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

• ClinicalTrials.gov Identifier: NCT04867941
• Recruitment Status: Completed
• First Posted: April 30, 2021
• Last Update Posted: April 30, 2021
• Sponsor: Acerta Pharma BV
• Information provided by (Responsible Party): Acerta Pharma BV

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Hepatic Insufficiency	Drug: ACP-196	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 2-Part, Open-Label, Single-Dose Study to Investigate the Influence of Hepatic Insufficiency on the Pharmacokinetics of ACP-196
• Actual Study Start Date: October 21, 2014
• Actual Primary Completion Date: February 2, 2015
• Actual Study Completion Date: February 2, 2015

Arms and Interventions

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 Name: 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 Name: 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 Name: 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 Name: Acalabrutinib

Outcome Measures

Primary Outcome Measures :

1. Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of ACP-196 [ Time Frame: 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 ]
2. Maximum Observed Plasma Concentration (Cmax) of ACP-196 [ Time Frame: 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 :

1. Area Under the Plasma Concentration-time Curve From Time 0 To Time of Last Measurable Concentration (AUC0-last) of ACP-196 [ Time Frame: 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 ]
2. Area Under the Plasma Concentration-time Curve From Time 0 To 24 Hours (AUC0-24) of ACP-196 [ Time Frame: 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 ]
3. Percent of AUC0inf Extrapolated (AUC%extrap) of ACP-196 [ Time Frame: 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 ]
4. Time of the Maximum Measured Plasma Concentration (Tmax) of ACP-196 [ Time Frame: 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 ]
5. Time of the Last Measurable Plasma Concentration (Tlast) of ACP-196 [ Time Frame: 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 ]
6. Apparent Terminal Elimination Rate Constant (λz) of ACP-196 [ Time Frame: 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 ]
7. Apparent Terminal Elimination Half-life (T1/2) of ACP-196 [ Time Frame: 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 ]
8. Apparent Total Body Clearance (CL/F) of ACP-196 [ Time Frame: 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 ]
9. Apparent Total Volume of Distribution (Vz/F) of ACP-196 [ Time Frame: 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 ]
10. Incidences of Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [ Time Frame: From Day 1 through 14 days after the last dose (approximately 4 months) ]
11. Incidences of Abnormal Vital Signs and Physical Examinations Reported as TEAEs [ Time Frame: Day 1 through Day 3 ]
12. Incidences of Abnormal Electrocardiograms (ECGs) Reported as TEAEs [ Time Frame: Day 1 through Day 3 ]
13. Incidences of Abnormal Clinical Laboratory Parameters Reported as TEAEs [ Time Frame: Day 1 through Day 3 ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Florida

Research Site

Miami, Florida, United States, 33136

Research Site

Orlando, Florida, United States, 32809

United States, Tennessee

Research Site

Knoxville, Tennessee, United States, 37920

Sponsors and Collaborators

Acerta Pharma BV

Investigators

• Study Director: Priti Patel, MD; Acerta Pharma BV

More Information

• Responsible Party: Acerta Pharma BV
• ClinicalTrials.gov Identifier: NCT04867941
• Other Study ID Numbers: ACE-HI-001
• First Posted: April 30, 2021
• Last Update Posted: April 30, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

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.

• 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 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.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Acerta Pharma BV:

ACP-196; Healthy participants; Mild hepatic impairment; Moderate hepatic impairment; Severe hepatic impairment; Pharmacokinetics; PK; Safety

Additional relevant MeSH terms:

Hepatic Insufficiency; Liver Failure; Liver Diseases; Digestive System Diseases; Acalabrutinib; Antineoplastic Agents