APDS/PASLI (Activated phosphoinositide 3-kinase delta syndrome/ p110d-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency)
Conditions
Interventions
Product Code: CDZ173
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: leniolisib
Current Sponsor code: CDZ173
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number:
Sponsors
Novartis Pharma Services AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Male and female patients age 12 to 75 years of age (inclusive), who have a documented APDS/PASLI-associated genetic PI3K delta mutation Patients with mutations in either PIK3CD or PIK3R1 can be included. • In part I and part II, patients must have nodal and/or extranodal lymphoproliferation, and clinical findings and manifestations compatible with APDS/PASLI such as a history of repeated oto-sinopulmonary infections and/or organ dysfunction (e.g., lung, liver). Additionally, in part II, patients must have at least one measurable nodal lesion on a CT or MRI scan. • At screening, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the patient has rested for at least three minutes. Sitting vital signs should be within the following ranges: ? - Systolic blood pressure, 90-139 mm Hg ? -Diastolic blood pressure, 50-89 mm Hg ? -Pulse rate, 50 - 100 bpm; up to 110 bpm in adolescents Are the trial subjects under 18? yes Number of subjects for this age range: 6 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 24 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 1
Exclusion criteria
Exclusion criteria: • Use of unstable i.v. Ig / s.c. Ig in the last 6 months before screening. Stable maintenance immunoglobulin regimen, as per local practice, such as regular injections with a consistent dosing interval (e.g., monthly) injections is acceptable • Previous or concurrent use of immunosuppressive medication such as: - use of an mTOR inhibitor (e.g., sirolimus, rapamycin, everolimus) or a PI3Kd inhibitor (selective or non-selective PI3K inhibitors) within 6 weeks prior to first dosing, however 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 cell depleters (e.g., rituximab) within 6 months prior to first dosing of study medication; if patients have received prior treatment with a B cell depleter, absolute B lymphocyte counts in the blood must have regained normal values. - Belimumab or cyclophosphamide within 6 months prior to first dosing of study medication. - Cyclosporine A, mycophenolate, 6-mercaptopurine, azathioprine or methotrexate within 3 months prior to first dosing of study medication. - Glucocorticoids above 25 mg prednisone or equivalent per day within 2 weeks prior to first dosing of study medication. - Other immunosuppressive medication where effects are expected to persist at start of dosing of study medication. • Current use of medication known to be strong inhibitors or moderate or strong inducers of isoenzyme CYP3A, if treatment cannot be discontinued or switched to a different medication prior to starting study treatment. • Current use of medications that are metabolized by isoenzyme CYP1A2 and have a narrow therapeutic index (drugs whose exposure-response indicates that increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes)). • Administration of live vaccines (this includes any attenuated live vaccines) starting from 6 weeks before study entry, during the study and up to 7 days after the last dose of CDZ173 • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study medication and for 2 days after stopping study treatment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • Part I: To assess the safety and tolerability as well as the dose-PD and PK/PD relationship of CDZ173 in patients with APDS/PASLI enabling dose selection for Part II • Part II: To assess the clinical efficacy of CDZ173 in patients with APDS/PASLI;Secondary Objective: • Part II: To assess the effect of CDZ173 on lymphadenopathy (nonindex lesions and spleen). • Part I and II: To assess the pharmacokinetics of CDZ173 in patients with APDS/PASLI • Part I and II: To assess the efficacy of CDZ173 to modify healthrelated quality of life in patients with APDS/PASLI • Part I and II: To assess the efficacy of CDZ173 by the Physician's Global Assessment and the Patient's Global Assessment • Part I and II: To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory components of the disease • Part I and II: To assess the treatment benefit to individual patients • Part II: To assess the safety and tolerability of CDZ173 in patients with APDS/PASLI;Primary end point(s): • Part I: All safety parameters (including AEs, physical exam, vital signs, ECG, safety laboratory (hematology, blood chemistry, urinalysis)) • Part I: Single and multiple dose concentrations of CDZ173 and pAkt inhibition in unstimulated and stimulated whole blood • Part II: Co-primary endpoint; o Change from baseline in the log10 transformed sum of product of diameters (SPD) in the index lesions selected as per the Cheson methodology from MRI/CT imaging. o Change from baseline in percentage of naïve B cells out of total B cells;Timepoint(s) of evaluation of this end point: From beginning to end of study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Part II: MRI/CT imaging – e.g. 3D volume of index and measurable non-index lesions selected as per the Cheson methodology, and 3D volume and bi-dimensional size of the spleen • Part I and II: Single dose CDZ173 PK parameters (including but not limited to Cmax and AUC) and trough evaluations after multiple dose • Part I and II: SF-36 (Short Form 36) Survey and WPAI-CIQ (Work Productivity Activity Impairment plus Classroom Impairment Questionnaire) • Part I and II: Visual analogue scales for PGA and PtGA (for Part II the PGA is a key secondary endpoint) • Part I and II: o C reactive protein (CRP), Lactate dehydrogenase (LDH) o For Part II additional: beta2 microglobulin, ferritin, fibrinogen and erythrocyte sedimentation rate (ESR) • Part I and II: Narratives • Part II: All safety parameters, including AEs, physical exam, vital signs, ECG, safety laboratory (hematology, blood chemistry, urinalysis);Timepoint(s) of evaluation of this end point: From beginning to end of study | — |
Countries
Belarus, Czechia, Czech Republic, France, Germany, Ireland, Italy, Netherlands, Russian Federation, United Kingdom, United States
Contacts
Public ContactMedical Information Services
Novartis Pharmaceuticals UK Limited
Outcome results
None listed