Study of Pembrolizumab in Locally Advanced Esophageal Adenocarcinoma

Phase 2

Active, not recruiting

• Conditions: Esophageal Adenocarcinoma
• Interventions: Drug: Pembrolizumab; Drug: Taxol; Drug: Carboplatin

• Registration Number: NCT02998268
• Lead Sponsor: 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.

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 Timeline

• Study First Submitted: 2016-11-29
• Study First Submitted QC: 2016-12-15
• Study First Posted: 2016-12-20
• Study Start: 2017-03-07
• Primary Completion: 2021-02-10
• Results First Submitted: 2024-04-09
• Results First Submitted QC: 2024-04-09
• Results First Posted: 2024-05-02
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-17
• Last Update Posted: 2025-03-19
• Study Completion: 2026-09

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 42

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1	Pembrolizumab	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.
Cohort 1	Carboplatin	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.
Cohort 1	Taxol	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.
Cohort 2	Pembrolizumab	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.
Cohort 2	Taxol	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.
Cohort 2	Carboplatin	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Major Pathological Response	Between approximately week 15 to 19	Tumor tissue will be assessed for major pathological response as defined as complete response or near complete response. Pathologic response was assessed by tumor regression grade. This is a pathologic assessment of the amount of residual cancer cells in the specimen and the degree of fibrosis in the sample specimen. A completer response is 0% residual cancer cells. A partial response is 10-50% residual cancer cells, and no response is \>50% residual cancer cells within the tumor specimen.

Secondary Outcome Measures

Name	Time	Method
R0 Resection Rate.	1 year	To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by R0 resection rate, which is reported as the number of participants achieving R0 resection.
Number of Participants That Remained Progression Free as of 1 Year	1 year	Number of participants that remained progression free (per RECIST v1.1) and alive as of 1 year
Overall Survival Rates	Until death from any cause or for a maximum of 5 years	To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by overall survival rates

Trial Locations

Locations (4)

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

USC Keck School of Medicine, Norris Cancer Center; 🇺🇸 Los Angeles, California, United States

Weill Cornell Medicine; 🇺🇸 New York, New York, United States

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States