A Study to Evaluate the Effect of Hepatic Insufficiency on the Pharmacokinetics (PK) of ACP-196

A 2-Part, Open-Label, Single-Dose Study to Investigate the Influence of Hepatic Insufficiency on the Pharmacokinetics of ACP-196

The study will evaluate the influence of hepatic insufficiency on the PK of ACP-196.

Study Overview

• Status: Completed
• Conditions: Hepatic Insufficiency
• Intervention / Treatment: Drug: ACP-196

Detailed Description

This is a 2-part study. Part 1 of the study will compare the PK of ACP-196 in participants with mild hepatic insufficiency (a score of 5 to 6, on the Child-Pugh scale) and moderate hepatic insufficiency (a score of 7 to 9, on the Child-Pugh scale) to healthy (mean) matched control participants for age and weight. Part 2 of the study, if it is conducted, will compare the PK of ACP-196 in participants with severe hepatic insufficiency (a score of 10 to 15 on the Child-Pugh scale) to the healthy control participants from Part 1. In Part 1, 6 participants with mild hepatic insufficiency, 6 participants with moderate hepatic, and 6 healthy control participants matched to the hepatic insufficiency groups according to mean age and mean weight will be enrolled. In Part 2, if conducted, 6 participants with severe hepatic insufficiency will be enrolled. The control group of Part 1 will be used for Part 2 PK comparison. 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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Research Site
    • Orlando, Florida, United States, 32809
      • Research Site
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All Participants:

• Continuous non-smokers or smokers (of fewer than 20 cigarettes/day or the equivalent). Participants must agree to consume no more than 10 cigarettes or equivalent/day from 24 hours before dosing and throughout the period of sample collection.
• Women participants must be of non-child bearing status and must have negative serum pregnancy test.
• Men of reproductible potential must be willing to abstain from heterosexual intercourse or refrain from sperm donation or use contraception during the study and through 90 days after the last dose of study drug.

Hepatic impaired participants:

• Body mass index (BMI) >= 19 and <= 40 kg/m^2, at screening.
• Have medical history, physical examination, vital signs, 12-lead ECGs, and laboratory safety tests consistent with a diagnosis of hepatic impairment, but is otherwise judged to be in good health as determined by the principal investigator (PI).
• Participant has a diagnosis of chronic (> 6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) hepatic insufficiency with features of cirrhosis due to any etiology.
• Part 1 only: Mild - Participant's score on the Child-Pugh scale must range from 5 to 6 (mild hepatic insufficiency) at screening. Moderate - Participant's score on the Child-Pugh scale must range from 7 to 9 (moderate hepatic insufficiency) at screening. For participants who have compensated hepatic insufficiency while on medical therapy, they should be classified by their pretreatment parameters.
• Part 2 only: Severe - Participant's score on the Child-Pugh scale must range from 10 to 15 (severe hepatic insufficiency) at screening. For participant's who have compensated hepatic insufficiency while on medical therapy, they should be classified by their pretreatment parameters.

Healthy control participants only:

• BMI >= 19 and <= 40 kg/m^2 at screening.
• Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs, or ECGs, as deemed by the PI. Liver function tests, and serum bilirubin, must be <= the upper limit of normal at screening.

Exclusion Criteria:

All participants:

• History or presence of clinically significant or unstable medical or psychiatric condition or disease in the opinion of the PI.
• 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.
• Any clinically significant condition that may affect ACP-196 absorption in the opinion of the PI, including gastric restrictions and bariatric surgery (eg, gastric bypass).
• Unable to refrain from or anticipates use of medicines defined in the protocol..
• Have been on a diet incompatible with the on-study diet, in the opinion of the PI, within the 28 days before the dose of study drug, and throughout the study.

Hepatic impaired participants only:

• History or presence of drug abuse within the past 2 years before screening.
• Positive results for the urine or breathalyzer alcohol test and/or urine drug screen at screening or check-in, unless the positive drug screen is due to prescription drug use and is approved by the PI and Acerta Pharma's medical monitor.
• Known history of HIV or hepatitis B virus (HBV) or active infection with hepatitis C virus (HCV). During screening, participants who have active HCV infection or unstable levels of transaminase consistent with active Hepatitis C, will be excluded.
• No hepatic impaired participant will be dosed in both Part 1 and Part 2.

Healthy control participants only:

• History or presence of clinically significant thyroid disease, in the opinion of the PI.
• History or presence of alcoholism and/or drug abuse within the past 2 years before screening.
• Positive results for the urine or breathalyzer alcohol test and/or urine drug screen at screening.
• Positive results at screening for hepatitis B surface antigen or HCV.
• Seated blood pressure is less than 90/40 mmHg or greater than 150/95 mmHg at screening.
• Seated heart rate is lower than 40 beats per minute (bpm) or higher than 99 bpm at screening.
• Hemoglobin level below the lower limit of normal at screening, and considered clinically significant by the PI.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part1: Mild hepatic insufficiency; Participants with mild hepatic insufficiency will receive a single oral dose of 50 mg ACP-196 (2 x 25 mg capsules) on Day 1 of the study.	Drug: ACP-196; All study participants will receive a single oral dose of 50 mg ACP-196 (2 x 25 mg capsules) on Day 1 of the study.; Other Names: Acalabrutinib
Experimental: Part 1: Moderate hepatic insufficiency; Participants with moderate hepatic insufficiency will receive a single oral dose of 50 mg ACP-196 (2 x 25 mg capsules) on Day 1 of the study.	Drug: ACP-196; All study participants will receive a single oral dose of 50 mg ACP-196 (2 x 25 mg capsules) on Day 1 of the study.; Other Names: Acalabrutinib
Experimental: Part 1: Normal hepatic function; Participants with normal hepatic function will receive a single oral dose of 50 mgACP-196 (2 x 25 mg capsules) on Day 1 of the study.	Drug: ACP-196; All study participants will receive a single oral dose of 50 mg ACP-196 (2 x 25 mg capsules) on Day 1 of the study.; Other Names: Acalabrutinib
Experimental: Part 2: Severe hepatic insufficiency; Participants with sever hepatic insufficiency will receive a single oral dose of 50 mg ACP-196 (2 x 25 mg capsules) on Day 1 of the study.	Drug: ACP-196; All study participants will receive a single oral dose of 50 mg ACP-196 (2 x 25 mg capsules) on Day 1 of the study.; Other Names: Acalabrutinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of ACP-196	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours (hrs) for all arms, additional timepoints at 36 and 48 hrs post dose for mild/moderate/severe hepatic insufficiency arms
Maximum Observed Plasma Concentration (Cmax) of ACP-196	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours (hrs) for all arms, additional timepoints at 36 and 48 hrs post dose for mild/moderate/severe hepatic insufficiency arms

Secondary Outcome Measures

Outcome Measure	Time Frame
Area Under the Plasma Concentration-time Curve From Time 0 To Time of Last Measurable Concentration (AUC0-last) of ACP-196	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours (hrs) for all arms, additional timepoints at 36 and 48 hrs post dose for mild/moderate/severe hepatic insufficiency arms
Area Under the Plasma Concentration-time Curve From Time 0 To 24 Hours (AUC0-24) of ACP-196	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours (hrs) for all arms, additional timepoints at 36 and 48 hrs post dose for mild/moderate/severe hepatic insufficiency arms
Percent of AUC0inf Extrapolated (AUC%extrap) of ACP-196	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours (hrs) for all arms, additional timepoints at 36 and 48 hrs post dose for mild/moderate/severe hepatic insufficiency arms
Time of the Maximum Measured Plasma Concentration (Tmax) of ACP-196	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours (hrs) for all arms, additional timepoints at 36 and 48 hrs post dose for mild/moderate/severe hepatic insufficiency arms
Time of the Last Measurable Plasma Concentration (Tlast) of ACP-196	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours (hrs) for all arms, additional timepoints at 36 and 48 hrs post dose for mild/moderate/severe hepatic insufficiency arms
Apparent Terminal Elimination Rate Constant (λz) of ACP-196	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours (hrs) for all arms, additional timepoints at 36 and 48 hrs post dose for mild/moderate/severe hepatic insufficiency arms
Apparent Terminal Elimination Half-life (T1/2) of ACP-196	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours (hrs) for all arms, additional timepoints at 36 and 48 hrs post dose for mild/moderate/severe hepatic insufficiency arms
Apparent Total Body Clearance (CL/F) of ACP-196	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours (hrs) for all arms, additional timepoints at 36 and 48 hrs post dose for mild/moderate/severe hepatic insufficiency arms
Apparent Total Volume of Distribution (Vz/F) of ACP-196	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours (hrs) for all arms, additional timepoints at 36 and 48 hrs post dose for mild/moderate/severe hepatic insufficiency arms
Incidences of Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	From Day 1 through 14 days after the last dose (approximately 4 months)
Incidences of Abnormal Vital Signs and Physical Examinations Reported as TEAEs	Day 1 through Day 3
Incidences of Abnormal Electrocardiograms (ECGs) Reported as TEAEs	Day 1 through Day 3
Incidences of Abnormal Clinical Laboratory Parameters Reported as TEAEs	Day 1 through Day 3

Collaborators and Investigators

• Sponsor: Acerta Pharma BV

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2014
• Primary Completion (Actual): February 2, 2015
• Study Completion (Actual): February 2, 2015

Study Registration Dates

• First Submitted: April 28, 2021
• First Submitted That Met QC Criteria: April 28, 2021
• First Posted (Actual): April 30, 2021

Study Record Updates

• Last Update Posted (Actual): April 30, 2021
• Last Update Submitted That Met QC Criteria: April 28, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; PK; Healthy participants; ACP-196; Moderate hepatic impairment; Mild hepatic impairment; Severe hepatic impairment
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency; Antineoplastic Agents; Acalabrutinib
• Other Study ID Numbers: ACE-HI-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing 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.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No