A Study in Healthy Male Subjects to Understand How Savolitinib When Taken With Midazolam Behaves Inside the Body

NCT04187456 | Completed Phase 1 FDA Drug

• 1 other identifier: D5084C00004
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

This study will be an open label, 2 period, fixed sequence study in healthy male subjects, performed at a single study center in the Unites States of America. The purpose of this study is to evaluate the effect of savolitinib on the PK of midazolam, a known cytochrome P450 (CYP) 3A substrate.

Conditions

Solid Tumors

Keywords

Pharmacokinetics; Safety; Small molecule kinase inhibitor; Open-label

Outcome Measures

Primary Outcomes (2)

• Midazolam: Area under the plasma concentration-time curve from time zero to infinity (AUC) ratio of geometric means of test treatment (midazolam + savolitinib), relative to reference treatment (midazolam alone).

  To assess the effect of savolitinib on the PK of midazolam.

  Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.

• Midazolam: Maximum observed plasma concentration (Cmax) ratio of geometric means of test treatment (midazolam + savolitinib), relative to reference treatment (midazolam alone).

  To assess the effect of savolitinib on the PK of midazolam.

  Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.

Secondary Outcomes (45)

• Midazolam: Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration [AUC(0-t)] ratios of geometric means of test treatment (midazolam + savolitinib), relative to reference treatment (midazolam alone).

  Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.

• Midazolam: Cmax

  Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.

• Midazolam: [AUC(0-t)]

  Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.

• Midazolam: Time to reach maximum observed plasma concentration (tmax)

  Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.

• Midazolam: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration time curve (t½,λz)

  Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.

Study Arms (1)

Midazolam + Savolitinib

EXPERIMENTAL

* Treatment Period 1: Single administration of midazolam (1 mg) will occur on Study Day 1, after a high fat, high calorie breakfast, followed by PK sampling for 24 hours. * Treatment Period 2: Single administration of midazolam 1 mg in combination with a single administration of savolitinib (600 mg), after a high fat, high calorie breakfast will occur on Study Day 5 and PK sampling will occur for 24 hours.

Drug: Savolitinib; Drug: Midazolam

Interventions

Savolitinib DRUG

Single dose (together with midazolam) on Study Day 5 after a high fat, high calorie breakfast.

Midazolam + Savolitinib

Midazolam DRUG

Single dose (alone) on Study Day 1 and single dose (together with savolitinib) on Study Day 5, both after a high fat, high calorie breakfast.

Midazolam + Savolitinib

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• 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 subjects, aged 18 - 65 years (inclusive) , with suitable veins for cannulation or repeated venipuncture.
• Have a body mass index (BMI) between 18 and 35 kg/m2 inclusive and body weight 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 upper limit of normal for the institution at screening.
• Have a calculated creatinine clearance (CrCL) greater than 80 mL/min using the Cockcroft-Gault formula at screening.
• Provision of a signed, written and dated informed consent for optional genetic/biomarker research. If a subject decline 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 the protocol..

You may not qualify if:

• Healthy subjects of Japanese ethnicity and any healthy subject that has 1 parent or grandparent (maternal or paternal) of Japanese ethnicity.
• History of any clinically significant disease or disorder which, in the opinion of the PI, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer'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.
• Planned in-patient surgery, dental procedure or hospitalizing during the study.
• Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the PI.
• Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
• Abnormal vital signs, after 5 minutes supine rest, defined as any of the following:
• (1) Systolic BP \< 90 mmHg or ≥ 140 mmHg (2) Diastolic BP \< 50 mmHg or ≥ 90 mmHg (3) Heart rate \< 45 or \> 85 beats per minute. 9 Any clinically significant 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 subjects 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. Subjects with QRS \> 110 ms but \< 115 ms are acceptable if there is no evidence of e.g., ventricular hypertrophy or pre-excitation.
• Mean resting correct QT interval (QTcF) \> 450 ms for men on screening obtained from 3 ECGs or history or factors that may increase the risk of QTcF prolongation such as chronic hypokalemia not correctable with supplements, congenital or familial long QT syndrome, or family history of unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes (TdP).

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Baltimore, Maryland, 21225, United States

Location

MeSH Terms

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; Midazolam

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; 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: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 3, 2019
• First Posted: December 5, 2019
• Study Start: December 27, 2019
• Primary Completion: March 6, 2020
• Study Completion: March 6, 2020
• Last Updated: August 19, 2021

Record last verified: 2020-08

Locations

US (1)