This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Welt, S. Articles by Kemeny, N. E. Search for Related Content PubMed PubMed Citation Articles by Welt, S. Articles by Kemeny, N. E.

Preliminary Report of a Phase I Study of Combination Chemotherapy and Humanized A33 Antibody Immunotherapy in Patients with Advanced Colorectal Cancer¹

Department of Medicine [S. W., N. E. K.] and the New York Branch of the Ludwig Institute for Cancer Research at Memorial Sloan-Kettering Cancer Center [G. R., C. W., L. S. C., A. J., E. A. R., L. J. O.], New York, New York 10021

Purpose: In previous studies, humanized A33 (huA33) demonstrated modest antitumor activity in chemotherapy-resistant colorectal cancer patients. In addition, unexpected major tumor responses were observed in patients treated with a specific chemotherapy regimen [carmustine, vincristine, fluorouracil, and streptozocin (BOF-Strep)] administered after huA33 protocols. We designed the present Phase I, open label, cohort, dose-escalation study of huA33 and a fixed dose of BOF-Strep to (a) determine the maximum tolerated dose of huA33 immunotherapy administered with chemotherapy, (b) determine whether chemotherapy modifies huA33 immunogenicity, and (c) develop preliminary information regarding antitumor activity.

Experimental Design: Stage IV fluorouracil/leucovorin and irinotecan-refractory colorectal cancer patients (n = 16) received escalating weekly doses of huA33 (5–40 mg/m²) with BOF-Strep chemotherapy.

Results: Four patients requiring radiotherapy or surgery were removed early. Of 12 evaluable patients, grade 3 and 4 neutropenia (n = 2) and grade 3 thrombocytopenia (n = 1) were observed. Seven of 12 (58.3%) patients developed anti-huA33 activity. Three patients had radiographic partial responses for 7.5, 5.5, and 14 months with greater than 85% decline in serum carcinoembryonic antigen levels. One mixed response (4.5 months with a serum carcinoembryonic antigen decline of 38%) was also observed.

Conclusions: huA33 can be safely combined with BOF-Strep chemotherapy. The present report provides compelling evidence supporting our previous observations of major antitumor activity with the combination of huA33 and BOF-Strep chemotherapy. huA33 is still immunogenic when administered with chemotherapy. Future studies to evaluate the immunogenicity of new huA33 antibodies and identify which drugs in the BOF-Strep regimen are critical for enhanced antitumor efficacy are planned.

This article has been cited by other articles:

				A. M. Scott, F.-T. Lee, R. Jones, W. Hopkins, D. MacGregor, J. S. Cebon, A. Hannah, G. Chong, P. U, A. Papenfuss, et al. A Phase I Trial of Humanized Monoclonal Antibody A33 in Patients with Colorectal Carcinoma: Biodistribution, Pharmacokinetics, and Quantitative Tumor Uptake Clin. Cancer Res., July 1, 2005; 11(13): 4810 - 4817. [Abstract] [Full Text] [PDF]

				G. Chong, F. T. Lee, W. Hopkins, N. Tebbutt, J. S. Cebon, A. J. Mountain, B. Chappell, A. Papenfuss, P. Schleyer, P. U, et al. Phase I Trial of 131I-huA33 in Patients with Advanced Colorectal Carcinoma Clin. Cancer Res., July 1, 2005; 11(13): 4818 - 4826. [Abstract] [Full Text] [PDF]

				A. P Levene, G. Singh, and C. Palmieri Therapeutic monoclonal antibodies in oncology J R Soc Med, April 1, 2005; 98(4): 146 - 152. [Full Text] [PDF]

				R. Stein and D. M. Goldenberg A humanized monoclonal antibody to carcinoembryonic antigen, labetuzumab, inhibits tumor growth and sensitizes human medullary thyroid cancer xenografts to dacarbazine chemotherapy Mol. Cancer Ther., December 1, 2004; 3(12): 1559 - 1564. [Abstract] [Full Text] [PDF]