A trial to test the effect of leniolisib in children from 1 to 6 years of age with APDS

Phase 3

Active, not recruiting

• Conditions: Activated Phosphoinositide 3-Kinase Delta Syndrome
• Interventions: Drug: Leniolisib

• Registration Number: 2022-502180-38-00
• Lead Sponsor: Pharming Technologies B.V.

Brief Summary

Part I

• to assess the clinical safety and tolerability of leniolisib in pediatric patients (aged 1 to 6 years) with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS)

• to assess the efficacy of leniolisib in pediatric patients (aged 1 to 6 years) with APDS

Part II

• to assess the long-term clinical safety and tolerability of leniolisib in pediatric patients (aged 1 to 6 years) with APDS.

Detailed Description

Part I will consist of a 12-week period to assess the safety and efficacy of treatment with leniolisib. Part II will consist of a 1-year, long-term, safety follow-up extension with a possible interim analysis.

The leniolisib doses to be used in study were selected based on safety, tolerability, PK, and PDx data from the adult Phase 2/3 study, as well as PK modeling data. In both parts of the study, leniolisib will be administered orally based on weight.

Study Timeline

• Study First Posted: 2024-08-06
• Last Update Posted: 2025-03-04

Recruitment & Eligibility

• Status: Ongoing, recruitment ended
• Sex: Not specified
• Target Recruitment: 4

Inclusion Criteria

1. Patient is male or female and between the age of 1 to 6 years old at time of the first study procedure.

2. Patient parent or legal guardian agrees patient will not participate in any other interventional study while enrolled in this study.

3. Patient weighs ≥8 and ≤37 kg at baseline.

4. Patient has a confirmed PI3Kδ genetic mutation of either the PIK3CD (APDS1) or PIK3R1 (APDS2) gene.

5. Patient has at least 1 measurable nodal lesion on magnetic resonance imaging or low-dose computed tomography within 6 months of screening.

6. 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).

7. Patient has the ability to ingest unaltered study-related medications without difficulty in the investigator's opinion.

8. At screening, vital signs (body temperature, systolic blood pressure [BP], diastolic BP, and pulse rate [PR]) will be assessed in the sitting position (infants may be assessed lying down) after the patient has been at rest for at least 3 minutes. Patient’s sitting vital signs should be within the following ranges: a. Systolic BP: Less than the 95th percentile adjusted for sex, age, and height percentile. b. Diastolic BP: Less than the 95th percentile adjusted for sex, age, and height percentile. c. Pulse rate: - Age <2 years: 100 to 190 beats per minute (bpm) - Age 2 to 6 years: 60 to 140 bpm

9. Institutional review board- or independent ethics committee (IEC)-approved written informed consent or assent and privacy language as per national and local regulations must be obtained from the patient and/or parent or legal guardian prior to any study-related procedures.

10. Patient parent or legal guardian is willing and able to complete the informed consent or assent process and comply with study procedures and visit schedule.

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. o 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. o 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. Glucocorticoids above a dose equivalent to either ≥2 mg/kg of body weight for body weights less than 10 kg or ≥20 mg/day for body weights ≥ 10 kg of prednisone or prednisolone or equivalent within 2 weeks prior to first dose of study medication. f. Other immunosuppressive medication where effects are expected to persist at start of dosing of study medication.

2. 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 or a positive QuantiFERON-TB Gold 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.

3. Patient is receiving concurrent treatment with another investigational therapy or use of another investigational therapy less than 4 weeks from the first study procedure.

4. 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.

5. Patient is currently using a medication known to be 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.

6. Patient is currently using medications that are metabolized by isoenzyme CYP1A2 and have a narrow therapeutic index (NTI) (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]).

7. Patient is currently using medications known to be organic anion transporter protein (OATP)1B1, OATP1B3, and breast cancer resistance protein (BCRP) substrates.

8. Patient had been administered live vaccines (this includes any attenuated 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.

9. Patient has clinically significant abnormalities in hematology or clinical chemistry (blood chemistry or urinalysis) parameters as determined by the investigator or medical monitor.

10. Patient has liver disease or liver injury as indicated by clinically significant abnormal liver function tests (LFTs) (alanine aminotransferase and aspartate aminotransferase >2.5 times upper limit of normal), history of renal injury or 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).

11. Patient has a known allergy or history of hypersensitivity to study defined medications or any ingredients of the medications, including the following common excipients: • Lactose monohydrate • Microcrystalline cellulose • Sodium starch glycolate (Type A) • Hypromellose • Magnesium stearate • Colloidal silicon dioxide • Opadry yellow.

12. Patient has moderate or severe hepatic impairment (Child-Pugh Class B or C).

13. Patient has a planned or expected major surgical procedure.

14. Patient or parent or legal guardian is unable or unwilling to comply with study procedures or is unable to travel for repeat visits.

15. Patient or parent or legal guardian is unwilling to keep study results or observations confidential or to refrain from posting confidential study results or observations on social media sites.

16. Patient or parent or legal guardian refuses to sign consent or assent form.

17. 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.

18. 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.

19. Patient has human immunodeficiency virus (HIV) infection (HIV 1 or 2) at screening.

20. Patient has a positive coronavirus disease 2019 result (polymerase chain reaction or antigen) within 1 week prior to first dose. The patient can be rescreened after a subsequent negative result.

21. 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.

22. 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.

23. Patient has a history of uncontrolled diabetes mellitus within 3 months of the first study procedure.

24. Patient has had major surgery requiring hospitalization or radiotherapy within 4 weeks prior to the first study procedure.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Leniolisib	Leniolisib	Leniolisib film-coated granules in 10, 15 and 20 mg strengths administered orally BID by body weight for 12 weeks for Part I and for 1 year for Part II.

Primary Outcome Measures

Name	Time	Method
Incidence of treatment-emergent AEs (TEAEs), SAEs, and AEs leading to discontinuation of study drug		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 clinical laboratory test results (hematology, blood chemistry, urinalysis)
Change from baseline in vital signs		Change from baseline in vital signs
Change from baseline in physical examination findings		Change from baseline in physical examination findings
Change from baseline in electrocardiograms (ECGs)		Change from baseline in electrocardiograms (ECGs)
Сhange from baseline in growth and physical development		Сhange 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		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.		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.
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).		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).

Secondary Outcome Measures

Name	Time	Method
Population pharmacokinetics (popPK) model that describes the appropriate covariates (eg, body weight and age) that influence leniolisib plasma PK in pediatric patients (from baseline to end of 12 weeks of treatment)		Population pharmacokinetics (popPK) model that describes the appropriate covariates (eg, body weight and age) that influence leniolisib plasma PK in pediatric patients (from baseline to end of 12 weeks of treatment)
PK parameters, as appropriate, including but not limited to: - maximum observed plasma concentration (Cmax) - minimum observed plasma concentration (Cmin) - time to reach Cmax (Tmax) - area under the plasma concentration-time curve from time 0 over the dosing interval (AUC0-τ) - terminal elimination half-life (t1/2) - apparent oral clearance at steady-state concentration (CLss/F) - apparent oral volume of distribution at steady state concentration (Vss/F)		PK parameters, as appropriate, including but not limited to: - maximum observed plasma concentration (Cmax) - minimum observed plasma concentration (Cmin) - time to reach Cmax (Tmax) - area under the plasma concentration-time curve from time 0 over the dosing interval (AUC0-τ) - terminal elimination half-life (t1/2) - apparent oral clearance at steady-state concentration (CLss/F) - apparent oral volume of distribution at steady state concentration (Vss/F)
Frequency of infections, use of antibiotics, and Ig replacement therapy		Frequency of infections, use of antibiotics, and Ig replacement therapy
Phosphorylated protein kinase B (pAKT) inhibition in whole blood.		Phosphorylated protein kinase B (pAKT) inhibition in whole blood.
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		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		Incidence of infections, use of antibiotics, and use of Ig replacement therapy

Trial Locations

Locations (2)

University Hospital Virgen Del Rocio S.L.; 🇪🇸 Sevilla, Spain

Unidade Local De Saude De Coimbra E.P.E.; 🇵🇹 Coimbra, Portugal

University Hospital Virgen Del Rocio S.L.

🇪🇸Sevilla, Spain

Olaf Neth

Site contact

0034955012940

oneth-ibis@us.es