relacorilant (CORT125134)

P2, N=125, Active, not recruiting, Corcept Therapeutics | Enrolling by invitation --> Active, not recruiting | N=75 --> 125

P3, N=137, Completed, Corcept Therapeutics | Active, not recruiting --> Completed

At the pituitary level, pasireotide is an approved somatostatin receptor ligand, and compounds targeting cell cycle regulation, cell signalling and epigenetics are now under investigation. Levoketoconazole and osilodrostat are novel steroid inhibitors, and relacorilant overcomes the adverse effects of mifepristone. Adrenal ACTH receptor blockage and immunotherapy could also play a role.

P3, N=360, Active, not recruiting, Corcept Therapeutics | Trial completion date: Jun 2025 --> Dec 2025 | Trial primary completion date: Jun 2024 --> Dec 2024

P1, N=35, Active, not recruiting, University of Chicago | Recruiting --> Active, not recruiting | N=24 --> 35

P3, N=130, Active, not recruiting, Corcept Therapeutics | Recruiting --> Active, not recruiting | Trial completion date: Mar 2024 --> Sep 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

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

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

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=75, Enrolling by invitation, Corcept Therapeutics

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

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

P3, N=360, Recruiting, Corcept Therapeutics

P1, N=30, Completed, Corcept Therapeutics

P1, N=8, Completed, Corcept Therapeutics

P1, N=32, Completed, Corcept Therapeutics

P1, N=30, Completed, Corcept Therapeutics

GR silencing in DTX-sensitive and -resistant PCa cells decreased LEDGF/p75 expression, and GR upregulation in enzalutamide-resistant cells correlated with increased LEDGF/p75 expression...The GR modulators exicorilant and relacorilant increased the sensitivity of chemoresistant PCa cells to DTX-induced cell death, and this effect was more pronounced upon LEDGF/p75 silencing. RNA-sequencing of DTX-resistant cells with GR or LEDGF/p75 knockdown revealed a transcriptomic overlap targeting signaling pathways associated with cell survival and proliferation, cancer, and therapy resistance. These studies implicate the GR-LEDGF/p75 axis in PCa therapy resistance and provide a pre-clinical rationale for developing novel therapeutic strategies for advanced PCa.

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).

Due to elevated liver functiontests, the patient couldn't have started ketoconazole and relacorilant treatment.Because of non-controlled DM, pasireotide treatment was contraindicated in her case.She didn't agree either for metyrapone treatment or for adrenalectomy. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*

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.

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.

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).

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.

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

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 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.