Sponsored Projects el pt

Project Alpha Kicks Off

Date: August 22, 2024

by Chaya Venkat

EGCG Trial Is on Its Way!

Related Articles:

Project Alpha Proposal;
Project Alpha Announcement;
Project Alpha Milestones.

It has been a long wait and has involved a lot of hard work on part of the researchers and even us chickens at CLL Topics. Hundreds of generous donors have put their money where their hearts are and have contributed to our fund-raising efforts. But finally it is official. Project Alpha begins recruiting patients today. This clinical trial has a number of “firsts”. It is the first formal clinical trial using EGCG (an extract of green tea) as a potential drug for treating CLL, in human volunteers. It is the first time that a patient group has worked closely with a premier institution such as Mayo Clinic to bring to the forefront a low toxicity therapy approach that is of interest to the patient community. It is the first time that a CLL patient group has sponsored and funded a clinical trial. It is the first time that CLL Topics has taken on such a challenging task. I can keep going, but you get the picture. I am as proud as I can be. You can read more of the background of “Project Alpha” by clicking on this link: CLL Topics Sponsored Projects.

There are two parts to this article. The first is our review of the clinical trial design, pros and cons. We give you inclusion and exclusion criteria, time frames, contact information, names and phone numbers where you can get additional information. As we point out every time we review a new clinical trial, there are costs and rewards associated with participating in any clinical trial, and this one is no exception. True, we do not expect too many risks in terms of toxicity. That is the whole point of our interest in EGCG as a potentially low toxicity drug. But there are other costs, such as your time and your money. We point these out, as well as why we think your participation is still justified, even it costs you a little of both time and money. The second part of this article is the transcript of a telephone interview I did with Dr. Neil Kay and Dr. Tait Shanafelt, the two lead researchers at Mayo Clinic for this clinical trial, to get their take on things. I suggest you read both parts, to get a good sense of what this trial is all about.

If you are interested in participating in this trial, I suggest you get on the horn at your earliest. I have a feeling this one is going to be “sold-out” pretty quickly.

Listing in clinicaltrials.gov	NCT00166335
Institution	Mayo Clinic, Rochester, MN
Clinical Trial Identifier	MC0419
Institution's Trial Listing	Mayo Clinic Trial Listing
Therapy Agents	Polyphenon E (EGCG from Green Tea Extract)
Trial Description	A Phase I/II Study of Daily Oral Polyphenon E in Asymptomatic, Rai Stage 0 -II Patients with CLL
Cancer Center Web Link	Mayo Clinic Rochester;
Principal Investigators	Neil E. Kay, MD; Tait Shanafelt, MD.
Contact Phone Number	(507) 266-1154
Additional Contact	Andrea Kukla   Tel: (507) 266-9953; Fax: (507) 284-2251
Sponsor	Supported by NCI and CLL Topics, Inc.

Who Should Participate in This Clinical Trial?

I wish I can say that a very low toxicity material such as green tea extract EGCG will “cure” all CLL patients, right now. That would be a foolish hope, and I would be a liar if I said I expected any such miracle. Wishful thinking should not get ahead of rational decision making. Last thing we want is patients with advanced or refractory disease foregoing more realistic therapy options because they are fixated on a “kinder and gentler” therapy, a “natural compound” that is going to cure them miraculously.

Who is most likely to benefit from EGCG therapy? Possibly patients with early stage disease, newly diagnosed patients whose CLL has not yet been “kicked up another notch” by prior therapy. This is a good place to start, where the clinical trial can get us some of the answers we need, before we can take this to the next stage of development. Hey, if the results look so great that these cautions are blown out of the water, that is the kind of problem we would love to have. More advanced case patients can always be recruited in later trials. The inclusion criteria are given below, they pretty much fit the profile of early stage patients. Please contact Mayo Clinic (contact information is given above), if you have additional questions on the inclusion or exclusion criteria.

Inclusion Criteria

• Grown up adult patient with confirmed CLL that has not been previously treated.
• No pregnant women or those breastfeeding babies.
• Mantle cell lymphoma must be ruled out by FISH. MCL is a much more aggressive disease, and sometimes it is possible to misdiagnose it for the more indolent CLL. MCL patients need therapy a whole lot sooner, and EGCG type of “kinder /gentler” therapy is not likely to be their best choice.
• You must be in generally good health, not likely to kick the bucket within the next 6 months.
• As we said above, this clinical trial is recruiting early stage patients only, those with Rai-stage 0, I, or II. If you do not know what exactly is involved in this staging system, here is a link that will tell you exactly what is involved: Staging Does Not Predict Survival
• As would be expected for early stage patients, you must not have any of the classic B-symptoms: extreme fatigue, unexplained weight loss, night sweats, fevers, frequent infections.
• You will not be able to participate if you have a massively swollen spleen, or node clusters that measure more than 10 cm in their longest dimension.
• Your CLL must not be galloping at a very fast clip, such as more than 50% increase in the last 2 months, or a projected of doubling time less than 6 months.
• Absolute neutrophil count above 1.5K, platelets count above 100K, hemoglobin higher than 11.0, liver and kidney functions not too out of whack. In other words, bilirubin, AST, ALT, creatinine, etc., within specific limits. Write to us or contact Mayo if you want the specific cutoff points on each of these measures.
• It is OK if you have AIHA (autoimmune hemolytic anemia), but not if it is so advanced as to need transfusions or steroid therapy in the last 10 weeks.
• No uncontrolled infections, and no heart attacks and the like in the last 6 weeks.
• No use of over-the-counter green tea or green tea extract in the last 8 weeks. This is an important point given how many of you are indulging in varieties of green tea products already. We will discuss the wash-out option in more detail below, allowing these folks to participate as well.
• You must be sane enough to sign on the dotted line after having understood the consent form, and you must be willing to return to the Mayo once a month for 6 months for check-ups.

For some helpful patient information, you can read the consent form for this trial by clicking here.

Come to think about it, this is end of August and we are talking of six months stretching out into the less-than-balmy winter of Rochester, Minnesota. Trust me, it gets very cold. Fortunately all the buildings are connected by underground tunnels or heated sky bridges. No one sticks their noses out if it can be helped, not unless they are dedicated fresh air fiends. Rumor has it Dr. Neil Kay indulges in a mean game of ice hockey, but perhaps that little foible may be forgiven in view of his Canadian background.

What Brand and How Much EGCG?

“EGCG” stands for epigallocatechin gallate. Try saying that quickly three times in a row. I got even Dr. Kay to trip on that one. EGCG is all the rage these days, you can even buy vitamin tablets that claim to have EGCG in them. There are literally hundreds of EGCG containing potions and pills you can get on the Internet, some of them with wild claims that should tip off the cautious consumer to just say No. Where does Mayo Clinic get their EGCG used in this clinical trial? The drug used is called “Polyphenon E” and it is supplied by the NCI for use in this clinical trial. Polyphenon E comes from Mitsui Norin, and this pharmaceutical grade EGCG product is not available to the general public. You can only get it in the context of this clinical trial.

How much EGCG? Aha. That is one of the major reasons for doing this clinical trial, to establish the right dosage for this drug. I wish I had a dollar for each of the emails I got in the last year from patients asking this question. I have become pretty good at dodging this question. How much EGCG is needed to get enough of a response to be worth it, and how much is too much in terms of unacceptable risk or toxicity? Remember, even the most “harmless” drugs can become dangerous at too high a level. The first part of this clinical trial recruits patients to establish the right dose. The second part then goes on to study the long term use of EGCG at this established dose.

The Clinical Trial Design

All patients who participate in this clinical trial will undergo a full medical examination as well as all the modern prognostic testing. This is an important point, and one we will discuss in more detail in our interview below with the Mayo investigators.

In the Phase-I of this trial, patients will be recruited in groups of three, each group getting escalating doses of EGCG (Polyphenon E capsules, taken orally twice a day, one hour before a major meal). Patients will take the EGCG capsules at home for 28 days, then return to Mayo for full laboratory testing and medical assessment. The Polyphenon E dose will escalate from a measly 400mg all the way to 4,000mg. The game plan calls for 6 groups of 3 patients each to check out this range of drug dosage. In other words, we are looking at a recruitment target of 18 patients (3 each at 6 dose levels) for this part of the trial. It is my understanding that roughly half of these 18 patients have already signed on. Patients recruited later on will get inducted into the higher dose levels.

At each dose level, patients recruited will be observed for a minimum of 4 weeks before the next group of 3 patients is treated with the next higher level of Polyphenon E. Patients will be monitored for hematological toxicity (anemia, neutropenia, thrombocytopenia), as well as the common adverse events defined by the NCI. The optimum dose (MTD, or Maximum Tolerated Dose) is defined as the dose level below the one that causes problems for 2 out of 3 patients in that dose group.

Once the correct dose level has been established in the first phase of the trial as described above, the Phase-II part of the trial will start, looking at long term treatment of patients at this established dose level. Here the target is for recruitment of a total of 33 patients. Unlike the first part of dose escalation study which will be conducted exclusively at Mayo Clinic, Rochester, MN, it is hoped that by the time the Phase-II of the trial starts it will be open for recruitment at more than one CRC (CLL Research Consortium) Center. That should make for substantially better access to patients. I understand the CRC as well as the CLL Global Research Foundation has expressed support for this clinical trial, even to the tune of coming up with some of the funding.

What Is in It for You?

That is a question you should never forget to ask, we hope we are training more patients to ask similar questions before they sign up for any clinical trial. It is a particularly interesting question with regard to this trial, since EGCG in various forms and different concentrations is available over the counter. If you fit the inclusion criteria, why should you sign up for this clinical trial, rather than doing your own thing, indulging in the EGCG product of your choice on your own? Here is our take on this issue. Write to us if you come up with your own comments or suggestions.

• Polyphenon E is a thoroughly tested product, pharmaceutical grade material that has met the stringent requirements of the NCI. The same thing cannot be said for any of the green tea products on the market. You cannot get this grade of Polyphenon E as a consumer, except in this clinical trial.
• When it finally comes down to it, none of us have a clue what constitutes the right dose. Too little, and all you are doing is flushing money down the toilet, literally. Too much, and you are putting your liver and kidneys at risk. The whole point of doing the clinical trial is to establish once and for all, under rigorous clinical trial setting, the perfect Goldilocks answer. Not too little and not too much.
• It is all too easy to poison yourself with indiscriminate use of “herbal” products. Herbal supplements can be potent drugs, and they can do a lot of mischief if taken without suitable guidance and monitoring. That is one major advantage of participating in this clinical trial. You will be well monitored and observed by some of the best experts in the field, at a major institution that has a credible track record of caring for CLL patients. For me, some of the higher doses of Polyphenon E that will be examined in this clinical trial are definitely out of the question, without the safety net of regular and professional monitoring for liver and kidney function.
• Each and every patient participating in this trial will get a full modern prognostic work-up. That includes FISH, ZAP-70, IgVH gene mutation status, CD38 levels, the works. That is one of the best thing about this trial, from my perspective. The two Principal Investigators who designed this clinical trial, Dr. Neil Kay and Dr. Tail Shanafelt, are also the authors of a paper we quote often, “Prognosis at Diagnosis”. This paper has been very effective in ushering in the era of modern prognostic testing for CLL patients, and making therapy decisions based on risk assessment. I am glad to report that these two researchers are practicing what they preach. The effects of EGCG therapy will be judged in the context of modern prognostic indicators. We have all read stories on the Internet chat rooms, from people who swore EGCG worked for them, and often enough exactly the opposite story, that it did nothing. Finally, we may have a chance to find out the profile of the patients in whom this low toxicity drug is more likely to work, and equally important, the patients in whom it is not likely to work.
• One major issue we discussed and negotiated with the Mayo team on behalf of our patients is this: patients who want to know the results of their prognostic testing will be told the results upon request. This is no small deal. Even with the availability of the Quest prognostic packages (Prognostic and Monitoring Test Packages), there is still a lot of hassle associated with getting these tests done, and not every one has sympathetic local oncologists or generous insurance companies to back them in this regard. Participation in this clinical trial will finesse that issue nicely. Mayo is one of the expert centers that defined the state of the art in CLL prognostic testing. It was my pleasure to have met Dr. Paul Kurtin and Dr. Gordy Dewald, two of the most highly regarded clinical pathologists in the country. Your will be able to count on the accuracy and credibility of the prognostic testing you will get at Mayo. All too often, test results that can be valuable information to individual patients gets buried under the label of “research confidential information”.
• This last point is an important one, and I am chagrined that it is not made as often as it should in the process of recruiting patients. Any number of patients trying out EGCG products on their own, then writing about their experiences on the chat rooms are not going to make one bit of difference in the long term. These anecdotes are soon forgotten, buried in the archives of some Internet forum. The next generation of patients will not benefit from your experiences. The only thing that will get this potentially valuable drug out there into main stream medical practice is if it goes through formal clinical trial testing at a highly regarded institution, supervised by researchers with unimpeachable reputations, and the results published in a peer-reviewed journal.

CLL is a familial disease. I am told it has more family connections than any of the other leukemias. A significant percent of our children, grandchildren and siblings are going to be diagnosed with this disease. And when that happens, it may happen to them at a younger age, and with a more aggressive form of the disease (Not the Worst Day of Your Life). Do we play Russian roulette, hoping that it won’t happen to us, our kids and grandkids? Let some other family bear the burden of family clusters of CLL? That attitude is not what we expect from a thoughtful, generous community. None of us can predict the future, the best we can do is look both sides of the street before we cross. We never know when the truck coming down the road has our name on it.

Participating in clinical trials is all a matter of balancing risks and rewards. I am happy to say I do not think there is substantial risk of toxicity in this clinical trial. The rewards may be pretty good, in terms of controlling the rate at which the disease progresses, if one is to believe the anecdotal information we have all read on the chat rooms. What is the cost? Your time and your money. Polyphenon E, the EGCG drug used in this study, is supplied free of charge to participants. But I have no doubt that you will be picking up the tab for travel to balmy Rochester once a month for 6 months. You are going to be paying out of your own pocket for food, lodging, transportation etc. If you are a working stiff, you have to make arrangements for time off, make plans for some one else to pinch hit for you at home. None of these are small issues. We all live very complex and interconnected lives. Only you can decide if you can afford this level of “cost”, before you participate in this trial. It will a bit easier when the second part of the trial is picked up at other CRC centers.

If you are already taking EGCG-containing products, and you wish to participate in this trial, you can. The thing to do is register for the trial and stop taking the EGCG product. A two month wash-out period is necessary, but my guess is that it would take at least that long to get all the paperwork in place.

There are interesting plans for expanding the role of EGCG in the future, by combining it with monoclonal antibodies such as Rituxan and Avastin. Sure, we have a bunch of patients who have been through the “RHK” protocol (The Difficult Case of the Round-headed Kid) and we have anecdotal information on how this combination of Rituxan + EGCG and Neupogen has worked out for these patients. That is a far cry from a credible and well conducted clinical trial combining EGCG with Rituxan and other monoclonal antibodies. Testing EGCG in formal clinical trials is an important first step, before we can get to testing its combination with other potentially synergistic drugs.

Ladies and gentlemen: we sponsored this trial, we are funding this clinical trial to the tune of a cool $70,000, we are sending out the check to Mayo today. This represents hard-earned money that we raised from patients, real money earned with real sweat. This is our trial, our contribution to our own community and future generations of CLL patients. Make us proud, participate if it fits your needs. Even if you cannot participate, by all means get the word out to as many other CLL patients as you can. This belongs to all of us, not just the ones that read CLL Topics on a regular basis.

Mayo Interview

Dr. Neil Kay and Dr. Tait Shanafelt Talk with Dr. Chaya Venkat

Spring, 2024

Chaya: Thank you so much for agreeing to this telephone interview. We think that it is important to document some of the details of your plans for Project Alpha for our patient group. We plan to publish a transcript of this interview on our website.

We have received your grant proposal and that has now been approved by our Board. We are delighted that CLL Topics is able to provide funding for this important project. While $70,000 is not a large sum of money in the grand scheme of things, it represents hard earned money collected in generous patient donations, and as such it is a huge expression of the grassroots support this project has in our patient community.

If I can get right to the subject matter, we understand that this is a phase I/II clinical trial with “Polyphenon E”, the green tea extract with EGCG. We are interested to know that you will be recruiting all stage patients with the condition that they have to be untreated. Am I correct?

Dr. Kay: That would have to be early stage patients.

Chaya: Oh, early stage patients only. How many are you planning to recruit for this study?

Dr. Shanafelt: In the Phase I portion we will be accruing 3 patients to each dose level per the usual approach. We anticipate probably going through 4-6 dose levels before we reach the recommended Phase II dose. So we are anticipating somewhere between 12 and 18 patients for the Phase I portion, but it could be fewer or could be more depending on the toxicities.

Chaya: How about the Phase II?

Dr. Shanafelt: The Phase II will be recruiting 33 patients.

Chaya: And these will be recruited only at Mayo Clinic Rochester?

Dr. Kay: Actually, we have a lot of interest from some of the other CRC (CLL Research Consortium) sites who wish to participate in this trial, so we may open it up to other CRC sites for the Phase II portion. We anticipate the Phase I portion will be at Mayo only, but the Phase II portion will likely involve other CRC sites. Each CRC site will have to put the protocol through its own IRB (Institutional Review Board) process if they desire to participate and go down that road.

Chaya: Has your own organization approved the protocol, has it passed IRB review? And, when will you start the actual recruitment?

Dr. Shanafelt: It has been a lengthy process but we finally have all the approvals needed to launch this trial. It has been through the CLL Core Group review, the Hematology Research Review at Mayo, the Mayo Clinic IRB and the National Cancer Institute for several reviews. It has now gone through the final review here at Mayo.

Chaya: So you expect you will start recruiting sometime in the Fall of 2024?

Dr. Shanafelt: That is our expectation.

Chaya: That is exciting news. We will be publishing our review of the trial design and contact information for patients who are interested in participating in this trial.

I’m sure you are very well ware that EGCG has become very popular in the patient community. So my next question is this: a lot of people are already taking it. Do you have a mechanism whereby people who are already taking it can still participate by a washout period of some sort?

Dr. Kay: Yes, that is a great question. We are aware of the likely widespread use of green tea or green tea extract supplements initiated by CLL patients. What we are doing is in essence, requiring a washout period. We think it is very reasonable to for patients to be eligible if they have been off the, if you will, “over the counter” supplements for at least two months.

Chaya: In other words, patients who have interest in participating in this trial may want to go off of the over-the-counter EGCG supplements now.

Dr. Kay: Yes, I think this would be appropriate for patients who are considering participating. We have a “wait list” currently at Mayo Clinic for some of our patients. I have been telling them that there will have to be a washout period. I assume that when this gets distributed on your website, people will be aware of that washout period, as well. So that will be a good way to disseminate the information regarding the trial and eligibility.

Chaya: You have a “wait list”; does this mean you are pretty much fully recruited already?

Dr. Kay: When we say, “wait list”, we have people who are interested. That doesn’t mean, necessarily, that that is full. No, currently it is not. What that really means is that people who have expressed an interest in being part of the trial when it opens will be contacted by us from that wait list.

Chaya: When the trial opens, it is going to be on a first come, first served formal basis?

Dr. Kay: Absolutely.

Chaya: I’m very happy to see that you have included a careful prognostic classification of patients that participate in this trial so that we can better understand who responds and who doesn’t respond and if there is any correlation between the response to EGCG and these prognostic indicators. An important question — from our perspective — will you be sharing the information on the the testing of prognostic indicators, however those come out, with each patient?

Dr. Kay: Yes, we will. First of all, with respect to CD 38 and the FISH tests, these are done routinely here, and are part of the standard workup. Thus we will make patients aware of their CD38 status, and also of any of the FISH abnormalities. That is routinely communicated here at Mayo. Now, with respect to the IgVH mutational status and the ZAP 70 status, these tests will be performed on all patients as part of this trial but these are still research tests. That doesn’t mean we can’t inform patients of the results, off-line. They will definitely be made aware of the results of all these tests if they so desire.

Chaya: In other words, if the patient contacts you and says I would like to know this information, you will be willing to share that with them?

Dr. Kay: Yes.

Chaya: That is great! I really appreciate that because for some of our patients, just getting these tests done has been a logistics nightmare. They are very expensive and not all insurance companies cover it. So since these tests are being done anyway as part of this trial, it really helps patients to have access to that information.

Dr. Kay: Good. I think the only caveat that we have to that is because these are research tests, the mutation status and ZAP-70 are often done in batches and the results don’t come back for one to three weeks, depending on when the next batch is run. So that information will be available to patients – it just doesn’t happen as instantaneously as the other more routine clinical tests.

Chaya: But when the results are available to you, they will be made available to the patient as well upon request?

Dr. Kay: Absolutely!

Chaya: Okay, that sounds good.

One of the “hot button” items we have identified is that many institutions do not announce their clinical trials on public websites, limit the announcement to their own institutional websites. We feel strongly that this limits access to information that should be available to all patients, and may even introduce recruitment bias. We hope you will be publishing this clinical trial on public domain places including www.clinicaltrials.gov?

Dr. Shanafelt: This has not been a routine procedure for Mayo in the past, but I can assure you we are doing our best to get this clinical trial posted on the public websites as well. We realize this is an important issue for the patient community.

Dr. Kay: Yes, I think that if that is an important issue for the community, we are happy to do this. I don’t see a problem.

Chaya: The problem is that right now you do publish trials, but only on your own website. M. D. Anderson publishes the trials they do on their website. There really is no one general site where a person can go and search the database and see all clinical trials that are of interest to that patient…where all the relevant clinical trials pop up that are open and are recruiting. The recent guidelines from many of the publishing houses is that clinical trials be published at a centralized public open domain place like www.clinicaltrials.gov. This is most important to facilitate patient participation in clinical trials.

Dr. Kay: Yes, your point is well taken and I think there are two issues to this one. One is to get the word out that this trial is up and running and no one is shielded from this information. The other is that you should know that we are very committed to prompt publication, whatever the results are. We are hopeful, of course, that this is going to be a positive trial. But we will report the outcome of this trial, regardless.

It is a very good point, and Dr Shanafelt and I are committed to publishing the findings regardless of outcome. We feel the same way as you do that all outcomes need to be published.

Chaya: The one comment that I had on your protocol in the grant proposal is that you will be looking at cell kill in terms of the angiogenesis pathways. But do you have plans to study the effect of EGCG in terms of telomerase inhibition, ROS generation, potential impact on reduction of incidence of skin cancer and some other areas that have been identified in research publications over the last year or so?

Dr. Kay: Yes, that is also an excellent question. Obviously, we are aware of the multiplicity of potential beneficial biological effects of EGCG. Our bias has been all along, and it is a somewhat calculated guess that this is working through inhibition of receptor tyrosine kinase pathway likely the angiogenesis pathway, but it could be others. Certainly we know that there have been other transcription factors such as NF Kappa B and reactive oxygen species effected by EGCG. There are a lot of other biologic targets that will need to be considered in any EGCG mechanistic study. I need to emphasize, however, that the one thing we find EGCG doing most reliably, in 80% of the CLL clones, is they are effectively killed by EGCG in association with the downregulation of components of the VEGF signaling pathway. So, our laboratory bias is that we need to look hard at the angiogenic pathway.

But, we do agree that other possibilities are there. In order to cover that base, we really couldn’t possibly do all the laboratory correlates in this one proposal, given that it is primarily a clinical protocol with some focused laboratory aims. So what we are doing is also submitting to the NCI another grant proposal for funding to cover other possible biologic effects of EGCG on CLL B cells. Thus we hope to have very broad-based laboratory aims covering such things as reactive oxygen species, telomerase impairment, and other signaling transcription factors that we think may be critical. We will be looking in a much more complete way at what EGCG may be doing on CLL B cells.

Chaya: Will you be using the samples and so on collected during the course of this trial?

Dr. Kay: This is the real power of our ability to work with CLL Topics to help get this clinical trial off the ground. We will be accruing blood samples for laboratory studies from this trial. Thus for the submitted NCI correlative laboratory proposal we will already have started to accrue samples and have started to do some biologic assays. Thus I can’t help but think that it is going to be a powerful combination of things that are going on prior to our NCI proposal submissions. Namely, that we are able to launch the study, start to do some biologic studies; generate important preliminary data and I know that will end up strengthening our NCI proposal for expanded study of the biological effects of EGCG in CLL.

Chaya: That is great! Talking about patient recruitment — one question that comes to my mind is that this is a 6-month trial when patients are supposed to be taking EGCG on a daily basis. Presumably they will be taking this at home, am I right?

Dr. Shanafelt: Yes.

Chaya: How often do they have to come to Minnesota for clinical examinations or whatever?

Dr. Shanafelt: They would come to Mayo Clinic, (or if participating at another CRC site in the Phase II portion, to that center), once monthly. Patients need to be seen every four weeks. At that point they would have an assessment of any side affects they are experiencing from the medication, an examination to evaluate any response in lymph nodes or any other exam findings that would be suggestive of side effects, then routine blood work to monitor affects on lymphocyte counts and other organ function.

Chaya: The reason I’m asking you this is while many insurance companies will cover what they call standard therapies and some even cover part of the expenses in clinical trials, I don’t know of too many insurance companies that cover travel costs. We are talking 6 visits, staying overnight in some cases. So, I hope you gentlemen realize that by participating in this clinical trial, the patient will be taking on some significant financial responsibility and out-of-pocket costs. So at the very least, we are very happy that you will be sharing their own prognostic information with them as a “thank you”, if you will. And the fact that they will be closely monitored and examined by the experts at Mayo once a month, that has great value to patients as well.

Dr. Shanafelt: Absolutely! The hope is, that at least during the Phase II portion, there will be a more widely distributed access to the trial for folks in other regions of the country who may not be able to travel to Minnesota. Hopefully, there will be CRC sites in multiple regions that would broaden the access to the trial.

Chaya: Are you able to say which CRC sites would be participating in this, Dr. Shanafelt?

Dr. Shanafelt: You know, we probably should not. There are several sites that have specifically expressed interest and for the phase II as we said earlier some will be involved, but it will comes down to specific sites that show sustained interest.

Chaya: Okay, fair enough. But you are reasonably confident that in Phase II there will likely be other sites besides Mayo?

Dr. Shanafelt: There are likely to be other sites, and, basically, we anticipate all CRC sites would have the ability to participate; it is just a question of whether the investigators at each site desires to participate. Currently, there is quite widespread interest in the consortium to see this trial up and running.

Chaya: We realize the EGCG trial is the first step in a series of inter-connected trials and that eventually your game plan is to combine EGCG with the anti-angiogenesis antibody, Avastin. Can you tell us a little bit more about that?

Dr. Shanafelt: Given our interest in angiogenesis and the VEGF pathway as one of the potential targets that we are looking at specifically, we are very interested in other agents that may also inhibit that pathway. We are preparing to open a phase II trial also in conjunction with the National Cancer Institute that looks at bevacizumab (Avastin) as monotherapy for treatment of relapsed and refractory CLL. So that trial will also be opening in the next couple of months. We are presently exploring the biological effects of Avastin on CLL B cells in the laboratory and have published some preliminary work on that recently. (Chaya, that trial is about to open here as well.)

We certainly share CLL Topics interest in developing not only effective treatment strategies, but also treatment strategies that have a favorable side affect profile to patients. And, to that end, targeting antibodies are certainly attractive. As part of the EGCG trial we will be exploring the combination of EGCG with multiple other agents in the laboratory including biologic agents such as Avastin and Rituximab, as well as other chemotherapy medications that have a proven effect in CLL such as nucleoside analogs and alkylating agents in an effort to define how this agent interacts with all the other therapeutic tools available to patients with CLL in order to devise optimal combinations in the future.

Chaya: Am I correct that one of the models you will consider includes using Rituxan along with EGCG ?

Dr. Shanafelt: Yes.

Chaya: Will this be done as a clinical trial or just in the lab?

Dr. Kay: Initially, that work is part of the NCI R-21 application, that we mentioned, which is a more comprehensive assessment of the effect of EGCG combinations in the laboratory. The combinations that are found to be effective would be those that would then be taken forward to clinical trials. The combinations that would be taken forward would be those deemed effective on one of two levels. Obviously, those that have the most effect to kill cells in the laboratory would be deemed of interest. But, if combinations of antibodies had an additive affect or a synergistic affect with each other, they would be deemed even more attractive to take forward even if they had less CLL B cell killing than combinations with cytotoxic agents due to the potential for a less side effects.

Also, let me add something to the bevacizumab (Avastin) story. We believe that angiogenesis is critical in disease progression where CLL patients with early stage may actually undergo an angiogenic switch. The attractiveness of studying bevacizumab (Avastin) with EGCG is therefore based on inhibition of the VEGF pathway, both internally and externally to most effectively downregulate the potential for angiogenic switching or more potently induce cell killing. So one of the reasons we are focusing on Avastin, is not so much that it is a monoclonal antibody, but that it may allow the internal/external inhibition of that pathway in combination with EGCG.

Chaya: Sort of getting at it from both sides of the equation.

Dr. Kay: Exactly.

Chaya: The reason I expressed interest in the combination of EGCG plus Rituxan is, and I’m sure you are aware of this, there has been a great deal of interest in the patient community in an approach we have dubbed the RHK protocol. You would be surprised how many patients have actually convinced their local oncologists to go along with them in trying the combination of EGCG + Rituxan + Neupogen (or Neulasta). We fully agree, this is not a formal clinical trial and we do not have statistically solid information. But on a purely anecdotal basis, a lot of patients are seeing what they consider very good results. They are very happy with the results that they are getting. Down the road, at some point, we will be looking for somebody who will do this as a full-fledged clinical trial with all the statistical support that such a trial would need. Therefore, the lab work that you are planning, combining EGCG with a host of other drugs including Rituxan, will come in very handy from our perspective.

Dr. Kay: Okay.

Chaya: Moving along, do you see a change in overall aspects of how CLL is being treated? There seems to have been a fundamental shift away from the conventional "watch and wait" for all CLL patients to one that is driven more by prognostics-based risk stratification. You know that CLL Topics has been pushing very hard for this modern prognostic testing prior to therapy decision in newly diagnosed CLL patients. Your own article “Prognosis at Diagnosis” as well as Tait and Dr. Tim Call’s article on the best practices at Mayo have been widely circulated, and received a great deal of interest in the patient community. Can you tell me a little bit more? Are you actually seeing this happening at the local community healthcare level?

Dr. Kay: Well, I can’t speak so much for the local community, but just to answer your question more generally, I think there is definitely more interest in doing more prognostic testing even for the early stage, low-grade, Rai 0-1 patient. That, at least pertains to the blood tests for CD 38 and FISH. The IgVH mutational status is very important. ZAP-70 testing is also important but both are either are still relatively hard to either get or, in the case of ZAP-70, to rely on. At Mayo Clinic, we are dedicated to getting risk stratification for all CLL patients regardless of their Rai stage. Because of the possibility that some of the early stage patients will be very high risk. To me, at least, right now, that is very important to do in a routine way because while I don’t think it impacts on therapy, at this point, I think it does impact on counseling. It does relate to the patient’s knowledge of his/her disease and the potential pace of it. And, it does alter how often patients should be monitored. So I think for prognostic testing, it is making a significant impact. I can’t really speak to how much this has changed community practice, but it certainly has altered our practice here.

With regard to treatment, we need to prove that treatment, early on, in early stage high-risk patients makes a difference. There is an effort being led by the NCI and also within the cooperative group to develop an early stage high-risk trial for those patients.

Chaya: Are those being classified as…?

Dr. Kay: Well, I believe that they will be classified as either having B cell clones that are IgVH gene mutated versus un-mutated.

Chaya: Okay.

Dr. Kay: You will probably hear a lot more about that soon. I believe it is going to be an inter-group cooperative trial. But, that is really as much as I can tell you about that right now. We have interest in developing an intervention for early stage patients.

Here at Mayo, the CLL Group is focused on assessing those patients who are deemed to be at highest risk for progression among early stage patients and asking the question “Can therapy delay progression and can it be given in a non-toxic way.” Dr. Zent is leading a trial at Mayo exploring this question, with a combination of rituximab and a one-month course of Alemtuzumab (Campath). So a very short course of Campath plus standard dose Rituxan for patients who have 17p or 11q deletions, or who are both IgVH unmutated and CD38 positive. That trial is aimed at trying to identify those patients we know with the prognostic tools presently available are at the highest risk for having an aggressive disease course, and treating them with a 4-week course of a combination monoclonal antibodies to see if we can impact their disease course in a non-toxic way. Trials like Dr. Zent’s trial are the first step to explore whether we should change the way we treat patients based on the new prognostic markers.

Chaya: Yes, we are aware of the Rituxan + short duration Campath clinical trial that Dr. Zent is conducting. In fact, we reviewed this trial in some detail on our website.

We understand that trial has been open at Mayo Clinic since November.

Patients don’t hear about these trials from their local healthcare providers, and unless there is some mechanism of bringing it to their attention, there is no way for them to know. A lot of patients write to me asking what should they do. Their local healthcare providers have not given them the counseling that says here are the trials that are open, that may be right for them. But, frankly, the health care providers themselves probably don’t know.
We hope this trial will be announced on the www.clinicaltrials.gov site?

Dr. Kay: I don’t know.

Chaya: If it is not, may we strongly urge that you do.

It is a very standard format so everyone reports new trials on the same basis. It becomes a very routine thing to do. It is an easy site to use, with a good search engine.

Dr. Kay: I personally think it is a good idea.

Chaya: I think that is something that is going to change, in the next 6 months. Public site registering of clinical trials is almost mandated by some of these publishing houses.

Moving on to another point, I would like to ask you regarding your sense of how it has been, working with a patient advocacy group. As you realize, this is the first time that there has been this kind of a partnership. We have enjoyed it tremendously on our side and found it most helpful and most useful. What are you going to do if there is a surplus of riches and you are mobbed by patients, with 200 people who want to participate in your EGCG trial?

Dr. Kay: Well, first of all, thank you for bringing this up because it has been a great pleasure for us to work with you and the organization in CLL Topics. I think, at one level, it is certainly a plus for both sides for both the CLL community, but certainly the academic community here at Mayo has benefited from hearing about issues that are important to the CLL patients. While we think we know the issues, the decibel levels have been raised to a point where whether these are issues that we agree or disagree upon, we are now having a much more active dialogue. So, that has got to be a plus. I think that other important point for this particular project, it has been driven, to a certain extent, by the efforts that CLL Topics has worked on, so you are to be congratulated for that.

Chaya: Thank you very much.

Dr. Kay: There is no question about that, and I mention that as often as I can. That doesn’t mean that we wouldn’t have done this without you folks; but it certainly has been aided greatly by getting comments and timely advice and continuing input as to how the protocol would be shaped. So this is very unique, this particular clinical trail, because of the unique collaboration between us, at Mayo, and CLL Topics.

Chaya: Yet, we have tried very scrupulously to stay out of the medical side of the clinical trial design because that is not our area of expertise.

Dr. Kay: Yes, we need to be clear about that. That is why I say, the trial would have been written very close to its current version. However the pace of the trial and direction to early stage patients, the issue about doing risk stratification, and informing patients who go on this trial about their risk stratification parameters and keeping our eye on the future needs of the community have all definitely been impacted because of the communication and the dialogue we have had with CLL Topics.

Chaya: Well, I kind of asked it in a facetious manner, but seriously, I am a little concerned about the number of patients who would like to avail of your expertise. Can the Mayo CLL team handle the work load?

Dr. Kay: Let me touch on that. You are right, sometimes you have to be careful what you wish for because you may actually get it. That is, there is a huge amount of interest in this trial, which is at one level, very gratifying, and another level, it is a little scary. We are currently developing resources to prepare for this. For several years now Mayo Clinic’s CLL group has worked to provide proper diagnosis, evaluation, prognostication, counseling, and treatment for CLL patients. Despite the progress in the care of patients with CLL worldwide more progress needs to be made. I guess that is where I see our continued interaction. That is, if we can continue to tell you where we are and where we want to go, CLL Topics is able to hear that and give us important feedback. CLL Topics then serves as a channel for patients to voice their thoughts and concerns back to the researchers and physicians.

Chaya: EGCG, to some extent is commercially available for those who are disappointed if they cannot participate in the trial, and I expect they can continue to take it if they wish on their own as they are doing right now, minus the benefits of the screening and the monitoring at the Mayo.

While there has been a great deal written in scholarly publications on the difficulty of recruiting patients for clinical trials, I believe that a large part of it is poor communication, inadequate methods of getting the message out to patients, and, frankly, if I may be blunt, not treating the patients as legitimate partners. You cannot recruit human beings for trials without engaging the human being in the dialogue.

We find that when we report on a new clinical trials on our website, the phone rings off the hook at the other end. The concept of actually participating in a dialogue with the patient as a legitimate member at the table, that is still bit of a novelty. It is important to get the information across and make them a part of the process. I believe many of the problems will go away once we get over that hurdle of communication. The EGCG trial, I think, is going to be a good one to see how long it takes to recruit and how it compares with prior track records for recruiting patients.

Dr. Kay: Just one other comment on that topic; I think you bring up a good point that EGCG is available outside of a research setting presently. Our commitment with this trial is to define the right dose of the medicine; to determine what toxicities/side effects the medicine has; define what the benefit of the medicine is for CLL patients; and, also, to explore what are the right combinations to use with this medicine. So, patients who are part of the trial will be the folks who help define those aspects. Given that the end-point of this trial will be a response end-point and not survival end-point, we should have a good sense of whether there is activity with this medication relatively quickly; meaning in a span likely of twelve months. If we do see activity, Mayo Clinic is ready to rapidly mobilize the resources for development of a large phase III trial .

Chaya: Will this be done at more treatment sites besides Mayo Clinic?

Dr. Kay: Absolutely. One other thing that popped in my mind as we were talking about this, we may want to have an ongoing dialogue, like we are doing now. Either, this way or maybe even having a patient/physician interaction where we talk about our long-term plans and where we are with the prognostic aspects and with the big picture of our clinical trial activities.

Chaya: We would be delighted. As you know, most of our Board members are patients. Keith Friedlander and I are the only two people on our Board who are not patients, but we are both patient family members. These issues are all close to our hearts.

Dr. Kay: One positive outcome of this dialogue might be that every six months we would want to have some sort of contact. Even though you and I communicate a lot, and you are terrific, and we appreciate those contacts, but perhaps in a more general way, we could have something every six months. This would allow for discussion about what is going on with the prognostic information database, how that effects risk stratification and counseling, and activity of our CLL clinical trials.

Chaya: To go back to a comment you just had, which is since people can take EGCG on their own (and it is commercially available), why should patients do it in this clinical trial?, We have already commented that patients need to make 6 trips to Mayo as part of participation in this trial. That is much money out-of-pocket and time, why would they do that?

Patients ask, “why should I participate in this clinical trial instead of doing it on my own with my local oncologist’s support?, Why should I participate in Dr. Zent’s trial or the EGCG trial with Dr. Kay?” My answer to them is you can try the same drug combination on your own and you may or may not get the benefit as the case may be; but your data will not be captured for the official record and it will not help the next generation that comes along. Most patients are also parents and often grandparents, and very concerned about familial CLL. That is an aspect that very few researchers focus on; I think it is very important they focus on it. More than having CLL ourselves, what scares us worse is our kids or grandkids having to face these same tough decisions.

Dr. Shanafelt: We totally agree.

Chaya: Therefore, we tell patients if you are going to do it anyway, why don’t you go the extra mile, make the extra effort, spend the extra dollars and time, but do it in a clinical trial so that your kids and your kid’s kids will have that much more information to go on? That is a very important point that should be made.

Dr. Shanafelt: Absolutely, and in an altruistic sense, as well, beyond even just their own relatives, the thirty to forty patients who participate in each of these individual trials, are really shaping the standard of practice for treatment of hundreds of thousands of people with CLL worldwide. For instance, this trial will be a first step to help determine whether or not all of these folks should be taking green tea extract. That is a question we don’t have an answer to yet and there are hundreds of thousands of people across the world wondering about it. The 40-50 people who participate in this trial will do a great deal to provide guidance to everyone else.

We actually have another project, that allows for consenting all CLL patients regardless of stage or treatment status that we see here to be put on an ongoing database where we track their clinical course and, also, the biological variables (IgVH mutation status, Zap-70 status, FISH status and level of angiogenic factors, etc.). This allows us to help improve prognostication for CLL patients everywhere as we talked about earlier. This is a major focus of Mayo Clinic’s research effort in CLL.

Chaya: I’m aware of this. My husband PC has participated in this project. We encourage all of our members who have a chance to do so to participate as well.

Dr. Kay: One of the things we say to our patients is that this participation is, obviously, voluntary, but they are contributing in a significant way to information that we intend to generate. So we can counsel patients better in the future. It is very powerful because we are not talking about 10 patients, we are talking about hundreds of CLL patients who have consented to allow us to do this and for us to see them on a relatively regular basis. So even in this biologic clinical correlation study, patients are giving a gift of knowledge that is not just benefiting them, but future generations.