title: Phase I trial of consensus interferon in patients with metastatic renal cell carcinoma: toxicity and immunological effects.
abstract: OBJECTIVE
  The purpose of our study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities, and effects on chemokine/cytokine gene expression in peripheral blood mononuclear cells (PBMCs) of consensus IFN (CIFN).
  
  
  METHODS
  Cohorts of three to six patients with metastatic renal cell carcinoma (RCC) were treated with escalating doses of CIFN (dose level I, 9.0 microg/m(2); dose level II, 15.0 microg/m(2); dose level III, 21.0 microg/m(2)) given s.c. three times weekly in 4-week cycles until progression. The cohort treated at the maximum tolerated dose was expanded to further define toxicity. An additional three patients were treated with i.v. CIFN (15.0 microg/m(2)) to evaluate route-related differences in gene expression. Cytokine and chemokine gene expression in PBMCs was assessed by reverse transcription-PCR.
  
  
  RESULTS
  A total of 25 patients (18 men and 7 women) were enrolled between January 28, 1999, and November 1, 2000, at dose levels I (n = 4), II (n = 14), and III (n = 7). Dose-limiting toxicity occurred at dose level III (21 microg/m(2)) and included grade-3 or -4 respiratory distress/failure (n = 3) and hypocalcemia (n = 1) occurring within the first cycle of treatment. Other severe toxicities included grade-3 neutropenia, thrombocytopenia, fatigue, and nausea/vomiting. Studies of cytokine and chemokine gene expression in PBMCs from eight patients revealed induction of IFN-gamma, IP-10, and Mig. I.V. administration was associated with a faster induction, but of shorter duration. There were no responses; however, 24 patients had stable disease of variable duration (4-32 weeks) and received a median of three cycles of treatment (range, 1-8 cycles). Overall median survival was 13.5 months, and was 12.7 months in the previously treated patients.
  
  
  CONCLUSIONS
  CIFN was safely administered s.c. three times weekly at doses up to 15.0 microg/m(2). Although there were no responses, the median survival was longer than expected in a previously treated patient population with metastatic RCC.
authors.affiliation: Experimental Therapeutics Program, Cleveland Clinic Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. hutsont@ccf.org
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Luis
authors.initials: L
authors.lastname: Molto
authors.forename: Tarek
authors.initials: T
authors.lastname: Mekhail
authors.forename: Paul
authors.initials: P
authors.lastname: Elson
authors.forename: James
authors.initials: J
authors.lastname: Finke
authors.forename: Charles
authors.initials: C
authors.lastname: Tannenbaum
authors.forename: Ernest
authors.initials: E
authors.lastname: Borden
authors.forename: Robert
authors.initials: R
authors.lastname: Dreicer
authors.forename: Thomas
authors.initials: T
authors.lastname: Olencki
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Bukowski
mesh_terms: D000328:Adult; D000368:Aged; D015139:Blotting, Southern; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000627:therapeutic use* / Q000633:toxicity*; D016898:Interferon-alpha; D007371:Interferon-gamma / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007370:Interferon Type I; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; C050739:interferon alfacon-1; D012313:RNA; D007371:Interferon-gamma