title: A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors.
abstract: OBJECTIVE
  This study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the i.v. pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors.
  
  
  METHODS
  In part 1, patients received escalating doses of danusertib (24-hour infusion every 14 days) without filgrastim (granulocyte colony-stimulating factor, G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was done in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3).
  
  
  RESULTS
  Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose-limiting toxicity in part 1 without G-CSF. Most other adverse events were grade 1 to 2, occurring at doses >or=360 mg/m(2) with similar incidence in parts 1 and 2. The maximum tolerated dose without G-CSF is 500 mg/m(2). The recommended phase 2 dose in part 2 with G-CSF is 750 mg/m(2). Danusertib showed dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18 to 26 hours. pH3 modulation in skin biopsies was observed at >or=500 mg/m(2). One patient with refractory small cell lung cancer (1,000 mg/m(2) with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline.
  
  
  CONCLUSIONS
  Danusertib was well tolerated with target inhibition in skin at >or=500 mg/m(2). Preliminary evidence of antitumor activity, including a partial response and several occurrences of prolonged stable disease, was seen across a variety of advanced refractory cancers. Phase II studies are ongoing.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. rb_cohen@fccc.edu
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Charu
authors.initials: C
authors.lastname: Aggarwal
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cheng
authors.forename: David R
authors.initials: DR
authors.lastname: Spigel
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Greco
authors.forename: Mariangela
authors.initials: M
authors.lastname: Mariani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Rocchetti
authors.forename: Roberta
authors.initials: R
authors.lastname: Ceruti
authors.forename: Silvia
authors.initials: S
authors.lastname: Comis
authors.forename: Bernard
authors.initials: B
authors.lastname: Laffranchi
authors.forename: Jurgen
authors.initials: J
authors.lastname: Moll
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D064127:Aurora Kinases; D001549:Benzamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C523797:danusertib