A PHASE 1 STUDY OF EMD 525797 (DI17E6), A HUMANIZED MONOCLONAL ANTIBODY TO HUMAN ΑV INTEGRINS, IN CRPC WITH BONE METASTASES AFTER CHEMOTHERAPY

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Abstract

Background

EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting αv integrins involved in tumor progression.

Methods

The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in metastatic castrate-resistant prostate cancer (mCRPC) patients. 24 patients (43-80 years) were treated with IV infusions of 250, 500, 1000, or 1500 mg EMD 525797 given over 1 h and received 3 doses (weeks 1, 3, and 5) before response assessment at the end of week 6. Patients without progressive disease could receive further doses every 2 weeks. Dose-limiting toxic effects (DLTs) were assessed over the first 6 weeks and safety was monitored until 4 weeks after the last administration of EMD 525797.

Results

Final analysis showed that 13 of 24 patients had a longer exposure time than expected(≥84 days): 7 patients had exposure times ≥126 days, 3 patients ≥280 days and 1 patient received EMD 525797 for 534 days. All patients experienced adverse events (AEs), and in 11 patients AEs were considered related to EMD 525797. 4 patients had generalized pruritus, erythema, or rash and 3 patients experienced fatigue, mucosal inflammation, or peripheral edema, but no patient had administration site reactions. Changes in clinical lab values were consistent with basic disease. No DLTs occurred. EMD 525797 showed a dose-dependent, nonlinear PK profile in line with a target-mediated drug disposition. Two patients of the 500 mg cohort had a marked decrease in prostate specific antigen. One of them also had primary tumor shrinkage and normalization of lymph node size. These patients had long-term anti-integrin treatment (297 and 534 days, respectively). Both patients showed additional pain relief.

Conclusions

EMD 525797 showed clinical activity in mCPRC patients in salvage setting, pain relief, and tumor regression. EMD 525797 is well tolerated without any premedication and did not show clinically relevant dose-related changes in the safety parameters assessed.

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