Clinical Trials /

Study of Pembrolizumab in Locally Advanced Esophageal Adenocarcinoma

NCT02998268

Description:

This is a randomized, multicenter phase II study of pembrolizumab in combination with chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma to examine the safety and efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma as assessed by 1 year disease free survival rate.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Pembrolizumab in Locally Advanced Esophageal Adenocarcinoma
  • Official Title: Randomized, Multicenter Phase II Study of Pembrolizumab in Combination With Chemotherapy and Chemoradiation in Locally Advanced Esophageal Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: 1602016966
  • NCT ID: NCT02998268

Conditions

  • Esophageal Adenocarcinoma

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaCohort 1
TaxolPaclitaxelCohort 1
CarboplatinCohort 1

Purpose

This is a randomized, multicenter phase II study of pembrolizumab in combination with chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma to examine the safety and efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma as assessed by 1 year disease free survival rate.

Detailed Description

      This is a randomized, multicenter phase II study of pembrolizumab in combination with
      chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma to examine the
      safety and efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation
      in locally advanced esophageal adenocarcinoma as assessed by 1 year disease free survival
      rate. The investigators primary aim is to examine the safety and efficacy of pembrolizumab in
      both pre-operative treatment paradigms for esophageal/GEJ carcinoma. The specific rationale
      for the investigators study design is rooted in three unanswered questions:

        1. does the addition of an immune check-point inhibitor (pembrolizumab) enhance the
           efficacy of cytotoxic therapy (chemotherapy with chemoradiation) as determined by
           response rates, nodal down-staging and 1 year disease free survival in comparison to
           historical controls,

        2. what are the pathological effects of combining pembrolizumab with chemotherapy alone,
           and

        3. what are the molecular (PD-L1 expression), immunological (TILs extent) and
           gene-expression signatures associated with the efficacy of pembrolizumab in the
           neoadjuvant setting.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1OtherSubjects in Cohort 1 receive conventional induction chemotherapy with taxol/ carboplatin followed by weekly chemoradiation (taxol/ carboplatin) with pembrolizumab. Following surgery, pembrolizumab is administered every 3 weeks for 1 year. Pembrolizumab dosing is 200 mg administered as a 30 minute IV infusion.
  • Pembrolizumab
  • Taxol
  • Carboplatin
Cohort 2ExperimentalSubjects in Cohort 2 receive pembrolizumab along with induction chemotherapy with taxol/ carboplatin followed by weekly chemoradiation (taxol/ carboplatin) with pembrolizumab. Following surgery, pembrolizumab is administered every 3 weeks for 1 year. Pembrolizumab dosing is 200 mg administered as a 30 minute IV infusion.
  • Pembrolizumab
  • Taxol
  • Carboplatin

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have histologically or cytologically confirmed esophageal or GEJ Siewert
             type I or II adenocarcinomas

          2. Clinical tumor stage should be T2-T4, N0-1, M0

          3. Be willing and able to provide written informed consent/assent for the trial

          4. Be 18 years of age or older on day of signing informed consent.

          5. Be a candidate for surgical resection.

          6. Be willing to provide tissue during endoscopic assessment of their tumor.

          7. Have a performance status of 0 or 1 on the ECOG Performance Scale.

          8. Demonstrate adequate organ function as defined below, all screening labs should be
             performed within 14 days of treatment initiation.

               -  Absolute neutrophil count (ANC) ≥1,500 /mcL

               -  Platelets≥100,000 / mcL

               -  Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion within 7 days of assessment

               -  Serum creatinine OR Measured or calculated creatinine clearance ≤1.5 X upper
                  limit of normal (ULN) OR

               -  ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
                  (Creatinine clearance should be calculated per institutional standard) (GFR can
                  also be used in place of creatinine or CrCl)

               -  Serum total bilirubin ≤ 1.5 X ULN OR

               -  Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN

               -  AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN

               -  Albumin >2.5 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 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

          9. Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 7 days 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.

         10. Female subjects of childbearing potential should 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 5.7.2). Subjects of childbearing potential are those who have not been
             surgically sterilized or have not been free from menses for > 1 year.

         11. Male subjects should 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.

        Exclusion Criteria:

          1. Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first dose of treatment.

          2. Evidence of metastatic disease.

          3. 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.

          4. Has a known history of active TB (Bacillus Tuberculosis)

          5. Hypersensitivity to pembrolizumab or any of its excipients.

          6. Has had a prior anti-cancer treatment, including chemotherapy, radiation, or
             monoclonal antibody (mAb).

          7. Has a known additional malignancy that is active. 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.

          8. Has a previous invasive malignancy treated with curative intent less than 3 years from
             time of registration. Exceptions include prostate cancer.

          9. 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.

         10. Has known history of, or any evidence of active, non-infectious pneumonitis.

         11. Has an active infection requiring systemic therapy.

         12. 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.

         13. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         14. 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.

         15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

         16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

         18. 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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease free survival rate
Time Frame:1 year
Safety Issue:
Description:To examine the safety and efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma as assessed by 1 year disease free survival rate

Secondary Outcome Measures

Measure:Pathologic complete response rate
Time Frame:1 year
Safety Issue:
Description:To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by pathologic complete response rate
Measure:R0 resection rate.
Time Frame:1 year
Safety Issue:
Description:To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by R0 resection rate.
Measure:Median survival rates.
Time Frame:1 year
Safety Issue:
Description:To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by median survival rates.
Measure:1 year overall survival rates.
Time Frame:1 year
Safety Issue:
Description:To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by 1 year overall survival rates
Measure:Reduction of local immune infiltration.
Time Frame:Up to 1 year post-surgery
Safety Issue:
Description:To explore the effect of the combination of pembrolizumab with chemotherapy as assessed by the local immune infiltration in each treatment group.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Weill Medical College of Cornell University

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