A Study in Healthy Subjects to Assess Bioavailability (Proportion of a Drug Which Enters the Circulation to Have an Active Effect) of Acalabrutinib Tablet and Protonpump Inhibitor Effect (Members of a Class of Medications That Inhibits in Gastric Acid Production) for Rabeprazole

NCT04564040 | Completed Phase 1 FDA Drug

• 1 other identifier: D8223C00005
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This Phase 1 study is being conducted to support the clinical development of acalabrutinib in hospitalized patients who are unable to swallow acalabrutinib tablet or capsule due to respiratory failure, eg, they may require endotracheal intubation for ventilator support and nasogastric (NG) tube placement, and it is important to have a clinically acceptable method to administer acalabrutinib via NG tube. Part 1 of the study is designed to evaluate relative bioavailability by comparing the pharmacokinetic (PK) of AT suspension in water administered via NG tube with the PK of acalabrutinib capsule suspension in flat COCA-COLA administered via NG tube. Additionally, the PPI effect will be evaluated by comparing the PK of AT suspension in water administered via NG tube plus rabeprazole with the PK of AT suspension in water administered via NG tube. Part 2 of the study is designed to evaluate the effect of NG administration on AT by comparing the PK of AT suspension in water administered via NG tube with the PK of AT orally administered with water.

Conditions

Mantle Cell Lymphoma; COVID-19

Keywords

Sequential; Proton-pump Inhibitor; Relative Bioavailability; Bruton Tyrosine Kinase Inhibitor

Outcome Measures

Primary Outcomes (12)

• Part 1 and 2: Area under plasma concentration-time curve from time zero to infinity (AUCinf)

  Part 1: Comparison of AUCinf of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of AUCinf of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

• Part 1 and 2: Area under the plasma concentration time curve from time zero to time of last quantifiable concentration (AUClast)

  Part 1: Comparison of AUClast of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of AUClast of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

• Part 1 and Part 2: Maximum observed plasma concentration (Cmax)

  Part 1: Comparison of Cmax of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of Cmax of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

• Part 1 and Part 2: Area under the plasma concentration-time curve from time zero to 24 hours post dose (AUC0-24)

  Part 1: Comparison of AUC0-24 of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of AUC0-24 of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

• Part 1 and 2: Time to reach maximum observed plasma concentration (tmax)

  Part 1: Comparison of tmax of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of tmax of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

• Part 1 and 2: Half-life associated with terminal slope (λz) of a semi-logarithmic concentrationtime curve (t1/2)

  Part 1: Comparison of t1/2 of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of t1/2 of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

• Part 1 and 2: Mean residence time of the drug in the systemic circulation from zero to infinity (MRT)

  Part 1: Comparison of MRT of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of MRT of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

• Part 1 and 2: Terminal elimination rate constant (λz)

  Part 1: Comparison of λz of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of λz of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

• Part 1 and 2: Apparent total body clearance of drug from plasms after extravascular administration (acalabrutinib only (CL/F)

  Part 1: Comparison of CL/F of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of CL/F of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

• Part 1 and 2: Apparent volume of distribution during the terminal phase after extravascular administration (acalabrutinib only) (Vz/F)

  Part 1: Comparison of Vz/F of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of Vz/F of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

• Part 1 and 2: Metabolite to parent ratio based on AUCinf and/or AUClast (M:P[AUC])

  Part 1: Comparison of M:P\[AUC\] of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of M:P\[AUC\] of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

• Part 1 and 2: Metabolite to parent ratio based on Cmax (M:P[Cmax])

  Part 1: Comparison of M:P\[Cmax\] of acalabrutinib and its metabolite (ACP-5862) following NG administration of AT suspension versus NG administration of acalabrutinib capsule suspension and to evaluate the effect of PPI (rabeprazole) on acalabrutinib and ACP-5862 PK profiles following NG administration of AT suspension. Part 2: Comparison of M:P\[Cmax\] of acalabrutinib and ACP 5862 following NG administration of AT suspension versus oral administration of AT.

  Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose), Day 2 (24 hours post-dose)

Secondary Outcomes (1)

• Number of subjects with serious and non-serious adverse events

  From screening visit (Day -28) to Follow-up visit (7-10 days after last dose or early termination)

Study Arms (2)

Acalabrutinib Treatment Sequence 1

EXPERIMENTAL

Part 1: Participants will receive Treatment A (100 mg AT suspension in water via NG administration) in Period 1, Treatment B (100 mg acalabrutinib capsule suspension via NG administration) in Period 2, and Treatment C (100 mg AT suspension in water via NG administration plus 20 mg rabeprazole) in Period 3. Part 2: Participants will receive Treatment D (100 mg AT suspension in water via NG administration) in Period 1 and Treatment A in Period 2.

Drug: Acalabrutinib Treatment A; Drug: Acalabrutinib Treatment B; Drug: Acalabrutinib Treatment C; Drug: Acalabrutinib Treatment D

Acalabrutinib Treatment Sequence 2

EXPERIMENTAL

Part 1: Participants will receive Treatment B in Period 1, Treatment A in Period 2, and Treatment C in Period 3. Part 2: Participants will receive Treatment A in Period 1 and Treatment D in Period 2.

Drug: Acalabrutinib Treatment A; Drug: Acalabrutinib Treatment B; Drug: Acalabrutinib Treatment C; Drug: Acalabrutinib Treatment D

Interventions

Acalabrutinib Treatment A DRUG

Participants will receive 100 mg AT suspension in water via NG tube.

Also known as: AT

Acalabrutinib Treatment Sequence 1; Acalabrutinib Treatment Sequence 2

Acalabrutinib Treatment B DRUG

Participants will receive 100 mg acalabrutinib capsule suspension via NG tube.

Also known as: Acalabrutinib capsule

Acalabrutinib Treatment Sequence 1; Acalabrutinib Treatment Sequence 2

Acalabrutinib Treatment C DRUG

Participants will receive 100 mg AT suspension in water via NG administration plus 20 mg rabeprazole.

Also known as: AT and Pariet® (raberprazole)

Acalabrutinib Treatment Sequence 1; Acalabrutinib Treatment Sequence 2

Acalabrutinib Treatment D DRUG

Participants will receive 100 mg AT orally.

Also known as: AT

Acalabrutinib Treatment Sequence 1; Acalabrutinib Treatment Sequence 2

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent form (ICF) prior to any study-specific procedures.
• Healthy adult male and female subjects aged 18 to 55 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
• Male subjects and their female partners/spouses must adhere to the contraception methods.
• Female subjects must have a negative pregnancy test at screening and on admission, must not be lactating, and must be of non childbearing potential, confirmed at screening.
• Have a body mass index between 18.5 and 30 kg/m\^2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive, at screening.
• Understands the study procedures in the ICF and willing and able to comply with the protocol.

You may not qualify if:

• History or presence of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
• History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs, as judged by the Investigator.
• Any clinically significant illness, medical/surgical procedure, or trauma within 30 days of the first administration of study medication.
• Any clinically significant abnormalities in hematology, coagulation, clinical chemistry, or urinalysis results, at screening and on first admission to the Clinical Unit, as judged by the Investigator and defined as:
• (i) Hemoglobin less than lower limit of normal. (ii) Platelet count less than lower limit of normal. (iii) Absolute neutrophil count less than the lower limit of normal. (iv) Prothrombin time, Activated partial thromboplastin time or International normalized ratio above upper limit of normal (ULN).
• (v) Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) or serum bilirubin (total and direct) \> 1.5 ULN.
• Any clinically significant abnormal findings in vital signs at screening and on first admission to the Clinical Unit, as judged by the Investigator, eg:
• (i) Systolic blood pressure (BP) \< 90 mmHg or ≥ 140 mmHg and diastolic blood pressure (DBP) \< 50 mmHg or ≥ 90 mmHg sustained for at least 10 minutes while resting in a supine position.
• (ii) Pulse \< 50 beats per minute (bpm) or \> 90 bpm.
• Any clinically significant abnormalities on standard 12-lead electrocardiogram (ECG) at screening and on first admission to the Clinical Unit, including but not limited to any of the following:
• (i) QTcF \> 450 millisecond (ms) or \< 340 ms or family history of long QT syndrome, (ii) Any significant arrhythmia, (iii) Conduction abnormalities: Clinically significant PR (PQ) interval prolongation (\> 240 ms); intermittent second or third degree atrioventricular (AV) block, or AV dissociation, Complete bundle branch block and/or QRS duration \> 120 ms.
• Any positive result on screening for serum hepatitis B virus antigen or hepatitis B core antibody, hepatitis C antibody, and human immunodeficiency virus antibody.
• Has received a new chemical or biological entity within 90 days or at least 5 half-lives, whichever is the longest, of the first administration of study medication in this study.
• 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 Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to acalabrutinib or rabeprazole.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Berlin, 14050, Germany

Location

MeSH Terms

Conditions

Lymphoma, Mantle-Cell; COVID-19

Interventions

acalabrutinib; Rabeprazole

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Dr. Rainard Fuhr

  Parexel

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2020
• First Posted: September 25, 2020
• Study Start: October 12, 2020
• Primary Completion: December 11, 2020
• Study Completion: December 11, 2020
• Last Updated: December 29, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Locations

DE (1)