title: Phase II trial of murine monoclonal antibody D612 combined with recombinant human monocyte colony-stimulating factor (rhM-CSF) in patients with metastatic gastrointestinal cancer.
abstract: In a Phase II study, 14 patients with metastatic gastrointestinal cancer received the mAb D612 (40 mg/m2, days 4, 7, and 11) in combination with recombinant human monocyte colony-stimulating factor [(rhM-CSF) 80 micrograms/kg/days 1-14]. The combined treatment was well tolerated and resulted in characteristic biological activity associated with each of the agents. Thus, 10 of 14 patients experienced D612-associated secretory diarrhea, which responded to the prostaglandin inhibitor Indomethacin in 5 of 7 patients. rhM-CSF therapy was associated with peripheral monocytosis (peak absolute monocyte count, 1444 +/- 394/mm3) and thrombocytopenia (nadir count, 78 +/- 10/mm3). Monocyte surface marker analysis revealed a high baseline expression of CD16+ cells in our patient population with an additional increase with rhM-CSF therapy. We observed a correlation between the degree of thrombocytopenia and the pretreatment CD16+ monocyte count. Of the plasma cytokines assayed, serum Neopterin demonstrated the most consistent increase during rhM-CSF therapy. There was a significant difference in the half-life of the first and last dose of D612 (35.8 +/- 2 versus 27 +/- 2.9 h; P < 0.05). Eleven of fourteen patients developed low-moderate levels of anti-D612 antibody. Despite the observed biological activity of both rhM-CSF and D612 and the previously described in vitro synergy, no clinical antitumor responses were observed in this Phase II study.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham 35294, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Saleh
authors.forename: M B
authors.initials: MB
authors.lastname: Khazaeli
authors.forename: R H
authors.initials: RH
authors.lastname: Wheeler
authors.forename: R P
authors.initials: RP
authors.lastname: Bucy
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.forename: M P
authors.initials: MP
authors.lastname: Everson
authors.forename: D H
authors.initials: DH
authors.lastname: Munn
authors.forename: J
authors.initials: J
authors.lastname: Schlom
authors.forename: A F
authors.initials: AF
authors.lastname: LoBuglio
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001772:Blood Cell Count; D016207:Cytokines / Q000097:blood; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000628:therapy*; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017452:Receptors, IgG / Q000032:analysis; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D016207:Cytokines; D017452:Receptors, IgG; D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor