Safety, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of Repeat Doses of Inhaled Nemiralisib in Patients With APDS/PASLI
Condition: Activated PI3K-delta Syndrome
Intervention: Nemiralisib
Intervention description: Participants will be administered nemiralisib
Intervention MeSH terms: Nemiralisib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: APDS; Safety; Pharmacokinetics; GSK2269557; PASLI

Summary:

      This is an open-label study conducted to investigate safety, pharmacokinetics and
      pharmacodynamics of repeat doses of inhaled nemiralisib (NEMI) in participants with activated
      phosphoinositide 3-kinase (PI3K) delta syndrome /p110 delta-activating mutation causing
      senescent T Cells, lymphadenopathy and immunodeficiency (APDS/PASLI)
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male and female subjects aged 18 or older at the time of signing the informed consent.

          -  Patients with a clinical phenotype consistent with APDS, including a history of
             recurrent (frequency greater than would be expected in an immunocompetent individual)
             ear, sinus or pulmonary infections, and who have a known type 1 APDS-associated
             genetic PI3K delta mutation (i.e. E1021K, N334K, E525K and C416R).

          -  Body weight >=45 kilograms (kg) and body mass index (BMI) >=18 kg/square meter (m^2)
             (inclusive)

          -  Male subject. Male subjects with female partners of child bearing potential must
             comply with the following contraception requirements from the time of first dose of
             study medication until completion of the follow-up telephone call at 1-2 weeks from
             last dose. Vasectomy with documentation of azoospermia. Male condom plus partner use
             of one of the following contraceptive options: 1. Contraceptive subdermal implant 2.
             Intrauterine device or intrauterine system 3. Combined estrogen and progestogen oral
             contraceptive, 4. Injectable progestogen 5. Contraceptive vaginal ring 6. Percutaneous
             contraceptive patches. This is an all inclusive list of those methods that meet the
             GSK definition of highly effective: having a failure rate of less than 1% per year
             when used consistently and, correctly and, when applicable, in accordance with the
             product label. For non-product methods (e.g. male sterility), the investigator
             determines what is consistent and correct use. The GlaxoSmithKline (GSK) definition is
             based on the definition provided by International Conference on Harmonisation (ICH).

          -  Female subject. A female subject is eligible to participate if she is not pregnant (as
             confirmed by a negative urine human chorionic gonadotrophin [hCG] test), not
             lactating, and at least one of the following conditions applies: 1. Non-reproductive
             potential defined as: Pre-menopausal females with one of the following: Documented
             tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up
             confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral
             Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea (in
             questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH]
             and estradiol levels consistent with menopause). Females on hormone replacement
             therapy (HRT) and whose menopausal status is in doubt will be required to use one of
             the highly effective contraception methods if they wish to continue their HRT during
             the study. Otherwise, they must discontinue HRT to allow confirmation of
             post-menopausal status prior to study enrolment. 2. Reproductive potential and agrees
             to follow one of the options listed in the Modified List of Highly Effective Methods
             for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior
             to the first dose of study medication and until completion of the follow-up telephone
             call at 1-2 weeks from last dose.

          -  Capable of giving signed informed consent as described in protocol which includes
             compliance with the requirements and restrictions listed in the consent form and in
             the protocol.

        Exclusion Criteria:

          -  Alanine aminotransferase (ALT) >2xupper limit normal (ULN) and bilirubin >1.5xULN
             (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
             bilirubin <35%).

          -  Current or chronic history of liver disease except where hepatomegaly is identified by
             their clinician to be secondary to APDS, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  Corrected QT interval (QTc) > 450 milliseconds (msec) or QTc > 480 msec in subjects
             with Bundle Branch Block

          -  A subject with a clinical abnormality or laboratory parameter(s) which is/are not
             specifically listed in the inclusion or exclusion criteria, outside the reference
             range for the population being studied may be included only if the investigator, in
             consultation with the Medical Monitor if required, agree and document that the finding
             is unlikely to introduce additional risk factors and will not interfere with the study
             procedures.

          -  Regular or chronic treatment with strong inhibitors of Cytochrome P450 (CYP) 3A4
             and/or CYP2D6 (this includes some anti-epileptic treatments, macrolide antibiotics,
             oral antifungal treatments and anti-tuberculosis therapy are prohibited from the
             screening visit until the end of treatment visit. Where clinically appropriate, an
             alternative drug in the same class (or unrelated class) that is not a strong CYP3A4
             and/or CYP2D6 inhibitor can, after signing informed consent, be substituted for the
             original strong inhibitor of these enzymes

          -  Use of unstable dosing regimen with intravenous (i.v.) immunoglobulin (Ig)
             /subcutaneous (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) is acceptable.

          -  Previous use of an mechanistic target of rapamycin (mTOR) antagonist (e.g. rapamycin,
             everolimus) or PI3K delta inhibitor (selective or non-selective PI3K inhibitors).

          -  History of regular alcohol consumption within 6 months of the study defined as an
             average weekly intake of >21 units for males or >14 units for females. One unit is
             equivalent to 8 grams (g) of alcohol: a half-pint (~240 milliliters [mL]) of beer, 1
             glass (125 mL) of wine or 1 (25 mL) measure of spirits.

          -  History of sensitivity to any of the study medications, or components thereof
             (including lactose) or a history of drug or other allergy (including a milk protein
             allergy) that, in the opinion of the investigator or Medical Monitor, contraindicates
             their participation.

          -  History of previous intolerance of the induced sputum procedure.

          -  Bronchoalveolar Lavage (BAL) sub study only: History of bronchospasm in response to
             the brochoscopy/BAL procedure

          -  Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
             result at screening or within 3 months prior to first dose of study treatment.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within 56 days.

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period prior to the first dose of study medication
             in the current study: 30 days, 5 half-lives or twice the duration of the biological
             effect of the investigational product (whichever is longer).

          -  A positive test for human immunodeficiency virus (HIV) antibody.

          -  Exposure to more than 4 investigational medicinal products within 12 months prior to
             the first dose of study medication.