Phase I PIANO Trial
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB77618 | 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: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:<p>Fecal microbiota transplantation (FMT) represents a potential strategy to overcome resistance to immune checkpoint inhibitors in patients with refractory melanoma; however, the role of FMT in first-line treatment settings has not been evaluated. We conducted a multicenter phase I trial combining healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in 20 previously untreated patients with advanced melanoma. The primary end point was safety. No grade 3 adverse events were reported from FMT alone. Five patients (25%) experienced grade 3 immune-related adverse events from combination therapy. Key secondary end points were objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses. The objective response rate was 65% (13 of 20), including four (20%) complete responses. Longitudinal microbiome profiling revealed that all patients engrafted strains from their respective donors; however, the acquired similarity between donor and patient microbiomes only increased over time in responders. Responders experienced an enrichment of immunogenic and a loss of deleterious bacteria following FMT. Avatar mouse models confirmed the role of healthy donor feces in increasing anti-PD-1 efficacy. Our results show that FMT from healthy donors is safe in the first-line setting and warrants further investigation in combination with immune checkpoint inhibitors. ClinicalTrials.gov identifier <a href='https://clinicaltrials.gov/study/NCT03772899' rel='noopener noreferrer' target='_blank'>NCT03772899</a> .</p>
2025-02-27 | MTBLS711 | MetaboLights
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:Combination therapies of chemotherapy and immune checkpoint inhibitors (ICIs) 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 (mFOLFIRINOX, 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 (LA) 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 (PBRs) 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).
2025-12-13 | GSE313101 | GEO
Project description:Tumor-associated macrophages correlate with poor prognosis and resistance to immune checkpoint inhibitor therapy in cancer patients. Disulfiram, a drug for alcoholism treatment, has been identified as an inhibitor for FROUNT, which facilitates chemokine-mediated macrophage accumulation to tumor sites. A combination of disulfiram with a PD-1 antibody synergistically inhibits tumor progression in the mouse model. Here, we performed the single-cell transcriptome analysis of gastric cancer specimens before and after treatment with disulfiram plus nivolumab. We explored the immunophenotypical features associated with the response to the treatment.
2022-11-27 | GSE189926 | GEO
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 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 Part 1, 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. Secondary and 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 harbored more circulating suppressive 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 warrants further exploration to better define mechanisms of resistance and potential therapeutic targets in this population with unmet clinical need.
2026-02-09 | GSE318418 | GEO
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:BTC represents a rare malignancy with unfavorable prognosis. Here we conducted a single-arm, multicenter, prospective phase Ⅱclinical study (ChiCTR2400080783) to evaluate the efficacy and safety of envafolimab and chidamide in combination with gemcitabine plus oxaliplatin (GEMOX) as first-line treatment. 10×scRNA-seq was adopted to conduct an initial exploration into the potential mechanisms underlying the efficacy of the combination regimen.
2025-07-31 | GSE301188 | GEO
Project description:Regorafenib has anti-tumor activity in patients with unresectable hepatocellular carcinoma (uHCC) with potential immunomodulatory effects, suggesting that its combination with immune checkpoint inhibitor may have clinically meaningful benefits in patients with uHCC. The multicenter, single-arm, phase 2 RENOBATE trial tested regorafenib-nivolumab as front-line treatment for uHCC. Forty-two patients received nivolumab 480 mg every 4 weeks and regorafenib 80 mg daily (3-weeks-on/1-week-off schedule). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). ORR per RECIST version 1.1 was 31.0%, meeting the primary endpoint. The most common adverse events were palmar-plantar erythrodysesthesia syndrome (38.1%), alopecia (26.2%) and skin rash (23.8%). Median PFS was 7.38 months. The 1-year OS rate was 80.5%, and the median OS was not reached. Exploratory single-cell RNA sequencing analyses of peripheral blood mononuclear cells showed that long-term responders exhibited T cell receptor repertoire diversification, enrichment of genes representing immunotherapy responsiveness in MKI67+ proliferating CD8+ T cells and a higher probability of M1-directed monocyte polarization. Our data support further clinical development of the regorafenib-nivolumab combination as front-line treatment for uHCC and provide preliminary insights on immune biomarkers of response. ClinicalTrials.gov identifier: NCT04310709 .
2023-12-31 | GSE243572 | GEO