A Study to Investigate the Effect of Single Dose of AZD6094 (600 mg) on Cardiac Repolarization in Healthy Volunteers

NCT03258515 | Completed Phase 1 FDA Drug

• 1 other identifier: D5084C00001
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

This is a randomized, placebo-controlled, double-blind, 3-way crossover phase I study being conducted on healthy volunteers to investigate the effect of single dose of AZD6094 (600 mg) on cardiac repolarization under well-controlled conditions in accordance with the International Council for Harmonization (ICH) E14 guidelines. An open-label Moxifloxacin (400 mg), a fluoroquinolone broad spectrum antibiotic will be used as a appositive control for the time between the start of the Q wave and the end of the T wave (QT) prolongation in accordance with ICH E14 guidelines, to establish assay sensitivity. The core study consists of screening period, 3 treatment period (AZD6094, placebo and moxifloxacin; with a minimum washout period of 14 days between each treatment period) and follow-up. The study drugs will be administered orally. The study is planned to determine effect of AZD6094 at therapeutic dose, safety and tolerability. This study provides adequate and well-controlled mechanisms to deal with potential bias, facilitate identification of effects related to investigational product (IMP) administration and tolerability issues.

Conditions

Solid Tumors

Keywords

Mesenchymal epithelial transition (MET) receptor; Small molecule kinase inhibitors; Moxifloxacin (Avelox); QT prolongation

Outcome Measures

Primary Outcomes (1)

• Effect of AZD6094 at single therapeutic dose (600 mg) on ventricular repolarization by analysis of change from baseline-corrected QT

  To assess the effect of AZD6094 at single therapeutic dose (600mg) on ventricular repolarization by assessing the time matched baseline-adjusted, placebo subtracted QTc interval corrected for RR (R waves on electrocardiogram \[ECG\]) by the Fridericia formula (QTcF). The ECGs -digital (dECG) and page (pECG) would be recorded during the study for the assessment of safety. Paper ECG for safety review will be performed following the dECG recordings and at additional intervals if required.

  At screening (28 days prior to Day 1 of treatment period 1), treatment period (At pre-dose on Day -1 to Day 3, 48 hours post-dose) and follow-up (14 days after discharge from the treatment period 3)

Secondary Outcomes (22)

• Effect of AZD6094 at therapeutic dose (600 mg) on additional time-matched ECG variables

  At screening (28 days prior to Day 1 of treatment period 1), treatment period (At pre-dose on Day -1 to Day 3, 48 hours post-dose) and follow-up (14 days after discharge from the treatment period 3)

• Effect of moxifloxacin 400 mg on Fridericia-corrected QT interval (QTcF) compared to placebo.

  At screening (28 days prior to Day 1 of treatment period 1), treatment period (At pre-dose on Day -1 to Day 3, 48 hours post-dose) and follow-up (14 days after discharge from the treatment period 3)

• Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC(0-∞)) assessment for AZD6094, its metabolites (M2 and M3) and moxifloxacin

  Treatment periods (At pre-dose (Day -1) and post-dose (30 min, 60 min, 90 min, 2 hours to 6 hours, 8 hours, 12 hours, 24 hours, 36 hours and 48 hours)

• Area under the plasma concentration-time curve from time zero to t hours after dosing (AUC(0-t)) assessment for AZD6094, its metabolites (M2 and M3) and moxifloxacin

  Treatment periods (At pre-dose (Day -1) and post-dose (30 min, 60 min, 90 min, 2 hours to 6 hours, 8 hours, 12 hours, 24 hours, 36 hours and 48 hours)

• Observed maximum concentration (Cmax) assessment for AZD6094, its metabolites (M2 and M3) and moxifloxacin

  Treatment periods (At pre-dose (Day -1) and post-dose (30 min, 60 min, 90 min, 2 hours to 6 hours, 8 hours, 12 hours, 24 hours, 36 hours and 48 hours)

Study Arms (6)

Cohort 1

EXPERIMENTAL

Participants will receive orally single dose of study drugs in the sequence of ABC. A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

Drug: AZD6094 200 mg; Other: Placebo; Drug: Moxifloxacin

Cohort 2

EXPERIMENTAL

Participants will receive orally single dose of study drugs in the sequence of ACB. A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

Drug: AZD6094 200 mg; Other: Placebo; Drug: Moxifloxacin

Cohort 3

EXPERIMENTAL

Participants will receive orally single dose of study drugs in the sequence of BAC. A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

Drug: AZD6094 200 mg; Other: Placebo; Drug: Moxifloxacin

Cohort 4

EXPERIMENTAL

Participants will receive orally single dose of study drugs in the sequence of BCA. A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

Drug: AZD6094 200 mg; Other: Placebo; Drug: Moxifloxacin

Cohort 5

EXPERIMENTAL

Participants will receive orally single dose of study drugs in the sequence of CAB. A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

Drug: AZD6094 200 mg; Other: Placebo; Drug: Moxifloxacin

Cohort 6

EXPERIMENTAL

Participants will receive orally single dose of study drugs in the sequence of CBA. A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

Drug: AZD6094 200 mg; Other: Placebo; Drug: Moxifloxacin

Interventions

AZD6094 200 mg DRUG

A potent and selective small molecule mesenchymal epithelial transition (MET) kinase inhibitor with significant antitumor activity.

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5; Cohort 6

Placebo OTHER

AZD6094 matching placebo without any pharmacological activity.

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5; Cohort 6

Moxifloxacin DRUG

A fluoroquinolone broad-spectrum antibiotic, produces a mild, but reproducible increase in QT interval corrected (QTc) in healthy normal participants at time to reach maximum concentration (tmax - approximately 2 hours (0.5 to 4 hours)). This effect is close to the ECG interval measured from the onset of the QRS complex (onset of the QRS complex to the J point) to the offset of the T wave (QT)/QTc effect that represents the threshold of regulatory concern, around 5 ms mean QTc interval prolongation.

Also known as: Avelox

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5; Cohort 6

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participants must fulfill the following criteria:
• Provision of signed and dated, written informed consent prior to any study specific procedure.
• Healthy vasectomized male participants with suitable veins for cannulation or repeated venipuncture, non-Japanese vasectomized male participants aged 18 to 55 years (inclusive) or male participants over 40 (and up to 55) years old not intending to father children.
• Body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh greater than 50 kg and no more than 100 kg.
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBL) less than or equal to the upper limit of normal for the institution.
• Have a calculated creatinine clearance (CrCL) greater than 80 mL/min using the Cockcroft-Gault formula at Screening.
• Provision of signed, written and dated informed consent for optional genetic/biomarker research. If a subject declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this Clinical Study Protocol (CSP).

You may not qualify if:

• Healthy participants of Japanese ethnicity and any healthy subject that has 1 parent or grandparent (maternal or paternal) that is Japanese.
• History of any clinically important 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 important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP.
• Planned in-patient surgery, dental procedure or hospitalization during the study.
• Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results as judged by the Investigator.
• Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus (HIV).
• Abnormal vital signs, after 10 minutes supine rest, defined as any of the following:
• \- SBP \< 90 mmHg or ≥ 140 mmHg; DBP \< 50 mmHg or ≥ 90 mmHg; HR \< 45 or \> 85 beats per minute.
• Any clinically important abnormalities in rhythm, conduction or morphology of the 12-lead resting ECG that may interfere with the interpretation of QTc interval changes. These include healthy participants with any of the following:
• Abnormal ST-T-wave morphology, particularly in the protocol defined primary lead (V2) or left ventricular hypertrophy.
• PR interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular pre-excitation).
• PR interval prolongation (\> 200 ms). Intermittent second (Type 1 second degree block \[Wenckebach Phenomenon\] while asleep is not exclusive\]) or third degree atrioventricular (AV) block, or AV dissociation.
• Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS \> 110 ms. Participants with QRS \> 110 ms but \< 115 ms are acceptable if there is no evidence of e.g. ventricular hypertrophy or pre-excitation.
• Prolonged QTcF \> 450 ms or shortened QTcF \< 340 ms or family history of long QT syndrome.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Baltimore, Maryland, 21225, United States

Location

Related Publications (2)

• Schalkwijk S, Sahota T, Verheijen RB, Harmer AR, Ahmed GF. Parent and Metabolite Concentration-QT Modeling to Evaluate QT-Interval Prolongation at Savolitinib Therapeutic Doses. AAPS J. 2021 Mar 17;23(3):46. doi: 10.1208/s12248-021-00573-1.

  PMID: 33733338 DERIVED

• Sahota T, Dota CD, Vik T, Yan W, Verheijen RB, Walker S, Li Y, Goldwater R, Ghiorghiu D, Mellemgaard A, Ahmed GF. A Randomized, Double-Blind, Placebo- and Positive-Controlled, Three-Way Crossover Study in Healthy Participants to Investigate the Effect of Savolitinib on the QTc Interval. Clin Pharmacol Drug Dev. 2021 May;10(5):521-534. doi: 10.1002/cpdd.896. Epub 2021 Jan 5.

  PMID: 33400845 DERIVED

Related Links

• Results of this clinical trial are available on www.astrazenecaclinicaltrials.com

MeSH Terms

Conditions

Long QT Syndrome

Interventions

1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine; Moxifloxacin

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Ronald Goldwater, MD

  PAREXEL Early Phase Clinical Unit Baltimore

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 11, 2017
• First Posted: August 23, 2017
• Study Start: September 6, 2017
• Primary Completion: March 24, 2018
• Study Completion: March 24, 2018
• Last Updated: February 20, 2020

Record last verified: 2020-02

Locations

US (1)