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A Phase I Clinical Trial of Murine Monoclonal Antibody D612 in Patients with Metastatic Gastrointestinal Cancer¹

Departments of Medicine [M. N. S., M. B. K., R. H. W., S. L., A. F. L.], Pathology [W. E. G.], Biostatistics [T. L], Nuclear Medicine [C. R.], and Radiation Oncology [R. M.], University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, Alabama 35294-3300, and the Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 [J.S.]

² To whom requests for reprints should be addressed, at University of Alabama at Birmingham Comprehensive Cancer Center, L. B. Wallace Tumor Institute-263, Birmingham, AL 35294-3300.

In a phase I study, 21 patients with metastatic adenocarcinoma of the gastrointestinal tract received the murine monoclonal antibody D612. This antibody is directed at a M_r 48,000 antigen restrictively expressed on tumors of the gastrointestinal tract and to a limited degree on normal gastrointestinal mucosa. Patients received total doses of 10-180 mg/m² administered as single or multiple doses of 1-100 mg/m² over an 8-day period. Dose-limiting toxicity was secretory diarrhea. A single dose of 100 mg/m² exceeded guidelines for maximal tolerated dose. Higher total doses were achieved in subsequent patients by using repeated administration of lower doses. Three of five patients receiving 60 mg/m² for 3 doses (180 mg/m² total dose) experienced grade 3 diarrhea and could not complete the prescribed course. The dose of 40 mg/m² administered on days 1, 4, and 8 (total dose, 120 mg/m²) has been selected as the dose for phase II studies.

The pharmacokinetics of D612 is best described by a one-compartment model with a mean t of 48 ± 3 h (SEM). Eighteen of 21 patients developed human anti-mouse antibody (HAMA). Patients who developed high levels of HAMA demonstrated a more rapid clearance of the day 8 dose than those who developed low levels of HAMA. In all patients studied, a component of HAMA was directed at the D612 variable region. With one exception, serum from all patients with detectable antibody to the D612 variable region demonstrated anti-paratope reactivity. Thirty-four % of known metastatic sites demonstrated uptake of radiolabeled D612. There were no objective antitumor responses in this phase I trial. The antitumor effect of D612 in vitro has been shown to be potentiated by interleukin 2 and recombinant human macrophage colony-stimulating factor. A phase II study of D612 administered in combination with cytokines that enhance human effector function is presently ongoing.

¹ This research is supported by Grant NO1 CM97611 of the National Cancer Institute and Grant R-01 CA45232-05.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/22/93. Accepted 7/22/93.

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