Pembrolizumab in Treating Patients with Refractory Advanced Esophageal Cancer That Cannot Be Removed by Surgery

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Status: Active


This phase II trial studies how well pembrolizumab works in treating patients with esophageal cancer that has spread to other places on the body, does not respond to treatment, and cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed, measurable, unresectable adenocarcinoma or squamous cell carcinoma of the esophagus; for the purposes of this study, undifferentiated carcinomas or adenosquamous carcinomas will be categorized as adenocarcinomas
  • The primary tumor must originate in the esophagus; tumors that involve the gastroesophageal (GE) junction must meet Sievert type 1 criteria: “adenocarcinoma of the distal oesophagus which usually arises from an area with specialized intestinal metaplasia of the oesophagus (i.e. Barrett’s oesophagus) and which may infiltrate the esophagogastric junction from above;” for the purposes of this protocol, this will be interpreted as: greater than 50% of the tumor must be above the GE junction or, alternatively, the tumor must involve the GE junction and arise in the setting of biopsy-documented Barrett’s esophagus (specialized intestinal metaplasia)
  • Patients must have received at least one prior therapy for unresectable disease; patients with recurrence within 6 months of completion of neoadjuvant or adjuvant therapy may be considered as having received one prior therapy for unresectable disease
  • Be willing and able to provide written informed consent for the trial
  • Have measurable disease based on irRECIST
  • Be willing to provide tissue from a newly obtained biopsy of a tumor lesion, most commonly an esophagogastroduodenoscopy (EGD) biopsy from the esophagus; newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the sponsor; please note, patients may not initiate therapy until the biopsy specimen is received at the Dana-Farber Cancer Institute
  • The first 15 patients with adenocarcinoma will be offered an optional tumor biopsy (typically EGD biopsy) at 8 weeks; starting with adenocarcinoma patient #16, patients must have an accessible tumor and must agree to tumor biopsy at 8 weeks; this will continue to be mandatory until a total of 20 patients have undergone biopsy at 8 weeks
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Female subject of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
  • Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
  • Absolute neutrophil count (ANC) >= 1,500 /mcL
  • Platelets >= 80,000/mcL
  • Hemoglobin >= 8.5 g/dL or >= 5.6 mmol/L
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCL]); creatinine clearance should be calculated per institutional standard
  • Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 X ULN OR =< 5 x ULN for subjects with liver metastases
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases
  • Albumin >= 2.8 mg/dL
  • International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

Exclusion Criteria

  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment; subjects requiring systemic steroids are excluded from the trial; the use of physiologic doses of corticosteroids may be approved after discussion with the sponsor
  • Has a known history of active TB (Bacillus tuberculosis)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: subjects with =< grade 2 neuropathy and alopecia are an exception to this criterion and may qualify for the study * Note: if subject received major surgery, they must wait >= 3 weeks prior to starting study treatment, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
  • Has known active central nervous system (CNS) 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 four weeks prior to the first dose of trial treatment 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
  • Has active autoimmune disease that has required systemic treatment in 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
  • Has an active infection requiring systemic therapy
  • Patients that require supplemental oxygen are excluded
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Has received a live vaccine within 30 days of planned start of study therapy * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
  • Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis

Locations & Contacts


Beth Israel Deaconess Medical Center
Status: Active
Contact: Eirini Pectasides
Phone: 617-667-2100 Email:
Brigham and Women's Hospital
Status: Active
Contact: Peter C. Enzinger
Phone: 617-632-6855 Email:
Dana-Farber Cancer Institute
Status: Active
Contact: Peter C. Enzinger
Phone: 617-632-6855 Email:
Massachusetts General Hospital
Status: Active
Contact: Justin F. Gainor
Phone: 617-724-4000 Email:

Trial Objectives and Outline


I. Evaluate the response rate, by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), of pembrolizumab in refractory, advanced esophageal adenocarcinoma patients.


I. Evaluate the response rate, by irRECIST, of pembrolizumab in refractory, advanced esophageal adenocarcinoma patients who are PD-L1 positive and negative.

II. Evaluate the progression-free survival (PFS) and overall survival (OS) as measured by the method of Kaplan and Meier in patients with refractory, advanced esophageal adenocarcinoma.

III. Evaluate the durability of pembrolizumab response in advanced esophageal cancer patients by measuring median overall survival and median progression free survival.

IV. Evaluate the safety and tolerability of pembrolizumab 200 mg, administered every three weeks, in advanced esophageal cancer.


I. Evaluate relationship between response rate, by irRECIST, and potential predictive biomarkers.

II. Evaluate the response rate, by irRECIST, of pembrolizumab in refractory, advanced, Western esophageal squamous cell carcinoma patients.


Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 35 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 12 weeks for up to 5 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type


Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Peter C. Enzinger

Trial IDs

Primary ID 16-293
Secondary IDs NCI-2017-00384 ID NCT02971956