Clinical Trials

The Basics of CLL Clinical Trials
Online Clinical Trial Resources
Tips for searching for clinical trials
Additional Websites That Offer Partial Listings of Lymphoma Trials

We at the CLL Information Group (CIG) have noted that at seminars and meetings doctors will frequently stress to patients the importance of clinical trials. They say, and correctly, that progress with drugs and the entire development of new methods of treatment is dependent on these trials. No new pharmaceutical can be approved without such trials.

Hundreds of lymphoma clinical trials are being conducted at hospitals, cancer centers and doctors’ offices. The government, pharmaceutical companies, universities and physician groups often sponsor them. The Food and Drug Administration, as well as the Institutional Review Board of the participating hospital or institution must approve each clinical trial phase. Your decision to participate in a cancer trial is an individual decision that should be made with your doctor after careful consideration of all of the potential risks and benefits. You may choose to discontinue participation in a clinical trial at any time.

Doctors rely on the results of phase three treatments, and, importantly, follow up against time, to establish the efficacy of a new program. It is, therefore, obvious, that without these trials progress in treatment benefits would indeed be much slower.

CIG, as we grow, has the stated objective of attempting to collect sufficient funding to become involved in sponsoring some clinical trails potentially of benefit to the CLL community of patients. Thus, CIG hopes to work with the medical establishment to support clinical research to help ourselves.

The Basics

Clinical trials are done to study new drugs and treatment strategies. Examples of what clinical trials might investigate include: 1) a novel drug that is not approved by the U.S. Food and Drug Administration (FDA) nor proven effective as treatment; 2) a new indication (use) for a drug already approved by the FDA as a treatment for a different disease; 3) compare a new treatment with a standard treatment in order to determine which one is more effective or has fewer side effects; 4) see how lifestyle changes can help patients; or 5) look for ways to prevent cancer from occurring. Clinical trials are conducted in hospitals, cancer centers and doctors’ offices and may be sponsored by various entities, including the government, pharmaceutical companies, academic centers and physician groups.

New drugs must pass through a rigorous approval process governed by the FDA. The trials used to assess these drugs are typically divided into three types, called phases.

Phase I

This often involves the “first in human” studies. Phase I studies are designed to determine the dose of the drug that will be subsequently studied and the drug’s toxicities. The drugs are first tested in laboratory animals in order to learn an approximate dose for use in humans and what toxicities might be seen. Once ready for human testing, a much lower dose than what was used in the laboratory animals is selected as the starting dose for the phase I study. This first dose level of a drug is then tested in a few patients, typically three to six, to make sure that the drug is tolerated at that dose. These patients are treated one at a time to minimize the number of patients exposed to a potentially harmful drug should unexpected toxicities arise. If none of the patients at the first dose level experience any toxicities, then a higher dose is tried. The dose is slowly escalated in this manner until toxicities develop or the desired treatment effect is achieved.

Phase II

Once the dose of a therapy is determined and shown to be safe in a Phase I trial, it is then ready to be tested in a Phase II study. Phase II studies aim to determine whether the therapies have any evidence of effectiveness. In a typical phase II study, 20-40 patients with similar or the same disease are all treated in the same manner. The investigators will determine a response rate (RR) for the drug in the disease. Based upon how high of a response rate is obtained, the decision will be made whether the drug should be further developed for the disease. Phase II studies might be used to generate preliminary data or data that is confirmatory and will be used in order to obtain FDA approval. There can be a great deal of variety regarding the amount of prior experience that is available with therapies being tested in phase II studies. Phase II studies are also done to investigate whether a therapy that is already approved for one type of disease might work in another.

Phase III

Phase III trials are performed to determine whether the treatments developed in phase I and II studies are better than what is currently considered the “standard of care.” Phase III studies often require a large number of patients. Once a patient elects to enroll in a phase III study, he is assigned to one of the treatment arms being studied. This is often done by a process called “randomization.” In randomization, a computer will assign the treatment the patient is to receive based on “luck of the draw” or similar to a coin toss. It is important to remember that this randomization process is done so that each treatment arm will have patients with similar characteristics and be free of bias. Additionally, no one knows which of the treatments being studied is better or if there even is a difference. That is why the study is being done, to learn if there is a difference. Another aspect of phase III trials is that they might involve “blinding.” Blinding is when the patients and their physicians do not know who is receiving an actual treatment and who is receiving a placebo, or “sugar pill.” Placebo-controlled trials are never done in a manner to deny patients an effective therapy. They are often done by adding a new therapy to what might be the standard therapy. For instance, assume drug A + B is the standard treatment for newly diagnosed patients with a particular type of cancer. It is thought that a new therapy, C, might help A + B be more effective. In order to test whether A + B + C is better than A + B, investigators might treat one group of patients with therapies A + B (standard therapy) and the other with therapies A + B + C (experimental arm).

When deciding whether to participate in a clinical trial, it is important to understand that it doesn’t necessarily signify a last resort for treatment. “Clinical trials aren’t just for patients who have no other options,” says Richard R. Furman, M.D., assistant professor of medicine at the Center for Lymphoma and Myeloma at Weill Cornell Medical College in New York City and renowned CLL expert. “The idea is to try and identify therapies that will allow patients with chronic lymphocytic leukemia to enjoy as normal a quality of life as possible for as long as possible. Our goal is to try to identify better therapies wherever they are necessary, which includes anytime there is not a curative therapy available.”

The good news for the more than 10,000 new patients diagnosed each year with chronic lymphocytic leukemia (CLL), as well as both relapsed and refractory (resistant to treatment) patients, is that there are many CLL-specific clinical trials underway. The broad categories of treatment types in these clinical trials include:

Novel cytotoxic chemotherapy—New agents with the traditional mechanisms of action seen in standard chemotherapy agents are constantly being identified. Agents in this category include Treanda^TM (bendamustine), Arranon ^® (nelarabine), and pixantrone, among many others.
Immunotherapy—Also called biologic therapy, immunotherapy uses parts of the immune system to fight the cancer. This most commonly is a monoclonal antibody. There are currently two antibodies used in treatment of CLL patients, Campath^® (alemtuzumab) and Rituxan^® (rituximab). Many new antibodies are currently being tested, including ofatumumab, SGN-40, LL1, and lumiluximab. Ofatumumab (Humax-CD20) is the furthest along, and is being tested in a phase II study in patients who are have not responded to Fludaraor Campath. “What makes HuMax-CD20 different for CLL patients is that it binds to a different place on the CD20 molecule than the other CD20 antibodies in development,” says Dr. Furman. “Rituximab was the first and only CD20 antibody approved for lymphoma, but its effectiveness as a single agent in CLL is limited. This is often thought of as a result of a low expression of CD20 on CLL cells. Humax-CD20 may have found a means around that problem by binding closer to the cell surface and being better able to activate complement.”
Transplantation—A bone marrow transplant takes healthy stem cells from either the patient (autologous) prior to chemotherapy treatment or from a donor (allogeneic). For autologous transplants, the idea is to treat the patient with high doses of chemotherapy. These doses are so high that they would cause irreparable damage to the bone marrow. But freezing bone marrow cells prior to chemotherapy protects them from chemotherapy damage. The cells are then infused back into patients, where they can repopulate and produce new blood cells. In allogeneic transplants, the goal is to use the donor’s immune system to attack the CLL. “Bone marrow transplants are not considered part of the standard care for CLL patients, and should be considered a study treatment,” says Dr. Furman. “Hopefully, as more data are generated, their potential as treatment for CLL will be better understood.”
Chemoimmunotherapy—This treatment combines standard chemotherapy with immunotherapy. One current phase II trial is investigating the monoclonal antibody HuMax-CD20 in combination with Fludara and Cyotaxan.
Targeted Therapies—These drugs block the growth and spread of cancer by interfering with specific molecules involved in tumor growth. Often these are molecules of particular importance to the cancer cells. Examples of these agents include GRN163L, a telomerase inhibitor, Revlimid®, a thalidomide derivative already approved by the FDA for multiple myeloma and myelodysplastic syndrome, and ABT-263, and inhibitor of bcl-2. “There has been one small trial supporting the use of Revlimid in CLL patients,” says Dr. Furman. “Even though Revlimid is already approved, its maker is now conducting a trial in CLL patients with refractory disease. Based on these results, the pharmaceutical company may make an application to the FDA for this indication for Revlimid.”
Idiotype Vaccine Therapy—“Idiotype is a unique part of an antibody that binds to the target of that antibody. Antibodies are located on the surface of all B-cells, including CLL cells. All CLL cells express the same antibody. The idiotype of the antibody on the CLL cell surface is a unique target itself, and that is what an anti-idiotype vaccine is,” explains Dr. Furman. “You are attempting to get patients to react against their own cells, but limiting it to the CLL cells by directing the immune response against the idiotype. A Phase I/II clinical trial testing MyVax® in CLL patients is currently underway.
Antisense Therapy—This treatment is designed to block the production of specific proteins, allowing targeted therapy to reach cancer cells without harming normal cells. Genasense^®, a bcl-2 antisense medication, has been shown to be effective when combined with fludarabine plus cyclophosphmide in relapsed and refractory CLL patients in a phase III trial, but it has not yet been approved by the FDA. The drug inhibits production of Bcl-2, a protein made by cancer cells that may block chemotherapy-induced cell death, making current chemotherapy treatment more effective.

Interview with Dr. Richard Furman

Coming soon

Online Clinical Trial Resources

The National Institutes of Health (NIH)

This site, sponsored by the National Library of Medicine and the National Institutes of Health includes hundreds of lymphoma trials sponsored by the NCI, health institutions and the pharmaceutical industry, with links to published medical literature. The goal of this website is to offer a comprehensive clinical trial resource that is easy to navigate. Under the resources section of this site are links for information on clinical trials, how to participate in a study, a glossary of clinical trial terms, and links for other resources.

The National Cancer Institute (NCI)

Although this site shares clinical trial summaries with the above www.clinicaltrials.gov website, the search process is different and may be preferred by some. Trial summaries are in two versions, one for patients and another for healthcare professionals. Also found here are many resources including listing recent developments and results; an overview for learning about clinical trials; and a comprehensive step by step detail on finding a clinical trial. Finally the NCI’s Information Service at 800-4-CANCER is available to provide more information on clinical trials and to request educational materials.

Lymphoma Research Foundation's Clinical Trials Information Service

The Lymphoma Research Foundation (LRF) provides a Clinical Trials Information Service to increase awareness about investigational treatments for lymphoma being evaluated at cancer treatment centers nationwide. LRF does not provide medical advice or endorse specific treatments; however, upon request, the Helpline staff will conduct a search for potential lymphoma treatment trials based upon medical information that you provide. You are strongly encouraged to discuss with your physician the summaries mailed to you by LRF. Your cancer specialist will be familiar with your medical history and can best evaluate all of the study criteria to determine if the clinical trial is appropriate for you.

Search Tips

When searching these government sites and the additional ones listed below, you might want to consider these tips:

Focus on what is important to you: Is traveling a restriction? Are you interested in a specific treatment option? Will you consider trials in early development?
Explore the site’s frequently asked questions (FAQs), tools and links for help.
Try different ways of searching for trials: by condition, treatment, and key terms (relapsed, etc.).
Conduct the search several times under general and specific criteria. This will give you practice and help access more possible results that apply.
If the site asks a series of questions for creating a search profile, if possible, provide as much information as known. This will help narrow down results to those that apply to your situation.
If available, create a registered account, which may allow you to save your search results. If this option is not available, add search results directly to your Internet provider’s list of favorites for later review.

Additional Websites That Offer Partial Listings of Lymphoma Trials

www.cancertrialshelp.org

Sponsored by the Coalition of National Cancer Cooperative Groups, the Coalition's website provides information on the clinical trial process, informed consent, insurance coverage, and questions to ask your doctor. This site also offers a link to the TrialCheck matching service, which allows patients to search for trials based on specific questions on their condition and save the results.

www.emergingmed.com

Emerging Med is a private commercial company offering a clinical trial matching and referral service. Visitors can create and save account profiles based on specific questions on their condition. Emerging Med’s referral service connects patients directly with the investigators of trials for which they may qualify.