PMID- 25488684 OWN - NLM STAT- MEDLINE DCOM- 20160818 LR - 20200206 IS - 1569-8041 (Electronic) IS - 0923-7534 (Linking) VI - 26 IP - 3 DP - 2015 Mar TI - 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. PG - 598-607 LID - 10.1093/annonc/mdu566 [doi] AB - 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. CI - (c) 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. FAU - Schoffski, P AU - Schoffski P AD - University Hospitals Leuven, Leuven, Belgium patrick.schoffski@uzleuven.be. FAU - Besse, B AU - Besse B AD - Institut Gustave-Roussy, Villejuif, France. FAU - Gauler, T AU - Gauler T AD - Westdeutsches Tumorzentrum Essen, Essen, Germany. FAU - de Jonge, M J A AU - de Jonge MJ AD - Erasmus MC Cancer Institute, Rotterdam, The Netherlands. FAU - Scambia, G AU - Scambia G AD - Centro di Ricerca ad Alta Tecnologia - Scienze Biomediche, Campobasso. FAU - Santoro, A AU - Santoro A AD - Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS, Rozzano. FAU - Davite, C AU - Davite C AD - Clinical Organization for Strategies & Solutions (CLIOSS) s.r.l., Nerviano, Italy. FAU - Jannuzzo, M G AU - Jannuzzo MG AD - Clinical Organization for Strategies & Solutions (CLIOSS) s.r.l., Nerviano, Italy. FAU - Petroccione, A AU - Petroccione A AD - Clinical Organization for Strategies & Solutions (CLIOSS) s.r.l., Nerviano, Italy. FAU - Delord, J-P AU - Delord JP AD - Institut Universitaire du Cancer, Oncopole, France. LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20141208 PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (Benzamides) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazoles) RN - EC 2.7.11.1 (Aurora Kinases) RN - M3X659D0FY (danusertib) SB - IM MH - Administration, Intravenous MH - Aged MH - Aurora Kinases/*antagonists & inhibitors MH - Benzamides/*administration & dosage/adverse effects MH - Breast Neoplasms/diagnosis/*drug therapy MH - Carcinoma, Non-Small-Cell Lung/diagnosis/drug therapy MH - Cohort Studies MH - Colorectal Neoplasms/diagnosis/*drug therapy MH - Drug Administration Schedule MH - Female MH - Humans MH - Lung Neoplasms/diagnosis/*drug therapy MH - Male MH - Middle Aged MH - Ovarian Neoplasms/diagnosis/*drug therapy MH - Prospective Studies MH - Protein Kinase Inhibitors/administration & dosage MH - Pyrazoles/*administration & dosage/adverse effects MH - Small Cell Lung Carcinoma/diagnosis/drug therapy MH - Treatment Outcome OTO - NOTNLM OT - aurora kinase inhibitor OT - breast cancer OT - colorectal cancer OT - lung cancer OT - ovarian cancer OT - pancreatic cancer EDAT- 2014/12/10 06:00 MHDA- 2016/08/19 06:00 CRDT- 2014/12/10 06:00 PHST- 2014/12/10 06:00 [entrez] PHST- 2014/12/10 06:00 [pubmed] PHST- 2016/08/19 06:00 [medline] AID - S0923-7534(19)31422-X [pii] AID - 10.1093/annonc/mdu566 [doi] PST - ppublish SO - Ann Oncol. 2015 Mar;26(3):598-607. doi: 10.1093/annonc/mdu566. Epub 2014 Dec 8.