An Open-label, Single Arm Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Leniolisib in Pediatric Patients (Aged 1 to 6 Years) with APDS (Activated Phosphoinositide 3-Kinase Delta Syndrome) Followed by an Open-label Long-term Extension
- Trial ID
- 2022-502180-38-00
- Protocol
- LE 3302
- Sponsor
- Pharming Technologies B.V.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **clinical safety** and tolerability of leniolisib in pediatric patients aged 1 to 6 years with Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS). This is crucial for determining the risk-benefit profile of leniolisib in this vulnerable population. Additionally, the study aims to evaluate the efficacy of leniolisib in these patients, which is essential for understanding its therapeutic potential in managing APDS. In Part II, the study will further assess the long-term clinical safety and tolerability of leniolisib, providing insights into its sustained use.
Secondary objectives include:
- Part I: Assessing the **pharmacokinetics** of leniolisib in pediatric patients with APDS.
- Part I: Evaluating the control of infectious complications associated with the disease.
- Part I: Evaluating changes in the mammalian target of rapamycin (mTOR) pathway pharmacodynamic parameters.
- Part II: Assessing the impact on lymphoproliferation, including index and non-index lesions and the spleen.
- Part II: Evaluating the long-term control of infectious complications of the disease.
Participants
The clinical trial involves a total of **11 participants** diagnosed with **Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS)**. The study population consists of both male and female pediatric patients aged between 1 to 6 years. Participants were selected based on specific criteria, including a confirmed PI3Kδ genetic mutation and the presence of nodal or extranodal lymphoproliferation with clinical findings consistent with APDS. The trial population is characterized by a vulnerable group due to their young age and specific health condition. Participants are required to have a body weight between 8 and 37 kg at baseline and must not be involved in any other interventional study during the trial. The study ensures that participants can ingest study-related medications without difficulty and have vital signs within specified ranges. The trial emphasizes the importance of obtaining informed consent from the patient's parent or legal guardian, ensuring compliance with study procedures and visit schedules.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, pharmacokinetics, pharmacodynamics, and efficacy of **leniolisib** in pediatric patients aged 1 to 6 years with **Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS)**. This open-label, single-arm study will be followed by a long-term extension phase. The trial is structured to include an initial treatment period of 12 weeks, with a maximum treatment duration of 64 weeks. The study will employ a comprehensive methodology to assess both short-term and long-term outcomes, focusing on clinical safety, tolerability, and efficacy. The trial will not be randomized or blinded, as it is an open-label study.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, weight, and genetic confirmation of the PI3Kδ mutation. The screening will also involve assessments of vital signs, laboratory tests, and imaging to establish baseline measurements. Following the screening, participants will attend regular follow-up visits throughout the treatment period to monitor safety and efficacy endpoints, including the incidence of treatment-emergent adverse events (TEAEs), changes in laboratory test results, and reductions in lymphoproliferation. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the overall impact of the treatment.
The expected length of participant involvement is up to 64 weeks, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent by the participant's parent or legal guardian. The trial aims to provide valuable insights into the management of APDS in young children, with a focus on improving clinical outcomes and quality of life for this patient population.
Treatment
The clinical trial involves the administration of **CDZ173/Leniolisib**, a pharmaceutical product formulated as film-coated granules in a single-dose container. The active substance in this medication is **leniolisib phosphate**, which is of chemical origin. The product is manufactured by Pharming Technologies BV and is designated as an orphan drug with the designation number EU/3/20/2339. The trial includes three different dosing regimens of CDZ173/Leniolisib, each tailored to assess the safety, pharmacokinetics, pharmacodynamics, and efficacy in pediatric patients aged 1 to 6 years with Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS).
The first dosing regimen involves a maximum daily dose of 80 mg, with a total maximum dose of 35,840 mg over a treatment period of 64 days. The administration route for this regimen is specified as "other use," indicating a non-standard method of delivery, potentially involving specialized administration techniques or devices.
The second dosing regimen provides a maximum daily dose of 60 mg, with a total maximum dose of 26,880 mg over the same 64-day treatment period. This regimen is administered orally, allowing for straightforward ingestion by the pediatric participants.
The third dosing regimen allows for a maximum daily dose of 100 mg, with a total maximum dose of 44,800 mg over 64 days. Similar to the second regimen, this is also administered orally, facilitating ease of use and compliance in the pediatric population.
Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the prescribed regimens. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, focusing solely on the evaluation of CDZ173/Leniolisib. The trial aims to provide comprehensive data on the safety and efficacy of leniolisib in the specified patient population, contributing to the understanding and management of APDS.
Efficacy
The efficacy of **leniolisib** in pediatric patients with Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) will be assessed through several primary and secondary endpoints. Primary efficacy endpoints include the reduction in lymphoproliferation as measured by magnetic resonance imaging (MRI) or low-dose computed tomography (CT) at the end of 12 weeks of treatment, and immunophenotype normalization assessed by changes from baseline in the proportion of naïve B cells among all B cells to the end of 12 weeks of treatment. Secondary endpoints involve the evaluation of a population pharmacokinetics (popPK) model that describes the appropriate covariates influencing leniolisib plasma pharmacokinetics in pediatric patients, as well as various pharmacokinetic parameters such as maximum observed plasma concentration (Cmax), minimum observed plasma concentration (Cmin), and area under the plasma concentration-time curve (AUC0-τ).
Additional secondary endpoints include the frequency of infections, use of antibiotics, and immunoglobulin replacement therapy, as well as the inhibition of phosphorylated protein kinase B (pAKT) in whole blood. Efficacy assessments will be conducted at specified timepoints, including the end of 12 weeks and at 1 year, using validated imaging techniques and laboratory tests. The study will also monitor the reduction in lymphoproliferation at 1 year, measured by the sum of the product of diameters (SPD) of index and measurable non-index lesions, and the 3D volume and sizes of the spleen and liver, where appropriate. These assessments will provide comprehensive data on the efficacy of leniolisib in managing APDS in the pediatric population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient is male or female and between the age of 1 to 6 years old at time of the first study procedure.
- Patient weighs ≥8 and ≤37 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 or low-dose computed tomography within 6 months of screening.
- 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 in the investigator's opinion.
- 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
- 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.
- 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.
- Patient parent or legal guardian agrees patient will not participate in any other interventional study while enrolled in this study.
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. 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.
- Patient has moderate or severe hepatic impairment (Child-Pugh Class B or C).
- 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.
- Patient has human immunodeficiency virus (HIV) infection (HIV 1 or 2) at screening.
- 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.
- 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 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.
- 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 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 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 (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]).
- 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 (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.
- Patient has clinically significant abnormalities in hematology or clinical chemistry (blood chemistry or urinalysis) 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 (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).
- 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.
- Patient has a planned or expected major surgical procedure.
- Patient or parent or legal guardian is unable or unwilling to comply with study procedures or is unable to travel for repeat visits.
- 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.
- Patient or parent or legal guardian refuses to sign consent or 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Portugal | Not Recruiting | 22 Jul 2024 | 2 |
 Spain | Not Recruiting | 22 Jul 2024 | 2 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CDZ173/Leniolisib | Test | FILM-COATED GRANULES IN SINGLE-DOSE CONTAINER | OTHER USE | 140 | 64 | PRD10234092 |
CDZ173/Leniolisib | Test | FILM-COATED GRANULES IN SINGLE-DOSE CONTAINER | ORAL USE | 140 | 64 | PRD10234061 |
CDZ173/Leniolisib | Test | FILM-COATED GRANULES IN SINGLE-DOSE CONTAINER | ORAL USE | 140 | 64 | PRD10233990 |