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

• Published in: Clinical cancer research Vol. 6; no. 12; pp. 4719 - 4724
• Main Authors: SMITH, Andrew M, JUSTIN, Timothy, MICHAELI, Dor, WATSON, Susan A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-12-2000
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies - metabolism; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines; Cholecystokinin - metabolism; Colorectal Neoplasms - drug therapy; Diphtheria Toxoid - adverse effects; Diphtheria Toxoid - immunology; Diphtheria Toxoid - pharmacokinetics; Diphtheria Toxoid - therapeutic use; Dose-Response Relationship, Drug; Female; Gastrins - adverse effects; Gastrins - antagonists & inhibitors; Gastrins - immunology; Gastrins - pharmacokinetics; Gastrins - therapeutic use; Humans; Immunotherapy; Kinetics; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Radioimmunoassay; Time Factors; Treatment Outcome; Adenocarcinoma; Antineoplastic agent; Rectal disease; Toxoid; Multicenter study; Immunotherapy; Phase II trial; Intestinal disease; Advanced stage; Colon; Humoral immunity; Human; Immune response; Antibody; Treatment efficiency; Malignant tumor; Diphtheria; Colonic disease; Infection; Antigen; Treatment; Gastrin; Rectum; Bacteriosis; Phase I trial; Digestive diseases; Conjugated compound; Growth factor
• EISSN: 1557-3265
• ISSN: 1078-0432

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 n m ; interquartile
range, 0.16–0.41 n m ) were detected between 4 and 12 weeks
after primary injection. The antigen binding capacity was high at
2.8 × 10 −9 m (interquartile range,
5.1 × 10 −10 to 7.25 × 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.