American Association for Cancer Research

Clinical Trials and Special Patient Populations

Clinical trials: What are they? What are phase I and phase II trials?

Therapeutic clinical trials treat patients. You may hear about phase I clinical trials—these are the first clinical trials that test a therapy in humans. These take place after a new drug is tested in the laboratory, in animals, and it’s been found to be safe. Typically, the drug also shows anti-cancer activity in the laboratory. The side effects are studied in dogs or rats or monkeys, and in the phase I trials, the drug is going to be tested in humans for the first time. The main purpose of the study is to look for side effects in people.

The second purpose of phase I trials is to pick the right dose of the drug for future testing. You start with a very small dose, make sure that there are no serious side effects, and then you increase the dose. You keep increasing the amount of the drug until you find the dose that gives side effects that are unacceptable. Older drugs usually wiped out your white cells at higher doses, and at that point we’d say the dose was too high. So we’d go to the next lower dose. For example, if we give 10 mg and people are fine, and then we give 15 mg and everybody gets their white counts wiped out, we’d say that the 15 mg dose was too high and that 10 mg is the right dose.

Once we find the right dose—and while we are looking for it—we pay attention to any inkling of clinical activity of the drug. Then, for example, if someone with breast cancer has tumor shrinkage on a phase I trial, this may lead us to test that drug further in breast cancer patients in phase II trials.

However, in phase I trials we generally treat people with all types of cancer. The usual requirement for a cancer patient to participate in a phase I trial is that all the standard treatment options have been exhausted. Phase I trials tend to be full of the common cancers, so usually most of the folks in phase I trials have lung, colon, breast and prostate cancer. For example, we don’t see a lot of brain tumors and liver cancers on these studies just because they are not as common.

Phase II studies are aimed at finding out if the drug works. Here all the patients have a particular tumor type. So if in phase I, there is evidence that a drug might be helpful for lung cancer, then in phase II, the drug is tested in lung cancer patients. If it looks like it might be helpful for breast cancer, then in phase II, it is tested in breast cancer patients. Also, in phase II trials, there’s just one dose of the drug, unlike phase I, which has multiple doses. Everybody has the same tumor in phase II and investigators look for evidence that the drug works for that type of cancer.

Now, let’s say that for lung cancer, our best treatment until now will shrink tumors in about three out of 10 people. If I do a phase II trial with a new drug and it shrinks the tumor in five out of 10 study participants, then this means the drug is promising and might be better than our best treatment. Such a drug might be further tested in phase III trials. In a phase III trial, we’re going to compare this new drug directly to the best standard treatment. And, if this new drug is better than our best treatment, then it becomes the new standard. So this is how we get new drug treatments for cancer. Sometimes, the new treatment may not be better than the old one, but it might have fewer side effects, and in that case, too, it can get approved.

So to summarize: Phase I studies enroll patients with all kinds of cancers. Typically, there’s no other effective treatment available to these patients. Phase II studies are for a defined patient population. For instance, in breast cancer, the treatments for women who are newly diagnosed are very good. So, a lot of times you are not going to test a new drug in newly diagnosed women for a phase II trial. Instead, you might test the new drug in what we call third-line therapy—in women who have taken two different chemotherapy regimens, such as Herceptin and Taxol and then Adriamycin. In a phase II study the participants all have to be in the same group—so, in the last example, everybody in the study should be a breast cancer patient who already tried two different chemotherapy treatments. Or, for example, if the drug is intended for pancreatic cancer, where the front-line treatment is not very good, then phase II could test the drug on newly diagnosed pancreatic cancer patients.

Sometimes a drug shows promise during phase I for many different types of tumors, and then there are different phase II studies for each type of tumor. There’s a new drug that was approved last year for lung cancer and mesothelioma called Alimta. We had studied it in phase I and saw activity in a broad range of tumors. So phase II studies were started for a lot of cancers, including breast, lung, mesothelioma, pancreas and colon. There are other times where activity is seen in only one tumor type, so then the drug is tested in only that one cancer.