title: Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses.
abstract: BACKGROUND
  A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011.
  
  
  METHODS
  Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs).
  
  
  RESULTS
  32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m(2). MTD was 10 mg/m(2); DLTs at 12 (2/4 patients) and 10 mg/m(2) (3/12) included thrombocytopenia and febrile neutropenia; diarrhoea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and Cmax from 1-10 mg/m(2). Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion.
  
  
  CONCLUSIONS
  TP300 had predictable hematologic toxicity, and diarrhoea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage.
  
  
  BACKGROUND
  EU-CTR2006-001345-33.
authors.affiliation: St James Institute of Oncology, University of Leeds & Leeds Teaching Hospitals Trust, Leeds LS9 7TF, United Kingdom.
authors.forename: D Alan
authors.initials: DA
authors.lastname: Anthoney
authors.forename: Jay
authors.initials: J
authors.lastname: Naik
authors.forename: Iain R J
authors.initials: IR
authors.lastname: Macpherson
authors.forename: Donna
authors.initials: D
authors.lastname: Crawford
authors.forename: John M
authors.initials: JM
authors.lastname: Hartley
authors.forename: Janet A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Saito
authors.forename: Masaichi
authors.initials: M
authors.lastname: Abe
authors.forename: Keith
authors.initials: K
authors.lastname: Jones
authors.forename: Masanori
authors.initials: M
authors.lastname: Miwa
authors.forename: Christopher
authors.initials: C
authors.lastname: Twelves
authors.forename: T R J
authors.initials: TR
authors.lastname: Evans
mesh_terms: D000328:Adult; D000368:Aged; D042931:Aldehyde Oxidase / Q000235:genetics; D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004249:DNA Damage; D004151:Dipeptides / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics; D006576:Heterocyclic Compounds, 4 or More Rings / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000139:chemically induced; D059004:Topoisomerase I Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D042931:Aldehyde Oxidase; D019389:Cytochrome P-450 CYP2D6; D004151:Dipeptides; D014453:Glucuronosyltransferase; D006576:Heterocyclic Compounds, 4 or More Rings; D011355:Prodrugs; D059004:Topoisomerase I Inhibitors; D000099148:UGT1A1 Enzyme; C558017:TP 300; C526436:AOX1 protein, human