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    Summary
    EudraCT Number:2016-001897-13
    Sponsor's Protocol Code Number:ITM-LET-01
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2017-12-19
    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 ConcernedFrance - ANSM
    A.2EudraCT number2016-001897-13
    A.3Full title of the trial
    A prospective, randomised, Controlled, Open-label, Multicentre phase III study to evaluate efficacy and safety of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide compared to targeted molecular therapy with Everolimus in patients with inoperable, progressive, somatostatin receptor-positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A prospective, randomised, Controlled, Open-label, Multicentre phase III study to evaluate efficacy and safety of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide compared to targeted molecular therapy with Everolimus in patients with inoperable, progressive, somato-statin receptor-positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET).
    A.3.2Name or abbreviated title of the trial where available
    COMPETE
    A.4.1Sponsor's protocol code numberITM-LET-01
    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 organisationABX-CRO advanced pharmaceutical services mbH
    B.5.2Functional name of contact pointDr. Ulrike Schorr-Neufing
    B.5.3 Address:
    B.5.3.1Street AddressBlasewitzer Straße 78-80
    B.5.3.2Town/ cityDresden
    B.5.3.3Post code01307
    B.5.3.4CountryGermany
    B.5.4Telephone number004935121444291
    B.5.5Fax number00493512144415
    B.5.6E-mailulrike.schorr-neufing@abx-cro.com
    D. IMP Identification
    D.IMP: 1
    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 Afinitor
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameAfinitor, Everolimus
    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.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number5 to 10
    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 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 injection/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 INN177Lu-Edotreotide
    D.3.9.3Other descriptive name177LU-DOTA-TYR3-OCTREOTIDE
    D.3.9.4EV Substance CodeSUB180350
    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.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 with inoperable, progressive, somatostatin receptor-positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET)
    E.1.1.1Medical condition in easily understood language
    This trial aims to investigate metastasised and / or locally advanced neuroendocrine tumours (NET) in patients with pancreatic NET or non-functional gastroenteric NET.
    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
    The primary objective is to demonstrate the efficacy of PRRT with 177Lu-edotreotide to prolong median progression-free survival (mPFS) in patients with inoperable, progressive, SSTR+ GEP-NET, compared to everolimus
    E.2.2Secondary objectives of the trial
    1. To assess overall survival (OS) during study period
    2. To determine objective response rates (ORR)
    3. To determine disease control rates (DCR)
    4. To determine the duration of disease control (DDC)
    5. To determine functional response rates (FRR)
    6. To assess the safety and tolerability of 177Lu-edotreotide in GEP-NET patients
    7. To determine the health-related quality of life (HRQL) in GEP-NET patients during and after therapy
    8. To evaluate symptomatic tumour response
    9. To evaluate the impact of patient characteristics
    10. To evaluate the impact of tumour histology
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Sub-study A: Repetitive Full Dosimetry Imaging (D1 – D4):
    Objective: The total absorbed doses (AD) to kidneys and tumour from four cycles of 177Lu-edotreotide (D1 – D4) will be estimated, by linear extrapolation of the AD measured during D1 with 7.5 GBq to the full dose of 30 GBq. Dosimetry will be measured, using serial planar and single time point SPECT imaging. To verify the accuracy of total AD estimations, based on a linear extrapolation of AD measured during D1, full dosimetric imaging will be repeated during subsequent cycles (D2 – D4) in a subgroup of approximately 20 patients, ready and able to undergo repetitive dosimetric imaging.

    Sub-study B: 3D Dosimetry SPECT/CT Imaging:
    Objective: Abdominal SPECT images (1-2 bed positions, covering liver, kidneys, tumour, as appropriate) will be acquired in a subgroup of approximately 20 patient of 177Lu-edotreotide group in addition to the compulsatory planar images at the following time points of 0.5, 6, 24, and 72 – 96 h after injection of 177Lu-edotreotide. SPECT imaging will be performed after planar imaging. The absorbed doses determined by 3D dosimetry, will be analysed in comparison to absorbed doses values obtained by planar (2D) and hybrid (2D/3D) dosimetry.
    E.3Principal inclusion criteria
    All patients must meet all of the following criteria:
    1. Written informed consent
    2. Male or female ≥ 18 years of age
    3. Histologically and clinically confirmed diagnosis of well-differentiated neuro-endocrine tumour of non-functional gastroenteric origin (GE-NET) or both functional or non-functional pancreatic origin (P-NET), grade G1 or G2 (Ki-67 < 20%), unresectable or metastatic
    4. Availability of existing biopsy specimen from primary tumour or metastasis or, if unavailable, willingness to undergo current biopsy for secondary central analysis
    5. Measurable disease per RECIST 1.1, on CT/MRI scans, defined as at least 1 lesion with ≥ 1 cm in longest diameter, and ≥ 2 radiological tumour lesions in total. A maximum of 5 target lesions visible on CT/MRI will be defined, thereof not more than 2 lesions per organ
    6. Somatostatin receptor positive (SSTR+) disease, as evidenced by SSTR imaging (SRI) within 4 months prior to randomisation, by:
    • 68Ga-based SSTR PET imaging (e.g. using 68Ga-edotreotide or 68Ga-DOTATATE), or
    • 111In-pentetreotide SSTR SPECT/planar imaging, or
    • 99mTc-octreotide SSTR SPECT/planar imaging
    All target lesions and ≥ 90% of non-target lesions need to be positive for SSTR, demonstrated by adequate tracer uptake, being defined as being “clearly differentiable from background”
    7. Radiological disease progression, defined as:
    • Progressive disease per RECIST 1.1. criteria, eviden-ced by consecutive morphological imaging (CT or MRI) with ≥ 90 days interval during the 12 months prior to randomisation
    8. Karnofsky performance status (KPS) scale ≥ 70
    9. Life expectancy of at least 6 months
    10. Glomerular filtration rate (GFR, MDRD) ≥ 60 mL/min/1.73 m^2
    E.4Principal exclusion criteria
    A patient will be excluded from participation in the trial if one or more of the following criteria are met:
    1. Known hypersensitivity to edotreotide or everolimus
    2. Known hypersensitivity to DOTA, lutetium-177, or any excipient of edotreotide or everolimus
    3. Known hypersensitivity to lysin, arginin, or any excipient of the nephroprotective amino acid solution
    4. Prior exposure to any peptide receptor radiotherapy (PRRT), including 177Lu-edotreotide, 90Y-edotreotide or other SSTR-targeting agents (e.g. 177Lu-octreotate or high-dose 111In-pentetreotide)
    5. Prior therapy with mTor inhibitors
    6. Prior EFR (extended field radiation) to GEP-NET lesions or radioembolisation therapy (e.g. 90Y microspheres,
    131I-lipiodol) with administration to the liver
    7. Therapy with an investigational compound and/or medical device within 30 days or 5 half-life periods (whichever is longer) prior to randomisation
    8. Current therapy with any prohibited medication
    9. Ongoing toxicity grade 2 from previous standard or investigational therapies (Common Terminology Criteria for Adverse Events [CTCAE] version 4.03)
    10. Indication for surgical lesion removal with curative potential
    11. Planned (for the period of study participation): chemotherapy, immunotherapy, radiation therapy, chemo-embolisation, bland embolisation, radio-embolisation, treatment with cyclosporine-A
    12. Neuroendocrine tumours, not meeting the inclusion criteria:
    • With known non-GEP-NET origin (e.g. pulmonary or gonadal primaries)
    • Functional GE-NET
    • NET with unknown primaries (CUP), manifesting as liver metastases
    • Poorly differentiated neuroendocrine carcinomas (grade G3)
    • NET for which no histological specimen for secondary histological analysis can be obtained
    13. Total hepatic tumour burden > 70%
    14. Brain metastases
    15. Secondary malignoma within previous 5 years (except basalioma)
    16. Serious non-malignant disease (e.g. psychiatric, infectious, autoimmune or metabolic), that may interfere with the objectives of the study or with the safety or compliance of the subject, as judged by the investigator
    17. Renal, hepatic, cardiovascular, or haematological organ dysfunction, potentially interfering with the safety of the study treatments, as follows:
    • Renal
    o Serum creatinine ≥ 1.5 x ULN, or creatinine clearance (GFR, MDRD) < 60 mL/min/1.73 m^2
    o Serum potassium > 5.0 mmol/l
    o Renal obstruction
    o Known nephropathy from any cause
    • Hepatic
    o Total bilirubin > 2.5 x ULN
    o AST or ALT > 2.5 x ULN
    o Alkaline phosphatase > 5 x ULN
    o Albumin < 3 g/dL, unless prothrombin time is within normal range
    o Known cirrhosis or other distinctly restricted liver function
    • Cardiovascular
    o New York Heart Association classification III & IV
    o Uncontrolled hypertension
    • Haematopoietic
    o Platelets ≤ 80 * 10^9/mL
    o Absolute neutrophil count (ANC) < 1,000/mL
    18. Pregnant or breast-feeding. Female patients of childbearing potential or male patients with female partners of childbearing potential not willing to practice effective contraception during the study period in the everolimus group and, in the PRRT group, for 66 days (10 half lives of 177Lu) after the last treatment cycle.
    19. Subjects not able to declare meaningful informed consent on their own (e.g. with legal guardian for mental disorders)
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint is progression-free survival (PFS). Diagnosis of progression will be established based on morphological imaging (MRI and/or CT) according to RECIST 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Progression-free survival (PFS) will be determined as time elapsed between randomisation and the date of first objective report of tumour progression (evaluated by RECIST criteria, 1.1)
    E.5.2Secondary end point(s)
    Secondary endpoints include overall survival (OS), parameters of morphological and functional tumour response, safety, health-related quality of life (HRQL). Furthermore, patient and tumour characteristics, as well as the degree of 177Lu-edotreotide uptake will be exploratively analysed as possible predictors of PRRT efficacy.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of study
    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 Yes
    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
    Dosimetry: To assess differences in tumour and kidney radiation dose estimates, obtained with 2D compared to hybrid (2D/3D) and 3D (SPECT) imaging
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    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
    Austria
    France
    Germany
    Italy
    Netherlands
    Poland
    South Africa
    Switzerland
    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 the study is defined as the last visit of the last patient or the last date of follow-up of toxicities, if required (whichever is the later).
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 300
    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)
    Study patients experiencing disease progression have to perform EoS visit. After withdrawal or EoS patients will be treated according to clinical practice at the discretion of the investigator. Everolimus patients may receive 177Lu-edotreotide therapy on a compassionate use basis. Dosing and assessments should match those of the 177Lu-edotreotide arm of the study.
    Survival information will be collected from all patients.
    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 Decision2017-12-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-15
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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