PMID- 24121453
OWN - NLM
STAT- MEDLINE
DCOM- 20140130
LR  - 20140104
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 72
IP  - 6
DP  - 2013 Dec
TI  - Phase 1 study of N(1),N(11)‑diethylnorspermine (DENSPM) in patients with advanced 
      hepatocellular carcinoma.
PG  - 1305-14
AB  - PURPOSE: 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.
FAU - Goyal, Lipika
AU  - Goyal L
FAU - Supko, Jeffrey G
AU  - Supko JG
FAU - Berlin, Jordan
AU  - Berlin J
FAU - Blaszkowsky, Lawrence S
AU  - Blaszkowsky LS
FAU - Carpenter, Amanda
AU  - Carpenter A
FAU - Heuman, Douglas M
AU  - Heuman DM
FAU - Hilderbrand, Sarah L
AU  - Hilderbrand SL
FAU - Stuart, Keith E
AU  - Stuart KE
FAU - Cotler, Scott
AU  - Cotler S
FAU - Senzer, Neil N
AU  - Senzer NN
FAU - Chan, Emily
AU  - Chan E
FAU - Berg, Carl L
AU  - Berg CL
FAU - Clark, Jeffrey W
AU  - Clark JW
FAU - Hezel, Aram F
AU  - Hezel AF
FAU - Ryan, David P
AU  - Ryan DP
FAU - Zhu, Andrew X
AU  - Zhu AX
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Antineoplastic Agents)
RN  - 121749-39-1 (N(1),N(11)-diethylnorspermine)
RN  - 2FZ7Y3VOQX (Spermine)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/adverse effects/pharmacokinetics/*therapeutic use
MH  - Carcinoma, Hepatocellular/*drug therapy/pathology
MH  - Female
MH  - Humans
MH  - Infusions, Intravenous
MH  - Karnofsky Performance Status
MH  - Liver Function Tests
MH  - Liver Neoplasms/*drug therapy/pathology
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Severity of Illness Index
MH  - Spermine/adverse effects/*analogs & derivatives/pharmacokinetics/therapeutic use
MH  - Treatment Outcome
EDAT- 2013/10/15 06:00
MHDA- 2014/01/31 06:00
CRDT- 2013/10/15 06:00
PHST- 2013/07/19 00:00 [received]
PHST- 2013/09/06 00:00 [accepted]
PHST- 2013/10/15 06:00 [entrez]
PHST- 2013/10/15 06:00 [pubmed]
PHST- 2014/01/31 06:00 [medline]
AID - 10.1007/s00280-013-2293-8 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2013 Dec;72(6):1305-14. doi: 
      10.1007/s00280-013-2293-8.