P2, N=75, Enrolling by invitation, Corcept Therapeutics | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P3, N=152, Completed, Corcept Therapeutics | Active, not recruiting --> Completed

P2, N=249, Active, not recruiting, Corcept Therapeutics | Recruiting --> Active, not recruiting

P3, N=218, Active, not recruiting, Ellodi Pharmaceuticals, LP | Recruiting --> Active, not recruiting

P2, N=90, Recruiting, University of Chicago | Not yet recruiting --> Recruiting

P3, N=360, Active, not recruiting, Corcept Therapeutics | Recruiting --> Active, not recruiting

P2, N=228, Recruiting, Corcept Therapeutics | Trial completion date: Nov 2027 --> May 2027 | Trial primary completion date: May 2027 --> Oct 2024

P3, N=130, Recruiting, Corcept Therapeutics | Trial completion date: Oct 2023 --> Mar 2024 | Trial primary completion date: Oct 2023 --> Mar 2024

P1, N=15, Completed, Corcept Therapeutics | Active, not recruiting --> Completed | N=26 --> 15

P2, N=198, Recruiting, Corcept Therapeutics | Trial completion date: Nov 2024 --> Nov 2027 | Trial primary completion date: May 2024 --> May 2027

Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.

P2, N=75, Enrolling by invitation, Corcept Therapeutics

P3, N=152, Active, not recruiting, Corcept Therapeutics

P3, N=200, Recruiting, Ellodi Pharmaceuticals, LP

P1, N=26, Active, not recruiting, Corcept Therapeutics | Phase classification: P1b --> P1

P1, N=10, Completed, Pop Test Oncology LLC | Recruiting --> Completed

P3, N=360, Recruiting, Corcept Therapeutics

P4, N=125, Recruiting, Alimera Sciences | Trial completion date: Sep 2024 --> Nov 2025 | Trial primary completion date: Sep 2024 --> Nov 2025

P1, N=30, Completed, Corcept Therapeutics

P1, N=30, Completed, Corcept Therapeutics

P1, N=32, Completed, Corcept Therapeutics

P1, N=8, Completed, Corcept Therapeutics

Women with platinum-resistant ovarian, primary peritoneal, or fallopian tube cancer who have received 1â3 lines of prior systemic anticancer therapy, including prior bevacizumab, and at least 1 line of platinum-based therapy are being enrolled. Results The primary endpoint is PFS assessed by blinded independent central review. Key secondary endpoints include OS, PFS by investigator assessment, objective response rate, best overall response, DoR, safety, pharmacokinetics, pharmacodynamics, patient-reported outcomes, and quality of life.Conclusion N/A

Intermittent relacorilant + nab-paclitaxel improved PFS, DOR, and OS compared with nab-paclitaxel monotherapy. On the basis of protocol-prespecified Hochberg step-up multiplicity adjustment, the primary end point did not reach statistical significance (P < .025). A phase III evaluation of this regimen is underway (ClinicalTrials.gov identifier: NCT05257408).

Preclinically, activity has been demonstrated against autoreactive T/B cells, immune-resistant lymphoma, xenografted human T-ALL, melanoma, and multiple myeloma. AVM0703 is also effective as neoadjuvant before chemoimmunotherapy or cell transplant.

P1/2, N=39, Completed, Corcept Therapeutics | Active, not recruiting --> Completed

In a randomized, controlled phase 2 study in patients with recurrent, platinum-resistant ovarian cancer (NCT03776812), gene changes were assessed in 139 patients after treatment with relacorilant + nab-paclitaxel (NP) or NP alone. CLEC10A and the genes correlated with its expression were found to be primarily expressed by a specific subset of dendritic cells, supporting previous reports that GR agonism can suppress dendritic cells. This analysis of CLEC10A and other identified GR target genes confirmed that systemic GR activity in patients with a range of solid tumors can be modulated pharmacologically, indicates that GR modulation may be associated with survival in patients with ovarian cancer, and provides new insights into the systemic functions of the GR in humans.

Recent studies revealed that VMF/PLX40-32 (vemurafenib, a selective inhibitor of mutant BRAF) increases mitochondrial respiration and reactive oxygen species (ROS) production in BRAF human melanoma cell lines...Thus, it is likely that a glucocorticoid receptor antagonist (RU486) could increase the efficacy of BRAF-related therapy in BRAF-mutated melanoma...Moreover, melanoma resistance was decreased if AKT and NF-κB signaling pathways were blocked. These findings highlight mechanisms by which metastatic melanoma cells adapt to survive and could help in the development of most effective therapeutic strategies.

Relacorilant sensitized PitNET organoid responsiveness to Pasireotide. Therefore, our study identified the potential therapeutic use of relacorilant in combination with somatostatin analogs and demonstrated the advantages of relacorilant over Mifepristone, supporting its further development for use in the treatment of CD patients.

Mifepristone is a progesterone and glucocorticoid receptor antagonist. Apoptotic action of mifepristone, interference of heterotypic cell adhesion to the basement membrane, cell migration, growth inhibition of various cancer cell lines, decreased epidermal growth factor expression, suppression of invasive and metastatic cancer potential, increase in tumor necrosis factor, downregulation of cyclin-dependent kinase 2, B-cell lymphoma 2, and Nuclear factor kappa B have opened its potential to be explored as anti-cancer treatment and its effects on leiomyoma. The drug needs to be studied more for the prospectus of its anti-glucocorticoid actions in a wider dimension beyond its acquiescence for the treatment of Cushing syndrome.

Glucocorticoid receptor (GR) antagonism with mifepristone has been shown to reverse the glucocorticoid-induced downregulation of SSTR2; however, the effects of GR modulation on SSTR2 expression in ACTH-secreting NETs, particularly corticotroph pituitary tumors, are not well known...Based on these findings, we propose that GR modulation in patients with ACTH-secreting NETs upregulates previously suppressed SSTR2s, resulting in tumor-specific antisecretory and anti-proliferative effects. The effect of relacorilant on pituitary corticotroph tumors is being investigated in an ongoing phase 3 study (NCT03697109; EudraCT 2018-003096-35).

We demonstrated that diosgenin suppressed COX-2 in human non-small-cell lung carcinoma A549 cells via nuclear factor-kappa B (NF-κB) translocation and the effects were reversed by a glucocorticoid receptor antagonist, RU486...Multiple immunohistochemical analyses showed that diosgenin had an effect on COX-2 and mPGES-1, particularly in the macrophages. Thus, we showed that diosgenin downregulated COX-2 and mPGES-1 via the glucocorticoid receptor and suppressed COX-2 and mPGES-1 in the macrophages of LPS-induced acute mouse liver injury.

Thus, GR antagonism may increase the abundance and function of NK and other immune cells in the tumor microenvironment, promoting immune response in GC+ ACC and other malignancies with GC+. This hypothesis will be tested in a phase 1 trial of relacorilant + ICI.

Data of immune checkpoint blockade with nivolumab, ipilimumab, pembrolizumab and avelumab is explored in detail...Progress in the treatment of ACC has faced challenges stemming from the rarity of the disease. Given recent advances in the understanding of the molecular pathogenesis of ACC, a window of opportunity has now opened to make significant progress in developing therapeutic options that target key pathways such as excessive glucocorticoid signaling, WNT signaling, cell cycle and immune checkpoints.

Importantly, these compounds lack biologically relevant AR/GR agonist activities. Overall, these preclinical findings support the selection of CB-03-10 for further development as an anticancer agent in cases where resistance to AR-targeted therapy or chemotherapy, via upregulation of GR activity, continues to limit the efficacy and duration of clinical benefit with these interventions.

P2, N=178, Active, not recruiting, Corcept Therapeutics | Recruiting --> Active, not recruiting

Structure-based modification of mifepristone (1) led to the discovery of novel mifepristone derivatives with improved selectivity profile...Furthermore, 15 demonstrated substantial inhibition of GR transcriptional activity in the GR positive HCC1806 triple negative breast cancer xenograft model. Overall, compound 15 is a promising GR antagonist candidate to clinically evaluate the impact of GR inhibition in reversal or prevention of therapy resistance.

Reduced abundance of immune cells and immune-related transcripts in GC+ ACC provides insight into the mechanisms by which GC may limit response to ICI therapy. GR antagonism may increase immune related transcripts, thus promoting tumor immune response in GC+ ACC and other malignancies with elevated GC activity. This hypothesis will be tested in a Phase 1 trial of relacorilant + ICI.

In addition, both PT150 and PT157 significantly increased nab-paclitaxel sensitivity in nab-paclitaxel-resistant isogenic PDAC cells. Our work has identified previously undescribed mechanisms of oncogenesis in several cancer types, as well as an efficacious class of novel compounds with the potential to inhibit them. Research Funding: Palisades Therapeutics/Pop Test Oncology LLC

In patients with advanced solid tumors, relacorilant + nab-paclitaxel systemically suppressed the expression of canonical GR-controlled genes (ptgs2 P< .001) and genes encoding candidate-immunomodulatory drug targets (cxcl8, ptger4, ido1; P< .001). Evidence of T-cell activation by relacorilant was observed in PBMCs, syngeneic mouse tumors, and patients with sustained response in a Phase 1 study. This supports the hypothesis that relacorilant can reverse immune suppression by endogenous cortisol in solid tumor cancers. Clinical studies with immune checkpoint inhibitors and relacorilant are planned.