A Study to Evaluate Safety, Pharmacokinetics, Pharmacodynamics, Food Effects, and Drug-drug Interactions of ACP-196 in Healthy Participants

A Phase 1, Single-center, Open-label, Sequential Dose-Escalation Study of ACP-196 in Healthy Subjects to Evaluate Safety, Pharmacokinetics, Pharmacodynamics, Food Effects, and Drug-Drug Interactions

This study is to evaluate the safety, pharmacokinetics/pharmacodynamics (PK/PD), food-effect, and drug-drug interaction study of ACP-196 in healthy participants.

Study Overview

• Status: Completed
• Conditions: Healthy Participants
• Intervention / Treatment: Drug: ACP-196; Drug: Itraconazole

Detailed Description

The study is divided into 3 parts. Part 1 will include 5 cohorts (Cohorts [C] 1 to 5) and participants will receive oral ACP-196 2.5 to 50 mg twice daily (BID) and 100 mg once daily (QD) on Day 1. In Part 2 (Cohort 6), participants will receive a single oral dose of 75.0 mg QD in a fasting and a fed state, with a 7-day washout period between the 2 doses. In Part 3 (Cohort 7), participants will receive a single oral dose of 50.0 mg QD alone on Day 1 and in combination with itraconazole on Day 9. Itraconazole 200 mg will be given twice daily (12 hours apart) with meals on Days 4 to 8 and once on Day 9 with ACP-196 under a fasting state in the morning.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tempe, Arizona, United States, 85283
      • Celerion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Body mass index (BMI) >=18.0 and <=30.0 kg/m^2.
• Healthy as determined by medical history and physical examination.
• Nonsmoker
• Normal clinical laboratory test results and ECG, or results with minor deviations which are not considered to be clinically significant in the judgment of the investigator.
• Men of and women of childbearing potential to follow protocol defined contraception methods.
• Women must have negative urine pregnancy test.
• Willingness and ability to swallow study drug capsules.

Exclusion Criteria:

• Prior or ongoing clinically significant illness, medical condition, medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results.
• Evidence of ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections).
• Women cannot be pregnant or breast feeding.
• Significant history of drug or alcohol abuse or addiction within 3 years before study screening or as evidenced by continuing medical complications of prior drug or alcohol use.
• History of blood or plasma donation within 90 days before first study drug administration.
• Currently drinking over 21 units/week of ethanol
• Drug toxicology screen positive for any prohibited drugs, illicit substances, or alcohol.
• Anticipated need for alcohol, tobacco, or any drug during the study drug administration and immediate follow-up periods.
• Relative to admission has any of the following exposures: has taken a prescription systemic medication within 14 days; has used an over-the counter systemic medication (other than acetaminophen) within 7 days; has ingested calcium supplements or calcium-containing vitamins within 7 days; has ingested grapefruit, grapefruit juice, or grapefruit-containing products within 7 days; has consumed alcohol within 48 hours; has taken acetaminophen within 24 hours.
• Positive test for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen or hepatitis B core antibody, or hepatitis C antibody.
• Unwillingness to avoid vigorous physical activity during inpatient clinic confinements.
• Part 2 only - Inability or unwillingness to eat all of the ingredients of the high-fat, high-calorie meal as specified in the protocol.
• Part 3 only - Known allergy to itraconazole or other azole compounds.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 Cohort 1; Participants will receive ACP-196 2.5 mg capsule orally BID on Day 1.	Drug: ACP-196; Participants will receive ACP-196 oral capsule(s) in all parts.; Other Names: Acalabrutinib
Experimental: Part 1 Cohort 2; Participants will receive ACP-196 5 mg (2 x 2.5 mg capsules) orally BID on Day 1.	Drug: ACP-196; Participants will receive ACP-196 oral capsule(s) in all parts.; Other Names: Acalabrutinib
Experimental: Part 1 Cohort 3; Participants will receive ACP-196 25 mg capsule orally BID on Day 1.	Drug: ACP-196; Participants will receive ACP-196 oral capsule(s) in all parts.; Other Names: Acalabrutinib
Experimental: Part 1 Cohort 4; Participants will receive ACP-196 50 mg (2 x 25 mg capsules) orally BID on Day 1.	Drug: ACP-196; Participants will receive ACP-196 oral capsule(s) in all parts.; Other Names: Acalabrutinib
Experimental: Part 1 Cohort 5; Participants will receive ACP-196 100 mg (4 x 25 mg capsules) orally QD on Day 1.	Drug: ACP-196; Participants will receive ACP-196 oral capsule(s) in all parts.; Other Names: Acalabrutinib
Experimental: Part 2 Cohort 6; Participants will receive ACP-196 75 mg (3 x 25 mg capsules) orally QD on Day 1 and Day 8.	Drug: ACP-196; Participants will receive ACP-196 oral capsule(s) in all parts.; Other Names: Acalabrutinib
Experimental: Part 3 Cohort 7; Participants will receive ACP-196 50 mg (2 x 25 mg capsules) orally QD on Day 1, itraconazole 200 mg capsules BID from Days 4 to 8 with meals and then ACP-196 50 mg (2 x 25 mg capsules) along with itraconazole 200 mg capsule QD on Day 9 under fasting state.	Drug: ACP-196; Participants will receive ACP-196 oral capsule(s) in all parts.; Other Names: Acalabrutinib; Drug: Itraconazole; Participants will receive itraconazole 200 mg capsules BID from Days 4 to 8 with meals and then 200 mg capsule QD on Day 9 under fasting state.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area Under the Concentration-time Curve From Time 0 to Last Quantifiable Concentration (AUC0-last) of ACP-196 in Parts 1, 2, and 3	Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of ACP-196 in Parts 1, 2, and 3	Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Maximum Observed Plasma Concentration (Cmax) of ACP-196 in Parts 1, 2, and 3	Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Time to reach Cmax (Tmax) of ACP-196 in Parts 1, 2, and 3	Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Terminal-elimination Half-life (T1/2) of ACP-196 in Parts 1, 2, and 3	Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Terminal-elimination Rate Constant (λz) of ACP-196 in Parts 1, 2, and 3	Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Time Delay Between the Time of Dosing and the First Measurable Concentration (tlag) of ACP-196 in Parts 1, 2, and 3	Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Incidences of Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	Part 1: Day 1 through Day 3; Part 2 and Part 3: Day 1 through Day 10
Incidences of Abnormal Vital Signs Reported as TEAEs	Part 1: Day 1 ( from 1 hr predose through 1 hr postdose); Part 2: From Day 1 (1 hr predose) through Day 8 (1 hr postdose); Part 3: From Day 1 (1 hr predose) through Day 9 (1 hr postdose)
Incidences of Abnormal Clinical Laboratory Parameters Reported as TEAEs	Part 1: From Day 1 to Day 2; Part 2 and Part 3: From Day 1 to Day 10
Incidences of Abnormal Electrocardiograms (ECGs) Reported as TEAEs	Part 1: Day 1 ( from 1 hr predose through 1 hr postdose); Part 2: From Day 1 (1 hr predose) through Day 8 (1 hr postdose); Part 3: From Day 1 (1 hr predose) through Day 9 (1 hr postdose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occupancy of Bruton's Tyrosine Kinase (BTK) by ACP-196 in Peripheral Blood Mononuclear Cells (PBMCs)	The BTK occupancy will be measured by BTK occupancy assay which measures percent of BTK occupied post baseline compared to the baseline, post administration of study drug. The BTK occupancy is defined as ACP-196 active-site occupancy of > 80% at 24 hours after the first dose administration.	1, 3, 12, 15, and 24 hrs after first dose on Day 1
Effect of ACP-196 on Biologic Markers of B-cell Function	The pharmacodynamics of ACP-196 will be evaluated in cluster of differentiation (CD) 69/CD86 expression. It will be considered as complete inhibition when biological markers of B-cell function (CD69 and CD86) inhibition ≥ 90%.	1, 3, 12, 15, and 24 hrs after first dose on Day 1

Collaborators and Investigators

• Sponsor: Acerta Pharma BV

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2014
• Primary Completion (Actual): May 22, 2014
• Study Completion (Actual): May 22, 2014

Study Registration Dates

• First Submitted: May 6, 2021
• First Submitted That Met QC Criteria: May 20, 2021
• First Posted (Actual): May 26, 2021

Study Record Updates

• Last Update Posted (Actual): May 26, 2021
• Last Update Submitted That Met QC Criteria: May 20, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Pharmacokinetics; PK; Healthy participants; Pharmacodynamics; Itraconazole; Acalabrutinib; Drug-drug interaction; ACP-196; Food effects
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Itraconazole; Acalabrutinib
• Other Study ID Numbers: ACE-HV-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.
• 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 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.

Drug and device information, study documents

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