A Study to Assess the Effects of Fluvoxamine on Savolitinib Exposure in Healthy Male Subjects

Healthy Male Subjects Clinical Trial

Official title:

A Phase I, Open-label, Fixed-sequence Study to Assess the Effects of Strong CYP1A2 Inhibitor (Fluvoxamine) on Savolitinib Exposure in Healthy Male Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05888207
• Other study ID #: D5084C00015
• Status: Completed
• Phase: Phase 1
• Start date: June 2, 2023
• Est. completion date: August 17, 2023

Study information

• Verified date: August 2023
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will assess the effects of strong CYP1A2 (Cytochrome P450 1A2) inhibitor (fluvoxamine) on savolitinib exposure in healthy male subjects, performed at a single clinical unit.

Description:

This study will be a Phase I, open-label, fixed-sequence, 2-treatment period study.

The study will consist of 2 periods. During period 1 of the study, each subject will receive a single oral dose of savolitinib following an overnight fast. A low-fat breakfast will be provided prior to dosing. There will be a minimum washout period of 10 days (14 days between two successive savolitinib doses) between period 1 and period 2.

During period 2 of the study, subject will take oral doses of fluvoxamine alone from Days 1 to 4. There would be no dietary restrictions for fluvoxamine dosing. On Day 5, subjects will take a single oral dose of savolitinib and oral dose of fluvoxamine. On Day 6, subject will receive an oral dose of fluvoxamine alone. Each subject would be involved in the study for 9 weeks (including screening window).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: August 17, 2023
• Est. primary completion date: August 17, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Healthy subjects with suitable veins for cannulation or repeated venipuncture.

• Male subjects must use barrier contraception.

• Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.

• Regular bowel movements.

Exclusion Criteria:

• 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.

• 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).

• Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, vital signs, 12 lead ECG and physical examination.

• QTcF > 450 ms or QT > 500 ms or other ECG abnormality making interpretation more difficult, as judged by the investigator, or a history of additional risk factors for Torsades de Points, which in the opinion of the investigator may put the subject at risk.

• Any positive result on screening for serum hepatitis B surface antigen OR anti-HBc antibody, indicative of active hepatitis B, hepatitis C antibody, or HIV antibody.

• History of latent or chronic infections.

• Known or suspected drug or alcohol abuse or positive drugs of abuse test. History of excessive alcohol assumption or chronic alcohol induced disease. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol.

• Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 1 month (30 days) of Visit 2 (Day -1 of Period 1) or 5 half lives whichever longer in this study or participation in a method development study (no drug) 1 month prior to Visit 2. The period of exclusion begins 1 month after the final dose or 5 half-lives after the final dose or 1 month after the last visit, whichever is the longest.

• History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity.

• Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the 6 months prior to screening.

• Use of any prescribed or non prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies (which include but are not limited to: kava, ephedra [ma hung], ginko biloba, dehydroepiandrosterone, yohimbe, saw palmetto and ginseng), 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 (> 5 half-lives) if the medication has a long half-life.

• Subject has clinical signs and symptoms consistent with COVID-19, or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission unless confirmed by a negative SARS CoV-2 PCR test.

• History of severe COVID-19 (hospitalization, extracorporeal membrane oxygenation, mechanically ventilated).

• Excessive intake of caffeine-containing drinks or food.

• Planned in-patient surgery, dental procedure, or hospitalization during the study.

• Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug.

• Received a seasonal flu vaccine (including H1N1, H1N5) 28 days prior to first dose of study drug.

Related Conditions & MeSH terms

• Healthy Male Subjects

Intervention

Drug:
• Savolitinib
Savolitinib will be administered as a single oral dose on Day 1 of Period 1 and on Day 5 of Period 2.
• Fluvoxamine
Only fluvoxamine will be administered as a twice daily oral dose from Days 1 to 4 of Period 2. On Day 5 of Period 2, subject will receive a twice daily oral dose of fluvoxamine along with savolitinib. On Day 6 of Period 2, subject will receive a twice daily oral dose of fluvoxamine alone.

Locations

Country	Name	City	State
United States	Research Site	Brooklyn	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum observed plasma (peak) drug concentration (Cmax) for savolitinib	To evaluate the effects of fluvoxamine on savolitinib Cmax in healthy male subjects after administration of a single oral dose.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Primary	Area under plasma concentration time curve from zero to infinity (AUCinf) for savolitinib	To evaluate the effects of fluvoxamine on savolitinib AUCinf in healthy male subjects after administration of a single oral dose.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) for savolitinib	To evaluate the AUClast of savolitinib when administered alone or in combination with fluvoxamine.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	AUClast for metabolites M2 and M3	To evaluate the AUClast of savolitinib metabolites (M2 and M3) when savolitinib is administered alone or in combination with fluvoxamine.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Cmax for metabolites M2 and M3	To evaluate the Cmax of savolitinib metabolites (M2 and M3) when savolitinib is administered alone or in combination with fluvoxamine.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	AUCinf for metabolites M2 and M3	To evaluate the AUCinf of savolitinib metabolites (M2 and M3) when savolitinib is administered alone or in combination with fluvoxamine.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Ratio of metabolite Cmax to parent Cmax (MRCmax)	To evaluate the MRCmax of savolitinib and its metabolites (M2 and M3) when savolitinib is administered alone.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Ratio of metabolite AUCinf to parent AUCinf (MRAUCinf)	To evaluate the MRAUCinf of savolitinib and its metabolites (M2 and M3) when savolitinib is administered alone.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Ratio of metabolite AUClast to parent AUClast (MRAUClast)	To evaluate the MRAUClast of savolitinib and its metabolites (M2 and M3) when savolitinib is administered alone.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Time to reach peak or maximum observed concentration or response following drug administration (tmax) for savolitinib and metabolites (M2 and M3)	To evaluate the tmax of savolitinib and its metabolites (M2 and M3) when savolitinib is administered alone.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Half life associated with terminal slope (?z) of a semi logarithmic concentration time curve (t1/2?z) for savolitinib and metabolites (M2 and M3)	To evaluate the t1/2?z of savolitinib and its metabolites (M2 and M3) when savolitinib is administered alone.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Terminal rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (?z) for savolitinib and metabolites (M2 and M3)	To evaluate the ?z of savolitinib and its metabolites (M2 and M3) when savolitinib is administered alone.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Number of data points used for ?z determination (?zN) for savolitinib and metabolites (M2 and M3)	To evaluate the ?zN of savolitinib and its metabolites (M2 and M3) when savolitinib is administered alone.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Apparent total body clearance of drug from plasma after extravascular administration (CL/F) for savolitinib	To evaluate the CL/F of savolitinib when savolitinib is administered alone.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F) for savolitinib	To evaluate the Vz/F of savolitinib when savolitinib is administered alone.	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
Secondary	Number of subjects with adverse events (AEs)	To assess additional safety and tolerability of savolitnib.	From screening (Day -28 to Day -2) to follow up visit (approximately 9 weeks)