title: Phase Ia/Ib trial of anti-GD2 chimeric monoclonal antibody 14.18 (ch14.18) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in metastatic melanoma.
abstract: We performed a phase Ia/Ib trial of chimeric anti-GD2 monoclonal antibody 14.18 (ch14.18) in combination with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to determine the maximum tolerated dose as well as immunologic and biologic responses to the regimen. Sixteen patients with metastatic malignant melanoma received escalating doses of ch14.18 (15-60 mg/m2) administered intravenously for 4 h on day 1. Twenty-four hours later, subcutaneous injections of rhGM-CSF were administered daily for a total of 14 days. Significant side effects were related to ch14.18 infusion and consisted of moderate to severe abdominal and/or extremity pain, blood pressure changes, headache, nausea, diarrhea, peripheral nerve dysesthesias, myalgias, and weakness. Dose-limiting toxicity was observed at 60 mg/m2 and consisted of severe hypertension, hypotension, and atrial fibrillation in one patient each, respectively. Significant increases in white blood cell count, granulocyte count, eosinophil count, and monocyte count occurred after rhGM-CSF treatment. Significant enhancement of in vitro and in vivo monocyte and neutrophil tumoricidal activity and antibody-dependent cellular cytotoxicity along with significant elevations in C-reactive protein and neopterin were observed. Despite these immunological and biological changes, no antitumor activity was seen. In short, the combination of ch14.18 and rhGM-CSF resulted in toxicity similar to that observed with ch14.18 alone without improvement in tumor response.
authors.affiliation: Department of Bioimmunotherapy, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Murray
authors.forename: E S
authors.initials: ES
authors.lastname: Kleinerman
authors.forename: S F
authors.initials: SF
authors.lastname: Jia
authors.forename: M G
authors.initials: MG
authors.lastname: Rosenblum
authors.forename: O
authors.initials: O
authors.lastname: Eton
authors.forename: A
authors.initials: A
authors.lastname: Buzaid
authors.forename: S
authors.initials: S
authors.lastname: Legha
authors.forename: M I
authors.initials: MI
authors.lastname: Ross
authors.forename: L
authors.initials: L
authors.lastname: Thompson
authors.forename: K
authors.initials: K
authors.lastname: Mujoo
authors.forename: P T
authors.initials: PT
authors.lastname: Rieger
authors.forename: M
authors.initials: M
authors.lastname: Saleh
authors.forename: M B
authors.initials: MB
authors.lastname: Khazaeli
authors.forename: S
authors.initials: S
authors.lastname: Vadhan-Raj
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005732:Gangliosides / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D016233:Immunotherapy, Active / Q000379:methods; D008297:Male; D008545:Melanoma / Q000556:secondary* / Q000628:therapy*; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D005732:Gangliosides; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C019403:ganglioside, GD2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor