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Clinical Trial Phases for Cytotoxic Therapies

Clinical Trial Phases for Cytotoxic Therapies


In general clinical trials are grouped into four different clinical trial phases (Phase 1 through 4). They are listed at the end of this section in a table to help you compare them.

These phases have been in use for many years and were designed to evaluate new cytotoxic chemotherapy agents. These drugs affect all fast growing cells, not differentiating among them to act specifically on a single cell type and they are usually associated with significant side effects. With the advent of targeted therapies, new designs are being examined and are discussed later in this section.


Phase 1 Clinical Trials

Once a drug shows promise in translational studies using mice or other lab animals, it must be studied in humans to confirm that it is an effective and safe treatment.

Goal of phase 1: What dose is safe?

In the most common trial design, the very first three patients in the trial receive a starting dose that is less than the dose that begins to kill mice in the preclinical lab experiments. This starting dose is low to insure that study patients will be safe. If these patients do not experience toxicities then the next three patients will receive a higher dose of the drug.

The dose given continues to be increased by smaller percentages using groups of three people until one person experiences a toxicity. This is termed a dose-limiting toxicity (DLT), as this is the highest amount of the drug that patients can tolerate before experiencing side effects.

When one patient develops a DLT, three additional patients are treated with the drug at the same dose. If no other DLT is observed, dose escalation continues. If a second DLT develops in more than 33% of patients (2 out of 6) at a given dose level, dose escalation stops. Usually, the preceding dose level, a dose at which fewer than 33% of patients experienced a DLT, is recommended for further study in a Phase II evaluation.

How many people are enrolled?
15-30 in one or two centers

Risk vs. benefit?
For patients considering a clinical trial, a Phase 1 trial involves the most risk and the least likelihood of benefit. This is because these trials determine the initial safety data and the correct dose is determined. Most patients will not receive a dose high enough to be of benefit.

How long will the study take?
About two years

Summary: Phase I studies provide valuable information about the relationship between dose and toxicity but rarely about dose and anticancer effect (whether the dose kills cancer cells better than the standard treatment drug).

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Phase II Clinical Trials

If a new treatment is found to be reasonably safe in Phase I clinical trials, the treatment can then be tested in a Phase II trial to see if it works the way researchers expect it will.

Goal of Phase II studies: Effectiveness- does it work?

Identify the most promising treatments for further testing and to screen out inactive drugs, all studies include either precisely defined measures of tumor response rate or in the case of adjuvant studies, progression free survival time. These trials also provide additional information about drug safety and some offer preliminary data on the effect of treatment on survival of patients.

Stop trial rules are set so that trials are either discontinued because the drug's activity is lower than what has been set as the minimal acceptable response rate, or because the therapy being tested is definitely more effective than established treatments. This is done so that patients' time is not wasted taking a marginally effective drug, or a new, very effective drug can be used for treatment.

How many people are enrolled?
Less than 100 people in a few centers

Risk vs. benefit?
This phase still carries quite a large risk for patients in the trial with little chance of benefit.

How long will the study take?
About two years to accrue enough patients

Summary: It is important to realize that Phase II trials rarely have an appropriate control group of patients and do not provide definitive survival results. Sometimes, randomized Phase II trials are conducted to determine which of several treatments studied performs best according to prespecified criteria. These trials do not have the statistical power from high numbers of people in order to detect small variations in response, but can be used to help in selecting the most promising regimen for Phase III studies.




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