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A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (EPIC)

ABSTRACT: A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (EPIC)

PROVIDER: PRJNA924050 | ENA |

REPOSITORIES: ENA

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A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (EPIC)

Project description:We designed a Phase II clinical trial testing the combination of guadecitabine (DNMTi) and atezolizumab (anti-PD-L1) with the goal to re-stimulate the immune mediated anticancer effects of immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma patients who were resistant to prior ICI treatment. No RECIST criteria responses were observed, however, patients could be separated into those with either progressive or stable disease outcomes. Analysis of the tumors did not show substantial DNA hypomethylation in the tumor or the upregulation of viral mimicry after two cycles of combination treatment. We did, however, observe that the therapy associated with immune activation of circulating immune cells and abundance of tumor-infiltrating CD8 T cells within the tumor, which were correlated with a longer survival outcome. Our results suggest that further studies to target the reprogramming of T cells with alternate methodologies may be of benefit in this disease setting.

2023-03-01 | GSE222933 | GEO

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (NGS)

2023-03-01 | GSE222932 | GEO

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy

Project description:A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy

| PRJNA924046 | ENA

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (NGS)

Project description:A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (NGS)

| PRJNA924049 | ENA

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy.

Project description:PurposeOn the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab [anti-programmed cell death ligand 1 (PD-L1)] together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy.Patients and methodsWe designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors.ResultsSafety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8-11 months) and survival (>14 months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients' plasma was associated with short survival.ConclusionsNo RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival.

| S-EPMC10233355 | biostudies-literature

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-03-01 | GSE222934 | GEO

A phase 1 study of guadecitabine plus cisplatin in platinum refractory germ cell tumors [Methylation]

Project description:Germ cell tumors (GCTs) can be cured with cisplatin-based therapy, although a clinically significant number of patents are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMA), we conducted a phase I trial [NCT02429466] of the next-generation HMA guadecitabine (SGI-110) in combination with cisplatin in patients with recurrent, cisplatin-resistant GCTs. The primary endpoint was safety and toxicity including DLT and MTD. A total of 14 patients were enrolled. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m2 guadecitabine followed by cisplatin 100 mg/m2. DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients qualified as complete responses by serum tumor marker criteria with survival of 16 and 26 months. Three patients also had stable disease for an overall response rate of 23% and clinical benefit rate of 46%. Genome-wide analysis pre- and post-guadecitabine indicated dramatic and widespread global DNA demethylation in cell-free plasma samples including in the promoters of genes of cancer related pathways. In summary, the combination of guadecitabine followed by cisplatin was tolerable and demonstrated biological activity in patients with platinum refractory GCTs.

2020-12-25 | GSE152802 | GEO

EPIC-HPS

Project description:EPIC-HPS

| PRJNA684138 | ENA

Progressing vs regressing melanoma metastases

Project description:We documented the transcriptional pattern of 3 progressing and 2 regressing synchronous melanoma metastases from the same patient following M-VAX treatment. Two-condition experiment, Progressing vs regressing metastases. 3 progressing and 2 regressing metastases extracted from the same patient after M-VAX immunotherapy. One replicate per array.

2010-09-11 | E-GEOD-24067 | biostudies-arrayexpress

EPIC-Italy at HuGeF

Project description:This Series contains data from 845 participants (188 men and 657 women) in the EPIC-Italy cohort that was produced at the Human Genetics Foundation (HuGeF) in Turin, Italy. At the last follow-up (2010), 424 participants remained cancer-free, 235 had developed primary breast cancer, 166 had developed primary colorectal cancer, and 20 had developed other primary cancers. Anthropometric measurements, and dietary and lifestyle information obtained by questionnaire are also available. A total of 845 samples from the EPIC-Italy cohort were analyzed.

2013-09-20 | E-GEOD-51032 | biostudies-arrayexpress

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