A Study to Evaluate the Amount of Drug That Becomes Available in the Blood Circulation When Savolitinib is Administered Alone and in Combination With Itraconazole

NCT04121910 | Completed Phase 1 FDA Drug

• 1 other identifier: D5084C00002
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

This study will be conducted to quantify the magnitude of the effect of itraconazole co-administration on the PK of savolitinib. The exposure to savolitinib is predicted to increase when co-administered with the potent cytochrome P (CYP) 3A4 inhibitor itraconazole since CYP3A4 (via CYP450) is involved in the metabolism and elimination of savolitinib.

Conditions

Solid Tumour

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Savolitinib area under plasma concentration-time curve from time zero to infinity (AUC) ratios of geometric means of test treatment (savolitinib+itraconazole), relative to reference treatment (savolitinib alone)

  To assess the effect of itraconazole on the PK of savolitinib

  Savolitinib,M2andM3:Treatment Periods1and3 (Study Days 1 and 18)pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose. Itraconazole:Treatment Period 3 (Study day 18)pre-dose, and 1 and 2 hours post-dose.

• Savolitinib maximum observed plasma concentration (Cmax) ratios of geometric means of test treatment (savolitinib+itraconazole), relative to reference treatment (savolitinib alone)

  To assess the effect of itraconazole on the PK of savolitinib

  Savolitinib,M2andM3:Treatment Periods1and3 (Study Days 1 and 18)pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose. Itraconazole:Treatment Period 3 (Study day 18)pre-dose, and 1 and 2 hours post-dose.

Secondary Outcomes (51)

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

  Savolitinib,M2andM3:Treatment Periods1and3 (Study Days 1 and 18)pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose. Itraconazole:Treatment Period 3 (Study day 18)pre-dose, and 1 and 2 hours post-dose.

• M2 and M3: Cmax ratios of geometric means of test treatment (savolitinib+itraconazole), relative to reference treatment (savolitinib alone)

  Savolitinib,M2andM3:Treatment Periods1and3 (Study Days 1 and 18)pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose. Itraconazole:Treatment Period 3 (Study day 18)pre-dose, and 1 and 2 hours post-dose.

• M2 and M3: AUC ratios of geometric means of test treatment (savolitinib+itraconazole), relative to reference treatment (savolitinib alone)

  Savolitinib,M2andM3:Treatment Periods1and3 (Study Days 1 and 18)pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose. Itraconazole:Treatment Period 3 (Study day 18)pre-dose, and 1 and 2 hours post-dose.

• M2 and M3: AUC(0-t) ratios of geometric means of test treatment (savolitinib+itraconazole), relative to reference treatment (savolitinib alone)

  Savolitinib,M2andM3:Treatment Periods1and3 (Study Days 1 and 18)pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose. Itraconazole:Treatment Period 3 (Study day 18)pre-dose, and 1 and 2 hours post-dose.

• Savolitinib, M2 and M3: Cmax

  Savolitinib,M2andM3:Treatment Periods1and3 (Study Days 1 and 18)pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose. Itraconazole:Treatment Period 3 (Study day 18)pre-dose, and 1 and 2 hours post-dose.

Study Arms (1)

Savolitinib and/or Itraconazole

EXPERIMENTAL

Treatment Period 1: Single administration of savolitinib (200 mg) will occur on Study Day 1 after a high-fat, high-calorie breakfast followed by PK sampling for 48 hours Treatment Period 2: Itraconazole will be administered (200 mg BID) on Study Day 15, and (200 mg QD) on Study Days 16 and 17, 1 hour before breakfast (and before dinner, when applicable) Treatment Period 3: A single combination of itraconazole (200 mg) 1 hour before breakfast + savolitinib (200 mg) after a high-fat, high-calorie breakfast on Study Day 18, and a single dose of itraconazole (200 mg) on Study Day 19, 1 hour before breakfast

Drug: Savolitinib; Drug: Itraconazole

Interventions

Savolitinib DRUG

On Study Day 1 and Study Day 18, savolitinib will be administered as single dose after a high-fat, high-calorie breakfast

Savolitinib and/or Itraconazole

Itraconazole DRUG

Twice daily on first day of dosing (Study Day 15) followed by once daily for 4 days (Study Day 16 - Study Day 19) administered 1 hour before any breakfast (and 1 hour before dinner on Study Day 15)

Savolitinib and/or Itraconazole

Eligibility Criteria

• Age: 18 Years - 65 Years
• 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 with suitable veins for cannulation or repeated venipuncture: non-Japanese male subjects aged 18 to 65 years (inclusive).
• Have a body mass index between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
• Alanine aminotransferase, aspartate aminotransferase and total bilirubin within normal limits for the institution at screening and Day -1.
• Have a calculated creatinine clearance greater than 60 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 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 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 hospitalisation during the study.
• Any clinically significant abnormalities in clinical chemistry, haematology, 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 at screening and Day -1, 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 (BPM) 9) 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 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 BBB, or intraventricular conduction delay with QRS \>110 ms. Subjects with QRS \>110 ms but \<115 ms are acceptable if there is no evidence of eg, ventricular hypertrophy or pre-excitation.
• Mean resting prolonged QTcF \> 450 ms or shortened QTcF \< 340 ms obtained from 3 ECGs.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Glendale, California, 91206, 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; Itraconazole

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 9, 2019
• First Posted: October 10, 2019
• Study Start: November 7, 2019
• Primary Completion: January 12, 2020
• Study Completion: January 12, 2020
• Last Updated: January 23, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)