1. 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.
- Author
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Schöffski P, Besse B, Gauler T, de Jonge MJ, Scambia G, Santoro A, Davite C, Jannuzzo MG, Petroccione A, and Delord JP
- Subjects
- Administration, Intravenous, Aged, Benzamides adverse effects, Breast Neoplasms diagnosis, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung drug therapy, Cohort Studies, Colorectal Neoplasms diagnosis, Drug Administration Schedule, Female, Humans, Lung Neoplasms diagnosis, Male, Middle Aged, Ovarian Neoplasms diagnosis, Prospective Studies, Protein Kinase Inhibitors administration & dosage, Pyrazoles adverse effects, Small Cell Lung Carcinoma diagnosis, Small Cell Lung Carcinoma drug therapy, Treatment Outcome, Aurora Kinases antagonists & inhibitors, Benzamides administration & dosage, Breast Neoplasms drug therapy, Colorectal Neoplasms drug therapy, Lung Neoplasms drug therapy, Ovarian Neoplasms drug therapy, Pyrazoles administration & dosage
- 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., 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., Clinical Trial Number: 2006-003772-35., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
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