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.

Trial registration: ClinicalTrials.gov NCT01220999.

Fig 1.

(A) Whole-body biodistribution of indium-111 labeled to CS-1008 (¹¹¹In-CS-1008) in patient 014, showing gradual blood-pool clearance and no specific normal tissue uptake. (B) ¹¹¹In-CS-1008 single-photon emission computed tomography and computed tomography (SPECT/CT) in patient 014 (left, SPECT; middle, CT; right, merged SPECT/CT), showing excellent uptake of ¹¹¹In-CS-1008 in tumor (arrow) in right lung by day 7.

Fig 2.

Quantitative tumor uptake of indium-111 labeled to CS-1008 (¹¹¹In-CS-1008; μg/mL) uptake after (A) week-1 and (B) week-6 infusions. Week-1 infusion showed linear increase in μg/mL ¹¹¹In-CS-1008 uptake in tumors across all dose levels. Week-6 infusion, at 2 mg/kg in all patients, showed consistent CS-1008 uptake compared with week-1 infusion, indicating no death receptor 5 saturation with repeat infusions.

Fig 3.

Whole-body [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) and computed tomography (CT) in patient 014 with a partial response on CT and partial metabolic response on PET. Axial (top row) and coronal (bottom row) images of maximum-intensity projection CT and [¹⁸F]FDG PET images are displayed. Metastatic lesions in the right and left lungs show substantial shrinkage after treatment (reduction in maximum standardized update value, 43% and 38%, respectively), with the shrinkage identified as early as 2 weeks after commencement of treatment with CS-1008.