Back to resultsPembrolizumab Plus Neoadjuvant Chemotherapy vs. Neoadjuvant Chemoradiotherapy for Locally Advanced ESCC (KEYSTONE-002) (KEYSTONE-002)
Primary Purpose
Esophageal Squamous Cell Carcinoma
Status
Recruiting
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
Pembrolizumab
Paclitaxel
Cisplatin
neoadjuvant chemoradiotherapy
Sponsored by
About this trial
This is an interventional treatment trial for Esophageal Squamous Cell Carcinoma focused on measuring esophageal squamous cell carcinoma, Immunotherapy, neoadjuvant therapy
Eligibility Criteria
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.
Sites / Locations
- Department of minimally invasive esophageal surgery, Tianjin Medical University Cancer Institute and HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Pembrolizumab+ Paclitaxel+Cisplatin+ Surgery+Pembrolizumab (228)
neoadjuvant chemoradiotherapy+ Surgery (114)
Arm Description
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 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
Outcomes
Primary Outcome Measures
Event Free Survival (EFS)
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)
OS is defined as the time from randomization to death due to any cause.
Disease Free Survival (DFS)
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)
MPR is defined as viable tumor comprised ≤ 10% of resected tumor specimens.
Objective response rate (ORR)
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)
PCR is defined as pT0N0M0
assessment in perioperation
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]
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)
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)
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).
Full Information
NCT ID
NCT04807673
First Posted
March 11, 2021
Last Updated
May 26, 2022
Sponsor
Tianjin Medical University Cancer Institute and Hospital
Collaborators
Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Shanghai Chest Hospital, Ruijin Hospital, Hebei Medical University Fourth Hospital, Harbin Medical University, Liaoning Tumor Hospital & Institute, Shanxi Province Cancer Hospital, Shandong Jining No.1 People's Hospital, Weifang People's Hospital, Tianjin Medical University General Hospital, Shandong Provincial Hospital
1. Study Identification
Unique Protocol Identification Number
NCT04807673
Brief Title
Pembrolizumab Plus Neoadjuvant Chemotherapy vs. Neoadjuvant Chemoradiotherapy for Locally Advanced ESCC (KEYSTONE-002)
Acronym
KEYSTONE-002
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)
Study Type
Interventional
2. Study Status
Record Verification Date
May 2022
Overall Recruitment Status
Recruiting
Study Start Date
December 1, 2021 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
May 2028 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Tianjin Medical University Cancer Institute and Hospital
Collaborators
Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Shanghai Chest Hospital, Ruijin Hospital, Hebei Medical University Fourth Hospital, Harbin Medical University, Liaoning Tumor Hospital & Institute, Shanxi Province Cancer Hospital, Shandong Jining No.1 People's Hospital, Weifang People's Hospital, Tianjin Medical University General Hospital, Shandong Provincial Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Esophageal Squamous Cell Carcinoma
Keywords
esophageal squamous cell carcinoma, Immunotherapy, neoadjuvant therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
342 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Pembrolizumab+ Paclitaxel+Cisplatin+ Surgery+Pembrolizumab (228)
Arm Type
Experimental
Arm Description
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
Arm Title
neoadjuvant chemoradiotherapy+ Surgery (114)
Arm Type
Experimental
Arm Description
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
Intervention Type
Biological
Intervention Name(s)
Pembrolizumab
Other Intervention Name(s)
Keytruda
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Paclitaxel
Intervention Description
Neoadjuvant period: paclitaxel 135mg/m^2 IV on Day 2 Q3W, and a total of three cycles.
Intervention Type
Drug
Intervention Name(s)
Cisplatin
Intervention Description
Neoadjuvant period: cisplatin 80 mg/m^2 IV on Day 2 Q3W, and a total of three cycles.
Intervention Type
Radiation
Intervention Name(s)
neoadjuvant chemoradiotherapy
Intervention Description
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
Primary Outcome Measure Information:
Title
Event Free Survival (EFS)
Description
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.
Time Frame
Up to approximately 2.5 years
Secondary Outcome Measure Information:
Title
Overall Survival (OS)
Description
OS is defined as the time from randomization to death due to any cause.
Time Frame
3 and 5 years
Title
Disease Free Survival (DFS)
Description
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.
Time Frame
3 and 5 years
Title
Major pathologic response (MPR)
Description
MPR is defined as viable tumor comprised ≤ 10% of resected tumor specimens.
Time Frame
1 month after resection
Title
Objective response rate (ORR)
Description
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.
Time Frame
1 month after resection
Title
Pathologic Complete Response (PCR)
Description
PCR is defined as pT0N0M0
Time Frame
1 month after resection
Title
assessment in perioperation
Description
R0 resection rate， Time of operation， Quantity of bleeding， Thoracic Drainage， Days of Hospitalization， Rate of Operative Complication， Mortality of perioperation
Time Frame
perioperative period
Title
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Description
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).
Time Frame
up to 16 months
Title
Quality of life differences (EORTC QLQ-C30)
Description
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).
Time Frame
2.5 years
Title
Quality of life differences (EORTC QLQ-OES18)
Description
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).
Time Frame
2.5 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Hongjing Jiang, MD,PhD
Phone
18622221069
Email
jianghongjing@tmu.edu.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Xiaobin Shang, MD,PhD
Phone
18622221071
Email
shangxiaobin@tmu.edu.cn
Facility Information:
Facility Name
Department of minimally invasive esophageal surgery, Tianjin Medical University Cancer Institute and Hospital
City
Tianjin
State/Province
Tianjin
ZIP/Postal Code
300060
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hongjing Jiang, MD,PhD
Phone
18622221069
Email
jianghongjing@tmu.edu.cn
First Name & Middle Initial & Last Name & Degree
Xiaobin Shang, MD,PhD
Phone
18622221071
Email
shangxiaobin@tmu.edu.cn
First Name & Middle Initial & Last Name & Degree
Hongjing Jiang, MD,PhD
First Name & Middle Initial & Last Name & Degree
Yin Li, MD,PhD
First Name & Middle Initial & Last Name & Degree
Zhigang Li, MD,PhD
First Name & Middle Initial & Last Name & Degree
Hecheng Li, MD,PhD
First Name & Middle Initial & Last Name & Degree
Peng Zhang, MD,PhD
First Name & Middle Initial & Last Name & Degree
Ziqiang Tian, MD,PhD
First Name & Middle Initial & Last Name & Degree
Jianqun Ma, MD,PhD
First Name & Middle Initial & Last Name & Degree
Yegang MA, MD,PhD
First Name & Middle Initial & Last Name & Degree
Shiping Guo, MD,PhD
First Name & Middle Initial & Last Name & Degree
Haibo Cai, MD
First Name & Middle Initial & Last Name & Degree
Hengxiao Lu, MD
First Name & Middle Initial & Last Name & Degree
Lin Zhang, MD,PhD
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
35433421
Citation
Shang X, Zhang W, Zhao G, Liang F, Zhang C, Yue J, Duan X, Ma Z, Chen C, Pang Q, Zhang W, Liu L, Ren X, Meng B, Zhang P, Ma Y, Zhang L, Li H, Kang X, Li Y, Jiang H. Pembrolizumab Combined With Neoadjuvant Chemotherapy Versus Neoadjuvant Chemoradiotherapy Followed by Surgery for Locally Advanced Oesophageal Squamous Cell Carcinoma: Protocol for a Multicentre, Prospective, Randomized-Controlled, Phase III Clinical Study (Keystone-002). Front Oncol. 2022 Mar 31;12:831345. doi: 10.3389/fonc.2022.831345. eCollection 2022.
Results Reference
derived
Learn more about this trial
Pembrolizumab Plus Neoadjuvant Chemotherapy vs. Neoadjuvant Chemoradiotherapy for Locally Advanced ESCC (KEYSTONE-002)
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