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    Summary
    EudraCT Number:2010-023957-12
    Sponsor's Protocol Code Number:RAPIDO
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-05-10
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2010-023957-12
    A.3Full title of the trial
    Randomized Multicentre Phase III study of short course radiation therapy followed by prolonged pre-operative chemotherapy and surgery in primary high risk rectal cancer compared to standard chemoradiotherapy and surgery and optional adjuvant chemotherapy.
    Estudio aleatorizado multicéntrico en fase III de radioterapia de corta duración seguida de quimioterapia preoperatoria de larga duración y cirugía en el cáncer rectal primario de alto riesgo en comparación con quimiorradioterapia convencional y cirugía y optima quimioterapia adyuvante
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Rectal cancer And Pre-operative Induction therapy followed by Dedicated
    Operation
    Cáncer rectal y tratamiento de inducción preoperatorio seguido de cirugía
    especializada
    A.4.1Sponsor's protocol code numberRAPIDO
    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 SponsorUniversity Medical Center Groningen (UMCG)
    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 supportMINISTERIO DE SANIDAD, SERVICIOS SOCIALES E IGUALDAD
    B.4.2CountrySpain
    B.4.1Name of organisation providing supportCONSORCIO DE APOYO A LA INVESTIGACION BIOMEDICA EN RED (CAIBER)
    B.4.2CountrySpain
    B.4.1Name of organisation providing supportFUNDACION INVESTIGACION HOSPITAL CLINICO DE VALENCIA
    B.4.2CountrySpain
    B.4.1Name of organisation providing supportDUTCH COLORECTAL GROUP
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportNORDIC GASTROINTESTINAL TUMOUR GROUP
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportDUTCH CANCER SOCIETY
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportSWEDISH CANCER SOCIETY
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCONSORCIO DE APOYO A LA INVESTIGACION BIOMEDICA EN RED (CAIBER)
    B.5.2Functional name of contact pointCONSORCIO DE APOYO A LA INVESTIGACI
    B.5.3 Address:
    B.5.3.1Street AddressCALLE MELCHOR FERNANDEZ ALMAGRO 3, PABELLON 13, SOTANO 1
    B.5.3.2Town/ cityMADRID
    B.5.3.3Post code28029
    B.5.3.4CountrySpain
    B.5.4Telephone number0034918222488
    B.5.5Fax number0034913877551
    B.5.6E-mailmsanchiz@caiber.net
    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 XELODA
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.1Product nameXELODA
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCAPECITABINE
    D.3.9.1CAS number 154361-50-9
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number150 to 500
    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 RoleComparator
    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 XELODA
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.1Product nameXELODA
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCAPECITABINE
    D.3.9.1CAS number 154361-50-9
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number150 to 500
    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 ELOXATIN
    D.2.1.1.2Name of the Marketing Authorisation holderSANOFI AVENTIS, S.A.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.1Product nameELOXATIN
    D.3.4Pharmaceutical form Solution for infusion
    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/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 OXALIPLATINO
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.1Product nameOXALIPLATINO
    D.3.4Pharmaceutical form Solution for infusion
    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/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 RoleComparator
    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 XELODA
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.1Product nameXELODA
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCAPECITABINE
    D.3.9.1CAS number 154361-50-9
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number150 to 500
    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 RoleComparator
    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 ELOXATIN
    D.2.1.1.2Name of the Marketing Authorisation holderSANOFI AVENTIS, S.A.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.1Product nameELOXATIN
    D.3.4Pharmaceutical form Solution for infusion
    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/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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: 7
    D.1.2 and D.1.3IMP RoleComparator
    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 OXALIPLATINO
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.1Product nameOXALIPLATINO
    D.3.4Pharmaceutical form Solution for infusion
    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/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    Primary rectal cancer with high risk of failing locally and/or
    systemically
    Cáncer rectal primario con alto riesgo de fracaso local o sistémico
    E.1.1.1Medical condition in easily understood language
    Primary rectal cancer
    Cancer rectal primario
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10038038
    E.1.2Term Rectal cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To increase the disease-free survival after 3 years follow-up.
    Aumentar la supervivencia libre de enfermedad después de 3 años de
    seguimiento.
    E.2.2Secondary objectives of the trial
    To describe the toxicity profile of the combined modality treatment in schedule.
     To determine the completion rate of the neo-adjuvant treatment.
     To determine the fraction of patients with a radical resection (negative CRM)
     To determine the pathological complete response rate (pCR).
     To determine the postoperative complications
     To describe the local recurrence rate after 3 years follow-up.
     To evaluate quality of life.
     To evaluate functional outcome.
     To increase overall survival after 5 years of follow-up.
     Describir el perfil de toxicidad del programa de tratamiento con la modalidad
    combinada.
     Determinar la tasa de finalización del tratamiento neoadyuvante.
     Determinar la fracción de pacientes con una resección radical (MCR negativo).
     Determinar la tasa de respuesta completa anatomopatológica (RCa).
     Determinar las complicaciones postoperatorias.
     Describir la tasa de recidiva local después de 3 años de seguimiento.
     Evaluar la calidad de vida.
     Evaluar el resultado funcional.
     Aumentar la supervivencia global después de 5 años de seguimiento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Primary tumour characteristics
     Biopsy-proven, newly diagnosed primary rectal adenocarcinoma, i.e. with the lowest part of the tumour less than 16 cm from the anal verge using a rigid rectoscope or flexible endoscope.
     Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically:
    o Clinical stage (c) T4a, i.e. overgrowth to an adjacent organ or structure like the
    prostate, urinary bladder, uterus, sacrum, pelvic floor or side-wall (according to
    TNM version 5).
    o cT4b, i.e. peritoneal involvement.
    o Extramural vascular invasion (EMVI+).
    o N2, i.e. four or more lymph nodes in the mesorectum showing morphological
    signs on MRI indicating metastatic disease. Four or more nodes, whether enlarged or not, with a rounded, homogeneous appearance is thus not sufficient.
    o Positive MRF, i.e. tumor or lymph node one mm or less from the mesorectal
    fascia.
    o Metastatic lateral nodes, > 1 cm (lat LN+)., see appendix G

    General
     Staging done within 5 weeks before randomization.
     No contraindications to chemotherapy, including adequate blood counts:
    - white blood count > or = 4.0 x 109/L
    - platelet count > or =100 x 109/L
    - clinically acceptable haemoglobin levels
    - creatinine levels indicating renal clearance of > or =50 ml/min
    - bilirubin < 35 μmol/l.
     ECOG performance score < or = 1, see appendix B.
     Patient is considered to be mentally and physically fit for chemotherapy as judged by the oncologist.
     Age > or = 18 years
     Written informed consent.
     Adequate potential for follow-up.
    Características del tumor primario
     Adenocarcinoma rectal primario recién diagnosticado y demostrado mediante
    biopsia, es decir, con la parte inferior del tumor a menos de 16 cm de distancia del borde anal utilizando un rectoscopio rígido o un endoscopio flexible.
     Tumor localmente avanzado que cumple al menos uno de los criterios siguientes en la RM pélvica, indicativo de alto riesgo de fracaso local o sistémico:
    o Estadio clínico (c) T4a, es decir, propagación a un órgano o estructura
    adyacente como la próstata, la vejiga urinaria, el útero, el sacro, el suelo
    pélvico o la pared lateral (según la versión TNM 5).
    o cT4b, es decir, afectación peritoneal.
    o Invasión vascular extramural (IVEM+).
    o N2, es decir, cuatro o más ganglios linfáticos en el mesorrecto con signos
    morfológicos en la RM indicativos de enfermedad metastásica. Por
    consiguiente, no es suficiente con la presencia de cuatro o más ganglios,
    agrandados o no, de aspecto redondeado y homogéneo.
    o FMR positiva, es decir, tumor o ganglio linfático a una distancia de 1 mm
    o menos de la fascia mesorrectal.
    o Ganglios mestastasicos laterales > 1 cm (lat LN+), véase apendice G

    Requisitos generales
     La estadificación se realizará en las 5 semanas anteriores a la aleatorización.
     No podrán existir contraindicaciones para la quimioterapia, como unos recuentos sanguíneos insuficientes:
    o recuento de leucocitos ≥ 4,0 x 109/l
    o recuento de plaquetas ≥ 100 x 109/l
    o cifras de hemoglobina clínicamente aceptables
    o concentraciones de creatinina indicativas de un aclaramiento renal de
    ≥ 50 ml/min
    o bilirrubina < 35 μmol/l.
     Puntuación del estado general ECOG ≤ 1, véase el apéndice B.
     Se considera que el paciente está mental y físicamente capacitado para recibir
    quimioterapia a criterio del oncólogo.
     Edad ≥ 18 años
     Consentimiento informado por escrito.
     Posibilidades razonables de seguimiento
    E.4Principal exclusion criteria
     Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen.
     Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn’s disease or active ulcerative Colitis.
     Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years.
     Known DPD deficiency.
     Any contraindications to MRI (e.g. patients with pacemakers).
     Medical or psychiatric conditions that compromise the patient’s ability to give informed consent.
     Concurrent uncontrolled medical conditions.
     Any investigational treatment for rectal cancer within the past month.
     Pregnancy or breast feeding.
     Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract.
     Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months.
     Patients with symptoms or history of peripheral neuropathy.
     Crecimiento extenso en la parte craneal del sacro (por encima de S3) o en las raíces nerviosas lumbosacras, lo que indica que la cirugía no será nunca posible, ni siquiera aunque se consiga una reducción importante del tamaño del tumor.
     Presencia de enfermedad metastásica o tumor rectal recidivante. Poliposis
    adenomatosa familiar (PAF) cólica, cáncer colorrectal no polipósico hereditario
    (CCNPH), enfermedad de Crohn activa o colitis ulcerosa activa.
     Neoplasias malignas concomitantes, excepto carcinoma basocelular de la piel
    tratado adecuadamente o carcinoma de cuello uterino in situ. Los pacientes con
    antecedentes de neoplasias malignas tienen que estar libres de enfermedad desde hace por lo menos 5 años.
     Deficiencia confirmada de DPD.
     Cualquier contraindicación para la RM (por ejemplo, pacientes con marcapasos).
     Trastornos médicos o psiquiátricos que comprometan la capacidad del paciente para otorgar su consentimiento informado.
     Trastornos médicos concomitantes no controlados.
     Cualquier tratamiento experimental para el cáncer rectal recibido en el último mes.
     Embarazo o lactancia.
     Pacientes con síndromes conocidos de malabsorción o ausencia de integridad física del tubo digestivo alto.
     Cardiopatía clínicamente significativa (es decir, activa) (por ejemplo, insuficiencia cardíaca congestiva, enfermedad coronaria sintomática y arritmia cardiaca, por ejemplo, fibrilación auricular, aunque se controle con medicación) o infarto de miocardio en los últimos 12 meses.
     Pacientes con signos o antecedentes de neuropatía periférica.
    E.5 End points
    E.5.1Primary end point(s)
    Disease-free survival after 3 years follow-up is the primary endpoint.
    El criterio de valoración principal es la supervivencia sin enfermedad después de 3 años de seguimiento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Disease-free survival will be computed as the time between randomization and either local or distant relapse or death caused by the rectal carcinoma whichever comes first. In case of nonrectal cancer related death patients will be censored at date of death. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour. Patients lost to follow-up will be censored the last date of patient visit.
    La supervivencia sin enfermedad se calculará como el tiempo transcurrido entre la
    aleatorización y la recidiva local o a distancia o la muerte causada por el carcinoma
    rectal, lo que ocurra antes. En el caso de muerte relacionada con un cáncer no rectal, se censurará a los pacientes fallecidos en la fecha de su muerte. En el caso de un segundo tumor primario, se censurará a los pacientes en la fecha del diagnóstico del segundo tumor primario. Los pacientes perdidos para el seguimiento serán censurados en la fecha de la última visita del paciente.
    E.5.2Secondary end point(s)
     Treatment associated toxicity, including surgical morbidity
     Completion rate of neo-adjuvant treatment
     Negative CRM (margin > 1 mm)
     pCR
     Postoperative complications
     Local recurrence at 3 years
     Overall survival
     Functional outcome
     Quality of life
     Toxicidad asociada al tratamiento, incluida la morbilidad quirúrgica
     Tasa de finalización del tratamiento neoadyuvante
     MCR negativo (margen 1 mm)
     RCa
     Complicaciones postoperatorias
     Recidiva local a los 3 años
     Supervivencia global
     Resultado funcional
     Calidad de vida
    E.5.2.1Timepoint(s) of evaluation of this end point
    Toxicity:All patients will be evaluable for toxicity from the time of their first treatment.
    Fraction of radical resection (CRM > 1 mm): will be evaluated according the pathology protocol described by Quirke et al.
    Complete pathological response (pCR):is done by the method described in section 6.
    Local recurrence: is described as relapse of tumour in the pelvic region.
    Distant relapse: is described as relapse of tumour outside the pelvic region.
    Local control: will be computed as the time between randomization and local relapse.
    Overall survival: will be computed as the time between randomization and all causes of death.
    Quality of Life (QoL):including functional outcome will be studied as described in Chapter 8
    Toxicidad:Todos los pacientes serán evaluables para el análisis de toxicidad desde el momento en que reciban su primer tratamiento. MCR > 1 mm:se evaluará según el protocolo de anatomía patológica descrito por Quirke y cols. RCa:se basa en el método descrito en el apartado 6. Recidiva local:se describe como recidiva del tumor en la región pélvica. Recidiva a distancia: se describe como una recidiva tumoral fuera de la región pélvica. Control local: se calculará como el tiempo transcurrido entre la aleatorización y la recidiva local. Supervivencia global: se calculará como el tiempo transcurrido entre la aleatorización y la muerte del paciente por cualquier causa. Calidad de vida (CV): incluido el resultado funcional, se evaluará según se describe en el capítulo 8.
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    Proteomics, genomics, and circulating tumour cell analyses of plasma and tumour tissue along the treatment schedule may provide insight in biomarkers associated with response and prognosis. A tissue block (or two-three cores for tissue microarray, TMA) will be collected from the preoperative biopsy (if sufficient material is available) and from the operative specimen.
    La proteómica, la genómica y el análisis de células tumorales circulantes en el plasma y de tejido tumoral durante todo el tratamiento pueden aportar información sobre los biomarcadores asociados a la respuesta y al pronóstico. Se tomará un bloque (de dos o tres núcleos para análisis de microarrays, TMA) de tejido de la biopsia preoperatoria (si hay suficiente material disponible) y del espécimen operativo
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 trial2
    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.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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 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
    Last patient visit
    última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial 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: 885
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 885
    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 state885
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 885
    F.4.2.2In the whole clinical trial 885
    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)
    Normal expexted treatment of the condition
    Tratamiento habitual esperado para esta enfermedad
    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 Decision2012-06-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-05-11
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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