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    Summary
    EudraCT Number:2020-000670-22
    Sponsor's Protocol Code Number:301
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2020-09-16
    Trial results View 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 ConcernedUK - MHRA
    A.2EudraCT number2020-000670-22
    A.3Full title of the trial
    A Phase I/II Dose-escalation and Expansion Cohort Trial of Intracerebroventricular Radioimmunotherapy Using 177Lu-DTPA-omburtamab in Pediatric and Adolescent Patients with Recurrent or Refractory Medulloblastoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    177Lu-DTPA-Omburtamab Radioimmunotherapy for Recurrent or Refractory Medulloblastoma
    A.3.2Name or abbreviated title of the trial where available
    177Lu-DTPA-Omburtamab Radioimmunotherapy for Recurrent or Refractory Medulloblastoma
    A.4.1Sponsor's protocol code number301
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04167618
    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, Inc.
    B.1.3.4CountryUnited States
    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 organisationCovance CAPS Ltd.
    B.5.2Functional name of contact pointGRS associate
    B.5.3 Address:
    B.5.3.1Street AddressWestacott Way
    B.5.3.2Town/ cityMaidenhead
    B.5.3.3Post codeSL6 3QH
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 7917 263776
    B.5.5Fax number+353 1246 0699
    B.5.6E-mailSubmissions@covance.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 name177Lu-DTPA-omburtamab
    D.3.2Product code 177Lu-DTPA-murine 8H9
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntracerebroventricular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOmburtamab
    D.3.9.1CAS number 1895083-75-6
    D.3.9.2Current sponsor code177Lu-DTPA-omburtamab
    D.3.9.3Other descriptive nameLU-177-6A10FAB-CHX-A-DTPA
    D.3.9.4EV Substance CodeSUB190912
    D.3.10 Strength
    D.3.10.1Concentration unit mCi millicurie(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number5 to 85
    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 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
    Medulloblastoma
    E.1.1.1Medical condition in easily understood language
    Medulloblastoma: Child brain cancer
    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 10066594
    E.1.2Term Medulloblastoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10027107
    E.1.2Term Medulloblastoma
    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
    The primary objective of Part 1 (dose-escalation phase) of this trial is to explore the tolerability of up to 2 cycles of intracerebroventricular 177Lu-DTPA-omburtamab treatment in pediatric and adolescent patients with recurrent or refractory medulloblastoma. The MTD and/or the RP2D for Part 2 will be determined.
    The primary objective of Part 2 (cohort-expansion phase) of this trial is to establish a safety profile of repeated dosing of 177Lu-DTPA-omburtamab in pediatric and adolescent patients with recurrent or refractory medulloblastoma.
    E.2.2Secondary objectives of the trial
    The secondary objectives of Part 1 (dose-escalation phase) are:
    •to evaluate the absorbed radiation doses to CSF and blood of 177Lu-DTPA-omburtamab after intracerebroventricular administration
    •to evaluate organ dosimetry of 177Lu-DTPA-omburtamab
    •to evaluate the PK profile of 177Lu-DTPA-omburtamab
    •to evaluate the investigator-assessed response
    •to evaluate the investigator-assessed duration of response (DoR)
    •to evaluate progression-free survival (PFS).
    The secondary objectives of Part 2 (cohort-expansion phase) are:
    •to evaluate the PK profile of 177Lu-DTPA-omburtamab
    •to evaluate the investigator-assessed response
    •to evaluate the investigator-assessed DoR
    •to evaluate PFS
    •to evaluate overall survival OS.
    The exploratory objectives in Part 1 and Part 2 are:
    •to assess whether B7-H3 is expressed in biopsies from primary tumor and/or metastasis.
    •to evaluate circulating tumor deoxyribonucleic acid (ctDNA) in CSF
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must satisfy all of the following criteria at the Screening Visit, unless otherwise stated:
    1. Histologically confirmed diagnosis of medulloblastoma.
    2. Available molecular classification according to World Health Organisation 2016 classification (Louis et al. 2016), as follows:
    a. SHH, Group 3, or Group 4
    3. Recurrent or refractory to frontline therapy, defined as:
    a. For Part 1 only: Recurrent (maximum of 2 recurrences) or refractory to frontline therapy. Prior frontline or second-line therapy may involve surgery, craniospinal irradiation, stereotactic radiosurgery, and multi-agent chemotherapy regimens.
    b. For Part 2 only: Recurrent (maximum of 1 recurrence) or refractory to frontline therapy. Patients with recurrent disease must have received second-line chemotherapy for progressive disease. Prior frontline or second-line therapy may involve surgery, craniospinal irradiation, stereotactic radiosurgery, and multiagent chemotherapy regimens.
    4. Be in cytological or radiographic remission, have residual disease, multifocal recurrent disease, or pure leptomeningeal disease.
    5. Performance status score of 50 to 100, inclusive, on the Lansky [<16 years] or Karnofsky [≥16 years] scales.
    6. Aged 3 to 19 years, inclusive, at the time of the first planned dose of trial treatment.
    7. Life expectancy of at least 3 months, as judged by the investigator.
    8. Acceptable hematological status prior to first dosing (hematological support is allowed if administered at least 1 week before administration of 177Lu-DTPA-omburtamab), defined as:
    a. Hemoglobin ≥8 g/dL
    b. White blood cell count ≥1000/μL.
    c. Absolute neutrophil count ≥1000/μL
    d. Platelet count ≥75 000/μL.
    9. Acceptable liver function prior to first dosing, defined as:
    a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 × upper limit of normal (ULN)
    b. Bilirubin ≤1.5 × ULN.
    10. Acceptable kidney function prior to first dosing, defined as:
    a. Estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2, calculated by the 2009 revised Bedside Schwartz Equation.
    11. Written informed consent from legal guardian(s) and/or child obtained in accordance with local regulations. Pediatric patients must provide assent as required by local regulations.
    E.4Principal exclusion criteria
    1. Obstructive or symptomatic communicating hydrocephalus as determined by Ommaya patency/CSF flow assessment.
    2. Residual disease (nodular or linear) measuring >5 mm in the smallest diameter.
    3. Ventriculoperitoneal (VP) shunts without programmable valves. Ventriculo-atrial or ventriculo-pleural shunts.
    4. Grade 4 nervous system disorder. Hearing loss or stable neurological deficits due to brain tumor are allowed.
    5. Uncontrolled life-threatening infection.
    6. Received radiation therapy, systemic or intrathecal cytotoxic chemotherapy, or intrathecal immunotherapy (corticosteroids not included) less than 3 weeks prior to the Screening Visit.
    7. Received any prior anti-B7-H3 treatment.
    8. Non-hematologic organ toxicity Grade 3 or above; specifically, any renal, cardiac, hepatic, pulmonary, and gastrointestinal system toxicity.
    9. Females of childbearing potential who are pregnant, breast feeding, intend to become pregnant, or are not using highly effective contraceptive methods or males who are not using highly effective contraceptive methods.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of Part 1 is the frequency, type, and duration of treatment-emergent AEs (TEAEs) and serious AEs (SAEs) after up to two 5-week treatment cycles. The MTD and/or the RP2D will be determined.
    The primary endpoint of Part 2 is the frequency, type, and duration of TEAEs and SAEs after up to five 5-week treatment cycles.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1: 5 weeks.
    Part 2: Analysis with occur after database lock
    E.5.2Secondary end point(s)
    Part 1
    •Analysis of lutetium-177 activity in blood and CSF including derivation of best-fit uptake and/or clearance parameters (maximum count, elimination half-life) of time-activity curves and residence times (i.e., cumulated activity in µCi·h/g).
    •Whole-body, organ, blood, and CSF radiation dosimetry.
    •Assessment of the PK profile of 177Lu-DTPA-omburtamab in serum and CSF.
    •Response, as defined by the Response Assessment in Pediatric Neuro-oncology (RAPNO) criteria (as determined from magnetic resonance imaging [MRI] assessments, neurological examination, and CSF cytology).
    •Objective response rate (ORR), calculated as the proportion of all evaluable patients achieving a response (partial response [PR] or complete response [CR]) as the best overall response at the time of assessment.
    •Investigator-assessed DoR, defined as the time from response (CR or PR) to progression.
    •PFS, defined as the time from first treatment to date of leptomeningeal progression or death from any cause, whichever comes first.

    Part 2
    •Description of the PK profile of 177Lu-DTPA-omburtamab in blood and CSF.
    •Response, as defined by the RAPNO criteria (as determined from MRI assessments, neurological examination, and CSF cytology).
    •ORR, calculated as the proportion of all evaluable patients achieving a response (PR or CR) as best overall response at the time of assessment.
    •Investigator-assessed DoR, defined as the time from first response (CR or PR) to progression.
    •PFS, defined as the time from first treatment to date of leptomeningeal progression or death from any cause, whichever comes first.
    •OS defined as the time from first treatment to date of death

    The exploratory endpoints for Part 1 and Part 2 are:
    •Expression of B7-H3 by semi-quantitative immunohistochemistry in archival biopsies (if available) from primary tumor and/or metastasis.
    •Change from baseline to EOT in level and mutation rate of ctDNA in CSF.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Dosimetry, Dose-escalation and Expansion Cohort Trial
    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 Yes
    E.7.1.3.1Other trial type description
    Dose-escalation and Expansion Cohort Trial
    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 concerned2
    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 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
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    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: 14
    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: 6
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2
    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 3 and 19 years, and therefore, informed consent from legal guardian(s) and/or child must be obtained in accordance with local regulation. Pediatric patients 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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 14
    F.4.2.2In the whole clinical trial 49
    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 deemed safe and justified by the investigator 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 Decision2020-11-10
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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