Marika Ciprotti1, Niall C Tebbutt1, Fook-Thean Lee1, Sze-Ting Lee1, Hui K Gan1, David C McKee1, Graeme J O'Keefe1, Sylvia J Gong1, Geoffrey Chong1, Wendie Hopkins1, Bridget Chappell1, Fiona E Scott1, Martin W Brechbiel1, Archie N Tse1, Mendel Jansen1, Manabu Matsumura1, Masakatsu Kotsuma1, Rira Watanabe1, Ralph Venhaus1, Robert A Beckman1, Jonathan Greenberg1, Andrew M Scott2. 1. Marika Ciprotti, Niall C. Tebbutt, Fook-Thean Lee, Sze-Ting Lee, Hui K. Gan, Wendie Hopkins, Fiona E. Scott, Andrew M. Scott, Ludwig Institute for Cancer Research; David C. McKee, Graeme J. O'Keefe, Sylvia J. Gong, Geoffrey Chong, Bridget Chappell, Andrew M. Scott, Austin Health, Melbourne, Australia; Martin W. Brechbiel, National Cancer Institute, Bethesda, MD; Archie N. Tse, Jonathan Greenberg, Daiichi Sankyo Co., Ltd, Parsippany, NJ; Mendel Jansen, Daiichi Sankyo Development Ltd, Gerrards Cross, Buckinghamshire, United Kingdom; Manabu Matsumura, Masakatsu Kotsuma, Rira Watanabe, Daiichi Sankyo Co., Ltd, Tokyo, Japan; Robert A. Beckman, Georgetown University Medical Center and Ralph Venhaus, Ludwig Institute for Cancer Research, New York, NY. 2. Marika Ciprotti, Niall C. Tebbutt, Fook-Thean Lee, Sze-Ting Lee, Hui K. Gan, Wendie Hopkins, Fiona E. Scott, Andrew M. Scott, Ludwig Institute for Cancer Research; David C. McKee, Graeme J. O'Keefe, Sylvia J. Gong, Geoffrey Chong, Bridget Chappell, Andrew M. Scott, Austin Health, Melbourne, Australia; Martin W. Brechbiel, National Cancer Institute, Bethesda, MD; Archie N. Tse, Jonathan Greenberg, Daiichi Sankyo Co., Ltd, Parsippany, NJ; Mendel Jansen, Daiichi Sankyo Development Ltd, Gerrards Cross, Buckinghamshire, United Kingdom; Manabu Matsumura, Masakatsu Kotsuma, Rira Watanabe, Daiichi Sankyo Co., Ltd, Tokyo, Japan; Robert A. Beckman, Georgetown University Medical Center and Ralph Venhaus, Ludwig Institute for Cancer Research, New York, NY. andrew.scott@onjcri.org.au.
Abstract
PURPOSE: CS-1008 (tigatuzumab) is a humanized, monoclonal immunoglobulin G1 (IgG1) agonistic antibody to human death receptor 5. The purpose of this study was to investigate the impact of CS-1008 dose on the biodistribution, quantitative tumor uptake, and antitumor response in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with mCRC who had received at least one course of chemotherapy were assigned to one of five dosage cohorts and infused with a weekly dose of CS-1008. Day 1 and day 36 doses were trace-labeled with indium-111 ((111)In), followed by whole-body planar and regional single-photon emission computed tomography (SPECT) imaging at several time points over the course of 10 days. RESULTS: Nineteen patients were enrolled. (111)In-CS-1008 uptake in tumor was observed in only 12 patients (63%). (111)In-CS-1008 uptake and pharmacokinetics were not affected by dose or repeated drug administration. (111)In-CS-1008 biodistribution showed gradual blood-pool clearance and no abnormal uptake in normal tissue. No anti-CS-1008 antibody development was detected. One patient achieved partial response (3.7 months duration), eight patients had stable disease, and 10 patients had progressive disease. Clinical benefit rate (stable disease + partial response) in patients with (111)In-CS-1008 uptake in tumor was 58% versus 28% in patients with no uptake. An analysis of individual lesions showed that lesions with antibody uptake were one third as likely to progress as those without antibody uptake (P = .07). Death-receptor-5 expression in archived tumor samples did not correlate with (111)In-CS-1008 uptake (P = .5) or tumor response (P = .6). CONCLUSION: Death-receptor-5 imaging with (111)In-CS-1008 reveals interpatient and intrapatient heterogeneity of uptake in tumor, is not dose dependent, and is predictive of clinical benefit in the treatment of patients who have mCRC.
PURPOSE:CS-1008 (tigatuzumab) is a humanized, monoclonal immunoglobulin G1 (IgG1) agonistic antibody to humandeath receptor 5. The purpose of this study was to investigate the impact of CS-1008 dose on the biodistribution, quantitative tumor uptake, and antitumor response in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with mCRC who had received at least one course of chemotherapy were assigned to one of five dosage cohorts and infused with a weekly dose of CS-1008. Day 1 and day 36 doses were trace-labeled with indium-111 ((111)In), followed by whole-body planar and regional single-photon emission computed tomography (SPECT) imaging at several time points over the course of 10 days. RESULTS: Nineteen patients were enrolled. (111)In-CS-1008 uptake in tumor was observed in only 12 patients (63%). (111)In-CS-1008 uptake and pharmacokinetics were not affected by dose or repeated drug administration. (111)In-CS-1008 biodistribution showed gradual blood-pool clearance and no abnormal uptake in normal tissue. No anti-CS-1008 antibody development was detected. One patient achieved partial response (3.7 months duration), eight patients had stable disease, and 10 patients had progressive disease. Clinical benefit rate (stable disease + partial response) in patients with (111)In-CS-1008 uptake in tumor was 58% versus 28% in patients with no uptake. An analysis of individual lesions showed that lesions with antibody uptake were one third as likely to progress as those without antibody uptake (P = .07). Death-receptor-5 expression in archived tumor samples did not correlate with (111)In-CS-1008 uptake (P = .5) or tumor response (P = .6). CONCLUSION:Death-receptor-5 imaging with (111)In-CS-1008 reveals interpatient and intrapatient heterogeneity of uptake in tumor, is not dose dependent, and is predictive of clinical benefit in the treatment of patients who have mCRC.
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