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EA2222 – A Randomized Phase III Study of Systemic Therapy With or Without Hepatic Arterial Infusion for Unresectable Colorectal Liver Metastases: The PUMP Trial
The study chair for this trial is Michael E. Lidsky, MD (Duke University Medical Center). The study co-chairs are Michael I. D’Angelica, MD (Memorial Sloan Kettering Cancer Center), Shishir K. Maithel, MD (Emory University/Winship Cancer Institute), Andrea Cercek, MD (Memorial Sloan Kettering Cancer Center), and Peter J. O’Dwyer, MD (University of Pennsylvania/Abramson Cancer Center).
Approximately 80% of patients with colorectal cancer that has spread to the liver will have lesions that are not able to be removed by surgery due to their location or size. Instead, patients with unresectable colorectal liver metastases (CRLM) receive systemic chemotherapy. Often, it may be given in combination with liver-directed therapies (e.g., trans-arterial embolization, ablation, or radiation). For only a few, first-line treatment may facilitate resection; the majority of patients do not have the benefit of surgery.
Many standard-of-care second-line or maintenance chemotherapy regimens are available, but none improve overall survival. This patient population needs new treatment approaches that lead to better outcomes.
One technique that has shown impressive improvements in overall survival for patients with CRLM is a hepatic arterial infusion (HAI) of floxuridine chemotherapy along with standard systemic chemotherapy. Second-line treatment with this regimen is the focus of the EA2222/PUMP clinical trial, which is now open to enrollment.
HAI chemotherapy entails the surgical implantation of a subcutaneous pump with a catheter that is inserted into the abdominal wall. This facilitates the delivery of high-dose chemotherapy directly into the hepatic artery, which is known to feed metastatic tumors in the liver. HAI chemotherapy is typically given concurrently with systemic therapy.
Prospective trials for unresectable CRLM have previously demonstrated a survival advantage for patients treated with HAI chemotherapy. These studies led to the approval by the U.S. Food and Drug Administration (FDA) in 2021 for Intera Oncology to manufacture the HAI pump for treating CRLM. However, it is only used in a few oncology centers because it requires specialized surgical and medical oncology training. Most of the time, it is not used until standard chemotherapy stops working.
In 2020, specialists from 59 cancer centers around the world that offer the procedure began collaborating through the HAI Consortium Research Network to perform studies. The network’s goals are to further improve HAI outcomes for patients, help launch new HAI centers, and make the procedure more widely available to patients. Clinical trial EA2222/PUMP was designed by its members, who determined that availability has grown to the point that it is feasible to conduct this multi-center trial, which aims to enroll 408 patients.
EA2222/PUMP study chair Dr. Lidsky and colleagues at Duke University, Memorial Sloan Kettering, and the University of Pennsylvania (see above) seek to determine if patients with persistently unresectable CRLM after first-line chemotherapy treatment have improved overall survival with HAI/floxuridine and systemic chemotherapy. All patients in the study will receive standard-of-care chemotherapy, with half randomized to also receive HAI/floxuridine. There are several secondary objectives to answer scientific and clinical questions deemed important by consortium members.
Floxuridine is in a class of medications known as antimetabolites, which slow or stop the growth of cancer cells, and is the cornerstone of HAI pump chemotherapy. Floxuridine has a short half-life and near-complete hepatic clearance. Drug concentrations in the liver reach up to 400 times that which could be achieved with intravenous delivery but without significant systemic exposure.
To be eligible for this study, patients must have unresectable liver-confined metastatic colorectal cancer. They must not have radiographically or clinically evident extrahepatic disease. Patients must also have received 3-6 months of first-line chemotherapy and have stable or responding disease.
Learn more about EA2222/PUMP at ecog-acrin.org.