A Study of the Pharmacokinetics, Biodistribution and Dosimetry of Granzyme-B Targeted [Cu-64]-Labeled PET Radiotracers in Adult Healthy Volunteers

Early Phase 1RecruitingNCT07774650

Ratio Therapeutics, Inc.12 enrolled

Overview

This is an exploratory clinical study of copper-64 \[Cu-64\]-labeled granzyme B (GzmB)-targeted compounds for PET/CT imaging. The goal is to determine how GzmB-Targeted \[Cu-64\]-labeled compounds are distributed in the body by assessing PET/CT images and blood samples, and to assess the safety profile after a single intravenous dose. Up to 6 healthy volunteers (3 female, 3 male) will receive one injection of a GzmB-targeted \[Cu-64\]-labeled compound, then undergo multiple whole-body PET/CT scans, blood and urine tests over about 24 hours, and a follow-up phone call around Day 7. Up to 2 GzmB-Targeted \[Cu-64\]-labeled compounds may be assessed (i.e. maximum of 12 healthy volunteers in total in the study). Researchers will look at the blood activity of GzmB-Targeted \[Cu-64\]-labeled compound and the organ distribution and movement of the product in the body. They will also evaluate any changes in physical examination assessments, vital signs, ECG, and clinical laboratory measurements from pre-administration to post-administration.

Granzyme B (GzmB) is a cytotoxic serine protease released by activated T cells and natural killer cells, and its release acts as a functional marker of immune engagement. GzmB-Targeted \[Cu-64\]-labeled compounds are being developed as PET/CT tracers to image immune activation and inflammation. This first-in-human Phase 0 study in adult healthy volunteers is designed to characterize the pharmacokinetics, biodistribution, radiation dosimetry, and safety of GzmB-targeted \[Cu-64\]-labeled compounds. Up to 6 participants (3 female, 3 male) will receive a single dose of a GzmB-targeted \[Cu-64\]-labeled compound, followed by serial whole-body PET/CT imaging, blood and urine sampling for pharmacokinetics and excretion, and safety assessments over approximately 24 hours post-dose, with a telephone follow-up at about 7 days. Up to 2 GzmB-Targeted \[Cu-64\]-labeled compounds may be assessed in the clinical trial (i.e. a maximum of 12 healthy volunteers in total in the study). Data from this study will support lead candidate selection and inform further clinical development of a \[Cu-64\]-labeled GzmB-targeted imaging agent.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

DIAGNOSTIC

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Adult male or female participants 18-60 years of age judged to be in good health by the Investigator 2. No clinically significant laboratory abnormalities; all tests of liver and kidney function within normal limits 3. Capable of giving signed informed consent, which includes compliance with requirements and restrictions listed in the ICF and this protocol 4. Female participants of childbearing potential and male participants who are fertile and have female partners of childbearing potential must agree to use adequate birth control throughout the study to the conclusion of follow-up. Exclusion Criteria: 1. Pregnant or breast-feeding female participants (female participants of childbearing potential must have negative pregnancy tests at Screening and pre-dose Day 0) 2. Inadequate venous access (at least two distinct access sites allowing for separate test agent administration and PK blood sampling are required) 3. Inability or unwillingness to undergo serial PET/CT imaging 4. Active infection or malignancy 5. Known or suspected inflammatory, autoimmune or fibrotic disease 6. Major surgery or other intensive medical treatment in the 3 months prior to planned study injection, as assessed by the investigator 7. Received a radioisotope within 7 physical half-lives of that radioisotope prior to planned study injection 8. Known allergy/hypersensitivity to PET/CT tracers or compounds similar to GzmB-Targeted Compounds 9. Concurrent participation in a clinical trial of investigational product(s) 10. Participation in other research protocols or clinical care where there was radiation exposure such that the exposure from the last year, in addition to the radiation exposure expected from participation in this clinical study, exceeds the effective dose of 50 mSv, which would be above the acceptable annual limit established by US federal guidelines 11. Significant intercurrent illness or psychiatric illness/social situation that could place the participant at undue risk during study participation, significantly alter study outcomes, or affect participant compliance with study requirements for dosing and evaluation, as determined by the investigator

Outcomes

Primary Outcomes

Determine the maximum concentration (Cmax) of radiation (Pharmacokinetics) in the blood after a single dose of the GzmB-Targeted [Cu-64]-labeled compound

Blood samples will be collected Pre-dose, immediately post-dose, 45 minutes, 1 \& 4 hours, \& 24 hours post dose. Radiation (PK) to be measured by gamma counter (KBq/mL).

Time frame: 24 hour period post injection.

Determine the time to maximum concentration (Tmax) in the blood after a single dose of the GzmB-Targeted [Cu-64]-labeled compound

Blood samples will be collected Pre-dose, immediately post-dose, 45 minutes, 1 \& 4 hours, \& 24 hours post dose. Time to maximum concentration to be measured in hours (h).

Time frame: 24 hour period post injection

Determine the area under the curve (AUC) in blood after a single injection of the GzmB-Targeted [Cu-64]-labeled compound

Blood samples will be collected Pre-dose, immediately post-dose, 45 minutes, 1 \& 4 hours, \& 24 hours post dose. AUC to be calculated by kilobecquerel x hours/milliliter (KBq x h/mL)

Time frame: 24 hour period post injection.

Determine the elimination half-life in the blood post a single injection of the GzmB-Targeted [Cu-64]-labeled compound

Blood samples will be collected Pre-dose, immediately post-dose, 45 minutes, 1 \& 4 hours, \& 24 hours post dose. Elimination to be measured by time to half of the product being excreted from the blood (as measured by gamma counter) in hours (h)

Time frame: 24 hour period post injection

Determine the clearance in the blood after single injection of the GzmB-Targeted [Cu-64]-labeled compound

Blood samples will be collected Pre-dose, immediately post-dose, 45 minutes, 1 \& 4 hours, \& 24 hours post dose. Clearance to be measured by milliliter/minute.

Time frame: 24 hour period post injection

Determine the volume of distribution in the blood after a single injection of the GzmB-Targeted [Cu-64]-labeled compound

Blood samples will be collected Pre-dose, immediately post-dose, 45 minutes, 1 \& 4 hours, \& 24 hours post dose. Volume to be measured by Liter

Time frame: 24 hour period post injection

Evaluate the organ distribution of radioactivity for a single dose of GzmB-targeted [Cu64]-labeled compound

Measuring the uptake in organs from a PET/CT. Imaging timepoints will be collected at 20 minutes post dose, 1 \& 4 hours and 24 hours post dose

Time frame: 24 hour period post injection

Evaluate the safety profile for a single dose of the GzmB-Targeted [Cu-64]-labeled compound in adult healthy volunteers

Determine the incidence, and severity of Treatment Emergent Adverse Events (TEAEs including SAEs).

Time frame: From injection to 8 days post injection

Secondary Outcomes

Evaluate the radiation absorbed dose estimates for organs for a single dose of the GzmB-Targeted [Cu-64]-labeled compound

Imaging timepoints will be collected at 20 minutes post dose, 1 \& 4 hours, and 24 hours post dose. PET/CT will be used to assess the whole body effective dose as measured by mGy/MBq.

Time frame: 24 hour period post injection

Evaluate the whole body effective dose estimated for a single dose of the GzmB-Targeted [Cu-64]-labeled compound

Imaging timepoints will be collected at 20 minutes post dose, 1 \& 4 hours, and 24 hours post dose. PET/CT will be used to assess the whole body effective dose as measured by mSv/MBq.

Time frame: 24 hour period post injection

Examine whole-body excretion of a single dose of the GzmB-Targeted [Cu-64] labeled compound

Urine samples will be evaluated for radioactivity levels of GzmB-Targeted \[Cu-64\]-labeled compound. Samples will be measured by gamma counter to evaluate the amount of radiation excreted in each interval Ae(t) (kBq)

Time frame: Samples will be taken continuously starting immediately post-dose through 24 hours post injection

Determine the total cumulative excretion over time in the urine (mL/min) for the GzmB-Targeted [Cu-64]-labeled compound

Samples will be taken continuously starting immediately post-dose through 24 hours post injection. Includes all quantified radioactivity as measured by gamma counter in urine up to the least measured timepoint.

Time frame: A 24 hour period post injection

Determine the renal clearance for the GzmB-Targeted [Cu-64]-labeled compound

Urine samples will be taken continuously starting immediately post-dose through 24 hours post injection. Renal clearance is the volume of urine entirely cleared of a substance by the kidneys over time L/h

Time frame: 24 hour period post injection

A Study of the Pharmacokinetics, Biodistribution and Dosimetry of Granzyme-B Targeted [Cu-64]-Labeled PET Radiotracers in Adult Healthy Volunteers

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts