What is a Clinical Trial?

Clinical trials are well-designed experimental treatment protocols that utilize new drugs, commonly referred to as novel agents, that: 1) have recently been discovered and have passed through rigorous testing in cell culture and animal models and have demonstrated preliminary safety in humans, but have not been approved by the Food and Drug Administration for any medical use (these are typically phase I and II clinical trials, see below); or 2) have been approved by the FDA for use in other types of lymphoma (or cancer), or for a different clinical scenario and now are investigated for a new indication (these are typically phase II and III clinical trials, see below).

There are several types of clinical trials. In general, clinical trials are divided into “phases” based on what is being studied and how far along the drug is in clinical development. They also can be classified based on what phase of the lymphoma (cancer) they are studying, i.e. newly diagnosed (never treated before) or lymphoma (cancer) that returned after 1 or more different treatments (referred to as relapsed or refractory disease). As a general rule, most of the new drug testing starts with phase I trials and involves patients with relapsed/refractory lymphoma (cancer). However, there are exceptions to the rule.

Phase I clinical trials are treatment protocols that investigate the use of new drugs in humans for the first time or established (approved) drugs in new combinations that have not been used before. The main objective of phase I trials is to establish safety in humans and to find the highest dose that humans can tolerate. Information about preliminary efficacy—effectiveness—is also collected. Typically, phase I trials allow patients with various (or all) types of cancer to participate; this helps to establish which cancers respond to the new drug(s) better. The chance of responding to treatment on phase I trials is unknown and, in fact, will not be determined at the end of the study due to different objectives (safety). The benefit of participation in phase I clinical trials for a particular lymphoma (cancer) patient is hard to estimate. Therefore, most of the time, these trials are reserved for patients with multiple relapses of their disease (after multiple failures of “old” treatment regimens), except for situations where new agents are added on to previously established drugs or combinations. At the very least, patients in the latter scenario would receive the best possible current treatment, but it’s likely they’d receive an additional benefit from a new agent (safety is still a primary objective of such studies). Phase I trials are very closely supervised by institutional, state and government (FDA) authorities for accuracy and ethical conduct, given the importance of the collected information and vulnerability of the patient population participating in these trials. The risks and benefits of participation in phase I clinical trials have to be thoroughly discussed with the treating physician, who is most often the responsible investigator on the trial and, therefore, may have an inherent bias towards it. Obtaining a second opinion consultation might also be helpful.

Phase II clinical trials test the efficacy of new drugs after their safety and maximum dose have been established in phase I trials. Preliminary information is usually available regarding their activity in certain types of lymphomas (cancers). During phase II trials there is no “control arm” or placebo (sugar pill/water) arm, and all participants receive the same dose and schedule of the investigational agent. Both the patient and their doctor know exactly what is being administered. Safety is still a major objective of these trials, but the main objective is how well the drug works in a particular clinical scenario (type of lymphoma, stage of treatment, with or without other drugs, etc.). Phase II trials usually have a more favorable risk/benefit ratio than phase I trials; patients with fewer prior treatments or treatment failures should really consider enrolling into these protocols if standard treatments are not very efficacious.

Phase III clinical trials are large studies that compare new agents or combinations to previous standard-of-care treatments. The objectives are typically to show either that a new treatment is better than the old one(s), or that it has similar efficacy but reduced toxicity. These studies always have a “control arm”—standard treatment—and an  “experimental arm”—new treatment—that is being studied. Most of the phase III trials are run across the country or internationally and require randomization (see below) to one treatment arm or another. They typically target a very specific disease situation and aim at proving one of the concepts above, such that the new treatment will be approved by the FDA for broad use (marketing) outside experimental protocols and will become a new standard-of-care. This is the final stage of new drug development, and typically by this time a lot of safety and efficacy information has been accumulated. In general, phase III trials present the most favorable risk/benefit ratio for patients, since at the very least they will receive the most effective treatment to date for their lymphoma (cancer), but may have a 50-75% chance (depending on study design) of receiving a potentially even better treatment. There are not many disadvantages of enrolling into phase III trials. Of note, in oncologic (cancer) trials the control arm of the randomized studies is almost never a placebo or “no treatment” option.

Randomized clinical trials can be either phase II or phase III and include a random (unpredictable) assignment of patients to one of the “arms” of the study. Different arms are assigned to different treatments. In most cases, randomized phase II trials compare different doses or schedules of the experimental drug (regimen), whereas in randomized phase III trials, experimental drugs (regimens) are typically compared to standard or established treatments. Of note, the randomization is by chance in most cases, i.e., neither the patient nor the physician has control over which arm the particular patient is assigned to. Randomizations can be 1:1 (equal chance to be in either arm of the study) or 2:1, 3:1, etc. (higher chance of being in the experimental arm than control/established arm). As mentioned above, randomization should not be a major deciding factor in whether or not to consider participation in a trial, since, at the very least, patients would receive the standard treatment (the best, current available treatment).

Blinded or double-blinded clinical trials are the types of randomized trials where neither the patient nor the physician know which of the drugs are administered (they come in an unidentified bag, or in a similar looking pill), experimental or standard of care. All of the attributes of randomized trials found above apply. Blinding helps provide the highest quality research information, such that the risk of false results is at a minimum. Just like randomization, blinding of the study should not be a factor in whether or not to participate in the study; it is a scientific method that helps the research integrity, but does not compromise the patient’s safety or chances of receiving the best possible therapy (whether standard or experimental).

Clinical trials present a unique opportunity for T-cell lymphoma and other cancer patients to receive therapy with potentially effective (or more effective) and potentially safer drugs that would not be available for broad medical use for a long time (or until the study is completed, analyzed, submitted and reviewed by the FDA or published in reputable medical journals). The main reason for such a delay is, of course, the need to prove to the best possible degree the safety and efficacy of new drugs before they are applied to a large number of people in routine practice everywhere.

It is important to understand that participation in a clinical trial is not necessarily a matter of a “last ditch effort” for those who have exhausted all other available options. For many patients with rare and serious cancers, like T-cell lymphomas, available treatment options might not be very efficacious and might only guarantee a cure for a small proportion of those affected. In many situations, choosing a clinical trial for initial therapy (at the time of diagnosis) or as the first salvage (rescue) treatment might be more reasonable than pursuing older, “traditional” treatment options. These older, “traditional” methods will more than likely fail the majority of patients and cause a lot of toxicity, which might compromise a patient from receiving future treatments. As a general rule, for any stage of disease (new diagnosis, first relapse, never responded to prior treatments, etc.), the lesser the chance the  “established treatment” has to cure or control the lymphoma (cancer), the higher the benefit of choosing a clinical trial as an option for therapy. One exception to the rule might be in situations where newly discovered drugs have shown significantly superior efficacy, even during early studies, than any of the previously reported (“old”) treatments, and when the new treatment promises a sizable reduction in the level of toxicity (severity of side effects) observed with “old” treatments.

These are some of the pros and cons when considering enrollment into a clinical trial.

Pros:

• Receiving therapy that will not be available for general use for a long time (sometimes years)
• Better monitoring
• Better education about the disease

Cons:

• Not knowing upfront whether the experimental treatment is better and/or safer                       
• More time consuming                                                                                                                               

For T-cell lymphoma patients, participation in clinical trials is particularly important. Current treatments for T-cell lymphomas are still suboptimal and/or very toxic. This is especially true for the majority of PTCL patients who are elderly and cannot tolerate intensive protocols that are required to give the best chance of cure. To view a complete list of the T-cell lymphoma clinical trials available in the United States, please visit the ‘Clinical Trials’ section of our website.