he Classic Phase I Trial: Primary ObjectivesA Phase I trial is a dose finding study where the primary objective is to determine the Maximum Tolerated Dose (MTD) of the treatment and to define the toxcities of the treatment. A Phase I trial represents the first test of the treatment in people, although there may be experience with closely related treatments. The classic Phase I trial is only intended to determine the dose and characterize the side effects, not to show whether the treatment is effective, but, of course, if it turns out the treatment actually is effective, patients can still benefit.The Classic Phase I Trial: Standard DesignThe standard Phase I design is a Dose Escalation trial in which successive small groups of patients (Called “cohorts”) are given successively higher doses of the treatment until some of the patients in a cohort experience unacceptable side effects. In most Phase I trials there are 3-6 patients in each cohort. The first cohort of patients in the trial typically get a rather low dose. If unacceptable side effects are not seen in the first cohort, the next cohort gets a higher dose. This continues until a dose is reached which is too toxic for a set fraction of patients, say one in three. Then the previous dose level is considered to be the Maximum Tolerated Dose (MTD). It’s important to realize that individual patients are only treated at a single dose level, although they may receive several treatments at that dose level. It’s also important to understand that the few patients who are treated at a dose above the MTD may not have serious problems. Even those patients who have dose limiting toxicity often are not permanently harmed – although the treatment has to be stopped due to the side effects. Also at any given dose level, some patients will have milder side effects than others, and some will not experience severe side effects even at doses above the MTD. I was treated in a Phase I trial at a dose level 50% greater than what was later selected as the MTD, yet I actually tolerated the treatment better than most of the patients who were treated at the MTD!Many Phase I studies are single institution studies, so, unlike later phase studies, you may not have choices as to where to get treated.Phase I Trials of Brand New DrugsThe patients in the first dose cohort of a Phase I trial of a new drug are the first humans ever to get that drug. Such a trial as close as you can get to the stereotype of a truly experimental treatment!Before any new drug can be given to humans, it must go through extensive pre-clinical testing in animals. The likely nature of the side effects and required effective dose can be extrapolated from the animal results, but there can still be surprises since animals are quite different from people. Because of this uncertainty, they typically start the trial with a very low dose, often one which is far too low to be effective, even if the drug is later found to be active.Phase I Trials of CombinationsCancer treatments often consist of a cocktail of several drugs, and many Phase I trials test a new combination of drugs rather than a new drug. Perhaps a drug is being added to a standard treatment already known to have some effectiveness, or perhaps two active drugs are being tested in combination in the hopes that the results will be superior to those with either drug alone. Combinations in Phase I trials can involve drugs which are not yet approved for general use. Typically the new drug, though not approved, has already shown promising results by itself. This was the case for the trial in which I participated, a Phase I trial of the then experimental drug, Interleukin-2 (IL-2), combined with Interferon. IL-2 was not yet approved, but was very promising. Interferon was an approved drug for other cancers and frequently used in my cancer, although without great effect. Theoretical and lab studies showed that the combination might be more effective than the individual drugs. Because it was already obvious that IL-2 was the most promising new treatment in years for my cancer, the Phase I trial I took part in was nothing whatever like a shot in the dark. Phase I trials of combinations are still dose escalation studies, but because the side effects of the individual drugs are known, the investigators have a better idea what doses are likely to be tolerable, what the side effects are likely to be, and what doses may be required for efficacy.Phase I Trials: VariationsPhase I trials often involve more than just the “dose” of the drug – when and how it’s given figure into the trial design as well. If a drug was previously given by 15 minute IV infusion five days a week, a new dose schedule involving continuous infusion with a portable pump will require a new Phase I trial. If this is a promising drug which is not yet approved, such a trial could be a relatively good bet, especially if you don’t qualify for a Phase II trial involving this drug.More biologically targeted drugs may have a different endpoint for their Phase I trials than the Maximum Tolerated Dose. Instead, the trial may strive to achieve the Maximum Biologically Effective Dose. If a drug has a specific molecular target which is unique to cancer cells, enough drug to completely saturate the target should achieve the maximum possible effect against the tumor and this dose may or may not cause significant side effects. Beyond the maximum saturation point, more will not be better, but it may be more toxic! If the effect on the molecular target can be measured during the trial, it may not be necessary to drive the dose to the level that side effects become limiting. Of course in this situation, it is still true that the Maximum Tolerated Dose could turn out to be less than the maximum biologic dose. In addition, when a particular molecular defect is targeted, eligibility criteria may include proof that your tumor has the defect in question, even in Phase I.Randomization in Phase I trials: Randomization is infrequent in Phase I trials. I have seen a few randomized Phase I trials where the objective of the trial was to test the tolerability of different, but similar, schedules of administration, rather than different doses. My impression is that in most cases there is truly little to suggest one arm of this type of randomized Phase I trial is more promising than another, and so this type of randomization in Phase I trials may be of little consequence to you.Phase I/II Trials: Phase I/II trials combine a Phase I and a Phase II trial of the same treatment into a single protocol. First the Phase I part of the trial is done, to determine the MTD. Then, more patients are treated at the MTD in the Phase II part, which follows immediately afterwards. The Phase I and Phase II parts are basically ordinary Phase I or Phase II trials, so you can analyze the trial as either a simple Phase I or Phase II trial, depending whether they’ve reached the Phase II part of the trial or are still in the Phase I part. The only way to find out is to talk to the investigators.Key Eligibility Rules For Phase I TrialsYou Must Have Advanced Cancer for Which There is No Satisfactory Treatment If there is an effective standard treatment for your type of cancer and situation, you’ll be required to have tried it before you are eligible for a Phase I trial, except that if the trial treatment is a variation on the standard treatment (say adding a new drug to the standard), it will almost certainly be required that you have not yet tried the standard treatment. Also if for some reason, the prior required treatment is contraindicated in your case, but the trial treatment is not contraindicated, you may be eligible even without prior treatment.Which treatments are considered to be effective seems to be somewhat at the discretion of the trial designers. Do not take the fact that a prior treatment is required to mean that this treatment is highly effective. By the same token, don’t take the fact that a standard treatment that you know of isn’t required to be a sign that treatment is less effective or less promising than the trial treatment. As an example, in my cancer the best drug treatment, Interleukin-2, (As of February 2002) is difficult to take, and only works for a few patients, but when it does work, as it did for me, it can work wonderfully. A surprising number of patients with my cancer are offered Phase I or early Phase II trials as first line treatment. Since most new treatments in early phase trials prove not to be an advance, if a treatment with even a low rate of durable success exists, such trials aren’t optimal first line treatment. If first line treatment fails, then trials of this nature are a better bet.The Classic Phase I Trial Admits Patients With any Type of Cancer No other phase cancer clinical trial is open to patients regardless of the type of cancer. If you have a rare cancer for which there are no Phase II or III trials, you may still be able to get into a Phase I trial! There are exceptions to this. If a treatment is designed to be effective in specific cancers from the outset, then Phase I trials may still be limited to those types of cancer. Seeing that a Phase I trial is limited to certain cancers is a clue that there is some reason to think those are the cancers where it is most likely to be effective!”Measurable Disease” is Not RequiredTumors whose size can be accurately determined are called “measurable.” In order to accurately determine the effect of the treatment on your cancer, you need to have measurable tumors, but since the primary objective of a Phase I trial is not to determine the effect on your tumors, but rather to set the MTD and define toxcities, measurable disease is not required. Measurable disease normally is required for Phase II trials, so patients with advanced cancer who don’t have measurable disease may still qualify for Phase I trials. See Steve’s Strategic Guide to Phase II Trials for a little more on measurable disease.Phase I Trials: StrategiesIs a Phase I Trial Appropriate for You?Because so many Phase I trials are truly experimental where there are no prior results in patients, and where the side effects and optimum dose are unknown, most patients would be better off choosing a later phase trial. Still, selected Phase I trials do represent an important opportunity for some. A carefully selected Phase I trial saved my life! Circumstances in which a Phase I trial may be particularly appropriate include:You don’t qualify for other trials because:You don’t have measurable disease and therefore can’t get into Phase II trials, and there are also no appropriate Phase III trials.You have a rare cancer for which there aren’t any Phase II or III trials.You don’t qualify for later phase trials for other reasons.The Phase I trial is a variation on treatment already known to be promisingSuch a trial could involve a new dosing schedule of a promising treatment. You should still see if there are Phase II trials of better known dosing schedules.Such a trial could be a combination where a new drug is being added to an already promising treatment. In this type of trial, you want to see that you will be getting a therapeutic dose of the already promising treatment plus the new drug. My Phase I trial was this of this type, and determining that the dose I would get was adequate was absolutely crucial to my decision to participate.Pay Attention to Dose!Ask the right questions about where the trial is nowPhase I trials are the only trials where the dose varies over the course of the trial. Evaluating a Phase I trial requires not only knowing what the treatment is, but what dose levels are planned, and where they’re at now. If you’re considering a Phase I trial, ask the doctor running the trial what dose cohort you would be in if you signed up, and also find out what the dose escalation scheme is. Ask what the side effects have been so far, particularly at the most recent dose level.The risk of too low a dose is greater than the risk of too high a dose! Because Phase I trials are focused on toxicity, the natural inclination is for patients to also focus on the risks of toxicity. It turns out that the conservative design of most Phase I trials means that far more patients get too low a dose than too high a dose. Even if you get a dose which is later determined to be above the MTD, the chances are that the side effects will be not be catastrophic. You may even tolerate the extra high dose without incident. I don’t mean to imply that there is never a significant risk from side effects in Phase I trials! Unexpected serious or even fatal side effects are always a possibility. But keep in mind that to get into a Phase I trial you have to have a cancer which is otherwise considered untreatable: Your risk from the disease is very high! In a Phase I trial, the greatest risk, by far, is the risk that treatment will not help you, not side effects, and if the dose is too low the treatment won’t help!Therefore: Avoid low dose levelsIn general, avoid the first few dose cohorts of a Phase I trial (Although you can’t choose your dose level in a given trial, you can most certainly choose your trial!). Most Phase I trials start with a very low dose and proceed through several dose levels before getting close to the MTD. The early cohorts of Phase I trials carry a major risk of getting too low a dose to do any good, even if the treatment later proves to be effective at the right dose! Dose escalation schemes vary, and some trials where they have a fairly good idea of the correct dose have only a few planned dose cohorts to begin with. So you need to learn about the treatment and about the plan for the trial in order to guess how far along in the dose escalation the trial is. If, by its nature or based on the pre-clinical testing, the treatment is expected to have significant side effects (like most cytotoxic drugs) and yet patients aren’t experiencing any, this could be a clue that suggests the trial is still in the early part of the dose escalation. If there is no reason to believe the treatment has to have side effects, as with vaccine therapy, definitely don’t rely on this.What to Do If No Trial is PromisingI constantly urge deciding on trials based on the prior human data. The problem is that for Phase I trials of brand new drugs there is, almost by definition, virtually no prior clinical data. The Phase I trial is the first test in humans! I also think predicting promise from pre-clinical animal and test-tube data is unreasonably difficult. Phase I trials of combinations may, of course, have a great deal of relevant data on closely related treatments. In the end if Phase I trials the only ones you qualify for, and there isn’t enough evidence to justify calling any promising, then you may want to make your decision on other grounds:Re-evaluate Non-Trial TherapiesTrying a treatment which has definitely helped a few would seem to have better odds than trying something which has yet to help anyone! Results from a small study with a few exceptional successes might not be worth considering in less desperate circumstances, but if there is nothing promising in clinical trials, and you find such a treatment through searching the literature, then you might be able to work with your oncologist to obtain it, particularly if the treatment only uses approved drugs.Choose an Innovative and “Different” TreatmentIf you’ve tried multiple cytotoxic chemotherapy regimens (or any other type of treatment) without results, perhaps an innovative treatment which works on entirely different principles would have a greater chance of helping you. Even if your tumor is entirely resistant to chemotherapy or immunotherapy it might respond to anti-angiogenic therapy or molecularly targeted therapies.Choose the Treatment with the Least Side EffectsIf nothing is promising and you’re going to try something, then you might as well try something which will have the least possible side effects. Of course in Phase I trials, the exact level of side effects is not known, but certain types of therapy can be expected to have heavy side effects, for instance intensive chemotherapy regimens or bone marrow transplants, while others such as many vaccine therapies can be expected to have minor side effects at worst. The doctors running any trial should be able to tell you a great deal about the side effects so far.Choose the Treatment that is Most ConvenientIt’s not worth traveling or switching doctors for treatment unless there is some reason to think your chances will be better that way. All other things being equal, you might as well choose a treatment that’s easy to get close to home.Dose Still CountsWhatever trial you pick, it’s still critically important to make sure you aren’t in the early dose cohorts as I discussed above!Consider No TreatmentThere is no rule that says you have be in treatment until you die or get into remission! At some point it you may decide it’s best to stop treatment and make the most of the time you have left. This is obviously an intensely personal decision. If you do decide to stop treatment be sure to look into Hospice. They are experts in comfort care at the end of life. You don’t have to be bedridden or in severe distress to start to take advantage of their services, so contact them sooner rather than later.
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