Neoadjuvant Immunotherapy Plus CRT Versus Neoadjuvant CRT for Locally Advanced Resectable ESCC

Официальное название

Neoadjuvant Immunotherapy Combined With Chemoradiotherapy Versus Neoadjuvant Chemoradiotherapy for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma (cII-III Stage): A Multi-center Prospective Randomized Clinical Trial

Обзор

The purpose of this study was to evaluate the safety, feasibility and outcome of anti-PD-1 antibody (Tislelizumab, BeiGene) combined with neoadjuvant chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by minimally invasive esophagectomy for locally advanced resectable esophageal squamous cell carcinoma (cII-III Stage) patient.

Подробное описание

It is a prospective randomized phase II\&III clinical trial sponsored by Shanghai Zhongshan Hospital with other twelve hospitals in China participating in. 476 patients with locally advanced resectable esophageal squamous cell carcinoma (cII-III Stage) are recruited and randomly assigned into the neoadjuvant chemoradiotherapy combined with immunotherapy group (nCRT plus anti-PD-1 Group) and the neoadjuvant chemoradiotherapy group (nCRT Group) according to the proportion of 1:1. The safety, efficacy of protocols and prognosis of patients are compared between the two regimens.

Вмешательства

• Процедура Neoadjuvant Chemoradiotherapy
  Chemotherapy: carboplatin (AUC 2 mg/mL per min) and paclitaxel (50 mg/m2 of body-surface area) were administered intravenously for five cycles, starting on days 1, 8, 15, 22, and 29. For each cycle, Carboplatin and paclitaxel were administered 30 minutes apart. Radiotherapy: A total radiation dose of 41.4 Gy was given in 23 fractions of 1.8 Gy, 5 days per week (Radiotherapy was performed on the 2nd, 3rd, 4th, 5th, and 6th day in each cycle, and only 3 times in the 5th cycle)
• Препарат Tislelizumab
  Tislelizumab (200mg/time) was administered intravenously on the 1st and 22nd day. The intravenous injection lasts about 30 minutes (micropump is recommended, intravenous bolus is prohibited, duration should be not less than 20 minutes and not more than 60 minutes);
• Процедура Ivor-Lewis or Mckeown Esophagectomy(Mckeown Esophagectomy recommended)
  After neoadjuvant therapy, patients in groups receive Ivor-Lewis or Mckeown Esophagectomy (Mckeown Esophagectomy recommended)

Первичные конечные точки

• Pathological response rate(pCR) [Срок оценки: Up to the date of pathological reports obtained since the date of randomization, up to 12 months]
• Overall survival(OS) [Срок оценки: Up to the date of death of any causes since the date of randomization, up to 36 months]

Вторичные конечные точки (8)

• Treatment related complications [Срок оценки: Up to 1 month after surgery since the data of randomization, up to 13 months]
• Progression-free survival(PFS) [Срок оценки: Up to the date of disease recurrence since the date of randomization, up to 36 months]
• R0 resection rate [Срок оценки: Up to the date of pathological reports obtained since the date of randomization, up to 12 months]
• Number and Location of positive lymph nodes [Срок оценки: Up to the date of pathological reports obtained since the date of randomization, up to 12 months]
• Overall Quality of life [Срок оценки: Up to the end of follow-up since the data of surgery, up to 36 months]
• Quality of life in eating and swallowing function [Срок оценки: Up to the end of follow-up since the data of surgery, up to 36 months]
• Recurrence-free survival (RFS) [Срок оценки: Up to the date of disease recurrence since the date of surgery, up to 36 months]
• Correlation between genetic profile and tumor response [Срок оценки: Up to the end of follow-up since the data of surgery, up to 36 months]

Критерии участия

Критерии включения

• Histologically-confirmed esophageal squamous cell carcinoma and whose tissue samples were taken before treatment;
• Tumors of the esophagus are located in the thoracic cavity;
• Pre-treatment stage as clinical II-III (AJCC/UICC 8th Edition)
• Age is between 18 years and 75 years;
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and expected survival time ≥12 months;
• Adequate cardiac function. All patients should perform ECG, and those with a cardiac history or ECG abnormality should perform echocardiography with the left ventricular ejection fraction > 50 %;
• Adequate respiratory function with FEV1≥1.2L, FEV1%≥50% and DLCO≥50% shown in pulmonary function tests ;
• Adequate bone marrow function (White Blood Cells >4x10\^9 /L; Neutrophil >2.0×10\^9 /L; Hemoglobin > 90 g/L; platelets>100x10\^9 /L);
• Adequate liver function (Total bilirubin <1.5x Upper Level of Normal (ULN); Aspartate transaminase(AST) and Alanine transaminase (ALT) <1.5x ULN);
• Adequate renal function (Glomerular filtration rate (CCr) >60 ml/min; serum creatinine (SCr) ≤120 µmol/L);
• The patient has provided written informed consent and is able to understand and comply with the study;

Критерии исключения

Exclusion Criteria associated with Cancer:

• Patients with histological non-squamous cell carcinoma;
• Patients with advanced non-operable or metastatic esophageal cancer;
• Pre-treatment stage as cM+, cN3 or cT4b(non-curatively-resectable verified by the local surgical investigator, AJCC/UICC 8th Edition) or cTis-1a, cT1bN0;
• Patients with another previous or current malignant disease which is likely to interfere with treatment or the assessment of response in the judgement of the local surgical investigator;
• Patients who have received or are receiving other chemotherapy, radiotherapy or targeted therapy;

Other Exclusion Criteria:

• Patients with autoimmune diseases history;
• Recently or currently taking Glucocorticoids or Immunosuppressants;
• Patients who underwent immunotherapy in the past;
• Allergy to any antibody drugs or allergy to Paclitaxel and Carboplatin.
• Past or currently suffering from chronic or recurrent autoimmune diseases;
• Patients with active infection of immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); HIV seropositivity; HBV DNA or HCV RNA positive;
• Patients with organ transplantation (including autologous bone marrow transplantation and peripheral stem cell transplantation);
• Patients with severe systematic intercurrent disease, such as active infection or poorly controlled diabetes; coagulation disorders; hemorrhagic tendency or under treatment of thrombolysis or anticoagulant therapy;
• Any patient with a significant medical condition which is thought unlikely to tolerate the therapies. Such as cardiac disease (e.g. symptomatic coronary artery disease or myocardial infarction within last 12 months), clinically-significant lung disease, clinically-significant bone marrow, liver, renal function disorder;
• Pregnant or lactating women and fertile women who will not be using contraception during the trial;
• Participation in another intervention clinical trial with interference to the chemotherapeutic or chemoradiotherapeutic intervention during this study or during the last 30 days prior to informed consent;
• Expected lack of compliance with the protocol.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Shanghai Zhongshan Hospital — Шанхай

Публикации

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• van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROS PMID 22646630
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• Yamamoto S, Kato K. Immuno-oncology for esophageal cancer. Future Oncol. 2020 Nov;16(32):2673-2681. doi: 10.2217/fon-2020-0545. Epub 2020 Aug 11. PMID 32777942
• Huang J, Xu J, Chen Y, Zhuang W, Zhang Y, Chen Z, Chen J, Zhang H, Niu Z, Fan Q, Lin L, Gu K, Liu Y, Ba Y, Miao Z, Jiang X, Zeng M, Chen J, Fu Z, Gan L, Wang J, Zhan X, Liu T, Li Z, Shen L, Shu Y, Zhang T, Yang Q, Zou J; ESCORT Study Group. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a mul PMID 32416073
• Liao XY, Liu CY, He JF, Wang LS, Zhang T. Combination of checkpoint inhibitors with radiotherapy in esophageal squamous cell carcinoma treatment: A novel strategy. Oncol Lett. 2019 Nov;18(5):5011-5021. doi: 10.3892/ol.2019.10893. Epub 2019 Sep 19. PMID 31612012

Идентификаторы

NCT: NCT04973306 · B2021-369R

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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