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Study of Pembrolizumab in Locally Advanced Esophageal Adenocarcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02998268
Recruitment Status : Active, not recruiting
First Posted : December 20, 2016
Last Update Posted : May 11, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Esophageal Adenocarcinoma Drug: Pembrolizumab Drug: Taxol Drug: Carboplatin Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized, Multicenter Phase II Study of Pembrolizumab in Combination With Chemotherapy and Chemoradiation in Locally Advanced Esophageal Adenocarcinoma
Actual Study Start Date : March 7, 2017
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Cohort 1

Subjects 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.

Drug: Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Other Name: Keytruda

Drug: Taxol
Taxol is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.
Other Name: Paclitaxel

Drug: Carboplatin
Carboplatin is a platinum coordination compound that is used as a cancer chemotherapeutic agent. Carboplatin produces predominantly interstrand DNA cross-links rather than DNA -protein cross-links.

Experimental: Cohort 2

Subjects 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.

Drug: Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Other Name: Keytruda

Drug: Taxol
Taxol is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.
Other Name: Paclitaxel

Drug: Carboplatin
Carboplatin is a platinum coordination compound that is used as a cancer chemotherapeutic agent. Carboplatin produces predominantly interstrand DNA cross-links rather than DNA -protein cross-links.




Primary Outcome Measures :
  1. Disease free survival rate [ Time Frame: 1 year ]
    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 :
  1. Pathologic complete response rate [ Time Frame: 1 year ]
    To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by pathologic complete response rate

  2. R0 resection rate. [ Time Frame: 1 year ]
    To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by R0 resection rate.

  3. Median survival rates. [ Time Frame: 1 year ]
    To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by median survival rates.

  4. 1 year overall survival rates. [ Time Frame: 1 year ]
    To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by 1 year overall survival rates

  5. Reduction of local immune infiltration. [ Time Frame: Up to 1 year post-surgery ]
    To explore the effect of the combination of pembrolizumab with chemotherapy as assessed by the local immune infiltration in each treatment group.


Other Outcome Measures:
  1. Prediction of tumor response. [ Time Frame: Up to 1 year post-surgery ]
    To examine whether anti PD1 therapy is associated with a transcriptomic signature of intra-tumoral immune activation predictive of response.

  2. Improved 1 year survival [ Time Frame: 1 year ]
    To examine whether anti PD1 therapy is associated with a transcriptomic signature of intra-tumoral immune activation predictive of improved 1 year survival.

  3. Induction of PD-L1 expression or induction of an inflammatory signature in tumors. [ Time Frame: Up to 1 year post-surgery. ]
    To examine whether chemotherapy is associated with induction of PD-L1 expression or induction of an inflammatory signature in tumors

  4. Association of anti-PD1 therapy with increased intra-tumoral immune cell infiltration. [ Time Frame: Up to 1 year post-surgery. ]
    To examine whether anti PD1 therapy is associated with increased intra-tumoral immune cell infiltration.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02998268


Locations
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United States, New York
Weill Cornell Medicine
New York, New York, United States, 10068
Sponsors and Collaborators
Weill Medical College of Cornell University
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Manish Shah, MD Weill Cornell Medicine
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Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT02998268    
Other Study ID Numbers: 1602016966
First Posted: December 20, 2016    Key Record Dates
Last Update Posted: May 11, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Adenocarcinoma
Esophageal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Paclitaxel
Carboplatin
Pembrolizumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological