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    Summary
    EudraCT Number:2017-001829-40
    Sponsor's Protocol Code Number:201
    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:2019-10-16
    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 number2017-001829-40
    A.3Full title of the trial
    A Pivotal Phase 2 Trial of Antibody Naxitamab (hu3F8) and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in High-Risk Neuroblastoma Patients with Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow
    Eine pivotale Phase-2-Studie mit dem Antikörper Naxitamab (hu3F8) und dem Granulozyten-Makrophagen-Koloniestimulierenden Faktor (GM-CSF) bei Hochrisiko-Neuroblastompatienten mit primärer refraktärer Erkrankung oder unvollständigem Ansprechen auf eine Salvage-Behandlung in Knochen und / oder Knochenmark
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study in which High-Risk Neuroblastoma Patients with Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow are treated with Antibody Naxitamab (hu3F8) (study drug) and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF). The tolerability and efficacy of the drug will be tested.
    Dies ist eine klinische Studie bei Hochrisiko-Neuroblastompatienten mit primärer refraktärer Erkrankung oder unvollständigem Ansprechen auf eine Salvage-Behandlung in Knochen und / oder Knochenmark. Die Patienten werden mit dem Antikörper Naxitamab (hu3F8) (Studienmedikament) und dem Granulozyten-Makrophagen-Koloniestimulierenden Faktor (GM-CSF) behandelt. Die Verträglichkeit und Wirksamkeit des Medikaments werden getestet.
    A.4.1Sponsor's protocol code number201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03363373
    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 SponsorY-mAbs Therapeutics A/S
    B.1.3.4CountryDenmark
    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 supportY-mAbs Therapeutics A/S
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKLIFO A/S
    B.5.2Functional name of contact pointVice President, Clinical
    B.5.3 Address:
    B.5.3.1Street AddressSmedeland 36
    B.5.3.2Town/ cityGlostrup
    B.5.3.3Post code2600
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4544222935
    B.5.6E-mailKlas.Raadberg@klifo.com
    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 namenaxitamab drug product
    D.3.2Product code Hu3F8
    D.3.4Pharmaceutical form Solution for 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 INNnaxitamab
    D.3.9.1CAS number 1879925-92-4
    D.3.9.2Current sponsor codeHu3F8 drug substance
    D.3.9.3Other descriptive nameHu3F8
    D.3.9.4EV Substance CodeSUB188982
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number3.6 to 4.4
    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.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 Leukine
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi-Aventis U.S. LLC
    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 nameLeukine
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSARGRAMOSTIM
    D.3.9.1CAS number 123774-72-1
    D.3.9.3Other descriptive nameGM-CSF
    D.3.9.4EV Substance CodeSUB10450MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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
    Treatment of high-risk neuroblastoma patients with primary refractory disease or incomplete response to salvage treatment in bone and/or bone marrow
    Behandlung von Hochrisiko-Neuroblastompatienten mit primärer refraktärer Erkrankung oder unvollständigem Ansprechen auf eine Salvage-Behandlung in Knochen und / oder Knochenmark.
    E.1.1.1Medical condition in easily understood language
    Treatment of high-risk neuroblastoma patients with primary refractory disease or incomplete response to salvage treatment in bone and/or bone marrow
    Behandlung von Hochrisiko-Neuroblastompatienten mit primärer refraktärer Erkrankung oder unvollständigem Ansprechen auf eine Salvage-Behandlung in Knochen und / oder Knochenmark.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10066595
    E.1.2Term Neuroblastoma recurrent
    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
    1. To evaluate the centrally assessed objective response rate (ORR) to naxitamab + GM-CSF
    E.2.2Secondary objectives of the trial
    1. To evaluate the safety of naxitamab + GM-CSF
    2. To evaluate Duration of Response (DoR) to naxitamab + GM-CSF
    3. To evaluate the complete response (CR) rate with naxitamab + GM-CSF
    4. To evaluate the investigator assessed objective response rate to
    naxitamab + GM-CSF
    5. To evaluate the pharmacokinetics (PK) of naxitamab
    6. To investigate the formation of Anti-Drug antibodies (ADAs)
    7. To evaluate the safety of naxitamab + GM-CSF in patients with
    positive ADA at trial entry
    Secondary objectives in long-term follow-up:
    8. To evaluate Progression-Free Survival (PFS) with naxitamab + GM-CSF
    9. To evaluate overall survival (OS) with naxitamab + GM-CSF
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Documented diagnosis of neuroblastoma (NB) as defined per INRC as
    a. histopathology of tumor biopsy, or
    b. Bone marrow (BM) aspirate or biopsy indicative of NB by histology, plus high blood or urine catecholamine metabolite levels or Myelocytomatosis Viral-Related Oncogene, Neuroblastoma derived (MYCN) amplification, or
    c. MIBG-avid lesion(s)
    2. High-risk NB patients with either primary refractory disease or incomplete response to salvage treatment (in both cases including SD, MR and PR) evaluable in bone and/or BM as defined in section 6.7. If disease is only present in bone the patient must have evaluable disease outside the radiation areas for being eligible in the trial, please see section 7.2.1. If disease is only present in the BM the involvement must be >5%.
    3. Life expectancy ≥6 months
    4. Age ≥12 months
    5. Acceptable hematological status, (hematological support is allowed if administered ≥1 week before first infusion of naxitamab), defined as:
    a. Hemoglobin ≥8 g/dL (5.0 mmol/L)
    b. White blood cell count ≥1000/μL
    c. Absolute neutrophil count (ANC) ≥500/μL
    d. Platelet count ≥25,000/μL
    6. Acceptable liver function defined as:
    a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 times upper limit of normal (ULN)
    b. Bilirubin ≤1.5 x ULN
    7. Acceptable kidney function defined as:
    a. Estimated Glomerular Filtration Rate (eGFR) >60 mL/min/1.73 m2
    calculated by the 2009 revised Bedside Schwartz Equation
    8. Written informed consent from legal guardian(s) and/or patient in accordance with local regulations. Children must provide assent as required by local regulations.
    E.4Principal exclusion criteria
    1. Any systemic anti-cancer therapy, including chemotherapy or immunotherapy, within 3 weeks of 1st dose of GM-CSF
    2. Evaluable NB outside bone and BM defined as follows:
    • MIBG-avid tumor: Definite MIBG uptake in tumor tissues outside bone and BM
    • MIBG nonavid tumor: Definite uptake in tumor tissues outside bone and BM on FDG-PET
    3. Actively Progressive Disease at trial entry according to Park criteria (Park et al. 2017) (see section 6.7)
    4. Existing major organ dysfunction CTCAE >Grade 2, with the exception of hearing loss, hematological status, kidney and liver function.
    5. Active life-threatening infection
    6. Prior treatment with naxitamab
    7. Karnofsky/Lansky score <50%
    8. Pregnancy or a woman who is breast-feeding (women of child-bearing potential must have a negative pregnancy test at screening). A woman of child-bearing potential is excluded if she does not agree to use highly effective contraception for a period of 40 days after the last naxitamab infusion section 9.2.5 in protocol. A sterilized or infertile woman is exempt from the requirement to use contraception after hu3F8 treatment: she must have undergone surgical sterilization (hysterectomy, or bilateral ovariectomy)
    9. Inability to comply with protocol requirements, including PK studies, as determined by the investigator
    10. History of allergy or known hypersensitivity to GM-CSF, yeast-derived products, or any component of GM-CSF or naxitamab
    11. History of anaphylactic reactions CTCAE grade 4 related to prior GD2 antibody therapy
    12. NB in central nervous system (CNS) within 6 months of 1st dose of GM-CSF
    13. Prior treatment with omburtamab (mu8H9) within 6 months of 1st dose of GM-CSF
    14. Patients who have had allogeneic hematopoietic stem cell transplantation (allo-SCT) or donor-lymphocyte-infusion (DLI). DLI or buffy coat infusion is defined as any kind of active allogenic lymphocyte suspension
    a. within 6 month of 1st dose of GM-CSF or
    b. with a lymphocyte count < 0.2 x109/L
    15. Patients who received Hematopoietic Progenitor Cell (HPC) boost or "top-up" of allogenic stem cells (lymphocyte-depleted) within 2 months of 1st dose GM-CSF.
    16. Any clinically meaningful abnormal finding in physical examination, vital signs, ECG, haematology, clinical chemistry, or urinalysis prior to inclusion into the trial, which in the opinion of the investigator, may put the subject at risk because of his/her participation in the study
    E.5 End points
    E.5.1Primary end point(s)
    1. Objective Response Rate (ORR), during the naxitamab Treatment period, centrally assessed according to the International Neuroblastoma Response Criteria (INRC)
    E.5.1.1Timepoint(s) of evaluation of this end point
    During and up to 101 weeks following the first naxitamab treatment
    E.5.2Secondary end point(s)
    1. Safety will be evaluated by the incidence of adverse events (AEs) and serious adverse events (SAEs) graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
    2. DoR, defined as the time from first objective response (CR or partial response (PR)) to PD; data will be censored at the date of last disease evaluation before new anti-NB treatment
    3. Complete response rate, during the naxitamab treatment period, centrally assessed according to the INRC
    4. ORR, during the naxitamab treatment period, investigator assessed according to the International Neuroblastoma Response Criteria (INRC)
    5. Assessment of the PK of naxitamab
    6. Assessment of ADA formation
    7. Intravenous (IV) opioid use during cycle 1 defined as total dosage of IV morphine (or equivalent opioid) administered 2 hours before infusion until 4 hours after end of infusion of naxitamab
    8. Intravenous (IV) opioid use for each cycle during the trial defined as total dosage of IV morphine (or equivalent opioid) administered 2 hours before infusion until 4 hours after end of infusion of naxitamab
    9. Number of hospitalization days related to naxitamab during cycle 1, defined as number of overnight stays. Hospitalizations required solely for protocol-specified assessments (e.g., PK sampling) or non-medical
    circumstances are excluded
    10. Number and percentage of infusion done in an outpatient settings
    11. In patients with positive ADA at trial inclusion, safety will be evaluated by the incidence of AEs and SAEs graded according to CTCAE, version 4.0

    Key secondary endpoints for long term follow-up:
    1. PFS, defined as the time from the 1st infusion of naxitamab until PD or death, whichever comes first; data will be censored at the date of last disease evaluation before new anti-NB treatment
    2. OS, defined as the time from the 1st infusion of naxitamab until death; data censored at last date known to be alive
    E.5.2.1Timepoint(s) of evaluation of this end point
    During and up to 101 weeks following the first naxitamab treatment
    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 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 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 EEA8
    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
    Canada
    Denmark
    Germany
    Hong Kong
    Spain
    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
    End of trial is defined as last patient last visit in the long-term follow-up period
    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 months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years10
    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: 95
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 7
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 82
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1
    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 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
    Patients could be between the ages of 1 year and 18 years and therefore informed consent from legal guardian(s) and/or child must be obtained in accordance with local regulations. Children must provide assent as required by local regulations
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 95
    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)
    Any treatment which is deemed safe and justified can be administered according to clinical practice and at the discretion of the investigator
    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 Decision2020-03-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-04
    P. End of Trial
    P.End of Trial StatusOngoing
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