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

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.

• Authors: Marika Ciprotti, Niall C Tebbutt, Fook-Thean Lee, Sze-Ting Lee, Hui K Gan, David C McKee, Graeme J O'Keefe, Sylvia J Gong, Geoffrey Chong, Wendie Hopkins, Bridget Chappell, Fiona E Scott, Martin W Brechbiel, Archie N Tse, Mendel Jansen, Manabu Matsumura, Masakatsu Kotsuma, Rira Watanabe, Ralph Venhaus, Robert A Beckman, Jonathan Greenberg, Andrew M Scott
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 33 Issue 24 Pg. 2609-16 (Aug 20 2015) ISSN: 1527-7755 [Electronic] United States
• PMID: 26124477 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by American Society of Clinical Oncology.

Chemical References

• Antibodies, Monoclonal, Humanized
• Indium Radioisotopes
• Radiopharmaceuticals
• tigatuzumab

Topics

• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (administration & dosage, pharmacokinetics)
• Cohort Studies
• Colorectal Neoplasms (diagnostic imaging, drug therapy, metabolism, pathology)
• Dose-Response Relationship, Drug
• Female
• Humans
• Indium Radioisotopes
• Male
• Middle Aged
• Neoplasm Metastasis
• Radionuclide Imaging
• Radiopharmaceuticals (administration & dosage, pharmacokinetics)
• Tissue Distribution