title: Phase I study of subcutaneously administered interleukin-2 in combination with interferon alfa-2a in patients with advanced cancer.
abstract: OBJECTIVE
  Although high-dose interleukin-2 (IL-2) can produce durable remissions in a subset of responding patients with renal cell carcinoma (RCC), this occurs in the setting of significant toxicity. The purpose of this study is to define the maximum-tolerated dosage (MTD) of IL-2 and interferon alfa-2a (IFN alpha-2a) that can be administered chronically on an outpatient basis.
  
  
  METHODS
  Fifty-three patients with advanced cancer of variable histology with good prognostic features were treated in six cohorts. Patients in cohorts one through five received IL-2 (1.5 or 3.0 x 10(6) million units (mU)/m2) Monday through Friday and IFN alpha-2a (1.5 or 3 x 10(6) mU/m2) daily for a 4-week cycle. In cohort six, IFN alpha-2a was given three times a week. Immunologic monitoring, including serum levels of soluble IL-2 receptor (sIL-2R) and neopterin, flow cytometry, and natural killer cell (NK) activity, were measured. Patients were evaluated for toxicity, response, and survival.
  
  
  RESULTS
  Almost all patients developed grade I/II toxicities commonly associated with cytokine therapy. Symptoms were most severe with the first treatment of each week. Dose-limiting toxicities included grade III fatigue, hypotension, and creatinine elevations. The MTD was 1.5 mU/m2 daily x 5 given subcutaneously repeated weekly for IL-2 and 1.5 mU/m2 daily subcutaneously (dose level 3) for IFN. Six of 25 assessable patients with RCC (24%) achieved a partial response (PR), including four of eight patients who were previously untreated. There were no objective responses in patients with other tumors, including 12 melanoma patients.
  
  
  CONCLUSIONS
  IL-2 and IFN alpha-2a can be given with tolerable toxicities on an outpatient basis and shows significant activity in patients with metastatic RCC.
authors.affiliation: Division of Cancer Treatment, National Cancer Institute, Bethesda, MD, USA. bgause@mail.ncifcrf.gov
authors.forename: B L
authors.initials: BL
authors.lastname: Gause
authors.forename: M
authors.initials: M
authors.lastname: Sznol
authors.forename: W C
authors.initials: WC
authors.lastname: Kopp
authors.forename: J E
authors.initials: JE
authors.lastname: Janik
authors.forename: J W
authors.initials: JW
authors.lastname: Smith
authors.forename: R G
authors.initials: RG
authors.lastname: Steis
authors.forename: W J
authors.initials: WJ
authors.lastname: Urba
authors.forename: W
authors.initials: W
authors.lastname: Sharfman
authors.forename: R G
authors.initials: RG
authors.lastname: Fenton
authors.forename: S P
authors.initials: SP
authors.lastname: Creekmore
authors.forename: J
authors.initials: J
authors.lastname: Holmlund
authors.forename: K C
authors.initials: KC
authors.lastname: Conlon
authors.forename: L A
authors.initials: LA
authors.lastname: VanderMolen
authors.forename: D L
authors.initials: DL
authors.lastname: Longo
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001708:Biopterins / Q000031:analogs & derivatives / Q000097:blood; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D019798:Neopterin; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011994:Recombinant Proteins; D012074:Remission Induction
chemical_list: D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D001708:Biopterins; D019798:Neopterin