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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Male Subjects
• Intervention / Treatment: Drug: Savolitinib; Drug: Fluvoxamine

Detailed 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).

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• United States
  • Maryland
    • Brooklyn, Maryland, United States, 21225
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Savolitinib/Savolitinib+Fluvoxamine; In period 1, subjects will receive a single oral dose of savolitinib on Day 1 after overnight fasting. Following minimum 10 days of washout after the last dose of savolitinib, in period 2 subjects will take oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5 subject will receive a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, subjects will receive a twice daily oral dose of fluvoxamine alone.

Drug: Savolitinib; Savolitinib will be administered as a single oral dose on Day 1 of Period 1 and on Day 5 of Period 2.; Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
Half life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t1/2λz) for savolitinib and metabolites (M2 and M3)	To evaluate the t1/2λz 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
Terminal rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (λz) for savolitinib and metabolites (M2 and M3)	To evaluate the λz 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
Number of data points used for λz determination (λzN) for savolitinib and metabolites (M2 and M3)	To evaluate the λzN 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
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
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
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)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel

Study record dates

Study Major Dates

• Study Start (Actual): June 2, 2023
• Primary Completion (Actual): August 17, 2023
• Study Completion (Actual): August 17, 2023

Study Registration Dates

• First Submitted: May 25, 2023
• First Submitted That Met QC Criteria: May 25, 2023
• First Posted (Actual): June 5, 2023

Study Record Updates

• Last Update Posted (Actual): August 29, 2023
• Last Update Submitted That Met QC Criteria: August 28, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Drug-drug interaction; Fixed-sequence; CYP1A2 inhibitor
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Anti-Anxiety Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Selective Serotonin Reuptake Inhibitors; Fluvoxamine
• Other Study ID Numbers: D5084C00015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal

Vivli.org. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No