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.