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Esophageal Squamous Cell CarcinomaPhase 2NCT03592407

Epacadostat and Pembrolizumab Before Surgery in Treating Participants With Stage II-III Esophageal or Gastroesophageal Cancer

A Phase 2 study testing Epacadostat, Laboratory Biomarker Analysis and Pembrolizumab in people with Esophageal Squamous Cell Carcinoma and Esophageal Adenocarcinoma, run by City of Hope Medical Center at 3 sites in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Epacadostat, Laboratory Biomarker Analysis and Pembrolizumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
3 sitesUnited States
Study dates
1 Jul 2018to Apr 2020
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Documented informed consent of the participant and/or legally authorized representative
  • Agreement to allow the use of archival tissue from diagnostic tumor biopsies
  • If unavailable, exceptions may be granted only with study principal investigator (PI) approval
  • Eastern Cooperative Oncology Group (ECOG) =< 2
  • Non-metastatic cancer of the esophagus OR esophagus and gastroesophageal junction (GEJ; tumor extending =< 2 cm into the stomach)
  • Confirmed stage II-III diagnosis of one of the following:
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  • Squamous cell; OR
  • Adenocarcinoma; OR
  • Mixed adenosquamous carcinoma
  • Deemed appropriate for neoadjuvant chemoradiation by the multidisciplinary team (surgeon, medical oncologist, and radiation oncologist)
  • Chemotherapy defined as weekly carboplatin/paclitaxel; AND
  • Radiation defined as external beam radiotherapy defined as: 50.4 gray (Gy) as per institutional and national treatment guidelines
  • Deemed appropriate for esophagectomy or repeat endoscopic biopsies if non-operative management is pursued
  • Absolute neutrophil count (ANC) >= 1500/mm^3 within 14 days prior to day 1 of study participation/1st endoscopic biopsy
  • Platelets >= 100,000/mm^3 within 14 days prior to day 1 of study participation/1st endoscopic biopsy
  • Serum total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN if total bilirubin levels > 1.5 x ULN within 14 days prior to day 1 of study participation/1st endoscopic biopsy
  • Aspartate aminotransferase (AST) =< 2 x ULN within 14 days prior to day 1 of study participation/1st endoscopic biopsy
  • Alanine aminotransferase (ALT) =< 2 x ULN within 14 days prior to day 1 of study participation/1st endoscopic biopsy
  • Creatinine =<1.5 x ULN OR for patients with Creatinine >1.5 x ULN Creatinine clearance of >=60 ml/min per 24 hour urine test or the Cockcroft-Gault formula
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN within 14 days prior to day 1 of study participation/1st endoscopic biopsy
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN
  • Female of childbearing potential only: negative urine or serum pregnancy test; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • 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
  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Who cannot join

  • Immune checkpoint inhibitor(s) (e.g. anti-PD-1, anti-CTLA4)
  • Indoleamine-2,3-dioxygenase (IDO) inhibitors
  • Radiotherapy within 21 days prior to day 1 of study participation
  • Investigational agent within 21 days prior to Day 1 of study participation
  • Live-virus vaccination within 30 days prior to Day 1 of study participation
  • Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 21 days of study participation
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  • Chronic systemic steroid therapy or on any other form of immunosuppressive medication
  • Monoamine oxidase inhibitors (MAOI) or any drug associated with MAOI activity
  • Any UGT1A9 inhibitors (including acitretin, amitriptyline, androsterone, cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17-beta), flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid glycyrrhizin, imatinib, imipramine, ketoconazole, linoleic acid supplements, mefenamic acid, and mycophenolic acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, phenytoin, probenecid)
  • Coumarin-based anticoagulants
  • Unstable or untreated brain/leptomeningeal metastasis
  • Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)
  • Severe hypersensitivity reaction to treatment with another antibody and/or hypersensitivity to epacadostat excipients
  • Active autoimmune disease that has required systemic treatment in the past 2 years
  • Known history of human immunodeficiency virus (HIV), hepatitis B or hepatitis C (with confirmation of negative hepatitis B surface antigen [HBsAg], hepatitis B virus [HBV] polymerase chain reaction [PCR], and hepatitis C virus [HCV] PCR)
  • History of pneumonitis (non-infectious) that required steroids or current pneumonitis
  • Known history of active tuberculosis
  • Diagnosed with or treated for cancer within the previous two years, other than histologies listed in inclusion criteria or non-melanoma carcinoma of the skin
  • Female only: pregnant or breastfeeding
  • Any othr condition that would, in the Investigator's judgement, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
  • Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • City of Hope Medical Center

    Duarte, California, 91010

  • City of Hope South Pasadena

    South Pasadena, California, 91030

  • City of Hope West Covina

    West Covina, California, 91790

Other trials in United States

About this study

Official title: A Phase 2 Trial of Neoadjuvant Pembrolizumab in Combination With Epacadostat (INCB024360) in Patients With Non-Metastatic Esophageal/Gastroesophageal Squamous Cell and Adenocarcinomas Treated With Neoadjuvant Chemoradiation: A Window-Of-Opportunity Study

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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:

  1. 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.

  1. 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.

Being tested
Epacadostat, Laboratory Biomarker Analysis, Pembrolizumab, Pharmacodynamic Study
Medical subject headings
Esophageal Squamous Cell Carcinoma, Adenocarcinoma Of Esophagus

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EpacadostatDrug

    Also called INCB 024360, INCB024360

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • PembrolizumabBiological

    Also called Keytruda, Lambrolizumab, MK-3475, SCH 900475

    Given IV

  • Pharmacodynamic StudyOther

    Also called PHARMACODYNAMIC

    Correlative studies

Study groups in NCT03592407
Study groupRoleWhat they receive
Treatment (epacadostat, pembrolizumab)ExperimentalStarting 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.
Receives: Drug: Epacadostat; Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab; Other: Pharmacodynamic Study

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline to 3 years

  2. 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.

    Measured: Up to 8 weeks

Secondary outcomes (5)

  1. 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.

    Measured: Up to 3 years

  2. 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.

    Measured: Up to 3 years

  3. 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.

    Measured: Up to 3 years

  4. Disease free survival (DFS)

    DFS will be determined using the Kaplan-Meier method.

    Measured: From start of neoadjuvant therapy up to 3 years

  5. Overall survival (OS)

    OS will be determined using the Kaplan-Meier method.

    Measured: From start of neoadjuvant therapy up to 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Jul 2018
  2. Study start1 Jul 2018 (estimated)
  3. Primary completionApr 2020 (estimated)
  4. Study completionApr 2020 (estimated)

Why it stopped: Safety concerns

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03592407
Sponsor's protocol ID
17302
Other IDs
NCI-2018-00682, 17302
Status last verified
Feb 2022
First submitted
30 Apr 2018
Last updated
8 Mar 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Epacadostat, Laboratory Biomarker Analysis and Pembrolizumab in people with Esophageal Squamous Cell Carcinoma and Esophageal Adenocarcinoma, run by City of Hope Medical Center at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 8 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: Baseline to 3 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03592407.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Mar 2022.

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