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/m(2)) 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.
PURPOSE: In previous studies, humanized A33 (huA33) demonstrated modest antitumor activity in chemotherapy-resistant colorectal cancerpatients. 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 cancerpatients (n = 16) received escalating weekly doses of huA33 (5-40 mg/m(2)) 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.
Authors: Jorge A Carrasquillo; Neeta Pandit-Taskar; Joseph A O'Donoghue; John L Humm; Pat Zanzonico; Peter M Smith-Jones; Chaitanya R Divgi; Daniel A Pryma; Shutian Ruan; Nancy E Kemeny; Yuman Fong; Douglas Wong; Jaspreet S Jaggi; David A Scheinberg; Mithat Gonen; Katherine S Panageas; Gerd Ritter; Achim A Jungbluth; Lloyd J Old; Steven M Larson Journal: J Nucl Med Date: 2011-07-15 Impact factor: 10.057
Authors: Lawrence T Dauer; Daniel C Boylan; Matthew J Williamson; Jean St Germain; Steven M Larson Journal: Health Phys Date: 2009-05 Impact factor: 1.316
Authors: Johanna C Bendell; Heinz-Josef Lenz; Theresa Ryan; Bassel F El-Rayes; John L Marshall; Manuel R Modiano; Lowell L Hart; Clint D Kingsley; Thomas J George; Daisuke Nakashima; Jordan D Berlin Journal: Invest New Drugs Date: 2014-04-03 Impact factor: 3.850