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    Summary
    EudraCT Number:2020-003605-55
    Sponsor's Protocol Code Number:74556
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-11-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2020-003605-55
    A.3Full title of the trial
    Combination of chemoTherapy aNd chemoradioTherapy for adenocarcinoma of the OESophagus and gastro-oesophageal junction with oligometastatic disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Chemotherapy followed by chemoradiotherapy for metastatic esophageal cancer
    A.3.2Name or abbreviated title of the trial where available
    TNT-OES-1 TRIAL
    A.4.1Sponsor's protocol code number74556
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorErasmus MC - University Medical Centre
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportErasmus MC - University Medical Center
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC - University Medical Centre
    B.5.2Functional name of contact pointSjoerd Lagarde
    B.5.3 Address:
    B.5.3.1Street Addressdr. Molewaterplein 40
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015GD
    B.5.3.4CountryNetherlands
    B.5.6E-mails.lagarde@erasmusmc.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Leucovorin
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFolic acid
    D.3.9.3Other descriptive nameFOLIC ACID
    D.3.9.4EV Substance CodeSUB07774MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number800
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Fluorouracil
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFluorouracil
    D.3.9.3Other descriptive nameFLUOROURACIL
    D.3.9.4EV Substance CodeSUB07721MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10400
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Oxaliplatin
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOXALIPLATIN
    D.3.9.1CAS number 61825-94-3
    D.3.9.4EV Substance CodeSUB09490MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number340
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Docetaxel
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDOCETAXEL
    D.3.9.3Other descriptive nameDocetaxel
    D.3.9.4EV Substance CodeSUB12492MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number340
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Carboplatin
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCarboplatin
    D.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Paclitaxel
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPaclitaxel
    D.3.9.3Other descriptive namePACLITAXEL SYNTHETIC
    D.3.9.4EV Substance CodeSUB179429
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients (18 – 75 years) who are diagnosed with adenocarcinoma of the oesophagus or GOJ with a resectable primary tumour and de-novo synchronous oligometastatic disease.
    Patiënten (18 - 75 jaar) met de diagnose adenocarcinoom van de slokdarm of gastro-oesofageale junctie met een resectabel primaire tumor en een de-novo synchrone oligometastase.
    E.1.1.1Medical condition in easily understood language
    Patients (18 – 75 years) who are diagnosed with adenocarcinoma of the oesophagus or GOJ with a resectable primary tumour and de-novo synchronous oligometastatic disease.
    Patiënten (18 - 75 jaar) met de diagnose adenocarcinoom van de slokdarm of gastro-oesofageale junctie met een resectabel primaire tumor en een de-novo synchrone oligometastase.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety and feasibility of a multimodal (combination of four cycles of FLOT CT and CROSS CRT) treatment regimen for patients with adenocarcinoma of the oesophagus or GOJ with limited distant metastatic disease.
    Om de veiligheid en haalbaarheid te beoordelen van een multimodaal behandelingsregime (combinatie van vier cycli van FLOT CT en CROSS CRT) voor patiënten met adenocarcinoom van de slokdarm of gastro-oesofageale junctie met beperkte metastatische ziekte op afstand.
    E.2.2Secondary objectives of the trial
    • To assess 1-year disease control rate (DCR) and objective response rate (ORR), both according to RECIST v1.1
    • To assess progression free survival and overall survival
    • To assess the number of patients with a clinically complete response
    • To evaluate QoL parameters (especially dysphagia, odynophagia, fatigue, and weight loss)
    • To assess the number of patients who proceed to local treatment of distant metastases or primary tumour.
    • Beoordeling van 1-jaars disease control rate (DCR) en de objectieve respons (ORR), beide volgens RECIST v1.1
    • Beoordeling van progressie-vrije overleving en algehele overleving
    • Beoordeling van het aantal patiënten met een klinisch complete respons
    • Evaluatie van kwaliteit van leven parameters (met name dysfagie, odynofagie, vermoeidheid en gewichtsverlies)
    • Bepalen van het aantal patiënten dat doorgaat met lokale behandeling van metastasen op afstand of primaire tumor.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must meet all of the following criteria:
    1. Histologically-proven, resectable adenocarcinoma of the oesophagus or GOJ according to the UICC TNM7 definition (appendix 2). Tumours of the oesophagus and tumours of which the epicentre is within 5 cm of the GOJ are eligible for inclusion in the trial in the case of adenocarcinomatous histology (Type 1 and Type 2 according to Siewert classification of oesophagogastric adenocarcinoma)
    2. Pre-treatment stage cT1N+ M1 or cT2-4a N0/N+, M1 (In case of stage cT4a, curative resectability has to be explicitly verified by the multidisciplinary tumour board.
    3. Oligometastatic disease, which for this study is defined as a maximum of four resectable/treatable metastatic lesions. These four lesions can be present in a maximum of two organs (liver, lung, bones, or adrenal gland). Lymph nodes are not counted as an organ. If metastatic retroperitoneal or supraclavicular lymph nodes are present, this lymph node site counts as one metastatic lesion, and together with the possible metastases in organs cannot exceed the four lesions.
    4. Age ≥ 18 years, <75 years.
    5. No prior abdominal, thoracic or cervical radiotherapy overlapping with the CROSS irradiation fields.
    6. No prior cytotoxic chemotherapy
    7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (see Appendix 1)
    8. Adequate cardiac function (cardiac function tests such as echocardiography only necessary in symptomatic patients).
    9. Adequate respiratory function (pulmonary function tests only necessary in symptomatic patients)
    10. Adequate bone marrow function (White Blood Cells >3x10^9/l; Haemoglobin mmol/L; platelets >100x10^9/l). In the event of transfusions, the last red blood cell transfusion should be more than 2 weeks before inclusion.
    11. 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
    12. Written informed consent and ability to understand the nature of the study and the study-related procedures and to comply with them
    13. Women of child-bearing potential must have a negative serum pregnancy test during screening period.
    14. Patients must be willing to use adequate contraception during the study and for 3 months after the end of the study.
    Om in aanmerking te komen voor deelname aan dit onderzoek, moet een proefpersoon aan alle volgende criteria voldoen:

    1. Histologisch bewezen, resectabel adenocarcinoom van de slokdarm of GOJ volgens de UICC TNM7-definitie (bijlage 2). Tumoren van de slokdarm en tumoren waarvan het epicentrum zich binnen 5 cm van de GOJ bevindt, komen in aanmerking voor inclusie in het onderzoek in het geval van adenocarcinomateuze histologie (type 1 en type 2 volgens Siewert-classificatie van oesofagogastrisch adenocarcinoom)

    2. Voorbehandelingsstadium cT1N + M1 of cT2-4a N0 / N +, M1 (In het geval van stadium cT4a moet de curatieve resectabiliteit expliciet worden geverifieerd door de multidisciplinaire tumorwerkgroep.

    3. Oligometastatische ziekte, die voor deze studie wordt gedefinieerd als maximaal vier resectabele / behandelbare metastasen. Deze vier laesies kunnen in maximaal twee organen aanwezig zijn (lever, long, botten of bijnier). Lymfeklieren worden niet als een orgaan meegeteld. Als er gemetastaseerde retroperitoneale of supraclaviculaire lymfeklieren aanwezig zijn, telt deze locatie als één metastatische laesie, en samen met de mogelijke metastasen in organen kunnen ze niet groter zijn dan de vier laesies.

    4. Leeftijd ≥ 18 jaar, <75 jaar.

    5. Geen eerdere abdominale, thoracale of cervicale radiotherapie die overlapt met de CROSS-bestralingsvelden.

    6. Geen eerdere cytotoxische chemotherapie

    7. Eastern Cooperative Oncology Group (ECOG) prestatiestatus 0-1 (zie bijlage 1)

    8. Adequate hartfunctie (hartfunctietesten zoals echocardiografie zijn alleen nodig bij symptomatische patiënten).

    9. Adequate ademhalingsfunctie (longfunctietesten alleen nodig bij symptomatische patiënten)

    10. Adequate beenmergfunctie (witte bloedcellen> 3x10 ^ 9 / l; hemoglobine mmol / l; bloedplaatjes> 100x10 ^ 9 / l). In het geval van transfusies moet de laatste transfusie van rode bloedcellen meer dan 2 weken voor opname plaatsvinden.

    11. Adequate nierfunctie (glomerulaire filtratiesnelheid> 50 ml / min) of serumcreatinine <= 1,5 x bovengrens van normaal (ULN) en voldoende leverfunctie (totaal bilirubine <1,5x bovengrens van normaal (ULN); aspartaattransaminase ( AST) <2,5x ULN en alanine transaminase (ALT) <3x ULN

    12. Schriftelijke toestemming en het vermogen om de aard van de studie en de studiegerelateerde procedures te begrijpen en deze na te leven

    13. Vrouwen die zwanger kunnen worden, moeten tijdens de screeningperiode een negatieve serumzwangerschapstest ondergaan.

    14. Patiënten moeten bereid zijn om adequate anticonceptie te gebruiken tijdens het onderzoek en gedurende 3 maanden na het einde van het onderzoek.
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    1. Patients with tumours of squamous, adenosquamous or other non-adenocarcinoma histology
    2. Patients with advanced irresectable or extensive metastatic oesophageal adenocarcinoma (involving 3 or more organs or more than 4 metastatic lesions)
    3. Patients with overt peritoneal dissemination, as detected on PET-CT or regular CT-scan. In patients in whom a diagnostic laparoscopy is indicated, tumour-positive cytology peritoneal fluid is also an exclusion criterion
    4. Oesophageal adenocarcinoma evaluated as not curatively-resectable by the multidisciplinary tumour board , for instance because ingrowth in the trachea
    5. Gastric carcinoma (according to UICC TNM7)
    6. Clinically significant (active) cardiac disease (e.g. symptomatic coronary artery disease or myocardial infarction within last 12 months)
    7. Clinically significant lung disease (Forced Expiratory Volume in one second (FEV1) <1.5 l)
    8. Peripheral neuropathy grade >1 according to CTCae v4.0
    9. Pregnant and lactating women, or patients of reproductive potential who are not using effective birth control methods. If barrier contraceptives are used, they must be continued by both sexes throughout the study.
    10. Participation, current or during the last 30 days prior to informed consent, in another intervention trial with interference to the chemotherapeutic or chemoradiotherapeutic intervention of this study
    11. Expected lack of compliance with the protocol
    12. Secondary primary cancer with the exclusion of basal cell carcinoma of the skin
    Een potentiële proefpersoon die aan een van de volgende criteria voldoet, wordt uitgesloten van deelname aan dit onderzoek:

    1. Patiënten met tumoren van plaveiselcel-, adenosquameuze of andere niet-adenocarcinoomhistologie

    2. Patiënten met gevorderd irresectabel of uitgebreid gemetastaseerd slokdarmadenocarcinoom (waarbij 3 of meer organen of meer dan 4 metastatische laesies zijn betrokken)

    3. Patiënten met uitgebreide peritoneale disseminatie, zoals gedetecteerd op PET-CT of reguliere CT-scan. Bij patiënten bij wie diagnostische laparoscopie geïndiceerd is, is tumorpositieve cytologie peritoneaal vocht eveneens een uitsluitingscriterium

    4. Slokdarm adenocarcinoom beoordeeld als niet curatief resectabel door de multidisciplinaire tumorwerkgroep, bijvoorbeeld door ingroei in de trachea

    5. Maagcarcinoom (volgens UICC TNM7)

    6. Klinisch significante (actieve) cardiale comorbiditeit (bijv. Symptomatische coronaire hartziekte of myocardinfarct in de afgelopen 12 maanden)

    7. Klinisch significante pulmonale comorbiditeit (geforceerd expiratoir volume in één seconde (FEV1) <1,5 l)

    8. Perifere neuropathie graad> 1 volgens CTCae v4.0

    9. Zwangere vrouwen en vrouwen die borstvoeding geven, of vruchtbare patiënten die geen effectieve anticonceptiemethoden gebruiken. Als barrière-anticonceptiva worden gebruikt, moeten deze door beide geslachten worden voortgezet gedurende het onderzoek.

    10. Deelname, lopend of gedurende de laatste 30 dagen voorafgaand aan geïnformeerde toestemming, aan een ander interventieonderzoek met interferentie met de chemotherapeutische of chemoradiotherapeutische interventie van dit onderzoek

    11. Verwacht gebrek aan naleving van het protocol

    12. Secundaire primaire tumor, met uitsluiting van basaalcelcarcinoom van de huid
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint is the tolerability of the combined regimens, defined as the number of patients that complete the administration of 4 x FLOT and CROSS CRT.
    Het primaire eindpunt is de verdraagbaarheid van de gecombineerde regimes, gedefinieerd als het aantal patiënten dat de toediening van 4 x FLOT en CROSS CRT voltooit.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At completion of both 4X FLOT and CROSS CRT
    Bij voltooing van zowel vier kuren FLOT als CROSS chemoradiotherapie.
    E.5.2Secondary end point(s)
    • the number of patients that experience disease progression at CRE-1 and are thus unable to complete the administration of 4 x FLOT and CROSS CRT
    • serious adverse events and adverse events from the time of their first treatment with chemotherapy according to the Common Terminology Criteria for Adverse Events CTCAE version 4.03
    • cumulative administered dose of each of the drugs in the FLOT regimen and number of carboplatin/paclitaxel chemotherapy cycles administered as part of CROSS CRT
    • tolerability of the combined regimen of 4x FLOT followed by CROSS CRT followed by another 4x FLOT CT, defined as the number of patients who complete this regimen out of the patients starting the second round of FLOT.
    • disease control rate, defined as the percentage of patients with stable disease, partial response or complete response according to RECIST criteria (v1.1) at 1 year
    • objective response rate, defined as the percentage of patients with partial response or complete response according to RECIST criteria (v1.1) at 1 year
    • progression free survival, defined as defined as time from inclusion to the date of the first documentation of progressive disease according to RECIST criteria (v1.1)
    • Overall survival (OS) calculated from the date of inclusion to death due to any cause. Patients still alive at last contact will be censored
    • clinical complete response (cCR), defined as the absence of residual locoregional disease at CRE-2
    • quality of life, as measured by quality of life questionnaires: EORTC QLQ-OG25 and EORTC-C30 (appendix 3 – 4)
    • the number of patients who proceed to local therapy of metastases and/or oesophagectomy
    • Surgical morbidity (Clavien-Dindo grade 3B or higher) and mortality (30 day and-or in hospital mortality). Morbidity and mortality: 30-day complications will be monitored according to the Dutch Society for Surgery complication registry as well as the Clavien-Dindo score.
    • Het aantal patiënten dat progressie van ziekte laat zien op CRE-1 en dus de toediening van 4 x FLOT en CROSS CRT niet kan voltooien

    • Ernstige ongewenste voorvallen (SAE) en ongewenste voorvallen (AE) vanaf het moment van eerste behandeling met chemotherapie volgens de Common Terminology Criteria for Adverse Events CTCAE versie 4.03

    • Cumulatieve toegediende dosis van elk van de geneesmiddelen in het FLOT-regime en aantal carboplatin / paclitaxel chemotherapiecycli toegediend als onderdeel van CROSS CRT

    • Verdraagbaarheid van het gecombineerde regime van 4x FLOT gevolgd door CROSS CRT gevolgd door nog eens 4x FLOT CT, gedefinieerd als het aantal patiënten dat dit regime voltooit van de patiënten die aan de tweede ronde FLOT beginnen.

    • Percentage van ziektecontrol, gedefinieerd als het percentage patiënten met stabiele ziekte, partiële respons of complete respons volgens RECIST-criteria (v1.1) na 1 jaar

    • Objectief responspercentage, gedefinieerd als het percentage patiënten met partiële respons of complete respons volgens RECIST-criteria (v1.1) na 1 jaar

    • Progressievrije overleving, gedefinieerd als de periode tussen datum van opname tot de datum van de eerste documentatie van progressieve ziekte volgens RECIST-criteria (v1.1)

    • Totale overleving (OS) gedefinieerd als de periode tussen datum van opname tot overlijden door welke oorzaak dan ook. Patiënten die bij het laatste contact nog in leven zijn, worden gecensureerd.

    • Clinical Complete Response (cCR), gedefinieerd als de afwezigheid van residuele locoregionale ziekte op CRE-2

    • Kwaliteit van leven, gemeten aan de hand van vragenlijsten over kwaliteit van leven: EORTC QLQ-OG25 en EORTC-C30 (bijlage 3 - 4)

    • Aantal patiënten dat doorgaat naar lokale therapie van metastasen en / of slokdarmresectie

    • Chirurgische morbiditeit (Clavien-Dindo graad 3B of hoger) en mortaliteit (30 dagen en / of ziekenhuissterfte). Morbiditeit en mortaliteit: 30-daagse complicaties worden gemonitord volgens de Complicatieregistratie Nederlandse Vereniging voor Heelkunde en de Clavien-Dindo-score.
    E.5.2.1Timepoint(s) of evaluation of this end point
    One year after completion of FLOT + CROSS
    1 jaar na voltooing FLOT + CROSS
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    The last visit of the last subject undergoing the trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Not different from the expected normal treatment of that condition
    Niet anders dan de verwachte normale behandeling van die aandoening
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-11-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-01-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-04-14
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