PHASE I STUDY OF HIGH DOSE CARBOPLATIN PLUS IL-1 ALPHA

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Thrombocytopenia induced by high-dose chemotherapy remains a significant clinical problem that limits dose intensification of many chemotherapy agents. In our phase I trial of IL-1alpha, we noted increased megakaryocytes in the bone marrow and an increase in the platelet count after IL-1alpha treatment. We designed the present trial to determine if IL-1alpha could ameliorate the thrombocytopenia induced by chemotherapy. We chose carboplatin to combine with IL-1alpha because it has considerable antitumor activity, but is limited by bone-marrow suppression, especially thrombocytopenia. This study has enrolled 52 patients to date. Eleven patients were in a control group and received carboplatin alone (800 mg/m2). Five patients each received IL-1alpha before carboplatin at 0.03, 0.1 and 0.3 mu-g/kg. Five patients received 0.03 mu-g/kg IL-1alpha after carboplatin and 11 patients each received 0.1 IL-1alpha after carboplatin and 10 patients received 0.3 mu-g/kg IL-1alpha after carboplatin. Toxicities observed in this trial were similar to those observed with previous trials of either agent alone. IL-1alpha treatment after carboplatin significantly accelerated platelet recovery and shortened the duration of severe thrombocytopenia at the 0.3 mu-g/kg IL-1alpha dose. Treatment with IL-la before high dose carboplatin had no effect. Five of 15 patients at the two highest IL-1alpha doses given after carboplatin had minimal thrombocytopenia. IL-1alpha treatment produced dose related increases in the serum level of IL-6 and G-CSF. This trial provides conclusive evidence that IL-1alpha treatment can significantly ameliorate chemotherapy induced thrombocytopenia.