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

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ClinicalTrials.gov Identifier: NCT02780713
Recruitment Status : Completed
First Posted : May 23, 2016
Last Update Posted : November 8, 2016
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

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.


Condition or disease Intervention/treatment Phase
Breast Cancer Drug: AZD9496 (Reference) Drug: AZD9496 Variant A Drug: AZD9496 Variant B Drug: AZD9496 Variant C Drug: AZD9496 Variant D Phase 1

Detailed Description:

A phase 1, open-label, single centre study to assess the pharmacokinetics, Safety and tolerability of different forms, formulations and doses of AZD9496 in healthy volunteers. This is a fixed sequence study with 5-sequential treatment periods. Each subject will receive 5 single doses of AZD9496 in different forms, formulations and doses.

  • Treatment period one will assess AZD9496 Variant A: 100mg.
  • Treatment period two will assess AZD9496 Reference form: 100mg.
  • Treatment period 3 will assess one of AZD9496 Variants, B, C or D: 100mg.
  • Treatment period 4 will assess one of AZD9496 Variants, B, C or D: 100mg.
  • Treatment period 5 will assess one of AZD9496 Variants A, B, C or D: *300mg. *Based on a review of pharmacokinetic and safety results from Treatment Periods 1, 3 and 4, a lower dose of 200 mg may be administered in Treatment Period 5.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study to Evaluate the Pharmacokinetic and Safety Profile of AZD9496 Following Single Dose Administration of Different Forms and Formulations in Healthy Subjects
Study Start Date : June 2016
Actual Primary Completion Date : September 2016
Actual Study Completion Date : September 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.

  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)
AZD9496 (Reference)

Drug: AZD9496 Variant A
AZD9496 Variant A.

Drug: AZD9496 Variant B
AZD9496 Variant B

Drug: AZD9496 Variant C
AZD9496 Variant C

Drug: AZD9496 Variant D
AZD9496 Variant D




Primary Outcome Measures :
  1. Pharmacokinetics: Area under the curve from time zero to time with last observation (AUC0-t) for AZD9496 and its metabolites at each treatment period [ Time Frame: 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 ]
    Area under the curve from time zero to time with last observation (AUC0-t) for AZD9496 and its metabolites at each treatment period

  2. Pharmacokinetics: Area under the curve from time zero to infinity (AUC) for AZD9496 and its metabolites at each treatment period [ Time Frame: 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 ]
    Area under the curve from time zero to infinity (AUC) for AZD9496 and its metabolites at each treatment period

  3. Pharmacokinetics: Maximum plasma concentration (Cmax) for AZD9496 and its metabolites at each treatment period [ Time Frame: 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 ]
    Maximum plasma concentration (Cmax) for AZD9496 and its metabolites at each treatment period

  4. Pharmacokinetics: Area under the curve from time zero to time with last observation (AUC0-t) for Variant A, B, C and D of AZD9496 compared to the AZD9496 Reference [ Time Frame: 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, C and D of AZD9496 compared to the AZD9496 Reference

  5. Pharmacokinetics: Area under the curve from time zero to infinity (AUC) for Variant A, B, C and D of AZD9496 compared to the AZD9496 Reference [ Time Frame: 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 (AUC) for Variant A, B, C and D of AZD9496 compared to the AZD9496 Reference

  6. Pharmacokinetics: Maximum plasma concentration (Cmax) for Variant A, B, C and D of AZD9496 compared to the AZD9496 Reference [ Time Frame: 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: Maximum plasma concentration (Cmax) for Variant A, B, C and D of AZD9496 compared to the AZD9496 Reference


Secondary Outcome Measures :
  1. Safety and tolerability of of single doses of AZD9496 Reference and AZD9496 Variants A, B, C and D [ Time Frame: pre dose and for 72 hours after each dose and 5 to 7 days after last dose ]
    Safety and Tolerability of different forms, formulations and doses of AZD9496 by assessing adverse events, ECG (e.g. QTc, RR intervals), Physical exam, vital signs and laboratory variables

  2. Pharmacokinetics: Area under the curve from time zero to 12 and 24 hours post-dose for AZD9496 and its metabolites at each treatment period [ Time Frame: 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 12 and 24 hours post-dose for AZD9496 and its metabolites at each treatment period

  3. Pharmacokinetics: Time to reach the Cmax (Tmax) for AZD9496 and its metabolites at each treatment period [ Time Frame: 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: Time to reach the Cmax (Tmax) for AZD9496 and its metabolites at each treatment period

  4. Pharmacokinetics: Effective half-life ( t½,eff) for AZD9496 and its metabolites at each treatment period [ Time Frame: 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: Effective half-life (t½,eff), for AZD9496 and its metabolites at each treatment period

  5. Pharmacokinetics: The terminal elimination half-life (t½,λz) for AZD9496 and its metabolites at each treatment period [ Time Frame: 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: The terminal elimination half-life (t½,λz) for AZD9496 and its metabolites at each treatment period

  6. Pharmacokinetics: Apparent volume of distribution (Vss/F) of AZD9496 and its metabolites at each treatment period [ Time Frame: 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: Apparent volume of distribution (Vss/F) of AZD9496 for AZD9496 and its metabolites at each treatment period

  7. Pharmacokinetics: Apparent oral clearance (CL/F) of AZD9496 and its metabolites at each treatment period [ Time Frame: 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: Apparent oral clearance (CL/F) of AZD9496 and its metabolites at each treatment period

  8. Pharmacokinetics: Apparent terminal elimination rate constant (λz) of AZD9496 and its metabolites at each treatment period [ Time Frame: 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: Apparent terminal elimination rate constant (λz) of AZD9496 and its metabolites at each treatment period

  9. Pharmacokinetics: Mean residence time (MRT) of AZD9496 and its metabolites at each treatment period [ Time Frame: 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: Mean residence time (MRT) of AZD9496 and its metabolites at each treatment period

  10. Pharmacokinetics: Metabolite to parent ratios (MRCmax, MRAUC0-t, MRAUC) at each treatment period [ Time Frame: 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: Metabolite to parent ratios (MRCmax, MRAUC0-t, MRAUC) at each treatment period


Other Outcome Measures:
  1. ECG parameter exposure response analysis [ Time Frame: Pre dose and at defined time points for up to 48 hours after each dose and 5 to 7 days after last dose. ]
    Exposure-response (E-R) analysis of the relationship of ECG parameters (e.g., QTc, RR intervals) to AZD9496 concentration



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Provision of signed and dated, written informed consent prior to any study specific procedures.
  2. Healthy male and/or female subjects aged 18 to 65 years with suitable veins for cannulation or repeated venipuncture.
  3. 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
  4. 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.
  5. 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.
  6. Values for AST, ALT, TBL, GGT and ALP must be at or below the upper limit of normal ranges at screening.

Exclusion Criteria:

  1. 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.
  2. 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.
  3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
  4. Previous history of venous or arterial thromboembolism or thrombophilia.
  5. 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).
  6. Any clinically significant abnormalities in clinical chemistry (other than Inclusion no.6), hematology, or urinalysis results at screening, as judged by the investigator.
  7. 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
  8. 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.
  9. Prolonged QTcF > 460 ms for females and QTcF > 450 ms for males or family history of long QT syndrome.
  10. PR (PQ) interval shortening < 110 ms or evidence of ventricular pre-excitation).
  11. PR (PQ) interval prolongation > 240 ms, intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block.
  12. Persistent or intermittent complete bundle branch block with QRS > 120 ms or evidence of pronounced ventricular hypertrophy or pre-excitation.
  13. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) antibody.
  14. Known or suspected history of drug abuse, as judged by the investigator.
  15. Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening.
  16. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol, as judged by the investigator.
  17. Positive screen for drugs of abuse, alcohol or cotinine at screening or on each admission to the unit.
  18. 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 AZD9496.
  19. Excessive intake of caffeine/xanthine containing drinks or food (e.g., coffee, tea, chocolate), as judged by the investigator.
  20. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
  21. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life Note: Hormonal replacement therapy is not allowed for females.
  22. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening
  23. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion is 3 months after the final dose from previous study or 1 month after the last visit of previous study, whichever is the longest. ote: Subjects consented and screened, but not dosed in this study or a previous phase I study, are not excluded.
  24. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives
  25. Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.
  26. Subjects who are vegans or have medical dietary restrictions.
  27. Subjects who cannot communicate reliably with the investigator.
  28. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02780713


Locations
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United States, Maryland
Research Site
Baltimore, Maryland, United States
Sponsors and Collaborators
AstraZeneca
Parexel
Investigators
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Principal Investigator: Dr. Ronald Goldwater Parexel
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02780713    
Other Study ID Numbers: D6090C00005
First Posted: May 23, 2016    Key Record Dates
Last Update Posted: November 8, 2016
Last Verified: November 2016
Keywords provided by AstraZeneca:
Breast cancer
Healthy volunteers
Pharmacokinetics
AZD9496
Safety
Tolerability
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases