LENIOLISIB PHOSPHATE for Activated Phosphoinositide 3-Kinase Delta Syndrome

Inclusion criteria

• {"criterion_text":"- 1. Patient is male or female and between the age of 1 to 6 years old at time of the first study procedure."}
• {"criterion_text":"- 10.\tPatient parent or legal guardian agrees patient will not participate in any other interventional study while enrolled in this study."}
• {"criterion_text":"- 2.\tPatient weighs ≥8 and ≤37 kg at baseline."}
• {"criterion_text":"- 3.\tPatient has a confirmed PI3Kδ genetic mutation of either the PIK3CD (APDS1) or PIK3R1 (APDS2) gene."}
• {"criterion_text":"- 4.\tPatient has at least 1 measurable nodal lesion on magnetic resonance imaging or low-dose computed tomography within 6 months of screening."}
• {"criterion_text":"- 5.\tPatient 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)."}
• {"criterion_text":"- 6.\tPatient has the ability to ingest unaltered study-related medications without difficulty in the investigator's opinion."}
• {"criterion_text":"- 7.\tAt 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.\tSystolic BP: Less than the 95th percentile adjusted for sex, age, and height percentile. b.\tDiastolic BP: Less than the 95th percentile adjusted for sex, age, and height percentile. c.\tPulse rate: -\tAge <2 years: 100 to 190 beats per minute (bpm) -\tAge 2 to 6 years: 60 to 140 bpm"}
• {"criterion_text":"- 8.\tInstitutional 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."}
• {"criterion_text":"- 9.\tPatient 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

• {"criterion_text":"- 1.\tPatient has previous or concurrent use of immunosuppressive medication such as: a.\tan mTOR inhibitor (eg, sirolimus, rapamycin, everolimus) or a PI3Kδ inhibitor (selective or non-selective PI3K inhibitors) within 6 weeks prior to first dose. o\tShort-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.\tB cell depleters (eg, rituximab) within 6 months prior to first dose of study medication. o\tIf patient has received prior treatment with a B cell depleter, absolute B lymphocyte counts in the blood must have regained normal values. c.\tBelimumab or cyclophosphamide within 6 months prior to first dose of study medication. d.\tCyclosporine A, mycophenolate, 6-mercaptopurine, azathioprine, or methotrexate within 3 months prior to first dose of study medication. e.\tGlucocorticoids 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.\tOther immunosuppressive medication where effects are expected to persist at start of dosing of study medication."}
• {"criterion_text":"- 18.\tPatient 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."}
• {"criterion_text":"- 10.\tPatient is receiving concurrent treatment with another investigational therapy or use of another investigational therapy less than 4 weeks from the first study procedure."}
• {"criterion_text":"- 2.\tPatient has a history or current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety for patients participating in the study such as: a.\tHistory of familial long QT syndrome or known family history of Torsades of Pointes. b.\tConcomitant clinically significant cardiac arrhythmias, eg, sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular block without a pacemaker. c.\tResting QTc (Fridericia preferred, but Bazett acceptable) >460 msec if the measurement is confirmed with an additional ECG repeated as soon as possible. d.\tConcomitant use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of the study."}
• {"criterion_text":"- 3.\tPatient 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."}
• {"criterion_text":"- 4.\tPatient 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])."}
• {"criterion_text":"- 5.\tPatient is currently using medications known to be organic anion transporter protein (OATP)1B1, OATP1B3, and breast cancer resistance protein (BCRP) substrates."}
• {"criterion_text":"- 6.\tPatient 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."}
• {"criterion_text":"- 7.\tPatient has clinically significant abnormalities in hematology or clinical chemistry (blood chemistry or urinalysis) parameters as determined by the investigator or medical monitor."}
• {"criterion_text":"- 8.\tPatient 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)."}
• {"criterion_text":"- 19.\tPatient has a known allergy or history of hypersensitivity to study defined medications or any ingredients of the medications, including the following common excipients: •\tLactose monohydrate •\tMicrocrystalline cellulose •\tSodium starch glycolate (Type A) •\tHypromellose •\tMagnesium stearate •\tColloidal silicon dioxide •\tOpadry yellow."}
• {"criterion_text":"- 9.\tPatient has moderate or severe hepatic impairment (Child-Pugh Class B or C)."}
• {"criterion_text":"- 20.\tPatient has a planned or expected major surgical procedure."}
• {"criterion_text":"- 21.\tPatient or parent or legal guardian is unable or unwilling to comply with study procedures or is unable to travel for repeat visits."}
• {"criterion_text":"- 22.\tPatient 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."}
• {"criterion_text":"- 23.\tPatient or parent or legal guardian refuses to sign consent or assent form."}
• {"criterion_text":"- 24.\tPatient 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."}
• {"criterion_text":"- 11.\tPatient has active hepatitis B (eg, hepatitis B surface antigen reactive) or active hepatitis C (eg, hepatitis C virus RNA [qualitative] is detected) at screening."}
• {"criterion_text":"- 12.\tPatient has human immunodeficiency virus (HIV) infection (HIV 1 or 2) at screening."}
• {"criterion_text":"- 13.\tPatient 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."}
• {"criterion_text":"- 14.\tPatient 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."}
• {"criterion_text":"- 15.\tPatient 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."}
• {"criterion_text":"- 16.\tPatient has a history of uncontrolled diabetes mellitus within 3 months of the first study procedure."}
• {"criterion_text":"- 17.\tPatient has had major surgery requiring hospitalization or radiotherapy within 4 weeks prior to the first study procedure."}

Primary endpoints

• {"endpoint_text":"- Incidence of treatment-emergent AEs (TEAEs), SAEs, and AEs leading to discontinuation of study drug","definition_or_measurement_approach":"Incidence collected and reported during the study treatment period as safety outcome (TEAEs, SAEs, and AEs leading to discontinuation)."}
• {"endpoint_text":"- Change from baseline in clinical laboratory test results (hematology, blood chemistry, urinalysis)","definition_or_measurement_approach":"Change from baseline measured using clinical laboratory tests (hematology, blood chemistry, urinalysis) compared to baseline values."}
• {"endpoint_text":"- Change from baseline in vital signs","definition_or_measurement_approach":"Change from baseline in vital signs assessed at scheduled visits (sitting vital signs; infants may be assessed lying down) compared to baseline."}
• {"endpoint_text":"- Change from baseline in physical examination findings","definition_or_measurement_approach":"Change from baseline in findings on physical examination recorded at scheduled visits compared to baseline."}
• {"endpoint_text":"- Change from baseline in electrocardiograms (ECGs)","definition_or_measurement_approach":"Change from baseline in ECG parameters (e.g., QTc) assessed at scheduled ECG assessments compared to baseline."}
• {"endpoint_text":"- Сhange from baseline in growth and physical development","definition_or_measurement_approach":"Change from baseline in growth and physical development parameters (measured at baseline and follow-up visits)."}
• {"endpoint_text":"- Reduction in lymphoproliferation as measured by MRI or low-dose CT at end of 12 weeks of treatment","definition_or_measurement_approach":"Reduction assessed by MRI or low-dose CT at end of 12 weeks of treatment (imaging assessment of nodal/extranodal lymphoproliferation)."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Immunophenotype measured by flow cytometry; endpoint is change from baseline in proportion of naïve B cells among all B cells at 12 weeks."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Composite of all collected safety parameters listed, assessed throughout treatment and follow-up."}

Secondary endpoints

• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Development of a popPK model using plasma concentration data from baseline to end of 12 weeks to identify covariates (eg, body weight, age) influencing leniolisib PK."}
• {"endpoint_text":"- PK parameters, as appropriate, including but not limited to: -\tmaximum observed plasma concentration (Cmax) -\tminimum observed plasma concentration (Cmin) -\ttime to reach Cmax (Tmax) -\tarea under the plasma concentration-time curve from time 0 over the dosing interval (AUC0-τ) -\tterminal elimination half-life (t1/2) -\tapparent oral clearance at steady-state concentration (CLss/F) -\tapparent oral volume of distribution at steady state concentration (Vss/F)","definition_or_measurement_approach":"Standard PK parameters to be derived from plasma concentration-time data over dosing interval (Cmax, Cmin, Tmax, AUC0-τ, t1/2, CLss/F, Vss/F)."}
• {"endpoint_text":"- Frequency of infections, use of antibiotics, and Ig replacement therapy","definition_or_measurement_approach":"Frequency counts of infections and recorded use of antibiotics and immunoglobulin replacement therapy during study period."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Imaging-based assessment at 1 year using SPD per Cheson methodology and 3D volumetric measures of spleen and liver where appropriate."}
• {"endpoint_text":"- Incidence of infections, use of antibiotics, and use of Ig replacement therapy","definition_or_measurement_approach":"Incidence counts of infections and recorded use of antibiotics and Ig replacement therapy over the observation period."}

Spain

Earliest CTIS Part Ii Submission Date

06-06-2024

Latest Decision Or Authorization Date

27-04-2026

Processing Time Days

690

Number Of Sites

1

Number Of Participants

2

Portugal

Earliest CTIS Part Ii Submission Date

14-06-2024

Latest Decision Or Authorization Date

21-04-2026

Processing Time Days

676

Number Of Sites

1

Number Of Participants

2

Primary sponsor

Full Name

Pharming Technologies B.V.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Netherlands

Contract research organisations

Name

Icon Clinical Research LLC

Responsibilities

Medical image analysis/reveiw (sponsorDuties code 15)

Name

Fortrea Inc.

Responsibilities

Multiple sponsorDuties (codes: 1,10,11,12,5)

Name

Almac Clinical Services Limited

Responsibilities

sponsorDuties code 14

Name

Sermes CRO

Responsibilities

Patient Reimbursement (sponsorDuties code 15)

Name

Blueclinical Investigacao E Desenvolvimento Em Saude Lda.

Responsibilities

sponsorDuties code 5

Third parties

• {"country":"France","full_name":"Eurofins Adme Bioanalyses","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Icon Clinical Research LLC","duties_or_roles":"sponsorDuties code: 15 (Medical image analysis/reveiw)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"sponsorDuties codes: 1,10,11,12,5","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"sponsorDuties code: 14","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"sponsorDuties code: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Aixial UK Limited","duties_or_roles":"sponsorDuties code: 6","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"sponsorDuties code: 15 (ECG procedures)","organisation_type":"Pharmaceutical company"}
• {"country":"Portugal","full_name":"Blueclinical Investigacao E Desenvolvimento Em Saude Lda.","duties_or_roles":"sponsorDuties code: 5","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Sermes CRO","duties_or_roles":"sponsorDuties code: 15 (Patient Reimbursement)","organisation_type":"Pharmaceutical company"}