title: First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours.
abstract: BACKGROUND
  PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly.
  
  
  METHODS
  Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data.
  
  
  RESULTS
  A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23-3.6 mg m(-2)) and 20 patients on the 3-h schedule (1.8-3.5 mg m(-2)). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m(-2). With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m(-2). Common PM00104-related adverse events at the RP2D comprised grade 1-2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ≥6 months.
  
  
  CONCLUSIONS
  PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.
authors.affiliation: Drug Development Unit, Royal Marsden NHS Foundation Trust, Sutton, UK.
authors.forename: T A
authors.initials: TA
authors.lastname: Yap
authors.forename: H
authors.initials: H
authors.lastname: Cortes-Funes
authors.forename: H
authors.initials: H
authors.lastname: Shaw
authors.forename: R
authors.initials: R
authors.lastname: Rodriguez
authors.forename: D
authors.initials: D
authors.lastname: Olmos
authors.forename: R
authors.initials: R
authors.lastname: Lal
authors.forename: P C
authors.initials: PC
authors.lastname: Fong
authors.forename: D S
authors.initials: DS
authors.lastname: Tan
authors.forename: D
authors.initials: D
authors.lastname: Harris
authors.forename: J
authors.initials: J
authors.lastname: Capdevila
authors.forename: C
authors.initials: C
authors.lastname: Coronado
authors.forename: V
authors.initials: V
authors.lastname: Alfaro
authors.forename: A
authors.initials: A
authors.lastname: Soto-Matos
authors.forename: C
authors.initials: C
authors.lastname: Fernández-Teruel
authors.forename: M
authors.initials: M
authors.lastname: Siguero
authors.forename: J M
authors.initials: JM
authors.lastname: Tabernero
authors.forename: L
authors.initials: L
authors.lastname: Paz-Ares
authors.forename: J S
authors.initials: JS
authors.lastname: de Bono
authors.forename: J A
authors.initials: JA
authors.lastname: López-Martin
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000145:classification / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C500383:PM 00104; D044005:Tetrahydroisoquinolines