RNA sequensing data of a phase 2 clinical trial of pancreatic ductal adenocarcinoma treated with entinostat in combination with nivolumab
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PROVIDER: PRJNA1041407 | ENA |
REPOSITORIES: ENA
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Project description:We conducted a single-center, open-label, Simon two-stage, phase II study of entinostat in combination with the PD1 inhibitor nivolumab in patients with advanced pancreatic ductal adenocarcinoma. Patients received oral entinostat 5 mg once a week. After a 14-day lead-in with entinostat monotherapy, patients concurrently receive entinostat 5 mg orally once a week plus nivolumab 240 mg intravenously until the time of progression or unacceptable toxicities.
2024-07-29 | GSE248014 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDA) is characterized by low cytotoxic lymphocytes, abundant immune-suppressive cells, and resistance to immune checkpoint inhibitors (ICI). Preclinical PDA models showed the HDAC inhibitor entinostat reduced myeloid cell immunosuppression, sensitizing tumors to ICI therapy. This phase II study combined entinostat with nivolumab (PD1 inhibitor) in patients with advanced PDA (NCT03250273). Patients received entinostat 5 mg orally once weekly for 14-day lead-in, followed by entinostat and nivolumab. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. Secondary endpoints included safety, duration of response, progression free-survival and overall survival. Between November 2017 and November 2020, 27 evaluable patients were enrolled. Three showed partial responses (11% ORR, 95% CI, 2.4%-29.2%) with a median response duration of 10.2 months. Median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.89 (95% CI, 1.381-2.301) and 2.729 (95% CI, 1.841-5.622) months. Grade ≥3 treatment-related adverse events occurred in 19 patients (63%), including decreased lymphocyte count, anemia, hypoalbuminemia, and hyponatremia. As exploratory analysis, peripheral and tumor immune profiles changes were assessed using CyTOF, mIHC, and RNA-seq. Entinostat increased dendritic cell activation and maturation. Gene expression analysis revealed an enrichment in inflammatory response pathways with combination treatment. Although the primary endpoint was not met, entinostat and nivolumab showed durable responses in a small subset of PDA patients. Myeloid cell immunomodulation supported the preclinical hypothesis, providing a basis for future combinatorial therapies to enhance clinical benefits in PDA.
| S-EPMC11557583 | biostudies-literature
Project description:Neoadjuvant modified FOLFIRINOX plus nivolumab in borderline-resectable pancreatic ductal adenocarcinoma: a pilot phase 1 trial
| PRJNA1380488 | ENA
Project description:Expression profiling of tumor samples obtained during CA209-038 (ClinicalTrials.gov Identifier: NCT01621490). The purpose of this study is to evaluate pharmacodynamic changes of nivolumab and nivolumab in combination with ipilimumab treatment on the biomarkers measured in the peripheral blood and tumor tissues of subjects with advanced melanoma (unresectable or advanced). Samples are rumor core needle biopsies obtained at trial enrolment (i.e. Screen) and/or at Cycle 1 Day 29 (i.e.Week 4) from Subjects With Advanced Melanoma (Unresectable or Metastatic) treated with nivolumab (BMS-936558,MDX-1106) 3 mg/kg solution intravenously every 2 weeks on Bristol-Myers Squibb clinical trial protocol CA209-038 Part 1 . Cohort 2 patients have progressed on anti-CTLA4 (ipilimumab) monoclonal antibody therapy. Values are from an interim lock of the trial data in July 2014. Best overall response (BOR) was defined using RECIST 1.1 criteria: tumor assessments between date of first dose and the date of first objectively documented progression, or the date of non-missing subsequent anti-cancer therapy (whichever occurs first) were used to derive BOR. MPCT is Maximum reduction in tumor size (index lesions only) up to first progression, and is the value typically shown on a waterfall plot.
2022-01-01 | E-MTAB-4030 | biostudies-arrayexpress
Project description:Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can improve responses when combined with immune checkpoint therapy (ICT). We conducted a phase I trial to determine the optimal dose of triplet therapy with sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma (ccRCC). The primary endpoint was safety. The addition of even a low sitravatinib dose of 35 mg daily to nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events (irAEs). Subsequent dose reduction of ipilimumab to 0.7 mg/kg in combination with nivolumab 3 mg/kg allowed safe escalation of sitravatinib up to 100 mg daily. Key secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Overall, the triplet combination in the dose-finding setting achieved an ORR of 45.5%, DCR of 86.4%, and a median PFS of 14.5 months with 72.7% of patients alive after a median follow-up of 15.7 months. Single-cell RNA-seq performed in longitudinally collected tumor biopsies from 12 patients treated with the triplet therapy identified a tumor cell-specific epithelial-mesenchymal transition (EMT)-like program associated with treatment resistance and poor outcomes in patients of this trial and in patients of the TCGA ccRCC cohort. Within the tumor microenvironment (TME), the emergence of treatment resistance was characterized by a transition from cytotoxic to exhausted T cell state and enrichment for M2-like myeloid cells. The observed changes in gene expression dynamics and cellular states in tumor cell and TME may help inform future strategies to optimize ICT efficacy.
2024-11-26 | GSE264586 | GEO
Project description:Combination therapies of chemotherapy and immune checkpoint inhibitors have failed to improve survival in pancreatic ductal adenocarcinoma (PDAC), except in rare MSI-H cases, despite their success in other solid tumors. Most prior studies have been conducted in advanced disease. Here, we present clinical, pathologic, and translational results from a phase 1b/2 investigator-initiated study evaluating neoadjuvant modified FOLFIRINOX (mFFX) plus nivolumab in patients with borderline-resectable (BR) PDAC. Among 28 patients enrolled, 22 (79%) proceeded to surgery. Treatment was well tolerated with no significant delays or surgical complications, meeting the primary endpoint. Among patients who underwent surgical resection, median disease-free survival was 19.7 months, median progression-free survival was 26 months (95% CI: 14.7-34.3) and median overall survival was 38 months (95% CI: 27.9-not reached). The regimen demonstrated an acceptable safety profile, with all Grade 3-4 treatment-related adverse events due to chemotherapy and no Grade 3 immune related adverse events observed. Treatment effects were assessed using paired pre- and post-treatment samples and by comparing post-treatment tumors from the nivolumab cohort to historical BR mFFX-only controls. In paired analyses, intra-tumoral CD8 T cells and plasma cells increased together; in between-group comparisons, plasma cells were significantly higher in the nivolumab cohort, with a modest CD8 T cell increase. Immunohistochemistry revealed that plasma cell abundance correlated with dense intra-tumoral lymphoid aggregates lacking germinal center-like morphology, a pattern consistent with extrafollicular B cell differentiation. Single-cell spatial transcriptomics identified irregular lymphoid aggregates with high plasma cell to B cell ratios that were enriched for terminally exhausted CD8 T cells and de-enriched for progenitor exhausted CD8 T cells and central memory CD4 T cells. Together, these findings implicate intra-tumoral LA disorganization and skewed T cell subsets as complementary features associated with limited efficacy of PD-1-based chemoimmunotherapy in PDAC. (Clinicaltrials.gov identifier: NCT03970252).
2025-12-15 | GSE313662 | GEO
Project description:As part of the preclinical research for a recently published trial of combination therapy with the HDAC inhibitor entinostat and the PD1 inhibitor pembrolizumab, an experiment was performed to determined the influence of entinostat and the BET inhibitor JQ1 on the transcriptome of three uveal melanoma cell lines. The cell lines were cultured and treated with either entinostat, JQ1 or DMSO and subjected to RNA-seq for identification of differentially expressed genes.
2021-09-09 | E-MTAB-11058 | biostudies-arrayexpress
Project description:Tumor core needle biopsies from kidney or metastatic sites obtained at trial enrollment i.e. Screen and/or at Cycle 2 Day 8 (i.e.Week 4) from metastatic clear cell RCC patients treated with 0.2mpk, 3mpk or 10mpk (as 2nd or further line of therapy; Arms A,B,C) or 10mpk (as first line therapy; Arm D) of nivolumab (BMS-936558,MDX-1106) on Bristol-Myers Squibb clinical trial protocol CA209-009.
2016-05-15 | E-MTAB-3218 | biostudies-arrayexpress
Project description:Background and aims: Immune checkpoint inhibition (ICI) and anti-angiogenic therapies are active in hepatocellular carcinoma (HCC), although patients with impaired hepatic function have worse outcomes. Methods: We conducted a multi-center, open-label phase II clinical trial to assess the safety and efficacy of the multikinase inhibitor, sorafenib, combined with nivolumab, in patients with advanced or unresectable HCC and varying liver function. In a Part 1 safety lead-in, we investigated the primary endpoint of the maximum-tolerated dose (MTD) of the combination in patients with Child-Pugh A or B7 HCC. In Part 2, we enrolled patients with Child-Pugh B HCC with the primary endpoint of grade >/=3 treatment-related adverse events (TRAE) incidence. Exploratory endpoints included immunologic biomarkers. Results: Overall, 25 patients were consented and 16 eligible patients enrolled. In Part 1, dose-limiting toxicity occurred in 1 of 6 patients in Dose Level -1, and 2 of 5 patients in Dose Level 1; Dose Level -1 was determined to be the MTD. In total, 69% of patients experienced a Grade >/=3 TRAE, with similar distribution for patients with Child-Pugh A and B liver function (70%, 95% CI: 0.35, 0.93 vs 66.7%, 95% CI: 0.22, 0.96). The objective response rate was 6%. We found that patients with Child-Pugh B liver disease harbored more circulating suppressive CD14+ monocytes at baseline. Conclusions: While the combination of sorafenib and nivolumab demonstrated acceptable safety at the MTD in both Child-Pugh subgroups, the objective response rate was below the pre-specified threshold to be declared worthy of further exploration. A distinct immune cell profile in Child-Pugh B patients may define mechanisms of resistance and potential therapeutic targets in this population with unmet clinical need
2025-12-12 | GSE313642 | GEO
Project description:Phase 2 study of Nivolumab and Entinostat in unresectable or metastatic cholangiocarcinoma and pancreatic adenocarcinoma
| PRJNA1102448 | ENA