Total Neoadjuvant Therapy for Lymph Node-positive Adenocarcinoma of the OESophagus and Oesophagogastric Junction

NCT06161818 | Recruiting Phase 2 DMC

• 2 other identifiers: TNT-OES-22025-521158-40-00
• Study Type: interventional
• Target: 216
• Locations: 1 country
• Sites: 10

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.

Conditions

Adenocarcinoma of the Esophagus; Esophageal Cancer

Keywords

Total Neoadjuvant Therapy; Chemotherapy; Chemoradiotherapy

Outcome Measures

Primary Outcomes (1)

• Progression-free survival

  To determine the progression-free survival (PFS) after TNT (both FLOT-CROSS and CROSS-FLOT), the PFS is defined as the time interval from randomization to the first event of locoregional failure after surgery, or locoregional progression leading to irresectability prior to surgery , progression to metastatic disease or death

  24 months

Secondary Outcomes (16)

• Feasibility, completion of treatment

  30 months

• Overall survival

  24 months

• Therapy-related toxicity

  30 months

• Dose reductions of TNT

  30 months

• Need of G-CSF

  60 months

Study Arms (2)

TNT FLOT-CROSS

EXPERIMENTAL

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.

Drug: FLOT-CROSS or CROSS-FLOT

TNT CROSS-FLOT

EXPERIMENTAL

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.

Drug: FLOT-CROSS or CROSS-FLOT

Interventions

FLOT-CROSS or CROSS-FLOT DRUG

Randomization between TNT FLOT-CROSS and TNT CROSS-FLOT

TNT CROSS-FLOT; TNT FLOT-CROSS

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with cT2-4aN+M0 resectable adenocarcinoma of the oesophagus 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 or FLOT (43). 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. Clinical M0 status must be determined by 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 (Appendix C).
• In case of no tumor or lymph node involvement below the diaphragm, the most proximal involved lymph node station cannot be higher than N4 (Appendix C).
• No prior abdominal, thoracic or cervical radiotherapy overlapping with the CROSS irradiation fields.
• No prior cytotoxic chemotherapy for oesophageal cancer.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 (44).
• Weight loss \<10%.
• Adequate cardiac and respiratory function (cardiac or pulmonary function tests such only necessary in symptomatic patients).
• 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.

You may not qualify if:

• Patients with tumours of squamous, adenosquamous or other non-adenocarcinoma histology.
• Patients who are eligible for and want to participate in the TRAP-2 trial (NCT05188313)
• 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 (37).
• 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 oesophageal cancer.
• Expected lack of compliance with the protocol.
• Limitations such as language barriers, dementia, or altered mental status that make it impossible for the participant to understand the study, provide informed consent, and complete quality of life questionnaires. Participants who do not speak the primary study language may still be included if the study information is adequately translated or explained (e.g., read aloud in their native language) and they demonstrably understand the study procedures.

Sponsors & Collaborators

• Erasmus Medical Center: lead

Study Sites (10)

Catharina Ziekenhuis

Eindhoven, North Brabant, Netherlands

NOT YET RECRUITING

Frisius medisch centrum

Leeuwarden, North Brabant, Netherlands

NOT YET RECRUITING

Elisabeth Tweesteden Ziekenhuis

Tilburg, North Brabant, Netherlands

NOT YET RECRUITING

Amsterdam UMC

Amsterdam, North Holland, Netherlands

NOT YET RECRUITING

Erasmus Medical Centre

Rotterdam, South Holland, Netherlands

RECRUITING

Ziekenhuisgroep Twente

Almelo, Netherlands

NOT YET RECRUITING

Antoni van Leeuwenhoek/Nederlands Kanker Instituut

Amsterdam, Netherlands

NOT YET RECRUITING

Gelre ziekenhuis

Apeldoorn, Netherlands

NOT YET RECRUITING

Leids Universitair Medisch Centrum

Leiden, Netherlands

NOT YET RECRUITING

Radboud Universitair Medisch Centrum

Nijmegen, Netherlands

NOT YET RECRUITING

Related Publications (1)

• van der Zijden CJ, Eyck BM, van der Gaast A, van Doorn L, Nuyttens JJME, van Lanschot JJB, Wijnhoven BPL, Mostert B, Lagarde SM. Chemotherapy aNd chemoradiotherapy for adenocarcinoma of the OESophagus and esophagogastric junction with oligometastases: Protocol of the TNT-OES-1 trial. Contemp Clin Trials Commun. 2022 May 28;28:100934. doi: 10.1016/j.conctc.2022.100934. eCollection 2022 Aug.

  PMID: 35669486 BACKGROUND

MeSH Terms

Conditions

Esophageal Neoplasms; Adenocarcinoma Of Esophagus

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases

Study Officials

• Bianca Mostert, MD, PhD

  Erasmus Medical Centre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bianca Mostert, MD, PhD

CONTACT

+31107041906; b.mostert@erasmusmc.nl

Esmee A de Bruijn, MD

CONTACT

0031107034523; e.debruijn@erasmusmc.nl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Arm A: FLOT-CROSS Arm B: CROSS-FLOT

Study Record Dates

• First Submitted: November 9, 2023
• First Posted: December 8, 2023
• Study Start: September 12, 2025
• Primary Completion (Estimated): September 1, 2029
• Study Completion (Estimated): December 1, 2029
• Last Updated: December 22, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

NL (10)