Pembrolizumab in Refractory Advanced Esophageal Cancer
Condition: Esophageal Cancer; Squamous Cell Esophagus Cancer; Adenocarcinoma Esophagus
MeSH terms: Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma
Intervention: Pembrolizumab
Intervention description: Immune checkpoint inhibitor
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 49.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Esophageal Cancer

Summary:

      This research study is studying a targeted therapy as a possible treatment for advanced
      esophageal cancer.

      The study intervention involved in this study is:

      -Pembrolizumab
    

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 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 oesophagogastric 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/assent for the trial.

          -  Be ≥ 18 years of age on day of signing informed consent.

          -  Have measurable disease based on irRECIST.

          -  Be willing to provide tissue from a newly obtained biopsy of a tumor lesion, most
             commonly an 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 ECOG Performance Scale (Appendix A).

          -  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 (Reference
             Section 6.3.2). 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.

          -  Demonstrate adequate organ function as defined below, all screening labs should be
             performed within 10 days of treatment initiation.

        Hematological

          -  Absolute neutrophil count (ANC) ≥1,500 /mcL

          -  Platelets ≥80,000 / mcL

          -  Hemoglobin ≥8.5 g/dL or ≥5.6 mmol/L

             -Renal

          -  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 (GFR can also
             be used in place of creatinine or CrCL) Creatinine clearance should be calculated per
             institutional standard.

             -Hepatic

          -  Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total
             bilirubin levels > 1.5 ULN

          -  AST (SGOT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

          -  ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

          -  Albumin > 2.8 mg/dL

             -Coagulation

          -  International Normalized Ratio (INR) OR Prothrombin Time (PT) ≤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

          -  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 (eg., 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., HBsAg reactive) or Hepatitis C (e.g., HCV 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.