Study of Pembrolizumab in Locally Advanced Esophageal Adenocarcinoma

Randomized, Multicenter Phase II Study of Pembrolizumab in Combination With Chemotherapy and Chemoradiation in Locally Advanced Esophageal Adenocarcinoma

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Esophageal Adenocarcinoma
• Intervention / Treatment: Drug: Pembrolizumab; Drug: Taxol; Drug: Carboplatin

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.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC Keck School of Medicine, Norris Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5848
      • University of Michigan
  • New York
    • New York, New York, United States, 10068
      • Weill Cornell Medicine
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed esophageal or GEJ adenocarcinoma
2. Clinical tumor stage should be T2 Npositive M0 or T3--T4, Nany, 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 active TB or a history of active TB within 10 years of registration (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) for their current diagnosis of esophageal adenocarcinoma.
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, basal cell squamous skin cancer, and cervical 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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 Names: 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 Names: 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 Names: 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 Names: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival rate	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	1 year

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prediction of tumor response.	To examine whether anti PD1 therapy is associated with a transcriptomic signature of intra-tumoral immune activation predictive of response.	Up to 1 year post-surgery
Improved 1 year survival	To examine whether anti PD1 therapy is associated with a transcriptomic signature of intra-tumoral immune activation predictive of improved 1 year survival.	1 year
Induction of PD-L1 expression or induction of an inflammatory signature in tumors.	To examine whether chemotherapy is associated with induction of PD-L1 expression or induction of an inflammatory signature in tumors	Up to 1 year post-surgery.
Association of anti-PD1 therapy with increased intra-tumoral immune cell infiltration.	To examine whether anti PD1 therapy is associated with increased intra-tumoral immune cell infiltration.	Up to 1 year post-surgery.

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Manish Shah, MD, Weill Medical College of Cornell University

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2017
• Primary Completion (Estimated): December 1, 2023
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: November 29, 2016
• First Submitted That Met QC Criteria: December 15, 2016
• First Posted (Estimated): December 20, 2016

Study Record Updates

• Last Update Posted (Actual): May 31, 2023
• Last Update Submitted That Met QC Criteria: May 30, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Adenocarcinoma; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Carboplatin; Paclitaxel; Pembrolizumab
• Other Study ID Numbers: 1602016966

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: No