Epigenetic Priming with Oral Decitabine/Cedazuridine Combined with Nivolumab in Unresectable or Metastatic Mucosal Melanoma: Clinical and Correlative Findings from a Phase Ib/II Trial.
5 affiliations
- 1Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
- 2Department of Pediatrics, School of Medicine, University of Colorado Cancer Center Biostatistics Core, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
- 3Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
- 4Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
- 5Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Abstract
Background/Objectives: Mucosal melanoma is a rare, aggressive melanoma subtype with lower response rates to immune checkpoint inhibitors than cutaneous melanoma. We previously identified reduced expression of innate immune pathogen-sensing pathway genes in mucosal melanoma, including components of the retinoic acid-inducible gene-I (RIG-I) pathway, and found that decitabine can induce re-expression of these immune genes and tumor-associated antigens. This study evaluated epigenetic immune priming with oral decitabine/cedazuridine (DEC-C) combined with nivolumab in patients with unresectable or metastatic mucosal melanoma. Methods: NCT05089370 was an open-label, single-center, single-arm phase Ib/II trial. Patients received DEC-C (35 mg decitabine/100 mg cedazuridine) orally for five days followed by nivolumab 480 mg every four weeks. The primary endpoint was safety and determination of the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR) and survival outcomes. Exploratory endpoints assessed immune and epigenetic correlates. Results: Eight patients were enrolled. Treatment-related adverse events occurred in seven patients (88%), with dose-limiting toxicities observed in three (38%). The RP2D was not established due to premature trial closure. At data cut-off, two patients remained on treatment with ongoing partial responses. The ORR was 25% (95% CI, 3.2-65), median progression-free survival was 3.0 months (95% CI, 2.1-not reached), and median overall survival was 7.2 months (95% CI, 4.4-not reached). Treatment significantly decreased global DNA methylation and induced RIG-I pathway genes in circulating immune cells. Conclusions: DEC-C plus nivolumab was associated with frequent treatment-related toxicities consistent with the known safety profiles of decitabine and nivolumab and demonstrated on-target epigenetic and immune activity in circulating cells. Although two partial responses were observed, the small sample size and wide confidence interval preclude conclusions regarding efficacy. These findings support future biomarker-integrated studies evaluating epigenetic immune-priming combinations in mucosal melanoma, with prospective optimization of dose, schedule, and treatment setting.
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BibTeX
@article{borgers2026epigenetic,
title = {{Epigenetic Priming with Oral Decitabine/Cedazuridine Combined with Nivolumab in Unresectable or Metastatic Mucosal Melanoma: Clinical and Correlative Findings from a Phase Ib/II Trial.}},
author = {Jessica S W Borgers and Cheng-Chang Wu and Theresa M Medina and Claire M Muckle and Elizabeth N Katsnelson and Phaedra A Whitty and Luke Mantle and Sapna P Patel and Dexiang Gao and Kimberly R Jordan and William A Robinson and Richard P Tobin and Martin D McCarter and Kasey L Couts},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18193172},
url = {https://europepmc.org/article/MED/42882866},
note = {CC BY},
}
RIS
TY - JOUR
TI - Epigenetic Priming with Oral Decitabine/Cedazuridine Combined with Nivolumab in Unresectable or Metastatic Mucosal Melanoma: Clinical and Correlative Findings from a Phase Ib/II Trial.
AU - Jessica S W Borgers
AU - Cheng-Chang Wu
AU - Theresa M Medina
AU - Claire M Muckle
AU - Elizabeth N Katsnelson
AU - Phaedra A Whitty
AU - Luke Mantle
AU - Sapna P Patel
AU - Dexiang Gao
AU - Kimberly R Jordan
AU - William A Robinson
AU - Richard P Tobin
AU - Martin D McCarter
AU - Kasey L Couts
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18193172
UR - https://europepmc.org/article/MED/42882866
AB - Background/Objectives: Mucosal melanoma is a rare, aggressive melanoma subtype with lower response rates to immune checkpoint inhibitors than cutaneous melanoma. We previously identified reduced expression of innate immune pathogen-sensing pathway genes in mucosal melanoma, including components of the retinoic acid-inducible gene-I (RIG-I) pathway, and found that decitabine can induce re-expression of these immune genes and tumor-associated antigens. This study evaluated epigenetic immune priming with oral decitabine/cedazuridine (DEC-C) combined with nivolumab in patients with unresectable or metastatic mucosal melanoma. Methods: NCT05089370 was an open-label, single-center, single-arm phase Ib/II trial. Patients received DEC-C (35 mg decitabine/100 mg cedazuridine) orally for five days followed by nivolumab 480 mg every four weeks. The primary endpoint was safety and determination of the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR) and survival outcomes. Exploratory endpoints assessed immune and epigenetic correlates. Results: Eight patients were enrolled. Treatment-related adverse events occurred in seven patients (88%), with dose-limiting toxicities observed in three (38%). The RP2D was not established due to premature trial closure. At data cut-off, two patients remained on treatment with ongoing partial responses. The ORR was 25% (95% CI, 3.2-65), median progression-free survival was 3.0 months (95% CI, 2.1-not reached), and median overall survival was 7.2 months (95% CI, 4.4-not reached). Treatment significantly decreased global DNA methylation and induced RIG-I pathway genes in circulating immune cells. Conclusions: DEC-C plus nivolumab was associated with frequent treatment-related toxicities consistent with the known safety profiles of decitabine and nivolumab and demonstrated on-target epigenetic and immune activity in circulating cells. Although two partial responses were observed, the small sample size and wide confidence interval preclude conclusions regarding efficacy. These findings support future biomarker-integrated studies evaluating epigenetic immune-priming combinations in mucosal melanoma, with prospective optimization of dose, schedule, and treatment setting.
SN - 2072-6694
ER -