Safety, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of Repeat Doses of Inhaled Nemiralisib in Patients With APDS/PASLI

Study Overview
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Brief Summary
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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)

Official Title
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An Open-label, Single Arm Study to Investigate the Safety, Pharmacokinetics and Pharmacodynamics of Repeat Doses of Inhaled Nemiralisib in Patients With APDS/PASLI

Conditions
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Activated PI3K-delta Syndrome

Intervention / Treatment
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* Drug: Nemiralisib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants recieving nemiralisib<br> | Drug: Nemiralisib<br>* Participants will be administered nemiralisib<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Serious Adverse Events (SAEs) and Any Non-serious Adverse Events (Non-SAEs) | An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations as judged by physician. Number of participants with any SAE and non-SAEs are presented. | Upto 7.5 months | 
| Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) | SBP and DBP were measured in participants in a semi-supine position after 5 minutes rest. Baseline value is defined as latest pre-dose (Day 1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. Not applicable (NA) indicates that standard deviation could not be calculated as a single participant was analyzed. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56, 83 and 84 | 
| Change From Baseline in Pulse Rate | Pulse rate was measured in participants in a semi-supine position after 5 minutes rest. Baseline value is defined as latest pre-dose (Day 1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. NA indicates that standard deviation could not be calculated as a single participant was analyzed. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56, 83 and 84 | 
| Change From Baseline in Respiratory Rate | Respiratory rate was measured in participants in a semi-supine position after 5 minutes rest. . Baseline value is defined as latest pre-dose (Day 1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. NA indicates that standard deviation could not be calculated as a single participant was analyzed. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56, 83 and 84 | 
| Change From Baseline in Body Temperature | Temperature was measured in participants in a semi-supine position after 5 minutes rest. Baseline value is defined as latest pre-dose (Day 1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. NA indicates that standard deviation could not be calculated as a single participant was analyzed. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56, 83 and 84 | 
| Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate | Single 12-lead ECGs were recorded at indicated timepoints using an ECG machine that automatically calculated the heart rate. Baseline value is defined as latest pre-dose (Day 1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56 and 83 | 
| Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval, QT Corrected Interval-Fredericia Interval (QTcF) and QTc Corrected by Bazett's Formula (QTcB) | Twelve lead ECGs were recorded at indicated timepoints. At each time point, ECG machine automatically measured QRS duration, uncorrected QT interval, QTcF interval and QTcB. Baseline value is defined as latest pre-dose (Day 1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56 and 83 | 
| Change From Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Aspartate Aminotransferase (AST) | Blood samples were collected for the analysis of clinical parameters including ALT, ALP and AST. Baseline value is defined as latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day -1) and at Days 14, 28, 56 and 83 | 
| Change From Baseline in Clinical Chemistry Parameters : Albumin and Total Protein | Blood samples were collected for the analysis of clinical chemistry parameter-albumin and total protein. Baseline value is defined as latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day -1) and at Days 14, 28, 56 and 83 | 
| Change From Baseline Values in Clinical Chemistry Parameters: Sodium, Potassium, Calcium, Glucose and Urea | Blood samples were collected for the analysis of clinical parameters including sodium, potassium, calcium, glucose and urea. Baseline value is defined as latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day -1) and at Days 14, 28, 56 and 83 | 
| Change From Baseline Values in Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine | Blood samples were collected for the analysis of clinical chemistry parameters: direct bilirubin, total bilirubin and creatinine. Baseline value is defined as latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day -1) and at Days 14, 28, 56 and 83 | 
| Change From Baseline Values in Clinical Chemistry Parameter: C-Reactive Protein | Blood samples were collected for the analysis of clinical chemistry parameter:C-Reactive Protein. Baseline value is defined as latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56 and 83 | 
| Change From Baseline for Hematology Parameters: Basophil, Eosinophils, White Blood Cells (WBC), Lymphocytes, Neutrophils, Monocytes and Platelets | Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, WBC, lymphocytes, neutrophils, monocytes and platelets at indicated timepoints. Baseline value is defined as latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day -1) and at Days 14, 28, 56 and 83 | 
| Change From Baseline for Hematology Parameter: Hemoglobin | Blood samples were collected for the analysis of hematology parameter: hemoglobin at indicated timepoints. Baseline value is defined as latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56 and 83 | 
| Change From Baseline for Hematology Parameter: Hematocrit | Blood samples were collected for the analysis of hematology parameter: hematocrit at indicated timepoints. Baseline value is defined as latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56 and 83 | 
| Change From Baseline in Hematology Parameter: Mean Corpuscular Volume (MCV) | Blood samples were collected for the analysis of hematology parameter: MCV at indicated timepoints. Baseline value is defined as latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56 and 83 | 
| Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin (MCH) | Blood samples were collected for the analysis of hematology parameters including MCH at indicated timepoints. Baseline value is defined as latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56 and 83 | 
| Change From Baseline for Hematology Parameter: Red Blood Cell Count | Blood samples were collected for the analysis of hematology parameter: Blood Cell Count at indicated timepoints. Baseline value is defined as latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. | Baseline (Day 1 pre-dose) and at Days 14, 28, 56 and 83 | 
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | FEV1 is used to assess pulmonary function using a spirometer at indicated timepoints. Baseline value is defined as the maximum measurement of the planned pre-dose measurements on Day 1, predose. Change from Baseline is defined as post-dose visit value minus Baseline value. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines | Baseline (Day 1: pre-dose) and at Day 1: 1 Hour post-dose; Day 2: 1 Hour post-dose; Day 14: Pre-dose; Day 14: 1 Hour post-dose and Day 83: Pre-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentration Following Administration of NEMI | Blood samples for pharmacokinetic analysis was collected at the indicated time points following administration of NEMI. NA indicates that standard deviation could not be calculated as a single participant was analyzed | Day 1: Pre-dose, 5 minutes, 3 hours and 24 hours post-dose; Days 14 and 83: pre-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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APDS, Safety, Pharmacokinetics, GSK2269557, PASLI