Clinical trial NCT06348355: A Positron-emission Tomography Study to Determine Brain Exposure of [11C]Savolitinib in Healthy Volunteers
Official title: A Phase I, Open-label, Positron-Emission Tomography Study to Determine Brain Exposure of [11C]Savolitinib in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2024-04-04
Enrollment: 7
Sex: ALL
Minimum age (years): 50
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: The purpose of this study is to measure brain exposure of \[11C\]savolitinib in healthy volunteers.

This study will determine brain exposure of \[11C\]savolitinib in up to 8 healthy volunteers under physiological conditions, ie, when the BBB is intact. The study design allows up to 3 site visits. Two PET examinations will be performed for each healthy volunteer. The first PET examination will use IV administration of \[11C\]savolitinib. The second PET examination using \[11C\]savolitinib will occur after a single oral dose of 300 mg of savolitinib. PET image analysis will include kinetic compartment modelling using arterial input function, and will generate a set of brain exposure parameters (eg, maximum %ID, maximum \[11C\]savolitinib concentration in brain, partition coefficients between brain and plasma).

Detailed description: This is a Phase I, open-label, non-randomised, single-centre study to determine brain distribution and exposure of \[11C\]savolitinib following IV bolus injections of a microdose in one cohort of healthy adult volunteers. The study is composed of the following parts:

Visit 1: Screening: Screening, including brain MRI, within 45 days prior to PET imaging

Visit 2: PET examination: Single microdose (≤ 10 μg) of \[11C\]savolitinib administered as an IV bolus at the start of PET imaging. Brain radioactivity measurements using PET/CT (radioactivity in brain) and radioactivity measurements in arterial blood (radioactivity in blood) will be taken over a maximum of 90 minutes. 300 mg savolitinib will be administered orally approximately 2 hours after the end of the first PET examination. The second microdose of \[11C\]savolitinib will be administered as IV bolus at approximately 2 hours after the oral administration of savolitinib, and a second PET examination will be conducted over 90 minutes. PET2 examination can be performed on a separate day, within 14 days after PET1, if it was not performed the same day due to technical/participant related reasons. Oral savolitinib will be given on the same day as the second PET examination.

Visit 3: Follow-up: Telephone assessment 7 days (± 3 days) after receiving the last microdose of \[11C\]savolitinib and PET examination

Eligibility criteria: Inclusion Criteria:

1. Healthy volunteers must be ≥ 50 to 65 years of age inclusive, at the time of signing the informed consent form and capable of giving informed consent.
2. Body weight within 50.0 - 100.0 kg and body mass index within the range 18.0 - 30.0 kg/m2 (inclusive).
3. Male or female with contraceptive use.

   a. Male volunteers: (i) does not wish to father any children in the 6 months after the study follow-up visit and must use condoms and spermicide with sexual partners who are pregnant or who could become pregnant from the time of dosing until 6 months after savolitinib administration.

   b. Female volunteers: Only females not of childbearing potential will be considered for enrollment in the study.

Exclusion Criteria:

1. Having known or suspected systemic infection (eg, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, tuberculosis), including previous or on-going infectious or autoimmune disease.
2. Current evidence of SARS-CoV-2 infection with some exceptions applied on a case by case basis.
3. Positive urine screen for drugs of abuse at screening visit, or known history of drug or alcohol abuse within the past year.
4. Any factors that may increase the risk of QTcF prolongation such as congenital of familiar long QT syndrome, chronic hypokalemia not correctable with supplements etc.
5. Any clinically significant abnormalities on 12-lead ECG, as judged by the investigator.
6. Central nervous system infarction, infection or focal lesions of clinical significance on MRI scans.
7. Brain MRI abnormalities that would interfere with image analysis, as determined by the PI
8. Presence of significant abnormalities in the medical history or physical examination or laboratory tests at screening that may interfere with the study or present a safety risk.
9. Current significant major or unstable respiratory, heart, cerebrovascular, haematological, hepatic, renal, gastrointestinal diseases, or other major disease.
10. Any concomitant medications known to be associated with Torsades de Pointes, potent inducers of cytochrome P450 3A4 (CYP3A4), strong inhibitor of CYP1A2, inhibitors or inducers of P-gp.
11. Participation in a research PET or PET/CT study in the previous 12 months, and as per the judgement of the PI participation in this study will not expose the volunteer to radiation in excess of internationally accepted limit.
12. History of autoimmune disease, severe/ongoing allergy or atopy, or history of hypersensitivity to drugs with a similar chemical structure or class to \[11C\]savolitinib/savolitinib or the excipients of \[11C\]savolitinib/savolitinib.

Primary outcomes:
measure: Percentage of injected radioactivity entering the brain (%ID) as %IDmax_brain
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
Secondary outcomes:
measure: The following endpoint: Cmax_brain SUV
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoint: Tmax brain
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoint: AUCbrain 0-90
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoint: AUCplasma 0-90
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoint: Kp
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoint: Kp,uu
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoint: VT
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoint: Cmax_brain SUV
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoint: Tmax brain
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoints: AUCbrain 0-90
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoints: AUCplasma 0-90
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoints: Kp
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoints: Kp,uu
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
measure: The following endpoints: VT
timeFrame: 0-90 minutes post IV dose of [11C]savolitinib
Other outcomes:
measure: Number of participants with safety findings, AEs
timeFrame: Through study completion, up to 69 days (including screening period)
Locations:
city: Solna
country: Sweden
facility: Research Site
Study officials:
affiliation: Karolinska Institutet
name: Jonas Svensson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: