Onapristone and Fulvestrant for ER+ HER2- Metastatic Breast Cancer After Endocrine Therapy and CDK4/6 Inhibitors (The SMILE Study)

Trial Status:
Enrollment in this Phase 2 study is open.

Trial Titles:
SMILE, Onward 201

For More Trial Information:
Please contact info@contextherapeutics.com or visit clinicaltrials.gov.

ClinicalTrials.gov Identifier:
NCT04738292 (Link)

Program (Target):
Onapristone extended release (ONA-XR) is a potent and specific antagonist of the progesterone receptor that is orally administered. Currently, there are no approved therapies that selectively target PR+ cancers. Preliminary preclinical and clinical data suggest that ONA-XR has anticancer activity by inhibiting the binding of progesterone receptor to chromatin, downregulating cancer stem cell mobilization, and blocking immune evasion. ONA-XR is an investigational drug that has not been approved for marketing by any regulatory authority.

Disease Indication:
Advanced or metastatic breast cancer.

Mechanism of Action:
The use of antiestrogen therapy combined with anti-DK4/6 inhibitor therapy in first line (1L) HR+ metastatic breast cancer (mBCa) results in a complex resistance profile. In the resistant setting, current standard of care agents (e.g., fulvestrant) are largely ineffective. Recent data suggests that Antiestrogen + CDK4/6i induce selective pressure that results in resistance that is driven through mutations that converge upon the progesterone receptor (PR).

These resistance mechanisms include:
(1) Persistent estrogen receptor signaling (wildtype and ESR1 mutated) [1]
(2) Persistent growth factor signaling via MAPK pathway upregulation [2]

[1] Bartels, Mod Path, 2018; Lopez-Knowles, BJC, 2018
[2] Razavi, Cancer Cell, 2018; de Leeuw, Clin Cancer Res, 2018

Principal Investigators:

• Sailaja Kamaraju, MD

• Kari Wisinski, MD

Trial Sites: