title: Phase I evaluation of recombinant tumor necrosis factor given in combination with recombinant interferon-gamma.
abstract: In light of in vitro and preclinical animal model data suggesting potential additive or synergistic antitumor effects from the combined use of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), we conducted a phase I study employing escalating doses of each agent in 36 patients with solid tumors to determine the maximum tolerated dose (MTD). Patients were given an intramuscular (i.m.) injection of IFN-gamma, followed 5 min later by an i.m. injection of TNF-alpha, each agent in different sites, every other day for ten doses over 20 days. Patients received 10, 50, or 100 micrograms/m2 of each agent throughout the treatment course. No dose modifications were made. Patients suffering serious toxicity had therapy stopped and were considered to be off-study. All patients experienced fatigue, and 36% spent over half their time in bed on treatment days. Fever and chills were nearly universal. Mild to moderate elevations in serum transaminase levels were noted in 44% of patients, and 44% developed transient microscopic hematuria. Although 81% of patients had anorexia, only 17% of patients lost more than 3 kg of body wt during the 3 weeks of therapy. Because two of three patients receiving 100 micrograms/m2 of both agents developed serious toxicity (one fever greater than 105 degrees F, one thrombocytopenia 43,000/mm3), the MTD was established to be 100 micrograms/m2 of IFN-gamma plus 50 micrograms/m2 of TNF-alpha. The use of aspirin did not significantly alter the toxic effects of the agents. One patient with melanoma had a mixed response and one patient with mesothelioma transiently cleared his ascites of malignant cells.
authors.affiliation: Biological Response Modifiers Program, National Cancer Institute-FCRDC, MD 21701.
authors.forename: J W
authors.initials: JW
authors.lastname: Smith
authors.forename: W J
authors.initials: WJ
authors.lastname: Urba
authors.forename: J W
authors.initials: JW
authors.lastname: Clark
authors.forename: D L
authors.initials: DL
authors.lastname: Longo
authors.forename: M
authors.initials: M
authors.lastname: Farrell
authors.forename: S P
authors.initials: SP
authors.lastname: Creekmore
authors.forename: K C
authors.initials: KC
authors.lastname: Conlon
authors.forename: H
authors.initials: H
authors.lastname: Jaffe
authors.forename: R G
authors.initials: RG
authors.lastname: Steis
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004341:Drug Evaluation; D004357:Drug Synergism; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage / Q000009:adverse effects; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma