Phase I Clinical Trials – A Changing Paradigm

May 16, 2012 at 10:19 pm 1 comment

Phase I clinical trials for cancer have traditionally focused on testing the safety of new drugs, enrolling only patients in advanced stages of disease who were counseled not to expect any personal benefit. As more targeted or “personalized” therapies emerge from the laboratory, the design of Phase I clinical trials is evolving to allow investigators to begin to look more closely at efficacy (how well a tumor is responding to therapy). In addition, investigators are testing not only new drugs but those that the FDA has approved for different types of cancer, which are now being studied in combination with previously approved breast cancer therapies.

Jennifer Wheler, MD

“The first thing I tell my patients is that Phase I trials come in all shapes and sizes,” says Jennifer Wheler, MD, Assistant Professor in the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine at the University of Texas, MD Anderson Cancer Center, in Houston, Texas. “With targeted therapies the old way of running clinical trials with Phase I, Phase II and Phase III components is becoming outdated,” she adds. According to Wheler, the important work now is to profile a patient’s tumor so that targeted therapies can be tested on individuals and personalized to the aberrations that are apparent in their disease.

“For instance, the PI3K pathway is an important aberration in breast cancer,” says Wheler, “and we’ll probably find that a significant proportion of breast cancer patients have an aberration in this pathway. This essentially means that targeting it with a new drug would be a useful thing.”

Wheler is currently lead investigator for a trial at MD Anderson (similar to Bolero-2, which was a Phase III trial for advanced breast cancer patients) that has enrolled over 100 cancer patients to test Anistrozole (Arimadex®), an anti-hormone therapy agent, in combination with Everolimus (Afinitor®), a therapy targeted to cellular growth. In this particular study, if a patient develops resistance to either of the two drugs, then the strategy is to add a third drug to try and overcome the resistance. This means that treatment in this Phase I trial is truly tailored to both a patient’s tumor biology and her response to therapy.

Pam Munster, MD

“Many patients will never consider a Phase I trial because they believe the drug being tested will be in such an early stage of its development that they will not benefit from taking it,” says Pam Munster, MD, Director, Early Phase Clinical Trials Unit and Leader, Developmental Therapeutics Program, at the University of California San Francisco, Helen Diller Family Comprehensive Cancer Center. “But we really try to make every effort to select the right drugs for patients, so they at least have a chance of a good response.”

Both Munster and Wheler assert that early studies involving new drugs are always carefully designed to monitor safety. The first patients admitted into a Phase I trial receive a very small dose of the drug. Only when investigators are satisfied that the side effects are not harmful, is the dose gradually increased or “escalated.” This is done until they have identified the highest dose that can be tolerated without side effects.

“We look very closely at the preclinical safety studies,” says Munster. “And we will take patients off a study as soon as we find out it is not helpful to her.”

For a patient, a Phase I trial may be the best chance she has to experience a new drug. This is because a patient accepted onto a Phase I trial is sure to receive a new drug. Someone who waits until the drug is tested in a Phase III trial may either not be eligible for the trial because of number of prior treatments or may end up randomized to a control group receiving the standard treatment of care or sometimes a placebo. There are no control groups in Phase I trials; everyone receives the drug.

The patients Munster enrolls in her trials tend to be those at the end stage of their disease who come onto a Phase I trial as a last resort. She explains that these individuals often have severely compromised overall health and are frequently very sick, which means it is hard to truly test the efficacy of the targeted drugs.    She believes that she would see better responses in patients whose disease had not progressed so far already.

“We would like to see patients at least considering a Phase I trial earlier in their treatment history,” says Munster. “In particular, now because there is more potential for her to personally benefit from therapy if appropriately selected.”

Entry filed under: Clinical trials history, Phase I trials. Tags: , , , .

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1 Comment Add your own

  • 1. Connie Maheshwari  |  May 31, 2014 at 5:55 pm

    Suzanne My name is Connie Maheshwari and I too am breast cancer stage 4 with mets to the liver. Is it possible to correspond. my email is


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