title: Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma.
abstract: OBJECTIVE
  A phase I study of patients with metastatic malignant melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of recombinant human interleukin-21 (rIL-21).
  
  
  METHODS
  Patients who had one or fewer prior systemic treatments for metastatic MM or RCC were treated with rIL-21 administered for two 5-day cycles on days 1 through 5 and 15 through 19 of a treatment course; rIL-21 was administered by rapid intravenous infusion in an outpatient setting. Cohorts of patients received doses ranging from 3 to 100 microg/kg/dose, and an expanded cohort was treated at the MTD. Patients with stable disease (SD) or better could receive additional treatment cycles.
  
  
  RESULTS
  Forty-three patients were treated (24 MM; 19 RCC), including 28 in the expanded cohort. Dose-limiting toxicities consisted primarily of transient grade 3 laboratory abnormalities. The MTD was estimated to be 30 microg/kg. The most common adverse events included flu-like symptoms, pruritus, and rash. Twelve patients received up to five additional two-cycle courses of treatment without cumulative toxicity, except for one patient with reversible grade 4 hepatotoxicity. Serum concentrations of rIL-21 increased in a dose-proportional manner. Dose-dependent increases in soluble CD25 reflected lymphocyte activation. Antitumor activity was observed in both MM (one complete response and 11 SD) and RCC (four partial responses, 13 SD).
  
  
  CONCLUSIONS
  Outpatient therapy with rIL-21 at 30 microg/kg was well tolerated, had dose-dependent pharmacokinetics and pharmacodynamics, and was associated with antitumor activity in patients with MM and RCC.
authors.affiliation: Seattle Cancer Care Alliance, 825 Eastlake Ave East, Mailstop G4-830, Seattle, WA 98109-1023, USA. jat@u.washington.edu
authors.forename: John A
authors.initials: JA
authors.lastname: Thompson
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Curti
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Redman
authors.forename: Shailender
authors.initials: S
authors.lastname: Bhatia
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Agarwala
authors.forename: Eric L
authors.initials: EL
authors.lastname: Sievers
authors.forename: Steven D
authors.initials: SD
authors.lastname: Hughes
authors.forename: Todd A
authors.initials: TA
authors.lastname: DeVries
authors.forename: Diana F
authors.initials: DF
authors.lastname: Hausman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007378:Interleukins / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D011994:Recombinant Proteins; D000098546:Interleukin-21