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    The EU Clinical Trials Register currently displays   39361   clinical trials with a EudraCT protocol, of which   6446   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2014-004735-39
    Sponsor's Protocol Code Number:M14NEC
    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:2015-10-19
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2014-004735-39
    A.3Full title of the trial
    Phase II Study of cisplatin and everolimus in patients with metastatic or unresectable neuroendocrine carcinomas (NEC) of extrapulmonary origin
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase II Study of cisplatin and everolimus in patients with metastatic or unresectable neuroendocrine carcinomas (NEC) of extrapulmonary origin
    A.4.1Sponsor's protocol code numberM14NEC
    A.5.4Other Identifiers
    Name:ABR nummerNumber:NL50842.031.14
    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 SponsorNKI-AVL
    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 supportNovartis
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNKI-AVL
    B.5.2Functional name of contact pointprincipal investigator
    B.5.3 Address:
    B.5.3.1Street AddressPlesmanlaan 121
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1066CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031205122569
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name cisplatine
    D.2.1.1.2Name of the Marketing Authorisation holderpharmachemie BV
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 namecisplatine
    D.3.4Pharmaceutical form Concentrate and solvent for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 Yes
    D.2.1.1.1Trade name Afinitor
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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
    D.3.2Product code L01XE10
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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) Yes
    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
    Patients with metastatic neuroendocrine carcinomas of extrapulmonary origin will be eligible
    E.1.1.1Medical condition in easily understood language
    Patients with metastatic neuroendocrine carcinomas of extrapulmonary origin will be eligible
    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
    Primary endpoint of this study will be Disease Control Rate (DCR), defined as the sum of Overall Response Rate (ORR) consisting of Complete (CR), Partial Response Rate (PR) and stable disease (SD), all according to RECIST 1.1
    E.2.2Secondary objectives of the trial
    Secondary endpoints will be Time to relapse; Progression-free survival (PFS); Disease-free survival (DFS); Overall survival (OS); Effect on the markers chromogranin A (CgA) and neuron-specific enolase (NSE); Safety of everolimus in combination with cisplatin.

    Exploratory objectives will be the discovery of biomarkers for treatment response; identification of resistance mechanisms; elucidation of driver events in NEC pathogenesis; identification of potential new targets for treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Pathologically confirmed unresectable locally advanced NEC where no curative (chemoradiation) treatment options are available, and/or metastatic NECs of extrapulmonary origin as first line therapy NEC of extrapulmonary origin (WHO 2010 classification; Ki67 >20 %) including merkel cell carcinoma.
    2. Measurable disease according to RECIST 1.1, on CT-scan or MRI
    3. ECOG Performance status 0-2 (see Appendix 2)
    4. Adequate bone marrow function as shown by: ANC≥1.5 x 109/L, Platelets ≥100 x 109/L, Hb >6 mmol/L
    5. Adequate liver function as shown by:
    Total serum bilirubin ≤1.5 ULN
    ALT and AST ≤2.5x ULN (≤5x ULN in patients with liver metastases)
    6. Adequate renal function: calculated creatinin clearance > 60ml/min. (Cockcroft-Gault formula)
    7. Life expectancy of at least 3 months.
    8. Male or female age ≥ 18 years.
    9. Signed informed consent.
    10. Able to swallow and retain oral medication.
    11. Locally advanced or Metastatic lesion(s) of which a histological biopsy can safely be obtained:
    a. Patients with safely accessible locally advanced or metastatic lesion(s) including bone lesions.
    b. Patients not known with bleeding disorders (such as hemophilia) or bleeding complications from biopsies, dental procedures or surgeries.
    c. Patients not using any anti-coagulant medication at the time of biopsy: all aspirin derivatives, NSAID’s, coumarines, platelet function inhibitors,
    heparins (including LMWHs) and oral factor Xa inhibitors are not allowed, unless medication can either be safely stopped or counteracted.
    d. Adequate coagulation status as measured by:
    i. PT < 1.5 x ULN or PT-INR < 1.5
    ii. APTT < 1.5 x ULN
    iii. On the day of biopsy in patients using coumarines: PT-INR < 1.5
    e. Biopsies should be performed at least two weeks after last bevacizumab administration (only in patients previously treated with bevacizumab).
    f. Patients not known with contraindications for lidocaine (or its derivatives)

    E.4Principal exclusion criteria
    1. Previous chemotherapy for metastatic or unresectable NEC of extrapulmonary origin. (prior peri-operative chemotherapy or chemoradiation for curative intention is allowed if at least 6 months have elapsed between completion of this therapy and enrolment into the study).
    2. Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, deforolimus )
    3. Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal cell carcinoma.
    4. Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus) or cisplatin
    5. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
    6. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary
    7. Patients who have any severe and/or uncontrolled medical conditions such as: a. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to randomization, serious uncontrolled cardiac arrhythmia. b. active or uncontrolled severe infection, c. liver disease such as cirrhosis, decompensated liver disease, and known history chronic hepatitis d. known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air), e. active, bleeding diathesis;
    8. Chronic treatment with corticosteroids or other immunosuppressive agents
    9. Known history of HIV seropositivity
    10. Pregnant or nursing (lactating) women
    11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 8 weeks after stopping study treatment.
    12. Sexually active males, unless they use a condom during intercourse while taking study medication and for 8 weeks after stopping study medication.
    13. History of documented congestive heart failure; angina pectoris requiring medication; evidence of transmural myocardial infarction on ECG; poorly controlled hypertension (systolic BP >180 mmHg or diastolic BP >100 mmHg); clinically significant valvular heart disease; or high risk uncontrollable arrhythmias.
    14. Patients with dyspnoea at rest due to complications of advanced malignancy or other disease, or who require supportive oxygen therapy.
    15. History or clinical evidence of brain metastases.
    16. Any investigational drug treatment within 4 weeks of start of study treatment.
    17. Radiotherapy within 4 weeks of start of study treatment (2 week interval allowed if palliative radiotherapy given to bone metastastic site peripherally and patient recovered from any acute toxicity).
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint of this study will be Disease Control Rate (DCR), defined as the sum of Overall Response Rate (ORR) consisting of Complete (CR), Partial Response Rate (PR) and stable disease (SD), all according to RECIST 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    28 patients need to be enrolled in the 1st stage. Of those 28 patients, at least 8 responses are needed in order to proceed to the 2nd stage of the trial (with less than 8 responses, the trial will be closed). If stage 2 is implemented, an additional 11 patients need to be recruited (total of 39 patients)
    E.5.2Secondary end point(s)
    Secondary endpoints will be Time to relapse; Progression-free survival (PFS); Disease-free survival (DFS); Overall survival (OS); Effect on the markers chromogranin A (CgA) and neuron-specific enolase (NSE); Safety of everolimus in combination with cisplatin.
    E.5.2.1Timepoint(s) of evaluation of this end point
    28 patients need to be enrolled in the 1st stage. Of those 28 patients, at least 8 responses are needed in order to proceed to the 2nd stage of the trial (with less than 8 responses, the trial will be closed). If stage 2 is implemented, an additional 11 patients need to be recruited (total of 39 patients)
    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) 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.8.3 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
    end of the trail: study treatment is given up to 6 cycles (every 3 weeks) of cisplatin/ everolimus.
    Everolimus may be continued if it is beneficial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    if accompanied by legal representative authorised to sign the informed consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state39
    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)
    All patients will be given up to 6 cycles of chemotherapy, unless withdrawn earlier due to unacceptable toxicity or PD. After 6 cycles of cisplatin and everolimus have been completed, patients will continue with single-agent everolimus until disease progression or unacceptable toxicity. After disease progression, the patients can be treated according to local study protocols or at the discretion of the treating physician and will be monitored for survival.
    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 Decision2015-10-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-10
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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