Supposing I told you that there was a drug being developed for CLL which killed CLL cells in the test tube, but had absolutely no effect on T cells. A drug that did as well for cells from Mantle cell leukemia and from Waldenstrom's Macroglobulinemia. Moreover it also killed CLL cells from patients who were refractory to fludarabine and had either 17p deletions or 11q deletions.
Supposing this drug had already been given to a couple of thousand people in an attempt to treat another (non-malignant) disease at roughly two-thirds the dose needed to kill CLL cells and it had virtually no toxicity.
Would you want to have it?
Surely there must be some drawbacks?
AS far as we know it has never been given to CLL patients so we do not know whether it will work in patients. There are really no animal models of CLL that it can be tested in. (The TCL-1 mouse described by Carlo Croce's group is sometimes thought of as a model of CLL, but it is a much more aggressive tumor).
How should the company proceed?
I tell this story, not because there is a particular drug being developed, but as a hypothetical exercise in drug development.
My ideal drug for CLL would be just like this. It would kill CLL cells but not T cells and it would kill CLL cells with deletions at 11q and 17p. I would also like it to be effective in those other two difficult lymphomas, mantle cell lymphoma and Waldenstrom's macroglobulinemia. Finally it would have no side effects.
In the old days I would just give it to a few of my patients and monitor what happened, but today that is not possible. For one thing you can no longer publish as a clinical trials something made up as you go along. It has to be registered as a clinical trial with a defined protocol. It would have to be part of a randomized controlled trial, and before we could do that we would have to do a phase 1 study which would establish the maximum tolerized dose, and a phase 2 study that establishes that it actually kills CLL cells in the patient. The phase 3 study would be a randomized comparison with the best available (or at least the best licensed)treatment.
For the phase 1 study the idea is to treat three (usually end-stage) patients at the same dose as has been given before, and to gradually increase the dose for each successive three patients until the side effects become intolerable. The increases are according to what is known as a modified Fibonacci series in which the next number is the sum of the two previous numbers (1.1.2.3.5.8.13.21 etc).
In the phase 2 study a minimum of 14 patients has to be studied. If none of the first 14 improve you can be 95% certain that the drug is a dud. If it works on some then you have to add patients up to somewhere between 20 and 45 so as to get an estimate of how well it works.
Then the drug can go forward for a comparative trial.
The problem is that this is all very costly, especially the last part. It's all very well for the big boys, Glaxo and Bristol Myers and Roche, but a small start-up doesn't want to waste money on a dud.
For our imaginary drug, we don't want to start testing it on treatment failures. They will all have damaged T cells, and the beauty of our drug is that it doesn't damage T cells. Ideally we would want to try it as a first line drug, because the real question we want to ask is can it kill CLL cells in a patient without killing T cells.
So the question I want to ask all my CLL readers is, "Would you be prepared to take part in a trial of such a drug as first line treatment?"
The question I would like to ask any ethical committee members who read this blog is "Would you be prepared to sanction it?"
9 comments:
As CLL patient, I would take the drug in a trial if it were under the care of a CLL specialist in whom I trust.
Given that this ideal drug has "virtually no toxicity" in patients with other cancers, I would have no problem participating in a trial.
Is this a trick question? Why would any CLL patient not want to take part in such a trial. I certainly would.
"...as first line treatment..." yes, certainly I would participate!
If the drug has no toxicity I would participate in a trial.
Remember it has no toxicity at the doses previously given ie two thirds of the dose that we think might be enough for CLL. The risk is that giving a bigger dose might be toxic in some unknown way.
"The risk is that giving a bigger dose might be toxic in some unknown way."
Since the chemotherapy drugs used in CLL have known toxicities, I would still be tempted to take my chances with this one, especially since it can work equally well on 11q cases, of which I am one.
My answer would be a definitive Yes. I think it depends on the basic personality make up of each individual. I am always ready to try something new, something that really might be the cure instead of "washing my clothes in dirty water." Other personality's would rather wait and see what happens to the trial rats and even then, drag their feet about a newer treatment.
Who on earth would want any medical professional to willy-nilly ‘make something up as they went along’! Thank goodness the old days are gone and for the protocal of phases 1, 2 & 3 which exists before a randomized controlled trial. In my view no medical professional however good they think they are should monitor anything alone – its arrogant and highly dangerous to think otherwise. The existing protocal protects patients from a these well meaning professional to go out alone on a whim, it also protects the teams who administer to the patients at all levels. The study into CLL and similar diseases as you are constantly posting - is very very specialised indeed with only a handful of medical professionals involved into its research. Perhaps, sharing the ideas with the ‘BIG BOYS’ is the way to go - they do have the finances and facilities to proceed within the protocal - which I repeat, not only exists to protect the patients in the trails but also the medical professionals who will be a team administering and monitoring the trials.
As you quoted in an earlier post, many medical professionals treating patients with CLL are themselves not up to speed with the latest and a less informed sufferer may not be able intellectually to discern the good from the not so good - CLL is not selective to any one group. To think a not so good could/might ‘make something up as they went along’ especially for a patient who has little knowledge but lots of trust in the professional - horrifies me. If a CLL specialist is on to something positive – share it – develop it within the protocal – go to the BIG BOYS if necessary. So what if they make the financial gains that’s a small price for getting closer to a cure – isn’t it!
I do recall a small ‘start-up’ experimenting recently at a London hospital, the three young men are now very, very sick indeed and have no support post the trails and I am led to believe the company went bust! (can you comment on that one?)
To answer your final question in the post - yes, after being well informed I would certainly be prepared to enter into a first line drug treatment - but only within the protocal set up to protect all sufferers and their medical support teams. Reading the responses to your post there would be no lack of volunteers for such a hypothetical imaginary drug. Yours, CLL Jan from Hindhead.
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