Total Neoadjuvant Therapy for Adenocarcinoma of the OESophagus and Oesophagogastric Junction: TNT-OES-2 Trial

Phase 2

Not yet recruiting

• Conditions: Adenocarcinoma of the Esophagus; Esophageal Cancer
• Interventions: Drug: FLOT-CROSS or CROSS-FLOT

• Registration Number: NCT06161818
• Lead Sponsor: Erasmus Medical Center

Brief Summary

Both neoadjuvant chemoradiotherapy (CROSS) and neoadjuvant chemotherapy (FLOT) have demonstrated overall survival benefit over surgery alone in esophageal and esophagogastric junction (EGJ) cancer. Despite these survival gains, the prognosis remains poor, especially in patients with nodal-positive adenocarcinoma (cN+ AC) (5-year survival 36%, compared to 55% for cN0). This highlights the need for more effective treatment options, and justifies treatment intensification in these patients.

The aim of this study is to determine the efficacy and feasibility of TNT FLOT-CROSS and TNT CROSS-FLOT in patients with resectable, cN+ AC of the esophagus or EGJ.

Detailed Description

This study hypothesize that the benefits of the locoregional control of CROSS combined with the systemic effect of FLOT lead to better disease control and survival in cN+ AC patients. This Total Neoadjuvant Treatment (TNT) strategy was found to be feasible in the previous TNT-OES-1 trial. The optimal sequence of CROSS and FLOT is yet unknown. Therefore, the hypothesis of this study is that the disease-free survival (DFS) of patients treated with TNT FLOT-CROSS and TNT CROSS-FLOT will be ≥10% compared to the DFS after CROSS in an appropriate historical cohort.

Study Timeline

• Status Verified: 2023-11
• Study First Submitted: 2023-11-09
• Study First Submitted QC: 2023-11-29
• Last Update Submitted: 2023-11-29
• Study First Posted: 2023-12-08
• Last Update Posted: 2023-12-08
• Study Start: 2024-07-01
• Primary Completion: 2029-09-01
• Study Completion: 2029-12-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 216

Inclusion Criteria

• Patients with cT2-4aN+M0 resectable adenocarcinoma of the esophagus or EGJ (Siewert type I-II) according to the 8th edition of the Union for International Cancer Control (UICC) TNM classification for Esophageal Cancer who are planned to undergo nCRT. In case of stage cT4a, curative resectability has to be explicitly verified by the multidisciplinary tumor board. Clinical N+ status should be determined by EUS or 18F-FDG PET/CT.
• Maximum of 4 cm ingrowth in the cardia, measured by upper endoscopy.
• In case of tumor and/or lymph node involvement below the diaphragm, the most proximal involved lymph node station cannot be higher than N7.
• In case of no tumor or lymph node involvement below the diaphragm, the most proximal involved lymph node station cannot be higher than N4.
• Age ≥ 18 years and <75 years.
• No prior abdominal, thoracic or cervical radiotherapy overlapping with the CROSS irradiation fields.
• No prior cytotoxic chemotherapy for esophageal cancer.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 (28).
• Weight loss <10%.
• Adequate cardiac and respiratory function (cardiac or pulmonary function tests such only necessary in symptomatic patients).
• Adequate bone marrow function (White Blood Cells >3x109/L; Hemoglobin >5.5 mmol/L; platelets >100x109/L). In the event of transfusions, the last red blood cell transfusion should be more than 2 weeks before inclusion.
• Adequate renal function (Glomerular Filtration Rate >50 ml/min) or serum creatinine ≤1.5 x upper limit of normal (ULN) and adequate liver function (total bilirubin <1.5x Upper Level of Normal (ULN); Aspartate transaminase (AST) <2.5x ULN and Alanine transaminase (ALT) <3x ULN.
• A negative serum pregnancy test in women of child-bearing potential during screening period.
• Use of adequate contraception during the study up to 3 months after the end of the study.
• Written informed consent and ability to understand the nature of the study and the study-related procedures and to comply with them.

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Exclusion Criteria

• Patients with tumors of squamous, adenosquamous or other non-adenocarcinoma histology.
• Patients who are eligible for the TRAP-2 trial (NCT05188313, i.e. HER2-positive tumor and no contra-indication for anti-HER2 treatment).
• Patients with overt hematogenous (organ) metastasis, distant lymphatic metastases (cervical/retroperitoneal), peritoneal or pleural dissemination, as detected on 18F-FDG PET/CT or regular CT-scan. In patients in whom a diagnostic laparoscopy is indicated (to assess resectability or to exclude peritoneal disease), tumor-positive cytology peritoneal fluid is also an exclusion criteria.
• Clinically significant (active) cardiac disease (e.g. symptomatic coronary artery disease of myocardial infarction within the last 12 months) or lung disease (forced expiratory volume in one second (FEV1) <1.5L).
• Peripheral neuropathy grade >1, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (18).
• Homozygous DPYD genotype (tested for *2A, *13, 2846A>T, and 1236G>A).
• Pregnant and lactating women, or patients of reproductive potential who are not using effective contraception. If barrier contraceptives are used, they must be continued by both sexes throughout the study.
• Other active malignancies with a prognosis interfering with that of esophageal cancer.
• Expected lack of compliance with the protocol.
• Language difficulty, dementia or altered mental status prohibiting the understanding and giving of informed consent and to complete quality of life questionnaires.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TNT FLOT-CROSS	FLOT-CROSS or CROSS-FLOT	Patients allocated to the TNT FLOT-CROSS arm will be treated with 4 cycles of FLOT chemotherapy followed by a response evaluation consisting of a CT-scan and upper endoscopy with bite-on-bite biopsies of the primary tumor site and of any other suspected lesions in the esophagus. Patients with distant metastases will go off-study. All other patients will proceed to CROSS chemoradiotherapy.
TNT CROSS-FLOT	FLOT-CROSS or CROSS-FLOT	Patients allocated to the TNT CROSS-FLOT arm will be treated with CROSS chemoradiotherapy followed by a response evaluation consisting of a CT-scan and upper endoscopy with bite-on-bite biopsies of the primary tumor site and of any other suspected lesions in the esophagus. Patients with distant metastases will go off-study. All other patients will proceed to FLOT chemotherapy.

Primary Outcome Measures

Name	Time	Method
Disease-free survival	24 months	To determine the disease-free survival after TNT (both FLOT-CROSS and CROSS-FLOT).

Secondary Outcome Measures

Name	Time	Method
Completion of therapy	30 months	To assess the feasibility of TNT FLOT-CROSS and TNT CROSS-FLOT, defined as the proportion of patients that complete the full TNT regimens.
Surgery-related outcomes	42 months	To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on surgery-related outcomes (i.e. proportion that proceed to esophagectomy as planned, radical (R0) resection rate).
Therapy-related mortality and toxicity	30 months	To determine therapy-related mortality and toxicity (according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0) of TNT FLOT-CROSS and TNT CROSS-FLOT.
30- and 90-day mortality	42 months	To assess the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on postoperative morbidity (Clavien-Dindo ≥3) and 30- and 90-day mortality.
The quality of life of patients treated with TNT FLOT-CROSS and TNT CROSS-FLOT according to the QLQ-C30	42 months	To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on quality of life.
Overall survival	24 months	To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on overall survival.
The quality of life of patients treated with TNT FLOT-CROSS and TNT CROSS-FLOT according to the QLQ-OG25	42 months	To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on quality of life.
Clinical and pathological response rates	42 months	To assess the clinical and pathological response rates after TNT FLOT-CROSS and TNT CROSS-FLOT.
Predictive biomarkers	63 months	To collect blood at baseline, first clinical response evaluation (CRE-1), CRE-2 and postoperatively to enable future ctDNA based translational studies looking for biomarkers predictive of disease recurrence and early response.
Future ctDNA analysis	63 months	To collect tissue at baseline, CRE-1, CRE-2 and resection to enable future ctDNA based translational studies looking for biomarkers predictive of disease recurrence and early response.