Total Neoadjuvant Therapy for lymph node-positive adenocarcinoma of the OESophagus and oesophagogastric junction: TNT-OES-2 trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02], Diseases [C] - Digestive System Diseases [C06]

Trial duration

12 Sep 2025 → ongoing

Decision date (initial)

2025-08-04

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

KWF Kankerbestrijding

External identifiers

EU CT number

2025-521158-40-00

ClinicalTrials.gov

NCT06161818

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

• To determine the progression-free survival at 2 years after TNT (either TNT FLOT-CROSS and TNT CROSS-FLOT combination)

Secondary objectives 10

1. • To assess the feasibility of TNT FLOT-CROSS and TNT CROSS-FLOT
2. • To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on overall survival
3. • To determine therapy-related toxicity of TNT FLOT-CROSS and TNT CROSS-FLOT
4. • To assess the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on postoperative morbidity and mortality
5. • To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on surgical outcomes
6. • To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on non-surgical outcomes
7. • To assess the clinical and pathological response rates after TNT FLOT-CROSS and TNT CROSS-FLOT
8. • To assess the proportion of distant metastases after TNT FLOT-CROSS and TNT CROSS-FLOT
9. • To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on quality of life
10. • To determine the PD-L1 combined positive score (CPS) of TNT FLOT-CROSS and TNT CROSS-FLOT before treatment and in metastases.

Conditions and MedDRA coding

oesophageal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. • 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 either EUS, CT-scan or 18F-FDG PET/CT. Clinical M0 status must be determined by 18F-FDG PET/CT.
2. • Adequate cardiac and respiratory function (cardiac or pulmonary function tests such only necessary in symptomatic patients).
3. • 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.
4. • 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.
5. • A negative serum pregnancy test in women of child-bearing potential during screening period.
6. • Use of adequate contraception during the study up to 3 months after the end of the study.
7. • Written informed consent and ability to understand the nature of the study and the study-related procedures and to comply with them.
8. • 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 at baseline
9. • No prior abdominal, thoracic or cervical radiotherapy overlapping with the CROSS irradiation fields.
10. • No prior cytotoxic chemotherapy for oesophageal cancer.
11. • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 (44).
12. • Not more than 10% weight loss in the last month before inclusion.
13. • The length of the primary tumor and the involved lymph nodes should be suitable for nCRT according to standard care, with the following considerations: If the tumor extends below the EGJ into the stomach, the bulk of the tumor must involve the oesophagus or the gastroesophageal junction, and tumor should be suitable for oesophagectomy with gastric conduit reconstruction, without the use of a colon interposition. In case of pathological lymph-nodes in the left or right lower paratracheal nodes (station 4R or 4L) (Appendix C), the patient can be included if nCRT is deemed beneficial for the patient and the radiotherapy toxicity is expected to be manageable. Patients with node involvement above this station are not eligible for inclusion.

Exclusion criteria 10

1. • Patients with tumours of squamous, adenosquamous or other non-adenocarcinoma histology.
2. • Patients who are eligible for and want to participate in the TRAP-2 trial (NCT05188313)
3. • 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.
4. • 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).
5. • Peripheral neuropathy grade >1, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (37).
6. • Homozygous DPYD genotype (tested for *2A, *13, 2846A>T, and 1236G>A)
7. • 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.
8. • Other active malignancies with a prognosis interfering with that of oesophageal cancer.
9. • Expected lack of compliance with the protocol.
10. • Language difficulty, dementia or altered mental status prohibiting the understanding and giving of informed consent and to complete quality of life questionnaires.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • The progression-free survival defined as the time interval from randomization to the first event of local failure, regional failure, progression to metastatic disease or death

Secondary endpoints 17

1. • 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
2. • Overall survival (OS), 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
3. • 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 (37)
4. • The rate of any grade mucositis, up to one month after the last administration of TNT
5. • The number of patients requiring dose reductions or treatment delays during CROSS and FLOT
6. • The number of patients requiring G-CSF as primary or secondary prophylaxis
7. • The number of serious adverse events (SAEs), up to one month after last administration of TNT
8. • Surgical morbidity (Clavien-Dindo ≥3) and mortality (30-day, 90-day and/or in-hospital mortality), monitored within the Dutch upper gastrointestinal cancer audit (DUCA) surgical complications registry (38)
9. • The proportion of resections that are radical (R0), microscopically irradical (R1) and macroscopically irradical (R2)
10. • The proportion of patients that is unable to undergo oesophagectomy due to clinical deterioration
11. • The proportion of patients that choose for an active surveillance strategy instead of surgery after CRE-2
12. • Clinical complete response (cCR) rate is defined as the percentage of patients without residual locoregional disease or distant metastases at CRE-2
13. • Pathological complete response (pCR) rate in those who underwent an oesophagectomy is defined as ypT0N0
14. • Major pathological response in those who underwent oesophagectomy, defined as Mandard 1-2 (39)
15. • The distant dissemination rate, defined as the proportion of metastases at 12 weeks after completion of TNT FLOT-CROSS or TNT CROSS-FLOT, detected by 18F-FDG
16. • Health-related quality of life (HRQoL), as measured by QoL questionnaires: EORTC QLQ-OG25 and EORTC-C30 (40, 41)
17. • The PD-L1 CPS will be measured as a continuous variable. This will be measured using the 28-8 monoclonal antibody.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Sponsor organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Contact name

E.A. de Bruijn

Public contact point

Organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Contact name

E.A. de Bruijn

Locations

1 EU/EEA country · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications