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 Journal Article

  

Authors:	Fury, M. G.; Lipton, A.; Smith, K. M.; Winston, C. B.; Pfister, D. G.
Article Title:	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
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/m 2 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. © 2007 Springer-Verlag.
Keywords:	adult; clinical article; controlled study; aged; unclassified drug; clinical trial; constipation; drug tolerability; advanced cancer; diarrhea; drug safety; gastrointestinal hemorrhage; hypertension; monotherapy; side effect; solid tumor; cancer patient; flow cytometry; neoplasms; controlled clinical trial; pain; leukopenia; nausea; thrombocytopenia; antineoplastic combined chemotherapy protocols; dehydration; combination chemotherapy; receptor, epidermal growth factor; dose-response relationship, drug; hematuria; monoclonal antibody; chill; drug dose escalation; drug fever; drug hypersensitivity; dyspnea; fever; gamma glutamyl transferase blood level; hyperglycemia; lung embolism; chemotherapy induced emesis; drug induced headache; dysphagia; hypotension; cytokines; antibodies, monoclonal; tumor necrosis factor alpha; neutrophil; interleukin 6; sepsis; alkaline phosphatase blood level; maximum tolerated dose; phase 1 clinical trial; drug half life; recombinant granulocyte colony stimulating factor; drug binding; tachycardia; dysuria; mdx 447; monoclonal antibody mdx 447; antibodies, bispecific; granulocyte colony stimulating factor, recombinant
Journal Title:	Cancer Immunology, Immunotherapy
Volume:	57
Issue:	2
ISSN:	0340-7004
Publisher:	Springer
Date Published:	2008-02-01
Start Page:	155
End Page:	163
Language:	English
DOI:	10.1007/s00262-007-0357-5
PUBMED:	17602224
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-36348965935&partnerID=40&md5=1db08ab4a25b3b1c8ed150348b294019
Notes:	--- - "Cited By (since 1996): 15" - "Export Date: 17 November 2011" - "CODEN: CIIMD" - "Source: Scopus"

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