title: Clinical, pharmacodynamic, and pharmacokinetic evaluation of BNC105P: a phase I trial of a novel vascular disrupting agent and inhibitor of cancer cell proliferation.
abstract: OBJECTIVE
  To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects.
  
  
  METHODS
  BNC105P was administered as a 10-minute infusion on days 1 and 8 of a 21-day cycle in a first-in-human phase I study. A dynamic accelerated dose titration method was used for dose escalation. Plasma concentrations of BNC105P (phosphate prodrug) and BNC105 (active agent) were determined. PD assessments were carried out using dynamic contrast enhanced (DCE)-MRI and analysis of a blood-borne biomarker.
  
  
  RESULTS
  Twenty-one subjects with advanced solid tumors were enrolled on 6 dose levels (range: 2.1-18.9 mg/m(2)). The recommended dose level was 16 mg/m(2) and was well tolerated. BNC105P (prodrug) rapidly converted to BNC105 with a half-life of 0.13 hours. Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours. Pharmacodymanically active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin (on-target action) being observed in PBMCs. DCE-MRI also indicated blood flow changes in the tumor lesions of a number of subjects.
  
  
  CONCLUSIONS
  BNC105P has a favorable toxicity profile at the recommended dose of 16 mg/m(2) and is associated with PD changes consistent with its known mechanism of action. Phase II studies in renal cancer and mesothelioma have commenced.
authors.affiliation: Peter MacCallum Cancer Centre/University of Melbourne, East Melbourne, Victoria, Australia.
authors.forename: Danny
authors.initials: D
authors.lastname: Rischin
authors.forename: David C
authors.initials: DC
authors.lastname: Bibby
authors.forename: Geoff
authors.initials: G
authors.lastname: Chong
authors.forename: Gabriel
authors.initials: G
authors.lastname: Kremmidiotis
authors.forename: Annabell F
authors.initials: AF
authors.lastname: Leske
authors.forename: Clayton A
authors.initials: CA
authors.lastname: Matthews
authors.forename: Shirley S
authors.initials: SS
authors.lastname: Wong
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rosen
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000840:Anisoles / Q000032:analysis; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001572:Benzofurans / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D002317:Cardiovascular Agents / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010755:Organophosphates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*; D014404:Tubulin / Q000097:blood / Q000378:metabolism
chemical_list: D000840:Anisoles; D000970:Antineoplastic Agents; C552092:BNC 105; C568089:BNC 105P; D001572:Benzofurans; D015415:Biomarkers; D002317:Cardiovascular Agents; D010755:Organophosphates; D011355:Prodrugs; D014404:Tubulin