title: Phase I study combining tumor necrosis factor with interferon-alpha and interleukin-2.
abstract: We evaluated the effects of the addition of escalating doses of tumor necrosis factor (TNF) to two fixed doses and schedules of a combination of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) to determine the maximum tolerated dose of this three-cytokine combination and its feasibility as an outpatient regimen. Eighteen patients with metastatic cancer were enrolled. Each course consisted of 3 consecutive weeks of treatment with IFN-alpha 9 x 10(6) IU/m2/day intramuscularly (i.m.) or subcutaneously (s.c.) days 1, 3, and 5 each week for 3 weeks plus IL-2 continuous infusion 1 x 10(6) IU/m2/day (group A) or 3 x 10(6) IU/m2/day (group B) days 1-5 each week for 3 weeks. TNF was administered only during the first week of each course intravenously (i.v.) for 2 h on days 1-5. The dose of TNF was escalated (40, 80, 120 micrograms/m2) in cohorts of 3 patients. The most common side effects were fever, chills, and fatigue in all patients. Grade 3-4 toxicity included anemia (3 patients), thrombocytopenia (1 patients), arrhythmia (2 patients), pulmonary edema (3 patients),- and weight loss (1 patient). Five patients withdrew from study due to toxicity. The combination of the three cytokines is feasible as an outpatient regimen in one of the following combinations: (a) TNF 80 micrograms/m2/day as 2-h infusion on days 1-5 + IL-2 1 x 10(6) IU/m2/day continuous infusion on days 1-5 for 3 weeks + IFN-alpha 9 x 10(6) IU/m2/day s.c. or i.m. on days 1, 3, and 5 for 3 weeks, or (b) TNF 40 micrograms/m2/day as a 2-h infusion on days 1-5 + IL-2 3 x 10(6) IU/m2/day continuous infusion on days 1-5 for 3 weeks + IFN-alpha 9 x 10(6) IU/m2/day s.c. or i.m. on days 1, 3, and 5 for 3 weeks.
authors.affiliation: Department of Medicine, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Eskander
authors.forename: H A
authors.initials: HA
authors.lastname: Harvey
authors.forename: E
authors.initials: E
authors.lastname: Givant
authors.forename: A
authors.initials: A
authors.lastname: Lipton
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000553:Ambulatory Care; D000740:Anemia / Q000209:etiology; D001145:Arrhythmias, Cardiac / Q000209:etiology; D015331:Cohort Studies; D005221:Fatigue / Q000209:etiology; D005240:Feasibility Studies; D005260:Female; D005334:Fever / Q000209:etiology; D006801:Humans; D007262:Infusions, Intravenous; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000628:therapy*; D011654:Pulmonary Edema / Q000209:etiology; D012074:Remission Induction; D012768:Shivering / Q000276:immunology; D013921:Thrombocytopenia / Q000209:etiology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015431:Weight Loss
chemical_list: D000276:Adjuvants, Immunologic; D016898:Interferon-alpha; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha