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

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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 13 Issue 10 Pg. e0204973 ( 2018) ISSN: 1932-6203 [Electronic] United States
• PMID: 30304013 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Delayed-Action Preparations
• Gonanes
• Receptors, Progesterone
• onapristone

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (drug therapy, pathology)
• Delayed-Action Preparations
• Female
• Gonanes (adverse effects, pharmacokinetics, therapeutic use)
• Half-Life
• Humans
• Middle Aged
• Nausea (etiology)
• Neoplasm Metastasis
• Neoplasm Recurrence, Local
• Receptors, Progesterone (metabolism)