title: Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumour, multi-institutional phase II study.
abstract: BACKGROUND
  This multi-centre phase II trial assessed the activity, safety (CTCAE 3.0) and pharmacokinetics (PK) of the pan-Aurora kinase inhibitor danusertib hydrochloride (PHA-739358) in breast (BC), ovarian (OC), pancreatic (PC), colorectal (CRC), small-cell (SCLC) and non-small-cell lung (NSCLC) cancers.
  
  
  METHODS
  Consenting adult patients with good performance and organ function with advanced/metastatic tumours who had failed systemic therapy were treated in independent, disease-specific cohorts with danusertib 500 mg/m(2) given as 24-h i.v. infusion every 14 days with until progression or unacceptable toxicity. A two-stage design was applied. Primary end point was the progression-free rate (PFR) at 4 months (RECIST1.1).
  
  
  RESULTS
  A total of 223 patients were enrolled with 219 actively treated. The median relative dose intensity of danusertib was similar for all tumour types (84.6%-99.6%). The median number of biweekly treatment cycles ranged from 3 to 4/patient (maximum 5-40 cycles/entity) and the median treatment duration varied between 7.6 and 10.0 weeks per histotype. Danusertib did not meet pre-specified protocol criteria for clinically relevant activity in any of the treated cancers. The PFR at 4 months was 18.4% in BC, 12.1% in OC, 10.0% in PC, 10.4% in NSCLC (all histotypes), 16.1% in squamous NSCLC and 0% in SCLC and CRC. Some radiological and/or biochemical indication of antitumor activity was seen in BC, OC, PC and NSCLC, including two confirmed partial responses. The most frequent drug-related non-laboratory adverse events (AEs) were fatigue/asthenia, nausea, diarrhoea, anorexia, vomiting, alopecia, constipation and pyrexia. Common laboratory AEs included haematological toxicity, hypalbuminaemia and increases in liver enzymes. Treatment was discontinued due to AEs in only 5.5% of patients. Plasma concentrations of danusertib were in line with results from earlier studies.
  
  
  CONCLUSIONS
  Single-agent danusertib did show only marginal anti-tumour activity in common solid tumours after failure of prior systemic therapies. The safety and PK profile was consistent with previous experience.
  
  
  BACKGROUND
  2006-003772-35.
authors.affiliation: University Hospitals Leuven, Leuven, Belgium patrick.schoffski@uzleuven.be.
authors.forename: P
authors.initials: P
authors.lastname: Schöffski
authors.affiliation: Institut Gustave-Roussy, Villejuif, France.
authors.forename: B
authors.initials: B
authors.lastname: Besse
authors.affiliation: Westdeutsches Tumorzentrum Essen, Essen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Gauler
authors.affiliation: Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: M J A
authors.initials: MJ
authors.lastname: de Jonge
authors.affiliation: Centro di Ricerca ad Alta Tecnologia - Scienze Biomediche, Campobasso.
authors.forename: G
authors.initials: G
authors.lastname: Scambia
authors.affiliation: Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS, Rozzano.
authors.forename: A
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Clinical Organization for Strategies & Solutions (CLIOSS) s.r.l., Nerviano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Davite
authors.affiliation: Clinical Organization for Strategies & Solutions (CLIOSS) s.r.l., Nerviano, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Jannuzzo
authors.affiliation: Clinical Organization for Strategies & Solutions (CLIOSS) s.r.l., Nerviano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Petroccione
authors.affiliation: Institut Universitaire du Cancer, Oncopole, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Delord
mesh_terms: D061605:Administration, Intravenous; D000368:Aged; D064127:Aurora Kinases / Q000037:antagonists & inhibitors*; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D055752:Small Cell Lung Carcinoma / Q000175:diagnosis / Q000188:drug therapy; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D064127:Aurora Kinases; C523797:danusertib
keywords: aurora kinase inhibitor; breast cancer; colorectal cancer; lung cancer; ovarian cancer; pancreatic cancer