title: Phase I study of lurbinectedin, a synthetic tetrahydroisoquinoline that inhibits activated transcription, induces DNA single- and double-strand breaks, on a weekly × 2 every-3-week schedule.
abstract: Background Lurbinectedin administered as a 1-h intravenous infusion every 3 weeks induces neutropenia, with the nadir usually occurring during the second week. This phase I study evaluated an alternative lurbinectedin dosing schedule consisting of a 1-h infusion on days 1 and 8 every 3 weeks. Patients and methods Twenty-one patients with advanced cancer received lurbinectedin using a standard cohort dose escalation design. Results Three dose levels of 3, 4, and 5 mg of lurbinectedin were explored. The recommended phase II dose was 5 mg, with 3 of 13 patients having dose-limiting toxicity (DLT), although grade 4 neutropenia occurred in 50% of patients. Other frequent toxicities were mild to moderate nausea and vomiting, fatigue, decreased appetite, stomatitis and asymptomatic creatinine and transaminase increases. No objective responses occurred, but prolonged stable disease was observed in 7 patients, including 3 with soft tissue sarcoma. Conclusion The recommended phase II dose of lurbinectedin is 5 mg, administered as a 1-h infusion on days 1 and 8 every 3 weeks. These data support further testing of this dose and schedule, particularly in soft tissue sarcoma.
authors.affiliation: University of Colorado Cancer Center, Aurora, CO, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: The University of Chicago, Chicago, IL, USA.
authors.forename: Manish R
authors.initials: MR
authors.lastname: Sharma
authors.affiliation: Pharma Mar, S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Szyldergemajn
authors.affiliation: University of Colorado Cancer Center, Aurora, CO, USA.
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.affiliation: The University of Chicago, Chicago, IL, USA.
authors.forename: David
authors.initials: D
authors.lastname: Geary
authors.affiliation: University of Colorado Cancer Center, Aurora, CO, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Diamond
authors.affiliation: Pharma Mar, S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez Teruel
authors.affiliation: Pharma Mar, S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: Arturo
authors.initials: A
authors.lastname: Soto Matos-Pita
authors.affiliation: Pharma Mar, S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: Jorge Luis
authors.initials: JL
authors.lastname: Iglesias
authors.affiliation: Pharma Mar, S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: Martin
authors.initials: M
authors.lastname: Cullell-Young
authors.affiliation: The University of Chicago, Chicago, IL, USA. mratain@medicine.bsd.uchicago.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002243:Carbolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004249:DNA Damage; D004334:Drug Administration Schedule; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D014158:Transcription, Genetic; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; D006576:Heterocyclic Compounds, 4 or More Rings; C568606:PM 01183
keywords: Lurbinectedin; Pharmacokinetics; Phase I study