Study of Leniolisib in Pediatric Patients (Aged 4 to 11 Years) with APDS (Activated Phosphoinositide 3-Kinase Delta Syndrome)
- Conditions
- Activated Phosphoinositide 3-Kinase Delta Syndrome
- Interventions
- Registration Number
- 2024-515489-15-00
- Lead Sponsor
- Pharming Technologies B.V.
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- Ended
- Sex
- Not specified
- Target Recruitment
- 6
Patient is male or female and between the age of 4 to 11 years old at the time of the first study procedure.
Patient parent/legal guardian agrees patient will not participate in any other interventional study while enrolled in this study.
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.
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.
Patient weighs ≥13 kg and <45 kg at baseline.
Patient has a 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/low-dose computed tomography within 6 months of screening.
Patient has nodal or extranodal lymphoproliferation and clinical findings consistent with APDS (e.g, a history of repeated oto-sinopulmonary infections and/or organ dysfunction consistent with APDS).
Patient has the ability to ingest unaltered study-related medications without difficulty in the investigator's opinion.
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
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.
Patient parent/legal guardian is willing and able to complete the informed consent/assent process and comply with study procedures and visit schedule.
Patient has previous or concurrent use of immunosuppressive medication such as: a. An mTOR inhibitor (e.g, sirolimus, rapamycin, everolimus) or a PI3Kδ inhibitor (selective or non selective PI3K inhibitors) within 6 weeks prior to first dose. b. B cell depleters (e.g, 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.
Patient is receiving concurrent treatment with another investigational therapy or use of another investigational therapy less than 4 weeks from the first study procedure.
Patient has active hepatitis B (e.g, hepatitis B surface antigen reactive) or active hepatitis C (e.g, hepatitis C virus RNA [qualitative] is detected) at screening.
Patient has human immunodeficiency virus (HIV) infection (HIV 1 or 2) at screening.
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.
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.
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.
Patient has a history of uncontrolled diabetes mellitus within 3 months of the first study procedure.
Patient has had major surgery requiring hospitalization or radiotherapy within 4 weeks prior to the first study procedure.
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.
Patient has a known allergy or history of hypersensitivity to study defined medications or any ingredients of the medications.
Patient has a history or current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety for patients participating in the study.
Patient has a planned or expected major surgical procedure.
Patient or parent/legal guardian is unable or unwilling to comply with study procedures or is unable to travel for repeat visits.
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.
Patient or parent/legal guardian refuses to sign consent/assent form.
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.
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.
Patient is currently using medications that are metabolized by isoenzyme CYP1A2 and have a narrow therapeutic index.
Patient is currently using medications known to be organic anion transporter protein (OATP) 1B1, OATP1B3, and breast cancer resistance protein (BCRP) substrates.
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.
Patient has clinically significant abnormalities in hematology or clinical chemistry parameters as determined by the investigator or medical monitor.
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 (e.g, 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).
Patient has moderate or severe hepatic impairment (Child-Pugh Class B or C).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Leniolisib Leniolisib Leniolisib - Film Coated Tablets Leniolisib tablets in 10 and 30 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 Part I: • Incidence of treatment-emergent AEs (TEAEs), SAEs, and AEs leading to discontinuation of study drug Part I: • Incidence of treatment-emergent AEs (TEAEs), SAEs, and AEs leading to discontinuation of study drug
Part I: • Change from baseline in clinical laboratory test results (hematology, blood chemistry, urinalysis) Part I: • Change from baseline in clinical laboratory test results (hematology, blood chemistry, urinalysis)
Part I: • Change from baseline in vital signs Part I: • Change from baseline in vital signs
Part I: • Change from baseline in physical examination findings Part I: • Change from baseline in physical examination findings
Part I: • Change from baseline in electrocardiograms (ECGs) Part I: • Change from baseline in electrocardiograms (ECGs)
Part I: • Change from baseline in growth and physical development Part I: • Change from baseline in growth and physical development
Part I: • Reduction in lymphoproliferation as measured by MRI or low-dose CT at end of 12 weeks of treatment Part I: • Reduction in lymphoproliferation as measured by MRI or low-dose CT at end of 12 weeks of treatment
Part I: • 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 I: • 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) 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)
- Secondary Outcome Measures
Name Time Method 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) 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)
Part I: • Frequency of infections, use of antibiotics, and Ig replacement therapy Part I: • Frequency of infections, use of antibiotics, and Ig replacement therapy
Part I: • Phosphorylated protein kinase B (pAKT) inhibition in whole blood Part I: • 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 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
Part II: • Incidence of infections, use of antibiotics, and use of Ig replacement therapy Part II: • Incidence of infections, use of antibiotics, and use of Ig replacement therapy
Trial Locations
- Locations (1)
Hopital Necker Enfants Malades
🇫🇷Paris, France
Hopital Necker Enfants Malades🇫🇷Paris, FranceBenedicte NevenSite contact+336508393573benedicte.neven@aphp.fr