A Study to Evaluate Relative Bioavailability, Proton Pump... | NCT04488016

Status Module

Name	Class
Acerta Pharma, LLC	OTHER

Description Module

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort 1 -Part 1	Experimental	Subjects will be randomized to one of 4 sequences ABC, BAC, ABD, or BAD. Subjects will receive 100 mg acalabrutinib capsule, fasted state (>10 h) in Treatment A , 100 mg acalabrutinib tablet (Variant 1), fasted state (>10 h) in Treatment B, 100 mg acalabrutinib tablet (Variant 1), fed state in Treatment C, Rabeprazole 20 mg ×1 (fasted) at 2 hours before administration of 100 mg acalabrutinib tablet (Variant 1)* and following prior administration of rabeprazole 20 mg BID (with meals) on Days -3, -2 and -1 in Treatment D.	Drug: Treatment A- Part 1 Drug: Treatment B- Part 1 Drug: Treatment C - Part 1
Cohort 2- Part 1	Experimental	Subjects will be randomized to one of 4 sequences ABC, BAC, ABD, or BAD. Subjects will receive 100 mg acalabrutinib capsule, fasted state (>10 h) in Treatment A , 100 mg acalabrutinib tablet (Variant 1), fasted state (>10 h) in Treatment B, 100 mg acalabrutinib tablet (Variant 1), fed state in Treatment C, Rabeprazole 20 mg ×1 (fasted) at 2 hours before administration of 100 mg acalabrutinib tablet (Variant 1)* and following prior administration of rabeprazole 20 mg BID (with meals) on Days -3, -2 and -1 in Treatment D.	Drug: Treatment A- Part 1 Drug: Treatment B- Part 1 Drug: Treatment C - Part 1
Cohort 3- Part 1	Experimental	Subjects will be randomized to one of 4 sequences ABC, BAC, ABD, or BAD. Subjects will receive 100 mg acalabrutinib capsule, fasted state (>10 h) in Treatment A , 100 mg acalabrutinib tablet (Variant 1), fasted state (>10 h) in Treatment B, 100 mg acalabrutinib tablet (Variant 1), fed state in Treatment C, Rabeprazole 20 mg ×1 (fasted) at 2 hours before administration of 100 mg acalabrutinib tablet (Variant 1)* and following prior administration of rabeprazole 20 mg BID (with meals) on Days -3, -2 and -1 in Treatment D.

Name	Type	Description	Arm Group Labels	Other Names
Treatment A- Part 1	Drug	Subjects will receive 100 mg acalabrutinib capsule, fasted state;	Cohort 1 -Part 1 Cohort 2- Part 1 Cohort 3- Part 1

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Maximum observed plasma concentration (Cmax)-Acalabrutinib	Part 1: To assess the relative bioavailability of the acalabrutinib tablet compared with acalabrutinib capsules in fasted state. Part 2: To assess the impact of drug substance particle size on the bioavailability of acalabrutinib tablets.	Day 1 and Day 2
Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast)-Acalabrutinib	Part 1: To assess the relative bioavailability of the acalabrutinib tablet compared with acalabrutinib capsules in fasted state. Part 2: To assess the impact of drug substance particle size on the bioavailability of acalabrutinib tablets.	Day 1 and Day 2
Area under plasma concentration-time curve from time zero to infinity (AUCinf)-Acalabrutinib	Part 1: To assess the relative bioavailability of the acalabrutinib tablet compared with acalabrutinib capsules in fasted state. Part 2: To assess the impact of drug substance particle size on the bioavailability of acalabrutinib tablets.	Day 1 and Day 2

Secondary Outcomes

Measure	Description	Time Frame
Cmax -ACP-5862	Part 1: To assess the ACP-5862 PK profile of the acalabrutinib tablet compared with acalabrutinib capsule in fasted state. Part 2: To assess the impact of drug substance particle size on the ACP-5862 PK profile of acalabrutinib tablets.	Day 1 and Day 2
AUClast-ACP-5862

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Provision of signed and dated, written informed consent prior to any study specific procedures.
Healthy adult male or female subjects aged 18 - 55 years with suitable veins for cannulation or repeated venipuncture.
Male subject must adhere to the contraception methods.
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.
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.
Understands the study procedures in the Informed Consent Form (ICF) and willing and able to comply with the protocol.
Willingness and ability to swallow study drugs, including the SmartPill.
Willingness to consume a standardized, high- calorie, high-fat FDA breakfast.

Exclusion Criteria:

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.
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.
Evidence of ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections).
Any clinically significant illness, medical/surgical procedure, or trauma within 30 days of the first administration of IMP.
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.
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.
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.
Any positive result on screening for serum hepatitis B surface antigen, hepatitis B core antibody (anti-HBc), hepatitis C antibody, and HIV antibody.
Known or suspected history of drug abuse, as judged by the PI.
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.
Plasma donation within 30 days of screening or any blood donation/loss more than 500 mL during the 90 days prior to screening.
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.
Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the 90 days prior to screening.
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.
Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
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.
Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the PI.
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.
Part 1 only: Inability or unwillingness to swallow SmartPill, including:

Subject has any of the following contraindications for the SmartPill:

A history of gastric bezoars
Swallowing disorders
Suspected or known strictures, fistulas or physiological/mechanical GI obstruction
History of GI surgery within 90 days of administration
Severe dysphagia to food or pills
Crohn's disease or diverticulitis
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.