Clinical trial NCT04488016: A Study to Evaluate Relative Bioavailability, Proton Pump Inhibitor (PPI) (Rabeprazole) Effect, Food Effect and Particle Size Effect of New Acalabrutinib Tablet in Healthy Subjects
Official title: A 2-Part, Phase I, Open-label, Single-Dose, Sequential Randomized Crossover Study of New Acalabrutinib Tablet in Healthy Subjects to Evaluate Relative Bioavailability, Proton Pump Inhibitor (Rabeprazole) Effect, Food Effect and Particle Size Effect
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Bioavailability
B-cell Lymphoid Cancer
Keywords: Bruton tyrosine kinase (BTK) inhibitor
Proton Pump Inhibitor (Rabeprazole) Effect
Food Effect
Particle Size Effect
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Acerta Pharma, LLC
First posted: 2020-07-27
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study will be a 2-part, open-label, single-center relative bioavailability, PPI effect, food-effect and particle size effect randomized crossover study of acalabrutinib tablets in healthy subjects (males or females). The study will be divided in 2 study parts; following a review of the safety and Pharmacokinetics (PK) data from Part 1, the study is planned to be continued with Part 2.

Detailed description: The study will be divided in 2 study parts; Part 1 of this study will be an open-label, 3-treatment-period, 4-treatment, single-center relative bioavailability, PPI effect, and food-effect randomized crossover study of a new acalabrutinib tablet in healthy subjects (males or females).

The relative bioavailability part of Study Part 1 is designed to investigate the PK of the acalabrutinib tablet compared with the PK of acalabrutinib capsule, when administered as a single dose with water under the fasted condition (\>10 hours). The PPI effect part of Study Part 1 is designed to compare the PK of acalabrutinib tablet with or without coadministration of the PPI rabeprazole. The food-effect part of Study Part 1 is designed to compare the PK of acalabrutinib tablet under fed and fasted conditions. For each subject, a SmartPill will be administered with 120 mL of still water followed immediately by a single oral dose of acalabrutinib tablet (Treatment B, C or D) or acalabrutinib capsule (Treatment A) administered with 120 mL of still water.

Study Part 1 will comprise:

* A screening period of maximum 28 days;
* Three treatment periods during which subjects will be resident from prior to the evening meal the night before dosing with Investigational medicinal product (IMP) (Day -1) until at least 48 hours after dosing; discharged on the morning of Day 3; and
* A Follow-up Visit within 7 to 10 days. There will be a minimum washout period of at least 7 days between each acalabrutinib administration.

A decision to continue with Study Part 2 will be made following a review of the preliminary data for relative bioavailability (acalabrutinib tablet versus acalabrutinib capsule), food effect, PPI effect, and safety observed in Part 1.

Part 2 of this study will be an open-label, 4-treatment-period, 4-treatment, single-center relative bioavailability, randomized crossover study to determine the effect of particle size on the PK of a single dose of acalabrutinib tablet in healthy subjects (males or females).

This relative bioavailability study is designed to investigate the PK of acalabrutinib tablets with various drug substance particle size distributions and the PK of acalabrutinib solution at a single oral dose of 100 mg under the fasted condition (\>10 hours).

Study Part 2 will comprise:

* A screening period of maximum 28 days;
* Four treatment periods during which subjects will be resident prior to the evening meal the night before dosing with IMP (Day -1) until at least 48 hours after dosing; discharged on the morning of Day 3; and
* A Follow-up Visit within 7 to 10 days. There will be a minimum washout period of at least 3 days between each acalabrutinib administration.

Eligibility criteria: Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures.
2. Healthy adult male or female subjects aged 18 - 55 years with suitable veins for cannulation or repeated venipuncture.
3. Male subject must adhere to the contraception methods.
4. Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening.
5. Have a Body mass index (BMI) between 18.5 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive at screening.
6. Understands the study procedures in the Informed Consent Form (ICF) and willing and able to comply with the protocol.
7. Willingness and ability to swallow study drugs, including the SmartPill.
8. Willingness to consume a standardized, high- calorie, high-fat FDA breakfast.

Exclusion Criteria:

1. History of any clinically significant disease or disorder which, in the opinion of the Principal Investigator (PI), may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study.
2. History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
3. Evidence of ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections).
4. Any clinically significant illness, medical/surgical procedure, or trauma within 30 days of the first administration of IMP.
5. Any clinically significant abnormalities in clinical chemistry, hematology, coagulation, or urinalysis results, at screening and first admission to the study unit (first treatment period) as judged by the PI, and defined as: (1) Serum Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and serum bilirubin (total and direct)

   \> Upper limit of normal (ULN). (2) Hemoglobin \< ULN.
6. Any clinically significant abnormal findings in vital signs at screening and first admission to the study unit (first treatment period), as judged by the PI.
7. Any clinically significant abnormalities on 12-lead ECG at screening and first admission to the study unit (first treatment period), as judged by the PI.
8. Any positive result on screening for serum hepatitis B surface antigen, hepatitis B core antibody (anti-HBc), hepatitis C antibody, and HIV antibody.
9. Known or suspected history of drug abuse, as judged by the PI.
10. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 90 days of the first administration of IMP in this study.

    The period of exclusion begins 90 days after the final dose or 30 days after the last visitwhichever is the longest.
11. Plasma donation within 30 days of screening or any blood donation/loss more than 500 mL during the 90 days prior to screening.
12. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the PI or history of hypersensitivity to drugs with a similar chemical structure or class to acalabrutinib or rabeprazole.
13. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the 90 days prior to screening.
14. Positive screen for drugs of abuse or cotinine at screening or on each admission to the study center or positive screen for alcohol on each admission to the study center.
15. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
16. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life. Hormone replacement therapy will not be allowed.
17. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the PI.
18. Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate) as judged by the PI. Excessive intake of caffeine defined as the regular consumption of more than 600 mg of caffeine per day (e.g., \>5 cups of coffee) or would likely be unable to refrain from the use of caffeine-containing beverages during confinement at the investigational site.
19. Part 1 only: Inability or unwillingness to swallow SmartPill, including:

Subject has any of the following contraindications for the SmartPill:

1. A history of gastric bezoars
2. Swallowing disorders
3. Suspected or known strictures, fistulas or physiological/mechanical GI obstruction
4. History of GI surgery within 90 days of administration
5. Severe dysphagia to food or pills
6. Crohn's disease or diverticulitis
7. Cardiac pacemakers or other implanted electromedical devices 20 Involvement of any AstraZeneca, Acerta Pharma, Parexel or study site employee or their close relatives. 21 Subjects who have previously received acalabrutinib. 22 Judgment by the PI that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements. 23 Subjects who cannot communicate reliably with the Investigator. 24 Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Primary outcomes:
measure: Maximum observed plasma concentration (Cmax)-Acalabrutinib
timeFrame: Day 1 and Day 2
measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast)-Acalabrutinib
timeFrame: Day 1 and Day 2
measure: Area under plasma concentration-time curve from time zero to infinity (AUCinf)-Acalabrutinib
timeFrame: Day 1 and Day 2
Secondary outcomes:
measure: Cmax -ACP-5862
timeFrame: Day 1 and Day 2
measure: AUClast-ACP-5862
timeFrame: Day 1 and Day 2
measure: AUCinf-ACP-5862
timeFrame: Day 1 and Day 2
measure: Area under the plasma concentration-time curve from time zero to 12 hours post-dose (AUC0-12) - Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: AUClast- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: AUCinf- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: Extrapolated area under the curve from tlast to infinity, expressed as percentage of AUCinf (%AUCextrap)- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: Cmax- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: Half-life associated with terminal slope of a semi-logarithmic concentration-time Curve (t½)- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: Time to reach maximum observed concentration (tmax)- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: Terminal elimination rate constant (Kel)- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: Relative bioavailability (Frel)- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: Apparent volume of distribution during the terminal phase after extravascular Administration (Vz/F)- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: ACP-5862 (metabolite) to acalabrutinib (parent) ratio (M/P) for Cmax- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: ACP-5862 (metabolite) to acalabrutinib (parent) ratio (M/P) for AUClast- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: ACP-5862 (metabolite) to acalabrutinib (parent) ratio (M/P) for AUCinf- Acalabrutinib and ACP-5862
timeFrame: Day 1 and Day 2
measure: Number of subjects with adverse events
timeFrame: From Screening to follow-up visit (7 to 10 days after last dose)
measure: Number of subjects with abnormal systolic and diastolic blood pressure
timeFrame: At screening (Day -28), Day -1, and Day 2
measure: Number of subjects with abnormal pulse rate
timeFrame: At screening (Day -28), Day -1, and Day 2
measure: Number of subjects with abnormal respiratory rate
timeFrame: At screening (Day -28), Day -1, and Day 2
measure: Number of subjects with abnormal body temperature
timeFrame: At screening (Day -28), Day -1, and Day 2
measure: Number of subjects with abnormal electrocardiogram (12-lead ECG)
timeFrame: At screening (Day -28), Day -1, and Day 2
measure: Number of subjects with abnormal physical examination
timeFrame: At screening (Day -28), Day -1, and Day 2
measure: Number of subjects with abnormal hematology -Cell count
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal electrolytes
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal hemoglobin (Hb)
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal hematocrit
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal mean corpuscular volume (MCV)
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal mean corpuscular hemoglobin (MCH)
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal mean corpuscular hemoglobin concentration (MCHC)
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal clinical chemistry
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Incidence of abnormal urinalysis
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal glucose (fasting)
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal C-reactive protein (CRP)
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal blood urea nitrogen (BUN)
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal thyroid-stimulating hormone (TSH)
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal T4
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal hematology- Differential count
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Percentage of subjects with adverse events
timeFrame: From Screening to follow-up visit (7 to 10 days after last dose)
measure: Number of subjects with abnormal electrolytes
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal electrolytes
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal clinical chemistry
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal clinical chemistry
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal clinical chemistry
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal clinical chemistry
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal clinical chemistry
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Number of subjects with abnormal clinical chemistry
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Incidence of abnormal urinalysis
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Incidence of abnormal urinalysis
timeFrame: At screening (Day -28), Day-1, Day 1, Day 2, and Follow-up visit (7-10 days after last dose)
measure: Taste
timeFrame: Day 1
measure: Smell
timeFrame: Day 1
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Research Site
state: Maryland
Study officials:
affiliation: PAREXEL Early Phase Clinical Unit Baltimore
name: Ronald Goldwater,, MD
role: PRINCIPAL_INVESTIGATOR
References: