E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Resectable locally advanced squamous cell carcinoma (SCC) of the esophagus |
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E.1.1.1 | Medical condition in easily understood language |
Cancer in the gullet (esophagus), which is possible to operate. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025899 |
E.1.2 | Term | Malignant neoplasm of esophagus |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025901 |
E.1.2 | Term | Malignant neoplasm of esophagus, unspecified |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The NEEDS trial has three co-primary objectives. First of all to demonstrate that dCRT with salvage esophagectomy as needed, is non-inferior to nCRT followed by surgery, regarding overall survival in patients with operable, locally advanced esophageal squamous cell carcinoma. A second co-primary objective, to be tested only if overall survival non-inferiority has been shown, is to determine the impact on HRQOL of each intervention aiming to show superiority, with regard to Global HRQOL, for dCRT with surgery only when needed, one year after randomization. A third co-primary objective, to be tested for superiority only if overall survival is non-inferior and Global HRQOL is superior, is eating restrictions. |
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E.2.2 | Secondary objectives of the trial |
• To study prespecified HRQOL endpoints relevant to esophageal cancer and effects of treatment for this disease, repeatedly during treatment and survivorship. • To determine event free survival, loco-regional and distal relapse rates and histological chemoradiotherapy response in the surgical specimen in the control arm. • To investigate the overall health economic impact of each intervention. • To investigate the impact on nutritional status of each intervention during follow-up. • To investigate if there are any gender differences in any of the endpoints. • To exploratively analyse putative tissue and liquid biomarkers for response to the different treatment strategies and long-term benefit. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biology of esophageal squamous cell carcinoma (ESCC). Protocol version 1.0, 15.01.2020. Objectives: 1. To understand the molecular drivers associated with response and resistance to chemoradiotherapy in ESCC 2. To explore the association between the immune microenvironment and benefit from chemoradiotherapy in ESCC 3. To understand whether ctDNA can be used as an early predictor of relapse in ESCC patients treated with definitive chemoradiotherapy and surgery 4. To explore whether ctDNA can be used instead of tissue biopsy to identify molecular drivers in ESCC.
Substudy 2: Volatile organic compounds (VOCs) for non-invasive surveillance. Protocol version 1.0, 15.01.2020. Objectives: 1. To evaluate if local or distant recurrence after definitive chemoradiotherapy can be non-invasively identified using analysis of urinary VOCs. 2. To evaluate if local or distant recurrence after surgical resection can be non-invasively identified using analysis of urinary VOCs. 3. To study if a unique urinary VOC pattern immediately after treatment is able to identify patients at high risk of recurrent disease after definite chemoradiotherapy or surgery. 4. To establish if a unique urinary VOC profile exists with the diagnosis of ESCC.
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E.3 | Principal inclusion criteria |
• Histopathologically confirmed SCC of the esophagus in locally advanced stages cT1 N+ or cT2-4a any N, M0 • Technically resectable disease according to the local multidisciplinary team conference (MDT)/tumor board • Age ≥ 18 years and ≤ 80 years. • Performance status ECOG 0-1. • Adequate organ function • Women of childbearing potential must have a negative serum or urine pregnancy test • Patients of childbearing/reproductive potential should use highly effective method of birth control measures during the study treatment period • Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment • Written informed consent
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E.4 | Principal exclusion criteria |
• Distant metastases • cT4b • Primary tumor not resectable without laryngectomy. • Impaired renal, hepatic, cardiac, pulmonary or endocrine status • Subjects not considered likely to tolerate multimodality treatment with chemoradiotherapy followed by esophagectomy. • Subjects with previous malignancies • Prior or concomitant treatment with radiotherapy or chemoradiotherapy with potential overlap of radiotherapy fields. • Known uncontrollable hypersensitivity to the components of the chemotherapeutic agents used in the trial regimens. • Inability to fully understand and digest study patient information or to comply with study instructions due to language difficulty or cognitive failure such as dementia or severe psychiatric disorder.
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E.5 End points |
E.5.1 | Primary end point(s) |
• The first co-primary endpoint of the NEEDS trial is overall survival (OS) with a minimum follow-up of 3 years, with a non-inferiority hypothesis for the experimental intervention dCRT with surveillance and salvage surgery only as needed, compared to the the control intervention nCRT with planned surgery. • A second co-primary endpoint is Global HRQOL one year after randomisation, using the EORTC QLQ-C30 instrument, which will be tested for superiority for the experimental intervention only if non-inferiority for OS has been shown. • If OS has been shown to be non-inferior and Global HRQOL superior the HRQOL domain of eating restrictions in the EORTC QLQ-OG25 instrument, will also be tested for superiority at one year after randomization. The primary objective of treatment for localised esophageal cancer is cure and there are no known surrogate endpoints that can replace OS in a pragmatic trial aiming to establish best practice. However, patient reported HRQOL during survivorship is so important that the above mentioned HRQOL endpoints qualify to be a co-primary endpoints. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54 and 60 months after surgery |
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E.5.2 | Secondary end point(s) |
• HRQOL will be assessed at baseline, meaning after inclusion and signing of the patient consent form but before start of treatment and thereafter 6, 12, 24, 36 and 60 months after randomisation. Specific, predefined quality of life endpoints of particular interest, beside the co-primary endpoints mentioned above, will be Global HRQOL, QLQ- C30 summary score, physical function, dyspnea, diarrhea, dysphagia and anxiety at all time-points mentioned above. • Event free survival (EFS), defined as time to relapse, initiation of any anti-tumor therapy beyond the study treatments, or death, whichever comes first • Loco-regional and distant relapse rates, including the relation of relapse location to the radiation field (in-field or out-field). • Histopathological response • Health economy will be assessed including patient-level medical resource use and societal costs due to sick-leave and other non-medical costs • Surgical complications • Treatment-related adverse events and toxicity • Nutritional outcomes • Gender stratified analyses of all endpoints • Exploratory analyses for putative tissue and liquid biomarkers for response |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54 and 60 months after surgery |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Surgery, Health related quality of life, Health economy |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Radiotherapy and surgery is part of treatment strategies |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Control arm: Chemotherapy, radiotherapy 41,4Gy, preplanned esofagectomy |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
India |
Belgium |
France |
Germany |
Norway |
Sweden |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |