title: Clinical and immunologic effects of subcutaneously administered interleukin-12 and interferon alfa-2b: phase I trial of patients with metastatic renal cell carcinoma or malignant melanoma.
abstract: OBJECTIVE
  Interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-2b) are pleiotropic cytokines with activity in renal cell carcinoma (RCC) and malignant melanoma (MM) as single agents. Preclinical studies suggest concurrent administration may have synergistic antitumor effects. We conducted a phase I trial of concurrent subcutaneous (SC) administration of IL-12 and IFN-alpha-2b in patients with metastatic RCC or MM to determine toxicity, maximum-tolerated dose, preliminary efficacy, and effects on chemokine/cytokine gene expression in peripheral blood mononuclear cells (PBMCs).
  
  
  METHODS
  Cohorts of three to six patients were treated with escalating doses of IL-12 (dose I, 100 ng/kg; dose II, 300 ng/kg; dose III, 500 ng/kg; dose IV, 500 ng/kg SC) given twice weekly and IFN-alpha-2b (dose I, 1.0 MU/m(2); dose II, 1.0 MU/m(2); dose III, 1.0 MU/m(2); dose IV, 3.0 MU/m(2) SC) three times weekly in 4-week cycles. Effects on gene expression were assessed by reverse transcriptase polymerase chain reaction.
  
  
  RESULTS
  Twenty-six patients (19 with RCC, seven with MM) were accrued at dose levels I (n = 3), II (n = 3), III (n = 13), and IV (n = 7). Dose-limiting toxicity included grades 3 and 4 hepatotoxicity and neutropenia/leukopenia. Patients received a median of three cycles of treatment. Two patients with RCC and one patient with MM had partial responses. Median survival was 13.8 months. Reverse transcriptase polymerase chain reaction on PBMCs revealed induction of IP-10, Mig, B7.1 (CD80), interleukin-5, and interferon gamma in selected patients.
  
  
  CONCLUSIONS
  Concurrent SC administration of IL-12 and IFN-alpha-2b is possible at the dose levels utilized. Recommended doses for phase II trials are 500 ng/kg IL-12 and 1.0 MU/m(2) IFN-alpha-2b. Consistent induction of IP-10 and Mig, as well as variable induction of B7.1, interleukin-5, and interferon gamma expression was noted in PBMCs.
authors.affiliation: Experimental Therapeutics Program, Department of Hematology and Medical Oncology, Taussig Cancer Center, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Gheath
authors.initials: G
authors.lastname: Alatrash
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Luis
authors.initials: L
authors.lastname: Molto
authors.forename: Amy
authors.initials: A
authors.lastname: Richmond
authors.forename: Cheryl
authors.initials: C
authors.lastname: Nemec
authors.forename: Tarek
authors.initials: T
authors.lastname: Mekhail
authors.forename: Paul
authors.initials: P
authors.lastname: Elson
authors.forename: Charles
authors.initials: C
authors.lastname: Tannenbaum
authors.forename: Thomas
authors.initials: T
authors.lastname: Olencki
authors.forename: James
authors.initials: J
authors.lastname: Finke
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Bukowski
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression; D006801:Humans; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D018664:Interleukin-12 / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D018664:Interleukin-12