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    Summary
    EudraCT Number:2017-000369-54
    Sponsor's Protocol Code Number:60725
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-06-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-000369-54
    A.3Full title of the trial
    Intra-arterial Lutetium-177- dotatate for treatment of patients with neuroendocrine tumor liver metastases
    Gerichtere behandeling van levermetastasen bij patiënten met neuroendocriene tumoren: Intra-arteriële behandeling met Lutetium-177-dotatate.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of patients with neuro-endocrine tumor liver metastases: liver directed therapy with intra-arterially administrated radionuclide lutetium-177-dotatate
    Gerichtere behandeling van levermetastasen bij patiënten met neuroendocriene tumoren: Intra-arteriële behandeling met Lutetium-177-dotatate.
    A.3.2Name or abbreviated title of the trial where available
    LUTIA
    LUTIA
    A.4.1Sponsor's protocol code number60725
    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 Utrecht
    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 supportUniversity Medical Center Utrecht
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Utrecht
    B.5.2Functional name of contact pointClinical Research Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressHeidelberglaan 100
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3584 CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31887551321
    B.5.5Fax number31887569589
    B.5.6E-mailtbosma@umcutrecht.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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/3/07/523
    D.3 Description of the IMP
    D.3.1Product nameLutathera
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraarterial use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN177Lu-DOTA0-Tyr3-Octreotate
    D.3.9.3Other descriptive nameLUTETIUM(177LU)-DOTA-(TYR3)-OCTREOTATE
    D.3.9.4EV Substance CodeSUB177319
    D.3.10 Strength
    D.3.10.1Concentration unit GBq gigabecquerel(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number29.6
    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 neuro-endocrine tumors with liver metastases with an indication for treatment with lutetium-177-dotatate
    E.1.1.1Medical condition in easily understood language
    Patients with neuro-endocrine tumors with liver metastases
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate if there is a difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe.
    E.2.2Secondary objectives of the trial
    To evaluate whether:
    - There is a difference in absolute values of mean tumor and healthy liver absorbed dose on post-treatment SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe?
    - There is a difference in post-treatment tumor response between the intra-arterial treated liver lobe and the intravenous treated liver lobe?
    - There is a dose-response relation between tumor absorbed dose and post-treatment tumor response?
    - There is toxicity and how toxicity is compared to historical controls?
    - There is sufficient uptake of 177Lu-dotatate in extrahepatic lesions?
    - There is sufficient uptake of 177Lu-dotatate in the contralateral lobe, compared to historical controls?
    - There is a difference in kidney uptake of 177Lu-dotate between the IA treated patients and historical controls?
    - There is a difference in T/N activity concentration ratio between different timepoints post-injection?
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    'Intra-arterial lutetium-177-DOTATATE dosimetry study, a substudy of the LUTIA trial'; version 1, 9-11-2018
    A subset of included patients will be scanned using SPECT/CT and total-body scans at multiple time-points post-injection to allow for comparison of uptake ratio’s at different time points and mean absorbed dose calculations. SPECT/CT allows for mean absorbed dose calculation in liver tumors and healthy liver tissue, while total-body imaging evaluates kinetics in extra-hepatic lesions. The subset of patients will receive a total of 4 SPECT/CT’s and 4 total-body acquisitions after their first treatment to evaluate pharmacokinetic properties of 177Lu-dotatate after intra-arterial injection. The four time points are ½-1, 4-5, 24±3 and 168±24 hours after administration of 177Lu-dotatate. Each patient who is eligible for the study, could optionally participate in the sub-study.
    Objective: Is there a difference in T/N activity concentration ratio between different timepoints post-injection?
    E.3Principal inclusion criteria
    - Patients must have given written informed consent.
    - Female or male aged 18 years and over.
    - Inoperable histologically proven neuro-endocrine tumor with indication for 177Lu-dotatate at enrollment time.
    - Well-differentiated neuro-endocrine tumor with a Ki67-index ≤ 20% and a mitotic count of ≤ 20.
    - Confirmed presence of somatostatin receptors on target lesions, based on somatostatin receptor imaging.
    - Life expectancy of 6 months or longer.
    - Eastern Cooperative Oncology Group (ECOG) performance score 0-1.
    - Hepatic metastases with at least one lesion ≥ 3 cm on cross sectional imaging in both the right and left liver lobe (i.e. left and right lobes are based on the hepatic arterial perfusion territory).
    - Presence of excessive liver metastases, defined as >25% tumor load.
    - Patients may or may not have extrahepatic metastases.
    - Patients must have clinical or radiological progressive disease.
    - Negative pregnancy test for women of childbearing potential.
    E.4Principal exclusion criteria
    - Any previous radioembolization, chemoembolization, or bland embolization, at any time, or surgery or radiofrequency ablation (or other ablative therapies) within 12 weeks prior to randomization in the study.
    - Prior external beam radiation therapy to the liver.
    - Interferons, Everolimus (mTOR-inhibitors) or other systemic therapies within 4 weeks prior to randomization in the study.
    - Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 hours before and 24 hours after the administration of 177Lu-dotatate, or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 4 weeks before the administration of 177Lu-dotatate, unless the tumor uptake on target lesions observed by imaging during continued Octreotide LAR treatment is higher than normal liver uptake.
    - Any unresolved toxicity greater than National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE version 4.03) grade 2 from previous anti-cancer therapy.
    - Serum bilirubin > Upper Limit of Normal (ULN), serum albumin <3.0 g/dL.
    - Glomerular filtration rate <50 ml/min.
    - Hb <5.5 mmol/L; leucocytes <3.0x109/L; platelets <100x109/L (at baseline; 75x109/L is sufficient for cycles 2-4).
    - Uncontrolled congestive heart failure (NYHA II, III, IV).
    - Uncontrolled diabetes mellitus.
    - Patients suffering from diseases with an increased chance of liver toxicity.
    - Patients suffering from psychic disorders that make a comprehensive judgement impossible, such as psychosis, hallucinations and/or depression. Patients who are declared incompetent.
    - Previous enrolment in the present study or previous treatment with 177Lu-dotatate.
    - Female patients who are not using an acceptable method of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device or tubal ligation) OR are less than 1 year postmenopausal or surgically sterile during their participation in this study (from the time they sign the consent form) to prevent pregnancy.
    - Male patients who are not surgically sterile or do not use an acceptable method of contraception during their participation in this study (from the time they sign the consent form) to prevent pregnancy in a partner.
    - Body weight over 150 kg.
    - Current spontaneous urinary incontinence.
    - Severe allergy for i.v. contrast (Visipaque®), used for CT evaluation and treatment angiography.
    E.5 End points
    E.5.1Primary end point(s)
    To assess if there is a difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe. The T/N activity concentration will be measured on SPECT/CT. For each liver lobe up to three tumors (i.e. all >3 cm) will be selected based on size (i.e. the largest lesions). The weighted average activity per voxel of these lesions will be divided by the normal liver tissue mean activity per voxel (i.e. a VOI with 3 cm diameter will be placed in the normal liver tissue) to calculate the T/N ratio. The T/N activity ratios of the second, third, and final treatment cycle will be assessed as secondary endpoint. Intra- and inter-patient differences will be studied.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be assessed after the first treatment cycle.
    E.5.2Secondary end point(s)
    - Difference in absolute values of mean tumor and healthy liver absorbed dose (in Gy) on post-treatment SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe: Dosimetry will be performed to measure mean tumor and healthy liver absorbed dose. Dosimetry will be performed on post-treatment SPECT/CT, which is performed 24 hours after administration of 177Lu-dotatate. The absolute absorbed dose in the IA treated liver lobe will be compared to the IV treated lobe.

    - Difference in post-treatment tumor response between the intra-arterial treated liver lobe and the intravenous treated liver lobe: The tumors are measured on CT and scored according to the Southwest Oncology Group (SWOG) solid tumor response criteria, RECIST 1.1, and mRECIST criteria. Scoring systems will be applied on the patient and liver level, separately.
    Because the eventual maximal shrinkage of the tumors may take months after completion of the therapy, we added the tumor response class ‘minimal response (MR)’, pertaining to a decrease in summed squares of tumor diameter more than 25% but less than 50%.

    The SWOG criteria are defined as follows:
    Complete response (CR) - Complete disappearance of all measurable and evaluable disease. No new lesions.
    Partial response (PR) - At least one measurable lesion, ≥ 50% decrease under baseline in the sum of the products of perpendicular diameters of all measurable lesions. No new lesions.
    Stable disease (SD) / no response - Does not qualify for CR, PR, or progression.
    Progression - 50% increase or an increase of 10 cm2 in the sum of products of all measurable lesions. OR clear worsening of evaluable disease, OR reappearance of any new lesion/site.


    - To assess if there is a dose-response relation between tumor absorbed dose and post-treatment tumor response: The tumor absorbed dose in both the IA and IV treated liver lobe will be calculated based on SPECT/CT as mentioned above. Tumor response will be measured on post-treatment follow-up imaging. With these parameters, a possible dose-response relation will be evaluated.

    - To assess safety and toxicity according to the common toxicity criteria on adverse events (CTCAE) version 4.02. The grade of toxicity refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline:

    Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
    Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL).
    Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.
    Grade 4 Life-threatening consequences; urgent intervention indicated.
    Grade 5 Death related to AE.

    - To assess if there is sufficient uptake of 177Lu-dotatate in extrahepatic lesions and the contralateral lobe (comparison will be made with historical data): The 177Lu-dotatate uptake of the extrahepatic lesions (e.g. pancreas, intestine) and contralateral lobe will be calculated on post-treatment SPECT/CT. These results will be compared to historical data in order to evaluate if these extrahepatic tumor sites and other lobe show sufficient uptake.

    - To assess if there is a difference in kidney uptake of 177Lu-dotate between the IA treated patients and historical controls: Kidney uptake will be calculated on post-treatment SPECT/CT and compared to historical controls in order to assess differences in uptake.

    - In a sub-study, pharmacokinetics will be evaluated using the acquisition of SPECT/CT imaging on multiple timepoints post-treatment. Dosimetry will be performed on sequential post-treatment SPECT/CT and total-body planar acquisitions, acquired 1, 5, 24 and 168 hours after administration of 177Lu-dotatate.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The T/N activity ratios of the second, third, and final treatment cycle will be assessed as secondary endpoint. Intra and inter patient differences will be studied.
    Safety, toxicity and sufficient uptake will be assessed after the first treatment cycle.
    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 No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    A within-subject controlled design is used
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Standard treatment (iv route)
    E.8.2.4Number of treatment arms in the trial1
    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 concerned3
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee 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 patient’s last visit.
    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
    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: 16
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state26
    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)
    Positive results of this trial may efficiently lead to a multicenter, international, randomized phase III trial. This phase III trial has the potential to make important changes in the treatment of metastasized NETs.
    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 Decision2018-06-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-27
    P. End of Trial
    P.End of Trial StatusOngoing
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