Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer Journal Article

Authors: Welt, S.; Scott, A. M.; Divgi, C. R.; Kemeny, N. E.; Finn, R. D.; Daghighian, F.; Germain, J. S.; Richards, E. C.; Larson, S. M.; Old, L. J.
Article Title: Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer
Abstract: Purpose: A phase I/II study was designed to determine the maximum- tolerated dose (MTD) of iodine 125-labeled monoclonal antibody A33 (125I- mAb A33), its limiting organ toxicity, and the uptake and retention of radioactivity in tumor lesions. Patients and Methods: Patients (N = 21) with advanced chemotherapy-resistant colon cancer who had not received prior radiotherapy were treated with a single 125I-mAb A33 dose. 125I doses were escalated from 50 to 350 mCi/m2 in 50-mCi/m2 increments. Radioimmunoscintigrams were performed for up to 6 weeks after 125I-mAb A33 administration. Results: All 20 patients with radiologic evidence of disease showed localization of 125I to sites of disease. Twelve of 14 patients, who underwent imaging studies 4 to 6 weeks after antibody administration, had sufficient isotope retention in tumor lesions to make external imaging possible. No major toxicity was observed, except in one patient with prior exposure to mitomycin who developed transient grade 3 thrombocytopenia. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild or absent, and in no case did stools became guaiac-positive. The MTD was not reached at 125I doses up to 350 mCi/m2. However, cytotoxicity assays demonstrated that patients treated with the highest dose had sufficiently high serum levels of 125I-mAb A33 to lyse colon cancer cells in vitro. Among 21 patients, carcinoembryonic antigen (CEA) levels returned to normal in one patient and decreased by 35% and 23%, respectively, in two patients; one additional patient had a mixed response on computed tomography. Additional, significant responses were observed in those patients treated with chemotherapy (carmustine [BCNU], vincristine, flourouracil, and streptozocin [BOF-Strep]) after completion of the 125I- mAb A33 study. Conclusion: Low-energy emission radioimmunotherapy with doses of up to 350 mCi/m2 of 125I-mAb A33 did not cause bowel or bone marrow toxicity. The modest antitumor activity in these heavily pretreated patients is encouraging because of lack of toxicity at the doses studied. The long radioactivity retention in tumors suggests that isotopes with a long half- life may have a therapeutic advantage, based on calculated dose delivery to tumor versus normal tissue. Due to the low bone marrow dose, further 125I trials with humanized mAb A33 are warranted, and controlled studies must be conducted to evaluate the combination of radioimmunotherapy and chemotherapy.
Keywords: adult; clinical article; human tissue; aged; middle aged; unclassified drug; human cell; clinical trial; histopathology; cisplatin; fluorouracil; advanced cancer; methotrexate; topotecan; phase 2 clinical trial; gastrointestinal symptom; thrombocytopenia; radiotherapy dosage; carcinoembryonic antigen; colonic neoplasms; vincristine; drug resistance, neoplasm; carmustine; monoclonal antibody; iodine 125; iodine radioisotopes; folinic acid; colon cancer; cytotoxicity, immunologic; phase 1 clinical trial; drug half life; mitomycin; radioimmunotherapy; floxuridine; antibody production; intravenous drug administration; streptozocin; radioisotope distribution; maximum permissible dose; levamisole; trimetrexate; radioimmunodetection; radioiodination; humans; human; male; female; priority journal; article; monoclonal antibody a33; recombinant interleukin 1
Journal Title: Journal of Clinical Oncology
Volume: 14
Issue: 6
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 1996-06-01
Start Page: 1787
End Page: 1797
Language: English
PUBMED: 8656247
PROVIDER: scopus
DOI: 10.1200/JCO.1996.14.6.1787
Notes: Article -- Export Date: 22 November 2017 -- Source: Scopus
Citation Impact
MSK Authors
  1. Chaitanya Divgi
    160 Divgi
  2. Ronald D Finn
    278 Finn
  3. Steven M Larson
    878 Larson
  4. Lloyd J Old
    436 Old
  5. Nancy Kemeny
    437 Kemeny
  6. Sydney   Welt
    76 Welt
  7. Andrew M. Scott
    62 Scott