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Esophageal CancerPhase 2TNT-OES-2NCT06161818

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

A Phase 2 study testing FLOT-CROSS or CROSS-FLOT in people with Esophageal Cancer and Adenocarcinoma of the Esophagus, run by Erasmus Medical Center at 10 sites in Netherlands.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

Both neoadjuvant chemoradiotherapy (CROSS) and neoadjuvant chemotherapy (FLOT) have demonstrated overall survival benefit over surgery alone in esophageal and esophagogastric junction (EGJ) cancer. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
FLOT-CROSS or CROSS-FLOT
Could I receive a placebo?
No, everyone receives an active treatment
How many people
216 participants
Where
10 sitesNetherlands
Study dates
12 Sep 2025to 1 Dec 2029
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).
  • Age ≥ 18 years. For patients aged 70 years or older, a geriatric screening tool (G8) should be used to assess functioning across the domains. If a patient has a score of 14 or lower on the G8, a comprehensive geriatric assessment (CGA) should be done prior to inclusion (Appendix D).
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  • 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 bone marrow function (White Blood Cells >3x109/L; Haemoglobin >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.

Who cannot join

  • 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)
  • 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 (37).
  • Homozygous DPYD genotype (tested for *2A, *13, 2846A>T, and 1236G>A)
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  • 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.

Trial locations and contacts

10 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Bianca Mostert, MD, PhD contact

+31107041906

b.mostert@erasmusmc.nl

Esmee A de Bruijn, MD contact

0031107034523

e.debruijn@erasmusmc.nl

10 sites in 1 country

Netherlands10 sites, 10 recruiting

  • Ziekenhuisgroep Twente

    Almelo

    Ronald Hoekstra, MD, PhD, 0031887087878, r.hoekstra@zgt.nl

    Not yet recruiting

  • Amsterdam UMC

    Amsterdam, North Holland

    Hanneke van Laarhoven, Prof, MD, PhD, 0031205669111, h.vanlaarhoven@amsterdamumc.nl

    Not yet recruiting

  • Antoni van Leeuwenhoek/Nederlands Kanker Instituut

    Amsterdam

    Johanna van Sandick, MD, PhD, 0031205129111, j.v.sandick@nki.nl

    Not yet recruiting

  • Gelre ziekenhuis

    Apeldoorn

    Karel Eechoute, MD, PhD, 0031881053300, k.eechoute@gelre.nl

    Not yet recruiting

  • Catharina Ziekenhuis

    Eindhoven, North Brabant

    Irene van Hellemond, MD, Phd, 0031402399111, irene.v.hellemond@catharinaziekenhuis.nl

    Not yet recruiting

  • Frisius medisch centrum

    Leeuwarden, North Brabant

    Marco Polee, MD, Phd, 0031582866666, m.polee@mcl.nl

    Not yet recruiting

  • Leids Universitair Medisch Centrum

    Leiden

    Marije Slingerland, MD, PhD, 0031715269111, m.slingerland@lumc.nl

    Not yet recruiting

  • Radboud Universitair Medisch Centrum

    Nijmegen

    Harm Westdorp, 0031243611111, harm.westdorp@radboudumc.nl

    Not yet recruiting

  • Erasmus Medical Centre

    Rotterdam, South Holland

    Bianca Mostert, MD, PhD, 0031107041906, b.mostert@erasmusmc.nl

    Esmee de Bruijn, MD, 0031107034523, e.debruijn@erasmusmc.nl

    Recruiting

  • Elisabeth Tweesteden Ziekenhuis

    Tilburg, North Brabant

    Laurens Beerepoot, MD, Phd, 0031132210000, l.beerepoot@etz.nl

    Not yet recruiting

Other trials in Netherlands

About this study

Official title: Total Neoadjuvant Therapy for Lymph Node-positive Adenocarcinoma of the OESophagus and Oesophagogastric Junction: a Phase II Study

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.

Read the detailed description

This study hypothesizes that the benefits of the locoregional control of CROSS combined with the systemic effect of FLOT leads 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 progression-free survival (PFS) of patients treated with TNT FLOT-CROSS and TNT CROSS-FLOT will be ≥10% compared to the PFS after CROSS in an appropriate historical cohort.

Being tested
FLOT-CROSS or CROSS-FLOT
Keywords
Total Neoadjuvant Therapy, Chemotherapy, Chemoradiotherapy
Medical subject headings
Esophageal Neoplasms, Adenocarcinoma Of Esophagus

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • FLOT-CROSS or CROSS-FLOTDrug

    Randomization between TNT FLOT-CROSS and TNT CROSS-FLOT

Study groups in NCT06161818
Study groupRoleWhat they receive
TNT FLOT-CROSSExperimentalPatients 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.
Receives: Drug: FLOT-CROSS or CROSS-FLOT
TNT CROSS-FLOTExperimentalPatients 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.
Receives: Drug: FLOT-CROSS or CROSS-FLOT

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: 24 months

Secondary outcomes (16)

  1. Feasibility, completion of treatment

    To assess the feasibility of TNT FLOT-CROSS and TNT CROSS-FLOT. Feasibility is defined as the proportion of patients that complete all 4 cycles of FLOT and all 5 chemotherapy cycles of CROSS, permitting dose reductions and delays.

    Measured: 30 months

  2. Overall survival

    To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on overall survival. OS is calculated from the date of randomization to the date of death due to any cause or, for patients alive at trial closure, date of last follow-up

    Measured: 24 months

  3. Therapy-related toxicity

    The number of patients with any major systemic therapy related toxicity, defined as grade ≥ 3 according to the Common Terminology Criteria for Adverse Events (CTCAE ) version 5.0), up to one month after the last administration of TNT

    Measured: 30 months

  4. Dose reductions of TNT

    The number of patients requiring dose reductions or treatment delays during CROSS and FLOT

    Measured: 30 months

  5. Need of G-CSF

    The number of patients requiring G-CSF as primary or secondary prophylaxis

    Measured: 60 months

  6. Postoperative morbidity and mortality

    To assess the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on postoperative morbidity (Clavien-Dindo ≥3) and 30- and 90-day mortality.

    Measured: 42 months

  7. Surgical-related outcomes

    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).

    Measured: 42 months

  8. Non-surgical related outcomes

    To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on non-surgical outcomes: the proportion of patients who choose for active surveillance instead of surgery after CRE-2

    Measured: 30 months

  9. Clinical response rate

    To assess the clinical response rates after TNT FLOT-CROSS and TNT CROSS-FLOT. Clinical complete response (cCR) rate is defined as the percentage of patients without residual locoregional disease or distant metastases at CRE-2, measured by PET-scan and bite-on-bite biopsies with endoscopy and EUS.

    Measured: 42 months

  10. Pathological response rate

    To assess the pathological response rate after TNT FLOT-CROSS and TNT CROSS-FLOT. Pathological complete response (pCR) rate in those who underwent an oesophagectomy is defined as ypT0N0. Major pathological response in those who underwent oesophagectomy, defined as Mandard 1-2.

    Measured: 42 months

  11. Distant metastases

    To assess the proportion of distant metastases after TNT FLOT-CROSS and TNT CROSS-FLOT at 6 weeks after completion of treatment

    Measured: 30 months

  12. Quality of life assessed by EORTC-C30

    The quality of life will be assessed with the EORTC-C30 questionnaire

    Measured: 42 months

  13. Quality of life assessed by EORTC QLQ-OG25

    To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on quality of life, assessed by the QoL questionnaires: EORTC QLQ-OG25

    Measured: 42 months

  14. The PD-L1 combined positive score (CPS)

    The PD-L1 combined positive score (CPS) of TNT FLOT-CROSS and TNT CROSS-FLOT before treatment and in metastases. The PD-L1 CPS will be measured as a continuous variable. This will be measured using the 28-8 monoclonal antibody.

    Measured: 42 months

  15. Predictive biomarkers

    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.

    Measured: 63 months

  16. Future ctDNA analysis

    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.

    Measured: 63 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Dec 2023
  2. Study start12 Sep 2025
  3. Primary completion1 Sep 2029 (estimated)
  4. Study completion1 Dec 2029 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Arm A: FLOT-CROSS Arm B: CROSS-FLOT
Masking
None (open label)
Enrolment
216 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06161818
Sponsor's protocol ID
TNT-OES-2
Other IDs
2025-521158-40-00, 2025
Acronym
TNT-OES-2
Status last verified
Dec 2025
First submitted
9 Nov 2023
Last updated
22 Dec 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 35669486

  • Klute KA, Shah MA. Evolving Therapeutics for Resectable Esophageal Adenocarcinoma. J Natl Compr Canc Netw. 2025 May;23(5):e257044. doi: 10.6004/jnccn.2025.7044.

    PubMed 40340830

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing FLOT-CROSS or CROSS-FLOT in people with Esophageal Cancer and Adenocarcinoma of the Esophagus, run by Erasmus Medical Center at 10 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 22 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Bianca Mostert, MD, PhD (+31107041906, b.mostert@erasmusmc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free survival (time frame: 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06161818, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Dec 2025.

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