A phase-I trial of the epidermal growth factor receptor directed bispecific antibody MDX-447 without and with recombinant human granulocyte-colony stimulating factor in patients with advanced solid tumors |
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Authors: | Matthew G Fury Allan Lipton Katherine M Smith Corinne B Winston David G Pfister |
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Institution: | (1) Division of Solid Tumor Oncology, Head and Neck Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA;(2) Department of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, USA;(3) Department of Clinical Laboratories, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA;(4) Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA |
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Abstract: | Introduction MDX-447 is a bispecific antibody directed against the epidermal growth factor receptor (EGFR) and the high affinity Fc receptor
(FcγRI). Preclinical data suggest that co-administration of granulocyte-colony stimulating factor (G-CSF) may enhance the
tumor cytotoxicity of bispecific antibodies.
Methods In group 1, patients received MDX-447 intravenously (IV) weekly. Dose levels of MDX-447 evaluated in group 1 were 1, 3.5,
7, 10, 15, 20, 30, and 40 mg/m2. In group 2, patients received MDX-447 IV weekly with G-CSF (3 mcg/kg/day) subcutaneously (days −3 to +2, 5–9, 12–16, etc.).
Dose levels of MDX-447 evaluated in group 2 were 1, 3.5, 7, 10, and 15 mg/m2.
Results Sixty-four patients with advanced solid tumors were treated. Forty-one patients received MDX-447 alone (group 1); 23 patients
received MDX-447 + G-CSF (group 2). Hypotension was the predominant dose-limiting toxicity (DLT) in both treatment groups,
with seven patients experiencing ≥grade 3 events. MDX-447 half-life (T1/2) ranged from 1.9 to 8.4 h, with no obvious differences between the two treatment groups. MDX-447 binding to neutrophils and
peak levels of circulating tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) were higher in group 2. The MTD for MDX-447
alone was 30 mg/m2. When G-CSF was given with MDX-447, treatment was not well tolerated and group 2 was closed early because of safety concerns,
with the last patient being treated at the 7 mg/m2 dose level. There were no objective complete or partial responses in either group.
Conclusion MDX-447 alone was generally well tolerated, but did not achieve objective tumor responses. The MTD for MDX-447 alone was 30 mg/m2 weekly. Co-administration of G-CSF with MDX-447 precluded meaningful dose escalation. |
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