A phase I clinical trial of murine monoclonal antibody D612 in patients with metastatic gastrointestinal cancer.

Authors

Mansoor Saleh, Aga Khan UniversityFollow
M B. Khazaeli, University of Alabama at Birmingham, USA
William Grizzle, University of Alabama at Birmingham, USA
Richard Wheeler, University of Alabama at Birmingham,USA
Sharon Lawson, University of Alabama at Birmingham, USA
Tiepe Liu, University of Alabama at Birmingham, USA
Charles Russell, University of Alabama at Birmingham, USA
Ruby Meredith, University of Alabama at Birmingham, USA
Jeffrey Schlom, University of Alabama at Birmingham, USA
Albert Lobuglio, University of Alabama at Birmingham,USA

Document Type

Article

Department

Haematology and Oncology, East Africa

Abstract

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_½ 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.

Comments

This work was published before the author joined Aga Khan University.

Publication (Name of Journal)

Cancer research

Recommended Citation

Saleh, M., Khazaeli, M. B., Grizzle, W., Wheeler, R., Lawson, S., Liu, T., Russell, C., Meredith, R., Schlom, J., Lobuglio, A. (1993). A phase I clinical trial of murine monoclonal antibody D612 in patients with metastatic gastrointestinal cancer.. Cancer research, 53(19), 4555-4562.
Available at: https://ecommons.aku.edu/eastafrica_fhs_mc_haematol_oncol/132