TY - JOUR
T1 - IRIS study
T2 - a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients
AU - On behalf of the IRIS trial participants
AU - Palmieri, Carlo
AU - Stein, Rob C.
AU - Liu, Xinxue
AU - Hudson, Emma
AU - Nicholas, Hanna
AU - Sasano, Hironobu
AU - Guestini, Fouzia
AU - Holcombe, Chris
AU - Barrett, Sophie
AU - Kenny, Laura
AU - Reed, Sadie
AU - Lim, Adrian
AU - Hayward, Larry
AU - Howell, Sacha
AU - Coombes, R. Charles
N1 - Funding Information:
We thank the women who took part in this study; the doctors, nurses and support staff at the following local sites: Royal Liverpool University Hospital (4 patients); University College London Hospital (3 patients); Beatson West of Scotland Cancer Centre (1 patient); Imperial College NHS Foundation Trust, London (10 patients); Western General Hospital (4 patients); The Christie NHS Foundation Trust (5 patients). We also thank the independent members of the trial steering committee (Prof David Miles (Chair); Dr Richard Simcock; Dr Laura Assersoh; Mr Olorunsola Agbaje) and the independent data monitoring committee (Alastair Thompson (Chair); Dr Mark. Beresford; Dr Louise Choo). IRIS was an NIHR Clinical Research Network portfolio trial and we acknowledge the help of the local research networks that supported recruitment at UK sites. We are grateful to Dr Nigel J. Clarke, Quest Diagnostics for support with the steroidogenic hormone profiling and aromatase inhibitor drug levels. We are particularly grateful to Adrienne Morgan, patient representative and member of Independent Cancer Patients? Voice for her input, guidance and help with patient information sheet and for her participation in the study steering committee meetings. The study was supported by a feasibility study award from Cancer Research UK (grant number C20208/A13392), and recruitment was supported via the National Institute for Health Research (NIHR), as well as an educational grant from IPSEN. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. RCS was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - Purpose: Irosustat is a first-generation, orally active, irreversible steroid sulfatase inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to a first-line aromatase inhibitor (AI) in patients with advanced BC to evaluate the safety of the combination and to test the hypothesis that the addition of Irosustat to AI may further suppress estradiol levels and result in clinical benefit. Experimental design: Postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had derived clinical benefit from a first-line AI and who subsequently progressed were enrolled. The first-line AI was continued and Irosustat (40 mg orally daily) added. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included safety, tolerability, and pharmacodynamic end points. Results: Twenty-seven women were recruited, four discontinued treatment without response assessment. Based on local reporting, the CBR was 18.5% (95% CI 6.3–38.1%) on an intent to treat basis, increasing to 21.7% (95% CI 7.4–43.7%) by per-protocol analysis. In those patients that achieved clinical benefit (n = 5), the median (interquartile range) duration was 9.4 months (8.1–11.3) months. The median progression-free survival time was 2.7 months (95% CI 2.5–4.6) in both the ITT and per-protocol analyses. The most frequently reported grade 3/4 toxicities were dry skin (28%), nausea (13%), fatigue (13%), diarrhoea (8%), headache (7%), anorexia (7%) and lethargy (7%). Conclusions: The addition of Irosustat to aromatase inhibitor therapy resulted in clinical benefit with an acceptable safety profile. The study met its pre-defined success criterion by both local and central radiological assessments.
AB - Purpose: Irosustat is a first-generation, orally active, irreversible steroid sulfatase inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to a first-line aromatase inhibitor (AI) in patients with advanced BC to evaluate the safety of the combination and to test the hypothesis that the addition of Irosustat to AI may further suppress estradiol levels and result in clinical benefit. Experimental design: Postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had derived clinical benefit from a first-line AI and who subsequently progressed were enrolled. The first-line AI was continued and Irosustat (40 mg orally daily) added. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included safety, tolerability, and pharmacodynamic end points. Results: Twenty-seven women were recruited, four discontinued treatment without response assessment. Based on local reporting, the CBR was 18.5% (95% CI 6.3–38.1%) on an intent to treat basis, increasing to 21.7% (95% CI 7.4–43.7%) by per-protocol analysis. In those patients that achieved clinical benefit (n = 5), the median (interquartile range) duration was 9.4 months (8.1–11.3) months. The median progression-free survival time was 2.7 months (95% CI 2.5–4.6) in both the ITT and per-protocol analyses. The most frequently reported grade 3/4 toxicities were dry skin (28%), nausea (13%), fatigue (13%), diarrhoea (8%), headache (7%), anorexia (7%) and lethargy (7%). Conclusions: The addition of Irosustat to aromatase inhibitor therapy resulted in clinical benefit with an acceptable safety profile. The study met its pre-defined success criterion by both local and central radiological assessments.
KW - Aromatase
KW - Breast cancer
KW - Endocrine therapy
KW - Sulfatase
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UR - http://www.scopus.com/inward/citedby.url?scp=85020696808&partnerID=8YFLogxK
U2 - 10.1007/s10549-017-4328-z
DO - 10.1007/s10549-017-4328-z
M3 - Article
C2 - 28612226
AN - SCOPUS:85020696808
VL - 165
SP - 343
EP - 353
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
SN - 0167-6806
IS - 2
ER -