Evaluation of Leniolisib Phosphate in Pediatric Patients Aged 4-11 with Activated Phosphoinositide 3-Kinase Delta Syndrome: Safety, Pharmacokinetics, and Efficacy
- Trial ID
- 2024-515489-15-00
- Protocol
- LE 3301
- 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 4 to 11 years with **Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS)**. This is crucial for determining the risk-benefit profile of leniolisib in this specific patient 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 further aims to assess the long-term clinical safety and tolerability of leniolisib, providing insights into its sustained use.
Secondary objectives include:
- Assessing the **pharmacokinetics** of leniolisib in pediatric patients with APDS.
- Evaluating the control of infectious complications of the disease in these patients.
- Evaluating changes in the **mammalian target of rapamycin (mTOR) pathway** pharmacodynamic parameters.
- Assessing the impact on lymphoproliferation, including index and non-index lesions and the spleen.
- Evaluating the long-term control of infectious complications of the disease.
Participants
The clinical trial involves a total of **15 participants** diagnosed with **Activated Phosphoinositide 3-Kinase Delta Syndrome** (APDS). The study population consists of both male and female pediatric patients aged between 4 to 11 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 includes individuals who are generally in a stable health condition, with vital signs within normal ranges adjusted for age, sex, and height. Participants are required to weigh between 13 kg and 45 kg at baseline. Lifestyle considerations such as diet and physical activity are not specified, but participants must be able to ingest study-related medications without difficulty. The trial population includes a vulnerable group, as it involves children, and informed consent was obtained from the parents or legal guardians. The sponsor has not provided additional information regarding lifestyle factors or other demographic details.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, pharmacokinetics, pharmacodynamics, and efficacy of **leniolisib** in pediatric patients aged 4 to 11 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. Participants will receive leniolisib in the form of film-coated tablets administered orally. The study will assess both short-term and long-term safety and tolerability, as well as the efficacy of the treatment in reducing lymphoproliferation and normalizing immunophenotype.
The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, weight, and genetic confirmation of the PI3Kδ mutation. Participants must have at least one measurable nodal lesion and be able to ingest the study medication without difficulty. The study will exclude individuals who do not meet these criteria or who are unable to comply with the study procedures. Following the screening, participants will undergo regular follow-up visits to monitor treatment-emergent adverse events (TEAEs), changes in clinical laboratory test results, vital signs, and physical examination findings. The primary endpoints include the incidence of TEAEs, changes from baseline in various clinical parameters, and reduction in lymphoproliferation as measured by MRI or low-dose CT.
The expected duration of participant involvement is up to 64 weeks, with the possibility of early termination if significant adverse events occur or if the participant is unable to adhere to the study protocol. The end-of-study visit will involve a comprehensive assessment of the participant's health status and the collection of final data on the study's primary and secondary endpoints. The trial is anticipated to conclude by July 2025, with recruitment having started in September 2023. Participants and their guardians must provide informed consent and agree to comply with the study's requirements, including the use of effective contraception where applicable.
Treatment
The clinical trial involves the administration of the experimental medication **CDZ173/Leniolisib**, which is formulated as a **film-coated tablet**. The active substance in this medication is **leniolisib phosphate**, a chemical compound. The medication is administered orally. Two dosage regimens are utilized in the study: one with a maximum daily dose of 120 mg and another with a maximum daily dose of 140 mg. The total maximum dose for the treatment period is 53,760 mg and 62,720 mg, respectively. The treatment period extends up to 64 days. The medication is not specifically formulated for pediatric use, although it is being tested in pediatric patients aged 4 to 11 years with Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS). The medication is designated as an orphan drug, indicating its use in rare conditions.
In addition to the experimental treatment, the study does not specify the use of any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is solely on evaluating the safety, pharmacokinetics, pharmacodynamics, and efficacy of leniolisib in the specified patient population. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen. The study is conducted under the sponsorship of Pharming Technologies BV, which is responsible for the development and provision of the investigational product.
Efficacy
The efficacy of **leniolisib** in pediatric patients with Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) will be assessed through a series of 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 the normalization of immunophenotype assessed by changes from baseline in the proportion of naïve B cells among all B cells. These assessments will be conducted at the end of the 12-week treatment period.
Secondary efficacy endpoints will evaluate the pharmacokinetics of leniolisib, including the development of a population pharmacokinetic (popPK) model that describes the influence of covariates such as body weight and age on leniolisib pharmacokinetics in pediatric patients. Additionally, the frequency of infections, use of antibiotics, and immunoglobulin replacement therapy will be monitored. Phosphorylated protein kinase B (pAKT) inhibition in whole blood will also be assessed. These parameters will be measured from baseline to the end of the 12-week treatment period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient is male or female and between the age of 4 to 11 years old at the time of the first study procedure.
- 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 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.
Exclusion Criteria
- 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 has a history or current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety for patients participating in the study.
- 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).
- 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 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 06 Sept 2023 | 6 |
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 TABLET | ORAL USE | 140 | 64 | PRD9615551 |
CDZ173/Leniolisib | Test | FILM COATED TABLET | ORAL USE | 120 | 64 | PRD9615553 |