Changing names, ownerships

Just when you were getting used to CAL-101, it is time to re-file this drug under a new acronym.  Calistoga Pharmaceutical has been bought out, lock stock and barrel, by Gilead Sciences.  Rumor has it CAL-101 was considered one of the crown jewels.  With new ownership comes the new name, GS-1101.  No doubt they will have a much more sexy brand name once the drug gets FDA approval and available commercially.  In the meantime, don’t get confused by this proliferation of drug titles.  CAL-101 is the same exact thing as GS-1101.

Below is my review of the design of their latest clinical trial.  Results of the trial itself will not be available for many moons.  This article reviews the design of the trial, because I think there are a couple of details here that may trip up patient recruitment.  Earlier on, I had several serious concerns about the trial design and my review would have been quite a bit more negative.  Fortunately, the company was willing to discuss my concerns in a detailed phone conversation.  It is a little bit complicated and you really need to understand your options before you sign up, but now I believe this trial is worth considering if you fit the inclusion criteria and you are looking to participate in this kinase inhibitor trial.

Trial Design

You can read the official description of the trial by clicking on the link to the clinicaltrials.gov citation.  I strongly urge you to read it.  It has inclusion criteria, contact information etc. Right now they are recruiting at four centers in the USA, including the prestigious Long Island Jewish Hospital.

Basically, they want to recruit 160 patients.  These guys will be randomly assigned to either of two arms, 80 in each arm.  One arm will get 8 infusions of Rituxan over a 24 week period, along with 150mg of CAL-101 pill, to be taken twice daily.  The other arm will be the control arm.  These guys will get the 8 infusions of Rituxan too, but instead of CAL-101 pills they will get placebo pills for the duration of the 24 weeks.  So, it boils down to comparing CAL101 + Rituxan versus Rituxan alone.

As you can see below, the study wants to recruit pretty advanced CLL patients.

  1. You must have been previously treated for CLL.  In other words, they do not want chemo virgins.
  2. You must fit the criteria for needing therapy to control the CLL now.
  3. They are looking to recruit patients whose disease is aggressive enough that they got only a short remission (less than 2 years) from their previous round of therapy.
  4. Patients must have other health problems (co-morbidities) or sufficient bone marrow damage from prior therapies that they are not considered fit to undergo additional chemoimmunotherapy.
  5. Patients should not be refractory to Rituxan.  (I wonder how they determine that?)

I will be the first to admit, this is going to be a pretty tough crowd.  That makes the trial design all the more important - as I attempt to explain below.

Late stage patients such as these guys do not have time to waste, their window of opportunity is rather limited and they need to be smart in their therapy choices.

The experimental arm (which uses CAL-101 + Rituxan) makes lots of sense.  As we have seen before, CAL-101 has the ability to flush CLL cells out of their comfortable and safe niches in the lymph nodes, where they are hard to reach and even harder to kill.  Patients treated with CAL-101 in earlier studies have seen remarkable and rapid shrinking of their swollen lymph nodes.  Of course, all those CLL cells driven out of the lymph nodes have to go somewhere and that somewhere is blood circulation.  A spike in peripheral blood lymphocyte counts (WBC, ALC) have been observed upon treatment with CAL-101.  This is not something that should freak you out.  It is not only expected, it is to be desired.  CLL cells out in open blood circulation are a lot more vulnerable and easier to kill.  Combining CAL-101 with Rituxan may give us the capability of (1) flushing out the CLL cells out of lymph nodes (2) killing them dead once they are out in the open.  This one-two punch is what makes this combination so interesting.  Incidentally, the new generation of kinase inhibitors such as CAL-101 and PCI-32765 do not seem to care about prognostic indicators.  In other words, even guys with poor prognostic indicators - including the dreaded 17p deletion - seem to respond nicely.

But since this is a two arm, randomized study, you do not have any guarantee that you will indeed end up in the CAL-101 + Rituxan arm.  You have a 50:50 chance of being placed in the control arm.  Patients in the control arm will get 8 infusions of Rituxan over a period of 24 weeks (6 months). The trial is also supposed to be “blind”, in the sense that the control arm folks will also get pills to swallow each day but in their case the pills are bogus - placebo pills.   I doubt the “blind” part of the trial will work out quite that way; I expect most patients will be able to tell whether or not they are getting CAL-101, based on how their nodes (and blood counts) behave. No shrinking of the nodes, no increase in blood lymphocyte counts means you are probably in the control arm.

I am willing to bet most patients will volunteer for this trial because they hope to be in the experimental arm.  It pays to be realistic.  Exactly half of you will be in the control arm.  As I discuss below in the editorial section, that poses some risks and questions.

As a single agent, Rituxan is not all that effective even under the best of circumstances (chemo naive and good prognosis patients) and it is not likely to do a whole heck of a lot for this crowd.  So, my concern prior to discussions with the company was simply this:  are the folks in the control arm being sacrificed with less than optimum treatment just so they serve as a reference point?  If that had been the case, I would have had real problems with this trial.  Why would anyone in the control arm hang around for 24 weeks if they experience disease progression while being treated with single agent Rituxan?  I hope you know by now, patients have an absolute right to walk out of any clinical trial, vote with their feet as it were.  I had visions of the researchers retaining most of their 80 patients in the experimental arm, while a large percentage of the control group dropped out of the trial.

As it turns out, there is an important loophole to finessing this dilemma. The company is also initiating a follow-on trial, an extension of this trial.  Here is the citation link to the extension trial.  Anyone in the original trial who is tolerating therapy but whose CLL progresses while being treated can switch over to this extension trial.  This too is a two arm trial, but everyone in it gets CAL-101.  The difference is that some of the patients will get the “standard” dose of 150mg twice daily, while others will get a heftier 300 mg twice daily.  In other words, the safety net for the control group folks is that if your CLL progresses while you are on single agent Rituxan, you can switch over to the extension trial and get put on CAL-101, without having to wait to complete the 8 infusions and the 24 week period.  Phew.  You can see why this is an important detail.

I have no doubt the results of this large scale and double arm trial will be of great importance in future FDA approval considerations.  If you decide to volunteer for this trial, my heartfelt thanks.  Your generosity and courage will pave the way for development of this and other kinase inhibitor drugs for other CLL patients.  But I want you to remember this:  informed consent means just that, your consent, after you are fully informed.  We do not yet know all the pros and cons of this new drug.  That is the whole point of doing this study, to learn more about it.  But there are other details that do impact your risk exposure and these are things you should know about. Volunteering without knowing what you are signing up for is a sucker’s game.  You may want to browse through my earlier articles on CAL-101 for additional details about this drug.  Much of the commentary below that I would like you to consider is my own layperson opinion.  As such, it is best presented under the editorial section.  I try hard to distinguish between official details and my own opinions, but sometimes the distinction is hard to make.

Editorial

“Straw-man comparisons” are all the rage these days.  Earlier, we wrote about another company getting FDA approval by comparing bendamustine against less-than-robust dose of chlorambucil.  Campath approvals in this country also involved similar shenanigans.  What is the surest way of making your particular drug look better?  Compare it against a drug / dosage  that is very likely to be a loser.  I have this girl friend who loves to be photographed standing next to me - the contrast makes her look so much slimmer and prettier.

The best chance of getting halfway decent remission statistics (overall response rate and percentage of CR remissions) with single agent Rituxan is if the patient is chemo naive and the prognostic factors are pointing to a less aggressive disease.  That is definitely not the profile of this patient group.  So, what are the chances that majority of the control arm will get decent responses using Rituxan only?  Slim, in my opinion.  Increasing the dose of Rituxan or giving 8 infusions of it rather than the standard 4 infusions is not going to make a huge difference.  The company argues otherwise, but I am willing to bet dollars to donuts that the results of this trial will prove me right to be skeptical about it.

Is this trial yet another straw-man comparison?  In my layperson opinion, yes.  If you were trot out these 160 patients before one of our highly regarded CLL experts, all of them with multiple layers of chemotherapy in their past and relatively aggressive disease to boot (as proven by less than two year remission the last time around), co-morbidities and possibly damaged bone marrow, I am willing to bet the expert would not consider single agent Rituxan as the best therapy choice for many of them. Heavy-duty chemotherapy is contra-indicated for these folks, but here are some other options that may be more interesting.

  1. If all we are looking for was more or less palliative therapy for these guys, an oral pill such as chlorambucil would be the choice.  The poor dears are not bothered with all the nasty intravenous infusions, they will get some symptomatic relief and that will be that.  What can you expect, patient had aggressive cancer and a lot of other medical problems as well. RIP, nothing to see here folks, move on please.
  2. If we are inclined to be a bit more creative and think a bit outside the box, we might consider Revlimid as the therapy choice.  It too is a pill, taken orally.  Taken at low doses it is relatively easy to  tolerate.  And unlike either chlorambucil or Rituxan, it is thought to increase immunoglobulin levels, something that might help general level of immunity in this rather frail group of patients.  Remember, these guys were specially recruited for having health problems in addition to late stage CLL, and many of them also had bone marrow damage from prior therapies - resulting in anemia, neutropenia etc.  It might be good to get some of the immune modulating effects of Revlimid.
  3. Yet another choice may be ofatumumab, since there is some evidence (not totally compelling evidence, but hey, we will take every ray of hope) that it works better than Rituxan.
  4. There are other single arm clinical trials with experimental drugs that may be worth considering.  GA-101, a third generation anti-CD20 monoclonal antibody similar to Rituxan and ofatumumab may be a good choice. ABT-263, a new BCL-2 inhibitor presently in clinical trials is another option to consider.

Patients have no choice in whether they get into the experimental arm or the control arm.  That choice is made for them through computerized  randomization. Since this is a 1:1 split, you have exactly 50% chance of getting into the experimental arm or the control arm.  Forcing 80 patients in the control arm to cool their jets for 24 weeks with less than effective single agent Rituxan therapy would have been hard to swallow.  Remember, the inclusion criteria mandated that their CLL had relapsed to the point where treatment was necessary.  Marking time for 6 months with less than effective therapy would have raised some ethical flags - I hope.  There is this little concept called “do no harm”.  We do not want to short change patients in the control arm, just to make the experimental arm look that much better.

What makes this trial palatable is that it offers patients whose disease progresses while they are in the trial to switch over to the next trial where everyone gets CAL-101.  Here is what I think will happen.  A significant majority of patients in the control arm of the trial (the guys getting just Rituxan) will have progressive disease. This is baked in the cake, since Rituxan is not likely to be all that effective in this tough patient cohort.  Before the 24 weeks are up, many of them would have moved to the extension trial, where everyone would have access to the kinase inhibitor CAL-101.  Company gets its favorable comparison to show to the FDA, even patients in the control arm get access to CAL-101.  Everyone is happy.  Sort of.  We live in interesting times.

Let us talk a bit about money.  As many of you have found out the hard way by now, not every insurance company covers participation in clinical trials.  Drug companies often cover the cost of their experimental drug, but you (or your insurance) is generally expected to cover the cost of so-called standard of care, which includes all the blood tests etc that would have been done routinely, as well as non-experimental drugs. So, my question to the company was this.  Who pays for the 8 infusions of Rituxan?  Many of our members have life-time caps on what their insurance companies will pay.  If you get randomized into the control arm, imagine having to pay for 8 infusions of Rituxan out of pocket or having it eat into your life-time cap of insurance coverage - especially if  like me you think single agent Rituxan is not your best choice at this stage of the game.  Fortunately, the company told me that in situations where there are issues with insurance coverage, they will also pick up the tab for Rituxan.  Please tuck this little point away someplace in your brain, it might come in handy.  Somehow, I do not think anyone will volunteer to pay for your Rituxan infusions, if you don’t raise the question yourself.

CAL-101 results that we reviewed in previous articles suggests the experimental arm is not likely to be free of adverse effects.  High grade pneumonia and neutropenia were seen in significant percentage of patients in previous trials using CAL-101.  Prophylactic protection such as Bactrim (against bacterial pneumonia), growth factors (Neupogen or Neulasta to combat neutropenia) are recommended, but not mandated by the trial.  If the local guy who is monitoring you for the duration of the trial is less than proactive, I strongly urge you to be your own best advocate.  You have heard about squeaky wheels getting oiled, have you not?  If you are a high risk candidate for contracting a painful case of shingles while you are on the trial, be sure to discuss this as well.  While it is not a good idea for our guys to get the shingles vaccine (it has live virus in it and contra-indicated for CLL patients), you might be well served by daily dose of Acyclovir, Famvir etc.

If at any time during the course of your participation in this trial you find yourself having difficulty breathing, if your oxygen saturation level begins to fall, make sure you contact the trial researchers right away. It may not be enough to head to the ER room, since the staff there may not be aware of the special circumstances.  Not all the pneumonia cases seen in kinase inhibitor trials have bacterial or viral origins, and in such cases they are not likely to be controlled by broad spectrum antibiotics or anti-virals.  It the problem is due to a drug induced  inflammatory cascade, the patient may need to be on large doses of prednisone to control the inflammation.  This is hardly standard operating procedure for ER docs treating garden variety pneumonia.  You are better off bringing it to the attention of the researchers who would know what to look for.

Another item I discussed with the company during out phone conversation was potential risk of tumor lysis syndrome, especially in the experimental group.  In brief, if CLL cells are killed in huge numbers and the cell kill happens more quickly than the body’s ability to handle the debris of dying cells, there is risk of your kidneys (and other organs) getting over-loaded.  This patient cohort is medically challenged group, with co-morbidities on top of CLL.  If as expected CAL-101 causes a massive increase in WBC, and this in turn leads to massive CLL cell kill by co-administered Rituxan, we may have a situation where there is too much of a good thing, too many CLL cells getting killed too quickly.  One of the drugs used to protect the liver where there is potential risk of toxicity is allopurinol.  Rasburicase is another drug, to be used as a second line of defense.  We have discussed tumor lysis syndrome and rasburicase in earlier articles.  Once again, the company told me they do not mandate the use of allopurinol ahead of start of therapy.  But they do not forbid it either.  It is up to the local guy taking care of the patient.  What if he is less than pro-active?  Aha.  That is where it helps if you, dear patient , know what to ask for.

This is an important clinical trial. If we want to see this new generation of kinase inhibitor drugs make it into commercial availability, we have to do our share of the heavy lifting and volunteer for such trials. If you have any other questions that you would like for me to bring to the attention of the company, let me know. I will do my best to get you their answers.  Last but not least, I asked the company whether they plan to thank the patients who volunteered for this clinical trial when they write up the results for publication.  I was given solemn guarantees that this would be done. Let me jump the gun a bit and thank you right now.

Site News

I had a great time meeting some of you at the CLL-PAG conference at Niagara Falls, Canada.  I am also looking forward to the UK Midlands CLL conference end of this month.  It will be sad visiting the UK CLL group and not seeing my friend Dr. Terry Hamblin.  His death continues to be a huge loss to our patient community.

I would also like to take this opportunity to announce our first CLL workshop for 2024.  It will be on Saturday, June 9th.  Location, Columbia MD.  As always, there is no charge for attendance.  The details regarding registration for the workshop are pretty much the same as on prior occasions and you can read them here.  We will be discussing some of the material I presented at the Canadian and UK conferences.  More details will be forthcoming in the next week or so, I just thought I would get the date out so that people can put it in their schedules.