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Clinical Trial Phases For Targeted Therapies

Clinical Trial Phases For Targeted Therapies


The field of oncology has undergone major changes since the beginning of the twenty first century. The progress in molecular and cellular biology has led to greater understanding of the cellular pathways, cellular proliferation and tissue invasion that result in the formation of cancer.

The mechanisms of carcinogenesis are also better understood with the fields of genomics and proteomics providing new information that can be used for better prevention, detection and diagnosis of cancer.

New drugs are presently in development that target specific molecules in pathways that are considered critical for tumor pathology and more importantly for the survival of the cancer cell.


Targeted therapy is the collective term used to describe all types of agents that will affect only the malignant cells, sparing the normal cells from the cytotoxic therapy.

This is typically because the target is usually present only on the or in malignant cells.


Although new designs including adaptive design are now being explored many of the same criteria listed in the cytotoxic trial table above are the same as those for targeted therapy trials. Only those aspects that are different are described below.


Phase 0 Clinical Trials: Exploring if and how a new drug works

Even though Phase 0 studies are conducted using humans, this is a newer type of study. Some cancer patients will likely be asked to take part in these kinds of studies, and it is important to understand how Phase 0 studies work.

These are exploratory studies that often use only a few small doses of a new drug in each patient. Phase 0 studies test to find out whether the drug reaches a tumor, how the drug acts in the human body, and how cancer cells respond to the drug.

A big difference between Phase 0 trials and the later phases of clinical trials is that there is no chance of a direct benefit to the patient participating in a Phase 0 trial. Because drug doses are low, there is also less risk to the patients in these studies compared to Phase I trials.

Phase 0 studies help researchers discover early on if drugs do not behave in the ways they are expected. If there are problems with the way the drug is absorbed or otherwise acts in the body, this should become very clear quickly in the course of a Phase 0 trial. This process can help avoid the delay and expense of finding out much later during Phase II or even Phase III clinical trials that the drug doesn't act as it was expected to based on lab studies.

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Phase 0 studies are not yet being used widely, and there are some drugs for which they would not be useful. These studies are very small, usually comprised of fewer than 20 people. They are not a required for testing a new drug, but are part of an effort to speed up and streamline the process of drug testing.


Phase 1 Trials

Safety is still one focus in Phase I trials but determining the best dose of a drug to administer is now more complicated and important.

Most of the available targeted agents to date produce less toxicity in humans than conventional chemotherapy because they do spare normal cells. These agents seem to work better at low doses so simply determining the MTD (maximum tolerated dose) to be used, as the main point of a Phase III study may not be the best approach. Thus for each new agent developed, a new strategy is often devised.

Establishing a biologically effective dose is another strategy besides MTD being explored. Instead of monitoring a clinical endpoint such as response rate, investigators attempt to evaluate changes in molecular markers that occur if the desired pathway is affected by the treatment; this has been previously determined in preclinical research.


Phase II Trials

Cytotoxic chemotherapy drugs are evaluated for activity in Phase II trials, with response rate used as the usual endpoint. Response is generally measured as tumor shrinkage: however, many new-targeted agents do not induce such responses but rather arrest tumor growth. Such treatments are said to be cytostatic rather than cytotoxic.

Adaptive designs are also being explored in this phase. These vary depending on the agent used. For example, a randomized discontinuation design can be utilized. The agent under study is administered to all patients in the trial initially, and an evaluation is performed after a predetermined period of time.

  • Patients who progress while on the drug are removed from the study and receive other treatment.
  • Patients who respond continue therapy
  • Patients who are stay stable are randomized either to continue the new agent or have standard treatment

Traditional randomization methods are better if slow-growing tumors are targeted and early responses are not expected.


Phase III Trials

The classic Phase III study using overall survival as the primary endpoint is still necessary to prove that a new, targeted treatment is more effective than standard therapy. When reliable assays to identify patients who are more likely to respond to targeted cytostatic drugs are not available, one approach is to assign patients randomly to either the new agent or standard treatment.



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