Phase 1A Safety Trial of Inhaled PK10571 (GB002)

Study Overview
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Brief Summary
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This is a phase 1A randomized double blind placebo controlled single ascending dose and multiple ascending dose trial of inhaled PK10571 (GB002) in healthy adult subjects.

Detailed Description
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This is a first-in-human, single-center, randomized, double-blind, placebo-controlled, two-part study in healthy adult males and females of non-childbearing potential. Double-Blind means neither the study subject nor the investigator knows if PK10571 or placebo is being given. Placebo means a capsule filled with a powder that does not contain the active drug, PK10571. Because the safety profile of PK10571 in humans is unknown and this is the first clinical study to assess PK10571 in humans, a single-ascending dose design will be used in Part A of the study going from a low dose to higher doses based on safety. Part B will be a multiple-ascending dose design to be run only after review of safety and measurement of drug levels in the blood from Part A. In the single ascending dose study (Part A) up to five doses may be given to different groups of study subjects based on safety and measurement of drug levels in the blood. Subjects will be randomized into one dose cohort to receive either PK10571 or placebo. Within each cohort, 6 subjects will receive active drug and 2 subjects will receive placebo. In the multiple ascending dose study (Part B), up to three doses of PK10571 will be tested. The daily dose will be administered daily for 7 days with close clinical monitoring. The dose for the first cohort of Part B will be determined by review of the safety and drug levels from Part A by the Safety Review Committee. The dose interval for the first cohort of Part B (i.e., once daily, twice daily, or up to three times daily) will be determined by review of the safety and drug levels in the blood from Part A by the Safety Review committee. Subsequent doses and dosing intervals will be determined by review of the safety and drug levels from the prior cohort.

Official Title
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A Phase 1A Single Ascending Dose and Multiple Ascending Dose Double-Blind, Placebo-Controlled, Randomized Trial of Oral Inhalation PK10571 in Healthy Adult Subjects

Conditions
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Safety Issues

Intervention / Treatment
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* Drug: GB002
* Device: Generic Dry Powder Inhaler
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females (if unable to become pregnant) Age 18-55 Body mass index (BMI) 18-32 kg/m^2 and minimum weight of 50 kg (110 lbs) Non-smoker Ability to give informed consent Ability to remain in study unit for duration of study and return for outpatient visits Ability to use dry powder inhaler (DPI) effectively (See full protocol for additional details.) Exclusion Criteria: Hospitalization within the 6 months prior to the first dose of study treatment History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the subject or the validity of the study results History or presence of active lung disease (i.e., asthma, chronic obstructive pulmonary disease [COPD], pulmonary fibrosis, hemoptysis, bronchiectasis) or prior intubation Currently uses an inhaler History or presence of heart disease (i.e., prior myocardial infarction [MI], coronary artery disease, heart failure, hypertension, pulmonary hypertension, valve disease, atrial fibrillation, other arrhythmia, or prolonged QT syndrome) History or presence of cancer (with the exception of basal cell skin cancer that has been effectively treated) History of diabetes mellitus History of thyroid disease other than hypothyroidism control with levothyroxine and documented normal thyroid-stimulating hormone (TSH) History of tuberculosis, Lyme disease, or other chronic or opportunistic infection. History of positive purified protein derivative (PPD) skin test, or positive PPD test at screening Has a positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV) at screening or has been previously treated for hepatitis B, hepatitis C, or HIV infection History of smoking within the past 15 years Is a female with a positive pregnancy test result, or who has the ability to become pregnant, or who is lactating Has forced expiratory volume in 1 second (FEV1) less than 80% predicted, forced vital capacity (FVC) ˂80% predicted, or resting oxygen saturation less than 97% on room air at screening or baseline Upper respiratory infection within the 3 months prior to the first dose of medication History of major bleeding or major surgical procedure of any type within 6 months prior to the first dose of medication History of minor bleeding disorders such as epistaxis, rectal bleeding (spots of blood on toilet paper), and gingival bleeding within 3 months before the study treatment History of bleeding disorder or coagulopathy Females with history of dysfunctional uterine bleeding, including history of menorrhagia or metrorrhagia, unless subject has had a hysterectomy. History of GI bleed Has used any over-the-counter (OTC) medication, nutritional or dietary supplements, herbal preparations, or vitamins within 7 days prior to the first dose of medication Has used any antiplatelet agents such as acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), clopidogrel (or similar agent) or anti-coagulants within 7 days prior to the first dose of medication Has used any prescription medication, except female hormonal replacement therapy, within 14 days prior to the first dose of study medication Has been treated with any known drugs that are moderate or strong inhibitors/inducers of CYP enzymes such as barbiturates, phenothiazines, cimetidine, carbamazepine, etc., within 30 days prior to the first dose of study medication and that in the Investigator's judgment may impact subject safety or the validity of the study results History of peripheral vascular disease History of autoimmune or collagen vascular disease History of sleep apnea History of clinically significant allergy to medications History of anaphylaxis History of liver disease History of alcohol or drug abuse Prolonged QTc on 12-lead ECG (i.e., QTc corrected using Fridericia's formula [QTcF] ˃450 msec), PR >210 msec, or QRS >110 msec at screening. Evidence of prior MI on ECG; presence of atrial fibrillation on ECG; presence of pre-excitation, 2nd or 3rd degree heart block, or abnormal waveform morphology that would preclude accurate measurement of the QT interval duration or other clinically significant abnormalities Chest x-ray reveals presence of infiltrate or other abnormality (mass, granuloma, fibrosis, pulmonary thickening, pleural effusion, pulmonary edema, wide mediastinum, cardiomegaly, or clinically significant increased interstitial markings) History of neurologic disorder (i.e., multiple sclerosis, amyotrophic lateral sclerosis [ALS], cerebrovascular accident [CVA], transient ischemic attach [TIA]) History of deep vein thrombosis or pulmonary embolus History of clotting disorder History of mental illness requiring drug treatment or hospitalization History of renal failure or proteinuria (defined as 1+ proteinuria: ≥75 mg/dL on isolated urinalysis) Test results greater than the upper limit of normal (ULN) for AST, ALT, or total bilirubin Out of range results on the following coagulation tests: INR, prothrombin time (PT), or partial thromboplastin time (PTT) Total cholesterol >250 mg/dL or triglycerides >300 mg/dL at screening (based on fasting lipid profile) Estimated creatinine clearance less than 60 mL/min Hemoglobin at screening of <11.5 g/dl (if female subject) or <12.5 g/dl (if male subject) Has a clinically significant abnormal finding on the physical exam, medical history, electrocardiogram (ECG), or clinical laboratory results at screening. Note: Subjects with abnormal laboratory results not specifically excluded by this protocol may be enrolled if the Investigator deems the out-of-range values as not clinically significant History of treatment with a kinase inhibitor Has been on a significantly abnormal diet during the 4 weeks preceding the first dose of study medication Has donated blood or plasma within 30 days prior to the first dose of study medication Has participated in another clinical trial (randomized subjects only) within 30 days prior to the first dose of study medication Has a positive urine screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, opiates) or cotinine Vital signs (measured sitting after 3 minutes rest) at screening that are not within the following ranges (inclusive): heart rate: 40-100 beats per minute [bpm]; systolic blood pressure (BP): 90-145 mmHg; diastolic BP: 50-95 mmHg. Out-of-range vital signs may be repeated once. Blood pressure will be measured in both arms at screening, with a 3-minute rest between each measurement. Predose vital signs will be assessed by the Principal Investigator or designee (e.g., a medically qualified sub-investigator) prior to study drug administration. The Principal Investigator or designee will verify the eligibility of each subject with out-of-range vital signs and document approval prior to dosing Significant difference (i.e., greater than 15 mmHg) between the systolic blood pressure in each arm at screening History of lactose intolerance

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1A<br>Dose 1 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. | Drug: GB002<br>* Inhaled GB002<br>* Other names: PK10571;Device: Generic Dry Powder Inhaler<br>* dry powder inhaler used for inhalation of active drug or placebo<br>Drug: Placebo<br>* Inhaled placebo<br>|
| Experimental: Cohort 2A<br>Dose 2 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. | Drug: GB002<br>* Inhaled GB002<br>* Other names: PK10571;Device: Generic Dry Powder Inhaler<br>* dry powder inhaler used for inhalation of active drug or placebo<br>Drug: Placebo<br>* Inhaled placebo<br>|
| Experimental: Cohort 3A<br>Dose 3 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. | Drug: GB002<br>* Inhaled GB002<br>* Other names: PK10571;Device: Generic Dry Powder Inhaler<br>* dry powder inhaler used for inhalation of active drug or placebo<br>Drug: Placebo<br>* Inhaled placebo<br>|
| Experimental: Cohort 4A<br>Dose 4 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. | Drug: GB002<br>* Inhaled GB002<br>* Other names: PK10571;Device: Generic Dry Powder Inhaler<br>* dry powder inhaler used for inhalation of active drug or placebo<br>Drug: Placebo<br>* Inhaled placebo<br>|
| Experimental: Cohort 5A<br>Dose 5 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. | Drug: GB002<br>* Inhaled GB002<br>* Other names: PK10571;Device: Generic Dry Powder Inhaler<br>* dry powder inhaler used for inhalation of active drug or placebo<br>Drug: Placebo<br>* Inhaled placebo<br>|
| Experimental: Cohort 1B<br>Dose 1 Multiple Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. | Drug: GB002<br>* Inhaled GB002<br>* Other names: PK10571;Device: Generic Dry Powder Inhaler<br>* dry powder inhaler used for inhalation of active drug or placebo<br>Drug: Placebo<br>* Inhaled placebo<br>|
| Experimental: Cohort 2B<br>Dose 2 Multiple Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. | Drug: GB002<br>* Inhaled GB002<br>* Other names: PK10571;Device: Generic Dry Powder Inhaler<br>* dry powder inhaler used for inhalation of active drug or placebo<br>Drug: Placebo<br>* Inhaled placebo<br>|
| Experimental: Cohort 3B<br>Dose 3 Multiple Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. | Drug: GB002<br>* Inhaled GB002<br>* Other names: PK10571;Device: Generic Dry Powder Inhaler<br>* dry powder inhaler used for inhalation of active drug or placebo<br>Drug: Placebo<br>* Inhaled placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A serious AE (SAE) is one that, in the view of either the investigator or Sponsor, results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. A TEAE is defined as any AE that has an onset on or after the first dose of study drug and before the end of study/end of treatment (EoS/ET) visit, or any pre-existing condition that has worsened in severity on or after the first dose of study drug and before the EoS/ET visit. | SAD: from first dose of study drug to 11 days, MAD: from first dose of study drug to 35 days | 
| Number of Participants With Vital Sign Findings Reported as TEAEs | Vital signs evaluated included blood pressure, pulse oximetry, respiratory rate, and temperature. | SAD: from first dose of study drug to 11 days, MAD: from first dose of study drug to 35 days | 
| Number of Participants With Clinically Significant Findings in Physical Examinations | Physical examination assessments included: physical exam for general appearance; head, ears, eyes, nose and throat; thyroid; lymph nodes; back and neck; heart; chest; lungs; abdomen; skin; and extremities, musculoskeletal and neurological. | SAD: from first dose of study drug to 11 days, MAD: from first dose of study drug to 35 days | 
| Number of Participants With Clinically Significant Changes From Baseline in ECG Data (Overall Interpretation) | 12-lead electrocardiograms (ECG) assessments included heart rate, PR interval, QRS duration, QT interval, QTc interval, QTc interval corrected using Bazett's formula (QTcB), QTc interval corrected using Fridericia's formula (QTcF), RR interval. | SAD: Baseline, Day 2, 24 hours; MAD: Baseline, Day 8, 24 hours | 
| Number of Participants With Clinically Significant Abnormal Findings in Pulmonary Function Tests | Pulmonary function tests included forced vital capacity; forced expiratory volume in 1 second (FEV1); forced expiratory flow 25%-75% (FEF25-75); percent predicted forced vital capacity; percent predicted FEV1; and percent predicted FEF25-75. | SAD: from first dose of study drug to 11 days, MAD: from first dose of study drug to 35 days | 
| Pharmacokinetic (PK) Analysis of Inhaled GB002: Maximum Concentration (Cmax), SAD |  | 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Time to Cmax (Tmax), SAD |  | 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Area Under the Curve From Time 0 Hours to Last Quantifiable Concentration (AUClast), SAD |  | 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Area Under the Curve From Time 0 Hours to Infinity (AUCinf), SAD |  | 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Apparent Terminal Elimination Half-Life (t1/2), SAD |  | 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Apparent Total Plasma Clearance (CL/F), SAD | CL/F is based on nominal (scheduled) dose. | 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Apparent Volume of Distribution (Vz/F), SAD | Vz/F is based on nominal (scheduled) dose. | 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Cmax After Dose 1, MAD |  | Days 1 and 7: 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Tmax After Dose 1, MAD |  | Days 1 and 7: 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Area Under the Curve From Time Zero to 24 Hours Postdose (AUC0-24), MAD |  | Days 1 and 7: 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Trough Plasma Concentration (Ctrough), MAD |  | Days 1 and 7: 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Accumulation Ratio (Rac) for Cmax After Dose 1, MAD |  | Days 7: 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Rac for AUC0-24, MAD |  | Days 7: 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Rac for Ctrough, MAD |  | Days 7: 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: t1/2, MAD |  | Day 7: 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Apparent Total Plasma Clearance at Steady-State (CLss/F), MAD |  | Day 7: 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration | 
| PK Analysis of Inhaled GB002: Vz/F, MAD |  | Day 7: 0 hour (predose), and then at 3, 10, 20, 30, 40 minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration |