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    The EU Clinical Trials Register currently displays   44020   clinical trials with a EudraCT protocol, of which   7318   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2015-005281-29
    Sponsor's Protocol Code Number:IVAC-ALL-1
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-01-15
    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 ConcernedGermany - PEI
    A.2EudraCT number2015-005281-29
    A.3Full title of the trial
    Prospective phase I/II study: Patient-individualized peptide vaccination based on whole exome sequencing with adjuvant GM-CSF in children with relapsed acute lymphoblastic leukemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Vaccination against childhood leukemia
    A.4.1Sponsor's protocol code numberIVAC-ALL-1
    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 Hospital Tuebingen
    B.1.3.4CountryGermany
    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 supportDKTK
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationChildren's University Hospital
    B.5.2Functional name of contact pointCenter for clinical studies
    B.5.3 Address:
    B.5.3.1Street AddressHoppe-Seyler-Str. 1
    B.5.3.2Town/ cityTuebingen
    B.5.3.3Post code72076
    B.5.3.4CountryGermany
    B.5.4Telephone number+4970712984711
    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 nameIndividualized peptides
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntradermal 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 Sargramostim
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi Aventis
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameSargramostim
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous 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 Yes
    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
    Relapsed acute lymphatic leukemia
    Rückfall einer akuten lymphatischen Leukämie
    E.1.1.1Medical condition in easily understood language
    Relapsed acute lymphatic leukemia
    Rückfall einer akuten lymphatischen Leukämie
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10000842
    E.1.2Term Acute lymphatic leukaemia
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10054444
    E.1.2Term Leukemia relapse
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective is to evaluate the safety, clinical toxicity and in vivo immunological effects of a patient-individualized peptide vaccination in pediatric patients with acute lymphoblastic leukemia who experienced ≥ 2nd relapse or ≥ 1st relapse after previous stem cell transplantation.
    Primary endpoint is "success of treatment" defined as a patient showing a vaccination-induced T-cell response without unacceptable toxicity and acute GvHD  Grade III or extensive chronic GvHD until day 120 (after 10 vaccinations).
    Therefore, a composite variable is used as primary endpoint: Treatment success is defined as a patient without
    1. unacceptable toxicities (grade 4 according to NCI-CTC)
    2. acute GvHD ≥ Grade III or extensive chronic GvHD
    and in whom
    3. a vaccine-specific response of CD4+ and/or CD8+ T cells could be induced
    The primary endpoint will be measured at day 120 after 10 vaccinations were administered.
    E.2.2Secondary objectives of the trial
    1. To evaluate CD8+ or CD4+ T-cell response over the vaccination period measured after completion of the study (16 vaccinations, week 36) and to analyze this with regard to the T-cell response at day 120.
    2. To evaluate changes in minimal residual disease during and after treatment (possible reduction of minimal residual disease (MRD) levels on day 36, 120 and 246 (after 6, 18 and 36 weeks and after 7, 10 and 16 vaccinations, respectively).
    3. To evaluate the relapse rate on days 99 and 246 (after 15 and 36 weeks).
    4. To evaluate the Event free survival (EFS) on days 99 and 246 (after 15 and 36 weeks).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • pediatric patients with ALL (T, B, pro-B, pre-B or c-ALL) ≥ CR3 or with ≥ 1st relapse after stem cell transplantation (SCT); hematological remission has to be reached (<5% blasts in bone marrow or detectable minimal residual disease (MRD) ≤5x10E-2) after salvage chemotherapy and/or subsequent SCT.
    • age 1-18 years.
    • Informed consent must be given by legal representatives
    E.4Principal exclusion criteria
    Subjects presenting with any of the following criteria will not be included in the trial:
    • Frank relapse (>5% leukemic blasts)
    • Ejection fraction <25%; on echocardiography
    • Creatinine-clearance <40ml/min;
    • Liver function abnormalities with bilirubin >4 mg/dL and elevation of transaminases higher than 400 U/L
    • Severe infection (HIV, Chronic active viral hepatitis)
    • Significant psychiatric disabilities, uncontrolled seizure disorders or severe peripheral neuropathy/ leukencephalopathy.
    • Acute GvHD grade III or IV or extensive chronic GvHD.
    • Signs of autoimmune disease (i.e. idiopathic thrombocytopenic purpura, autoimmune haemolytic anemia)
    • Need for immunosuppressive drugs
    • Concurrent severe or uncontrolled medical disease which by assessment of the treating physician could compromise participation in the study
    • Women during pregnancy and lactation.
    • History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
    • Participation in other clinical trials or observation period of competing trials.
    • No leukemic blasts available for DNA extraction and cryopreservation requirements.
    • Females of childbearing potential (FCBP1) that do not agree
     to utilize two reliable forms of contraception simultaneously or practice complete abstinence from heterosexual contact for at least 28 days before starting study drug, while participating in the study (including dose interruptions), and for at least 28 days after study treatment discontinuation and must agree to regular pregnancy testing during this timeframe
    • Males that do not agree
     to use a latex condom during any sexual contact with FCBP while participating in the study and for 28 days following discontinuation from this study, even if he has undergone a successful vasectomy
     to refrain from donating semen or sperm while on and for 28 days after discontinuation from this study treatment.
    • Subjects that do not agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
    • All subjects that do not agree not to share medication.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint is "success of treatment" defined as a patient without unacceptable toxicity and acute GvHD  grade III or extensive chronic GvHD and showing a vaccination-induced T-cell response.
    Thus, a composite variable is used as primary endpoint: Treatment success is defined as a patient without
    1. unacceptable toxicities (grade 4 according to NCI-CTC)
    2. acute GvHD ≥ grade III or extensive chronic GvHD
    and in whom
    3. a vaccine-specific response of CD4+ and/or CD8+ T cells as defined in 6.3.2 could be induced
    The primary endpoint will be analyzed after 8 and 13 patients have reached visit 11 and will be given in % treatment success.
    E.5.1.1Timepoint(s) of evaluation of this end point
    d 120
    E.5.2Secondary end point(s)
    To evaluate CD8+ or CD4+ T-cell response over the vaccination period measured after completion of the study (16 vaccinations, week 36) and to analyze this with regard to the T-cell response at day 120.
    The amount of CD8+ and CD4+ T-cell response at week 36 will be evaluated and compared to week 18 using a paired t-test. The amount at all time points documented will be displayed graphically.
    2. To evaluate changes in minimal residual disease during and after treatment (possible reduction of minimal residual disease (MRD) levels on day 36, 120 and 246 (after 6,18 and 36 weeks and after 7, 10 and 16 vaccinations, respectively). A reduction of 1 log will be considered clinically relevant and the endpoint is defined as reduction of 1 log yes / no.

    The percentage of successful reductions at several time points over the study (36d, 120d and 246d) will be displayed graphically.
    3. To evaluate the relapse rate on days120 and 246 (after 18 and 36 weeks).
    Relapse rate will be analyzed using Kaplan-Meier-Methods
    4. To evaluate the Event free survival (EFS) on days 120 and 246 (after 18 and 36 weeks).
    Event free survival will be analyzed using Kaplan-Meier-Methods
    The analysis results of all secondary endpoints are regarded as being descriptive.
    E.5.2.1Timepoint(s) of evaluation of this end point
    d 36, 120 and 246
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    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 concerned6
    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 Study: after enrollment of 30 patients.
    The trial may be prematurely terminated, if in the opinion of the sponsor and coordinating investigator there is sufficient reasonable cause. Written notification documenting the reason for study termination will be provided to the investigators.
    Serious adverse drug reactions / not justifiable toxicity
    Substantial changes in risk-benefit considerations
    New insights from other trials
    Insufficient efficacy
    • Insufficient recruitment rate
    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 Yes
    F.1.1Number of subjects for this age range: 13
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 7
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 6
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state13
    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)
    Patients will be carefully monitored according to the centers policy. In general, 1-2 visits per year will be carried out until 10 years after allogeneic stem cell transplantation. Clinical status and remission status will be assessed.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-06-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-01
    P. End of Trial
    P.End of Trial StatusOngoing
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