A Phase 2, Single-Arm Trial of Relacorilant in Combination With Nab-Paclitaxel and Gemcitabine in Patients With Previously Untreated Metastatic Pancreatic Adenocarcinoma (TRIDENT)

This is a Phase 2, single-arm study to evaluate the safety and efficacy of relacorilant in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic adenocarcinoma (PDAC).

More details:

Study treatment will be comprised of relacorilant, combined with nab-paclitaxel and gemcitabine. Each patient will receive relacorilant 150 mg administered orally under fed conditions, once daily for 3 consecutive days on the day before (excluding Cycle 1 Day -1), the day of, and the day after nab-paclitaxel (100 mg/m\^2) and gemcitabine (1000 mg/m\^2) infusions. Nab-paclitaxel and gemcitabine will be administered on Days 1, 8, and 15 of each 28-day cycle. Patients will receive study treatment until they reach progressive disease (PD), experience unmanageable toxicity, or until other discontinuation criteria are met.

Overview

Relacorilant (CORT125134) is an investigational, oral, selective glucocorticoid receptor (GR) modulator/antagonist. It is being studied for endogenous Cushing’s syndrome (hypercortisolism) and as a chemosensitizer with nab-paclitaxel in solid tumors, notably platinum‑resistant ovarian cancer. Dosing in trials includes once‑daily titration (100–200 mg and higher) in Cushing’s syndrome—150 mg QD falls within the “low‑dose” cohort—and intermittent 150 mg around chemotherapy infusions in oncology. (frontiersin.org)

Mechanism of action

• Competitive antagonism of the glucocorticoid receptor, designed to blunt pathologic cortisol signaling without meaningful activity at the progesterone receptor (a differentiation from mifepristone). In Cushing’s studies, clinical benefit occurred without drug‑induced hypokalemia or vaginal bleeding typically linked to PR antagonism. (frontiersin.org)
• In oncology, GR blockade is intended to reverse cortisol‑mediated anti‑apoptotic signaling (for example via SGK1/DUSP1) and restore sensitivity to microtubule agents such as paclitaxel/nab‑paclitaxel. (ascopubs.org)

Efficacy

Cushing’s syndrome (endogenous hypercortisolism) - Phase 2, open‑label, dose‑finding (n=34 treated): low‑dose cohort 100–200 mg QD (includes 150 mg); response rates (predefined) were 41.7% for hypertension and 15.4% for hyperglycemia. High‑dose (250–400 mg) responses were 63.6% and 50.0%, respectively. (frontiersin.org) - Phase 3 GRACE, randomized‑withdrawal: after open‑label improvement, continued relacorilant reduced the odds of loss of blood pressure control vs placebo (OR 0.17; P=0.02). Open‑label data also showed improvements in blood pressure and glucose parameters. Peer‑reviewed publication is pending; results have been presented and summarized by the sponsor and independent medical news outlets. (ir.corcept.com) - Long‑term open‑label extension (interim analysis): up to 6 years’ treatment associated with sustained blood pressure improvements and favorable cardiometabolic markers. (endocrinepractice.org)

Oncology (with nab‑paclitaxel) - Ovarian cancer, randomized phase 2 (n=178): intermittent relacorilant 150 mg the day before/of/after each weekly nab‑paclitaxel improved PFS vs nab‑paclitaxel alone (HR 0.66; P=0.038) and duration of response; OS HR 0.67 (P=0.066) at preplanned analysis. Continuous 100 mg QD did not significantly improve outcomes. ORR was similar across arms. (pubmed.ncbi.nlm.nih.gov) - Ovarian cancer, phase 3 ROSELLA (n=381): relacorilant (150 mg intermittent) + nab‑paclitaxel improved PFS by blinded review (HR 0.70; median 6.54 vs 5.52 months; P=0.0076). Interim OS favored the combination (HR 0.69; median 15.97 vs 11.50 months) without meeting the stringent interim alpha; safety largely consistent with nab‑paclitaxel exposure. (pubmed.ncbi.nlm.nih.gov)

Safety

• Cushing’s syndrome (Phase 2): common adverse events ≥20% included back pain, headache, peripheral edema, nausea, extremity pain, diarrhea, and dizziness; no drug‑induced hypokalemia or vaginal bleeding were observed. (frontiersin.org)
• GRACE: sponsor‑reported and meeting‑presented data indicate relacorilant was generally well tolerated; during randomized withdrawal, adverse event rates were similar to placebo. (ir.corcept.com)
• Oncology combinations: in the phase 2 ovarian study, grade ≥3 events included neutropenia, anemia, peripheral neuropathy, and fatigue/asthenia, comparable across arms with growth‑factor use as needed. In ROSELLA, higher grade ≥3 neutropenia and anemia were seen with the combination, consistent with increased nab‑paclitaxel exposure. (pubmed.ncbi.nlm.nih.gov)
• Phase 1 in healthy volunteers showed relacorilant was generally well tolerated up to 250 mg/day for 14 days; half‑life ~11–19 h, supporting QD dosing. (pubmed.ncbi.nlm.nih.gov)

Dosing notes relevant to “150 mg QD”

• Cushing’s trials used once‑daily titration; 150 mg QD was within the low‑dose range evaluated prospectively (100–200 mg QD) and associated with clinical responses in the phase 2 study. Regulatory‑grade, fixed‑dose conclusions specific to exactly 150 mg QD await full phase 3 publication and labeling. (frontiersin.org)
• In oncology, the regimen that improved outcomes uses 150 mg intermittently around nab‑paclitaxel infusions, not continuous 150 mg QD. Continuous daily dosing studied with chemotherapy was 100 mg QD. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Frontiers in Endocrinology (Phase 2 Cushing’s): clinical outcomes and safety across 100–200 mg and 250–400 mg QD cohorts. (frontiersin.org)
• Journal of Clinical Oncology (Phase 2 ovarian cancer): intermittent 150 mg around nab‑paclitaxel improved PFS and DOR; OS trend. (pubmed.ncbi.nlm.nih.gov)
• PubMed (Phase 3 ROSELLA): randomized phase 3 results in platinum‑resistant ovarian cancer (PFS benefit; interim OS). (pubmed.ncbi.nlm.nih.gov)
• Clinical Pharmacology in Drug Development (Phase 1): first‑in‑human PK/PD, safety supporting QD use. (pubmed.ncbi.nlm.nih.gov)
• Endocrine Practice (2025 OLE interim): long‑term safety/efficacy signals in Cushing’s. (endocrinepractice.org)
• Meeting/sponsor summaries for GRACE (Phase 3 Cushing’s) until peer‑reviewed publication is available. (ir.corcept.com)

Notes: Relacorilant remains investigational in the United States as of October 7, 2025; consult ongoing regulatory updates and eventual labeling for definitive dosing and safety information. (trial.medpath.com)

Last updated: Oct 2025

Inclusion Criteria:

* Signed and dated informed consent form prior to screening procedures

* Histologic diagnosis or cytologic diagnosis of pancreatic adenocarcinoma (PDAC)

* Initial diagnosis of metastatic disease occurred ≤6 weeks prior to enrollment in the study

* Life expectancy of ≥3 months

* Radiographic confirmation of metastatic disease with at least 1 distant tumor metastasis measurable on radiology imaging per RECIST version 1.1 criteria

* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

* Able to provide informed consent and comply with protocol requirements

* Able to swallow and retain oral medication and does not have uncontrolled emesis

* Has adequate gastrointestinal absorption

* Received no prior systemic anticancer therapy to treat metastatic disease

* If a patient received prior treatment of PDAC with chemotherapy, disease progression must have occurred \>12 months after completing the last dose, and no persistent treatment-related toxicities can be present.

* Adequate organ function

* Negative pregnancy test for patients of childbearing potential

* Agree to use protocol defined precautions to avoid pregnancy

Exclusion Criteria:

* Any major surgery within 4 weeks prior to enrollment

* Prior treatment as follows:

1. Radiotherapy, surgery, chemotherapy, immunotherapy, investigational therapy for the treatment of metastatic disease

2. Systemic, inhaled, or prescription strength topical corticosteroids within 5 times the half-life of the corticosteroid used prior to first dose of study drug

* Received gemcitabine or nab-paclitaxel to treat their PDAC

* Known germline or somatic breast cancer gene (BRCA) mutation

* Peripheral neuropathy from any cause \>Grade 1

* Medical conditions requiring chronic or frequent treatment with corticosteroids

* History of severe hypersensitivity or severe reaction to any of study drugs or their excipients

* Concurrent treatment with mifepristone or other glucocorticoid receptor modulators.

* Uncontrolled condition(s) which, may confound the results of the trial or interfere with the patient's safety or participation

* Active infection with HIV, hepatitis C or hepatitis B virus

* Known untreated parenchymal brain metastasis or uncontrolled central nervous system metastases

* History of other malignancy within 3 years prior to enrollment

* Taking protocol-prohibited medications

* Concurrent treatment with other investigational treatment studies for cancer

* Has received a live vaccine within 30 days prior to the study start date