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    The EU Clinical Trials Register currently displays   44043   clinical trials with a EudraCT protocol, of which   7319   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:2022-001624-14
    Sponsor's Protocol Code Number:LE3301
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2022-07-18
    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 ConcernedFrance - ANSM
    A.2EudraCT number2022-001624-14
    A.3Full title of the trial
    An Open-Label, Single Arm Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Leniolisib in Pediatric Patients (Aged 4 to 11 Years) With APDS (Activated Phosphoinositide 3-Kinase Delta Syndrome) Followed By an Open-Label Long-Term Extension
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Leniolisib in Pediatric Patients (Aged 4 to 11 Years) with APDS (Activated Phosphoinositide 3-Kinase Delta Syndrome)
    A.4.1Sponsor's protocol code numberLE3301
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05438407
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/556/2022
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPharming Technologies B.V.
    B.1.3.4CountryNetherlands
    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 supportPharming Technologies B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPharming Technologies B.V.
    B.5.2Functional name of contact pointClinical Department
    B.5.3 Address:
    B.5.3.1Street AddressDarwinweg 24
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 CR
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31 71 5247400
    B.5.6E-mailclinical@pharming.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/20/2339
    D.3 Description of the IMP
    D.3.1Product nameLeniolisib
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLeniolisib
    D.3.9.1CAS number 1354691-97-6
    D.3.9.3Other descriptive nameLeniolisib phosphate
    D.3.9.4EV Substance CodeSUB195650
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/20/2339
    D.3 Description of the IMP
    D.3.1Product nameLeniolisib
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLeniolisib
    D.3.9.1CAS number 1354691-97-6
    D.3.9.3Other descriptive nameLeniolisib phosphate
    D.3.9.4EV Substance CodeSUB195650
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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.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
    Activated Phosphoinositide 3-Kinase Delta Syndrome
    E.1.1.1Medical condition in easily understood language
    APDS (Activated Phosphoinositide 3-Kinase Delta Syndrome) is a rare disease caused by genetic variations in either the PIK3CD gene or the PIK3R1 gene
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10078281
    E.1.2Term Activated PI3 kinase delta syndrome
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part I:
    • To assess the clinical safety and tolerability of leniolisib in pediatric patients (aged 4 to 11 years) with APDS
    • To assess the efficacy of leniolisib in pediatric patients (aged 4 to 11 years) with APDS

    Part II:
    • To assess the long-term clinical safety and tolerability of leniolisib in pediatric patients (aged 4 to 11 years) with APDS
    E.2.2Secondary objectives of the trial
    Part I:
    • To assess the pharmacokinetics (PK) of leniolisib in pediatric patients (aged 4 to 11 years) with APDS
    • To evaluate control of infectious complications of the disease
    • To evaluate changes in mammalian target of rapamycin (mTOR) pathway pharmacodynamics (PDx) parameters

    Part II:
    • To assess impact on lymphadenopathy (non-index lesions and spleen)
    • To evaluate long-term control of infectious complications of the disease.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patient is male or female and between the age of 4 to 11 years old at time of the first study procedure. Females should be of nonchildbearing potential at screening.
    • Patient weighs ≥13 kg and <45 kg at baseline.
    • Patient has confirmed PI3Kδ genetic mutation of either the PIK3CD (APDS1) or PIK3R1 (APDS2) gene.
    • Patient has at least 1 measurable nodal lesion on magnetic resonance imaging (MRI)/low-dose computed tomography (CT).
    • Patient has nodal or extranodal lymphoproliferation and clinical findings consistent with APDS (eg, a history of repeated oto-sino-pulmonary infections and/or organ dysfunction consistent with APDS).
    • Patient has the ability to ingest unaltered study-related medications without difficulty.
    E.4Principal exclusion criteria
    • Patient has previous or concurrent use of immunosuppressive medication such as:
    a. An mTOR inhibitor (eg, sirolimus, rapamycin, everolimus) or a PI3Kδ inhibitor (selective or non-selective PI3K inhibitors) within 6 weeks prior to first dose.
    i. Short-term use for up to a total of 5 days is allowed but only up to 1 month prior to enrollment in the study.
    b. B cell depleters (eg, rituximab) within 6 months prior to first dose of study medication.
    i. If patient has received prior treatment with a B cell depleter, absolute B lymphocyte counts in the blood must have regained normal values.
    c. Belimumab or cyclophosphamide within 6 months prior to first dose of study medication.
    d. Cyclosporine A, mycophenolate, 6-mercaptopurine, azathioprine, or methotrexate within 3 months prior to first dose of study medication.
    e. Systemic glucocorticoids above a dose equivalent to either ≥2 mg/kg of body weight or ≥20 mg/day of prednisone/prednisolone or equivalent.
    f. Other immunosuppressive medication where effects are expected to persist at start of dosing of study medication.
    • Patient has a history or current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety for patients participating in the study such as:
    a. History of familial long QT syndrome or known family history of Torsades de Pointes.
    b. Concomitant clinically significant cardiac arrhythmias, eg, sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular block without a pacemaker.
    c. Resting QTc (Fridericia preferred, but Bazett acceptable) >460 msec if the measurement is confirmed with an additional ECG repeated as soon as possible.
    d. Concomitant use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of the study.
    • Patient is currently using a medication known to be strong inhibitor or moderate or strong inducer of isoenzyme CYP3A (see Table 2), if treatment cannot be discontinued or switched to a different medication prior to starting study treatment.
    • Patient is currently using medications that are metabolized by isoenzyme CYP1A2 and have a narrow therapeutic index (drugs whose exposure- response indicates that increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns [eg, Torsades de Pointes]).
    E.5 End points
    E.5.1Primary end point(s)
    Part I:
    • Incidence of treatment-emergent AEs (TEAEs), SAEs, and AEs leading to discontinuation of study drug
    • Change from baseline in clinical laboratory test results (hematology, blood chemistry, urinalysis)
    • Change from baseline in vital signs
    • Change from baseline in physical examination findings
    • Change from baseline in electrocardiograms (ECGs)
    • Change from baseline in growth and physical development
    • Reduction in lymphadenopathy as measured by MRI or low-dose CT at end of 12 weeks of treatment
    • Immunophenotype assessed by changes from baseline in the percentage of naïve B cells to total B cells to end of 12 weeks of treatment

    Part II:
    • All safety parameters (including TEAEs, SAEs, AEs leading to discontinuation of study drug, physical exam, vital signs, ECGs, growth and physical development, and clinical laboratory results)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part I:
    • Incidence of TEAEs, SAEs, AEs, safety laboratory tests and vital signs at all visits
    • Physical Examination of at Screening/Visit 1, Visit 2, Visit 6, Early Treatment D/C and EoS visit
    • Tanner Staging at Screening/Visit 1 and Visit 6
    • EGC at Visit 2, Visit 4, Visit 6 and EoS Visit
    • Height at Visit 2, Visit 6, Early Treatment D/C
    • MRI / CT-scan at screening, if not available within 6 months, at Visit 6 and/or Early Treatment D/C
    • Immunophenotyping at Visit 2, Visit 4, Visit 5 and Visit 6


    Part II:
    • Incidence of TEAEs, SAEs, AEs, safety laboratory tests and vital signs at all visits
    • Physical Examination at V10/EOT, Early Treatment D/C
    • Tanner Staging at V10/EOT Visit
    • EGC at V7, V8, V9, V10 and EoS visit
    • Height at V10, Early Treatment D/C
    E.5.2Secondary end point(s)
    Part I:
    • Population pharmacokinetics (popPK) model that describes the appropriate covariates (eg, body weight and age) that influence leniolisib PK in pediatric patients (from baseline to end of 12 weeks of treatment)
    • Frequency of infections, use of antibiotics, and immunoglobulin replacement therapy
    • pAKT and pS6 inhibition in whole blood

    Part II:
    • Reduction in lymphadenopathy as measured by MRI or low-dose CT at 1 year, as measured by 3D volume of index and measurable non-index lesions selected as per the Cheson methodology, 3D volume and 3D sizes of spleen and liver, where appropriate
    • Incidence of infections, use of antibiotics, and use of immunoglobulin replacement therapy
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part I:
    • PK samples at Visit 2, Visit 4 and Visit 6
    -up to 4 blood samples will be collected on any 1 day during the 12-week period, according to randomized assignment to 1 of 3 PK sampling groups
    • Frequency of infections, use of antibiotics, and immunoglobulin replacement therapy at all study visit
    • Soluble biomarkers at Screening/Visit 1 and Visit 6

    Part II:
    • Frequency of infections, use of antibiotics, and immunoglobulin replacement therapy at all study visit
    • MRI, CT-scan at Visit 8, Visit 10/EOT visit and Early Treatment D/C
    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 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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 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
    Japan
    United States
    France
    Netherlands
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days26
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days29
    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: 15
    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: 15
    F.1.1.6Adolescents (12-17 years) No
    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 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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 5
    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)
    After completion of the study, no further study treatment will be made available to pediatric patients, unless a prolongation of this study or a compassionate use is provided.
    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 Decision2022-09-20
    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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