title: Phase I trial of concurrent twice-weekly recombinant human interleukin-12 plus low-dose IL-2 in patients with melanoma or renal cell carcinoma.
abstract: OBJECTIVE
  To maintain interferon gamma (IFNgamma) induction by recombinant human interleukin-12 (rhIL-12) and enhance its activity against melanoma and renal cell cancer, a regimen of twice-weekly intravenous (IV) rhIL-12 was modified to include concurrent low-dose subcutaneous (SC) IL-2 in a phase I dose escalation study.
  
  
  METHODS
  Patients received 6-week cycles of twice-weekly IV rhIL-12 at doses of 300 to 500 ng/kg. Midway through cycle 1, low-dose SC IL-2 was added. The IL-2 was escalated from 0.5 to 6.0 MU/m2. Grade 3 elevations of hepatic ALT, AST, or alkaline phosphatase were not considered dose-limiting unless values were more than 10 times normal. During cycle 1, patients underwent immune monitoring to assess the effect of IL-2 on lymphocyte activation and cytokine production induced by rhIL-12.
  
  
  RESULTS
  Twenty-eight patients were enrolled onto the study. The maximum-tolerated dose (MTD) was 500 ng/kg rhIL-12 plus 3 MU/m2 IL-2. Toxicities related to the addition of IL-2 at the MTD included fever or chills, anemia, fatigue, nausea or vomiting, and orthostatic hypotension. At the MTD, IL-2 significantly augmented IFNgamma and IFNgamma-inducible protein-10 production by rhIL-12 and led to a three-fold expansion of natural killer cells. There was one major clinical response (partial response) as well as two pathologic responses; all occurred in melanoma patients. Stable disease for three to six cycles was only observed at or above the MTD in melanoma and renal cell cancer patients.
  
  
  CONCLUSIONS
  The addition of concurrent low-dose IL-2 to rhIL-12 is well tolerated, restores and maintains immune activation by rhIL-12, and has clinical activity. This regimen should be further investigated in phase II studies in untreated patients with melanoma or renal cell cancer and in other rhIL-12-responsive malignancies.
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. gollo001@mc.duke.edu
authors.forename: Jared A
authors.initials: JA
authors.lastname: Gollob
authors.forename: Korina G
authors.initials: KG
authors.lastname: Veenstra
authors.forename: Robert A
authors.initials: RA
authors.lastname: Parker
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.forename: Daniel
authors.initials: D
authors.lastname: Clancy
authors.forename: Linda
authors.initials: L
authors.lastname: Tutin
authors.forename: Henry
authors.initials: H
authors.lastname: Koon
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000008:administration & dosage; D007376:Interleukin-2 / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D007376:Interleukin-2; D018664:Interleukin-12