A Study to Evaluate the Effect of an Acidic Formulation of Acalabrutinib (ACP-196), Acidic Beverage, or Grapefruit Juice on the Pharmacokinetics (PK) of ACP-196 Alone and Coadministered With Omeprazole

Study Overview
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Brief Summary
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This study will evaluate the effect of an acidic formulation of Acalabrutinib (ACP-196), acidic beverage, or grapefruit Juice on the PK of ACP-196 alone and coadministered with omeprazole.

Detailed Description
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This is a 3-part study. Each part of the study will compare the effect of an acidic formulation of ACP-196, acidic beverage (orange drink), or grapefruit juice on the PK profile of ACP-196 alone and when coadministered with omeprazole. Participants will be enrolled into Part 1 of the study first and then subsequent participants will be randomized in a 1:1 ratio to either Part 2 or Part 3 of the study. Participants will be screened within 28 days before the dose. Participants will be contacted approximately 14 days after the last dose of study drug administration to determine if any adverse event has occurred since the last dose of study drug.

Official Title
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A Phase 1, Single-center, Open-label, Fixed-sequence, 4-period, 3-part Study in Healthy Adult Subjects to Evaluate the Effect of an Acidic Formulation of Acalabrutinib (ACP-196), Acidic Beverage, or Grapefruit Juice on the Pharmacokinetics of Acalabrutinib Alone and Coadministered With Omeprazole

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: ACP-196
* Drug: Omeprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Continuous non-smoker who has not used nicotine-containing products for ≥ 3 months before the first dose. Body mass index (BMI) >= 18.0 and =< 32.0 kg/m^2 at screening. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs, or electrocardiograms, as deemed by the principal investigator (PI). Liver function tests must be =< the upper limit of normal range (ULN) at screening for inclusion. Men and women of reproductive potential to follow protocol defined contraception methods. Women must have negative serum pregnancy test results. Willing and able to take the study drug with 240 mL of orange drink (Part 2) or grapefruit juice (Part 3). Exclusion Criteria: Participant is mentally or legally incapacitated, or has significant emotional problems at the time of the screening visit or expected during the conduct of the study. Participant with known fruit allergies. History or presence of clinically significant medical or psychiatric condition or disease (eg, cardiovascular, respiratory, hepatic, gastrointestinal, renal, genitourinary, endocrine, neuromuscular, rheumatologic, oncologic, cutaneous or other disorders), in the opinion of the PI. History of any illness that, in the opinion of the PI, might confound the results of the study or poses an additional risk to the subject by their participation in the study. Presence of any clinically significant, ongoing systemic bacterial, fungal or viral infections in the opinion of the PI. History or presence of alcoholism or drug abuse within the past 2 years before screening. History of bleeding diathesis (eg, hemophilia, von Willebrand disease). Any clinically significant condition that may affect acalabrutinib absorption in the opinion of the PI, including gastric restrictions and bariatric surgery (eg, gastric bypass). History or presence of clinically significant thyroid disease, in the opinion of the PI. Women who are pregnant or breastfeeding. Positive urine drug or alcohol results at screening or check-in. Positive urine cotinine at screening. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV). Seated blood pressure is < 90/40 mm Hg or > 140/90 mm Hg at screening. Seated heart rate is lower than 40 beats per minute (bpm) or higher than 99 bpm at screening. Have been on a diet incompatible with the on study diet, in the opinion of the PI, within the 28 days before the first dose of study drug, and throughout the study. Unable to refrain from or anticipates the use of protocol defined medicines: Donation of blood or significant blood loss within 56 days before the first dose of study drug. Plasma donation within 7 days before the first dose of study drug. Prior exposure to acalabrutinib (ACP-196). History or presence of clinically significant hypersensitivity or idiosyncratic reaction to acalabrutinib, omeprazole, related compounds (eg, substituted benzimidazoles, other azole compounds), or any inactive ingredients. History or presence of liver disease and Clostridium difficile-associated diarrhea.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 (Acidic formulation)<br>In Part 1 of the study, the participants will receive Dose 1 of ACP-196 (reference or acidic formulation as applicable) with 240 mL water in 4 treatment schedules on Day 1, Day 3, Day 8 (with omeprazole), and Day 10 (with omeprazole). | Drug: ACP-196<br>* In Parts 1, 2, and 3, participants will receive oral Dose 1 of ACP-196 (reference or acidic formulation as applicable) on Day 1, Day 3, Day 8, and Day 10.<br>* Other names: Acalabrutinib;Drug: Omeprazole<br>* Participants will receive omeprazole in all parts as: on Day 8 and Day 10 with water in Part 1; on Day 8 with water and on Day 10 with acidic beverage in Part 2; on Day 8 with water and on Day 10 with grapefruit juice in Part 3.<br>|
| Experimental: Part 2 (Orange drink)<br>In Part 2 of the study, the participants will receive Dose 1 of ACP-196 (reference formulation) with 240 mL water or acidic beverage as applicable in 4 treatment schedules on Day 1, Day 3, Day 8 (with omeprazole), and Day 10 (with omeprazole). | Drug: ACP-196<br>* In Parts 1, 2, and 3, participants will receive oral Dose 1 of ACP-196 (reference or acidic formulation as applicable) on Day 1, Day 3, Day 8, and Day 10.<br>* Other names: Acalabrutinib;Drug: Omeprazole<br>* Participants will receive omeprazole in all parts as: on Day 8 and Day 10 with water in Part 1; on Day 8 with water and on Day 10 with acidic beverage in Part 2; on Day 8 with water and on Day 10 with grapefruit juice in Part 3.<br>|
| Experimental: Part 3 (Grapefruit juice)<br>In Part 3 of the study, the participants will receive Dose 1 of ACP-196 (reference formulation) with 240 mL water or grapefruit as applicable in 4 treatment schedules on Day 1, Day 3, Day 8 (with omeprazole), and Day 10 (with omeprazole). | Drug: ACP-196<br>* In Parts 1, 2, and 3, participants will receive oral Dose 1 of ACP-196 (reference or acidic formulation as applicable) on Day 1, Day 3, Day 8, and Day 10.<br>* Other names: Acalabrutinib;Drug: Omeprazole<br>* Participants will receive omeprazole in all parts as: on Day 8 and Day 10 with water in Part 1; on Day 8 with water and on Day 10 with acidic beverage in Part 2; on Day 8 with water and on Day 10 with grapefruit juice in Part 3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of ACP-196 in Parts 1, 2, and 3 |  | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours on Days 1, 3, 8, and 10 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of ACP-196 in Parts 1, 2, and 3 |  | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours on Days 1, 3, 8, and 10 | 
| Maximum Observed Plasma Concentration (Cmax) of ACP-196 in Parts 1, 2, and 3 |  | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours on Days 1, 3, 8, and 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of AUC0inf Extrapolated (AUC%extrap) of ACP-196 in Parts 1, 2, and 3 |  | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours on Days 1, 3, 8, and 10 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6h) of ACP-196 in Parts 1, 2, and 3 |  | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours on Days 1, 3, 8, and 10 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC0-12h) of ACP-196 in Parts 1, 2, and 3 |  | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours on Days 1, 3, 8, and 10 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of ACP-196 in Parts 1, 2, and 3 |  | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours on Days 1, 3, 8, and 10 | 
| Apparent Terminal Elimination Rate Constant (λz) of ACP-196 in Parts 1, 2, and 3 |  | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours on Days 1, 3, 8, and 10 | 
| Apparent Terminal Elimination Half-life (T1/2) of ACP-196 in Parts 1, 2, and 3 |  | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours on Days 1, 3, 8, and 10 | 
| Apparent Total Plasma Clearance (CL/F) of ACP-196 in Parts 1, 2, and 3 |  | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours on Days 1, 3, 8, and 10 | 
| Apparent Total Volume of Distribution (Vz/F) of ACP-196 in Parts 1, 2, and 3 |  | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours on Days 1, 3, 8, and 10 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24h) of Omeprazole in Parts 1, 2, and 3 |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours on Days 8 and 10 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Omeprazole in Parts 1, 2, and 3 |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours on Days 8 and 10 | 
| Maximum Observed Plasma Concentration (Cmax) of Omeprazole in Parts 1, 2, and 3 |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours on Days 8 and 10 | 
| Time of the Maximum Measured Plasma Concentration (Tmax) of Omeprazole in Parts 1, 2, and 3 |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours on Days 8 and 10 | 
| Apparent Total Plasma Clearance (CL/F) of Omeprazole in Parts 1, 2, and 3 |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours on Days 8 and 10 | 
| Apparent Total Volume of Distribution (Vz/F) of Omeprazole in Parts 1, 2, and 3 |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours on Days 8 and 10 | 
| Number of Participants With Treatment emergent Adverse Events (TEAEs) and Treatment emergent Serious Adverse Events (TESAEs) in Parts 1, 2, and 3 |  | From Day 1 through 14 days after the last dose (approximately 2 months) | 
| Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs in Parts 1, 2, and 3 |  | From Day 1 through 24 hours post last dose on Day 10 (approximately 2 months) | 
| Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs in Parts 1, 2, and 3 |  | From Day 1 through 24 hours post last dose on Day 10 (approximately 2 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PK, Acalabrutinib, ACP-196, Healthy volunteers, Pharmacokinetics, Acidic Formulation, Acidic Beverage, Grapefruit Juice, Omeprazole, Fixed-sequence