A Study to Assess the Pharmacokinetics and Safety of Different Forms and Formulations of AZD9496 in Healthy Subjects

NCT02780713 | Completed Phase 1 Results

• 1 other identifier: D6090C00005
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase 1 open label single centre study of AZD9496 administered orally in healthy volunteers. The study design involves single administration of different forms, formulations and doses of AZD9496. The study is designed to investigate these different AZD9496 variants. The study will evaluate the pharmacokinetic profiles and the safety and tolerability of the different forms, formulations and doses of AZD9496 This is a fixed sequence study with 5-sequential treatment periods in healthy volunteers. Each volunteer will receive 5 single doses of AZD9496 in different forms, formulations and doses.

Conditions

Breast Cancer

Keywords

Breast cancer; Healthy volunteers; Pharmacokinetics; AZD9496; Safety; Tolerability

Outcome Measures

Primary Outcomes (6)

• Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period.

  To evaluate maximum observed plasma concentration (Cmax) for AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation.

  Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period

• Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period

  To evaluate the area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUC (0-t) of AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation

  Regular Pharmacokinetic measurement: At Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period

• Pharmacokinetics: Maximum Plasma Concentration (Cmax) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference

  To evaluate maximum plasma concentration (Cmax) of capsule variants by comparing with reference AZD9496

  Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period

• Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference

  To evaluate area under curve from time zero to time with last observation (AUC0-t) of variants by comparing with reference AZD9496

  Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period

• Pharmacokinetics: Area Under the Curve From Time Zero to Infinity for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference

  To evaluate area under the curve from time zero to time infinity (AUC 0-infinity) of variants by comparing with reference AZD9496

  Regular Pharmacokinnetic measurement Pre-dose, 0.5, 1, 1.5, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24, and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period

• Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period

  To evaluate area under the curve from time zero to infinity (AUC 0-infinity) for AZD9496 and its metabolites

  Regular pharmacokinetic measurement pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period

Secondary Outcomes (9)

• Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period

• Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period

  Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period

• Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period.

  Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period

• Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period

• Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period

Study Arms (1)

AZD9496

EXPERIMENTAL

This is a fixed sequence study with 5-sequential treatment periods in healthy volunteers. Each volunteer will receive 5 single doses of AZD9496 in different forms, formulations and doses. 1. Treatment period 1 will assess AZD9496 Variant A: 100mg. 2. Treatment period 2 will assess AZD9496 Reference: 100mg. 3. Treatment period 3 will assess one of AZD9496 Variants, B, C or D: 100mg. 4. Treatment period 4 will assess one of AZD9496 Variants, B, C or D: 100mg. 5. Treatment period 5 will assess one of AZD9496 Variants A, B, C or D: \*300mg. \*Based on a review of PK and safety results from Treatment Periods 1, 3 and 4, a lower dose of 200 mg may be administered in Treatment Period 5

Drug: AZD9496 (Reference); Drug: AZD9496 Variant A; Drug: AZD9496 Variant B; Drug: AZD9496 Variant C; Drug: AZD9496 Variant D

Interventions

AZD9496 (Reference) DRUG

AZD9496 (Reference)

AZD9496

AZD9496 Variant A DRUG

AZD9496 Variant A.

AZD9496

AZD9496 Variant B DRUG

AZD9496 Variant B

AZD9496

AZD9496 Variant C DRUG

AZD9496 Variant C

AZD9496

AZD9496 Variant D DRUG

AZD9496 Variant D

AZD9496

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Healthy male and/or female subjects aged 18 to 65 years with suitable veins for cannulation or repeated venipuncture.
• Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria: Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and FSH levels in the post-menopausal range (OR) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation
• Male subjects aged 18 to 39 years must be vasectomized. Male subjects aged 40 to 65 years must either be vasectomized or have no intention of fathering a child for a period of 6 months after receiving the last dose of IMP.
• Have a body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive.
• Values for AST, ALT, TBL, GGT and ALP must be at or below the upper limit of normal ranges at screening.

You may not qualify if:

• History 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 (GI), 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 IMP.
• Previous history of venous or arterial thromboembolism or thrombophilia.
• History of endometrial polyps, endometrial cancer, atypical endometrial hyperplasia, or other endometrial disorders unless subjects have undergone total hysterectomy and there is no evidence of active disease (females only).
• Any clinically significant abnormal findings in supine vital signs, after 10 minutes of supine rest, at screening and/or admission to the unit, defined as: (a) Systolic blood pressure \< 90 mmHg or ≥ 150 mmHg (b) Diastolic blood pressure \< 50 mmHg or ≥ 95 mmHg and (c) Heart rate \< 45 or \> 90 beats per minute
• Any clinically important abnormalities in rhythm, conduction or morphology of the resting 12-lead ECG that, as judged by the investigator, that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology or pronounced left ventricular hypertrophy.
• Prolonged QTcF \> 460 ms for females and QTcF \> 450 ms for males or family history of long QT syndrome.
• PR (PQ) interval shortening \< 110 ms or evidence of ventricular pre-excitation).
• PR (PQ) interval prolongation \> 240 ms, intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block.
• Persistent or intermittent complete bundle branch block with QRS \> 120 ms or evidence of pronounced ventricular hypertrophy or pre-excitation.
• Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) antibody.
• Known or suspected history of drug abuse, as judged by the investigator.
• Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening.
• Known or suspected history of alcohol or drug abuse or excessive intake of alcohol, as judged by the investigator.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Baltimore, Maryland, 21225, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

AZD9496

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Limitations and Caveats

Data from all analysed secondary pharmacokinetic parameters are presented.

Results Point of Contact

• Title: AZD9496 Global clinical leader
• Organization: AstraZeneca AB

ClinicalTrialTransparency@astrazeneca.com

+46317761000

Study Officials

• Dr. Ronald Goldwater

  Parexel

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: May 20, 2016
• First Posted: May 23, 2016
• Study Start: June 2, 2016
• Primary Completion: September 20, 2016
• Study Completion: September 20, 2016
• Last Updated: August 25, 2021
• Results First Posted: August 25, 2021

Record last verified: 2021-08

Locations

US (1)