ASH 2013: Dr Jeff Sharman Discusses the Ideal Design of Phase 3 Trials with Novel Agent versus the Reality in the Community

As a patient, it is easy to be critical of study design.

Case in point: The phase 3 trial of rituximab (R) plus idelalisib (I) versus rituximab plus placebo presented at ASH 2013 in New Orleans.

Wait a minute, we patients scream. One arm of this trial is offering us a monotherapy option that is not recommended by most CLL experts because it produces a lousy response rate in the middle single digits. In the trial, lymph node response rate was a meager 4% for the R+ placebo versus 93% for the arm with the two active agents. And the duration of the response for the R alone is less that six months.

In comparison, in the R+I arm, median progression free survival has not been reached, and remarkably, even overall survival was improved, something unheard of in CLL just a few years ago when FCR was shown to be the first drug combination to add years to our lives.

All the data from the late breaking abstract can be accessed here. It is powerful, but one must ask, does idelalisib look so good because it was being compared to a straw man?

Is this an ethical way to conduct a trial?

Dr. Jeff Sharman, a regular on this web site, is both a community based oncologist and the medical director of hematology research for The US Oncology Network.

He points the pros and cons of the controversial trial design.

Watch the video and form your own opinion before I give you my bottom line.

First Dr. Sharman does a good job reminding us the difference between a phase 1, 2 and 3 trial.



So what do you think?

At first,  I was dismayed by the trial, from a patient's perspective, but when we have a trial design where we are pretty much guaranteed that we will get idelalisib if we need it, and in either arm we  can avoid chemotherapy, on further reflection I am more sanguine about this kind of trial.

The science bothers me more than the ethics. In the study, the results with idelalisib are very impressive and would likely have stood up to a much more active comparator arm, but in this case it was a massive mismatch as evidenced by the unheard of gargantuan P number (p = 1.3 x 10^-30 ). In other words, the odds of getting this result by chance alone was not one in a million or one in a billion or one in a trillion, but about one in 10 followed by 30 zeros.

So what is my take away message?

First, I am OK with most trials that have a cross-over built in from the get-go, and especially fond of those that offer us a chance to avoid chemotherapy.

Second, idelalisib is clearly going to be a powerful addition to our armamentarium for treating CLL. 
In this study it took on a tough bunch of patients.The median number of prior therapies was three. The test subjects were all considered too unhealthy to get traditional chemotherapy. Nearly half were 17p deleted and 17 out of 20 were unmutated. We are told that all the risk groups responded better to the idelalisib arm, but the abstracts doesn't give us much detail.

So, bottom line, unless my need to get my disease under control was so acute that I could not risk the delay in getting a response if I was randomized to the R+ placebo arm, I wouldn't hesitate to enroll in a similar trial if I needed therapy.

Based on this and other positive studies, I hope and suspect idelalisib will be approved for CLL in the USA before the end of the year. And that will be a good thing for the CLL community.

ASH 2013: Jan Geissler & Giora Sharf Part 2 on Adherence, the High Cost of Cancer Medications, and the Importance of Clear Communication

In the second part of my interviews from ASH 2013 with two smart patient advocates in the CML world, Jan Geissler and Giora Sharf reveal the results of their important study done in conjunction with their non-profit umbrella organization, The CML Advocates Network.

Before I get too far into my analysis of the results, let me first applaud Giora and Jan for doing all the hard work in making this possible.

Not only did they recognize an unmet need, they realized that their opinions would only be respected with valid research backing them up.

Then they had to not only design, develop, and ultimately score, review, interpret, write-up and present the data, they first had to procure the funding, find the doctors willing to help, and have developed over years a strong participating network of patients ready to jump in and help.

As someone in the throes of establishing a new CLL-focused non-profit organization, let me assure you, none of this comes easily. It was earned with hard work and trust.

More news soon on how this nascent disease specific non-profit will benefit anyone touched by CLL in very focused, local, unique and practical ways while not recapitulating what is already being done so well by the LLS and LRF, two great organizations that supply excellent background disease information and much more and also provide high quality large group meetings with top flight reviews of the basics in CLL in their breakout sessions. Here is my report from the last LRF meeting. I was also privileged to be asked to volunteer to speak on self advocacy this past weekend at the LLS Blood Cancer Conference in Los Angeles. I plan to share those slides I developed here and on the LLS web site soon.

Our new non-profit will be working with smaller interactive groups and be strongly focused on the cutting edge of research. More to come. I am so excited. This will make a high difference.

But I digress.

If you haven't seen the first part of the interview or you just want to revisit it, please click here.

If you want to read their fine paper, please click here.

The first few minutes of this section of the ASH 2013 interview identifies some of the high risk markers for skipping our medications.

Later we discuss the issue of the high cost of the medication. Not surprising this is a well recognized risk. Should I eat or take my pills?  For more on this important issue, browse through my blog and take a look at this paper on cost of oral medications and adherence in CML.

Many pharmaceutical companies (see the You & I Access program as an example for ibrutinib) have generous program to help defer the cost. The LLS can be a big help, but properly constructed, well conceived, and revenue neutral oral parity laws (where the percentage of the cost borne by the patient for oral drugs and IV drugs is similar) are not only possible but are desperately needed to avoid all these welcomed but ultimately stopgap measures.

Finally, as Jan says: "Adherence is partnership." The patients, the doctors, and the patient groups getting the word out about the importance of clear communication and understandings.

Ultimately good communication is the most critical and fortunately the most malleable piece of the puzzle.

Here is the video:

Please pardon the abrupt finish. You didn't miss anything but a technical glitch.

More soon from ASH, more on adherence, and more about the new non-profit to help those of us with CLL with better support and communication.

Ibrutinib (Imbruvica) is Approved for CLL

No matter who we are or where we are in our lives with CLL, today is a great day.

Ibrutinib was approved as mono-therapy for CLL patients who have had at least one prior therapy.

That is a very broad indication and that's good.

What that means is that the majority of us who might benefit from ibrutinib because we need treatment for CLL for a second time can now get it outside of a clinical trial.

The obvious folks left out with this present indication are those with high risk treatment naive CLL such as those with 17p deletion who need front line therapy now.

Will it be used off label?

It already is. Patients have been getting it for CLL already before this approval.

Will it be used in combinations with chemo and mAbs (monoclonal antibodies)?

I am sure it will be. Lots of trials addressing this.

Will it be used up front for those with 17p deletion.

I sure hope so. These too has been and is being studied.

There are several stage three trials ongoing to address all these issues and more. This accelerated approval is just the first step, but it is a giant step. I am sure the indications and labeling will change and broaden as more data is collected and we learn more. The FDA is very conservative and not very speculative.

But from today forward, those of us in the USA facing the need for therapy for our CLL, ibrutinib has just become a real possibility, and probably a near certainty if we had at least one prior therapy. That is a pretty low bar to jump over.

And at least for those of us not on Medicare, the support to help patients afford the medication from Pharmacyclics is strong.

For those of us already in ibrutinib trials (especially continuation trials such as the one I am in), I am not sure what this will mean. Will our bodies and our blood still be wanted? Time will tell and I suspect some but not all trials will be terminated.

For those outside the USA, this is a positive step, but hardly a guarantee that Imbruvica will soon be a pharmacy near you. Politics and budgets are different in every country, and that is why we need active and informed patients and providers to advocate for our best choices

Still this is a day to celebrate. Time for victory dance.

Here is the official press release from Pharmacyclics.

ASH 2013: Giora Sharf and Jan Geissler Discuss Mediation Adherence or “Drugs don’t work in patients who don’t take them.” – C. Everett Koop

I am introducing a new subject, namely the importance of taking our medications as prescribed.

What we call this simple behavior has been undergoing some changes as we have shifted from the more paternal old school term of "compliance" to the newer shared decision making model inherent in the recently most popular term "adherence". 

I  wrote an entire article on this important semantic issue a few years ago and will be updating it here as there has been further evolution in this topic of what these world imply about our world view.

I plan to spend some time on this subject over the next few months because it becoming increasingly important to all of us with CLL, in fact to any of us with any chronic disease.

This is especially true in the cancer world and there is much we can learn from the poster child of game changing targeted therapy where you simply swallow with a glass of water, imatinib or Gleevec, and poof….your cancer is no longer an issue.

It is hard to exaggerate the importance of the development of imatinib. For CML (chronic myelogenous leukemia) patients it changed a former life ending cancer (unless you had a successful but very risky bone marrow transplant) to a chronic disease controlled with taking a pill. The development strategy involved also fundamentally changed forever how all cancer could ideally be controlled.

Ibrutinib and idelalisib and all the new oral meds or TKIs are products of the process that was first so successfully deployed with Gleevec. First understand the biology of the cancer, figure out what is uniquely driving the malignant cells and then block it and try to block little or nothing else.

Targeted therapy.

The Pulitzer Prize winning book, The Emperor of All Maladies by Siddhartha Mukherjee is must reading for anyone dealing with cancer, and much of it is about the history of imatinib.

But even a wonder drug doesn't work if we don't take it. 

30% of CML patients are not taking their life saving medications, and that is the leading cause of developing resistance to therapy.

So please listen to what my friends from the CML world have to say about adherence from ASH 2013.

Giora Sharf and Jan Geissler are not physicians but CML patients turned advocates and researchers  who presented important research at ASH about why people don't take the pills that are saving their lives.

Here is part 1.

More on this and other news from ASH soon.

ASH 2013: Dr. Jennifer Brown Discusses the New Data on Obinutuzumab (GA-101 or Gazyva)

At ASH 2013, there was much to celebrate for those us with CLL.

This interview was recorded immediately after Dr. Jennifer Brown of Dana Farber had moderated an exciting CLL press conference in that same noisy press room.

While the small molecules that can be taken orally such as ibrutininb, idelalisib, ABT-199 and even the newer IPI-145 and ONO 4059 may have hogged much of the headlines over the last few year in the CLL world, there was important news about a new and better monoclonal antibody or mAb, namely obinutuzumab.

This one, like rituximab and ofatumumab, is directed against CD20, a surface protein found on all B cells, good and bad.

So like its fellow anti-CD20 mAbs, obinutuzumab knocks out all our B cells, leaving us at an increased risk for new infections and reactivation of old ones such as hepatitis B.

A bit of a background on another mAB first.

I have to say after all the excitement following the the approval of the second generation fully humanized CD20 antibody, ofatumumab, I have been disappointed in the results. Its main advantage seems to be for anyone allergic to rituximab, lovingly called "mouse juice" by the thousands of us who have had it dripped into our arms at infusion centers across the world because of its unholy but magic mix of mouse and human proteins (especially strange to think about if you are vegan like me). Despite high doses of pre-medications with steroids and antihistamines, some of us patients just can't get our bodies to stay calm in the presence of the mouse antigen and let the antibody do its important work. That is where ofatumumab has shined. No mouse proteins, so those who could not tolerate "Vitamin R" had an option. But the impressive improvement in efficacy over rituximab that I and many others were hoping for has not really materialized.

Obinutuzumab tells a different story. People are living longer significantly longer as Dr. Brown will detail on camera. The results are clearly better. The bar with rituximab was already set pretty high. Rituximab might be a lousy CLL drug on its own, but as a dancing partner it makes everyone look like a Fred Astaire (or Ginger Rogers). Its addition to FC forming the "gold standard" of FCR was the first time that any therapy was shown to prolong survival in CLL.

Dr. Brown of Harvard now gives us even better news on obinutuzumab.

But first we review how it was engineered to get these strong results and explains why being the first type 2 anti-CD20 antibody is so important to its efficacy.

And she discusses the management of the higher risk of infusion reactions. Please remember that although these new antibodies have no murine proteins, they can still cause rather severe infusion reactions, precisely because the bind so strongly to our B cells and are such potent killers.

Here is Dr. Jennifer Brown:



Remember too that this drug is already approved for CLL. From the package insert: in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

As I have reviewed in a prior post, this is a very limited indication, and much of its benefit would be expected to come in its use with other more potent combinations than with chlorambucil and for patients who have relapsed or who are refractory to other therapies including other mAbs. I would hope that it appropriate use off label is not rebuffed by the payers.

I expect soon to see a growing number of trials mixing and matching the new TKIs with obinutuzumab to get us that elusive CR. We need more trials. To get to our ultimate goal, a cure, we must first get to and pass CR, and most of the TKIs are leaving stalled on 3rd base with some persistent measurable disease. These new oral wonder drugs still need a teammate to get us home to a cure, and obinutuzumab is a very strong candidate to play that role.

That is the future I want. Rational non-chemo combinations edging us closer to a cure. It can't come soon enough. But we need more creative trials and more brave risk takers to make them happen.