Pembrolizumab Plus Neoadjuvant Chemotherapy vs. Neoadjuvant Chemoradiotherapy for Locally Advanced ESCC (KEYSTONE-002) (KEYSTONE-002)

A Multicenter Randomized, Controlled Phase III Clinical Trial of Pembrolizumab Plus Paclitaxel and Cisplatin Versus Neoadjuvant Chemoradiotherapy Followed by Surgery for Locally Advanced Esophageal Squamous Cell Carcinoma (KEYSTONE-002)

The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus paclitaxel, cisplatin as neoadjuvant therapy followed by surgery, and pembrolizumab as adjuvant therapy, compared with neoadjuvant chemoradiotherapy and surgery for locally advanced ESCC in multicenter.

Study Overview

Detailed Description

Preoperative chemoradiotherapy with radical surgery is the recommended treatment for locally advanced esophageal squamous cell carcinoma (ESCC) in the NCCN guidelines. But many patients refused or abandon radiotherapy because of the intolerable adverse effects. The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus paclitaxel, cisplatin as neoadjuvant therapy followed by surgery, and pembrolizumab as adjuvant therapy, compared with neoadjuvant chemoradiotherapy and surgery for locally advanced ESCC in multicenter. The primary study hypothesis is that Event Free Survival (EFS) is superior with pembrolizumab plus neoadjuvant chemotherapy compared with neoadjuvant chemoradiotherapy in participants with ESCC.

Study Type

Interventional

Enrollment (Anticipated)

342

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • Tianjin
      • Tianjin, Tianjin, China, 300060
        • Recruiting
        • Department of minimally invasive esophageal surgery, Tianjin Medical University Cancer Institute and Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Hongjing Jiang, MD,PhD
        • Principal Investigator:
          • Yin Li, MD,PhD
        • Sub-Investigator:
          • Zhigang Li, MD,PhD
        • Sub-Investigator:
          • Hecheng Li, MD,PhD
        • Sub-Investigator:
          • Peng Zhang, MD,PhD
        • Sub-Investigator:
          • Ziqiang Tian, MD,PhD
        • Sub-Investigator:
          • Jianqun Ma, MD,PhD
        • Sub-Investigator:
          • Yegang MA, MD,PhD
        • Sub-Investigator:
          • Shiping Guo, MD,PhD
        • Sub-Investigator:
          • Haibo Cai, MD
        • Sub-Investigator:
          • Hengxiao Lu, MD
        • Sub-Investigator:
          • Lin Zhang, MD,PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Histologically confirmed esophageal squamous cell carcinoma;
  2. R0 resectable thoracic esophageal cancer, cT1-3N1-2M0, cT2-3N0M0 (AJCC V8 TNM classification);
  3. No suspicious metastatic lymph nodes on the clavicle;
  4. Have a performance status of 0 or 1 on the ECOG Performance Scale;
  5. Age 18-75 years old, both men and women;
  6. Be willing and able to provide written informed consent/assent for the trial;
  7. Demonstrate adequate organ function ;
  8. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours before 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;
  9. Be willing to provide tissue, blood, and urine samples. Tissue should be from a newly obtained core or excisional biopsy of a tumor lesion through repeated biopsies. Newly-obtained is defined as a specimen obtained up to 4 weeks (28 days) before initiation of treatment on Day 1.
  10. Have not received systemic or local treatment for esophageal cancer in the past.

Exclusion Criteria:

  1. Ineligibility or contraindication for esophagectomy;
  2. Prior therapy (operation, radiotherapy, immunotherapy, or chemotherapy) for esophageal cancer
  3. Active autoimmune disease or history of autoimmune disease;
  4. Requiring systemic treatment with either corticosteroids or other immunosuppressive medications;
  5. Subjects with a history of symptomatic interstitial lung disease;
  6. History of allergy to study drug components;
  7. Women must not be pregnant or breast-feeding;
  8. Patient has received prior chemotherapy, radiotherapy, target therapy ,and immune therapy for this malignancy or any other past malignancy;
  9. Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pembrolizumab+ Paclitaxel+Cisplatin+ Surgery+Pembrolizumab (228)

Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 every 3 weeks (Q3W), paclitaxel 135mg/m^2 IV on Day 2 Q3W, and cisplatin 80 mg/m^2 IV on Day 2 Q3W, a total of three cycles. All treatments will be beginning on Day 1 of each 3-week dosing cycle. Surgery should be done within 4-6 weeks after the last neoadjuvant treatment. After surgery, pembrolizumab 200 mg IV on Day 1 Q3W lasting one year.

Surgery: McKeown esophagectomy

Neoadjuvant period: pembrolizumab 200mg IV D1, Q3W, and preoperative therapy with three cycles.

Adjuvant period: pembrolizumab 200 mg IV D1, Q3W, up to one year, which should be performed within 3-6 weeks after surgery.

Other Names:
  • Keytruda
Neoadjuvant period: paclitaxel 135mg/m^2 IV on Day 2 Q3W, and a total of three cycles.
Neoadjuvant period: cisplatin 80 mg/m^2 IV on Day 2 Q3W, and a total of three cycles.
Experimental: neoadjuvant chemoradiotherapy+ Surgery (114)

neoadjuvant chemoradiotherapy 41.4Gy(1.8Gy×23 fractions) with five cycles of TP(Paclitaxel 50mg/m^2 on D1 and Cisplatin 25mg/m^2 D1, repeated every week. Surgery should be done within 4-6 weeks after the last neoadjuvant treatment.

Surgery: McKeown esophagectomy

neoadjuvant chemoradiotherapy 41.4Gy(1.8Gy×23 fractions) with five cycles of TP(Paclitaxel 50mg/m^2 on D1 and Cisplatin 25mg/m^2 D1, repeated every week

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event Free Survival (EFS)
Time Frame: Up to approximately 2.5 years
EFS is defined as the time from randomization to the first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by investigator, or recurrence, or metastasis, or death due to any cause, whichever occurs first. For this analysis, EFS will be assessed in participants with ESCC.
Up to approximately 2.5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pathologic Complete Response (PCR)
Time Frame: 1 month after resection
PCR is defined as pT0N0M0
1 month after resection
Major pathologic response (MPR)
Time Frame: 1 month after resection
MPR is defined as viable tumor comprised ≤ 10% of resected tumor specimens.
1 month after resection
Disease Free Survival (DFS)
Time Frame: 3 and 5 years
Percentage of Participants With DFS, as Assessed by RECIST 1.1. DFS is defined as the time from randomization to the first documented disease progression of local recurrence or distant metastasis or death due to any cause.
3 and 5 years
Overall Survival (OS)
Time Frame: 3 and 5 years
OS is defined as the time from randomization to death due to any cause.
3 and 5 years
Objective response rate (ORR)
Time Frame: 1 month after resection
ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by investigator. For this analysis, ORR will be assessed in all participants.
1 month after resection
assessment in perioperation
Time Frame: perioperative period
R0 resection rate, Time of operation, Quantity of bleeding, Thoracic Drainage, Days of Hospitalization, Rate of Operative Complication, Mortality of perioperation
perioperative period
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time Frame: up to 16 months
All participants with treatment-related adverse events as assessed by National Cancer Institute Common Terminology Criteria for Adverse Event,Version 4.0(CTC AE4.0).
up to 16 months
Quality of life differences (EORTC QLQ-C30)
Time Frame: 2.5 years
The quality of life will be assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer patients (EORTC QLQ-C30) questionnaire. Patients will be invited to finish the questionnaire at the first day of randomization, before surgery and after surgery (3m, 6m, 12m and 24 months).
2.5 years
Quality of life differences (EORTC QLQ-OES18)
Time Frame: 2.5 years
The quality of life will be assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer patients (EORTC QLQ-OES18) questionnaire. Patients will be invited to finish the questionnaire at the first day of randomization, before surgery and after surgery (3m, 6m, 12m and 24 months).
2.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2021

Primary Completion (Anticipated)

December 31, 2023

Study Completion (Anticipated)

May 1, 2028

Study Registration Dates

First Submitted

March 11, 2021

First Submitted That Met QC Criteria

March 17, 2021

First Posted (Actual)

March 19, 2021

Study Record Updates

Last Update Posted (Actual)

June 1, 2022

Last Update Submitted That Met QC Criteria

May 26, 2022

Last Verified

May 1, 2022

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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