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First trial of multi-targeted inhibitor in patients with metastatic colorectal cancer

Although the median survival rate for patients with metastatic colorectal cancer has doubled over the past decade, it remains only about 24 months. Innovative therapeutic approaches are needed to treat this malignancy, which is the second most frequent cause of cancer-related death in the United States. Jeffrey Meyerhardt, MD, MPH (DFCI) is currently leading a clinical trial that combines two targeted agents − the new dual-action inhibitor ZD6474 and cetuximab, a much-studied antibody against epidermal growth factor receptor (EGFR) − with the chemotherapy drug irinotecan to see whether this triple combination may provide added benefits compared with standard second- and third-line treatments for advanced disease.

Objectives and importance of this trial

Although ZD6474 has been tested in patients with lung cancer, this is one of the first trials studying ZD6474 in patients with colorectal cancer. The purpose of the study is to test the safety of combining ZD6474 with cetuximab and irinotecan (often used as second- or third-line therapies, alone or in combination); to define the maximum tolerated dose of ZD6474; and to measure response rate, progression-free survival, and overall survival. While cetuximab and/or irinotecan have prolonged survival in some cases, new strategies are still needed in previously treated patients, says Meyerhardt.

The triple combination theoretically offers many different avenues to tumor cell death. Cetuximab blocks the external portion of EGFR (a transmembrane protein overexpressed in some tumors) so that a ligand cannot activate it, explains Meyerhardt; at the same time, ZD6474 blocks the internal portion of EGFR, thus shutting off the signals promoting cell growth and proliferation. Moreover, ZD6474, one of the new generation of multi-targeted therapies, also inhibits the vascular endothelial growth factor (VEGF) receptor, involved in angiogenesis.

“The utility of combining these two targeted agents is not known,” says Meyerhardt. “We want to see if by adding ZD6474 we can make cetuximab more effective.” Investigators also will explore specific molecular alterations in patient tumors to look for potential biomarkers that predict responsiveness or resistance to the triple agent combination.

At the dose-finding phase of the study, patients are enrolled in cohorts of three. For the first two weeks, patients receive standard doses of cetuximab weekly by infusion and ZD6474 daily as an oral agent (the initial group receives 100 mg and, once this dose is determined to be safe, subsequent groups receive 200 mg or 300 mg). At week three, patients begin receiving irinotecan if there are no dose-limiting toxicities in the cohort. Every week thereafter, patients continue to receive cetuximab weekly, irinotecan every other week, and a dose of ZD6474 daily. “After eight weeks, we check whether the patient’s tumor is stable or shrinking,” says Meyerhardt. “If there’s growth, then this combination is not helping, so we take patients off the trial and discuss alternatives.”

Meyerhardt hopes that not only will the study define the safe dose for this combination, but that these targeted agents will offer some advantages. “Multiple trials have already shown the efficacy of irinotecan and cetuximab,” he says. “So we know what median progression-free survival should look like. When this trial is done, we’ll probably have about 20 patients treated with this combination, so that we can say at least in a small sample size whether this treatment looks better. If so, then we can test it in a larger setting where we can compare the triple combination with just irinotecan and cetuximab. We’re hoping that combining two targeted agents will increase progression-free survival in the metastatic setting.”

Protocol title
ZD6474, Cetuximab, and Irinotecan in Patients With Metastatic Colorectal Cancer

Principal investigator
Jeffrey Meyerhardt, MD, MPH (DFCI)

More information
For eligibility criteria, contact information, and sites, go to NCT00436072 on ClinicalTrials.gov.

—Lonnie Christiansen