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    Summary
    EudraCT Number:2021-001086-20
    Sponsor's Protocol Code Number:DP-1111-02CT
    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:2021-06-11
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2021-001086-20
    A.3Full title of the trial
    A Prospective, Randomized, Controlled, Open-label, Multicenter Trial to Evaluate Efficacy, Safety and Patient- reported Outcomes of Peptide Receptor Radionuclide Therapy (PRRT) with Lutetium (177Lu) Edotreotide compared to Best Standard of Care in Patients with Well-differentiated Aggressive Grade 2 and Grade 3, Somatostatin receptor-positive (SSTR+), Neuroendocrine Tumors of GastroEnteric or Pancreatic Origin (COMPOSE)
    Estudio prospectivo, aleatorizado, comparativo, sin enmascaramiento, multicéntrico, para evaluar la eficacia, seguridad y los resultados percibidos por los pacientes de la terapia con péptidos marcados con radionúclidos (PRRT) (lutecio [177Lu] edotreotida) en comparación con el tratamiento de referencia en pacientes con tumores neuroendocrinos de origen gastroentérico o pancreático (TNE-GEP) bien diferenciado, agresivo, de grado 2 o de grado 3 y que exprese receptores de la somatostatina (SSTR+) (COMPOSE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Lutetium (177Lu) Edotreotide versus Best Standard of Care in Well-differentiated Aggressive Grade 2 and Grade 3 GEP-NETs
    Lutecio [177Lu] Edotreotida en comparación con el tratamiento de referencia en tumores neuroendocrinos de origen gastroentérico o pancreático (TNE-GEP) bien
    diferenciado, agresivo, de grado 2 o de grado 3
    A.3.2Name or abbreviated title of the trial where available
    COMPOSE
    COMPOSE
    A.4.1Sponsor's protocol code numberDP-1111-02CT
    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 SponsorITM Solucin GmbH
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportITM Solucin GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPSI Pharma Support Poland Sp. z.o.o.
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street AddressHrubieszowska 6b Str.
    B.5.3.2Town/ cityWarsaw
    B.5.3.3Post code01-209
    B.5.3.4CountryPoland
    B.5.4Telephone number+48515104702
    B.5.5Fax number+4822210 0220
    B.5.6E-mailjoanna.wictorwicz@psi-cro.com
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1269
    D.3 Description of the IMP
    D.3.1Product name177Lu-Edotreotide
    D.3.2Product code 177Lu-DOTATOC
    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 INNLutetium (177Lu-Edotreotide)
    D.3.9.1CAS number 321835-55-6
    D.3.9.3Other descriptive name• 177Lu-DOTATOC
    D.3.9.4EV Substance CodeSUB185275
    D.3.10 Strength
    D.3.10.1Concentration unit GBq gigabecquerel(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number7.5
    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 Yes
    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 NA
    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 nameEverolimus
    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 INNeverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.2Current sponsor codeeverolimus
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 3
    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 NA
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameCapecitabine
    D.3.4Pharmaceutical form Film-coated 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.3.9.3Other descriptive nameCAPECITABINE
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 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 NA
    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 nametemozolomide
    D.3.4Pharmaceutical form
    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 INNtemozolomide
    D.3.9.1CAS number 85622-93-1
    D.3.9.3Other descriptive nameTEMOZOLOMIDE
    D.3.9.4EV Substance CodeSUB10889MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.2.1.2Country 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 namefolinic acid
    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 INNfolinic acid
    D.3.9.1CAS number 1492-18-8
    D.3.9.4EV Substance CodeSUB13910MIG
    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 NA
    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 nameFluorouracil
    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.3.9.1CAS number 51-21-8
    D.3.9.3Other descriptive name5-FLUOROURACIL
    D.3.9.4EV Substance CodeSUB07721MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 NA
    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 nameOxaliplatin
    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/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
    Well-differentiated Aggressive Grade2 and Grade 3, Somatostatin receptor-positive (SSTR+), Neuroendocrine Tumors of GastroEnteric or Pancreatic Origin (GEP-NET)
    Tumores neuroendocrinos de origen gastroentérico o pancreático (TNE-GEP) bien diferenciado, agresivo, de grado 2 o de grado 3 y que exprese receptores de la somatostatina (SSTR+)
    E.1.1.1Medical condition in easily understood language
    Aggressive metastasized and / or locally advanced neuroendocrine tumours (NET) of gastroenteric or pancreatic origin
    Tumores neuroendocrinos (TNE) agresivos con metástasis y/o localmente avanzados de origen gastroentérico o pancreático
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10077559
    E.1.2Term Gastroenteropancreatic neuroendocrine tumour disease
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the efficacy of PRRT with lutetium (177Lu) edotreotide in the treatment of aggressive Grade 2 (G2; Ki67 between 15 and 20, both inclusive) and Grade 3 (G3; Ki-67 above 20 up to 55, inclusive) SSTR+ GEP-NETs compared to best standard of care (investigator’s choice [from the protocol comparator list]).
    Demostrar la eficacia de la terapia con péptidos marcados con radionúclidos (PRRT) (lutecio [177Lu] edotreotida) en el tratamiento de los TNE-GEP SSTR+ agresivos, de grado 2 (G2; Ki67 entre 15 y 20, ambos inclusive) y de grado 3 (G3; Ki67 por encima de 20 y hasta 55, ambos inclusive) en comparación con el tratamiento de referencia (seleccionado por el investigador [de la lista de tratamientos comparativos que se incluye en el protocolo]).
    E.2.2Secondary objectives of the trial
    1. To further demonstrate the efficacy of PRRT with lutetium (177Lu) edotreotide.
    2. To assess the impact of PRRT with lutetium (177Lu) edotreotide on trial patient’s health-related quality of life (HRQL) and neuroendocrine functional tumor symptoms during and after therapy in comparison to best standard of care.
    3. To assess the safety and tolerability of PRRT with lutetium (177Lu) edotreotide in trial patients compared to control treatment options.
    1. Demostrar en mayor medida la eficacia de la PRRT con lutecio (177Lu) edotreotida.
    2. Evaluar el efecto de la PRRT con lutecio (177Lu) edotreotida sobre la calidad de vida relacionada con la salud (CDVRS) de los pacientes y los síntomas del tumor neuroendocrino funcional durante el tratamiento y después de este, en comparación con el tratamiento de referencia.
    3. Evaluar la seguridad y la tolerabilidad de la PRRT con lutecio (177Lu) edotreotida en los pacientes del estudio, en comparación con las opciones terapéuticas de control.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provided written informed consent.
    2. Patients aged ≥ 18 years (fully mature per local regulations).
    3. Histologically confirmed diagnosis of unresectable, well-differentiated GEP-NETs, with a Ki-67 index between 15 and 55, inclusive. This should be at least confirmed by a local pathological report of a biopsy specimen of the primary tumor or metastasis, or, if unavailable, willingness to undergo current biopsy for local analysis before randomization.
    4. In the investigator’s opinion, eligible to receive treatment with at least one of the following: CAPTEM, everolimus or FOLFOX according to individual risk-benefit assessment, institutional protocols, the local Prescribing Information, local regulations or the local guidelines.
    5. At least 1 measurable site of disease per RECIST v1.1 using contrast computed tomography (CT)/magnetic resonance imaging (MRI). Patients who are allergic to IV contrast may be imaged without.
    6. SSTR+ disease, as evidenced by 68Ga-based or 64Cu-based (if approved according to local regulations) SSTR positron emission tomography (PET) somatostatin receptor imaging (SRI; 68Ga-DOTATOC, 68Ga-DOTATATE or 64Cu-DOTATATE) within 4 months prior to randomization and as close as possible to the fluorodeoxyglucose (FDG) PET.
    a. The majority of the CT/MRI lesions have to be SSTR+.
    b. The SSTR PET SRI should be repeated at randomization if the scan is not within 28 days of the randomization date.
    7. All patients need to undergo a FDG PET scan within 4 months prior to randomization and as close as possible to the PET SRI.
    a. The majority of FDG PET-positive lesions have to be SSTR+.
    8. Patients may be treatment naïve (first-line) or have a maximum of one prior line of therapy, including SSAs (second-line).
    a. Patients on any prior antineoplastic therapy (including SSAs) must have radiological disease progression (according to RECIST v1.1) within the 4 months prior to randomization, based on the investigator’s assessment.
    b. Patients who progress on SSAs may enter the trial continuing on the same dose if required for symptom control.
    9. Karnofsky performance status scale ≥ 60.
    1. Haber proporcionado el consentimiento informado por escrito.
    2. Pacientes de al menos 18 años (completamente maduros de acuerdo con la normativa local).
    3. Diagnóstico confirmado histológicamente de TNE-GEP irresecable, bien diferenciado, con un índice de Ki-67 de entre 15 y 55, ambos inclusive. Dicho diagnóstico debe confirmarse al menos mediante un informe anatomopatológico local con una pieza de biopsia del tumor primario o de metástasis o, en caso de no estar disponible, el paciente debe estar dispuesto a someterse a una nueva biopsia para su análisis local antes de su aleatorización.
    4. A criterio del investigador, el paciente debe considerarse idóneo para recibir al menos uno de los siguientes tratamientos: CAPTEM, everolimus o FOLFOX, de acuerdo con la evaluación riesgo-beneficio en cada paciente, los protocolos institucionales, la ficha técnica local y la normativa o las directrices locales.
    5. Presentar al menos 1 localización mensurable de la enfermedad según los resultados de una tomografía computarizada (TC) / una resonancia magnética nuclear (RMN) con contraste y de acuerdo con los criterios RECIST v1.1. En caso de que el paciente sea alérgico al contraste i.v., las pruebas de imagen pueden realizarse sin contraste.
    6. Enfermedad SSTR+ de acuerdo con los resultados de una tomografía por emisión de positrones (PET) de receptores de la somatostatina con 68Ga o 64Cu (si está aprobado de acuerdo con la normativa local) (68Ga‑DOTATOC, 68Ga-DOTATATE o 64Cu‑DOTATATE) en el transcurso de los 4 meses anteriores a la aleatorización y lo más cerca posible de la PET con fluorodeoxiglucosa (FDG).
    a. La mayoría de las lesiones en la TC/RMN deben ser SSTR+.
    b. La PET de receptores de la somatostatina debe repetirse en el momento de la aleatorización si la prueba de imagen no se ha realizado en el transcurso de los 28 días anteriores a la fecha de aleatorización.
    7. Todos los pacientes deben someterse a una PET con FDG en el transcurso de los 4 meses anteriores a la aleatorización y lo más cerca posible de la PET de receptores de la somatostatina.
    a. La mayoría de las lesiones que presenten resultados positivos en la PET con FDG deben ser SSTR+.
    8. Los pacientes pueden no haber recibido tratamiento (primera línea) o, como máximo, haber recibido una línea previa de tratamiento, incluidos los análogos de la somatostatina (segunda línea).
    a. Los pacientes que hayan recibido algún tratamiento antineoplásico (incluidos los análogos de la somatostatina) deben haber presentado progresión radiológica de la enfermedad (de acuerdo con los criterios RECIST v1.1) en el transcurso de los 4 meses anteriores a la aleatorización de acuerdo con la evaluación del investigador.
    b. A los pacientes cuya enfermedad progrese durante el tratamiento con análogos de la somatostatina se les podrá incluir en el estudio y podrán continuar recibiendo la misma dosis si es necesario para controlar los síntomas.
    9. Un estado funcional ≥ 60 en la escala de Karnofsky.
    E.4Principal exclusion criteria
    1. Known hypersensitivity to 177Lu, edotreotide, DOTA, any of the comparators, or any excipient or derivative (e.g. rapamycin).
    2. Known hypersensitivity to lysine, arginine, or any excipient of the nephroprotective amino acid solution (AAS) given concurrently with the lutetium (177Lu) edotreotide infusion.
    3. Prior external beam radiation therapy (EBRT) to more than 25% of the bone marrow.
    4. Prior selective internal radiation therapy.
    5. Prior PRRT.
    6. Received chemotherapy, mammalian target of rapamycin (mTOR) inhibitors, vascular endothelial growth factor (VEGF) pathway inhibitors, immunotherapy, interferon, chemo-embolization, bland embolization, cyclosporine A, locoregional treatment (e.g. cytoreduction surgery, radiofrequency ablation [RFA], liver directed intra-arterial intervention) or SSAs within 4 weeks prior to randomization into the trial. Patients may be treated with SSAs for symptom control, but they must have remained on the same dose of the SSA as at the time of demonstrated disease progression.
    7. Any major surgery within 4 weeks prior to randomization in the trial.
    8. Therapy with an investigational compound and/or medical device within 30 days or 7 half-life periods (whichever is longer) prior to randomization.
    9. Patients who have received a live attenuated vaccine up to 4 weeks prior to randomization.
    10. Patients with brain metastases.
    11. Other known malignancies, (except non-invasive skin cancer and carcinoma of the cervix in situ), unless definitively treated and proven no evidence of recurrence for 5 years.
    12. Serious non-malignant disease (e.g. psychiatric, infectious, autoimmune, metabolic or dementia), that may interfere with the objectives of the trial or with the safety or compliance of the patient, as judged by the investigator.
    13. Renal, hepatic, cardiovascular, or hematological organ dysfunction, potentially interfering with the safety of the trial treatments, as follows:
    a. Renal
    i. Glomerular filtration rate (GFR) < 50 mL/min/1.73 m2 (calculated by the CKD-EPI formula [local laboratory])
    ii. Creatinine clearance < 50 mL/min calculated by the Cockcroft Gault method
    iii. Renal tract obstruction
    b. Hepatic
    i. Total bilirubin > 3 × upper limit of normal (ULN)
    ii. Albumin < 30 g/L
    iii. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 5 × ULN
    iv. Known ascites
    c. Cardiovascular
    i. Heart failure (New York Heart Association [NYHA] classification III and IV)
    ii. Uncontrolled hypertension
    d. Hematopoietic
    i. Platelets ≤ 75 × 10e9/L
    ii. Absolute neutrophil count (ANC) < 1.5 × 10e9 cells/L
    iii. Hemoglobin (Hb) concentration < 5.0 mmol/L (< 8.0 g/dL)
    e. Any other ongoing hematological or renal Grade 2 toxicity or other Grade 3 toxicity from previous standard or investigational therapies (NCI-Common Terminology Criteria for Adverse Events [CTCAE] version 5.0).
    14. Current spontaneous urinary incontinence.
    15. Pregnancy and breast-feeding:
    a. Female patients of childbearing potential or male patients with female partners of childbearing potential, unless willing to practice full and true sexual abstinence or who are surgically/permanently sterile (hysterectomy, or vasectomy), or female patients whose male partners have medically successful vasectomy (provided the partner is the sole sexual partner of the female patient of childbearing potential), or who are not willing to practice highly effective contraception in combination with a barrier method of contraception (e.g. condom).
    Contraception methods that are considered highly effective are:
    i. Oral or non-oral (injected or implanted) non-estrogen progesterone-based hormonal method; oral, intravaginal, or transdermal combined estrogen and progesterone-based hormonal methods;
    and/or
    ii. Intrauterine device (IUD), and/or intrauterine hormone-releasing system (IUS).
    iii. Bilateral fallopian tubal ligation.
    Note: Sexual abstinence or the contraception methods described above must be followed throughout the entire trial period and for the following durations after last trial drug administration: 6 months for CAPTEM; 8 weeks for everolimus; 6 months for FOLFOX; 66 days for PRRT (10 half lives of 177Lu).
    b. Women who are breast-feeding.
    16. Patients not able to declare meaningful informed consent on their own (e.g. with legal guardian for mental disorders) or any other vulnerable population to that sense (e.g. persons institutionalized, incarcerated etc.).
    1. Hipersensibilidad a 177Lu, edotreotida, al DOTA, a cualquiera de los tratamientos comparativos o a cualquier excipiente o derivado (por ejemplo, rapamicina).
    2. Hipersensibilidad a la lisina, la arginina o a cualquier excipiente de la solución de aminoácidos (SAA) nefroprotectora que se administre de forma concomitante con la infusión de lutecio (177Lu) edotreotida.
    3. Haber recibido radioterapia externa en más del 25 % de la médula ósea.
    4. Haber recibido radioterapia interna selectiva.
    5. Haber recibido anteriormente PRRT.
    6. Haber recibido quimioterapia, inhibidores de la diana de la rapamicina en células de mamíferos (mTOR), inhibidores de la vía del factor de crecimiento endotelial vascular (VEGF), inmunoterapia, interferón, quimioembolización, embolización simple, ciclosporina A, tratamiento locorregional (por ejemplo, cirugía de citorreducción, ablación por radiofrecuencia [ARF], intervención intraarterial dirigida al hígado) o análogos de la somatostatina en el transcurso de las 4 semanas anteriores a la aleatorización en el estudio. Los pacientes pueden haber recibido análogos de la somatostatina para el control de los síntomas, pero deben continuar con la misma dosis de dichos análogos que estuvieran recibiendo cuando se demostró la progresión de la enfermedad.
    7. Haberse sometido a cualquier cirugía mayor en el transcurso de las 4 semanas anteriores a la aleatorización en el estudio.
    8. Haber recibido tratamiento con un compuesto en fase de investigación y/o un producto sanitario en el transcurso de los 30 días o 7 semividas (lo que sea mayor) anteriores a la aleatorización.
    9. Pacientes que hayan recibido una vacuna atenuada elaborada con microbios vivos en el transcurso de las 4 semanas anteriores a la aleatorización.
    10.Pacientes con metástasis cerebrales.
    11.Presencia de otras neoplasias malignas (salvo los casos de cáncer de piel no invasivo y carcinoma in situ del cuello uterino), a menos que se hayan tratado de forma definitiva y no haya habido signos de recurrencia durante 5 años.
    12.Enfermedad no neoplásica de carácter grave (por ejemplo, enfermedades psiquiátricas, infecciosas, autoinmunitarias, metabólicas o demencia) que pueda interferir con los objetivos del estudio o con la seguridad o el grado de cumplimiento del paciente, de acuerdo con el criterio del investigador.
    13.Disfunción renal, hepática, cardiovascular o hematológica que pueda interferir en la seguridad de los tratamientos del estudio, según se muestra a continuación:
    a. Renal:
    i. (FG) <50 ml/min/1,73 m2 (de acuerdo con la fórmula CKD-EPI [laboratorio local])
    ii. Aclaramiento de creatinina <50 ml/min, calculado de acuerdo con la
    fórmula de Cockcroft y Gault.
    iii. Obstrucción de las vías urinarias
    b. Hepática
    i. Bilirrubina total >3 veces el LSN
    ii. Albúmina <30 g/l
    iii. AST / ALT >5 x LSN
    iv. Presencia de ascitis
    c. Cardiovascular
    i. Insuficiencia cardíaca (clase III y IV de acuerdo con la clasificación de
    la NYHA)
    ii. Hipertensión sin controlar
    d. Hematopoyética
    i. Plaquetas ≤75 × 109/l
    ii. Recuento absoluto de neutrófilos (RAN) <1,5× 109 células/l
    iii. Hb <5,0 mmol/l (<8,0 g/dl)
    e. Cualquier otra toxicidad hematológica o renal de grado 2 en curso u otra toxicidad de grado 3 asociada con tratamientos de referencia o en fase de investigación previos (según los CTCAE versión 5.0 del NCI).
    14.Presentar en la actualidad incontinencia urinaria espontánea.
    15.Embarazo y lactancia:
    a. Pacientes que puedan quedarse embarazadas, o pacientes con parejas que puedan quedarse embarazadas en edad fértil, a menos que estén dispuestos a practicar una abstinencia sexual total y verdadera o que sean estériles de forma quirúrgica/permanente (histerectomía o vasectomía), o pacientes femeninas cuyas parejas masculinas se hayan sometido a una vasectomía médicamente satisfactoria (siempre que la pareja sea la única pareja sexual de la paciente femenina en edad fértil), o que no estén dispuestos a utilizar un método anticonceptivo eficaz en combinación con un método anticonceptivo de barrera (por ejemplo, preservativo).
    Los métodos anticonceptivos que se consideran muy eficaces son:
    i. Métodos hormonales no estrogénicos orales u de otro tipo (inyectados o implantados) que incluyen progesterona; métodos hormonales combinados orales, intravaginales o transdérmicos que contienen estrógeno y progesterona;
    y/o
    ii. Dispositivo intrauterino (DIU) y/o un sistema intrauterino (SIU) de liberación de hormonas.
    iii. Ligadura de ambas trompas de Falopio.
    Nota: La abstinencia sexual o los métodos anticonceptivos descritos deben seguirse a lo largo de todo el estudio y durante los siguientes períodos tras la última administración del medicamento del estudio: 6 meses para CAPTEM; 8 semanas para everolimus; 6 meses para FOLFOX; 66 días para PRRT (10 semividas de 177Lu).
    b. Mujeres que se encuentren en etapa de lactancia.
    16.Pacientes que no puedan otorgar por sí mismos su consentimiento informado
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS)
    Supervivencia libre de progresión (SLP)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 12±2 Weeks from Randomization Until Adequately Documented Disease Progression. The same is also valid for the PFS follow-up period.
    Cada 12±2 semanas desde la aleatorización hasta la progresión de la enfermedad adecuadamente documentada. Lo mismo es válido para el periodo de seguimiento de la SLP.
    E.5.2Secondary end point(s)
    Secondary endpoints
    1. Further demonstration of efficacy:
    For all endpoints based on RECIST v1.1, main analyses will be based on blinded, central assessment. Local assessments will be presented as sensitivity analyses.
    1.1 Objective response rate (ORR), defined as the proportion of randomized patients with complete response (CR) or partial response (PR) (RECIST v1.1).
    1.2 Overall survival (OS), defined as the time from randomization until death.
    1.3 Duration of response (DoR), defined as the time from experiencing first CR or PR until the next progressive disease (PD) (RECIST v1.1).
    1.4 Disease control rate (DCR), defined as the proportion of randomized patients with CR, PR or stable disease (SD) (RECIST v1.1).
    1.5. Duration of disease control (DDC), defined as the time from experiencing CR, PR or SD until the next subsequent PD (RECIST v1.1).
    2. 2. HRQL (European Organization for Research and Treatment of Cancer [EORTC] quality of life questionnaire [QLQ]-C30 and –GI.NET21):
    2.1.Maximum HRQL improvement in total scores relative to baseline.
    2.2.Duration of maximum HRQL improvement, defined as the time from maximum improvement until subsequent deterioration.
    2.3.Time to HRQL deterioration, defined as the time from randomization until first HRQL deterioration.
    3. Safety and tolerability based on adverse events, laboratory data and vital signs.
    Criterios secundarios de valoración
    1. Demostración adicional de la eficacia:
    En lo que respecta a todos los criterios de valoración que se basen en los criterios RECIST v1.1, los análisis principales se basarán en una evaluación centralizada y con enmascaramiento. Las evaluaciones locales se presentarán como análisis de sensibilidad.
    1.1 Tasa de respuestas objetivas (TRO), definida como la proporción de pacientes aleatorizados que alcancen una respuesta completa (RC) o una respuesta parcial (RP) (RECIST v1.1).
    1.2 Supervivencia global (SG), definida como el período comprendido entre la aleatorización y el fallecimiento del paciente.
    1.3 Duración de la respuesta (DdR), definida como el período comprendido entre la fecha de la primera RC o RP hasta la siguiente progresión de la enfermedad (PE) (RECIST v1.1).
    1.4 Tasa de control de la enfermedad (TCE), definida como la proporción de pacientes aleatorizados con RC, RP o enfermedad estable (EE) (RECIST v1.1).
    1.5 Duración del control de la enfermedad (DCE), definida como el período desde que el paciente presente RC, RP o EE hasta la siguiente PE (RECIST v1.1).
    2. 2 cuestionarios sobre la CDVRS (Cuestionarios de Calidad de Vida
    [QLQ]-C30 y GI.NET21 de la European Organization for Research and Treatment of Cancer)
    2.1 Mejoría máxima en la CDVRS (puntuaciones totales) en comparación con el período inicial.
    2.2 Duración de la mejoría máxima en la CDVRS, definido como el período comprendido entre la fecha en la que se constató la mejoría máxima y el posterior deterioro.
    2.3 Tiempo transcurrido hasta el deterioro de la CDVRS, definido como el período comprendido entre la aleatorización y la fecha en la que se constate por primera vez el deterioro de la CDVRS.
    3. Seguridad y tolerabilidad de acuerdo con los acontecimientos adversos, los parámetros analíticos y las constantes vitales.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. and 2. as for the primary end point.
    3.:
    - at day of cycle 1
    - at day of cycles 2 to 4 (pre-dose and at dosing)
    - at day of cycles 5 and 6 (pre-dose, at dosing and post-dose)
    - at the end of treatment
    1. y 2. como para el criterio primario.
    3.:
    - en el día del ciclo 1
    - en el día de los ciclos 2 a 4 (antes de la dosis y con la dosis)
    - el día de los ciclos 5 y 6 (antes de la dosis, con la dosis y después de la dosis)
    - al final del tratamiento
    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 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) 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 Yes
    E.8.2.3.1Comparator description
    Tratamiento de referencia según el investigador
    Standard of Care as per investigator choice
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    France
    Germany
    India
    Italy
    Netherlands
    Spain
    Sweden
    United Kingdom
    United States
    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
    The End of Study (EOS) for each patient is defined as the date at which the patient has been followed up for 2 years after documented disease progression or has died, or is the date of last contact if the patient is lost to follow-up, whichever occurs first.
    La fecha en la que el paciente ha sido seguido durante 2 años después de la progresión documentada de la enfermedad o ha fallecido, o es la fecha del último contacto si el paciente está perdido para el seguimiento, lo que ocurra primero.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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: 135
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 67
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state51
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 138
    F.4.2.2In the whole clinical trial 202
    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)
    Any further new anti-cancer treatment initiated according to treating physician prescription will be allowed during the trial long-term follow-up (i.e. after disease progression according to RECIST 1.1) and will be recorded as per protocol
    Durante el seguimiento a largo plazo del ensayo (es decir, después de la progresión de la enfermedad según RECIST 1.1) se permitirá cualquier nuevo tratamiento anticancer iniciado según la prescripción del médico tratante y se registrará según el protocolo
    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 Decision2021-08-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-07-27
    P. End of Trial
    P.End of Trial StatusOngoing
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