Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers

Paul H Cottu, Jacques Bonneterre, Andrea Varga, Mario Campone, Alexandra Leary, Anne Floquet, Dominique Berton-Rigaud, Marie-Paule Sablin, Anne Lesoin, Keyvan Rezai, François M Lokiec, Catherine Lhomme, Jacques Bosq, Alice S Bexon, Erard M Gilles, Stefan Proniuk, Veronique Dieras, David M Jackson, Alexander Zukiwski, Antoine Italiano, Paul H Cottu, Jacques Bonneterre, Andrea Varga, Mario Campone, Alexandra Leary, Anne Floquet, Dominique Berton-Rigaud, Marie-Paule Sablin, Anne Lesoin, Keyvan Rezai, François M Lokiec, Catherine Lhomme, Jacques Bosq, Alice S Bexon, Erard M Gilles, Stefan Proniuk, Veronique Dieras, David M Jackson, Alexander Zukiwski, Antoine Italiano

Abstract

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 PRpos 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 APRpos 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.

Conflict of interest statement

Jacques Bonneterre is a consultant to Arno Therapeutics and Invivis Pharmaceuticals. Keyvan Rezai, François Lokiec, Jacques Bosq, and Alice S Bexon are consultants to Arno Therapeutics. Erard M Gilles is an employee of Invivis Pharmaceuticals and consultant to Arno Therapeutics. Stefan Proniuk and David M. Jackson are employees and stock owners of Arno Therapeutics. Alexander Zukiwski is CEO and stock owner of Arno Therapeutics. Paul H Cottu, Andrea Varga, Mario Campone, Alexandra Leary, Anne Floquet, Dominique Berton-Rigaud, Marie-Paule Sablin, Anne Lesoin, Catherine Lhomme, Veronique Dieras, and Antoine Italiano have no relevant conflicts of interest to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Study design.
Fig 1. Study design.
Flow chart of the two parts of the study.
Fig 2. CONSORT diagram.
Fig 2. CONSORT diagram.

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