Date: August 11, 2005
by Chaya Venkat
We are all familiar with the high response rates seen in the FCR (fludarabine + cyclophosphamide + Rituxan) combination pioneered by M. D. Anderson. The combination of Rituxan with more conventional chemotherapy agents has shown significant increases in overall response, especially in early stage patients, as seen in the RF trial at Ohio State, (Fludarabine Monotherapy Is No Longer the Gold Standard), the R+HDMP trial at UCSD (Rituxan plus HDMP) or the R+FC trials at M. D. Anderson. The high percentages of complete responses (including the coveted “pcr negative” molecular remissions PCR Negative Remission: Is This a Cure?) are very gratifying. But only time will tell if these patients with their hard-earned CRs are “cured”, in the plain English sense of the word. While many of these patients continue to be in remission, some have relapsed even after getting a pcr negative remission, suggesting that the final chapter of this story is yet to be told.
By now you should be aware of a school of thought that says attacking the cancer from many different directions all at once is the way to go. The idea is that such an attack gives the cancer cells no avenue of escape, kills all of the cancer cells in one fell swoop. This is a “Shock and Awe” high-risk approach that may or may not be the best option in indolent cancers such as CLL that affect the immune system. In keeping with this well-established view of cancer and how best to combat it, a new clinical trial has begun recruiting patients at M. D. Anderson (perhaps at other centers as well, I do not know), where their FCR format has been “kicked up another notch”, to quote a popular chef. This new phase II trial calls for a combination of FCR+M, with the addition of mitoxantrone (“M”) to the well known FCR combination. It is being tested as front-line therapy for chemo-naïve patients. Patients are currently being recruited for this trial. Several of you who have volunteered for the trial and yet more that are considering participation have written to me in the past few days. It is time for us to review what is known, suggest some questions to think about and discuss with your doctors prior to making your decision about participating in this clinical trial.
|Listing in clinicaltrials.gov||Not listed|
|Institution||M. D. Anderson Cancer Center|
|Clinical Trial Identifier||2005-01-06|
|Therapy Agents||Mitoxantrone, Fludarabine,
Rituximab plus Pegfilgrastim
|Cancer Center Web Link||M. D. Anderson website link|
|Principal Investigator||Stefan Faderl, MD|
|Contact Phone Number||(713) 792-6161; (800) 392-1611|
OSI Pharmaceuticals, Inc.
After the publication of this article and our exchange of correspondence with Dr. Faderl at MDACC, a listing for this clinical trial was received by the NIH on November 14, 2005 and subsequently published on www.clinicaltrials.gov.
We are pleased to see that another of our concerns has been addressed in the published listing which has a new exclusion criterion, #6, screening out patients with known cardiac problems described as: "Symptomatic heart disease (NYHA class>=3) or LV ejection fraction <40% (by MUGA or echocardiogram)". See (NCT00254410).
Editor's Note II
As of May, 2006, the trial listing on the NIH website notes that this clinical trial has been suspended for reasons not given.
Mitoxantrone (brand name Novantrone) has been around a long time, even though it may be new to us in the CLL community. This agent belongs to a group of medicines called cytotoxic antibiotics. Doxorubicin is a well known member of this family. These are synthetic medicines that have been derived from compounds found in certain bacteria and fungi. Mitoxantrone's exact mechanism of action is unknown but it seems to work in two ways. It inserts itself into the strands of DNA inside your cells and prevents them from making additional DNA and proteins. It also appears to interfere with an enzyme called topoisomerase II which is involved in DNA replication. All this prevents the cell from growing and therefore it dies. One of its major uses has been for treating AML and multiple sclerosis.
Neurology. 2004 Dec 28;63(12 Suppl 6):S15-8.
Mechanism of action of mitoxantrone
MS Clinic of Central Texas, 7200 Wyoming Springs Dr., Suite 1100, Round Rock, TX
Mitoxantrone, a synthetic anthracenedione, was developed in the 1980s as a doxorubicin analogue in a program to find a cytotoxic agent with decreased cardiotoxicity compared with doxorubicin. It was approved by the FDA in 1987 for the treatment of adult acute myeloid leukemia and in 1996 for symptomatic hormone-refractory prostate cancer. In 2000, mitoxantrone was approved by the FDA for the treatment of worsening relapsing-remitting multiple sclerosis (MS), secondary progressive MS, and progressive-relapsing MS. Mitoxantrone is taken up rapidly by tissues, from which it is released slowly, and the terminal half-life ranges from 8.9 hours to 9 days. The highest concentrations of the drug are typically found in the thyroid, liver, and heart, and the drug persists in the body for as long as 272 days. Mitoxantrone is effective in reducing disease progression through a variety of different mechanisms of action. For example, it suppresses the proliferation of T cells, B cells, and macrophages. It impairs antigen presentation and decreases the secretion of proinflammatory cytokines. Mitoxantrone enhances T-cell suppressor function and inhibits B-cell function and antibody production. Finally, it inhibits macrophage-mediated myelin degradation. Compared with interferon betas, mitoxantrone has a broad range of actions and has effects on many different types of immune cells.
We do not know how mitoxantrone is going to work in the new combination proposed in this clinical trial. That is the whole point of doing clinical trials, to find the answers to questions such as this. Given the potency of this drug, it would be a safe bet that even higher response statistics can be expected from the combination of FCR+M. Hopefully the results of this clinical trial will be published promptly, and the participants followed long enough to get meaningful information. In the mean time, we can look at some interesting articles that are already available to us, to shed some light on this new combination. I have said this many times: managing your CLL and making smart therapy choices is all about balancing risks versus rewards of the options available to us. We are all adults here, we know that just about every chemotherapy drug out there has some level of risk associated with it. The important thing is to know about it ahead of time, so that your decision is a well-informed one. Even more important, knowing the potential risks means it might be possible to take pre-emptive precautionary measures.
The abstract below is from the Royal Marsden, highly regarded expert center and with Dr. Catovsky as the lead author. 24 CLL patients were treated with FC+M. In other words, the new clinical trial at M. D. Anderson adds on Rituxan to the combination in this abstract, that is the new twist. We also do not know if the drug dosages and scheduling are comparable between the Royal Marsden study and the MDA clinical trial. I am trying to nail down these details and I will update you as soon as I find out. But this abstract is not a bad place to start, as we judge the potential risks and rewards of the FCR+M combination. At least now we have a handle on the FC + M part of it, and the “R” part of it is quite familiar to most of us.
The 24 CLL patients were of the heavily pre-treated variety. Most of them had been exposed to fludarabine and some were refractory. 8 out of the 24 patients got a CR (“Complete Response”). The remissions lasted a median of 19 months, and the median survival was 42 months. But what blew me away was the high level of neutropenia (57%), infection complications (43%), transformation to the much more dangerous large cell lymphoma (the dreaded Richter’s Syndrome) as well as acute myeloid cancer. 6 out of the 24 patients (that is a whopping 25%) morphed from their original CLL to the much more dangerous RS and AML. This is one aggressive combination, with or without addition of Rituxan!
Leuk Lymphoma. 2004 May;45(5):945-50.
Fludarabine, cyclophosphamide and mitoxantrone in relapsed or refractory chronic lymphocytic leukemia and low grade non-Hodgkin's lymphoma.
Hendry L, Bowen A, Matutes E, Swansbury J, Catovsky D.
Academic Department of Haematology and Cytogenetics, The Royal Marsden NHS Trust, Fulham Road, London SW3 6JJ, UK.
A regimen combining fludarabine, cyclophosphamide and mitoxantrone (FCM) was used to treat 29 patients with relapsed or refractory chronic lymphocytic leukemia (CLL, N = 24) and low-grade non-Hodgkin's lymphoma (NHL, N = 5) based on evidence suggesting synergism between the 3 drugs. Patients were treated with mitoxantrone 5mg/m2 i.v. day 1 only, fludarabine 25 mg/m2 i.v. for 3 days or 24 mg/m2 orally for 5 days, cyclophosphamide 250 mg/m2 i.v. for 3 days or 150 mg/m2 orally for 5 days inclusive. Eighteen patients had previously received fludarabine and most were heavily pretreated with 40% having >2 prior treatments. A median number of 4 FCM courses (range of 1-9) were given. The response rate was 78.5%: 32% complete remission, 25% nodular partial remission, 21.5%, partial remission. Median duration of response was 19 months and median survival was 42 months. Sixteen patients (57%) developed neutropenia to < 0.5 x 10(9)/l and 12 (43%) infectious complications. Four patients developed large cell lymphoma (Richter's syndrome) and 2 acute myeloid leukemia. FCM is a useful combination for relapsed or refractory CLL and low grade NHL with high response rates and long duration of response. The role of FCM as first line therapy deserves study as well as its combination with the monoclonal antibody Rituximab.
PMID: 15291353 [PubMed - indexed for MEDLINE]
The whole rationale for initiating multiple drug therapy is based on the concept of synergy. If drug A works so-so, and drug B is not the best thing since sliced bread either, will we get a better bang for the buck by combining A+B? Will we get 2+2 equals more than 4? Remember, the whole game is to get more bang (higher response rates), without paying more bucks (toxicity and adverse effects).
The logic of adding new drugs is based on the concepts of “non-overlapping toxicities” and “maximum tolerable dose”. To bring this home in a way you cannot miss, drug A may cause you to barf, while drug B may cause you to take up residence in the bathroom. Just so long as the problem associated with each drug is different and does not overlap with the other one, the idea is that you should be able to handle it, there is no increase in the individual pain associated with either of the issues by its lonesome self! As for maximum tolerable dose, that is the whole point of doing these early phase trials (also called dose escalation trials), to find out how high they can go on the dosages. The idea is to go high enough to kill the cancer, but stop short of where the patient cries out “uncle!”
As we pointed out earlier, we do not know if there is synergy between the four drugs that will be used in FCR+M clinical trial. However, we do have information on how the new kid on the block (mitoxantrone) gets along with the heavy hitter on the FCR team, namely fludarabine. The abstract below comes from M. D. Anderson itself, authored by some of the best known experts in the CLL landscape.
The study was based on 88 CLL patients, no small cohort. There were patients who were chemo-naïve, as well as those who have had alkylating agent therapy (such as cyclophosphamide) and fludarabine therapy. Some of the patients were refractory to fludarabine. Every patient got fludarabine + mitoxantrone. In the previously untreated patients, the best of the bunch, 20% of the patients got a full CR. The researchers note that this was not significantly different from what would be expected from just single agent fludarabine, based on their own institution's experience. In other words, this clinical trial with a substantial patient cohort showed no synergy between fludarabine and mitoxantrone - and that is a disappointment. As in the Marsden results above, this paper also reports myelosuppression and infections as the most common problems.
Cancer. 2004 Jun 15;100(12):2583-91.
Fludarabine and mitoxantrone for patients with chronic lymphocytic leukemia.
Tsimberidou AM, Keating MJ, Giles FJ, Wierda WG, Ferrajoli A, Lerner S, Beran M, Andreeff M, Kantarjian HM, O'Brien S.
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
BACKGROUND: The objective of the current study was to assess the efficacy of combination therapy with fludarabine and mitoxantrone in patients with B-cell chronic lymphocytic leukemia (CLL).
METHODS: Eighty-eight patients were treated with fludarabine 30 mg/m(2) intravenously daily for 3 days and mitoxantrone 10 mg/m(2) on Day 1 (FN). Patients were divided into four groups based on expected response to single-agent fludarabine. These four groups included previously untreated patients, patients who previously were treated with alkylating agents, patients who were successfully treated with alkylating agents and fludarabine but who developed recurrent disease, and patients whose disease was refractory to fludarabine with or without alkylating agents.
RESULTS: The overall response rate was 66%. The response rates were 83% in previously untreated patients, 87% in patients previously treated with alkylating agents, 50% in patients whose disease was not refractory to fludarabine at the start of therapy, and 25% in patients whose disease was refractory to fludarabine. The complete remission (CR) rate was 20% for previously untreated patients, which was not significantly different from the CR rate for a group of historical control patients who were treated with single-agent fludarabine. The median follow-up was 8 years for surviving patients. The median progression free survival was 24 months for all patients and 34 months for previously untreated patients. The median overall survival was 40 months, and the median survival of previously untreated patients was 88 months. The most common toxicities were myelosuppression and infection. Eleven patients (12.5%) developed a second malignancy after a median of 62 months.
CONCLUSIONS: The FN regimen did not have a significant advantage over fludarabine alone in the treatment of patients with CLL.
Fortunately for us, mitoxantrone has been around for quite a while, and there is a long track record. Its potency is undisputed, along with its siblings doxorubicin, epirubicin, etc. The issues we will review in this section are its potential risks, some of which are not trivial. The single biggest risk factor for use of mitoxantrone is cardiac toxicity. To see how BC Cancer Agency rates the risk check out this link: B. C. Cancer Agency on Mitoxantrone.
Cardiotoxicity is cumulative across members of the anthracycline (daunorubicin, doxorubicin, epirubicin, idarubicin) and anthracenedione (mitoxantrone) class of drugs. Patients who have received these drugs are at increased risk of toxicity and should be carefully monitored. The cumulative dose is lower in patients who have received radiation to the mediastinal area or concomitant therapy with other cardiotoxic agents such as cyclophosphamide.
Mitoxantrone can cause chromosomal aberrations in animals and is mutagenic in bacterial systems. Its safe use in pregnancy and its effects on fertility have not been established. Breast feeding is not recommended due to the potential secretion into breast milk.
Maximum life time dose restrictions
I have to admit I was taken aback when I read the “Dear Doctor” letter that was sent out by Serono, the company that manufactures Novantrone, a branded version of mitoxantrone. These letters are sent out under FDA mandate, when post marketing surveillance identifies new or increased risks that have not been identified up to that point. This letter is a very recent one, pointing out that even in the case of “old” drugs such as this there are new things to be learned. There are three pages to this letter, I am quoting the opening paragraphs so that you get the gist of it. You can read the full text by clicking on the links below. (Do bear in mind that Novantrone is the brand name for mitoxantrone.) This is serious stuff folks.
For Health Care Professionals: Dear HCP Document (PDF format)
For Patients: Patient Information (PDF format)
Dear Healthcare Professional:
This letter is sent to you to supplement previously provided information concerning the risks of cardiotoxicity associated with NOVANTRONE® (mitoxantrone for injection concentrate) treatment for multiple sclerosis (MS) and also provides supplemental information regarding secondary acute myelogenous leukemia (AML) reported in MS patients treated with NOVANTRONE®.
Reports received through post-marketing surveillance, have shown that diminished cardiac function may occur early on in the treatment with NOVANTRONE®. Therefore, the Product Labeling for NOVANTRONE® was updated in March 2005 to state that cardiac monitoring of MS patients should be performed at baseline and prior to administration of every dose of NOVANTRONE®.
The advisory goes on to say the following about the cardiac monitoring of cancer patients:
In cancer patients, the risk of symptomatic congestive heart failure (CHF) was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m 2 . For this reason, patients should be monitored for evidence of cardiac toxicity and questioned about symptoms of heart failure prior to initiation of treatment. Patients with multiple sclerosis who reach a cumulative dose of 100 mg/m 2 should be monitored for evidence of cardiac toxicity prior to each subsequent dose. Ordinarily, patients with multiple sclerosis should not receive a cumulative dose greater than 140 mg/m 2 . Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with NOVANTRONE® may occur at lower cumulative doses whether or not cardiac risk factors are present.
Cardiotoxicity can occur at any time during NOVANTRONE® therapy, and the risk increases with cumulative dose. Congestive heart failure (CHF), potentially fatal, may occur either during therapy with NOVANTRONE® or months to years after termination of therapy. All patients should be carefully assessed for cardiac signs and symptoms by history and physical examination prior to start of NOVANTRONE® therapy. Baseline evaluation of left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated radionuclide angiography (MUGA) should be performed.
The cardiac toxicity risk of mitoxantrone and its more famous kissing cousins such as doxorubicin has been well documented over the years. More recently, attention has been drawn to their potential involvement in causing treatment-related myelodysplasia (see the abstract below), especially when combined with other chemotherapy drugs such as purine analogs (fludarabine) and /or alkylating agents (cyclophosphamide). Two highly regarded physicians who responded to our request confirmed that they would routinely do an echocardiogram or MUGA scan prior to start of therapy with mitoxantrone and similar drugs, to establish baseline cardiac function of the patient. They would also make sure they kept an eye on overall dose the patient received, as well as the use of other medications and / or radiation therapy that would eat away at the margin of safety. I understand this is the norm both in the U.S and in Europe. (The FDA-mandated "dear Doctor" letter specifically cites cyclophosphamide and mediastinal radiation as exacerbating factors.)
The present standard in the U.S. requires that all patients should get the echocardiogram or MUGA scan before start of therapy. Similar scans prior to each dose of mitoxantrone are now mandated for multiple sclerosis patients, but not mandated for cancer patients. The logic seems to be that MS patients are more at risk of heart disease than cancer patients. I do not know if this is so or if the FDA will change the requirement in the future by mandating cardiac screening prior to each dose of mitoxantrone for cancer patients as well. I am particularly concerned that CLL patients undergoing combination chemotherapy, such as the FRC+M trial we are discussing here, are more likely to be at risk, due to the overlapping cardiac toxicity profiles of the drugs involved. It also stands to reason that not all cancer patients are the same. On average, CLL patients tend to be older, and as we age we all tend to be more at risk of cardiac problems.
With this clearly identified extra risk of adding mitoxantrone to the FCR combination, I cannot help but wonder what is to be gained by doing so. To get higher response rates? Heck, we are told the FCR overall response rates are already sky high, at 90% or more. This is a point of diminishing results. To get higher CR rates, or higher rates of pcr negatives responses? Perhaps. But I feel we need to be aware of the risk side of the equation. Will these higher rates of CR or pcr negative molecular remissions be purchased at the risk of increased myelosuppression, increased risk of therapy related myeloid cancers, increased risk of heart disease, increased risk of Richter’s transformation? These are not trivial questions. We hope we get some answers to these from the research community.
Last but not least, we understand that this study protocol will measure overall response rates as the criteria of success. We respectfully suggest that from the patient's perspective, overall survival is a much more critical endpoint.
Blood. 2005 Jun 15;105(12):4573-5. Epub 2005 Mar 1.
Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha.
McLaughlin P, Estey E, Glassman A, Romaguera J, Samaniego F, Ayala A, Hayes K, Maddox AM, Preti HA, Hagemeister FB.
Department of Lymphoma/Myeloma, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 429, Houston, TX
Treatment-related myelodysplasia (t-MDS) occurs less frequently with the nucleoside analogs than with DNA-damaging agents such as alkylators or topoisomerase II inhibitors. In a chemoimmunotherapy trial conducted between 1997 and 2003 in patients with stage IV indolent lymphoma, 202 patients were treated and 8 have developed MDS between 1 and 5 years after therapy, including 4 who received only fludarabine, mitoxantrone, and dexamethasone (FND) for 6 to 8 courses, with or without rituximab, followed by interferon alpha (IFN-alpha). Complex cytogenetic abnormalities were present in all patients. Abnormalities of chromosome 7 were present in 6 of the 8 patients, 3 of whom received only FND +/- rituximab and IFN-alpha. The abnormalities of chromosome 7 were monosomy 7 in 4 patients (1 of which had add 7p in the remaining chromosome); 1 del 7q; and 1 der 7. MDS with features classically associated with DNA-damaging agents can occur following therapy with FND, with or without rituximab, and IFN-alpha.
This clinical trial raises, once again, the whole issue of clinical trials, who should participate and why, what exactly is meant by informed consent. All of them are thorny issues, and not things that can be dismissed blithely.
The first thing to recognize is that different and entirely appropriate agendas may be at play when patients are recruited for clinical trials. The financial incentive of the drug companies and the health care services industry is the easiest one to recognize - none of us have a problem with identifying it, whether we sympathize or not. The more troublesome one is the potential for conflict between the admirable drive of researchers to find a cure for future generations of CLL patients, and the more focused agenda of helping the specific, individual patient standing in front of the physician. I am not sure how I would resolve this conflict, if I were the one wearing the white coat. Where does the researcher give way to the physician?
As patients, we too have our own conflicts of interest. All of us, as ethical and altruistic members of the human race would like to do what we can to benefit future generations of CLL patients. This is particularly true in the case of cancers that have familial risks - none of us would want our children or grand-children to face the same tough decisions that we are facing today (Not the Worst Day of Your Life). But, in addition to these philanthropic urges, we have a more immediate and very personal desire to prolong our own lives. We make the therapy choices that are going to make a difference to our own health and longevity.
Here are some points that we must consider when making the decision to participate in early phase clinical trials:
It really bothered me to read that potentially fatal congestive heart failure can happen months or even years after completion of therapy, as a risk factor in mitoxantrone. It is a good question to ask how long the researchers will monitor you and keep an eye out for potential problems along these lines, after the study is completed.
These are tough and worrisome things to think about. No one should make these decisions on an impulse or without taking the time to think things through. It is important to consult with your local oncologist as well and get him or her on board because that resource may be your first line of defense if something should go wrong. When it comes down to it, there are no slam-dunk right or wrong decisions in CLL. There are only decisions that are right or wrong for you and your family. Only you can make that call. All I am suggesting is to take the decision to participate in a clinical trial seriously, take the time necessary to make the right decision for you and your family. Fortunately for us, CLL is a sufficiently indolent disease that it is not going to get away from you if you take a few days to think things over before you sign on the dotted line.
Editor's Note: We have written to Dr. Stefan Faderl (the letter is reproduced below) with a draft of this article and our questions and comments on this clinical trial. We were able to reach him at his office at MD Anderson prior to the publication of this article. While he did not respond to the letter at that point, we invited him to do so at his convenience. A link is provided at the end of this letter to his detailed response, as well as our comments and a related critique by Dr. Terry Hamblin. We also contacted OSI Pharmaceuticals, the sponsor of this clinical trial and the marketer of Novantrone (the brand name for mitoxantrone), for their comments. We are awaiting their response.
To Dr. Stefan Faderl, MD
Subject: FCR+M clinical trial (2005-0106)
Dear Dr. Faderl:
I am writing to you regarding clinical trial 2005-0106 announced on the M. D. Anderson website, where you are listed as the Principal Investigator. I understand this is a Phase-II clinical trial, looking to establish efficacy of fludarabine, cyclophosphamide, mitoxantrone, Rituxan (FCR+M) and pegfilgrastim as frontline therapy for CLL patients.
Please allow me to introduce myself. I am founder and president of CLL Topics Inc., an Internet-based non-profit CLL patient education organization (www.clltopics.org). We represent a large and motivated patient group, our publication gets more than 25,000 visitors every month from all over the world. We try to provide our patient-members with well documented reviews of cutting edge CLL research, clinical trial information, prognostics and therapy options. Several of our members who are considering participating in your clinical trial have written to us looking for additional information.
After doing our due diligence, we have written an article that we will be publishing on our website in the next couple of days. We would very much like to have your input into our review before we publish it, and we are therefore sending you a private link (below) to our article. Please do take the time to read our review.
After looking up this clinical trial announcement on the M. D. Anderson website, we are particularly concerned that there is no mention of physical screening of volunteers for potential cardiac problems, prior to participating in this mitoxantrone containing regimen. In view of the “Dear Healthcare Provider” letter that was sent April, 2005 by the Serono, at the request of the FDA, this seems to be the prudent thing to do. We understand some patients have already been through the first cycle of this trial at M. D. Anderson, with instructions to their local healthcare providers for administering the following cycles. Do these instructions specify physical cardiac assessment prior to each dose of mitoxantrone, as strongly recommended now in the new guidelines?
CLL patients and their families march to a faster drumbeat. Our very lives depend on getting accurate information in a timely fashion. We want to be sure that our review is both accurate and timely. We will be more than happy to publish your response to this email on our website, as well as correct any factual errors in our article. I look forward to hearing from you at your earliest convenience. My contact information is given below. Your time and attention are much appreciated.
Dr. Chaya Venkat
Read Dr. Faderl's response, our comments and a critique by Dr. Terry Hamblin in " More on Mitoxantrone plus FCR".
You can also read our comparison of the M. D. Anderson protocol discussed here with information we have on a multi-center British trial launched in 2004: FMC plus R, Brit Version.
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Topic: Clinical Trials