| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Activated Phosphoinositide 3-Kinase Delta Syndrome |
|
| E.1.1.1 | Medical 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.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10078281 |
| E.1.2 | Term | Activated PI3 kinase delta syndrome |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part I:
• To assess the clinical safety and tolerability of leniolisib in pediatric patients (aged 4 to 11 years) with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (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.2.2 | Secondary 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 in pediatric patients (aged 4 to 11 years) with APDS
• To evaluate changes in mammalian target of rapamycin (mTOR) pathway pharmacodynamic (PDx) parameters
Part II:
• To assess impact on lymphoproliferation (index-, non-index lesions and spleen)
• To evaluate long-term control of infectious complications of the disease. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is male or female and between the age of 4 to 11 years old at the time of the first study procedure.
2. Patient weighs ≥13 kg and <45 kg at baseline.
3. Patient has a confirmed PI3Kδ genetic mutation of either the PIK3CD (APDS1) or PIK3R1 (APDS2) gene.
4. Patient has at least 1 measurable nodal lesion on magnetic resonance imaging/low-dose computed tomography within 6 months of screening.
5. 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).
6. Patient has the ability to ingest unaltered study-related medications without difficulty in the investigator's opinion.
7. At screening, vital signs (systolic blood pressure [BP], diastolic BP, and pulse rate) will be assessed in the sitting position after the patient has been at rest for at least 3 minutes. Patient’s sitting vital signs should be within the following ranges:
• Systolic BP: Less than the 95th percentile adjusted for sex, age, and height percentile.
• Diastolic BP: Less than the 95th percentile adjusted for sex, age, and height percentile.
• Heart rate (HR):
i) Age 4 to <10 years: 60 to 140 bpm
ii) Age ≥10 years: 50 to 100 bpm
8. Institutional review board-/independent ethics committee-approved written informed consent/assent and privacy language as per national and local regulations must be obtained from the patient and parent/legal guardian prior to any study-related procedures.
9. Patient parent/legal guardian is willing and able to complete the informed consent/assent process and comply with study procedures and visit schedule.
10. Patient parent/legal guardian agrees patient will not participate in any other interventional study while enrolled in this study.
11. Female patients should be of non-childbearing potential at screening (should not have reached menarche). Male patients with partners of childbearing potential should be willing to use a highly effective method of contraception for at least 30 days after the last study procedure if at risk of pregnancy.
12. Female patient and parent/legal guardian must agree to the following if menses develops after screening, up to 30 days after the last study procedure:
• True sexual abstinence defined as refraining from heterosexual activity during the entire period of the study through 6 months post-study or
• Using a highly effective method of contraception for at least 30 days after the last study procedure if at risk of pregnancy. |
|
| E.4 | Principal exclusion criteria |
1. 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.
b. B cell depleters (eg, rituximab) within 6 months prior to first dose of study medication.
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.
2. Patient has a history or current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety for patients participating in the study.
3. Patient is currently using a medication known to be a strong inhibitor or moderate or strong inducer of isoenzyme cytochrome P450 (CYP)3A, if treatment cannot be discontinued or switched to a different medication prior to starting study treatment.
4. Patient is currently using medications that are metabolized by isoenzyme CYP1A2 and have a narrow therapeutic index.
5.Patient is currently using medications known to be organic anion transporter protein (OATP)1B1, OATP1B3, and breast cancer resistance protein (BCRP) substrates
6. Patient had been administered live vaccines starting from 6 weeks before the anticipated first study drug administration, during the study, and up to 7 days after the last dose of leniolisib.
7. Patient has clinically significant abnormalities in hematology or clinical chemistry parameters as determined by the investigator or medical monitor.
8. Patient has liver disease or liver injury as indicated by clinically significant abnormal liver function tests (alanine aminotransferase and aspartate aminotransferase >2.5 times upper limit of normal), history of renal injury/renal disease (eg, renal trauma, glomerulonephritis, or one kidney only), or presence of impaired renal function as indicated by a serum creatinine level >1.5 mg/dL (133 μmol/L).
9. Patient has moderate or severe hepatic impairment (Child-Pugh Class B or C).
10. Patient is receiving concurrent treatment with another investigational therapy or use of another investigational therapy less than 4 weeks from the first study procedure.
11. Patient has active hepatitis B (eg, hepatitis B surface antigen reactive) or active hepatitis C (eg, hepatitis C virus RNA [qualitative] is detected) at screening.
12. Patient has human immunodeficiency virus (HIV) infection (HIV 1 or 2) at screening.
13. Patient has a positive coronavirus disease 19 result (polymerase chain reaction or antigen) within 1 week prior to first dose. The patient can be rescreened after a subsequent negative result.
14. Patient has a history of malignancy (except lymphoma) within 3 years before the first study procedure or has evidence of residual disease from a previously diagnosed malignancy.
15. Patient has a previous diagnosis of lymphoma that has been treated with chemotherapy, radiotherapy, or transplant within 1 year of the first study procedure or is anticipated to require lymphoma treatment within 6 months of the first study procedure.
16. Patient has a history of uncontrolled diabetes mellitus within 3 months of the first study procedure.
17. Patient has had major surgery requiring hospitalization or radiotherapy within 4 weeks prior to the first study procedure.
18. Patient has uncontrolled chronic or recurrent infectious disease (with the exception of those that are considered to be characteristic of APDS) or evidence of tuberculosis infection as defined by a positive Mantoux tuberculin skin test at screening. If presence of latent tuberculosis is established, then treatment according to local country guidelines must have been completed before patients can be considered for enrollment.
19. Patient has a known allergy or history of hypersensitivity to study defined medications or any ingredients of the medications.
20. Patient has a planned or expected major surgical procedure.
21. Patient or parent/legal guardian is unable or unwilling to comply with study procedures or is unable to travel for repeat visits.
22. Patient or parent/legal guardian is unwilling to keep study results/observations confidential or to refrain from posting confidential study results/observations on social media sites.
23. Patient or parent/legal guardian refuses to sign consent/assent form.
24. Patient has other underlying medical condition that, in the opinion of the investigator, would impair the ability of the patient to receive or tolerate the planned procedures or follow-up. |
|
| E.5 End points |
| E.5.1 | Primary 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 lymphoproliferation as measured by MRI or low-dose CT at end of 12 weeks of treatment
• Immunophenotype normalization assessed by changes from baseline in the proportion of naïve B cells among all 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 examination, vital signs, ECGs, growth and physical development, and clinical laboratory results)
|
|
| E.5.1.1 | Timepoint(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.5.2 | Secondary end point(s) |
Part I:
• 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 Ig replacement therapy
• Phosphorylated protein kinase B (pAKT) inhibition in whole blood
Part II:
• Reduction in lymphoproliferation as measured by MRI or low-dose CT at 1 year, as measured by SPD 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 Ig replacement therapy
|
|
| E.5.2.1 | Timepoint(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.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If 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.8.7 | Trial 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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