A multicentre Multi-Arm Multi-Stage (MAMS) randomized trial on treatment options for localized squamous esophageal cancer
试验速览
- 阶段
- 2/3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 1,011
- 试验地点
- 1
研究概览
简要总结
Esophageal cancer is a major health burden in India, with squamous cell carcinoma (ESCC) accounting for nearly 80% of cases. Current multimodality treatments such as neoadjuvant chemotherapy (NACT), neoadjuvant chemoradiation (NACRT), perioperative chemotherapy, and adjuvant immunotherapy,show variable benefits and lack global consensus on the optimal approach for resectable locally advanced ESCC. High recurrence rates (40–50%) persist despite available treatments. Evidence shows promising activity of immunotherapy, especially nivolumab, in advanced and adjuvant settings, and early studies suggest improved pathological complete responses when used neoadjuvantly. However, these studies are limited and lack large randomized trials. There is also interest in evaluating low-dose immunotherapy, which may provide clinical benefit at significantly lower cost, particularly relevant for low-HDI settings. To address the uncertainty around the best treatment strategy, this study uses a Multi-Arm Multi-Stage (MAMS) randomized designto simultaneously compare multiple regimens and allow addition or dropping of arms over time.
The trial compares the current standard (NACRT plus surgery) with two experimental approaches that incorporate low-dose nivolumab:
-
Arm A: NACRT (CROSS regimen) followed by Surgery
-
Arm B: Neoadjuvant FLOT plus low-dose nivolumab followed by Surgery
-
Arm C: NACRT (CROSS) plus low-dose nivolumab followed by Surgery
The study will begin with a pilot/run-in phase in up to 5 centres to test feasibility. After successful completion, full recruitment will continue across participating sites.Pre-Screening: All patients with potentially resectable ESCC at participating centres wil undergo review of available clinical and diagnostic information, including history, comorbidities, performance status, basic labs, imaging (CT/PET-CT), endoscopy, and other standard evaluations. Consent will be obtained for using biopsy samples in optional biomarker analyses.
Screening: Eligible patients (histologically proven ESCC, no prior treatment, appropriate stage, adequate organ function) will be counselled and undergo informed consent. Missing investigations will completed as per standard care. Patients with poor nutrition or uncontrolled diabetes will undergo 2–3 weeks of optimization before re-evaluation. The screening window is up to 21 days from consent.
Randomization: Patients meeting all eligibility criteria will receive a study ID and will be randomized centrally (1:1:1) to Arms A, B, or C using minimization, stratified by centre and nodal status. Additional endocrine labs will be performed for patients assigned to nivolumab-containing arms.
Treatment: Each arm has a defined neoadjuvant regimen, Arm A has weekly carboplatin plus paclitaxel with concurrent radiation (CROSS) for 5 weeks followed by Surgery within 8 weeks, Arm B has FLOT chemotherapy plus low-dose nivolumab every 14 days for 4 cycles followed by Surgery within 8 weeks and in Arm C patients will receive low-dose nivolumab 2 weeks prior to CROSS followed by CROSS regimen plus nivolumab (weeks 1, 3, 5) followed by Surgery within 8 weeks.
Before each treatment cycle, clinical assessment, toxicity review, and lab tests will be performed. Quality-of-life questionnaires (EORTC QLQ-C30, OES-18) will be collected at predefined time points. Pharmacokinetic samples for nivolumab will also be taken from consenting patients.
Surgery: Standardized esophagectomy procedures will be performed across centres. Postoperative complications will be monitored for 30 days and classified using ECCG/Clavien-Dindo criteria.
Follow up: Follow-up will start 3 months post-surgery and will continue every 3 months for 3 years, then 6 monthly till progression or death. Assessments include symptoms, clinical exam, toxicity evaluation, endocrine labs for immunotherapy arms, QoL questionnaires, and imaging (CT/PET-CT every 6 months for 3 years, then annually). After progression, only survival status and subsequent therapy will be recorded.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- None
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •Newly diagnosed Histologically proven squamous carcinoma of esophagus
- •No prior surgery (except endoscopic biopsy) or chemotherapy or radiation
- •Pre-treatment stage cT1N+ M0 or cT2-4a N0/N+, M0 (In case of stage cT4a, curative resectability has to be explicitly verified and documented by the local surgical investigator prior to randomization)
- •No invasion of the tracheobronchial tree or presence of tracheoesophageal fistula.
- •Sexually active patients of childbearing potential must implement effective contraceptive practices during the study when treated with chemotherapy.
- •Age greater than 18 years, willing to give written informed consent.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0–2
- •Adequate cardiac function.
- •Patients with a history of cardiac illness should have a cardiology consultation and should have a left ventricular ejection fraction greater than 50 % (determined by echocardiography)
- •Adequate bone marrow function (White Blood Cells greater than 3000/cumm; Hemoglobin greater than 8 g/dl; platelets greater than 100,000/cumm)
- •Adequate renal function (Calculated Glomerular filtration rate – Cockroft Gault Formula greater than 60 ml/min)
- •Adequate liver function (Total bilirubin less than 3 g/dL, SGOT/SGPT less than 5X upper limit of normal, Albumin greater than 3g/dL).
排除标准
- •Patients with adenosquamous or adenocarcinoma histology
- •Cervical esophageal cancers
- •Inability to provide informed consent due to psychological, social, and other factors
- •Dementia or altered mental status that would prohibit the understanding and giving of informed consent
- •A history of malignancies other than esophageal cancer before enrolment, excluding non-melanoma skin cancer, in situ cervical cancer, or cured early prostate cancer;
- •Comorbidities which will not allow administration of chemotherapy, radiation or immunotherapy or will preclude esophagectomy • CTC grade greater than 1 peripheral neuropathy; • Poorly controlled diabetes mellitus ( HbA1C greater than 8) (These patients will be rescreened after the consultation with Physician and optimization of the oral hypoglycaemics and/or insulin) • Known or suspected allergy or hypersensitivity to monoclonal antibodies, any ingredients of Nivolumab , paclitaxel, and cisplatin; • Preexisting or coexisting bleeding disorder • New York Heart Association Class III/IV and history of active angina.
- •Documented myocardial infarction within the 6 months preceding registration (pretreatment ECG evidence of infarct only will not exclude patients).
- •Patients with a history of significant ventricular arrhythmia requiring medication or congestive heart failure.
- •History of 2nd or 3rd degree heart blocks • Liver dysfunction – Child-Pugh B or C • Active organ infections including pneumonia, pulmonary tuberculosis, pyelonephritis, HIV, active hepatitis B (HBV DNA greater than or equal to 2000 IU/mL or 104 copies/mL) and hepatitis C (positive for hepatitis C antibody and HCV RNA levels higher than the lower limit of the assay).
- •• American Society of Anaesthesiologist (ASA) score 3 or more • Autoimmune disease • History of organ transplantation or allogeneic bone marrow transplantation
- •For Female Participants • Pregnancy • Lactating women • Women of child bearing potential (WOCBP) or their partners who are unwilling to practice contraception.
研究者
Dr C S Pramesh
Tata Memorial Hospital, Mumbai