Dosing of Ibrutinib and Other Oral Agents

"Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy."

PARACELSUS

Recently there has been some discussions among those of us who hang out at online at CLL forums such as ACOR and CLLSLL Yahoo Groups about the dosing of ibrutinib.

I am a strong believer in the power of these online communities to help us cope with our disease.

The problem inherent in peer to peer counsel is not the inaccuracy of the advice given as that also sadly too often occur in professional to patient counsel. The problem is more the lack of authority afforded any particular response. That said, if respect is earned, several regular contributors have earned my respect with their well reasoned and researched frequent comments online.

Often, especially with cutting edge therapies, the patient community is better informed about their rare disorder than the community healthcare professional who must handle the full spectrum of illness his or her chosen specialty demands.

For more on this subject see this article in BMJ  provocatively titled: What happens when patients know more than their doctors? Experiences of health interactions after diabetes patient education: a qualitative patient-led study

Case in point: Dosing of ibrutinib.

The only approved dose for ibrutinib is four tablets a day for mantle cell lymphoma (MCL), which by the way is usually a nastier disease than CLL. The Imbruvica dosing is right on the package insert.

So the community oncologist dutifully looks up what the dose to use for CLL, and finding no FDA sanctioned guidance, recommends using the MCL dose. After all,  the somewhat arbitrary dose of rituximab is the same across a wide spectrum of illness.  Arbitrary because, according to legend, the original dosing was based upon how much rituximab was available, divided by how many trial patients needed it. That worked out to be 375/M² and the rest is history.

The circumstances are less arbitrary with ibrutinib. We know that ibrutinib works by irreversibly blocking BTK through covalent binding to cysteine-481. We know that the sweet spot for getting that site fully saturated is somewhere between two and three 140 mg. capsules a day.

Moreover we know that mutation of cysteine-481binding site is an important cause of late resistance. Ibrutinib no longer fits, and the BTK pathway, and thus BCR signaling continues unabated. Not a good thing.

One sure way to increase the odds of that sinister development is to start with a low dose of ibrutinib that only partially blocks the site, but allows a significant population of lymphocytes to continue to express BTK. That is the last thing we want in cancer therapy. What we want is a SHOCK AND AWE approach to cancer. We don't want the cancer cells retreating, regrouping, and later coming back to get us by probing our weak points.

Worse yet, the up and coming second generation BTK inhibitors also seem to bind at the exact same site, so if we become resistant to oneBTK inhibitor, we may be resistant to them all. A strong incentive to get the full dosing the right from the start.

So when a doctor suggests slowly going from one to two to three or more capsules a day, it is OK for a patient to say: Can we please get a second opinion from someone with more experience with the particular drug? (Of course, there is always the possibility of the individual's extenuating circumstances that we just don't know).

Some drugs for good reasons such as allopurinol in gout needs very slow upward titration to prevent increased painful flares, but ibrutinib and most of the other TKIs should almost never be dosed that way.

Bottom line: The standard dose for CLL is three 140 mg. capsules once a day, for MCL four 140 mg. capsules once a day. Sometimes those doses can be adjusted due to adverse events or hepatic disease or concomitant medications that effect its clearance (more on that topic, specifically on the CYP3A4 pathway in another post). Short of end stage renal disease or dialysis where there is no data to go by, no dose adjustments are needed as less than 1% of the drug is excreted unchanged by the kidneys.

The right dose is more than important, it is mission critical.

iwCLL 2013: Dr. Byrd Discusses If and When to Stop and the Long Term Use of Ibrutinib

In this last part of my interview with Dr. Byrd from iwCLL 2013 in Koln, Germany, he speculates on the issues of long term risks of using ibrutinib, and the complex concerns about stopping the medication.

This segment's posting was delayed due to some technical issues, so please look back to the prior part one and part two to get oriented.

The updated news from ASH 2013 about the long term safety concerning ibrutinib continues to be encouraging. Most problems, including serious infections, occur most often in the first six months. The longer we take the pill, the fewer the problems.

The data on late relapses is still very thin because they are so few and far between, but it is clear that they do occur, mostly in the usual suspects, those of us who have been heavily treated or have high risk and unstable genomics such as deletion 17p or 11q.

Sadly, the Kaplan Meier curves are not longer straight lines going out towards eternal life, but they are still pretty great. Below are the ones from about six months ago from NEJM. The latest data is little changed.

KAPLAN MEIER CURVES FROM DR. BYRD'S ARTICLE IN NEJM 7/4/2013

Will they continue there downward droop? Will it accelerate? We don't know the answers yet.

Because every step down is a lost life, we are not being greedy when we want the great results to be even greater.

Dr. Byrd does make an interesting and important point about going off meds. Most relapses occurred in those who had only been medication for a short time, and without the selection pressure of ibrutinib blocking the BTK pathway, there is no survival advantage to mutating past it and therefore little likelihood that we will see that resistance develop off med. That's good news and if confirmed in clinical trials and hopefully soon, in real life experiences, could have major implications on how we dose the medication and control the cost.

Here is the video:


Since that meeting, we do have some answers to a few of the questions that were unanswered in Germany.

We know what the pills cost. About $91 each retail. About what was expected.

We are seeing some new interesting late side effects. In contrast to the minor annoyance of brittle nails, some of us are enjoying thicker, curlier and darker hair.

Maybe there is a whole new marketing opportunity for Pharmacylics and Janssen. Insurance may be hesitant to pay that kind of cost for control of cancer, but the price of vanity has no limits.

I will let you be the judge on the effects on yours truly.

Selfie from my Balcony 1/19/14

The News about Ibrutinib from My Infusion Chair, The Resonate Trial, and Lancet Oncology

Yesterday, I was at the infusion center for my IVig and got back one of the most normal lab results since my diagnosis. No anemia, normal neutrophils and lymphs and a healthy platelet count. Chemistry panel was fine too. LDH and uric acid  in the healthy range.

I credit my wife's famous cajun gingerbread, full of iron in the guise of blackstrap molasses.

I had stretched out my infusions to every 8 weeks and was rewarded with a very nasty respiratory infection just before ASH. Although I take my IVig for ITP and not for infection prevention, I sure didn't mind if I enjoy a twofer. 

Let me pause here for a minute. If I can go a full 8 weeks with little drop in my platelets, it could be argued that I don't need the IVig. One could question if there enough of it around after almost two months to be doing whatever it does to protect my platelets from destruction? However my blood level go IGG was still >500 at the 8 week mark, lower than normal, but still respectable and suggesting to me that it still may be having an impact on stopping the auto-immune process.

The only way to "test that hypothesis" is to "test that hypothesis", and with my few near death experiences with single digit platelets and bleeding fading into my past, there is no way I am risking a return to that wasteland. That is why I have been so slow and deliberate in extending the time between infusions.

in terms of the other advantage of the IVig, did my first bad infection since my transplant comes as a result of going 8 weeks between getting my IGG topped up? My local oncologist, Dr. Sharma, thinks not and that it was just my bad luck. If he is right, the flip side might mean that my five years of being infection free were also not a result of the infusions of someone else's antibodies. 

I have decided to play it safe and drop back to 6-7 weeks between visits to the infusion chair.

Now let's talk about what's going on not to this single trial rat, but to a whole swath of brave volunteers.

The press release below from Pharmacyclics  (click on the 1st PR) tells us what many of already expected based on our experience and that of fellow CLLers: Ibrutinib is a superior treatment for many of us.

Sure is for me and a bunch of friends.

So positive were the results that when the independent team looked at the data, they decided to stop the trial because it would have been unethical to continue as those getting ofatumumab were not doing as well as those on imbrutinib.

This can only help move the time of approval for CLL closer, but since this trial was on relapsed and refractory patients, those wanting ibrutinib frontline are likely to be left wanting. The FDA works in mysterious ways so but I am hoping for a quick and broad approval in the next two months. 

The second article from Medscape reviews the same study but also reports on the data out of Dr. O'Brien's phase 1b/2 trial of monotherapy  just published in Lancet.  Ibrutinib in treatment-naive elderly patients had a mildly disappointing 71% response rate and an encouraging 13% complete response rate. Side effects were the predictable, with more than two of three in the study having diarrhea. There was one patient who did have a serious drop in the platelet count.

Here is the 1st press release:

SUNNYVALE, Calif., April 18, 2013 /PRNewswire/ -- Pharmacyclics, Inc. (Nasdaq: PCYC) announced today that the enrollment target of 350 patients for its Phase III study using ibrutinib monotherapy versus ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL/SLL), (RESONATE™) was achieved on April 3, 2013. As of today, additional 41 patients were screened and are allowed to participate in this study which has now been officially closed to enrollment.

The primary endpoint of this study is to demonstrate a clinically significant improvement in progression-free survival with ibrutinib when compared to ofatumumab. A pre-defined number of progression events will trigger an interim analysis. We would expect to have a read out from the interim analysis during the 1st quarter 2014. If the treatment effect of ibrutinib in comparison to ofatumumab is deemed statistically favorable by an independent review committee a discussion with the FDA and other health authorities for a potential early filing can take place.

"In addition to our outstanding team, we are grateful to the patients, their treating physicians, and the clinical sites for their participation in our RESONATE study and their strong support of the ibrutinib program," said Maria Fardis , Chief of Oncology Operations and Alliances at Pharmacyclics.

Pharmacyclics also announced the completion of enrollment of the planned 110 patients in the Phase II single-arm study using ibrutinib in patients with mantle cell lymphoma (MCL) who progress after bortezomib therapy and have received at least one prior rituximab-containing chemotherapy regimen, SPARK (MCL2001). This global study is conducted by Janssen Research & Development, LLC, and its primary endpoint is overall response rate, which is scheduled to be evaluated 6 months from the completion of enrollment. Further updates to this study will be provided by Janssen.

As previously announced Pharmacyclics expects to file a New Drug Application (NDA) with the FDA for the use of ibrutinib in patients with relapsed or refractory MCL prior to year-end. In the time before a potential U.S. marketing approval Pharmacyclics will strive to provide early access to ibrutinib under an Early Access Program (EAP). EAPs are clinical studies and allowed under certain circumstances by the FDA. They are designed to provide a mechanism for access to an investigational drug to treat patients with a serious or immediately life-threatening disease or condition until the time of an anticipated U.S. marketing approval. A multicenter, open-label EAP, conducted by Janssen, will be initiated in the United States with ibrutinib for relapsed or refractory MCL patients. Information about this program is posted and updated on www.clinicaltrials.gov.

"The completion of the enrollment of our first Phase III study with ibrutinib, ahead of schedule, is an important milestone for our clinical development plan and a real achievement for our company," said Bob Duggan CEO and Chairman of Pharmacyclics. "As of today we have initiated 5 Phase III studies together with our partner Janssen and we currently have registered with the US National Institute of Health 28 clinical trials using ibrutinib. Thus far over 1200 patients have been dosed in our studies and we are making excellent progress in the development of this investigational drug, as underscored by the most recent three Breakthrough Therapy Designations we received from the FDA. It is Pharmacyclics' goal to advance science and drug development in the hopes of making a significant difference for the betterment of patients with serious unmet needs, and we are steadily progressing towards that worthy goal."

About Ibrutinib

Ibrutinib was designed to specifically target and selectively inhibit an enzyme called Bruton's tyrosine kinase (BTK). BTK is a key mediator of at least three critical B-cell pro-survival mechanisms occurring in parallel – regulation of apoptosis, cell adhesion, and cell migration and homing.

The effectiveness of ibrutinib alone or in combination with other treatments is being studied in several B-cell malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Waldenström's macroglobulinemia and multiple myeloma. To date 5 Phase III trials have been initiated with ibrutinib and a total of 28 trials are currently registered on www.clinicaltrials.gov. Janssen Biotech, Inc. and Pharmacyclics entered a collaboration and license agreement in December 2011 to co-develop and co-commercialize ibrutinib.

Ofatumumab is manufactured by Glaxo Group Limited and distributed by GlaxoSmithKline.

Bortezomib is marketed and distributed by Millennium Pharmaceuticals, Inc.

SOURCE Pharmacyclics, Inc.

Here is the second article from Medscape. My trial doctor, Dr. Byrd participated as did many whom you have seen interviewed here. The article has links to the publication in Lancet. Thanks you Medscape for this nice overview.  Dr. Brown raises the unanswered questions about timing, combinations (she mentions the combo with rituximab, but I would vote for obinutuzumab myself), and relapse with Richter's.

CLL Trial Stopped as Ibrutinib Shows Significant Benefits

Zosia Chustecka

January 09, 2014

A phase 3 clinical trial in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) has been stopped early after significant benefit was seen with ibrutinib (Imbruvica, Pharmacyclics/Janssen).

The novel drug, a first-in-the class inhibitor of Bruton's tyrosine kinase, is currently awaiting approval for use in CLL (with a decision expected from the US Food and Drug Administration before the end of February); it was approved in November 2013 for use in mantle cell lymphoma.

Ibrutinib has stirred up considerable excitement in hematology circles, with experts describing it as a "turning point" in the treatment of CLL and "a step change" in the treatment of mantle cell lymphoma.

The trial that has just been stopped because of benefit, known as RESONATE, was a phase 3 study conducted at more than 70 clinical sites across 10 countries. It involved 391 patients with relapsed or refractory CLL or SLL who had received at least 1 previous therapy. A head-to-head comparison trial, it pitched the oral drug ibrutinib against the intravenous drug ofatumumab (Arzerra, GlaxoSmithKline), which was approved for CLL in 2009.

According to a press release from Pharmacyclics, an interim analysis of this trial showed that patients on ibrutinib had a statistically significant improvement in progression-free survival (the primary end point of the study), as well as in overall survival (a secondary end point), when compared with ofatumumab.

No further details were given, and the results are due to be presented at an upcoming meeting.

As a result of this finding, the Independent Data Monitoring Committee recommended that the trial be stopped and that any patients on ofatumumab be offered treatment with ibrutinib.

Earlier Trial Now Published

An earlier trial with ibrutinib showing "encouraging" efficacy in elderly patients with previously untreated CLL has just been published in the January issue of the Lancet Oncology.

The results come from a phase 1b/2 study, conducted in the United States, of 29 patients with CLL and 2 patients with SLL who had previously not been treated. (This was a part of a larger study — the greater part of this study was conducted in patients who had been previously treated, and these results were reported last year.)

All patients were at least 65 years of age, and most patients (74%) were at least 70 years old. They all received oral ibrutinib once daily at a dose of 420 mg (some initially received the higher dose of 840 mg, but this was discontinued after comparable activity of the 2 doses was shown).

After a median follow-up of 22.1 months, a complete response was reported in 4 patients (13%), a partial response in 17 (55%), and a nodular partial response in 1 (3%). The overall objective response rate was 71% (22 of 31 patients).

The authors, led by Susan O'Brien, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, say the trial shows that ibrutinib is well tolerated and effective in older patients with CLL, and support the continued assessment of this drug in this population of patients.

Notably Good Toxicity, But Questions Remain

In an accompanying comment, Jennifer Brown, MD, from the Dana-Farber Cancer Institute in Boston, comments that the toxicity profile of single-agent ibrutinib was "notably good, with low myelosuppression and few infections," and this makes it "potentially very appealing as a therapeutic option, especially for elderly patients."

An interesting feature of ibrutinib activity is that most patients have prolonged stable remissions (i.e., persistent disease, rather than complete remissions), Dr. Brown comments. However, this persistence of disease does raise the concern that resistant clones can emerge over time, she notes, adding that this has been reported in patients who have relapsed on ibrutinib

An additional concern is that this may result in Richter's transformation, in which CLL is transformed into an aggressive lymphoma, which can be fatal, she adds. This has also been reported in patients who have relapsed on ibrutinib (in 1 patient in this current study, and in 7 of 11 patients in the other part of this trial).

These concerns emphasize some of the remaining questions on how to best use ibrutinib, and in particular if it may be best to use the drug in combination with an agent that produces deeper remissions, Dr. Brown adds.

The only agent so far to have shown an early definitive overall survival benefit in CLL is rituximab (Rituxan, Genentech/Roche), and hence a combination of ibrutinib with rituximab is very appealing — and trials of this combination are in progress, she notes.

Despite the unanswered questions, there is hope that ibrutinib, which is the first of several extremely active novel agents coming out of development, will lead to "striking benefit for patients in the coming years," Dr. Brown comments.

Lancet Oncol. 2014;15:3-5, 48-58.  Abstract

The research is moving forward, but there are still leaves so many questions unanswered and I am so impatient.

iwCLL 2013: Prof Hallek Discusses a Focused Role of Chemo-Immunotherapy

In this brief second part of a three part interview from iwCLL 2013, Professor Hallek precisely defines the populations that do well with chemo-immunotherapy.

It is important to keep in mind that it was only with the addition of rituximab, an anti- CD20 monoclonal antibody,  to a chemo backbone of FC, comprising together the "gold standard" therapy of FRC, that a survival advantage was first shown. Prior to the German study presented at ASH only a few years ago that proved FCR prolonged lives, no therapy had been shown to help us live a day longer.

At iwCLL 2013, we learn some very important new wrinkles on exactly who it is that benefits from FRC.

There should be no debate that the role of CIT (chemo-immonotherapy such as FCR or Bendamustine -Rituximab or BR) is shrinking. Who benefits is a shrinking pool of CLL patients with very specific demographics and FISH findings and the good news that they are mutated. This argues strongly that we should never consider FCR without first knowing our mutation status and our FISH results.

The debate is whether there is any role at all for CIT even in that select population.

The question how intense the CIT protocol should be or what is best approach may soon be moot with all the new kinase inhibitors changing everything, but at ASH 2013 a few months later we did learn that FCR has deeper longer remissions than BR but at the price of more toxicities, so the answer is as always in CLL: It depends on the patient. More on this ASH abstract later

Listen to Professor Hallek discuss who should consider CIT and who should not.

iwCLL 2013: Dr. Michael Hallek Discusses Clinical Trials in Germany versus the USA and BR versus FCR

Happy New Year.

I am in Alameda, enjoying babysitting my 7 month old and 2 1/2 year old granddaughters. Needless to say, finding a second to get any work done is tough, but the joy of being with them makes my inefficiency a small price to pay.

Today, I am returning to share additional relevant interviews from iwCLL a few months ago.

In the first part of my interview on September 11, the last day of iwCLL 2013, Professor Hallek first discusses some of the differences in clinical trials on either side of the pond.

One subject Prof. Hallek does not mention is the greater willingness of European patients to be randomized in a trial. Canadians and Americans prefer more control in deciding their therapy, and that helps explain the generally lower accrual in North American studies that have two or more randomized arms. I admit that one reason I was drawn to my trial, the official title being,  An Open-label, Phase 1b/2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, and Ofatumumab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Prolymphocytic Leukemia, was that I was assured that I would be getting PCI-32765, AKA, ibrutinib, AKA, Imbruvica. Phase 3 trials rarely offer that certainty, unless there is a cross-over and that is a big ongoing issue.

Keep in mind that the  calculus of accrual is entirely different when we are looking at the new non-chemo agents, where trials offering some of the exciting new drugs have filled at record rates.

Also don't miss the professor's definition of young.

I like it.

Next, Prof. Hallek, presages with great accuracy what was going to be announced a few months later  in at an abstract presented in New Orleans at ASH 2013, namely that BR is gentler on the marrow, but less effective than FCR. His take on what to do with that data is the real gem in our conversation. Listen to how he describes tailoring of the therapy to the individual patient.

Dr. Jeff Sharman whose interviews have and will continue to pop up here, has a nice review of the ASH data on his excellent blog.

Here is Professor Hallek, who was very busy chairing iwCLL, so I very much appreciate his time.  Sadly when my flight to New Orleans was canceled, I had to also cancel my follow-up interview at ASH, but we get the full story here and from the abstract.

Many, myself included, wonder if the whole question of BR versus FCR is moot as the era of chemo-immunotherapy may be ending in CLL. We have spent many blog posts discussing this issue, and we aren't finished yet.

Here is Professor Hallek:



More soon.