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Keeping Pace: How New Data Can Affect Ongoing Clinical Trials

March 16, 2016, by Jo Anne Zujewski, M.D.

Credit: iStock

Phase III cancer clinical trials almost always compare a new treatment with the existing standard of care. With science moving so rapidly, research results sometimes outrace a trial’s design and the trial has to be recalibrated to include newer treatments.

One current example of this need for trial redesign is a recently opened NCI-sponsored clinical trial led by the ECOG-ACRIN Cancer Research Group, called EA1131, for women with triple-negative breast cancer, a subtype of breast cancer that is notoriously difficult to treat. Women in the trial must have had chemotherapy before surgery—known as neoadjuvant chemotherapy—but still have some evidence of cancer in their breast or lymph nodes at the time of surgery (residual disease). Under the trial’s initial design, after surgery, patients were to be randomly assigned to receive either adjuvant therapy with a platinum chemotherapy drug or no additional therapy, which was the standard of care when the trial opened in May 2015.

Shortly after the trial began enrolling patients, surprising results from a joint Japanese and Korean clinical trial, called CREATE-X (Capecitabine for Residual Cancer as Adjuvant Therapy), were announced. Participants in this trial—which included women with hormone receptor-positive or triple-negative breast cancer who had residual disease after neoadjuvant therapy—were randomly assigned to adjuvant therapy with the chemotherapy drug capecitabine or to no additional therapy.

The results of CREATE-X, which were presented at the San Antonio Breast Cancer Symposium in December 2015, showed that women treated with capecitabine lived longer without their cancer recurring than those who had no additional therapy. The CREATE-X findings presented a potential option for treatment of women who have persistent breast cancer at the time of surgery after receiving modern combination chemotherapy.

The results of CREATE-X have not yet been published in a peer-reviewed journal. But, given the impressive initial results with capecitabine in this patient population, NCI and the trial leaders from ECOG-ACRIN decided that the best course of action was to temporarily halt the EA1131 trial to allow for a careful review of the available data from CREATE-X. One confounding factor is that people of Japanese descent metabolize capecitabine differently from Caucasians and, therefore, may tolerate higher doses of this drug than the dose used in the United States, and we are taking this factor into account when considering dosing levels in the U.S.

Although our work is not yet complete, we have already decided that the trial will no longer test whether adjuvant therapy with a platinum chemotherapy agent is superior to no additional therapy. Instead, it will now compare two forms of adjuvant therapy: a platinum chemotherapy drug versus capecitabine.

Once the trial reopens this Spring, the patients who were originally enrolled in the trial will be allowed to stay in the trial, but will need to discuss this new information with their physicians.

Jo Anne Zujewski, M.D.
Head, Breast Cancer Therapeutics
NCI Cancer Therapy Evaluation Program

Capecitabine is not currently approved by the Food and Drug Administration for women with residual breast cancer after presurgical chemotherapy. Women currently undergoing treatment (outside of this clinical trial) should be advised that, although the drug can be used off-label, insurers may not cover its use in this setting.

In addition to their impact on EA1131, the CREATE-X results may influence other trials that are still being developed. For example, NCI is developing a trial of the checkpoint inhibitor pembrolizumab (Keytruda®) in women with triple-negative breast cancer. Under the initial trial concept, patients who had previously received adjuvant capecitabine would not have been eligible for the study. But now we are considering allowing such patients to enroll, expanding eligibility for this trial of an exciting immunotherapy drug.

The review of trial results from outside the United States is just one example of a process that has been in place for a long time in NCI’s Cancer Therapy Evaluation Program. We’re set up for a rapid response to new information that may affect trials in our portfolio, and we can modify trial protocols if necessary.

Temporarily closing a trial while it is being amended to incorporate new information is uncommon, and is done only if the data warrant, as in this case. As always, the focus of our efforts is to efficiently bring safe and effective new therapies to patients.

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