A Patient Sponsored & Funded Clinical Trial Initiative by CLL Topics
Project Alpha - A Proposal
September 22, 2003
by Chaya Venkat
I would like to propose a clinical trial for a frontline therapy option that combines low toxicity with good response rate and long remissions, for CLL patients in low to medium risk categories. If you like this idea, read on. With strong grassroots support from the CLL Topics membership maybe we can do something about getting it off the drawing board.
There are plenty of good reasons why Rituxan has become the central piece in therapy options for B-cell cancers, either as a monotherapy, or in combination with more conventional chemotherapy agents such as Fludarabine and Cyclophosphamide. We have devoted a large number of the articles on this website to discussing Rituxan therapy, how it works, why it does not work better for CLL, our wish list for improvements, and so on. You can read all those details in the earlier articles. This article is devoted to putting it all together, and come up with a combination that I think finesses many of the "on the one hand and then on the other hand" frustrations of making a first therapy choice.
The classification of CLL patients into groups based on modern prognostic indicators and making therapy choices appropriate for each group is so obviously the right thing to do, I am at a loss to explain why this is not done routinely. The days of knee-jerk "Watch & Wait" advice for all CLL patients are over. One size does not fit all and it is high time for a risk-adapted approach in treating CLL patients. That is the title of the first abstract below, and the same theme is reflected in the next two abstracts as well. The fourth abstract deals with the 1995 paper comparing W&W with Chlorambucil therapy in patients diagnosed and treated in the 1980's. A lot has changed since then, and it would be a shame to subject patients diagnosed in recent years to logic that is outdated. W&W was a good strategy back then. Now we know that as the disease progresses, you are at risk of developing autoimmune diseases of various sorts, more bulky disease that is harder to treat, and there is risk of "clonal evolution" over time that may land you with a more malignant mutation than the one you had at early stage. Getting away from the W&W strategy and opting for earlier intervention, keeping the CLL tumor load under control, not letting it compromise other systems in your body, are all things that may make sense provided we can find low-toxicity, high-response-rate and long-lasting therapy options for early stage patients.
What I would like, and I am sure you folks would agree, is a frontline therapy where response rates are in the same ball-park as the ones we see with FRC and RF chemotherapy combo treatments, with large percentage of CRs. I also like the long remissions possible with these combination chemotherapies, but without the nagging neutropenia, myelosuppression and general risk of opportunistic infections like shingles, pneumonia, etc. And I think it can be done, for low to medium risk CLL patients, with technologies and drugs that are here and now, not pipe dreams. I think it can be done, if only we put together all the pieces of the puzzle. And I would like to take this all the way from concept to reality, by sponsoring and funding the clinical trial ourselves. This is a dream I have been mulling in my head for quite a while and I have named it Project Alpha. You will find much of the logic that went into definition of Project Alpha in my prior articles. There is a collection of links at the end of this article that will take you to some of these prior essays.
A member of our "Editorial Board" called it "The Lego Project". Most of you with children and grandchildren have tripped over the brightly-colored, inter-locking building blocks. Project Alpha uses the building blocks already available to us. We do not have to "invent" the blocks, nor do we have to "discover" the interlocking synergy of the selected blocks with each other. All we have to do here is put together the pieces to build a structure that has value to us as patients.
Why is this not being done already? I am not sure I know the answer to that one. This is a ripe, low hanging fruit, ready for the plucking, just right for a patient-sponsored and patient-funded clinical trial. We don't care if there is no scientific glory to be had in putting together this Lego project, we are not looking to get our names in scientific journals, build high-profile careers. We are not going to apply for patents, or make money selling this approach. We can afford to look for solutions from only one perspective, do they work for CLL patients?
Summing it up, I want a low toxicity, high response rate, long remission therapy choice as an early intervention option for CLL patients.
Project Alpha : Technology issues
1. Barring a very small percentage of patients who are allergic to it, Rituxan has a remarkably low toxicity profile. The first infusion related side effects are not too much of a problem for majority of people, and can be controlled to a large degree with suitable pre-medications and slowing down the rate of infusion.
2. Unfortunately, Rituxan by itself is not sufficiently effective in CLL, and while regular maintenance approach with re-treatment every six months may work for some patients, too many CLL patients do not respond well enough to Rituxan to begin with, or develop resistance after a few rounds. The low response rate is perhaps because the CD20 marker targeted by Rituxan is not expressed by enough of the CLL cells at a high enough concentration, and also perhaps because immune compromised patients do not have sufficient neutrophils and macrophages to provide the cell kill assist needed. Both problems can be handled to some degree by combining Rituxan therapy with GM-CSF (granulocyte macrophage colony stimulating factor, trade name "Leukine"). This cytokine increases the expression of CD20 marker, and also increases the number and effectiveness of the neutrophils and macrophages available to provide cell kill assistance. This combination has been tried in NHL, with encouraging results. Both Rituxan and Leukine are well-understood drugs, with extensive track records of use and good toxicity profiles. I am delighted that at long last it is our turn, the recent announcement of Rituxan plus GM-CSF clinical trial for CLL at M.D. Anderson is excellent news. I understand this will be a multi-center clinical trial
Besides GM-CSF, we can consider two other drugs that show promise as boosters of Rituxan's performance. These are interleukin-2 (IL-2), and the recently announced PT-100. Both have been through phase one clinical trials. Combination of IL-2 plus Rituxan has been tested in NHL, and the combination of Rituxan plus with PT-100 for CLL has just been announced as a clinical trial at M. D. Anderson.
3. I fully expect that the combination of Rituxan plus GM-CSF (or PT-100 or IL-2) will increases the overall response rate and the percentage of CRs in early stage and chemo-naive patients. So far, we have dealt with the low toxicity and the high response rate issues. The last leg of this tripod is the all-important issue of duration of response. Right now, responses with plain Rituxan therapy last any where from 6 months to about a year, even in CLL patients that respond well to the monoclonal antibody. We have to find some way of keeping the remission from petering out.
We have discussed the role of NF-kB pathway in cancer cell proliferation and accumulation in other articles on this website. As patients, we can try to keep the lid on NF-kB, by using supplements such as curcumin, green tea and resveratrol. But these compounds are not well characterized, their quality varies widely depending on where you buy them. Even more important, there are few well-established guidelines on dosage, safety and efficacy. Since these orally taken compounds are absorbed through the gut to different levels by different individuals, it is hard to establish standard guidelines for their use, or protect ourselves from unintended side-effects.
4. NSAIDs such as R-Flurbiprofen are better defined. They may well be the missing piece of the puzzle since they have low toxicity and are easily absorbed upon oral administration. These small molecule drugs have easy access and are able to inhibit CLL cell proliferation and survival, with the result that they may prolong the precious remission after Rituxan + GM-CSF. Long-term use of most NSAIDs has the potential for GI tract ulcers and bleeding, and R-Flurbiprofen is expected to do better on that front than the standard garden variety of Flurbiprofen.
5. Also discussed at great length on this website are a new series of drugs called NO-NSAIDs. These are an exciting class of new drugs made by adding a nitric oxide (NO) releasing group to conventional NSAIDs. The one that has caught my attention is NO-aspirin. It is already in Phase - II clinical trials for colon cancer, as well as a bunch of other diseases including heart disease, Alzheimer's disease etc. It is several thousand-fold more potent in killing many different kinds of cancer cells than its parent, regular aspirin. That potency translates into smaller required doses. Smaller doses plus the protective effects of gradual NO release makes these drugs very good at doing their job of inhibiting growth of cancer cells, without worries about GI tract bleeding or ulcers upon extended use.
Summing it up, Project Alpha is a well defined, patient sponsored, and patient funded clinical trial of Rituxan plus immune booster (GM-CSF or IL-2 or PT-100) therapy, followed by daily oral administration of a non-toxic drug to prolong the remission (NF-kB inhibitors such as R-Flurbiprofen or NO-aspirin), as frontline therapy for early stage and good prognosis patients. Personally, I would be willing to define remissions that are at least 50% longer than Rituxan monotherapy as a success and hopefully we can do better than that.
Project Alpha: How to Make It Happen in Real Time
Sitting on our hands patiently means many of us who are in the right stage for this approach, right now, will most likely not be able to make use of it by the time some one gets around to doing the clinical trial and it finally making it available to the average patient. I find that hard to accept. Project Alpha describes this single, well-defined clinical trial for CLL patients that I think can be sponsored and funded by CLL Topics. The success of this project, whether it even gets off the starting block, depends on you. With strong grassroots support, this project is quite feasible. Without that support, well, why bother? If the project is a thundering success, I can think of a bunch more that we can consider. CLL is a bit of an orphan disease. It would be nice to have our voices heard, our perspective taken into consideration.
Project Alpha is defined with naive and early stage patients in mind, those with good prognosis, as a potential frontline therapy. This is because there are several restrictions on the kinds of things we can or should do as patients, in sponsoring clinical trials. For example, I would be reluctant to embark on trials involving late stage patients, or patients with poor prognosis or complicated medical situations, where the potential for harm is too high. I do not feel we have the knowledge or expertise needed to make the right choices in such cases. Also excluded would be very complex trials, or those that require extensive hospital stays or even frequent trips to the infusion room. Besides the safety issues, another obvious reason for this is money: complex trials are more expensive to conduct.
If we are able to tag on to the back-end of a Rituxan + immune booster (GM-CSF, or IL-2, or PT-100) trial already spoken for, focusing on remission prolonging drugs (R-Flurbiprofen or NO-aspirin) that can be administered orally either by local oncologists or the patients themselves, it would cut down the cost of the clinical trial a great deal. Continuing along the lines of "do no harm", I looked for drugs with an excellent profile of safety and low toxicity. If we can ride on the back of clinical trials of the drugs in question in other studies, where in-vivo toxicity (lack there of!) and dosage guidelines have been established, Project Alpha can get off to a quick start without having to do pure Phase - I type dose escalation and toxicity studies. The prior history of the drugs in other clinical trials should also help in getting regulatory approval for our project. Last but not least, I would like to focus on high potential drugs that no one is pushing to study for B-cell malignancies, at least in the near term.
Project Alpha is defined using these criteria. I think you will find this a very modest project, perhaps some of you will find it too modest. But I think it is important for us to learn to crawl before we walk or run marathons. And for those of you in higher risk categories and more advanced disease, I say this to you. While Project Alpha is not directly applicable to you at this point, we need your poignant urgency to be clearly heard by the medical community. May be the knowledge gained from clinical trials such as this will be helpful to you down the road. But may be the only reward you will get is knowing that you have participated in this community effort, helped your fellow patients with your generosity.
Summing it up, Project Alpha is an attempt to pick the ripe and low hanging fruit sooner, to benefit patients now, rather than waiting for some one to get around to it in a few years, more or less.
Project Alpha: Action Plan
If the technical merits of the proposal are acceptable to CLL Topics community, the action plan for Project Alpha could be relatively simple.
1. Identify and work with a credible and interested CLL expert to carry out the study as Principle Investigator (PI), potentially as the back end of a Rituxan + immune booster trial. Project Alpha is our vision, but it is the PI who defines the details of the trial protocol, such as profile of volunteers, number of patients to be recruited, end points of the study, monitoring strategy, interface with regulatory agencies, access to results for trial sponsors with appropriate filters to protect individual patient confidentiality and so on.
2. Negotiate with Myriad or NicOx for supply of their R-Flurbiprofen or NO-aspirin for this trial.
3. Working with the PI, define the time frame for the study to get off the ground, and a reasonably sound estimate of the dollar number. Get approval from the appropriate regulatory agencies for the clinical trial. This is where the credibility and reputation of the PI would be a huge asset.
4. Register CLL Topics as a non-profit organization, recruit patient members to be on our Board, and get into a fund-raising campaign. I am very interested in making sure we have 100% transparency and financial accountability. Every one who works on Project Alpha does so pro-bono, this is a strictly volunteer effort. No boondoggles, no slush funds, no board meetings in Hawaii, no nepotism. Members of CLL Topics Board do not get a reserved slot on Project Alpha clinical trial. Fund-raising will be done at both the national level, through the CLL Topics website, as well as in local communities with local volunteers taking charge of the local campaigns. No doubt each local volunteer group will come up with their own innovative ways of doing this, all ideas and efforts are welcome, as long as they are done with scrupulous attention to transparency and financial accountability.
5. In my opinion, Project Alpha can be carried out for relatively small dollar number, well within our capabilities, especially if we are able to tag on to the back-end of a Rituxan + immune booster trial already spoken for. The fund raising stops as soon as we meet our target goal. I would not want fund raising to become a chronic activity for CLL Topics, our main charter is patient education and empowerment. New projects down the road will be considered on their own merits, in the light of the post-trial evaluation of how we managed this first project.
6. Use the resources of CLL Topics as well as other support groups to increase patient awareness of Project Alpha. We need to mobilize grassroots support for fund raising, volunteers for the clinical trial, each and every aspects of this project.
7. We would want Project Alpha to become a template for future projects, where by virtue of patients putting their money where their mouths are, literally, we would have a better chance of having our voices heard in the future. Our collaborative and constructive role during the whole process will give us credibility and contacts within the research community, drug companies and regulatory agencies. It is high time CLL patients became active partners in the process of finding solutions for this dreadful disease.
8. It is equally important to understand what Project Alpha is NOT. It is not a vehicle for patients to invent science, or to practice medicine without a license. We can short-circuit the waiting time for potentially valuable technology to become generally available to our CLL patient community, by sponsoring clinical trials of this sort. We can sponsor, fund-raise, increase awareness and grassroots support for this and other clinical trials. We might even try to make sure our voices are heard before the regulatory agencies and review boards. But we do not attempt to run the clinical trials ourselves, we do not select the participants in the clinical trials or set the guidelines for such selection, we do not make medical recommendations, we do not interfere on the medical side of things at all, period. All those things are up to the qualified and trained professionals.
We Need Feedback
But before we can make the decision to launch this new project for CLL Topics, your opinion needs to be heard. Please use the following link to send us your email with your comments and answers to the questions raised below: .
Here are some questions for you to consider in your feedback:
I am not kidding when I say this idea stops here, right now, without strong grassroots support from you. To be blunt, if the patient community that CLL Topics represents is not interested in this project, it is not something that we should be taking on.
what do you think? It is your call, Go or No Go?
Ned Tijdschr Geneeskd. 2003 Jan 18;147(3):104-9.
Chronic lymphocytic leukemia: high time for a risk-adapted approach
Kater AP, van Oers MH.
Academisch Medisch Centrum/Universiteit van Amsterdam, afd. Hematologie, Postbus 22.660, 1100 AD Amsterdam.
B cell chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the Western world. It is wrongly considered to be an indolent disease: even patients with Binet stage A can have disease-related morbidity, necessitating treatment in about 50% of them, and over 25% of these patients will die of CLL-related causes. It was recently discovered that there are in fact 2 subtypes of CLL: a pre-germinal centre type. Characterised by unmutated genes which code for the variable parts of immunoglobulin chains (IgV), and a post-germinal centre variant, characterised by IgV somatic mutations. This IgV-gene mutational status as well as surface expression of CD38 and characteristic cytogenic abnormalities has recently been shown to be powerful prognostic factors. Furthermore, over the past few years new treatment modalities have been developed including purine analogues, immunotherapy with monoclonal antibodies and stem cell transplantation. Therefore it is time to substitute the present policy used for the vast majority of patients (i.e. an expectant approach, if needs be followed by initial treatment with chlorambucil) with an approach based on the patient's individual risk profile. This should preferably be done within the framework of clinical trials.
Hematology. 2002 Feb;7(1):33-41.
Chronic lymphocytic leukaemia--the haematologic basis for diagnosis and treatment.
Jacobs P, Wood L.
The Department of Haematology and Boone Marrow Transplant Unit incorporating the Searll Research Laboratory for Cellular and Molecular Biology, Constantiaberg Medi-Clinic, Cape Town, South Africa.
Clinically diagnosis may be incidental when absolute lymphocytosis is uncovered at routine medical examination. More usually there is a recurrent sinopulmonary infection reflecting a varying degree of humoral and cellular immune deficiency. Autoimmune phenomena may result in haemolytic anaemia or thrombocytopenia. Expanding tumour bulk underlies the lymphadenopathy which may be prominent. Diagnosis is confirmed on morphology of the smear where atypical variants need to be distinguished from other indolent lymphoproliferative disorders. Immunophenotyping is indispensable in classification. Prognosis is predicated by cytogenetics and markers of tumour biology that include beta-2 microglobulin and peripheral blood lymphocyte doubling time. Management is dictated by symptoms and signs of progression superimposed upon performance status that includes age. Disease that is asymptomatic and truly indolent, particularly in the elderly, qualifies for a careful watch-and-wait policy. In other circumstances stratification to therapy requires entry into peer-reviewed protocols if optimal outcome is to be achieved. Established regimens, of demonstrably equal efficacy, are pulsed single-agents exemplified by chlorambucil or combinations of cyclophosphamide with vincristine and prednisone. The purine analogues, particularly when administered with an alkylating agent and mitoxantrone, are emerging as superior options. In selected patients any properly accredited program will make provision for escalation in chemotherapy requiring haematopoietic stem cell transplantation on the one hand or use of serotherapy with CD52 antibodies on the other. Less commonly, but in a defined subgroup, immunoglobulins directed against membrane CD20 may be effective. Perspective for the generalist is anchored in recognising that the previous cavalier approach to drug medication, with or without radiotherapy, is unwise whereas integrated management is now the international standard of practice. The previous anachronism of dabbling by occasional therapists is to be deprecated since this will generally deny patients access to proper diagnosis and risk-adjusted multi-disciplinary treatment.
Int J Hematol. 2001 Jan;73(1):32-8.
New aspects on the pathogenesis, diagnostic procedures, and therapeutic management of chronic lymphocytic leukemia.
Wendtner CM, Schmitt B, Bergmann M, Rohnisch T, Buhmann R, Hallek M.
Medizinische Klinik III, Ludwig-Maximilians-University of Munich, Germany.
Chronic lymphocytic leukemia of the B-cell type (B-CLL) is the most frequently occurring leukemia in the Western hemisphere. Until 10 years ago, the basic medical approach to this disease was expectative and palliative. Chemotherapy with alkylating agents such as chlorambucil used to be the main therapeutic option, and only patients at advanced stages of B-CLL were treated. With the advent of new treatments such as purine analogs, high-dose therapy followed by hematopoietic progenitor support, monoclonal antibodies, and further immunotherapies, this paradigm is about to change. By using these combinations, younger patients with active disease are now treated with the goal of a long-lasting remission. More sophisticated techniques allow characterization of some of the underlying molecular genetic aberrations and (together with new serum parameters) more accurate prediction of individual prognoses than with the clinical staging systems. With the help of these developments, patients with B-CLL will be managed according to their individual risk with a watch-and-wait strategy in patients with the most indolent form of the disease, conventional chemotherapy with alkylating agents and/or purine analogs in patients at intermediate risk, and aggressive high-dose chemotherapy (followed by immunotherapy) in patients with the most aggressive form of the disease.
Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia.
Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P.
Unite d'Immuno-Hematologie et d'Immunopathologie, Institut Pasteur, Paris, France.
BACKGROUND: To determine whether chlorambucil treatment benefits patients with indolent chronic lymphocytic leukemia (CLL), we conducted two randomized trials in 1535 patients with previously untreated stage A CLL.
METHODS: In the first trial, 609 patients were randomly assigned to receive either daily chlorambucil or no treatment; in the second trial, 926 patients were randomly assigned to receive either intermittent chlorambucil plus prednisone or no treatment. Median follow-up for the first and second trials exceeded 11 and 6 years, respectively. The end points were overall survival, response to treatment, and disease progression.
RESULTS: Treatment of indolent CLL did not increase survival in either trial. In the treated group, as compared with the untreated group, the relative risk of death was 1.14 (95 percent confidence interval, 0.92 to 1.41; P=0.23) in the first trial and 0.96 (95 percent confidence interval, 0.75 to 1.23; P=0.74) in the second trial, with 76 percent and 69 percent of patients, respectively, having a response to therapy. Although chlorambucil slowed disease progression, there was no effect on overall survival. In the untreated group in the first trial, 49 percent of patients did not have progression to more advanced disease and did not need therapy after follow-up of more than 11 years; however, 27 percent of patients with stage A CLL died of causes related to the disease.
CONCLUSIONS: Chlorambucil does not prolong survival in patients with stage A CLL. Since deferring therapy until the disease progresses to stage B or C does not compromise survival, treatment of indolent CLL is unnecessary.
This article is dated October 1, 2003 and appears in the section titled "The Immune System".
by Chaya Venkat
By now most of you are aware of our efforts to initiate a patient sponsored and patient funded clinical trial for early stage and good prognosis patients. I am happy to report that we have received overwhelming support from the patient community. Based on this mandate from you folks, we are moving right along with making this project a reality.
I will update you periodically as we get further along with this exciting project.
Sunshine in Sedona - Photograph by Alan Amster