title: A phase I study of MN-029 (denibulin), a novel vascular-disrupting agent, in patients with advanced solid tumors.
abstract: OBJECTIVE
  MN-029 (denibulin HCl) is a novel vascular-disrupting agent that reversibly inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor vascular endothelial cells. This study determined the safety, pharmacokinetics, and acute anti-vascular effects of MN-029.
  
  
  METHODS
  Patients were treated with escalating doses of MN-029 (4.0-225 mg/m(2)) administered IV at 3-week intervals. This first-in-human study followed an accelerated titration design, with intra-patient dose escalation. Plasma samples were assayed to determine PK parameters. DCE-MRI scans were acquired at baseline and at 6-8 h post-dose.
  
  
  RESULTS
  Thirty-four patients received 151 infusions of MN-029. The most common toxicities of MN-029 included nausea and vomiting (which appeared to be dose related), diarrhea, fatigue, headache, and anorexia. No clinically significant myelotoxicity, stomatitis or alopecia was observed. There was no evidence of cumulative toxicity in patients receiving multiple courses of therapy. The cohort at 180 mg/m(2) was expanded to six patients due to a reversible episode of acute coronary ischemia, without sequelae and with preservation of myocardial function. Two dose-limiting toxicities occurred at 225 mg/m(2), a transient ischemic attack and grade 3 transaminitis, thus ending dose escalation. Pharmacokinetic data indicated dose-related increases in C                            (max) and AUC values, although substantial inter-subject variability was observed. No objective responses were noted; however, five patients had stable disease ≥6 months. A significant linear correlation was found between reduction in K                            (trans) and exposure to MN-029.
  
  
  CONCLUSIONS
  MN-029 was generally well tolerated and showed decrease in tumor vascular parameters. The maximum tolerated dose was 180 mg/m(2).
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA. alejandro.d.ricart@pfizer.com
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Ricart
authors.forename: Edward A
authors.initials: EA
authors.lastname: Ashton
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Cooney
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Brell
authors.forename: Maria A
authors.initials: MA
authors.lastname: Feldman
authors.forename: Kale E
authors.initials: KE
authors.lastname: Ruby
authors.forename: Kazuko
authors.initials: K
authors.lastname: Matsuda
authors.forename: Mark S
authors.initials: MS
authors.lastname: Munsey
authors.forename: Gerardo
authors.initials: G
authors.lastname: Medina
authors.forename: Angela
authors.initials: A
authors.lastname: Zambito
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Scot C
authors.initials: SC
authors.lastname: Remick
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; C506648:denibulin