Pembrolizumab With Locally Delivered Radiation Therapy for the Treatment of Metastatic Esophageal Cancers

A Pilot Study Combining Pembrolizumab With Locally Delivered Radiation Therapy for the Treatment of Metastatic Esophageal Cancers

The investigators propose to treat patients with metastatic esophageal cancers and dysphagia with two fractions of brachytherapy followed by pembrolizumab. The brachytherapy is hypofractionated and will provide a radiation dose of sufficient intensity to induce the release of tumor-derived antigens and trigger an antitumor immune response. The simplicity of the design should maximize the chance to examine the hypothesis that radiotherapy can induce an immune response, which can then be augmented by pembrolizumab treatment. Success in this study would provide the impetus to conduct further trials aimed at developing this unique strategy as a more broadly applicable therapeutic option in the treatment of patients suffering from these deadly cancers, and will provide important mechanistic insights into the relationship between radiation treatment and immune therapy augmentation.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer; Cancer of the Esophagus
• Intervention / Treatment: Drug: Pembrolizumab; Radiation: Brachytherapy

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Any patient with metastatic esophageal cancer that is deemed a candidate for brachytherapy for local control or treatment of dysphagia as determined by treating physician
• Presence of an evaluable metastatic lesion (locoregional lymph nodes are acceptable)
• At least 18 years of age.
• ECOG performance status 0-2

• Adequate bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Hemoglobin ≥ 9 g/dL
  • Total bilirubin ≤ 1.5 x IULN OR Direct bilirubin ≤ IULN for patients with total bilirubin > 1.5 x IULN
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN (or ≤ 5 x IULN for patients with liver metastases)
  • Serum creatinine ≤ 1.5 x IULN OR Creatinine clearance by Cockcroft-Gault ≥ 60 mL/min/1.73 m2 for patients with creatinine levels > 1.5 x IULN
  • INR or PT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants
  • aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of a anticoagulants
• Sexually active women of childbearing potential and men must agree to use contraceptive methods prior to study entry, for the duration of study participation, and for 120 days after the last dose of pembrolizumab. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Either enrolled in HRPO# 201107221 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information for Patients with Gastrointestinal Cancers"), which facilitates the collection of specimens for correlative studies, or consenting to collection of blood and tissue as part of this protocol for research testing.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• Prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
• Received a live vaccine within 30 days prior to the first dose of pembrolizumab. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab.
• Currently receiving any other investigational agents, has participated in a study of an investigational agent, or use of an investigational device within 4 weeks of the first dose of pembrolizumab.
• Has received systemic therapy within 4 weeks of the first dose of pembrolizumab.
• Known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of MK-3475 and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab or other agents used in the study.
• Uncontrolled intercurrent illness that would limit compliance with study requirements. This would include, but is not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, immunosuppression, autoimmune conditions, underlying pulmonary disease, or psychiatric illness/social situations.
• Has an active autoimmune disease requiring systemic treatment within the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 72 hours of study entry.
• Known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected).
• Known history of active TB.
• Known history of HIV (HIV 1/2 antibodies).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Pembrolizumab and Brachytherapy; Brachytherapy dose=16 Gy delivered in 2 fractions of 8 Gy per fraction, separated by 7-10 days between fractions.; Pembrolizumab started within 1 week after completion of brachytherapy administered as an intravenous infusion with a dose of 200 mg. It will be given every 3 weeks.; Research endoscopic biopsy for 8 consented patients will take place 1-2 weeks after initiation of brachytherapy.

Drug: Pembrolizumab; Provided by Merck.; Other Names: Keytruda; MK-3475; Radiation: Brachytherapy; It will be delivered using a high-dose-rate Ir-192 afterloader via a dedicated esophageal applicator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety as Measured by Number of Participants With Grade 3 or Higher Treatment Related Adverse Events	The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for all toxicity reporting. In general, CTCAE version 4.03 has the following definitions for the grading scale: Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4: life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE.	Through 30 days after completion of treatment (median length of adverse event follow-up 106 days, full range 42-1023 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Percent Change in Esophageal Tumor Length as Measured by Endoscopy		Prior to brachytherapy and once anytime between 2-6 months after start of pembrolizumab (up to approximately 7 months post-baseline)
Change in Esophageal Lumen Size as Measured by Endoscopy		Prior to brachytherapy, at 1-2 weeks after initiation of brachytherapy (optional), and 2-6 months after start of pembrolizumab
Worst Grade of Dysphagia Experienced by Participant	The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for all toxicity reporting. Grade 1: symptomatic, able to eat regular diet; Grade 2: symptomatic and altered eating/swallowing; Grade 3: severely altered eating/swallowing; tube feeding or TPN or hospitalization indicated; Grade 4: life-threatening consequences; urgent intervention indicated; Grade 5: death.	From start of treatment through 8 weeks post-pembrolizumab (median length of dysphagia follow-up 132 days, full range 42-1049 days)
Overall Response as Measured by Immune-Related Response Criteria (irRC)	- Response and progression will be evaluated in this study using Immune-Related Response Criteria.; irCR, complete disappearance of all lesions (whether measurable or not, and no new lesions) - confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented; irPR, decrease in tumor burden ≥ 50% relative to baseline - confirmed by a consecutive assessment at least 4 weeks after first documentation; irSD, not meeting criteria for irCR or irPR, in absence of irPD; irPD, increase in tumor burden ≥ 25% relative to nadir (minimum recorded tumor burden) - confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented; Patients are considered to have irPR or irSD even if new lesions are present as long as they meet the respective thresholds of response as described above. Furthermore, patients are not considered to have irPD if new lesions are present and the tumor burden of all lesions.	Through completion of treatment (median length of treatment 76 days, full range 25-993 days)
Median Progression-free Survival (PFS)	PFS was defined as the duration from the first infusion of pembrolizumab until disease progression or death (whichever occurred first).	Up to 1 year after completion of treatment (median length of treatment 76 days, full range 25-993 days)
Median Overall Survival (OS)	OS was defined as the duration from the first infusion of pembrolizumab until death.	Up to 1 year after completion of treatment (median length of treatment 76 days, full range 25-993 days)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Cliff Robinson, M.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2016
• Primary Completion (Actual): September 24, 2020
• Study Completion (Actual): August 3, 2021

Study Registration Dates

• First Submitted: December 24, 2015
• First Submitted That Met QC Criteria: December 24, 2015
• First Posted (Estimated): December 30, 2015

Study Record Updates

• Last Update Posted (Actual): March 18, 2026
• Last Update Submitted That Met QC Criteria: February 24, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Esophageal Neoplasms; Therapeutics; Radiotherapy; pembrolizumab; Brachytherapy
• Other Study ID Numbers: 201603087

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes