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Phase I/II Study of G17-DT, an Anti-Gastrin Immunogen, in Advanced Colorectal Cancer¹

Academic Unit of Cancer Studies, University of Nottingham, Nottingham NG7 2UH, United Kingdom [A. M. S., T. J., S. A. W.], and Aphton Corporation, Woodlands, California 95776 [D. M.]

Gastrin is a growth factor for colorectal cancer, and therefore, anti-gastrin hormone therapy has a potential role in treatment of this disease. The gastrin immunogen gastrin-17-diphtheria toxoid (G17-DT; Gastrimmune) produces anti-G17 antibodies that have been shown to be effective in the treatment of colorectal carcinoma in preclinical models. Fifty patients with advanced colorectal cancer were treated with G17-DT in a multicenter, sequential group, open label Phase I/II study. Primary injections with two booster doses were given by i.m. injection. The main aim of the study was to assess the safety and efficacy of the production of anti-gastrin antibodies. Locally developed and standard WHO toxicity measurements with RIA and Scatchard analysis for antibody assessment were used. One center measured tumor response radiologically. Eighty % of patients produced a measurable antibody response. Antibodies of high affinity (median K_d, 0.295 nM; interquartile range, 0.16–0.41 nM) were detected between 4 and 12 weeks after primary injection. The antigen binding capacity was high at 2.8 x 10^-9 M (interquartile range, 5.1 x 10^-10 to 7.25 x 10^-9 M). The treatment was well tolerated with no systemic side effects seen. Myalgia at the injection site was seen in 46% of patients with severe pain caused by the formation of a sterile abscess seen in 14% of patients. The abscesses were all drained under ultrasound guidance, and the patients recovered fully within 6 weeks. No radiological responses were seen, but two patients had stable disease. G17-DT immunization produces anti-G17 antibodies in patients with advanced colorectal cancer. The antibodies were of an affinity high enough to compete with the cholecystokinin B/gastrin receptor for G17 binding with adequate capacity to neutralize postprandial gastrin surges. Additional dose-ranging studies have been performed in patients with gastric cancer using 100- and 200-µg doses of G17-DT formulated without adjuvant and the emulsifier aluminum monostearate. In addition, the effect of immunizing at different time intervals has been determined.

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