Part 2 can be read independently of Part 1. Part 1 focuses on some of the benefits of clinical trials and attempts to dispel a couple of myths. Part 2 is more focused on the specifics.
What is a clinical trial?
A clinical trial is a research study that is designed to answer a very specific question. Questions vary. Researchers may be asking if they can improve survival by changing the way a medication is given, such as by combining with other drugs or delivering in shorter time intervals. Other clinical trials may focus on side effects to determine if they can be lessened. For new drugs, researchers first need to ask what dose can be given safely before testing to determine if they have the desired anti-cancer effect in patients. When searching for a clinical trial in the NIH search engine (link below), one can look at the primary and secondary “outcome measures” to understand the question and purpose of the particular clinical trial. Because this is a blog dedicated to cancer patients, my focus here is on cancer treatment trials, but there are other studies that have to do with cancer prevention or screening that people without cancer may participate in. There are also trials open to cancer patients for drugs to treat or prevent side effects of cancer treatment. Examples would include trials of new drugs to prevent specific infections or to treat nausea and vomiting.
What do we mean by the phase of trial?
The different phases are 1, 2, 3, & 4. Each phase has specific objectives.
This is the starting point when a new drug is first used in humans. Before a drug is ever conceived or synthesized, the pathways in cancer biology important for cancer survival and therefore potential targets for new drugs must be elucidated by researchers. Next is finding small molecules or antibodies that interfere with these pathways. Then before a phase 1 clinical trial can be done, preclinical research on cultured cells and animals is the first type of studies done to evaluate for efficacy and toxicity. If a drug shows promising preclinical results, then clinical researchers can apply to the FDA to get it approved as an IND (investigation new drug). Finally, they can design a phase 1 trial to test the drug in humans, but they must get the approval of an IRB (Institutional review board) before recruiting patients. This preclinical phase can take a number of years to complete but is meant to ensure ethical and safe trials.
Whereas drug trials for many diseases may include healthy volunteers and doses are kept well below any toxic range, chemotherapy drugs are treated differently. Many chemotherapy drugs work better at very intense dosing levels and have side effects that abdicate their use in healthy volunteers. Since there is typically improved efficacy with the higher dosing, these trials tend to enroll patients with advanced cancers where there are no standard treatments. The purpose of the phase 1 study is to find the appropriate dosing. The newer biological drugs that are targeted to the cancer cells typically have a better safety profile and are dosed more similarly to other drugs. More traditional chemotherapies are drugs that are cytotoxic, which means that they are toxic to all dividing cells both cancerous and healthy. The principal for using these drugs is to benefit from the fact that cancer cells divide (grow) at a faster rate compared to healthy cells and these drugs are more toxic to cancerous cells. Although higher dosing typically improves efficacy, dose is limited by the toxic effect that it has on our healthy cells. Therefore phase 1 trials which have the objective of finding the appropriate dose, escalate the dose during the trial to find the maximum tolerated dose. That is how high can the dose be without near life-threatening events. This gives a little insight into how difficult it can be to tolerate cancer therapy. Typically all patients in phase I trials get the drug, the dose that they get might vary depending on when they enroll.
Since phase 1 trials are the earliest stage of use of a drug in humans, they are the least likely to be directly beneficial to the patient participating, but typically the participants have no standard alternatives. I make several generalizations here so it is important to still investigate the options that are available for the particular type of cancer that you have. There are certain boutique therapies such an immunotherapy that are just offered in trial form and other targeted therapy where safety profile may be known better from studies that have been done on similar agents, where some of my generalizations do not apply. But overall phase I trials are fairly small studies that just have the goal of finding the best dose to continue with in a phase 2 trial.
Although they can be beneficial to the patient, most patients do not benefit directly from participating in phase 1 trials. Typically patients enrolled in these trials have advanced disease that has failed other therapies. There are exceptions to this so it always good to investigate options and discuss them with your doctor. But as with all cancer therapy this is another layer of uncertainty. There is always hope in the unknown, that this could be the drug that could be beneficial to you. More likely the hope is that you are helping future patients with the same disease, since your case is being recorded and will help lead to less uncertainty for someone else.
A difficulty with phase 1 trials is that side effect profiles are more unknown compared with other medications that you have gotten during your cancer care.
A phase 2 trial builds off what was learned in the phase 1 trial, but now the study goals are extended to evaluate if the drug has an effect on the cancer. These studies are typically larger then phase 1 studies so they also continue to evaluate safety and dosage in a larger patient population. Statisticians help the physician determine how many patient are needed to be able to answer the study question. The hope is always that you will get a drug that would have such a profound impact that a statistician would almost not be needed to interpret the results, but in many cases the results do require analysis and results are more subtle. It will take another generation of studies to learn how to combine a drug with other active agents and how to use it at earlier stages of disease.
Sometimes these trials will be designed with phases 1 and 2 combined into a single larger trial so that both objectives of dose and efficacy information can be gathered together.
A phase 2 example
Just over a decade ago, one of the most important drugs used today in chronic myeloid leukemia (CML) was first approved by the FDA after phase 1 and 2 trials showed very good positive results. The drug Gleevec (imatanib) is of the newer class of targeted therapies and works by blocking the product of a gene that is produced only in the cancer cells and is critical for the vitality of the cancer cells that have this gene. Patients in the early studies had advanced disease which had no standard treatment. All patients in the study were treated with Imatinib. The study clearly showed that more patients had a positive response. Since that time more studies have been done leading to routine use of this drug in early stages of CML. These successful trials led to the development of an entire class of drugs that works in a similar way and that can be used in CML and other cancers where similar pathways are important for the vitality of the cancer.
Phase 3 trials enroll many more patients then phase 1 or 2. Unlike early phase trials that usually enroll patients with advanced cancers, phase 3 study participants have all stages from newly diagnosed to advanced cancers. In my last post, I discussed the fact that most children with the diagnosis of cancer in the U.S. are enrolled in clinical trials. This is because of the availability of phase 3 trials at all academic pediatric cancer centers. These trials typically compare standard therapy to a slightly new therapy. In cases where the standard therapy has good responses, there is often not much difference between the standard arm and the experimental arm. Participants do not need to be concerned that one patient will get multi-agent chemotherapy and the other person a single-agent, new biological-targeted therapy.
One way that I typically explain this to patients is by explaining that the experimental arm of the study is not in fact using experimental drugs, but that their child will be getting drugs that we have been using for years and that we know have good activity against the cancer. If there is a new drug it is typically added into the study arm but not used as a single agent and has already shown some efficacy in phase 2 trials.
Why are drug often used together in a single cycle of chemotherapy? One idea is to combine drugs that work on different pathways in the cancer cells. This is done to prevent giving a survival advantage to a particular subset of cells within a tumor. Tumors have multiple subsets of cells. If you give a single agent then you preferentially kill one subset and this can drive the growth of a resistant subset. The idea behind using multi-agent chemotherapy is to prevent this tumor resistance. (Feel free to comment with a question if this is not an understandable concept since the idea hinges on knowledge of cellular biology). Another consideration in determining a combination is side-effect profiles, so that a new drug is added to an old treatment regimen without too great additive side effects.
Patients in phase 3 studies are randomized. This concept is explained in a previous post. One cannot assign a patient to a specific arm as a physician, because that would either mean that the groups are really not equal or would introduce the physician’s own rationale or guess (bias) into the determination of study groups. The reason the two arms are being compared is because we physicians do NOT know which arm is better and the only way to determine if one is superior is to compare the options on similar groups. So if we choose to go on a study, a computer randomly generates which arm that we will go onto. Once this is assigned, the doctor will let us know which arm and will treat us with the medications that it assigns, but our doctor will continue to be our doctor and make treatment decisions. If an issue arrises and our doctors decide it is best for us not to continue on the study, we can be taken off the study. Ultimately, the doctor main concern is treating us.
The strict guidelines that exist in studies are designed to make sure patients get the best therapy. Studies of studies have shown that patients do even a little bit better just because they’re being treated on a trial. I think this is because the guidelines created are built from shared experience, so that even small institutions are able to draw on the experience of larger centers. Another benefit is having data monitoring and safety boards (DSMBs) that process data gathered from multiple patients and multiple centers as the trial is in process. This means our doctor is alerted to new side effects and/or potential problems. Furthermore, if one arm is clearly seen to be superior, the study will immediately close and all patients will be transferred to the superior arm. More commonly, there are small incremental improvements with each generation of clinical trials, and it is not until the trial is completed that one can truly determine if the new therapy is better and will be the “new” standard arm. Finally, our treatment and the data that our cancer generates through its responses to the therapy are being used to shape the future of oncology.
In pediatric Acute Lymphoid Leukemia (ALL), one study compared using two different steroid preparations and equivalent dosing to see if there was an advantage to one. Both drugs have efficacy and had been shown to have anti-leukemia effects. The trial demonstrated superiority of one preparation over another, and therefore future trials based on these results went on to use the more effective steroid preparation.
Phase 4 studies are less common than phase 3 and take place after a new drug has been used in phase 1-3 trials and approved for standard use. It further evaluates long-term side effects and effectiveness.
How to get more information:
The National Cancer Institute website is an excellent site for a summary of different types of cancer including the current standard treatment. www.cancer.gov/cancertopics
This site also has a searchable inventory of all clinical trials in both industry and academic centers. www.cancer.gov/clinicaltrials/search Trials that are currently accepting new patients have an “active” status.
The National Institutes of Health has a larger inventory of clinical trials that includes trials for many different types of diseases: www.clinicaltrials.gov
A couple of additional notes:
Trials are carefully designed to gather the information that they need to determine if a new therapy is safe and effective. Because of the constraints of the trial they need to pick very precise patient populations. In order to get these precise populations, studies have “inclusion and exclusion criteria” that are specific factors that a patient may and may not have in order to participate. Phase 1 and 2 trials tend to have more specific criteria then phase 3 trials. These websites list these inclusion and exclusion criteria. Our doctor is our best resource to understand if our case meets the clinical qualifications for a particular study. But just because we don’t qualify for one study does not mean that we won’t qualify for another.
Searching for clinical trials also helps us identify who and where are some of the leading experts for studies in our type of cancer. Maybe helpful information when looking for a second opinion. Most have contact information for a trial nurse or coordinator. It is best to discuss with our doctor first since trial coordinators need a lot of detailed information, and often our doctor can best communicate those details.
I will post a set of questions that you can use to help make sure that you get the information that you need from the information on the web and from your doctor.
link to part 1