A Phase 2 interventional study of Epacadostat and Laboratory Biomarker Analysis in Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma and Gastroesophageal Junction Adenocarcinoma, sponsored by City of Hope Medical Center. Withdrawn at 3 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-03-08.
Sponsored by City of Hope Medical Center · Phase 2, Interventional, and Treatment
This phase II trial studies the side effects of epacadostat and pembrolizumab and to see how well they work before surgery in treating participants with stage II-III esophageal or gastroesophageal cancer. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of the tumor cells to grow and spread. Giving epacadostat and pembrolizumab before surgery may work better in treating participants with stage II-III esophageal or gastroesophageal cancer.
PRIMARY OBJECTIVES:
I. To establish that the combination of epacadostat and pembrolizumab will lead to an increase in tumor infiltrating cytotoxic T-cells and circulating cytotoxic T cells and a reduction in immunosuppressive Tregs and myeloid-derived suppressor cells (MDSCs) in esophageal/gastroesophageal junction (GEJ) tumors that can arise after treatment with neoadjuvant chemoradiation.
II. To assess safety and tolerability of pembrolizumab and epacadostat (immunotherapy) in this patient population.
SECONDARY OBJECTIVES:
I. To evaluate pathologic complete response rate (path CR) and correlate with tumor T-cell response.
II. To evaluate complete clinical response rate (clinical CR) and subsequent avoidance of esophagectomy and correlate with tumor T-cell response.
III. To evaluate toxicities with the combination of pembrolizumab and epacadostat in this treatment setting.
IV. To evaluate disease-free survival (DFS) and overall survival (OS) in this treatment population.
EXPLORATORY OBJECTIVES:
I. To measure changes in whole genome serum micro ribonucleic acid (miRNA) signatures before and after protocol therapy and correlate with tumor/immune/stromal cell miRNA expression profiling determined by deep sequencing.
II. To assess the role of circulating miR-23a as serum biomarker given its role as an oncomir in esophagastric cancer and reporting in the literature of suppressing tumor cytotoxic T cells in preclinical models.
III. To correlate diversity in the gut microbiome with path CR and clinical CR after treatment with pembrolizumab and epacadostat.
IV. To measure serial plasma kynurenine/tryptophan ratio levels as a pharmacodynamic marker of increased IDO1 activity and response.
V. Association of PD-L1 expression, microsatellite stability and/or IDO1 expression and pathological complete response (pCR) rate.
OUTLINE:
Starting 14 days after completion of standard of care chemoradiotherapy, participants receive epacadostat orally (PO) twice daily (BID) during weeks 3-8 and pembrolizumab intravenously (IV) over 30 minutes on day 1 of weeks 3 and 6 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at one month and then every 3 months in year 1, every 4 months in year 2, and every 6 months in year 3.
2,004 studies on the registry are indexed under Adenocarcinoma; 375 are open to participants now.
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Agreement to allow the use of archival tissue from diagnostic tumor biopsies
Confirmed stage II-III diagnosis of one of the following:
Deemed appropriate for neoadjuvant chemoradiation by the multidisciplinary team (surgeon, medical oncologist, and radiation oncologist)
Agreement by women of childbearing potential (WOCBP) and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 120 days after the last dose of protocol therapy
Exclusion Criteria:
Starting 14 days after completion of standard of care chemoradiotherapy, participants receive epacadostat PO BID during weeks 3-8 and pembrolizumab IV over 30 minutes on day 1 of weeks 3 and 6 in the absence of disease progression or unacceptable toxicity.
Drug: Epacadostat · Other: Laboratory Biomarker Analysis · Biological: Pembrolizumab · Other: Pharmacodynamic Study
Given PO
Also known as: INCB 024360, INCB024360
Correlative studies
Given IV
Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475
Correlative studies
Also known as: PHARMACODYNAMIC
Temporal anti-tumor immune response defined as tumor infiltrating cytotoxic T-cells, circulating T-cells, T regulatory cells (Tregs), and myeloid-derived suppressor cells (MDSCs) in tumor and blood samples
Patient demographics and baseline disease/prior treatment characteristics will be summarized using descriptive statistics. Descriptive statistics will be used to summarize the gene expression profile in tissue/blood. Changes in these measures during and after treatment (when measured) will also be summarized by descriptive statistics and tables/plots. Various statistical analyses will be used to explore the association between these gene expression measures (at different time points and the changes over time) with clinical outcomes. For the exploratory correlation of these endpoints with response, analyses comparing groups of participants defined by response may be conducted by two-sample t-test or Wilcoxon rank sum test.
Time frame: Baseline to 3 years
Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0
All participants evaluable for toxicity will be included in the toxicity analysis. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Time frame: Up to 8 weeks
Pathological complete response (CR)
Will be defined as no residual cancer cells, including lymph nodes under pathologic examination of the surgically resected specimen and/or a Tumor Regression Score of 0 by the College of American Pathologists (CAP) Cancer Protocol for Esophageal Carcinoma. Pathological response will be determined per CAP Cancer Protocols and will utilize a modified Ryan scheme. For pathological CR, all participants evaluable for response will be included in the analysis. Pathological CR rate will be estimated by the proportion of participants achieving pathological CR along with the 95% exact binomial confidence interval.
Time frame: Up to 3 years
Clinical complete response
Defined as no radiographic evidence of disease of positron emission tomography/computed tomography (PET/CT) or CT imaging. For clinical CR, all participants evaluable for response will be included in the analysis. Clinical CR rate will be estimated by the proportion of participants achieving clinical CR along with the 95% exact binomial confidence interval.
Time frame: Up to 3 years
Incidence of adverse events per CTCAE v 4.0
All participants evaluable for toxicity will be included in the toxicity analysis. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Time frame: Up to 3 years
Disease free survival (DFS)
DFS will be determined using the Kaplan-Meier method.
Time frame: From start of neoadjuvant therapy up to 3 years
Overall survival (OS)
OS will be determined using the Kaplan-Meier method.
Time frame: From start of neoadjuvant therapy up to 3 years
This study is withdrawn, as verified in Feb 2022. You cannot join it, but the record below documents what was studied.
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