Apristor (onapristone XR) / Context Therap, Tyligand - LARVOL DELTA

ELONA: Study of Elacestrant in Combination With Onapristone in Patients With Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P1/2 | N=4 | Terminated | Sponsor: Context Therapeutics Inc. | Phase classification: P1b ➔ P1/2 | N=67 ➔ 4 | Active, not recruiting ➔ Terminated; Sponsor decision to discontinue onapristone development.

Enrollment change • Phase classification • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Basket study of oral progesterone antagonist onapristone extended-release in combination with anastrozole in progesterone receptor-positive recurrent adult-type granulosa cell tumor of the ovary. (PubMed, Int J Gynecol Cancer) - "The study did not meet its primary end point. Although the combination of onapristone extended-release and anastrozole was well-tolerated, there were no objective responses in patients with progesterone receptor-positive adult-type granulosa cell tumor."

Journal • Oncology • Ovarian Cancer • Solid Tumor • PGR

A Phase II Trial of Onapristone and Fulvestrant for Patients With ER+ and HER2- Metastatic Breast Cancer. (PubMed, Clin Breast Cancer) - "The study regimen was well-tolerated with no significant toxicities. Future studies may evaluate antiprogestins with various combinations such as targeted therapies."

Journal • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

OATH: Onapristone and Anastrozole for the Treatment of Refractory Hormone Receptor Positive Endometrial Cancer (clinicaltrials.gov) - P2 | N=14 | Active, not recruiting | Sponsor: Thomas Jefferson University | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Endometrial Adenocarcinoma • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Oncology • Solid Tumor • ER • PGR

A Study of Onapristone ER Alone Or In Combination With Anastrozole in Gynecologic Cancers That Respond to Progesterone (clinicaltrials.gov) - P2 | N=34 | Completed | Sponsor: Memorial Sloan Kettering Cancer Center | Active, not recruiting ➔ Completed | Trial completion date: Apr 2025 ➔ Sep 2024 | Trial primary completion date: Apr 2025 ➔ Sep 2024

Combination therapy • Pan tumor • Trial completion • Trial completion date • Trial primary completion date • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Solid Tumor

Basket study of oral progesterone antagonist onapristone extended release in progesterone receptor-positive recurrent granulosa cell, low-grade serous ovarian cancer, or endometrioid endometrial cancer. (PubMed, Gynecol Oncol) - "The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed."

Journal • Pan tumor • Endometrial Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • PGR

A Study of Onapristone ER Alone Or In Combination With Anastrozole in Gynecologic Cancers That Respond to Progesterone (clinicaltrials.gov) - P2 | N=34 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Apr 2024 ➔ Apr 2025 | Trial primary completion date: Apr 2024 ➔ Apr 2025

Combination therapy • Pan tumor • Trial completion date • Trial primary completion date • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Solid Tumor

Immune targeting progesterone receptor in hormone receptor positive breast cancer (AACR 2024) - "Lastly, we engineered 1st generation adenoviral vectors encoding mouse and human PR and utilized two antiprogestins (Mifepristone and Onapristone) in vivo. We found that murine PR-A and PR-B can confer robust P4 signaling that is linked to an immunosuppressive phenotype in vivo. We developed a PR vaccine that elicited PR-specific T cell responses in vivo. We are currently examining the mechanisms that underlie PR-mediated immunosuppression and exploring the potential of PR vaccines in HR⁺BC."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CD8 • ER • IFNG • PGR

Context Therapeutics Reports Third Quarter 2023 Operating and Financial Results - "Research and development (“R&D”) expenses were $4.5 million for the third quarter 2023, as compared to $2.1 million for the same period in 2022. The increase in R&D expenses was driven by higher CTIM-76 contract manufacturing costs and preclinical costs as a result of ongoing IND-enabling studies and activities. This increase was partially offset by a decrease in onapristone extended release (“ONA-XR”) expenses, primarily due to the Company’s decision in March 2023 to discontinue the development of ONA-XR and focus on the development of CTIM-76."

Commercial • Discontinued • Solid Tumor

Onapristone and Fulvestrant for ER+ HER2- Metastatic Breast Cancer After Endocrine Therapy and CDK4/6 Inhibitors (The SMILE Study) (clinicaltrials.gov) - P2 | N=11 | Terminated | Sponsor: University of Wisconsin, Madison | Trial completion date: Mar 2025 ➔ May 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Mar 2024 ➔ Apr 2023; funding

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

OATH: Onapristone and Anastrozole for the Treatment of Refractory Hormone Receptor Positive Endometrial Cancer (clinicaltrials.gov) - P2 | N=14 | Active, not recruiting | Sponsor: Thomas Jefferson University | N=25 ➔ 14

Enrollment change • Endometrial Adenocarcinoma • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Oncology • Solid Tumor

OATH trial: A phase II clinical trial evaluating the combination of onapristone with anastrozole for women with hormone receptor positive endometrial cancer—Preliminary results. (ASCO 2023) - P2 | "Preliminary results of dual hormonal blockade using ONA and ANA in heavily pretreated pts with EC suggest that this combination ONA + ANA has promising activity and is well tolerated. Clinical trial information: NCT04719273."

Clinical • P2 data • Endometrial Cancer • Oncology • Solid Tumor

Onapristone and Fulvestrant for ER+ HER2- Metastatic Breast Cancer After Endocrine Therapy and CDK4/6 Inhibitors (The SMILE Study) (clinicaltrials.gov) - P2 | N=11 | Active, not recruiting | Sponsor: University of Wisconsin, Madison | Recruiting ➔ Active, not recruiting | N=39 ➔ 11

Combination therapy • Enrollment change • Enrollment closed • Metastases • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

Basket study of oral progesterone antagonist onapristone extended release (ONA-XR) in progesterone receptor positive (PR+) recurrent granulosa cell (GCT), low-grade serous ovarian (LGSOC), or endometrioid endometrial cancer (EEC). (ASCO 2022) - P2 | "Funded by: Pharmaceutical/Biotech Company. ONA-XR was well tolerated and exhibited a 12-month PFS rate of 20.1% and a CBR of 35.7% in patients with GCT. No objective responses were observed. Cohorts 1-3 have closed to accrual, with 2 patients continuing active treatment for >18 months."

Pan tumor • Anemia • Cardiovascular • Endometrial Cancer • Febrile Neutropenia • Hematological Disorders • Infectious Disease • Nephrology • Neutropenia • Oncology • Ovarian Serous Adenocarcinoma • Pain • Solid Tumor • PGR

A Study of Letrozole, Palbociclib, and Onapristone ER in People With Metastatic Breast Cancer (clinicaltrials.gov) - P1b | N=0 | Withdrawn | Sponsor: Memorial Sloan Kettering Cancer Center | N=28 ➔ 0 | Trial completion date: Sep 2023 ➔ Apr 2023 | Recruiting ➔ Withdrawn | Trial primary completion date: Sep 2023 ➔ Apr 2023

Circulating tumor DNA • Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial withdrawal • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2 • PGR

Onapristone and Anastrozole for the Treatment of Refractory Hormone Receptor Positive Endometrial Cancer (clinicaltrials.gov) - P2 | N=25 | Active, not recruiting | Sponsor: Thomas Jefferson University | Recruiting ➔ Active, not recruiting

Enrollment closed • Endometrial Adenocarcinoma • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Oncology • Solid Tumor

A phase 2 trial of onapristone in combination with fulvestrant for patients with ER-positive and HER2-negative metastatic breast cancer after progression on endocrine therapy and CDK4/6 inhibitors. (ASCO 2023) - "Clinical Trial Registration Number: NCT 4738292."

Clinical • Combination therapy • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Z-Endoxifen prevents aggressive mammary cancers in mice by inhibiting cell proliferation and creating a tumor suppressive microenvironment. (PubMed, Biomed Pharmacother) - "We examined the efficacy of the selective ER modulator (Z-endoxifen) as monotherapy and in combination with the selective progesterone receptor modulators (onapristone and ulipristal acetate) in the tamoxifen-insensitive C3(1)/SV40TAg mouse mammary tumorigenesis model. The expression of genes associated with cell cycle, cell proliferation and extracellular matrix remodeling was similarly repressed by endoxifen and UPA however only endoxifen significantly downregulated prominent genes associated with poor prognosis (Col11a1, Il17b, Pdgfa, Tnfrsf11a). Our results indicate that endoxifen can prevent breast cancers, even when tamoxifen-resistant, through its role in favorable tissue remodeling and immunomodulation."

Journal • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Immune Modulation • Immunology • Oncology • Solid Tumor • COL11A1 • COL1A1 • ER • PDGFA • PGR • TNFRSF11A

ELONA: Study of Elacestrant in Combination With Onapristone in Patients With Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P1b | N=67 | Active, not recruiting | Sponsor: Context Therapeutics Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

ctDNA-guided adaptive therapy escalation in ER+ MBC: A phase 1b study with Letrozole, Palbociclib and Onapristone ER (SABCS 2022) - "Recent preclinical studies further suggest that onapristone adds to inhibition of cell proliferation when combined with CDK4/6 inhibitors and fulvestrant. The trial is currently open to enrollment at MSKCC. Contact Information: Dragoj@mskcc.org; Jhaverik@mskcc.org"

Circulating tumor DNA • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • HER-2 • PGR

Pooled analysis of onapristone extended release (ONA ER) in metastatic cancer patients (pts): A review of liver safety. (ASCO 2019) - P1/2; " Of 88 pts who received ONA ER for a median 8 weeks (3-51), 59% were female, median age 68 (36-89), 99% Caucasian, 28% had liver metastases (mets), 48% bone mets and 17% also took abiraterone (ABI), which has liver toxicity. The safety experience for ONA ER has been reassuring but must continue to be characterized. For new ONA ER studies, weekly liver chemistry monitoring is planned for the first 4 weeks with Q2W monitoring thereafter. The occasional G3 elevations in serum AST, ALT or bilirubin will prompt interruption, but re-starting treatment at a lower dose should be possible for most pts."

Retrospective data

ELONA: An open-label, phase 1b-2 study of elacestrant, in combination with onapristone in patients with estrogen receptor-positive, progesterone receptor-positive, HER2-negative advanced or metastatic breast cancer (SABCS 2022) - "The clinical anticancer activity of onapristone, in immediate release formulation, has been previously documented in patients with hormone therapy-naïve (Robertson et al, 1999) or tamoxifen- resistant (Jonat et al, 2002) breast cancer (BC). No prior chemotherapy regimen in the metastatic setting is allowed. The phase 1b dose-escalation portion of the study will evaluate dose-limiting toxicities (DLTs) of the combination in up to 4 cohorts of 6 patients each."

Clinical • Combination therapy • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

The SMILE Study: A phase II trial of onapristone in combination with fulvestrant for patients with ER-positive and HER2-negative metastatic breast cancer after progression on endocrine therapy and CDK 4/6 inhibitors (SABCS 2022) - "Prior ET with tamoxifen or aromatase inhibitor therapy in the adjuvant or metastatic setting is allowed. The primary objective is to evaluate the objective response rate; secondary objectives include safety and tolerability, progression-free survival, disease control rate, and duration of response. Other correlates include optional functional imaging of PgR binding with 18F-FFNP PET/CT and biomarker analysis (ER, total PgR, HER2, Ki67, CD24, CD44, LDH1, KLF4, CK 5/6, PhosphoSer294-PgR on tissue samples, ESR1 mutations, and circulating tumor DNA analysis)."

Clinical • Combination therapy • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CD24 • ER • HER-2 • KLF4 • PGR

Context Therapeutics Highlights Clinical Responses from the Phase 2 OATH Clinical Trial Evaluating ONA-XR for the Treatment of Endometrial Cancer (GlobeNewswire) - P2 | N=25 | OATH (NCT04719273) | "Context Therapeutics Inc....announced that two patients have achieved a confirmed partial response (PR) among the first 12 patients (9 evaluable) enrolled in the Phase 2 OATH clinical trial evaluating the potential of Context’s oral progesterone receptor antagonist onapristone extended release (ONA-XR) in combination with anastrozole (ANA) to treat hormone receptor positive (HR+) metastatic endometrial cancer (EC)....Preliminary data from the ongoing Phase 2 OATH clinical trial evaluating the combination of ONA-XR with ANA in HR+ EC found that ONA-XR plus ANA demonstrated a 4-month progression free survival (PFS) rate of 77% and an overall response rate (ORR) of 22%....Updated data regarding the Phase 2 OATH trial is expected to be provided in Q2 2023."

P2 data • Endometrial Cancer • Gynecologic Cancers • Oncology • Solid Tumor

Context Therapeutics Highlights 2023 Corporate Priorities and Pipeline Milestones (GlobeNewswire) - "ELONA Phase 1b/2 breast cancer trial open and enrolled first patient: In January 2023, Context enrolled the first patient in the ELONA study, an open-label, Phase 1b/2 breast cancer clinical trial being conducted in partnership with The Menarini Group ('Menarini'). The ELONA study is designed to explore the efficacy of ONA-XR in combination with elacestrant, Menarini’s selective estrogen receptor degrader, in patients with locally advanced or metastatic breast cancer who have received prior treatment with a CDK4/6 inhibitor."

Trial status • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Oncology