Evidence Of Efficacy Of Antibody Directed Enzyme Prodrug Therapy (ADEPT) In A Phase I Trial In Patients With Advanced Carcinoma: Abstract LB-200

Main Category: Cancer / Oncology
Article Date: 16 Apr 2008 - 3:00 PDT

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A two-step drug therapy that selectively targets tumors may hold promise for some patients with advanced cancers, according to results of a clinical trial directed by researchers in London.

Scientists at the University College London's Cancer Institute and the Royal Free Hospital used a technique called antibody-directed enzyme prodrug therapy (ADEPT) in 43 patients with previously treated, advanced colorectal, gastro-esophageal, breast, gallbladder, peritoneal, appendix, or pancreatic cancers, or cancers of unknown primary site. The patients received one, two or three ADEPT treatments over a period of two to 10 days, at dosages ranging from 37 mg/m2 to 3,226 mg/m2.

"We found clinically significant responses in 44 percent of patients," said senior author Richard H. Begent, M.D., professor of oncology at the University College London's Cancer Institute. "These results support the case for conducting a randomized phase II clinical trial."

ADEPT is a two-step treatment for cancer that uses an antibody to carry an enzyme directly to the cancer cells. First, an antibody is given with an enzyme attached. Next, a prodrug (inactive anti-cancer drug) is administered. When the prodrug comes in contact with the enzyme, the resulting chemical reaction activates the anti-cancer drug, which is then able to destroy cancer cells while sparing nearby healthy tissue.

In this trial, the researchers gave patients an intravenous dose of MFECP1, a recombinant fusion protein consisting of a fragment of an antibody raised against the substance carcinoembryonic antigen (CEA), which is produced by the cancer, and carboxypeptidase G2 (CPG2), an enzyme that activates a prodrug. Then, researchers gave patients an intravenous bis-iodo phenol mustard prodrug which is activated by the enzyme within the cancer.

Anti-enzyme antibody developed in 40 percent of patients having a single treatment, 75 percent of patients after two treatments and 100 percent of patients after three treatments.

In addition, imaging scans showed that four of nine patients had partial response, meaning their tumors shrank, at a total prodrug dosage of at least 900 mg/m2. This response was confirmed by a 25 percent reduction in blood levels of CA 19-9, a tumor marker, in three patients who had raised levels before treatment. Stable disease, as defined by RECIST criteria, was seen in 69 percent of patients who had a total prodrug dose of at least 900 mg/m2.

The most common side effects were thrombocytopenia (low platelet count) and neutropenia (low white blood cell count). Side effects were deemed tolerable.

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