A phase I/II dose escalation study of apolizumab (Hu1D10) using a stepped-up dosing schedule in patients with chronic lymphocytic leukemia and acute leukemia

Abstract

Apolizumab (Hu1D10), a humanized monoclonal anti- Human leukocyte antigen -DR β-chain antibody, mediates apoptosis of chronic lymphocytic leukemia (CLL) cells in vitro. We conducted a phase I/II dose-escalation study of thrice-weekly apolizumab (1.5, 3.0, 5.0 mg/kg/dose) for 4 weeks in relapsed CLL. Two of six patients at 5.0 mg/kg/dose developed treatment-related dose-limiting toxicity (aseptic meningitis, hemolytic uremia). Other toxicities included infusion toxicity, urticaria, and headache. Eleven patients were enrolled in a phase I/II expansion to evaluate the maximum tolerated dose (MTD) of 3.0 mg/kg/dose. In total, 23 patients were enrolled (22 CLL, 1 ALL). Nineteen patients with CLL were treated at or above the MTD. One partial response was observed, and three patients had stable disease exceeding 6 months. Pharmacokinetic analysis demonstrated a dose-dependent C_max increase and serum antibody accumulation after week 1 of therapy. Given the toxicity and lack of efficacy in this and other trials in lymphoma and solid tumors, further development of apolizumab was discontinued.

Keywords:

• Antibody-based immunotherapy
• lymphoid leukemia
• immunotherapeutic approaches

Acknowledgements

This work was supported by the National Cancer Institute (U01 CA 76576 to MRG, R01 CA102504 to J. C. B., and 1 K23 CA102276-01A1 to T. S. L.), the Sidney Kimmel Cancer Research Foundation (J. C. B.), The Leukemia and Lymphoma Society (J. C. B.), and The D. Warren Brown Foundation (J. C. B.).