cells out of lymph node environment. Once out in the open, the cancer cells seem to be much more vulnerable to natural cell death, thereby bringing down the initial spike in WBC. No doubt this can be further enhanced down the road by coupling the kinase inhibitors with other drugs capable of killing the CLL cells in the blood.
No one knows whether the remissions obtained through kinase inhibitors will last, once the drug is discontinued. Early indications (and that is all they are, early indications) is that once the drug is discontinued, grow back of the CLL is pretty quick. In other words, these drugs may need to be viewed differently than more conventional therapy regimens. We are not really talking about getting long lasting remissions. These drugs are more likely to be maintenance drugs, something that the patient stays on indefinitely.
Which raises the question of long term toxicity of the drugs; equally important, will the drugs retain their efficacy when taken for a long time or will the CLL cells find a way around them and thereby develop resistance; some of the many questions that need to be answered.
As I understand the NIH protocol, patients who do well on the drug will be able to continue taking it for 12 months at the NIH. Thereafter, there is a possibility that patients may be able to continue for a further period of time – under the care of their local physicians (presumably the drug company has an interest in continuing to supply the drug to patients, in order to study long term effects).
I am in the process of participating in a study at MDACC that has “requests” for BMB’s. In addition to the first one I had about 2 years ago to nail my diagnosis, I’ve now had 2 more. And I’ve learned a few things.
To preface: if you are going to be part of a study and a procedure such as a BMB can provide quality data, it’s my opinion that it’s incumbent on the participant to provide as much data as possible. Not having the requested BMB’s performed is like withholding other information from the researchers such as muscle aches, gastric distress, headaches… *ALL* the data needs to be collected where possible. It’s an eyes wide open thing as far as I am concerned. If you are not willing to give full disclosure, including giving up some tissue, you are not being the most effective research subject you can be.
As for actually doing the BMB’s:
1) Do not be a hero. Even if you’ve had it before, you are going to get a bit worked up. Take the versed, whether oral or IV, and give it a chance to do its thing.
2) The local anesthetic will do its job if given the opportunity. To that end, tell the “driller” to slow down. An extra minute for each dose of the ‘caine to work its magic goes a very long way.
3) It has been my experience that the one thing that I can do after the procedure that will result in the greatest amount of reduction in discomfort is to walk. It seems counter intuitive, but just being sedentary made for days of ache and walking like an old man. As soon as they let me get up and move, I do. A really long, steady walk (from the Main building at MDACC to the skywalk that goes across Holcombe, over to the Mays Clinic building and back… at least once). It does help a lot.
Please help do good science. Give data.
Sit up, you guys. Chalk one up for patient advocacy.
For the longest time, the “official” response to any questions about clearing CLL cells from the bone marrow environment by kinase inhibitors has been an ambiguous and went something like this: the blood counts look good, therefore we can infer the bone marrow must be doing well too. Nothing to worry your pretty little head about. Nothing to see here, move along.
I will admit to a couple of experts getting a little sore at me for not letting this issue go, for “scaring” patients unnecessarily.
Well, here is the latest comment from no less than Dr. Furman on the CLL/SLL Yahoo site.
Fri Dec 23, 2011
CAL-101 (now GS-101) and PCI-32765 are both remarkably effective on lymphadenopathy, but less so on bone marrow. They do have impact on marrow but not nearly as dramatic as what is seen on the lymph nodes.
Rick Furman, MD
Exactly how “non-dramatic” is the bone marrow clearance – or lack thereof? Only better designed trials with good science backing them (including before and after bone marrow biopsies) will answer such questions. I am not saying this means the drugs are of no use. I am saying we need to know the facts, all the facts, when we make therapy decisions – since it is our bodies, our lives on the line. More transparency please.
“Only better designed trials with good science backing them (including before and after bone marrow biopsies) will answer such questions.”
And that is ~precisely~ why the study in question on this page should attempt to get as many as possible of the participants to agree to before-and-after BMB’s. (Perhaps this should be a trial ~requirement~ rather that a request.) (?)
It would be nice to have one study provide ~all~ the answers (and not just “answers to some questions and only inferences about the other questions”) related to single agent PCI-32765 treatment.
Dear Chaya:
I am a 59-year-old female with 17p deletion diagnosed August 2009. I was unable to get into the last PCI32765 MDA trial because I was not 65. I thought there was supposed to be a similar trial offered Dec-Jan-Feb at MDA-Houston and I was invited to participate. I have not heard any update on it; have you?
Because I am bi-racial (Japanese and German), I have been told that chances of finding a SCT match are slim. That is why I am willing to fly to the East Coast from Arizona (your old stomping ground) for this clinical trial.
Thank you for the information. I am praying I can get in. I have been quietly following you since I was diagnosed. I also have been a university researcher and professor, and appreciate your science background and your translation of articles to layman’s terminology.
La Verne Abe Harris
Chaya,
This will hardly be the last word on the BMB debate but I am passing this link around to get feedback from doctors & patients. I have not had time to do further research on this technique but at first glance it looks promising.
http://www.pnas.org/content/108/52/21194.abstract?etoc
My guess is that even if this technique is valid or even a superior substitute to the BMB it would have to become accepted as a standardized test, meaning it would take awhile to get it into the clinical setting.
I am currently reviewing discovery award proposals for promising blood cancer studies and drug development approaches for the Defense Dept. and I am seeing a shift toward the use of investigational tools that bode well for the eventual replacement of the BMB with a more accurate and less invasive “barbaric practice” of coring out marrow.
If nodes can vary in quantity and variety of cancer cells then I would stick my neck out to speculate that the same may hold for bone marrow. The current BMB samples only one spot whereas a blood based assay or some other sophisticated scanning device could theoretically do a more comprehensive job.
I plan on asking Dr. Byrd to evaluate the possible use of this sequencing technique and will report back. Patient advocacy means engaging doctors and researchers with concerns and new ideas. Medical technology is progressing rapidly and we are an important part of what gets implemented.
I picked up the linked info from ACOR Listserv thanks to Dick Morris.
WWW
It’s official !! The trial received IRB approval last week and now it’s posted on the clinicaltrials.gov site ..
Here it is ..
http://clinicaltrials.gov/ct2/show/NCT01500733?term=NCT01500733&rank=1
And note that for the “any age arm”, you are eligible even if you have tp53 malfunction without 17p deletion.
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