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Relacorilant With Pembrolizumab: A Phase 1b, Open-Label Study of a Selective Glucocorticoid Receptor Modulator Combined With a Checkpoint Inhibitor for Patients With Adrenocortical Carcinoma With Excess Glucocorticoid Production

Adrenocortical carcinoma (ACC) is an aggressive cancer with poor response to chemotherapeutic and immunotherapeutic agents. About half of ACCs produce glucocorticoids (GC), and the presence of GC excess (hypercortisolism) is correlated with decreased survival in patients with ACC. The broad immunosu...

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Detalles Bibliográficos
Autores principales: Habra, Mouhammed Amir, Hammer, Gary D, Kebebew, Electron, Worden, Francis P, Raj, Nitya, Hallanger-Johnson, Julie E, Grauer, Andreas, Moraitis, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089943/
http://dx.doi.org/10.1210/jendso/bvab048.188
Descripción
Sumario:Adrenocortical carcinoma (ACC) is an aggressive cancer with poor response to chemotherapeutic and immunotherapeutic agents. About half of ACCs produce glucocorticoids (GC), and the presence of GC excess (hypercortisolism) is correlated with decreased survival in patients with ACC. The broad immunosuppressive effects of GC may contribute to the limited efficacy of immune checkpoint inhibitors, such as pembrolizumab, in these patients. Antagonism of the glucocorticoid receptor (GR) has the potential to increase immune-related transcripts, thus promoting tumor immune response in ACC with GC excess. To test this hypothesis, we introduce a phase 1b study evaluating the combined treatment of relacorilant (CORT125134, Corcept Therapeutics) with pembrolizumab in patients with advanced ACC and hypercortisolism (NCT04373265). Relacorilant is a selective (no activity at other steroid receptors), oral GR modulator in development for Cushing syndrome and, in combination with chemotherapy, for various solid tumors. In healthy subjects, prednisone causes rapid reductions in eosinophils, lymphocytes, and osteocalcin and rapid increases in neutrophils. Relacorilant ameliorates these effects. In a phase 2 study in patients with endogenous Cushing syndrome treated with relacorilant, improvements in the signs and symptoms of GC excess were seen. The primary objective of this study is to determine the safety and efficacy of the recommended regimen of relacorilant with pembrolizumab in patients with advanced ACC and hypercortisolism. Pembrolizumab infusion will occur on day 1 of each 21-day cycle, and relacorilant will be administered once daily, starting 3 days before the first pembrolizumab infusion. Relacorilant doses will be escalated in 100-mg increments (100 mg up to 400 mg, as tolerated). Patients will receive treatment until they experience disease progression or unacceptable toxicity. Approximately 20 adults with confirmed advanced, unresectable and/or metastatic ACC will be enrolled. GC excess must be documented by either ACTH <10 pg/mL and serum cortisol >1.8 µg/dL after dexamethasone suppression testing (DST), or the presence of two of the following criteria: elevated urinary free cortisol; high late-night salivary cortisol; and DST cortisol >1.8 µg/dL. Assessments will include safety, tolerability, and efficacy. Secondary objectives include a determination of the non-progression rate at 27 weeks, evaluation of progression-free survival, overall survival, duration of response, and an assessment of the effect of the combination on clinical manifestations of hypercortisolism. This will be the first clinical study to evaluate whether GR antagonism promotes tumor response in patients with ACC and GC excess treated with checkpoint inhibitors.