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

Patrick Schöffski, B. Besse, T. Gauler, M. J A de Jonge, G. Scambia, A. Santoro, C. Davite, M. G. Jannuzzo, A. Petroccione, J. P. Delord

Research output: Contribution to journalArticle

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/m2 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)598-607
Number of pages10
JournalAnnals of Oncology
Volume26
Issue number3
DOIs
Publication statusPublished - 2015

Keywords

  • Aurora kinase inhibitor
  • Breast cancer
  • Colorectal cancer
  • Lung cancer
  • Ovarian cancer
  • Pancreatic cancer

ASJC Scopus subject areas

  • Oncology
  • Hematology

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