title: Phase 1 study of N(1),N(11)‑diethylnorspermine (DENSPM) in patients with advanced hepatocellular carcinoma.
abstract: OBJECTIVE
  N(1),N(11)-diethylnorspermine (DENSPM), a synthetic analog of the naturally occurring polyamine spermine, can induce polyamine depletion and inhibit tumor cell growth. The objectives of this phase I study were to assess the safety, maximum-tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of DENSPM in advanced HCC.
  
  
  METHODS
  Patients with measurable advanced HCC, Child-Pugh A or B cirrhosis, CLIP score ≤3, and Karnofsky score ≥60 % were eligible. DENSPM was given as a short intravenous infusion on days 1, 3, 5, 8, 10, and 12 of each 28-day cycle. The starting dose of 30 mg/m(2) was escalated at a fixed increment of 15 mg/m(2) until the MTD was identified. The plasma pharmacokinetics of DENSPM for the first and last doses given in cycle 1 was characterized.
  
  
  RESULTS
  Thirty-eight patients (male 79 %; median age 61 years; Child-Pugh A 84 %; ≥1 prior systemic therapy 45 %) were enrolled and treated. The most common adverse events (AEs) ≥grade 1 were fatigue (53 %), nausea (34 %), diarrhea (32 %), vomiting (32 %), anemia (29 %), and elevated AST (29 %). The most common grade 3-4 AEs were fatigue/asthenia (13 %), elevated AST (13 %), hyperbilirubinemia (11 %), renal failure (8 %), and hyperglycemia (8 %). The MTD was 75 mg/m(2). There were no objective responses, although 7/38 (18 %) patients achieved stable disease for ≥16 weeks. The overall mean (±SD) total body clearance for the initial dose, 66.3 ± 35.9 L/h/m(2) (n = 16), was comparable to the clearance in patients with normal to near normal hepatic function. Drug levels in plasma decayed rapidly immediately after the infusion but remained above 10 nM for several days after dosing at the MTD.
  
  
  CONCLUSIONS
  N(1),N(11)-diethylnorspermine treatment at the MTD of 75 mg/m(2), given intravenously every other weekday for two consecutive weeks of each 28-day cycle, was relatively well tolerated in patients with advanced HCC including those with mild-to-moderate liver dysfunction. This administration schedule provided prolonged systemic exposure to potentially effective concentrations of the drug. Stable disease was seen in 18 % of patients receiving DENSPM treatment. Further evaluation of DENSPM monotherapy for advanced HCC does not appear to be justified because of insufficient evidence of clinical benefit in the patients evaluated in this study.
authors.forename: Lipika
authors.initials: L
authors.lastname: Goyal
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Jordan
authors.initials: J
authors.lastname: Berlin
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Blaszkowsky
authors.forename: Amanda
authors.initials: A
authors.lastname: Carpenter
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Heuman
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Hilderbrand
authors.forename: Keith E
authors.initials: KE
authors.lastname: Stuart
authors.forename: Scott
authors.initials: S
authors.lastname: Cotler
authors.forename: Neil N
authors.initials: NN
authors.lastname: Senzer
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Carl L
authors.initials: CL
authors.lastname: Berg
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D017567:Karnofsky Performance Status; D008111:Liver Function Tests; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012720:Severity of Illness Index; D013096:Spermine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C059685:N(1),N(11)-diethylnorspermine; D013096:Spermine