Take your pills - ibrutinib dosing matters!

When we are investigating new drugs that have never been tested before, we start with what's called a phase 1 study.  Historically, the goal of a phase 1 study was to define the "maximum tolerated dose." In the era of traditional cytotoxic chemotherapy, you knew you had arrived at that dose when patients simply couldn't handle any more - it was just to much. Perhaps they had too much nausea or vomiting, or the liver couldn't handle it anymore, kidneys failed, or some other toxicity made it clear that you had reached the limits of human tolerance.  As researchers, we just hoped we could get the drug levels high enough without causing too much damage.  If we achieved blood levels that we expected to kill the cancer cells without irreparably harming the patient in the process - that was victory.

Many of the new drugs challenge that paradigm.  When treatments effectively target the specific molecular abnormality with a cancer cell we can see considerably more efficacy while at the same time reducing toxicity.  This has led to the concept of "optimal biologic dose."  Instead of pushing the dose to the max, you only increase the dose as far as you need to - often with substantially less side effects than the traditional therapies.

Unfortunately, "optimal biologic dose" is much harder to define than "maximum tolerated dose."  It presumes that we have effective and accurate means of actually measuring what were trying to do.  While it may come as a surprise to many patients, the unfortunate reality is that there is an enormous amount of human judgment as well as a paucity of clear data involved in early clinical trials. Things are not as scientifically certain in early trials compared to the level of data we have later in a drugs like cycle.  Furthermore, we often need to generalize to the larger population from a very small subset of patients that are appropriate for a phase I study.

There is new data regarding the dosing of Ibrutinib that I think is really important to consider.

Most drugs inhibit enzymes in what we call a "reversible" fashion.  This means that the particular target is turned off only when you have high enough levels of the drug in the blood.  Ibrutinib is a little bit different, it is what we call a "covalent" inhibitor.  When you swallow a pill of Ibrutinib it gets into the bloodstream and either quickly binds to the BTK protein or it gets eliminated from the body.  Within just a few hours of taking a pill there is virtually no free drug in the blood.  Instead, it is all bound to the BTK protein - completely shutting down that signaling pathway until the cell makes more BTK.  This is very different than most oral drugs where we are trying to make sure the levels are still high enough right before you take your next dose.

When you had a sore throat as a kid, the doctor always said to be sure to take all your pills so that the bacteria didn't become resistant.  It is virtually a scientific paradigm that exposing bacteria to inadequate antibiotic dosing creates resistance.  The same is probably true in leukemia and lymphoma with some of the new drugs.  A CLL cell that has its B-cell receptor signaling pathway completely inhibited has a hard time escaping that inhibition.  If that same pathway is only partially inhibited however, it will try to find ways to escape.   This is why the discovery of mutations in the BTK protein that confer resistance to Ibrutinib or so important. These can only arise in cells that have survived the BTK inhibitor long enough to figure out how to thrive under the suppressive influences of Ibrutinib.

Dose intensity can be measured in two key ways.  The first is how many days you take it out of how many days you are supposed to take it.  We already know in other chronic leukemias like CML, adherence to Gleevec (imatinib) is the biggest predictor of treatment success.  Heck, it is even true in breast cancer with hormonal agents.  Now it looks like the same is true in CLL.  Sometimes side effects force you to hold therapy - but prolonged drug holds are undesirable.  Patients who had drug holds in excess of 8 days were almost three times more likely to experience a disease progression (link to ASCO 2015 abstract here).  

The second way dose intensity is measured reflects what dose you take daily compared to the "optimal biologic dose."  There was a very compelling presentation at AACR a few months ago  (I am still trying to figure out how to link to the actual poster, but here is link to the session).  The study title was "Population Pharmacokinetic-Pharmacodynamic (PKPD) Modeling of Ibrutinib in Subjects With B-Cell Malignancies" by Poggesi et al. (prize to the first person who figures out how to find the actual poster).  I need to get a little technical for a minute - stick with me.

As I wrote above, ibrutinib has a cool property that is unique compared to most drugs.  Since it covalently (or irreversibly) binds to BTK, we can do a blood draw, isolate the CLL cells, purify the BTK protein, and look to see how many molecules of the BTK protein are "bound" to a molecule of ibrutinib.  This is what we call, "receptor occupancy."  The higher the occupancy, the more drug is bound to the protein, and the more the pathway is shut off.

You can then ask how many people have how much of their BTK protein "occupied" or inhibited by ibrutinib at different doses.  If we set the bar pretty low at 75% occupancy, any dose above 280mg (two pills) is pretty effective.  96% of patients achieve that level of occupancy at any of those doses.  that may seem good but unfortunately, that low bar means that the pathway is only 75% "turned off."  It is more like a dimmer switch on the lights instead of an on/off.  75% occupied means that there is a lot of room for cells to try to discover ways to become resistant.  If you set the bar much higher at 90% occupancy, the standard CLL dose of 420mg (three pills) can accomplish that in 86% of patients but only 75% of patients who take two pills and 53% of patients taking on pill.  In short - dose matters.  You get more complete pathway inhibition with higher doses of ibrutinib.

What we don't really know what level of pathway inhibition is optimal for CLL treatment.  It is tempting to think that 100% occupancy in 100% of subjects might be much better at preventing eventual resistance - but honestly, we do not know if that might mean higher levels of side effects. How could we get there?  Well, perhaps we didn't actually define the "optimal biologic dose" correctly in the original phase I study.  We pretty much stopped escalating dose because it seemed to be doing what we wanted it to do in the relatively small population of patients we were studying.

I would be curious to go back and do a "dose optimization" study to see if we could modify either the dosing schedule or the actual dose taken to see if we could make ibrutinib work better than it already does.  I also worked on another BTK inhibitor that is no longer in development called CC-292.  We never really got it to behave as well as ibrutinib until we started giving it to patients twice daily. Other BTK programs are looking at this as well.  Another way of potentially addressing such drug limitations is by adding a second drug that acts through different mechanisms.  This should ONLY be done in the context of a research study.  We have three such studies within the US Oncology network of sites (and here as well) including the addition of ublituximab (an updated version of rituximab), the combination of a BTK and PI3K inhibitor, or even BTK in combination with one of the new immune checkpoint inhibitors - pembrolizumab. 

Doctors tend to reduce doses when there are problems.  It is how we think about so many different clinical problems, that we tend to assume it is smart decision making.  In my own patients, I am concerned that dose reductions or prolonged dose interruptions may be causing ibrutinib to be less effective than if we can maintain the dose intensity.

To leave a comment, click on the title of this blog post.  It will open up the blog post in a separate window with a comment field at the bottom.  All comments are reviewed by myself before being allowed to be posted - be patient, I'm a busy guy.

Thanks for reading.

Video update from IWCLL

I had the chance to meet up with Andrew Schorr in Germany at the IWCLL meeting. We taped this interview to provide an overview of where the new CLL drugs may best fit into an individuals treatment plan.  Hopefully it is a good summary for you and puts things into a more focused perspective.

Andrew does a great job collecting the voices of many experts and putting them into one place. If you haven't made a contribution to his efforts, you might want to think about doing so. We are lucky to have him out on the front lines.

I apologize for being a little long winded in response to his questions.  So much exciting stuff to talk about, I had a hard time containing myself.




                         

ASCO update 2013

Andrew Schorr and Brian Koffman have done a fantastic job putting together videos to help educate CLL patients about the state of the art in CLL.  I appreciate the opportunity to interview with them - they are a great team and a fantastic resource for CLL patients looking for good information about what is out there.

In this interview we talked about a number of new investigational medications that many CLL patients have heard of including ibrutinib, idelalisib, obinituzumab, and ABT-199.  Hopefully this gives some new insight into the importance of research participation.

Ibrutinib Resistance

ASCO abstracts are out.  It feels like Christmas Morning and I am 5 years old (that is probably a very sad commentary about myself).

I'm part way through the CLL stack and Abstract 7041 jumps out at me as a MAJOR discovery:

They took CLL cases treated with ibrutinib and sequenced the entire exome in patients who became resistant (an exome sequence is not as comprehensive as a genome but it is still pretty dang impressive).

In resistant cases, they found that the binding site for ibrutinib on BTK had been mutated in two cases and in a third case, an enzyme downstream of BTK acquired a mutation that turned the protein on.

This is big because it can tell us why patients become resistant to the drug.  It is always a good sign that you have hit a very important target when the mechanisms of resistance show how important the pathway actually is.  In other words, you know the BCR is important because the CLL cells that become resistant have discovered a way to reactivate the BCR.  The next step is figuring out  how to get those patients to be sensitive again (perhaps using idelalisib?)

The other significant finding of the paper is that ibrutinib does not result in a bunch of new genetic changes in the same way FCR might.

History of Ibrutinib

Where do drugs come from?  Sometimes they come from places far removed from where they were originally intended to go.  The history of ibrutinib development is detailed in this article published in Forbes magazine.  As David aptly points out – these drugs can come out of left field with wild histories.  Lots of people played important roles – and I think it is a fantastic read.  I would highly encourage any patient with CLL or NHL take the time to read it (yes I am proud to get a couple of personal mentions).

 The Wild Story Behind A Promising Experimental Cancer Drug

Ibrutinib is coming soon.  The FDA has given signals that it may receive preliminary approval toward the end of this year or early next year.  This drug combines impressive clinical efficacy with limited toxicity – a formula that is very exciting for patients with the disease.  It may seem like things are moving at a glacial pace (read my post on why it takes so long), but in the perspective of many people close to the action – it is clear that this is getting moved as quickly as things can go.

Unfortunately the initial approval will not serve as broad permission for any oncologist to prescribe it to any patient.  It will probably have a narrow, “indication” at first for patients with relapsed Waldenstrom’s Macroglobulinemia and MantleCell Lymphoma having received some specific prior therapies.  Second – I predict that patients with 17pdeleted CLL will get the next, “indication.”  Over the next 1-3 years we will see the “indications” slowly expand in different patient populations

“Indications” matter because insurance companies pay close attention to what the FDA has approved.  Different insurance companies take very different attitudes regarding “off label” prescribing of drugs.  For a drug likely to cost nearly $90k per year (my guess only) – insurance will likely look quite closely at who is receiving it.  While CLL patients will greet the approval – it may still take a while for them to access the medicine.  That is why getting involved in research studies is so important!!!!

Patient Power: "What is Hot in CLL"

I had the pleasure of meeting Andrew Schorr at ASH this past December.  Andrew is a CLL patient who has an absolutely fantastic website called patientpower.  I highly encourage you look through his material.

He asked me, "What is hot in CLL?"  There is a lot going on in CLL.  Here is the interview (I will try to directly embed this on my blog once I figure out how)

An Expert's Perspective: Why New CLL Treatments Supersede FCR from Patient Power® on Vimeo.

WVCI ASH 2012 Abstracts

ASH abstracts are out.  I recently posted on how to carefully evaluate the news.  Over next several weeks I want to draw attention to those abstracts that I think are most noteworthy.  In the meantime, I thought I would put the links to the studies our center has participated in.  Most of these represent collaborations with leaders in CLL and NHL.  It has been a good year in CLL/NHL and I think we are really on the verge of substantial change in the field.

Ibrutinib Is an Irreversible Molecular Inhibitor of Interleukin-2 Inducible Kinase: Expanding Therapeutic Potential and Modulating a Th1 Selective Pressure in CD4 T-Cells

Combinations of the Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor Gs‑1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Previously Treated, Indolent Non-Hodgkin Lymphoma: Results From a Phase I Study

Variation in Health-Related Quality of Life by Line of Therapy of Patients with Chronic Lymphocytic Leukemia

The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment Naïve (TN) and Relapsed or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Patients Including Patients with High-Risk (HR) Disease: New and Updated Results of 116 Patients in a Phase Ib/II Study

Combinations of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kdelta) Inhibitor GS–1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Results From a Phase I Study

A Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas:  Interim Results

The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma

How do ibrutinib and idelalisib work?

I've had a lot of traffic on my site from patients looking for information on ibrutinib and CAL-101.   I thought that the paper published by Hassan Jumaa this week helped shed more light on the unique activity in CLL:

Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling



The substance of the article is that the B-Cell Receptor (aka antibody or BCR) from patients with CLL continuously triggers cell growth because it reacts with itself.   The BCR is the one of the main determinants of B cell fate.  It has long been suspected that the CLL cells may encode a BCR which recognizes either something inside of a patients body or perhaps even is triggered by an external stimulus that is common such as Tom Kipps earlier paper indicating that it might be part of the CMV virus that is recognized.

Recombinant antibodies encoded by IGHV1-69 react with pUL32, a phosphoprotein of cytomegalovirus and B-cell superantigen


In either case, constant signaling through the BCR gives an unending "growth signal" to the cancer cells.  It adds to the argument that the BCR signaling pathway therefore represents a key "node" in B cell survival - ie. it is one of the main "pro-growth" factors in CLL.  It follows therefore that drugs that interrupt this pathway would interfere with the growth / survival signals given by the receptor.

Since the first three enzymes in the pathway are Syk, BTK, and PI3K it is not a surprise that drugs affecting these three enzymes act in similar manner. 

Double click on the image if you actually want to be able to see it.



Fostamatinib (syk) led the way and showed that the target was of value but the drug has had a difficult time gaining traction as the main development focus of the drug was for rheumatoid arthritis. 

Richard Miller (CEO of pharmacyclics at the time and occasional attending physician at Stanford) had the opportunity to see some of our patients respond to fostamatinib.  His company was developing a drug PCI-32765 (only recently named ibrutinib) which in hibited the next enzyme in the pathway - BTK.  He got it polished up for a clinical trial which we developed over several weeks.  Ibrutinib is a remarkable drug in CLL and much has been written about it.  Much more will be written about it.

About the same time a small Seattle Bio-pharmaceutical company had created a drug that inhibits PI3K - the next enzyme in the pathway.  PI3K is a little different in that it integrates important signals from a variety of cell surface receptors.  Those signals that tend to make a cell survive turn on PI3K and those that signal cell death turn off PI3K.  PI3K is actually a large family of proteins but the "delta-isoform" seems to be specific for B cells.  Their drug initially called CAL-101 (after one of the early founders of the company turned onto highway 101 in Palo Alto and decided that would be the name of the drug) now renamed GS-1101 (after acquisition by Gilead) shuts off PI3K and has considerable reported activity in CLL and NHL.

The point is the following: CLL cells proliferate in response to signaling through the B cell receptor.  Drugs that target the pathway that transmits the signal inside of the cell turn off that proliferation and make the cancer cells less able to survive.  The new finding in Hasaan's paper is that the source of the signal may be that the B cell receptor reacts with itself instead of the invading micro-organism it was supposed to attack.