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

Academic Article

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 Mr 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 tV2 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 NOl CM97611 of the National Cancer Institute and Grant R-01 CA45232-05.2 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 35294-3300.3 The abbreviations used are: TAA, tumor-associated antigen; MTD, maximum tolerated dose; HAMA, human anti-mouse antibody; HPLC, high-pressure liquid chromatography; ADCC, antibody-dependent cell-mediated cellular cytotoxicity; M-CSF, macrophage colony-stimulating factor; anti-Id, antibody to the D612 variable region; PMN, polymorphonuclear leukocyte.4 J. Schlom, personal communications. © 1993, American Association for Cancer Research. All rights reserved.
  • Author List

  • Saleh MN; Khazaeli MB; Grizzle WE; Wheeler RH; Lawson S; Liu T; Russell C; LoBuglio AF
  • Start Page

  • 4555
  • End Page

  • 4562
  • Volume

  • 53
  • Issue

  • 19