title: Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data.
  
  
  METHODS
  Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity.
  
  
  RESULTS
  The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested.
  
  
  CONCLUSIONS
  SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.
authors.affiliation: Drug Development Office, Cancer Research UK, Cancer Research UK Drug DNA Interactions Research Group, and University College London Cancer Institute, London, United Kingdom. d.hochhauser@ucl.ac.uk
authors.forename: Daniel
authors.initials: D
authors.lastname: Hochhauser
authors.forename: Timothy
authors.initials: T
authors.lastname: Meyer
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Spanswick
authors.forename: Jenny
authors.initials: J
authors.lastname: Wu
authors.forename: Peter H
authors.initials: PH
authors.lastname: Clingen
authors.forename: Paul
authors.initials: P
authors.lastname: Loadman
authors.forename: Margaret
authors.initials: M
authors.lastname: Cobb
authors.forename: Lindsey
authors.initials: L
authors.lastname: Gumbrell
authors.forename: Richard H
authors.initials: RH
authors.lastname: Begent
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Duncan
authors.initials: D
authors.lastname: Jodrell
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001570:Benzodiazepinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004247:DNA / Q000378:metabolism; D006657:Histones / Q000032:analysis; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: C423343:1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione); D000970:Antineoplastic Agents; D001570:Benzodiazepinones; C468783:H2AX protein, human; D006657:Histones; D011758:Pyrroles; D004247:DNA