title: A phase I, dose-escalation study of volasertib combined with nintedanib in advanced solid tumors.
abstract: BACKGROUND
  Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study determined the maximum tolerated dose (MTD) and pharmacokinetics of volasertib combined with nintedanib, a potent and orally bioavailable triple angiokinase inhibitor, in patients with advanced solid tumors.
  
  
  METHODS
  This open-label, dose-escalation trial recruited patients with advanced metastatic solid tumors following failure of conventional treatment (NCT01022853; Study 1230.7). Volasertib was administered by intravenous infusion over 2 h, starting at 100 mg in the first dose cohort. Nintedanib was administered orally at a dose of 200 mg twice daily. The first treatment cycle comprised 28 days (days 1-7 and days 9-28: nintedanib; day 8: volasertib). From cycle 2 onwards, volasertib was administered on day 1 of a 21-day cycle and nintedanib was administered days 2-21. The primary objective was the MTD of volasertib in combination with nintedanib.
  
  
  RESULTS
  Thirty patients were treated. The MTD of volasertib plus fixed-dose nintedanib was 300 mg once every 3 weeks, the same as the recommended single-agent dose of volasertib in solid tumors. Two of 12 assessable patients treated with the MTD experienced dose-limiting toxicities [grade 3 increased alanine aminotransferase (ALT); grade 3 ALT increase and grade 3 increased aspartate aminotransferase]. Disease control [stable disease (SD)/partial response (PR)/complete response (CR)] was achieved in 18 patients (60%): 1 CR (breast cancer), 1 PR (nonsmall-cell lung cancer), and 16 patients with SD. Volasertib showed that multiexponential pharmacokinetic behavior and co-administration of nintedanib had no significant effects on its exposure.
  
  
  CONCLUSIONS
  Volasertib could be combined with fixed-dose nintedanib at the recommended single-agent dose. At this dose, the combination had a manageable safety profile without unexpected or overlapping adverse events, and showed antitumor activity.
authors.affiliation: Director of New Drug Development Unit, European Institute of Oncology, Milan filippo.debraud@istitutotumori.mi.it.
authors.forename: F
authors.initials: F
authors.lastname: de Braud
authors.affiliation: Department of Medical Oncology, Polytechnic University of the Marche Region, Ancona.
authors.forename: S
authors.initials: S
authors.lastname: Cascinu
authors.affiliation: Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of New Drugs Development, European Institute of Oncology, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Spitaleri
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Pilz
authors.affiliation: Boehringer Ingelheim Italia S.p.A., Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Clementi
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Sikken
authors.affiliation: Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of New Drugs Development, European Institute of Oncology, Milan, Italy.
authors.forename: T
authors.initials: T
authors.lastname: De Pas
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D011621:Pteridines / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; C541363:BI 6727; D007211:Indoles; D011621:Pteridines; C530716:nintedanib
keywords: Plk1; advanced cancer; angiogenesis; nintedanib; phase I trial; volasertib