An open-label, non-randomized, within-patient dose-finding study followed by a randomized, subject, investigator and sponsor-blinded placebo controlled study to assess the efficacy and safety of CDZ173 in patients with APDS/PASLI (Activated phosphoinositide 3-kinase delta syndrome/ p110*-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency)

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 3

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, 90-160 mmHg
* Diastolic blood pressure, 50-95 mmHg
* Pulse rate, 40 - 100 bpm; up to 110 bpm in adolescents

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 PI3K* 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 drugs 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.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Part I:<br /><br>- To assess the safety and tolerability of CDZ173 in patients with APDS/PASLI:<br /><br>All safety parameters (including AEs, physical exam, vital signs, ECG, safety<br /><br>laboratory (hematology, blood chemistry, urinalysis))<br /><br>- To assess the dose-PD and PK/PD relationship of CDZ173 in patients with<br /><br>APDS/PASLI for dose: Single and multiple dose concentrations CDZ173 and pAkt<br /><br>inhibition in unstimulated and stimulated whole blood<br /><br><br /><br><br /><br>Part II: Co-primary endpoint;<br /><br>- Change from baseline in the log10 transformed sum of product of diameters<br /><br>(SPD) in the index lesions selected as per the Cheson<br /><br>methodology from MRI/CT imaging.<br /><br>- Change from baseline in percentage of naïve B cells out of total B cells</p><br>

Secondary Outcome Measures