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Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers
INTRODUCTION: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended rele...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179222/ https://www.ncbi.nlm.nih.gov/pubmed/30304013 http://dx.doi.org/10.1371/journal.pone.0204973 |
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author | Cottu, Paul H. Bonneterre, Jacques Varga, Andrea Campone, Mario Leary, Alexandra Floquet, Anne Berton-Rigaud, Dominique Sablin, Marie-Paule Lesoin, Anne Rezai, Keyvan Lokiec, François M. Lhomme, Catherine Bosq, Jacques Bexon, Alice S. Gilles, Erard M. Proniuk, Stefan Dieras, Veronique Jackson, David M. Zukiwski, Alexander Italiano, Antoine |
author_facet | Cottu, Paul H. Bonneterre, Jacques Varga, Andrea Campone, Mario Leary, Alexandra Floquet, Anne Berton-Rigaud, Dominique Sablin, Marie-Paule Lesoin, Anne Rezai, Keyvan Lokiec, François M. Lhomme, Catherine Bosq, Jacques Bexon, Alice S. Gilles, Erard M. Proniuk, Stefan Dieras, Veronique Jackson, David M. Zukiwski, Alexander Italiano, Antoine |
author_sort | Cottu, Paul H. |
collection | PubMed |
description | INTRODUCTION: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. METHODS: An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PR(pos) tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. RESULTS: The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36–84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2–44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APR(pos) endometrial carcinoma. CONCLUSION: Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation. |
format | Online Article Text |
id | pubmed-6179222 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61792222018-10-19 Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers Cottu, Paul H. Bonneterre, Jacques Varga, Andrea Campone, Mario Leary, Alexandra Floquet, Anne Berton-Rigaud, Dominique Sablin, Marie-Paule Lesoin, Anne Rezai, Keyvan Lokiec, François M. Lhomme, Catherine Bosq, Jacques Bexon, Alice S. Gilles, Erard M. Proniuk, Stefan Dieras, Veronique Jackson, David M. Zukiwski, Alexander Italiano, Antoine PLoS One Research Article INTRODUCTION: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. METHODS: An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PR(pos) tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. RESULTS: The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36–84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2–44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APR(pos) endometrial carcinoma. CONCLUSION: Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation. Public Library of Science 2018-10-10 /pmc/articles/PMC6179222/ /pubmed/30304013 http://dx.doi.org/10.1371/journal.pone.0204973 Text en © 2018 Cottu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Cottu, Paul H. Bonneterre, Jacques Varga, Andrea Campone, Mario Leary, Alexandra Floquet, Anne Berton-Rigaud, Dominique Sablin, Marie-Paule Lesoin, Anne Rezai, Keyvan Lokiec, François M. Lhomme, Catherine Bosq, Jacques Bexon, Alice S. Gilles, Erard M. Proniuk, Stefan Dieras, Veronique Jackson, David M. Zukiwski, Alexander Italiano, Antoine Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers |
title | Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers |
title_full | Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers |
title_fullStr | Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers |
title_full_unstemmed | Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers |
title_short | Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers |
title_sort | phase i study of onapristone, a type i antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179222/ https://www.ncbi.nlm.nih.gov/pubmed/30304013 http://dx.doi.org/10.1371/journal.pone.0204973 |
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