Phase-I trial of intravenous continuous infusion of tumor necrosis factor in advanced metastatic carcinomas

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Abstract
Fifteen patients with advanced metastatic adenocarcinomas were treated in a phase-I study with continuous intravenous 24h infusion of recombinant tumor necrosis factor α (TNF-α) in order to determine the maximum tolerated dose (MTD) and associated side-effects. Patients received 40–400 μg/m2 TNF-α once (arm A) or twice (arm B) weekly for a scheduled treatment period of 2 months. The observed systemic side-effects resembled those reported for interferons and included fever, chills, fatigue, headaches, myalgias, thrombocytopenia, prostration, and malaise. Dose-limiting toxicities, resulting in a median MTD of 200 μg/m2 for 24h, were fever, chills, fatique, myalgias, and thrombocytopenia. Out of 15 patients, 11 showed tumor progression, and 3 sustained in no change for over 2 months of treatment. A minor response was seen in 1 patient with a colorectal carcinoma and liver metastases. To reduce side-effects, patients were treated either with paracetamol or indomethacin. Higher MTDs were observed in patients treated with indomethacin. No detectable plasma TNF-α levels or TNF antibodies were measured under therapy (plasma TNF-α<20 pg/ml). We conclude that TNF-α appears to have some antineoplastic activity in patients with adenocarcinomas since 4 patients remained in no change or showed a minor response.