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

Sponsor

Tianjin Medical University Cancer Institute and Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04807673

Collaborator

Cancer Institute and Hospital, Chinese Academy of Medical Sciences (Other), Shanghai Chest Hospital (Other), Ruijin Hospital (Other), Hebei Medical University Fourth Hospital (Other), Harbin Medical University (Other), Liaoning Tumor Hospital & Institute (Other), Shanxi Province Cancer Hospital (Other), Shandong Jining No.1 People's Hospital (Other), Weifang People's Hospital (Other), Tianjin Medical University General Hospital (Other), Shandong Provincial Hospital (Other)

342

Enrollment

Location

Arms

Anticipated Duration (Months)

4.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Esophageal Squamous Cell Carcinoma	Biological: Pembrolizumab Drug: Paclitaxel Drug: Cisplatin Radiation: neoadjuvant chemoradiotherapy	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

342 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Dec 1, 2021

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

May 1, 2028

Arms and Interventions

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	Biological: Pembrolizumab 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 Drug: Paclitaxel Neoadjuvant period: paclitaxel 135mg/m^2 IV on Day 2 Q3W, and a total of three cycles. Drug: Cisplatin 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	Radiation: neoadjuvant chemoradiotherapy 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

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

Biological: Pembrolizumab

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

Drug: Paclitaxel

Neoadjuvant period: paclitaxel 135mg/m^2 IV on Day 2 Q3W, and a total of three cycles.

Drug: Cisplatin

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

Radiation: neoadjuvant chemoradiotherapy

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

Outcome Measures

Primary Outcome Measures

Event Free Survival (EFS) [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.

Secondary Outcome Measures

Overall Survival (OS) [3 and 5 years]
OS is defined as the time from randomization to death due to any cause.
Disease Free Survival (DFS) [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.
Major pathologic response (MPR) [1 month after resection]
MPR is defined as viable tumor comprised ≤ 10% of resected tumor specimens.
Objective response rate (ORR) [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.
Pathologic Complete Response (PCR) [1 month after resection]
PCR is defined as pT0N0M0
assessment in perioperation [perioperative period]
R0 resection rate， Time of operation， Quantity of bleeding， Thoracic Drainage， Days of Hospitalization， Rate of Operative Complication， Mortality of perioperation
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [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).
Quality of life differences (EORTC QLQ-C30) [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).
Quality of life differences (EORTC QLQ-OES18) [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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed esophageal squamous cell carcinoma;
R0 resectable thoracic esophageal cancer, cT1-3N1-2M0, cT2-3N0M0 (AJCC V8 TNM classification);
No suspicious metastatic lymph nodes on the clavicle;
Have a performance status of 0 or 1 on the ECOG Performance Scale;
Age 18-75 years old, both men and women;
Be willing and able to provide written informed consent/assent for the trial;
Demonstrate adequate organ function ;
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;
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.
Have not received systemic or local treatment for esophageal cancer in the past.

Exclusion Criteria:

Ineligibility or contraindication for esophagectomy;
Prior therapy (operation, radiotherapy, immunotherapy, or chemotherapy) for esophageal cancer
Active autoimmune disease or history of autoimmune disease;
Requiring systemic treatment with either corticosteroids or other immunosuppressive medications;
Subjects with a history of symptomatic interstitial lung disease;
History of allergy to study drug components;
Women must not be pregnant or breast-feeding;
Patient has received prior chemotherapy, radiotherapy, target therapy ，and immune therapy for this malignancy or any other past malignancy;
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.