Background: Extended release onapristone (onapristone ER) is a progesterone receptor (PR) antagonist that inhibits hormone-mediated PR activation and stabilizes PR association with corepressors, resulting in an antineoplastic effect when applied alone or in combination with antiestrogen therapy to breast cancer cells in vitro. Recent preclinical studies further suggest that onapristone adds to inhibition of cell proliferation when combined with CDK4/6 inhibitors and fulvestrant. Elevations in ctDNA can precede overt disease progression by a matter of months in metastatic breast cancer and may represent an opportunity for proactive therapeutic intervention. Trial Design: This is an investigator initiated open-label, single institution phase 1b study of onapristone ER added as escalation therapy in patients with ER+, PR+, HER2 negative MBC, who have detectable ctDNA after six months of treatment with letrozole and palbociclib in the first line. The study is supported by Context Therapeutics and will involve two stages. Stage 1 is a dose escalation/de-escalation phase of 18 patients maximum, in which the safety and recommended phase 2 dose (RP2D) will be established for onapristone ER when used in combination with letrozole and palbociclib. In stage 2, the dose expansion phase, the RP2D of onapristone will be combined with letrozole and palbociclib in 10 patients to further explore the tolerability of the regimen. ctDNA will be collected serially while patients are on this triplet therapy. Eligibility Criteria: This study will enroll patients with radiologically measurable or evaluable metastatic or unresectable ER+/PR+/HER2-negative MBC in whom a tumor-derived somatic mutation can be detected in ctDNA at a variant allele fraction of 0.5% or greater after 6 months (+/- 4 weeks) of treatment with first line letrozole and palbociclib without progression, using our in house CLIA certified MSK-ACCESS assay. Adequate organ function and functional status for enrollment are stipulated in the protocol. Specific Aims: The primary objective of this study is to define the safety, tolerability, and recommended phase 2 dose of onapristone ER used in combination with letrozole and palbociclib. Secondary objectives include to investigate ctDNA response rate of the triplet therapy regimen, to gather early data regarding the 6-month clinical benefit rate , overall response rate , and progression free survival of this triplet escalation therapy regimen in high risk ctDNA+ patients, and to evaluate the pharmacokinetics of Onapristone ER when used in combination with letrozole and Palbociclib. Exploratory objective include to describe ctDNA dynamics during antiprogestin therapy escalation in ER+ MBC, as well as the molecular features present in responders vs. non-responders using ctDNA and pre-treatment tissue. Target Accrual: The total planned cohort for the phase I dose escalation is a maximum of 18 patients across 3 dose levels, and the total planned cohort for the dose expansion is 10 patients, with an anticipated maximum total of 28 patients. We will allot for 5 additional patients to account for inevaluability during the dose escalation and expansion portions of the trial. The trial will be open to enrollment at MSKCC in July 2021.

Citation Format: Joshua Z Drago, Elaine M Walsh, Mithat Gonen, Michael F Berger, Mark E Robson, Sarat Chandarlapaty, Pedram Razavi, Komal Jhaveri. Circulating tumor DNA-guided adaptive therapy escalation in ER+ MBC: A phase 1b study with letrozole, palbociclib and onapristone ER [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-04-01.