Leniolisib for Immune Dysregulation in PIDs

Eligibility Criteria

• 1. Subjects 12 to 75 years of age.
• 2. Diagnosed with a PID due to disease-causing pathogenic or likely pathogenic variant(s) in the following genes: SOCS1, PTEN, CTLA4, NFKB1 (only those variants leading to NFKB pathway activation), or FAS (germline or somatic), or diagnosed with RAS associated leukoproliferative disorder (and not juvenile myelomonocytic leukemia \[JMML\]) due to somatic variants in NRAS or KRAS.
• 3. Subjects must have 1 or more of the following:
• * One or more blood cytopenias related to the underlying PID defined as hemoglobin \<10 g/dL, platelet count \<100,000/µL, or neutrophil count \<1000/µL
• * Splenomegaly evident by CT imaging with craniocaudal spleen measurement \>10 cm
• * Lymphadenopathy evident by CT imaging with at least 1 measurable index lymph node (long axis \>1.5 cm) as per Cheson methodology
• * GLILD or other PID-related ILD with quantifiable CT chest imaging findings evident on baseline CT scan
• 4. At screening, vital signs.
• * Systolic blood pressure 80-139 mm Hg
• * Diastolic blood pressure 50-89 mm Hg
• * Pulse rate 50-110 bpm
• * Oxygen saturation 93-100%
• 5. Subjects or their legal representatives (for subjects under the age of 18 years) must be able to provide written informed consent.
• 1. Subject has had a successful hematopoietic stem-cell transplant (HSCT).
• 2. Previous or concurrent use of immunosuppressive medication, such as:
• * Use of an mTOR inhibitor or a PI3Kδ inhibitor within 3 weeks prior to first dosing .
• * Rituximab or other B-cell depleting antibodies, belimumab, cyclophosphamide, or alemtuzumab within 6 months prior to first dosing.
• * Cyclosporine A, mycophenolate mofetil, 6-mercaptopurine, azathioprine, methotrexate, tacrolimus, ruxolitinib, or other JAK inhibitors within 3 weeks prior to first dosing.
• * Corticosteroids above 25 mg prednisone or equivalent per day within 2 weeks prior to first dosing.
• * Other immunosuppressive agents expected to have a significant impact on immune cell number or function.
• * Abatacept is allowed during study if the subject has been receiving a stable dosing regimen for more than 3 months prior to first dosing.
• 3. Subject is receiving concurrent treatment with another investigational therapy or use of another investigational therapy less than 4 weeks or 5 half-lives (whichever is longer) prior to first dosing.
• 4. History of hypersensitivity to the study drug or to drugs of similar chemical classes.
• 5. Current use of medication known to be a strong inhibitor, or moderate or strong inducer, of isoenzyme P450 CYP3A.
• 6. Current use of medications that act as BCRP, OATP1B1, and OATP1B3 substrates.
• 7. Subject has a history or current electrocardiogram (ECG) abnormalities indicating a significant risk of safety for subjects participating in the study
• 8. History of acquired immunodeficiency diseases, including a positive HIV test result at screening.
• 9. Uncontrolled chronic or recurrent infectious disease (except those considered to be characteristic of a PID) or evidence of tuberculosis infection
• 10. Any surgical or medical condition which may jeopardize the subject in case of participation in the study, or might significantly alter the absorption, distribution, metabolism, or excretion of drugs.
• 11. A positive hepatitis B surface antigen, positive hepatitis B PCR, positive hepatitis C PCR, or positive hepatitis C antibody result at screening.
• 12. Administration of live vaccines starting from 6 weeks before first dose of study medication.
• 13. Subject has a previous diagnosis of lymphoma within 1 year of the first dose of study medication.
• 14. Subject has a history of malignancy (except lymphoma) within 3 years before the first dose of study medication, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
• 15. Subject has uncontrolled post-transplant lymphoproliferative disease (PTLD)-like EBV related lymphoproliferative disease.
• 16. Donation or loss of 400 mL or more of blood within 8 weeks before the first dose.
• 17. Subject has had major surgery requiring hospitalization or radiotherapy within 4 weeks prior to the first dose or has a planned or expected major surgical procedure during the study period.
• 18. Pregnant or nursing (lactating) individuals,.
• 19. Individuals of child-bearing potential, unless they are using highly effective methods of contraception.