Study to Assess the Effect of Food and Acid Reducing Agents on the Absorption of Capivasertib in Healthy Participants

An Open-label, Randomized, Crossover Study in Healthy Subjects to Evaluate the Effect of Food and Acid Reducing Agent(s) on the Pharmacokinetics of Capivasertib

This is a two-part, open-label, randomized, crossover study in healthy subjects (vasectomized males and women of non-childbearing potential), performed at 2 study centers

Study Overview

• Status: Completed
• Conditions: Solid and Hematological Malignancies
• Intervention / Treatment: Drug: Capivasertib; Drug: Rabeprazole

Detailed Description

Part 1 of the study will comprise:

• A screening period of maximum 28 days.
• Three treatment periods [Treatment A: Single oral dose of capivasertib in overnight fasted state, Treatment B:Single oral dose of capivasertib in fed state (high-fat, high-calorie breakfast) and Treatment C:Twice daily oral doses of rabeprazole for 3 days and a single dose on Day 1, and a single oral dose of capivasertib in fasted conditions] during which subjects will be resident from the morning of Day -1 (Day -4 for subjects receiving rabeprazole [Treatment C]) and discharged after the last pharmacokinetic (PK) sample collection, 48 hours after dosing of capivasertib of each treatment period.
• A final visit 7 to 14 days after the last capivasertib PK sample in Treatment Period 3.

Part 2 of the study will only be initiated if the findings from Part 1 show an interaction or are inconclusive. Part 2 of the study will comprise:

• A screening period of at least 28 days.
• Three treatment periods [Any 3 treatments: Treatment D:Single oral dose of capivasertib in overnight fasted state, Treatment E: Single oral dose of capivasertib in fed state (low-fat, low-calorie breakfast), Treatment F: Single oral dose of capivasertib in partially fasted conditions (food restricted from 2 hours prior to dosing until 1 hour after dosing), Treatment G: Single oral dose of capivasertib and single dose of famotidine in fasted condition and Treatment H: Twice daily oral doses of rabeprazole for 3 days (Days -3 to -1) and a single oral dose of capivasertib in fed state] during which subjects will be resident from the morning of Day -1 (Day -4 for subjects receiving rabeprazole [Treatment H]) and will be discharged after the last PK sample collection 48 hours after dosing of capivasertib of each treatment period.
• A final visit 7 to 14 days after the last capivasertib PK sample in Treatment Period 3.

The interim results from Part 1 indicated a potentially clinically relevant food interaction only and therefore Treatments D, E, and F will be studied in Part 2.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14050
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Healthy male and female subjects aged 18 to 58 years with suitable veins for cannulation or repeated venipuncture.

• Females must not be lactating and must be of non-childbearing potential, confirmed at screening:

  1. Postmenopausal defined as aged > 40 years and amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle stimulating hormone levels in the postmenopausal range.
  2. Documentation of irreversible/permanent surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation, at least 6 months prior to screening.
• Male subjects must be vasectomized, at least 6 months prior to screening, with documented post-procedural medical assessment of surgical success.
• Have a body mass index between 18.0 and 29.9 kg/m^2 (inclusive) for males and 18 to 32 kg/m^2 (inclusive) for females; and weigh at least 50 kg and no more than 100 kg inclusive.
• Non-smoker, defined as a subject who has not smoked previously or who has discontinued smoking.

Exclusion Criteria:

• History of any clinically significant disease or disorder.
• History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
• Any clinically significant abnormal findings in vital signs at screening and/or admission to the study center.

• Clinically significant abnormalities in glucose metabolism defined by any of the following:

  1. Diagnosis of diabetes mellitus type I or II (irrespective of management).
  2. Blood glucose value ≥ 5.9 mmol/L after fasting for at least 8 hours, at screening or on admission to study center.
  3. Glycosylated hemoglobin > upper limit of normal (up to 6.2% [44 mmol/mol]).
• Any positive result on screening for serum hepatitis B surface antigen or antibody to hepatitis B core antigen, hepatitis C antibody, and human immunodeficiency virus antibody.
• Known or suspected history of drug abuse.
• Has received another new chemical entity within 3 months of the first administration of IMP in this study.
• Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months 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 capivasertib, rabeprazole, or famotidine.
• Subjects who have previously received capivasertib.
• Subject has a positive test result for Severe acute respiratory syndrome coronavirus 2 reverse transcription polymerase chain reaction on admission.
• Subject has clinical signs and symptoms consistent with Coronavirus Disease 2019 (COVID-19) (eg, fever, dry cough, dyspnea, sore throat, anosmia/hyposmia, loss or reduced taste, and fatigue) or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission.
• History of severe COVID-19 (hospitalization, extracorporeal membrane oxygenation, mechanically ventilated).
• Subjects who are regularly exposed to the risk of COVID-19 infection as part of their daily life (eg, health care professionals working in COVID-19 wards or at emergency departments).
• Subjects who have had a COVID-19 vaccine within 3 weeks prior to screening or are planning to get a COVID-19 vaccine during the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment ABC; Participants will be randomized to receive oral doses of Treatment A, Treatment B and Treatment C.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.; Drug: Rabeprazole; Participants will receive twice daily oral doses of rabeprazole for 3 days (Days -3 to -1) and a single dose on the morning of Day 1 for Treatment C.
Experimental: Treatment ACB; Participants will be randomized to receive oral doses of Treatment A, Treatment C and Treatment B.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.; Drug: Rabeprazole; Participants will receive twice daily oral doses of rabeprazole for 3 days (Days -3 to -1) and a single dose on the morning of Day 1 for Treatment C.
Experimental: Treatment BAC; Participants will be randomized to receive oral doses of Treatment B, Treatment A and Treatment C.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.; Drug: Rabeprazole; Participants will receive twice daily oral doses of rabeprazole for 3 days (Days -3 to -1) and a single dose on the morning of Day 1 for Treatment C.
Experimental: Treatment BCA; Participants will be randomized to receive oral doses of Treatment B, Treatment C and Treatment A.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.; Drug: Rabeprazole; Participants will receive twice daily oral doses of rabeprazole for 3 days (Days -3 to -1) and a single dose on the morning of Day 1 for Treatment C.
Experimental: Treatment CAB; Participants will be randomized to receive oral doses of Treatment C, Treatment A and Treatment B.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.; Drug: Rabeprazole; Participants will receive twice daily oral doses of rabeprazole for 3 days (Days -3 to -1) and a single dose on the morning of Day 1 for Treatment C.
Experimental: Treatment CBA; Participants will be randomized to receive oral doses of Treatment C, Treatment B and Treatment A.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.; Drug: Rabeprazole; Participants will receive twice daily oral doses of rabeprazole for 3 days (Days -3 to -1) and a single dose on the morning of Day 1 for Treatment C.
Experimental: Treatment DEF; Participants will be randomized to receive oral doses of Treatment D, Treatment E and Treatment F.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.
Experimental: Treatment DFE; Participants will be randomized to receive oral doses of Treatment D, Treatment F and Treatment E.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.
Experimental: Treatment EDF; Participants will be randomized to receive oral doses of Treatment E, Treatment D and Treatment F.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.
Experimental: Treatment EFD; Participants will be randomized to receive oral doses of Treatment E, Treatment F and Treatment D.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.
Experimental: Treatment FDE; Participants will be randomized to receive oral doses of Treatment F, Treatment D and Treatment E.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.
Experimental: Treatment FED; Participants will be randomized to receive oral doses of Treatment F, Treatment E and Treatment D.	Drug: Capivasertib; Participants will receive single oral dose of capivasertib on Day 1 for Treatments A, B, C, D, E and F.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of Capivasertib	Maximum observed plasma (peak) drug concentration (Cmax) of capivasertib when administered alone under fed and fasted conditions, and in combination with acid reducing agent(s) rabeprazole and famotidine (if required).	Part 1 and Part 2: From Day 1 to Day 3
AUCinf of Capivasertib	Area under plasma concentration time curve from zero to infinity (AUCinf) of capivasertib when administered alone under fed and fasted conditions, and in combination with acid reducing agent(s) rabeprazole and famotidine (if required).	Part 1 and Part 2: From Day 1 to Day 3
AUClast of Capivasertib	Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) of capivasertib when administered alone under fed and fasted conditions, and in combination with acid reducing agent(s) rabeprazole and famotidine (if required).	Part 1 and Part 2: From Day 1 to Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with serious and non-serious adverse events	Safety and tolerability of capivasertib when administered alone under fed and fasted conditions, and in combination with acid reducing agent(s) rabeprazole and famotidine (if required).	Part 1: From Screening (Day -28 to Day -5) upto Follow-up Visit/Early Termination (7 to 14 days); Part 2: From Screening (Day -28 to Day -2) upto Follow-up Visit/Early Termination (7 to 14 days)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2021
• Primary Completion (Actual): May 4, 2022
• Study Completion (Actual): May 4, 2022

Study Registration Dates

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

Study Record Updates

• Last Update Posted (Actual): May 9, 2022
• Last Update Submitted That Met QC Criteria: May 6, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Crossover; Acid reducing agent; Food effect; Serine/threonine specific protein kinase inhibitor
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Hematologic Diseases; Hematologic Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Rabeprazole
• Other Study ID Numbers: D3614C00005; 2021-000836-74 (EudraCT Number)

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 requests 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 refer 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
• product manufactured in and exported from the U.S.: No