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/

We performed a phase Ia/Ib trial of chimeric anti-GD2 monoclonal antib ody 14.18 (ch14.18) in combination with recombinant human granulocyte- macrophage colony-stimulating factor (rhGM-CSF) to determine the maxim um 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/m(2)) administered intravenousl y for 4 h on day 1. Twenty-four hours later, subcutaneous injections o f rhGM-CSF were administered daily for a total of 14 days. Significant side effects were related to ch14.18 infusion and consisted of modera te to severe abdominal and/or extremity pain, blood pressure changes, headache, nausea, diarrhea, peripheral nerve dysesthesias, myalgias, a nd weakness. Dose-limiting toxicity was observed at 60 mg/m(2) and con sisted 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 oc curred after rhGM-CSF treatment. Significant enhancement of in vitro a nd in vivo monocyte and neutrophil tumoricidal activity and antibody-d ependent cellular cytotoxicity along with significant elevations in C- reactive protein and neopterin were observed. Despite these immunologi cal and biological changes, no antitumor activity was seen. In short, the combination of ch14.18 and rhGM-CSF resulted in toxicity similar t o that observed with ch14.18 alone without improvement in tumor respon se.