title: First-in-human phase I study of Lurbinectedin (PM01183) in patients with advanced solid tumors.
abstract: OBJECTIVE
  Lurbinectedin (PM01183) binds covalently to DNA and has broad activity against tumor cell lines. This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose for PM01183 as a 1-hour intravenous infusion every three weeks (q3wk).
  
  
  METHODS
  Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design.
  
  
  RESULTS
  PM01183 was safely escalated over 200-fold, from 0.02 to 5.0 mg/m(2). Dose doubling was utilized, requiring 15 patients and nine dose levels to identify DLT. The recommended dose was 4.0 mg/m(2), with one of 15 patients having DLT (grade 4 thrombocytopenia). Clearance was independent of body surface area; thus, a flat dose of 7.0 mg was used during expansion. Myelosuppression, mostly grade 4 neutropenia, occurred in 40% of patients but was transient and manageable, and none was febrile. All other toxicity was mild and fatigue, nausea and vomiting were the most common at the recommended dose. Pharmacokinetic parameters showed high interindividual variation, though linearity was observed. At or above the recommended dose, the myelosuppressive effect was significantly associated with the area under the concentration-time curve from time zero to infinity (white blood cells, P = 0.0007; absolute neutrophil count, P = 0.016). A partial response was observed in one patient with pancreatic adenocarcinoma at the recommended dose.
  
  
  CONCLUSIONS
  A flat dose of 7.0 mg is the recommended dose for PM01183 as a 1-hour infusion q3wk. This dose is tolerated and active. Severe neutropenia occurred at this dose, although it was transient and with no clinical consequences in this study.
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona; PharmaMar, S.A., Colmenar Viejo, Madrid, Spain; and Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: María Elena
authors.initials: ME
authors.lastname: Elez
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: David
authors.initials: D
authors.lastname: Geary
authors.forename: Teresa
authors.initials: T
authors.lastname: Macarulla
authors.forename: S Peter
authors.initials: SP
authors.lastname: Kang
authors.forename: Carmen
authors.initials: C
authors.lastname: Kahatt
authors.forename: Arturo Soto-Matos
authors.initials: AS
authors.lastname: Pita
authors.forename: Carlos Fernandez
authors.initials: CF
authors.lastname: Teruel
authors.forename: Mariano
authors.initials: M
authors.lastname: Siguero
authors.forename: Martin
authors.initials: M
authors.lastname: Cullell-Young
authors.forename: Sergio
authors.initials: S
authors.lastname: Szyldergemajn
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D019540:Area Under Curve; D002243:Carbolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
chemical_list: D002243:Carbolines; D006576:Heterocyclic Compounds, 4 or More Rings; C568606:PM 01183