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Pilot Trial of Arginine Deprivation plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

ABSTRACT: Pilot Trial of Arginine Deprivation plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

PROVIDER: PRJNA836946 | ENA |

REPOSITORIES: ENA

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Pilot Trial of Arginine Deprivation plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

Project description:Metastatic uveal melanoma (UM) remains challenging to treat, with objective response rates to immune checkpoint blockade (ICB) much lower than in primary cutaneous melanoma (CM). Besides a lower mutational burden, the overall immune-excluded tumor microenvironment of UM might contribute to the poor response rate. We therefore aimed at targeting deficiency in argininosuccinate synthase 1, which is a key metabolic feature of UM. This study aimed at investigating safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy ADI-PEG 20. 9 patients were enrolled in this pilot study. The combination therapy was safe and tolerable with absence of immune related adverse events (irAE) of special interest but with 4 of 9 patients experiencing a CTCAE grade 3 AE. No objective responses were observed. All except one patient developed anti-drug antibodies (ADA) within a month of treatment initiation and therefore did not maintain arginine depletion. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at baseline in metastases.

2022-05-13 | GSE202687 | GEO

Biopsies from advanced melanoma before and/or after treatment with nivolumab

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

Phase II Clinical and Immune Correlate Study of Adjuvant Nivolumab plus Ipilimumab for High-Risk Resected Melanoma

Project description:Background: Adjuvant therapy for high-risk resected melanoma with PD-1 blockade results in median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of nivolumab (NIVO) in Checkmate-915, did not result in increased RFS. A pilot phase II adjuvant study of either standard or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative studies. Methods: Patients (pts) with resected stages IIIB/IIIC/IV melanoma received either IPI 3mg/kg and NIVO 1mg/kg (cohort 4) or IPI 1mg/kg and NIVO 3mg/kg (cohorts 5 and 6) induction therapy every three weeks for 12 weeks, followed by maintenance NIVO. Peripheral blood samples at baseline and on-treatment were assessed by flow cytometry for potential biomarkers. Peripheral CD8+ T-cells were assessed by RNA-Seq. Results: High rates of grade 3-4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of patients in cohorts 4, 5 and 6 respectively. At a median of 63.9 months of follow up, 16/56 pts (29%) relapsed. For all patients, at five-years, RFS was 71% (95% CI: 60, 84), and overall survival was 94% (95% CI: 88, 100). Expansion of CD3+CD4+CD38+CD127-GARP- T-cells, an on-treatment increase in CD39 expression in CD8+ T-cells, and T-cell expression of phosphorylated STAT2 and STAT5 were associated with relapse. Conclusions: Adjuvant IPI/NIVO at the induction doses used resulted in excellent relapse-free survival, albeit with a high rate of grade 3-4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T-cells and STAT signaling pathways with relapse.

2022-12-02 | GSE219251 | GEO

Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study.

Project description: Not available

| S-EPMC7319717 | biostudies-literature

Nivolumab+Ipilimumab+RT in MSS mCRC

Project description:This research is being done to study the effects of the combination of ipilimumab, nivolumab, and radiation therapy in people with metastatic microsatellite stable colorectal cancer. This research study involves the following drugs and interventions: * Ipilimumab * Nivolumab * Radiation Therapy

| 2353637 | ecrin-mdr-crc

Nivolumab plus ipilimumab in advanced melanoma.

Project description: Not available

| S-EPMC5698004 | biostudies-literature

Gene expression of prostate tumor tissues treated with leuprolide acetate plus ipilimumab

Project description:To study the immune response of the prostate tumor tissues after the leuprolide acetate plus ipilimumab, we compared the gene expression of 6 post-therapy with 3 pre-therapy samples. We identified 690 differential expressed genes (DEGs). Pathway analysis showed that these genes are associated with critical immune pathways such as CTLA4 signaling, antigen presenting etc.

2017-02-08 | GSE77910 | GEO

A Study of Nivolumab, Nivolumab Plus Ipilimumab, or Investigator’s Choice Chemotherapy for the Treatment of Participants With Deficient Mismatch Repair (dMMR)/Microsatellite Instability High (MSI-H) Metastatic Colorectal Cancer (mCRC)

Project description:The main purpose of this study is to compare the clinical benefit, as measured by Progression-Free Survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS), achieved by nivolumab in combination with ipilimumab or by nivolumab monotherapy in participants with Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) metastatic colorectal cancer (mCRC). This study will also compare nivolumab plus ipilimumab combination vs chemotherapy for treatment of MSI-H/dMMR mCRC participants.

| 2310012 | ecrin-mdr-crc

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.

Project description: Not available

| S-EPMC5972549 | biostudies-literature

A pilot study of the Bruton's tyrosine kinase inhibitor ibrutinib in combination with nivolumab in patients with metastatic solid tumors

Project description:Background: Preclinical work has demonstrated that ibrutinib inhibits the generation, migration and immunosuppressive function of myeloid-derived suppressor cells (MDSC). A pilot study tested the combination of ibrutinib and nivolumab in patients with metastatic solid tumors. Methods: Sixteen patients with metastatic solid malignancies were treated with ibrutinib (420 mg) daily and nivolumab (240 mg) IV on days 1 and 15 of 28 day cycles. Ibrutinib dosing started 7 days before cycle 1 of nivolumab and was given until cycle 1, day 8 of nivolumab. The effect of ibrutinib alone and in combination with nivolumab on circulating MDSC and immune subsets and cytokine/chemokine levels were measured. Single-cell RNA and TCR sequencing was also performed. Results: The most common treatment-related AEs were fatigue (31%) and anorexia (31%). Five patients had a clinical response (4 partial, 1 complete). Four patients had stable disease at 3 months. Median progression-free survival was 3.5 months and median overall survival 10.8 months. MDSC levels increased following 7 days of single-agent ibrutinib compared to baseline (21.91% vs. 27.67%). There was increased T cell proliferation in response (33.9% vs. 40.06%, p<0.01) to the combination regimen. Plasma levels of CCL2, CCL3, CCL4, CCL13, IL- 8, and VEGF-α decreased with ibrutinib treatment. Ibrutinib treatment altered the transcriptional state of the myeloid cell compartment and led to increased cancer-associated TCR clonotypes. Conclusion: The combination of ibrutinib and nivolumab was well tolerated and ibrutinib significantly impacted MDSC and T cell function in patients with solid metastatic tumors.

2022-06-24 | GSE178882 | GEO

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