Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer

<jats:sec><jats:title>Purpose</jats:title><jats:p> 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). </jats:p></jats:sec><jats:sec><jats:title>Patients and Methods</jats:title><jats:p> 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 (<jats:sup>111</jats:sup>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. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> Nineteen patients were enrolled. <jats:sup>111</jats:sup>In-CS-1008 uptake in tumor was observed in only 12 patients (63%). <jats:sup>111</jats:sup>In-CS-1008 uptake and pharmacokinetics were not affected by dose or repeated drug administration. <jats:sup>111</jats:sup>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 <jats:sup>111</jats:sup>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 <jats:sup>111</jats:sup>In-CS-1008 uptake (P = .5) or tumor response (P = .6). </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> Death-receptor–5 imaging with <jats:sup>111</jats:sup>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. </jats:p></jats:sec>