Apristor (onapristone XR)

P2, N=34, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025

P2, N=11, Terminated, University of Wisconsin, Madison | Trial completion date: Mar 2025 --> May 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Mar 2024 --> Apr 2023; funding

P2, N=14, Active, not recruiting, Thomas Jefferson University | N=25 --> 14

P2, N=11, Active, not recruiting, University of Wisconsin, Madison | Recruiting --> Active, not recruiting | N=39 --> 11

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.

P1b; N=28 --> 0 | Trial completion date: Sep 2023 --> Apr 2023 | Recruiting --> Withdrawn | Trial primary completion date: Sep 2023 --> Apr 2023

Clinical Trial Registration Number: NCT 4738292.

P1b, N=67, Active, not recruiting, Context Therapeutics Inc. | Recruiting --> Active, not recruiting

P1b, N=67, Recruiting, Context Therapeutics Inc. | Not yet recruiting --> Recruiting

P1b, N=67, Not yet recruiting, Context Therapeutics Inc.

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).

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

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.

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.

P1; Recruiting --> Completed | Trial completion date: Oct 2022 --> Apr 2021 | Trial primary completion date: Apr 2022 --> Apr 2021

Moreover, the selective PI3K inhibitor alpelisib (ALP) has been approved for the treatment of PIK3CA-mutated endocrine resistant MBC. The objective of this study was to evaluate the efficacy of ONA in combination with fulvestrant (FUL) and palbociclib (PAL) or ALP in different PDX models established from ER and PR positive breast cancers. PDX models were established from primary tumors or biopsies from bone metastases from endocrine therapy patients with progressing tumors... PR expression was found in 1/9 PDX established from primary breast tumors and 4/8 PDX established from bone metastases. ONA in vivo activity was tested in 2 PDX of bone metastases: PDX BC1101 (PR low) and BC1117 (PR high). BC1101 showed amplification of FGFR1 and CCND1 genes, while BC1117 has an activating mutation of PIK3CA gene.

ONA XR significantly increases suppression of tumor cell proliferation in PgR-high primary breast cancer. The safety profile was consistent with that previously reported. Additional correlative analysis including gene expression will be presented.

Recent preclinical studies further suggest that onapristone adds to inhibition of cell proliferation when combined with CDK4/6 inhibitors and fulvestrant. 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.

Prior ET with tamoxifen or aromatase inhibitor therapy in the adjuvant or metastatic setting is allowed. Other correlates include optional functional imaging of PgR binding with 18 F-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). The study was approved in January 2021, and enrollment is active at the time of this submission.

P1; Trial completion date: Oct 2021 --> Oct 2022 | Trial primary completion date: Apr 2021 --> Apr 2022

P1b; N=28; Recruiting; Sponsor: Memorial Sloan Kettering Cancer Center; Not yet recruiting --> Recruiting; Trial completion date: May 2023 --> Sep 2023; Trial primary completion date: May 2023 --> Sep 2023

P2, N=39, Recruiting, University of Wisconsin, Madison | Not yet recruiting --> Recruiting

P1b; N=28; Not yet recruiting; Sponsor:Memorial Sloan Kettering Cancer Center

The following human cancers known to be associated with the classic nuclear receptor that have responded to either the P receptor modulator mifepristone or onapristone, include breast, uterine, ovarian, and prostate cancer. Larger series are needed to determine the true beneficial effect of this type of therapy. Positive beneficial effects in case reports, at least provide the basis for selection of which cancers to evaluate in a larger series.

The study was approved in July 2020 and recruitment started in November 2020. Seven patients have been enrolled at the time of this submission.

P2, N=39, Not yet recruiting, University of Wisconsin, Madison

P1, N=10, Recruiting, SOLTI Breast Cancer Research Group | Not yet recruiting --> Recruiting | Trial completion date: Mar 2021 --> Oct 2021 | Trial primary completion date: Nov 2020 --> Apr 2021

P1, N=10, Not yet recruiting, SOLTI Breast Cancer Research Group | Initiation date: Nov 2019 --> Nov 2020

Importantly, we were able to reverse this inhibition by treating with onapristone, an anti-progestin currently being investigated in breast cancer clinical trials. Additionally, we have found that an interferon-related gene signature (composed of ISGs) is inversely correlated with PR expression in human tumors. We speculate that PR inhibition of interferon signaling may contribute to creating an immunosuppressed microenvironment and reversal of this through anti-progestins may present a novel therapeutic target to promote immune activity within the tumor.