A Study in Healthy Subjects to Assess the Pharmacokinetics of Savolitinib When Administered Alone and in Combination With Rifampicin

NCT04118842 | Completed Phase 1 FDA Drug

• 1 other identifier: D5084C00003
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase I, open-label, 3 treatment period, fixed-sequence study in healthy non-Japanese male subjects, aged 18 to 65 years (inclusive), performed at a single study centre. Treatment Period 1 will establish the single dose pharmacokinetic (PK) profile of savolitinib. Dosing of daily rifampicin during Treatment Period 2 will result in maximal induction of the CYP450 enzymes including CYP3A4. Treatment Period 3 will then establish the single dose PK profile of savolitinib under maximum CYP450 induction conditions. Comparison of the PK profile of savolitinib between Treatment Period 1 and Treatment Period 3 will quantify the effect of CYP450 enzyme induction.

Conditions

Solid Tumors

Keywords

Solid tumors; Small-molecule kinase inhibitor

Outcome Measures

Primary Outcomes (2)

• Savolitinib: Maximum plasma concentration (Cmax) ratios of geometric means of test treatment (savolitinib+rifampicin), relative to reference treatment (savolitinib alone)

  To assess the effect of rifampicin on the PK of savolitinib

  Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration

• Area under the curve (AUC) ratios of geometric means of test treatment (savolitnib+rifampicin) relative to reference treatment (savolitinib alone)

  To assess the effect of rifampicin on the PK of savolitinib

  Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration

Secondary Outcomes (49)

• Number of subjects with adverse events

  Only SAEs at Screening; AEs from Study Days 1 to 34

• Number of subjects with abnormal findings in systolic blood pressure (BP)

  At Screening, and from Study Days 1 to 14 and Study Days 20 to 22

• Number of subjects with abnormal findings in diastolic BP

  At Screening, and from Study Days 1 to 14 and Days 20 to 22

• Number of subjects with abnormal findings in pulse rate

  At Screening, and from Study Days 1 to 14 and Study Days 20 to 22

• Number of subjects with abnormal findings in electrocardiograms (ECGs) (12-lead ECGs)

  At Screening, and from Study Days 1 to 34

Study Arms (1)

Savolitinib and/or Rifampicin

EXPERIMENTAL

Treatment Period 1 consists of 16 days starting with admission on Study Day -1, followed by a single dose administration of savolitinib on Day 1, followed by a washout period of at least 14 days. Subjects will be discharged from the Study Centre on Study Day 3, after the last PK sample is collected Treatment Period 2 consists of 6 days, starting with admission on Study Day 14, followed by QD dose administrations of rifampicin for 5 consecutive days (Study Day 15 to Study Day 19) Treatment Period 3 consists of 4 days, starting immediately after Treatment Period 2, comprising of a single dose administration of savolitinib on Study Day 20 and QD dose administration of rifampicin on Study Day 20 and Study Day 21. Subjects will be discharged from the Study Centre on Study Day 22, after the last PK sample is collected

Drug: Savolitinib; Drug: Rifampicin

Interventions

Savolitinib DRUG

Patients will receive a single dose on Study Day 1 and Study Day 20. Savolitinib will be administrated after a high fat, high calorie breakfast to reduce the risk of adverse events.

Savolitinib and/or Rifampicin

Rifampicin DRUG

Patients will receive Rifampicin once daily on Study Day 15, 16, 17, 18, 19, 20 and 21. Rifampicin will be administered 1 hour before breakfast.

Also known as: Rifampin

Savolitinib and/or Rifampicin

Eligibility Criteria

• Age: 18 Years - 65 Years
• Gender Eligibility Details: 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 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, AST and total bilirubin less than or equal to the upper limit of normal for the institution.
• Have a calculated creatinine clearance 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.

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 Principal Investigator (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, 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 investigational medicinal product (IMP).
• Planned in-patient surgery, dental procedure or hospitalization 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 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 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, incomplete bundle branch block, or intraventricular conduction delay 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 hypokalaemia 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).
• Known or suspected history of drug abuse, as judged by the PI. 11 Current smokers or those who have smoked or used nicotine products within the previous 30 days.

Sponsors & Collaborators

• AstraZeneca: lead

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; Rifampin

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

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 4, 2019
• First Posted: October 8, 2019
• Study Start: October 17, 2019
• Primary Completion: February 26, 2020
• Study Completion: February 26, 2020
• Last Updated: April 3, 2020

Record last verified: 2020-03

Locations

US (1)