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Clinical Trials

Meeting With Berlex Labs

June 29, 2004

by Chaya Venkat

FluCam-106

Last week PC and I met with Berlex Labs in Seattle, at their request. Berlex is the U.S. distributor of Campath, fludarabine and Leukine (GM-CSF).  I am sure they make or distribute other great stuff, but these days I am not ashamed to admit I have tunnel vision: if the drug has nothing to offer CLL patients, I am not interested. And for those of you with "inquiring minds", yes, Berlex did offer us an honorarium for our time. Both PC and I chose to have their entire check made out to Mayo Clinic, earmarked for CLL research and Project Alpha. So both of us are still as pure as the driven snow, no taint of pharmaceutical money to cloud our judgment.

We met with Berlex's marketing and clinical team. They wanted our input and perspective as patient advocates, and we were happy to give it to them. We also participated in a CLL patient focus group discussion. All in all, nice folks, great town, very interesting conversations, tiresome airports and flights. I have tried to capture much of what we discussed with Berlex, as well as a little background information where I though it might be useful to you.

Fludarabine and Campath:  Major Drugs on the CLL Landscape

Let's face it, like it or not chemotherapy is an important weapon in our arsenal against CLL and fludarabine is as big as they come in the list of chemotherapy agents for CLL. It has long been the "gold standard" for CLL, and even now it plays a major role in combination therapies such as FRC and RF. But please do read our recent article on the use of single agent fludarabine as front line therapy: Fludarabine Monotherapy No Longer the Gold Standard. The Ohio State clinical trial of (Rituxan + fludarabine) combination has demonstrated clear survival advantage over single agent fludarabine. At this point in time, the other Berlex CLL-specific drug, Campath, is the only monoclonal antibody that has been approved for CLL as single agent therapy. Rituxan has not been approved in this role. And yet, more and more patients are choosing Rituxan-based therapies, either as single agent or in combinations, and oncologists are going along with that, sometimes prescribing Rituxan for off-label use. For many patients, the line-up of escalating therapy intensity goes something like this right now:

  • Watch & Wait (and Worry);

  • Rituxan as single agent ;

  • Rituxan plus various immune system modulators, such as Neupogen, high dose corticosteroids, Leukine, IL-2, PT-100 and so on;

  • Rituxan plus fludarabine (and/or cyclophosphamide, depending on where you go for your expert opinion);

  • All, some or none of the above, plus Campath for extra oomph or consolidation of minimum residual disease;

  • bone marrow transplant (auto, mini-allo, full allo).

Obviously, this list is an oversimplification, and does not fit all cases. There are other drugs such as Pentostatin (purine analog similar to fludarabine), older generation drugs like chlorambucil, new stars that are yet to prove their worth such as flavopiridol, disappointments like Genasense, double helping of monoclonal scenarios like (Rituxan + Campath), the odd "gene therapy" and externally grown armies of killer T-cells thrown in for good measure. A few well-constructed clinical trials have addressed frontline and second-line therapy with Campath, but this is hardly setting the patient community buzzing with excitement. What gives? No wonder Berlex's Campath team wanted to meet with us. 

Here Is Why We Think Patients May Be Voting With Their Feet for Rituxan-Based Therapy:

  • Campath targets not only B-cells, but also T-cells and NK cells. Recent studies have shown that with Campath therapy the immune suppression is deep and across the board, and some of the cell lines are mere ghosts of their former selves even 18 months after end of Campath therapy. Ask us for a reference, if you wish to read the article.

  • Campath has a history of significantly more infusion-related adverse effects than Rituxan. The fact is, intravenous Campath administration can be a real bitch, but Campath administered as a subcutaneous injection has been a lot more tolerable from the patients' perspective. I wonder why any one would still use intravenous Campath administration?

  • There is significant risk of opportunistic infections with Campath, but this is now much better controlled with mandatory pre-medications to guard against them. However, one question that has been bugging me: why is there no push to use growth factors such as Neupogen, to help boost neutrophil counts? Surely these intrepid fighters of our immune system can help hold the line against infections after Campath therapy? Good to know neutrophils do not express CD52, so they are not likely to get killed by the Campath that is still sloshing around your system for at least a few weeks after the last shot.

  • The recent German clinical trial using Campath for consolidation of minimum residual disease had to be halted mid-stream, due to unacceptable level of adverse effects. While a similar trial at M. D. Anderson was taken to completion, in this reporter's opinion those results were none too pleasant either. You may want to read Hitting a Home Run With Campath Consolidation? to refresh yourself on the details of this experience.

  • With good reason, patients may be choosing to keep Campath for a rainy day, when and if they stop responding to Rituxan-based therapies.

  • There is a wealth of excellent technical papers describing Rituxan pharmacology and mechanism of action, providing the comfort factor to local oncologists, patient advocates like me and patients like you. Much less so with Campath - frankly, we (and the research community) are still not clear how exactly Campath works. Couple that with the remarkably low infusion-related side effects of Rituxan, it is easy to see why Rituxan is the path of least resistance for most of us and our oncologists.

  • Genentech is an extremely powerful marketing machine, and it is hard to miss the name Rituxan at any of the major conferences, oncology journals or even the lay press. I ran into several of their very persuasive sales reps in oncologists' offices, even got a ball-point pen. No doubt Rituxan is offered at very attractive "bulk discount" prices to oncologists. This is a billion-dollar ball game for Genentech.

However, It Is Not In Patients' Interest to Let This Become a One-horse Race:

Let me get my personal opinion right on the table, so you can judge what I have to say in the context of my acknowledged bias. I think Campath is a very important monoclonal in our fight against CLL, and it is in our interest to support research and clinical development of this and other such drugs. Here are my reasons: 

  • Not all CLL patients respond to Rituxan - some patients express hardly any CD20 on their CLL cells, the marker that is targeted by Rituxan. 

  • On the other hand, Campath's target, CD52, is  abundantly expressed by just about every B-cell in your body. Just about all CLL patients respond to Campath, in some fashion.

  • Campath responses are more robust, deeper, and seem to last longer than those from Rituxan therapy. 

  • The "kinder & gentler" response to Rituxan therapy may be reflecting nothing more than a shallow response. When Rituxan based therapy is goosed up with immune modulators such as Neupogen, so that the response is deeper and more robust, this may be a paralleled by an increase in the risk of opportunistic infections.  Do read Latest on Harvey, about a patient whose Rituxan-based therapy led to very low absolute lymphocyte counts, and, sure enough, opportunistic herpes infections. 

  • There is a great deal of cross-talk between B-cells and T-cells and one of the hallmarks of CLL is the very high risk of autoimmune diseases, some of them precipitated by corruption of the T-cell compartment by the malignant CLL B-cells. Getting rid of the whole kit and caboodle may not be such a bad idea, a little bit like firing the entire corrupt police department as well as the politicians that were on the take.

  • Campath therapy protocols are improving, both in efficacy as well as in controlling side-effects. It may be time to revisit the earlier bad press since it may no longer be relevant. (Read Campath - Looking Better and Better.)

  • A recent excellent report from our European CLL experts confirms an important point: Campath works in fludarabine refractory and poor cytogenetics patients. This has not been shown to be the case with Rituxan. In fact, CLL patients with prior chemotherapy under their belt do not show much of a response to Rituxan monotherapy.

  • Last, but not least: even if you are well set in your therapy choices and you do not think you will ever need Campath-based therapy, stop and think. Remember that article Not the Worst Day of Your Life? Familial CLL is a nightmare reality that none of us who are parents and grandparents can afford to forget. You may not need Campath. Your kids just might. What you do now to progress this technology will help other CLL patients down the road, one of whom may be your own kid or grandkid.

I hate to see a one-horse race. It really takes at least two players to keep our capitalist system working right. Where would be the incentive for improvements in Rituxan and related products, if Genentech had no competition?

"FluCam 106"

Berlex is interested in a clinical trial that compares head-to-head the Ohio State type (Rituxan + fludarabine) combination against Campath + fludarabine. This trial is called "FluCam 106" (some of these guys should go back to marketing 101. Personally, I think the "Round Headed Kid" or RHK protocol is a lot cuter name. But then, I admit I am biased). Here is a link to the official trial announcement at the NCI website. Here are some of the details of FluCam 106:

  • The trial is under the able supervision of Dr. John Gribben of Dana Farber. That is about as credible as it gets.

  • It is a multi-center trial. Twenty nine locations are identified in the NCI official trial announcement, listed alphabetically by state. 

  • They are looking to recruit 150 patients, a large enough group to yield statistically meaningful information. I am glad to see this - it is frustrating to deal with under-powered and almost anecdotal studies that are called clinical trials these days. In such trials patients are risked in the name of 'cool' science and skimpy data of dubious value.

  • Patients will be randomized into two arms: one arm will get Rituxan + fludarabine, the other arm will get Campath + fludarabine. Make sure you understand this part. Once you volunteer for this trial, you do not get to choose which of the two arms you will be in, the computer will assign you to either arm, in a random fashion.

  • Both arms will be supported by appropriate prophylactic medications to protect against infections.

  • The eligibility criteria require patients with one (and just one, no more and no less) prior exposure to therapy.

  • Both arms of the study have heavy duty blood monitoring, including three (count them, three) bone marrow biopsies.

  • The trial has been open for 10 months, they have recruited 12 patients thus far. A little on the slow side, even for these days.

It is no secret the average community-based oncologists make much of their annual income based on difference between the "bulk discount price" they pay for expensive oncology drugs, and the much larger figure they are permitted to bill insurance companies or Medicare. This is a huge financial disincentive for referring patients to clinical trials.  That is the single biggest reason why cancer clinical trials in this country are doing so poorly at recruiting volunteers. Patients just don't hear about them from their community-based oncologists! The solution is simple: recruit patients directly, without going through the local oncologist as middleman. This is where the Internet and patient advocacy groups like CLL Topics can make a huge difference. We are interested in the clinical research, we will participate and help the process. But only if we are taken seriously as legitimate partners in the process, our voices heard, our input sought. It seems this is a "novel" idea, to have patients considered as something more than passive cancer victims in the clinical trial process. Well, time to change that outmoded paradigm, don't you think? 

Recruit Where the Interest Is, Among Patient Communities

Here is the advice we gave the Berlex team. They listened very politely and we even think we convinced them on some of the issues. But if I have learned one thing in my business career, no deal is a done deal, not until it is really done. As some guy said, at this point the fat lady is just humming and a lot can change. 

  • Get away from IV Campath, once and for all. Subcutaneous injection is now the standard of care for Campath. I am glad to see this is the case in FluCam 106.

  • Systemic corticosteroids to control infusion-related side effects worry me. One of the comments of the German MRD study team was that greater use of systemic corticosteroids may have been the cause of higher than expected adverse effects in their study. Why not use local corticosteroid cream, at the injection site?  This is not my bright idea, this suggestion comes from an accredited Campath expert, Dr. Geoff Hale. Geoff, you are a scholar and a gentleman.

  • We strongly urge the use of growth factor support to control the depth and duration of immune suppression after Campath based therapies. Not only will this help protect patients against neutropenia at a time when they are also lymphopenic, there is the intriguing idea that both Neupogen and Leukine are known to interfere with the SDF-1 and CXCR4 interaction that keeps CLL cells tethered in their cozy lymph node homes. Kicking them out into the peripheral blood will make them that much easier to kill. This is one part of the rationale behind our "RHK" protocol. (read Adhesion, Homing and Resistance to Therapy and The Difficult Case of the Round-Headed Kid). It makes even more sense in the context of monoclonal therapy, since neither Rituxan nor Campath are particularly good at clearing lymph nodes.

  • Since Campath has a stronger response compared to its rival Rituxan in the case of patients with poor prognostic cytogenetics, we suggested that Berlex should be pushing FISH analysis for all it is worth and in this way play to their strengths. (Read What Type of CLL Do You Have?, FISHing for Answers, What You and Your Oncologist Need to Know about CLL (aka Mayo Best Practices).) Frankly, we suggested that Berlex should start a CLL patient registry, with free FISH testing for all registered CLL patients. I am sure they can negotiate a hugely discounted price for the FISH testing from the several commercial labs that now offer CLL FISH panel, much better price than we can get one patient at a time. Talk about winning friends in the patient community. Who needs ball point pens or T-shirts advertising Campath? Give us FISH instead. You know, I can't bet on this but I think we might have actually "sold" this idea.

  • We need greater disclosure. Why is it so hard to get the full blown details of the clinical trial protocol? Every time I ask for this (and this is not just Berlex's problem but across the board) I am told the document is proprietary and confidential. I just don't get it. They are asking patients to sign informed consent forms, risk their very lives, and the protocol that will be followed by the clinical trial team is considered not appropriate reading material for patients? How is this informed consent? Surely this is against the spirit of the Declaration of Helsinki, which laid down very strict ethical regulation of trials involving human subjects? And here I thought the AMA was one of the original signatories to that declaration!

  • Forget the deep dark secrets of the full clinical trial protocol, how can patients make decisions about enrolling when it is sometimes so hard to get even a full listing of all the locations where a trial is offered? Trials like the FluCam 106 protocol last several months and the monitoring stretches out even more. No one wants to travel far from home for cancer therapy, if it can be helped. For the patient, this is an important part of the decision making. Clearly, this information should be widely available. As you can see from the listing in the NCI website, FluCam106 has the distinction of being offered in 29 widely dispersed sites.

  • In the real world of people living on retirement income or even just social security, cost of clinical trial enrollment is a real issue. Often, medical insurance pays for "standard and regular care", and the clinical trial sponsors pay for extra drugs and testing that is required for the clinical trial. But no one pays for travel costs, hotel costs, food bills while away from home and other similar out-of-pocket costs. I think the Berlex team is now convinced that this has to be changed. But again, check before you sign on the dotted line, make sure you understand who takes care of the expenses.

  • Believe it not, the abbreviated clinical trial description of FluCam 106 on the web right now says (in capital letters for emphasis!) that the trial does not pay for any of the drugs. Huh? That does not compute. Fortunately, I think this one has also been reconsidered and the trial sponsor will pick up the costs of the Campath and Fludarabine. Question to ask, what happens if you are randomized into the Rituxan + fludarabine arm? Who pays for the drugs then? You know me, trust but verify. Choosing a clinical trial is at least as important as buying a new car. You do ask for a written price quote from the salesman, right?

  • Three bone marrow biopsies are on the protocol as of now. I suppose this is not too much to ask, if every one is guaranteed an expert such as "Larry" at M. D. Anderson, the guy has magic hands. Most of you will be getting your protocol administered at a local centerGetting a bone marrow biopsy done by someone who has not done a zillion of them and gotten good at it is not a trivial thing. We tried to convince Berlex that three BMBs are an overkill since a recent article by Kennedy, et. al., has developed a very nice correlation between peripheral blood data and bone marrow involvement. Ask us if you want to read the full article. Guys, it does not have to hurt for it to work well.

  • Last but not least, there is a real shortage of credible Campath-related information. In the absence of published literature, I have no option but be shameless and pester the few contacts I have in the research community with my many questions. Don't you think it makes sense for Berlex to give an "educational grant" to an unimpeachable Campath expert, who is then willing and able to answer patients' questions regarding this important drug? You have no idea how difficult it is to get busy folks like Dr. Gribben to answer email questions from pushy people like me, especially to answer the questions "on the record" and OK for publication.

In summary, I think it was a very fruitful meeting. It says a lot that this company is actually soliciting our opinion and advice (OK, PC and I might have gone a little over the top on the advice bit, but hey you get nothing unless you ask for it, right?). I hope this is a trend and the empowerment that goes with the development of on-line patient communities will finally get us a seat at the table. We have the most at stake in these clinical trials, our lives and our children's lives. Full disclosure and good faith recruitment that takes the patients' perspective into account when designing clinical trials just may work, cut through the so-called patient apathy and distrust. 

If Berlex comes through with formal acceptance of any of these recommendations, we will publish their letter on our website as well. Patients sign very formal contractual documents when they volunteer for clinical trials, we ask for no less from the sponsors of the trials.

 

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