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

• ClinicalTrials.gov Identifier: NCT04807673
• Recruitment Status: Recruiting
• First Posted: March 19, 2021
• Last Update Posted: April 1, 2021
• Sponsor: Tianjin Medical University Cancer Institute and Hospital
• Collaborators: Cancer Institute and Hospital, Chinese Academy of Medical Sciences; Shanghai Chest Hospital; Ruijin Hospital; Shanghai Zhongshan Hospital; Fudan University; Hebei Medical University Fourth Hospital; Harbin Medical University; Liaoning Tumor Hospital & Institute; Tang-Du Hospital; Shanxi Province Cancer Hospital; Shandong Jining No.1 People's Hospital; Weifang People's Hospital
• Information provided by (Responsible Party): Tianjin Medical University Cancer Institute and Hospital

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 (Clinical Trial)
• Estimated 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)
• Estimated Study Start Date: May 2021
• Estimated Primary Completion Date: May 2023
• Estimated Study Completion Date: May 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 Name: 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 :

1. 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.

Secondary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: 3 and 5 years ]
   OS is defined as the time from randomization to death due to any cause.
2. 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. Major pathologic response (MPR) [ Time Frame: 1 month after resection ]
   MPR is defined as viable tumor comprised ≤ 10% of resected tumor specimens.
4. 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.
5. Pathologic Complete Response (PCR) [ Time Frame: 1 month after resection ]
   PCR is defined as pT0N0M0
6. 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
7. 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).
8. 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).
9. 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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Hongjing Jiang, MD,PhD; 18622221069; jianghongjing@tmu.edu.cn

Contact: Xiaobin Shang, MD,PhD; 18622221071; shangxiaobin@tmu.edu.cn

Locations

China, Tianjin

Department of minimally invasive esophageal surgery, Tianjin Medical University Cancer Institute and Hospital; Recruiting

Tianjin, Tianjin, China, 300060

Contact: Hongjing Jiang, MD,PhD 18622221069 jianghongjing@tmu.edu.cn

Contact: Xiaobin Shang, MD,PhD 18622221071 shangxiaobin@tmu.edu.cn

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: Lijie Tan, MD,PhD

Sub-Investigator: Haiquan Chen, MD,PhD

Sub-Investigator: Ziqiang Tian, MD,PhD

Sub-Investigator: Jianqun Ma, MD,PhD

Sub-Investigator: Yegang MA, MD,PhD

Sub-Investigator: Tao Jiang, MD,PhD

Sub-Investigator: Shiping Guo, MD,PhD

Sub-Investigator: Haibo Cai, MD

Sub-Investigator: Hengxiao Lu, MD

Sponsors and Collaborators

Tianjin Medical University Cancer Institute and Hospital

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Shanghai Chest Hospital

Ruijin Hospital

Shanghai Zhongshan Hospital

Fudan University

Hebei Medical University Fourth Hospital

Harbin Medical University

Liaoning Tumor Hospital & Institute

Tang-Du Hospital

Shanxi Province Cancer Hospital

Shandong Jining No.1 People's Hospital

Weifang People's Hospital

More Information

• Responsible Party: Tianjin Medical University Cancer Institute and Hospital
• ClinicalTrials.gov Identifier: NCT04807673
• Other Study ID Numbers: TianjinCIH20210096
• First Posted: March 19, 2021
• Last Update Posted: April 1, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tianjin Medical University Cancer Institute and Hospital:

esophageal squamous cell carcinoma; Immunotherapy; neoadjuvant therapy

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Squamous Cell; Esophageal Squamous Cell Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Squamous Cell; Esophageal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases; Paclitaxel; Pembrolizumab; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological