title: Phase I trial of interferon alpha2b and liposome-encapsulated all-trans retinoic acid in the treatment of patients with advanced renal cell carcinoma.
abstract: BACKGROUND
  Studies suggest that retinoic acid (RA) can augment the antitumor effects of interferon-based therapy in patients with advanced renal cell carcinoma (RC); however, this benefit has not been achieved convincingly using oral formulations of 13-cis RA and all-trans RA. Liposome-encapsulated all-trans RA (ATRA-IV) has improved pharmacokinetics with increased and prolonged ATRA serum levels compared with oral retinoids.
  
  
  METHODS
  Cohorts of 3-6 patients with progressive metastatic RC received a dose of 3 MU interferon alpha2b per day subcutaneously, which was escalated weekly to 5 MU and then to 10 MU, plus ATRA-IV beginning at a dose of 90 mg/m(2) intravenously three times per week (Monday, Wednesday, and Friday), with a planned escalation to a maximum of 140 mg/m(2).
  
  
  RESULTS
  Two of the initial five patients experienced Grade 3 leukopenia while receiving 3 MU interferon and 90 mg/m(2) ATRA-IV. Therefore, the trial was amended to begin ATRA-IV at a dose of 15 mg/m(2) three times per week with a planned escalation by 15 mg/m(2) per cohort plus interferon-alpha at a dose of 3 MU subcutaneously 5 days per week (Monday through Friday), which was escalated weekly to 5 MU and then to 10 MU. Twelve patients were treated on the revised schedule. Toxicity was mild and included Grade 2 anemia (n = 7 patients), leukopenia (n = 2 patients), nausea (n = 2 patients), fatigue (n = 2 patients), fever (n = 2 patients), hepatic toxicity (n = 1 patient), edema (n = 1 patient), neurocortical toxicity (n = 1 patient), headache (n = 1 patient), and infection (n = 1 patient). One patient developed hyperthyroidism, and one patient required admission for bacteremia from a line infection. Dose limiting toxicity was Grade 3 hepatic toxicity, which was observed at a dose of 30 mg/m(2) ATRA-IV in 2 of 6 patients. Only 2 of 12 patients agreed to a dose escalation up to 10 MU interferon-alpha. Of 12 patients who were evaluable for response, 2 patients (17%) had a partial response in bone and lung, including 1 partial response of > 91 weeks' duration, at a dose of 15 mg/m(2) ATRA-IV three times per week and 5 MU interferon-alpha. Five additional patients experienced stable disease, two of whom had disease progression in bone only.
  
  
  CONCLUSIONS
  The acceptable toxicity profile and preliminary efficacy results suggest that this regimen warrants further evaluation. ATRA-IV (15 mg/m(2) TIW) and interferon-alpha (3 MU Monday through Friday escalated weekly to 5 MU and to 7 MU) are recommended for further study in patients with advanced RC.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Goldberg
authors.forename: Manuel
authors.initials: M
authors.lastname: Vargas
authors.forename: Alyssa S
authors.initials: AS
authors.lastname: Rosmarin
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Milowsky
authors.forename: Nicholas
authors.initials: N
authors.lastname: Papanicoloau
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
authors.forename: Gary
authors.initials: G
authors.lastname: Shelton
authors.forename: Kevie
authors.initials: K
authors.lastname: Feit
authors.forename: Daniel
authors.initials: D
authors.lastname: Petrylak
authors.forename: David M
authors.initials: DM
authors.lastname: Nanus
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008081:Liposomes; D011994:Recombinant Proteins; D014212:Tretinoin