Clinical trial NCT05244798: Sintilimab Plus NCT or NCRT Versus NCRT for ESCC
Official title: Neoadjuvant Chemotherapy or Neoadjuvant Chemoradiotherapy Plus Sintilimab Versus Neoadjuvant Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: a Multicenter, Randomized, Controlled, Phase III Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Esophageal Squamous Cell Carcinoma
Lead sponsor: Sichuan Cancer Hospital and Research Institute
Sponsor class: OTHER
Collaborators: name: Peking University Cancer Hospital & Institute
name: Tianjin Medical University Cancer Institute and Hospital
name: Hebei Medical University Fourth Hospital
name: Anhui Provincial Hospital
name: The First Affiliated Hospital with Nanjing Medical University
name: Anyang Tumor Hospital
name: Shantou Central Hospital
name: Innovent Biologics (Suzhou) Co. Ltd.
name: GeneCast Biotechnology Co., Ltd.
First posted: 2022-02-17
Enrollment: 420
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: Comparative analysis of patients with resectable locally advanced esophageal squamous cell carcinoma treated with neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy combined sintilimab versus neoadjuvant chemoradiotherapy.

Detailed description: The research process is divided into three stages: firstly, the stage of screening period for 14 days. Qualified subjects will enter the treatment period after completion of screening examination and evaluation. And then, the stage of treatment period: Experimental group (group A) received sintilimab combined with neoadjuvant chemotherapy regimen: preoperative neoadjuvant, sintilimab (D1 administration) combined with chemotherapy (TP regimen: albumin-paclitaxel + carboplatin, D1 administration) for 2 cycles. Every 3 weeks, there was a dosing cycle (Q3W). The experimental group (group B) received neoadjuvant sintilimab combined concurrent chemoradiotherapy: preoperative sintilimab (D1 administration) combined with neoadjuvant concurrent chemoradiotherapy. Chemotherapy regimen: TP regimen: albumin-paclitaxel + carboplatin, D1 administration, 2 cycles. Every 3 weeks, there was a dosing cycle (Q3W). Radiotherapy regimen: according to IMRT treatment plan, the total dose was 41.4Gy, divided into 23 times, 5 days a week. And the control group (group C) received neoadjuvant chemoradiotherapy and the regimen was similar with group B. Surgery was performed 6-8 weeks after completion of neoadjuvant therapy. If the patient without vital tumor cells in primary and lymph nodes after surgery, they only need regular follow-up visit. If the patients with non-pCR resected, those patients need to receive adjuvant immunotherapy. And if the patients with non-R0 resected, the regimen of those patients need to carefully decide based on multidisciplinary team discussed. Lastly, the stage of postoperative assistance, the researchers selected postoperative treatment according to the guidelines for the diagnosis and treatment of esophageal cancer. Patients were followed up for efficacy and safety within 90 days after surgery, once every 3 months for 2 years and once every 6 months for 2-5 years.

Eligibility criteria: Inclusion criteria:

1. Aged 18 to 75, both sexes;
2. Patients with histologically confirmed locally advanced (cT1N2-3M0 or cT2-4aN0-3M0) thoracic esophageal squamous cell carcinoma (8th UICC-TNM stage);
3. Cervical contrast-enhanced CT showed no suspicious metastatic lymph nodes. Imaging examination showed no systemic metastasis.
4. R0 resection is expected to be achieved;
5. Physical state ECOG 0 \~ 1;
6. No previous antitumor therapy for esophageal cancer, including chemotherapy, radiotherapy (including radiotherapy planned during the study), hormone therapy, and immunotherapy;
7. Measurable lesions (according to RECIST v1.1);
8. There was no operation contraindications in the evaluation of various organ functions before operation;
9. The following laboratory tests confirm that the bone marrow, liver and kidney functions meet the requirements for study participation:

   * Hemoglobin ≥90g/L;
   * White blood cell count ≥ lower limit of laboratory normal;
   * Neutrophil absolute value (ANC) ≥1.5×109/L;
   * Platelet count ≥100×109/L; Total bilirubin ≤1.5× upper limit of normal (ULN);
   * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN;
   * Prothrombin time ≤16 seconds and international normalized ratio ≤1.5×ULN; Creatinine ≤1.5×ULN or Cr clearance ≥50 mL/min (calculated using Cockcroft-Gault formula);
10. Fertile women must consent to use effective contraception (e.g. intrauterine devices, birth control pills, or condoms) during the study medication period and within 60 days of the last study medication, have a negative serum pregnancy test within 7 days before study enrollment, and be non-lactating; Men agree that they must use effective contraception during the study medication period and for 60 days after the last study medication;
11. The informed consent must be understood and signed.

Exclusion criteria:

Patients who met any of the following criteria were excluded from the study:

1. Malignant tumors other than esophageal cancer (cured localized tumors, including cervical carcinoma in situ, skin basal cell carcinoma and prostate carcinoma in situ, were not excluded) had occurred within 5 years before randomization; Prostate cancer patients receiving hormone therapy with DFS for more than 5 years were not excluded).
2. Patients with high blood tendency who had a history of gastrointestinal bleeding within 6 months before randomization, or had coagulopathy at the time of enrollment, or were receiving thrombolysis or anticoagulant therapy;
3. Severe cardiovascular and cerebrovascular diseases:

   • New York Heart Association (NYHA) class II or higher congestive heart failure, unstable angina, myocardial infarction, poorly controlled arrhythmias, or cerebrovascular accidents within 12 months before randomization.

   LVEF (left ventricular ejection fraction) \<50% on echocardiography. Corrected QT interval (QTc) \>480ms (calculated using Fridericia's method; if QTc was abnormal, three consecutive tests were performed at 2 min intervals and the mean value was taken).

   Medically difficult to control hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥100mmHg) (based on the average of ≥2 measurements).

   • A previous hypertensive crisis or hypertensive encephalopathy.
4. Previous history of interstitial lung disease or pneumonia requiring steroid treatment at enrollment;
5. Had active tuberculosis at the time of randomization, or had received anti-tuberculosis therapy within 1 year before randomization;
6. Asthma at random requiring intermittent use of bronchodilators or other medical interventions;
7. Patients with infectious diseases requiring systemic treatment (oral or intravenous administration) within 4 weeks before randomization; for active hepatitis, effective treatment was required before enrollment;
8. Severe unhealed wounds, active ulcers, and untreated fractures at random;
9. Combined with other inoperable conditions;
10. The previous operation resulted in the inability to use stomach instead of esophagus to reconstruct the digestive tract in this operation;
11. Was receiving systemic steroid therapy (more than 10mg of prednisone daily or equivalent) or other immunosuppressive agents during the 2 weeks prior to randomization;
12. Severe allergy to chemotherapy drugs (albumin paclitaxel or cisplatin) or any monoclonal antibody;
13. Has had an active autoimmune disease requiring systemic treatment (i.e., immunomodulatory drugs, corticosteroids, or immunomodulatory drugs) in the past 2 years; However, replacement therapy (e.g., thyroxine, insulin, or replacement therapy with physiologic corticosteroids for adrenal or pituitary insufficiency) is not considered systemic therapy and is allowed for use and enrollment;
14. Previous organ transplant recipients;
15. If HBsAg(+) and/or HBcAb(+) are required, HBV DNA must be \< 500IU/mL. (If the lower limit of the local center's minimum detectable value is higher than 500IU/mL, after discussion with the sponsor, Enrollment was determined on a case-to-case basis) and continued to receive effective anti-HBV therapy that was already in use during the study period, or entecavir or tenofovir therapy was started prior to study medication;
16. Hcv-rna testing should be performed if HCV antibody is positive, and HCV-RNA\>10\^3 copy number /mL should be excluded;
17. Co-infection with HIV;
18. In the judgment of the investigator, there are other circumstances that are not suitable for participating in the study.

Primary outcomes:
measure: Pathology complete response rate, pCR
timeFrame: 3 months after the surgery
Secondary outcomes:
measure: Treatment related adverse event, TRAE
timeFrame: 3 months after the surgery
measure: Major Pathological Remission rate, MPR
timeFrame: 3 months after the surgery
measure: Rate of R0 resection
timeFrame: 3 months after the surgery
measure: Events Free Survival, EFS
timeFrame: Through study completion, an average of 1 year.
measure: Overall Survival,OS
timeFrame: 5 years after inclusion
measure: disease-free survival, DFS
timeFrame: 5 years after inclusion
measure: Disease Control Rate, DCR
timeFrame: 3 years after inclusion
measure: Objective Response Rate, ORR
timeFrame: 3 years after inclusion
measure: Circulating tumor DNA, ctDNA
timeFrame: Before neoadjuvant therapy, before surgery, 1, 6, 12, 18, 24 months after surgery
Other outcomes:
Locations:
city: Chengdu
country: China
facility: Sichuan Cancer Hospital and Research Institute
state: Sichuan
Study officials:
References: