Clinical trial NCT04807673: Pembrolizumab Plus Neoadjuvant Chemotherapy vs. Neoadjuvant Chemoradiotherapy for Locally Advanced ESCC (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
Overall status: RECRUITING
Phase: PHASE3
Conditions: Esophageal Squamous Cell Carcinoma
Keywords: esophageal squamous cell carcinoma
Immunotherapy
neoadjuvant therapy
Lead sponsor: Tianjin Medical University Cancer Institute and Hospital
Sponsor class: OTHER
Collaborators: name: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
name: Shanghai Chest Hospital
name: Ruijin Hospital
name: Hebei Medical University Fourth Hospital
name: Harbin Medical University
name: Liaoning Cancer Hospital & Institute
name: Shanxi Province Cancer Hospital
name: Jining First People's Hospital
name: Weifang People's Hospital
name: Tianjin Medical University General Hospital
name: Shandong Provincial Hospital
First posted: 2021-03-19
Enrollment: 342
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Event Free Survival (EFS)
timeFrame: Up to approximately 2.5 years
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: 3 and 5 years
measure: Disease Free Survival (DFS)
timeFrame: 3 and 5 years
measure: Major pathologic response (MPR)
timeFrame: 1 month after resection
measure: Objective response rate (ORR)
timeFrame: 1 month after resection
measure: Pathologic Complete Response (PCR)
timeFrame: 1 month after resection
measure: assessment in perioperation
timeFrame: perioperative period
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: up to 16 months
measure: Quality of life differences (EORTC QLQ-C30)
timeFrame: 2.5 years
measure: Quality of life differences (EORTC QLQ-OES18)
timeFrame: 2.5 years
Other outcomes:
Locations:
city: Tianjin
country: China
facility: Department of minimally invasive esophageal surgery, Tianjin Medical University Cancer Institute and Hospital
state: Tianjin
Study officials:
References:
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.