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    Summary
    EudraCT Number:2014-000614-64
    Sponsor's Protocol Code Number:VIRUSNET201401
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2015-09-27
    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 ConcernedSweden - MPA
    A.2EudraCT number2014-000614-64
    A.3Full title of the trial
    Study of recombinant adenovirus in patients with neuroendocrine neoplasms; safety and efficacy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of neuroendocrine neoplasms with genetically modified adenovirus
    Behandling av neuroendokrina neoplasmer med genmodifierade adenovirus
    A.3.2Name or abbreviated title of the trial where available
    RADNET
    A.4.1Sponsor's protocol code numberVIRUSNET201401
    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 SponsorDepartment of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory, Uppsala University
    B.1.3.4CountrySweden
    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 supportOncolytic virus fund, Uppsala University
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUppsala University
    B.5.2Functional name of contact pointDept of IGP, Rudbeck laboratory
    B.5.3 Address:
    B.5.3.1Street AddressDag Hammarskjölds väg 20
    B.5.3.2Town/ cityUppsala
    B.5.3.3Post code751 85
    B.5.3.4CountrySweden
    B.5.4Telephone number+46(0)70344 9579
    B.5.6E-mailmagnus.essand@igp.uu.se
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAd5PTD(CgA-E1AmiR122)
    D.3.2Product code AdVince
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntrahepatic use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAd5PTD(CgA-E1AmiR122)
    D.3.9.3Other descriptive nameAdVince
    D.3.9.4EV Substance CodeSUB169656
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms million organisms
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10 000 to 1 000 000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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
    Neuroendocrine neoplasms (NENs) is a heterogeneous group with varying symptoms, tumor biology and treatment response. NENs may occur in any organ, most commonly they are observed in the gastroenteropancreatic system and lungs. Most NEN patients are diagnosed at advanced stage, 65% of them will die within 5 years. The only curative treatment is surgery with complete resection of the primary tumor. However, more than 50% of patients exhibit metastatic disease, where there is no cure.
    E.1.1.1Medical condition in easily understood language
    Neuroendocrine neoplasms (NENS) are often observed in the gatroenteropancreatic tissue. The only curative treatment is surgery. However, > 50% of patients exhibit metastases, where there is no cure.
    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 10071542
    E.1.2Term Neuroendocrine carcinoma metastatic
    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
    The primary objective of this study is to evaluate the safety of repeated infusions of AdVince into the hepatic artery in patients with metastatic NENs and if possible determination of maximum tolerated dose (MTD).
    E.2.2Secondary objectives of the trial
    Secondary objectives include the following:
    (a) to evaluate the anti-tumoral efficacy of AdVince infusions on metastatic neuroendocrine tumors
    (b) to determine the replication profile of AdVince
    (c) to determine the humoral and cytokine-mediated immune responses to AdVince
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject's written informed consent
    2. Histologically confirmed NEN of gastrointestinal, pancreatic or bronchial origin
    3. Disease progression verified over the last 6 months on CT or MRI using criteria employed in standard practice at the local hospital
    4. Disease that is not considered resectable for potential cure or tumor reduction
    5. Standard anti-cancer therapy exhausted according to the European Society of Medical Oncology (ESMO) guidelines for GEP-NETs and according to the European Neuroendocrine Tumor Society (ENETS) guidelines for lung carcinoids
    6. Adequate liver perfusion ensured e.g. by patent portal vein, patent hepatic veins
    7. Liver dominant disease with involvement of < 60% of liver parenchyma
    8. Karnofsky performance status of ≥70%
    9. Life expectancy of ≥ 6 months
    10. ≥ 18 years of age
    11. Must use a reliable method of contraception if sexually active and of reproductive potential*
    12. Plasma creatinine < 105 µg/ml
    13. AST, ALT < 5.0-fold upper limit of normal
    14. Total bilirubin < 3.0-fold upper limit of normal
    15. PT/INR < 2.0 and PTT within normal limits
    16. Neutrophils > 1,500/µl, haemoglobin > 100 g/L, platelets > 100,000/µl
    17. Patients with functioning NEN should have cover by somatostatin analog
    E.4Principal exclusion criteria
    18. Known chronic liver dysfunction before the development of metastatic cancer (e.g., cirrhosis, chronic hepatitis)
    19. Active infection, including documented HIV and hepatitis C
    20. Any viral syndrome diagnosed within the previous 2 weeks
    21. Systemic anti-cancer therapy (except for somatostatin analogues) within the previous 4 weeks before the first treatment
    22. Radiotherapy to the target tumor site within the last 24 weeks from the baseline CT scan.
    23. Evidence of clinically significant immunosuppression such as primary immunodeficiency state such as Severe Combined Immunodeficiency Disease
    24. Requirement of treatment with corticosteroids (prednisone >10 mg/day or equivalent)
    25. Concomitant malignancy
    26. Pregnant or lactating females
    27. Prior participation in any research protocol that involved administration of adenovirus vectors
    28. Treatment with any other investigational therapy within the last 4 weeks, organ transplantation prior to treatment, severe cardiovascular, metabolic or pulmonary disease
    29. Continuing treatment with any other cancer therapy
    E.5 End points
    E.5.1Primary end point(s)
    (a) Number of Adverse Events (AE) according to CTCA v 4.03, probably or possibly reated to the study drug or local injuries caused by the administration procedure
    (b) Identify Dose Limiting Toxicity (DLT), if possible
    (c) Changes in laboratory parameters and vital signs over time vs baseline values
    E.5.1.1Timepoint(s) of evaluation of this end point
    AE reported from the first study-related procedure until 30 days following the last dose.
    DLT from first until last injection of Advince
    Laboratory efficacy parameters: at baseline (before first treatment), before and after each injection. Biological serum markers before and 24, 48 and 72 h after each treatment.
    Laboratory safety parameters:
    - at baseline visit before cycle 1
    - at treatment baseline: within 24 hrs before each treatment cycle 2-8
    - after each treatment cycle 1-8 (24 h, 48 h and 72 h),
    - at Evaluation 1 visit
    - at Evaluation 2 visit
    - at check-up visits (approximately 8 days after each treatment)
    - at follow-up visits
    Local injuries: Checked at each administration of Advince.
    E.5.2Secondary end point(s)
    (a) Tumor size and tumor metabolic activity by:
    - Computer tomography (CT) and/or positron emission tomography (PET) and/or magnetic resonance imaging (MRI) before first and after last treatment cycle
    - Hormone level screening (biological markers)
    - Progression-free survival (PFS) 24 weeks after 4th cycle.
    (b) Viral replication by adenovirus quantification of in patients’ blood on day 1, 8, 22 and 50; before and 24h after injection, as well as 72h after injection by QRT-PCR.
    (c) Humoral response by detection of anti-adenovirus neutralizing antibodies at baseline, day 8 and day 50. Cytokine-mediated immune response is determined by cytokine measurement in plasma at baseline, 24h and 72h (optional) following virus injections.
    E.5.2.1Timepoint(s) of evaluation of this end point
    -CR and/or PET and/or MRI before first cycle of treatment and after last cycle of treatment.
    -Hormone level screening at: Baseline (pretreatment). Day before treatment cycles 2-4, 5-8. 24h, 48h and 72h after each cycle. At evaluation 1 and 2. At check-ups day 30, day 58, approx. 8 days after cycles 5-8, follow-up 16 weeks after last treatment and every 12 weeks until progressive disease.
    -Progression-free survival 24 weeks after cycle 4.
    -Quantification of Adenovirus genome copies in blood at day 1, 8, 22 and 50, before and 24h, 72h after each injection.
    -Detection af anti-adenovirus antibodies at baseline, on day 8 and day 50. Cytokine measurement at baseline and 24h, 72h following injection of virus for cycles 1-4.
    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 Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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 follow-up visit of the last patient.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    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: 17
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 15
    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)
    There will not be any post trial treatment. However, there will be a possibility to receive another four cycles of treatment(cycle 5-8) within the study. Each patient case will be discussed separately and continuation of treatment within the study may be achievable if efficacy of the IP has been observed measured as stable disease or partial responses according to RECIST 1.1 criteria.
    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 Decision2015-12-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-15
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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