The most important thing to know about Phase I trials is that they are not intended to demonstrate whether the treatment works. They are primarily intended to see how toxic the treatment is. Investigators use Phase I clinical trials to determine the maximally tolerated dose of a compound, its major side effects, and to test the best means of administering the treatment (intravenously, by pills, etc.). If a patient's cancer goes into remission as the result of a Phase I clinical trial, everyone will be delighted, but that is not the main point of the study.

While all Phase I trials concentrate on toxicity rather than efficacy, there's an important difference between Phase I cancer trials and trials for less serious conditions. For less serious conditions, the participants in the clinical trial are typically healthy volunteers, and it's not until Phase II that the treatment is given to people with the condition the treatment is intended for.

But since most potential cancer treatments by their nature are highly toxic, it would be unethical to test them on healthy subjects. For that reason, investigators typically recruit people with advanced cancer to participate in Phase I cancer trials.

What kind of person would be eligible for a Phase I cancer trial? Most likely it would be a patient who has exhausted all known beneficial therapy, or with a cancer for which there is no known beneficial therapy. But you wouldn't necessarily have to be terminal with a life expectancy of only a certain number of weeks.

Phase I trials typically include a relatively small number of patients, usually no more than ten to thirty. From animal experiments the investigators will have developed an estimate of the proper dose for humans. The patients will generally be divided into several groups. The first group will receive a relatively low dose of the treatment. If they show no unacceptable side effects, the second group will be given a higher dose, and so on. This dose escalation continues until one group shows an unacceptable level of side effects. The dose used in the previous group is then designated the maximally tolerated dose, also called the MTD.

Steve Dunn began investigating cancer treatments and clinical trials when, in August 1989 at the age of 32, he was diagnosed with kidney cancer. Surgery in October of that year revealed that his cancer had metastasized.

I looked very hard for a trial that would combine an adequate dose of interferon and interleukin-2. I knew that interleukin-2 had been shown to be highly promising in many other trials, so this was not like the typical Phase I trial where you're trying some brand new drug. The particular trial I found was Phase I only because they were using a different brand of interleukin than had been tested previously.

I knew that Phase I trials were dose escalation trials, and I asked them what the different doses were. Looking at the doses, I realized from my reading that the first dose cohort would be 50 percent of what they were guessing would be the Phase II dose, the second dose cohort would be at the probable Phase II dose, and the third would be 50 percent higher. I asked which one I would be in, and it turned out fortunately that I would be in the third one. I wanted to get a really, really high dose. If I had been in the first dose cohort, I would have walked, but I probably would have stayed for the second one.

The endpoint of the trial was not efficacy. The end point was setting the dose. But I knew that it was a trial that had some substantial potential for being efficacious. In most Phase I trials the first people in the trial get too low a dose. You don't even know if the stuff works in most cases, and then you get an amount which is almost certainly not enough to make it work even if it does work. If you are hoping for efficacy, you should find out where they are in the dose escalation and make sure you're not first.

Some experts in the ethics of clinical trials are critical of the conduct of some Phase I cancer trials.¹ Their studies have revealed that patients considering Phase I trials are often misinformed, being led to believe that the trial is intended to assess not just toxicity, but also efficacy. It's easy to see how this can happen. The patient is not the only one looking for hope in what may seem to be a hopeless situation. The investigators too have high hopes for the treatment they've designed, even though they're well aware that it's in the most preliminary stage of human testing.

In a survey of 30 cancer patients who had decided to enter a Phase I trial, 85 percent indicated that they entered the trial because of the possibility of therapeutic benefits. However, only 22 percent of the group actually expected to receive that benefit, an indication that in that trial, at least, most patients correctly understood that the probability of receiving some personal benefit would be low.² In another survey of 37 cancer patients who enrolled in a Phase I trial, 70 percent indicated that they had enrolled to get the best medical care, not out of altruism.³

Some people close to the cancer clinical trial scene believe that it's permissible for investigators to communicate--and for patients to expect--therapeutic intent in a Phase I trial, even if there may not be a strong probability that the experimental treatment will be effective. And some Phase I trial designs are being changed so there are more opportunities for the patients to benefit. One example is the increasing use of intra-patient escalation, so that the first patients in the trial don't only get the lowest dose. They would be put on the higher dose if other patients can tolerate that dose. In addition, Phase I trial protocols often specify that a patient who seems to be benefiting from the treatment can continue receiving it even after the trial concludes.

Advantages of Phase I trials

• It's a chance to receive a treatment that may be better than anything else out there years before it hits the market.

• Although its toxicity in humans is unknown, the treatment has already been tested extensively in the laboratory, in the test tube and on animals. The investigators will have a good estimate of the proper human dose, and an idea of its side effects.

• In fact, the substance may have already been tested in humans for other illnesses, so its toxic effects may be relatively well understood.

• Unlike Phase II trials, Phase I trials do not require measurable disease. This term refers to tumors whose size can be easily measured, such as most nodules in the lung. Many cancers, such as kidney or prostate cancer that have metastasized to the bone, are not considered to be measurable, although they may be evaluable.

• Even though Phase I trials are not intended to establish efficacy, if the treatment seems to be working, you most likely will be able to continue treatment even after the end of the trial.

• Phase I trials are never randomized; all participants receive the experimental treatment.

• Even if the treatment does not work for you personally, you may take comfort in knowing that your participation in the trial will help other cancer patients down the road, and it will also help the advancement of medical science.

Disadvantages of Phase I trials

• Phase I trials are meant to test a substance's toxicity and not whether it works on cancer.

• You may be among the first humans to be given this treatment. It may well have serious side effects, possibly leading to serious illness or even permanent damage.

• The treatment may be ineffective against your cancer, or it may be no better than standard treatments.

• You may be given too low a dose for it to be effective.

• Phase I trials tend to be shorter than Phase II and III trials. You may therefore not receive the treatment for a long enough time for it to be fully effective.

• Since Phase I trials are typically conducted at a single location, you may have to travel long distances for treatment.

Notes

1. Benjamin Freedman, "The Ethical Analysis of Clinical Trials: New Lessons For and From Cancer Research," in: Harold Y. Vanderpool (editor), The Ethics of Research Involving Human Subjects: Facing the 21st Century (Frederick, Maryland: University Publishing Group, Inc. 1996): 319-38.

2. C. Daugherty et al., "Perceptions of Cancer Patients and Their Physicians Involved in Phase I trials." Journal of Clinical Oncology 13 (1995): 1062-72.

3. L. H. Yoder et al., "Expectations and Experiences of Patients with Cancer Participating in Phase I Clinical Trials." Oncology Nursing Forum 24 (1997): 891-96.

4. This and similar lists of the advantages and disadvantages of different types of clinical trials are adapted in part from Chapter 19 of Non-Hodgkin's Lymphomas by Lorraine Johnston (Cambridge, Massachusetts: O'Reilly & Associates, 1999).