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.

IVIG: FDA Demands More Prominent Notification of the Risk of Blood Clots

I get IVIG for my ITP. It used to be every three weeks, but now I have been able to stretch it out to every six and my counts are still great. No one is really sure how it works for ITP, but there are theories that it coats my platelets and protects them from premature destruction. I also enjoy the added benefit of protection against infections.

But it comes with risks. I have discussed some before including infusion reactions and allergies, and renal disease. It is an expensive pooled blood product, so there is always the theoretical risk of an occult infection, but there is such extensive safety measures in place that I don't worry much about that one.

Now the FDA is highlighting the risk of blood clots (thrombosis) in a boxed warning.

Ironically those of us with ITP already have a simultaneously higher risk of both bleeding and clotting. How lucky can you be?

I don't plan to stop getting the infusions, though there is a good chance my ITP is no longer active, but why take the chance. Instead I will try to avoid hopping on a plane the day after an infusion as has been in the case many times in the past. Hydration, being active, and my omega 3 rich diet might also help mitigate risk. So would aspirin, but that's not for me with all my platelet problems in the past.

This is the communication directly from the FDA:

Vaccines, Blood & Biologics FDA Safety Communication: New boxed warning for thrombosis related to human immune globulin products. Date: June 10, 2013 Purpose: FDA has analyzed recent data that has strengthened the association between the use of intravenous, subcutaneous and intramuscular human immune globulin products and the risk of thrombosis. Additional caution regarding the use of these products is warranted. Summary of Safety Issue 1 Recommendations for Patients 2 Recommendations for Health Professionals 3 Summary of Safety Issue The U.S. Food and Drug Administration (FDA) is requiring manufacturers to add information on thrombosis to th current boxed warning in the labels of all intravenous human immune globulin products and to add a boxed warning to the labels of all subcutaneous and intramuscular human immune globulin products to highlight the risk of thrombosis and to add information on its mitigation. A retrospective analysis of data from a large health claims-related database, as well as continued postmarketing adverse event reports of thrombosis have strengthened the evidence for an association between the use of intravenous, subcutaneous, and intramuscular human immune globulin products and the risk of thrombosis. This information necessitates a boxed warning for the entire class of products. Human immune globulin products are used in a variety of conditions, both on and off-label, by healthcare professionals who may not be aware of the thrombosis risk and measures that could be taken to mitigate this risk. Although all human immune globulin products already contain some information related to the risk of thrombosi in the current WARNINGS and PRECAUTIONS sections of their labels, FDA recognizes that the communication of this risk and its mitigation are not standardized. FDA proposes that for thrombosis a more prominent placement of risk information and a uniform approach for communicating the risk and its possible mitigation will help to reduce the occurrence of these serious adverse events. The information on thrombosis in the boxed warning states: Thrombosis may occur regardless of the route of administration. Risk factors include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. For patients at risk of thrombosis, administer at the minimum concentration available and at the minimum rate of infusion practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Recommendations for Patients Patients should be aware of this risk and discuss this risk with their healthcare professionals. Be aware that thrombosis is associated with human immune globulin products. Talk to your healthcare professional about any risk factors or concerns you may have with human immune globulin products. Contact your healthcare professional if you develop any signs or symptoms of thrombosis during or after receiving human immune globulin. Signs or symptoms of thrombosis may include: pain and/or swelling of an arm or leg with warmth over the affected area discoloration of an arm or leg unexplained shortness of breath

chest pain or discomfort that worsens on deep breathing unexplained rapid pulse
chest pain
numbness or weakness on one side of the body

Recommendations for Healthcare Professionals

Healthcare professionals should be aware of the risk for thrombosis with human immune globulin products and ensure appropriate patient selection and monitoring.
Discuss with your patients the risk of thrombosis associated with these products.
Carefully consider risk factors when selecting patients for treatment with human immune globulin products
Monitor patients carefully for signs and symptoms of thrombosis both at the time of infusion and after infusion and encourage patients to report any signs or symptoms.
Report adverse events involving human immune globulin products to the FDA MedWatch program.

New Adverse Event for Ibrutinib: Brittle Nails

The Registration Trials that are ongoing are purposed not only to find out if the strong response rates seen in the earlier phase 1 and 2 trials hold up with larger and different populations of patients, but also to look for early signals of unanticipated side effects of adverse events.

But problems with medications can show up very late in the game.

Who would have guessed that pregnant mothers who received DES (Diethylstilbestrol) in what turned out to be a futile attempt to reduce the risk of miscarriage would see a problem a generation later when it was realized that their daughters exposed in utero had an increased risk of a rare vaginal and cervical cancer.

And while a good number of the brave first patients out of the handful that entered the phase 1 trial of ibrutinib are still doing well on drug, at the time of this writing I don’t believe that anyone has been on the medicine for even four years, and most of us for much shorter times.

Therefore we should not be surprised as our experience grows with the new generation of treatments heading rapidly for FDA approval when new possible concerns pop up.

I didn’t get a chance to ask Dr. Byrd when he spoke on the early results with ibrutinib in Stockholm at the same meeting where I too lectured (I gave a patient’s perspective on having CLL and how my life was impacted by both the disease and by my dramatic response to the new medicine) about the incidence or statistical significance of what to me was an unknown adverse event: brittle fingernails.

That explains why my career as a hand model will never get off the ground. My fingernails break easily and I must keep then very short at all times to avoid them tearing. Reaching in and out of my carry-on bag with its computer sleeve and tight pockets where I stuff my papers and medications is like a dance in a minefield for my fingertips, and they are often the worse for wear after my travels.

I also am certain just as we all know that when someone asks us if our nose is itchy, our noses are more likely to itch, awareness of the possibility of any problem increases the incidence of the problem. I will now join the ranks of those ibrutinib subjects reporting brittle nails, though for me the fashion consequences are much less significant compare to the women who enjoy growing and painting their nails and who, I bet, were much more astute and observant than me in pointing out this problem early on.

I just thought it was a consequence of my vegan way. Maybe it is.

In the big scheme of things, jagged fingernails are not a biggie. Sure beats pneumonia or neutropenia. Still could it be a marker of a bigger problem?

What’s next? Split ends? This isn’t so crazy. Many chemo drugs not only cause your hair to fall out, but when it grows back, it grows in curlier due to the broken bisulfide bonds.

Will our future doctors be able to walk into our exam room, check our fingernails, and assess if we have been compliant with taking our medications?

Time will tell, but I am pleased that so far, so few nasty signals are popping up.