Adverse Reaction to Diagnostic Agents and Kits NosPhase 1TRACKNCT02921373
Tracking Peripheral Blood Mononuclear Cells With Fluorine MRI
A Phase 1 study testing 19F Cell Sense-labeled PBMC and MRI in people with Adverse Reaction to Diagnostic Agents and Kits Nos, run by Gregory A. Dekaban at 1 site in Canada.
Trial summary
Cell-based therapies in the form of stem cell-based or immune cell-based therapies are becoming important treatment options that are either approved for clinical use or are showing promise in clinical trials. Read more about this study
- Who is it for?
- Ages 40 to 85 yearsHealthy volunteers can take part
- Conditions the study is for
- Adverse Reaction to Diagnostic Agents and Kits Nos
- What is being tested?
- 19F Cell Sense-labeled PBMC and MRI
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteCanada
- Study dates
- Jul 2019to Dec 2022
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 85 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Men diagnosed with confirmed adenocarcinoma of the prostate
- No history of skin hypersensitivities or allergies.
- Normal liver functions as defined by alanine aminotransferase (ALT) (3-36 U/L) and aspirate aminotransferase (AST) levels (10-34 U/L)
- Normal kidney function by monitoring urea (2.5-8.0 ηmol/L) and creatine (70-120 μmol/L [for males]) concentrations.
- Normal complete blood count with differential
- Body Weight between 40 and 110 kg (relates to being able to fit in scanner)
- Body Mass Index < 30 (relates to being able to fit in scanner)
- Negative for (HIV, HTLV1\&2, Hep A, B, C, syphilis) infection as determined by approved serological testing.
Who cannot join
- Contraindication to venipuncture and donation of 100-160 mL of blood
- Active infection (not limited to HIV, HTLV1\&2, Hep A, B, C, syphilis)
- Participants are on active chemotherapy (not including castrate hormone therapy), radiation therapy or immunosuppressive therapy (i.e. steroid use, anti-transplant rejection drugs, depleting antibodies)
- Participants who are unable to have an MRI scan (e.g. history of head or eye injury involving metal fragments, implanted electrical device (such as a cardiac pacemaker), conductive implants or devices such as skin patches, body piercing or tattoos containing metallic inks, severe heart disease (including susceptibility to heart rhythm abnormalities), claustrophobia, etc.)
- Participants with known allergies to phenol red, β-lactams and β-lactam derivative
- Participants with known allergies to streptomycin sulfate and gentamicin sulfate
- Participants with unforeseen conditions that are deemed unsafe or inappropriate for the study (e.g. participants who are claustrophobic and cannot undergo an MRI) as per the discretion of the principal investigator.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase I Study Evaluating the Feasibility of Using Fluorine-19 Cell Sense to Image Human Peripheral Blood Mononuclear Cells In Vivo
Cell-based therapies in the form of stem cell-based or immune cell-based therapies are becoming important treatment options that are either approved for clinical use or are showing promise in clinical trials. One of the issues regarding cell-based therapies is that, once the cells are injected into a subject, there is no easy way to track where they go, assess whether adequate numbers of cells arrive at the intended therapeutic target and for how long they persist at a given location. To address this issue non-invasive imaging methods have been developed using magnetic resonance imaging (MRI). When used with an appropriate cell labelling contrast agent, Cellular MRI can track cells non-invasively in vivo. Detection of cells is accomplished with an inert imaging agent containing the MRI sensitive fluorine-19 (19F) nuclei. The objective of this study is to demonstrate that 19F-MRI is safe to use in humans so that it can subsequently be used to track cell-based immunotherapies in future clinical trials. The long term goal is to be able to quantify immune cell migration to secondary lymphoid tissues and potentially to tumors and correlate to therapeutic outcomes.
Read the detailed description
Background: None of the currently available Good Manufacturing Practices (GMP)-grade MRI cell labelling agents are approved for use in Canada. There is one iron oxide nanoparticle GMP grade preparation that is commercially available but it is not suitable for labelling the immune cell populations the investigators are interested in tracking in vivo. The investigators have, instead, chosen to develop the commercially available, GMP-grade 19F-based perfluorocarbon, known as Cell Sense, for the purpose of tracking immune cell-based vaccine therapies in vivo. This agent has been successful used in a phase I clinical trial in United States and is approved for a second trial current recruiting, under the oversight of the FDA.
The cell tracing agent Cell Sense (CS-1000) is an inert, non-metabolizable tracer. As CS-1000 is taken-up and incorporated into the cell traditional pharmacodynamic and pharmacokinetic analyses in animals and humans are not appropriate, as adsorption and biodistribution will vary with cell type, and therefore have not been done. In vitro studies of toxicity towards various cell types did not yield evidence of adverse effects on various cell functions. Cell Sense also was shown to be non-mutagenic using the Ames and Forward thymidine kinase (TK) assays. Some limited skin irritation was observed when >2,500 fold more Cell Sense than expected to be maximally injected into humans was injected intradermally into rats.
Examples of MRI cell tracking labels include superparamagnetic iron oxide nanoparticles and 19F-containing compounds such as perfluorocarbons. The advantage of using cellular MRI to track cells is that a non-radioactive tracer is used that is suitable for longitudinal studies. MRI offers 3D imaging with exquisite soft tissue contrast. The additional advantage of using 19F over iron-based agents is that 19F is a positive, easily quantifiable contrast cell labelling agent. Furthermore, there is no 19F-background MRI signal in humans whereas MRI involving iron can be confounded by different imaging artifacts and it is a negative contrast agent that is difficult to accurately quantify. The investigators are particularly interested in whether immune cells arrive in secondary lymphoid organs such as lymph nodes.
Study Design:
Open label, dose escalating, single centre, phase I study that will accrue (a) 6 healthy adults and (b) 6 prostate cancer patients.
Three healthy adults and three prostate cancer patients will be enrolled into the first cohort. Whole blood (150 ml) will be obtained by venipuncture. After processing of the blood to obtain peripheral blood mononuclear cells (PBMC), half of the PBMC will be treated with Cell Sense for 8-24 hours. Given the robustness of our data using 5 donors during dry runs, the investigators do not propose to compare labeled vs unlabeled cells as release criteria. However, the investigators will be collecting this data for information and research purposes. Three million (3 x 106) Cell Sense labeled autologous PBMC will be administered intradermally to the cohort 1 subjects. The three healthy adults and the 3 prostate cancer subjects will be tested concurrently.
If no grade 2 or higher adverse events are observed with the 1st cohort, concurrent enrolment will proceed to recruit a second set of 3 healthy adult subjects and the second set of 3 prostate cancer patients. The second cohort of subjects will be subjected to the same design but with an escalation of the dose to 2-3 x 107 Cell Sense-labeled autologous PBMC administered intradermally.
Endpoints:
Primary Endpoints:
Determine the feasibility of using Cell Sense to detect and monitor the migration of PBMC in humans
Secondary Endpoints:
- Confirm and further optimize the 19F Cell Sense detection and Hydrogen- 1 (1H) anatomical imaging parameters for imaging using the 19F/1H dual coil.
- Determine if Cell Sense-labeled PBMC migration to the draining lymph node can be detected.
- Determine if the lymph nodes in the area of interest imaged change in size on the injected side compared to the contralateral side.
- Quantify the number of Cell Sense-labeled PBMC detected.
- Evaluate safety parameters (toxicity) as defined by:
- adverse events.
- serious adverse events.
- changes in laboratory determination and vital sign parameters as assessed by medical history, physical examination and clinical laboratory tests.
The following categories will be used to grade any adverse events:
- Grade 1: does not interfere with daily activity,
- Grade 2: interferes with daily activity, no treatment required, except paracetamol,
- Grade 3: prevents daily activity or requires treatment.
- Grade 4: Life-threatening
NIH and FDA (or CTCAE v 4.0) guidelines will be used to determine the severity of adverse events
- Being tested
- 19F Cell Sense-labeled PBMC, MRI
- Keywords
- perfluorocarbon imaging, peripheral blood mononuclear cells, cancer immunotherapy, prostate cancer, MRI
- Medical subject headings
- Prostatic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
19F Cell Sense-labeled PBMCBiological
Peripheral blood mononuclear cells (PBMC) will be isolated from patient whole blood samples and labeled in a GMP facility with GMP grade 19F Cell Sense imaging agent.
These cells will be re-administered to the patient prior to imaging.
MRIDevice
Participants will undergo Magnetic Resonance Imaging (MRI) at 1 hour and 24 hours following PBMC administration
| Study group | Role | What they receive |
|---|---|---|
| Prostate Cancer Patients | Experimental | Up to 6 Male prostate cancer patients with metastatic, castration resistant prostate cancer will be enrolled.
19F Cell Sense-labeled PBMC (3 million cells) will be injected intradermally into the upper thigh of each participant above the inguinal lymph node. MRI will be used to image the administration site. Receives: Biological: 19F Cell Sense-labeled PBMC; Device: MRI |
| Healthy Volunteers | Experimental | Up to 6 male or female healthy volunteers will be enrolled.
19F Cell Sense-labeled PBMC (3 million cells) will be injected intradermally into the upper thigh of each participant above the inguinal lymph node. MRI will be used to image the administration site. Receives: Biological: 19F Cell Sense-labeled PBMC; Device: MRI |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants with treatment-related adverse effects as assessed by CTCAE v4.0
Measured: 12 months
Secondary outcomes (2)
Number of patients with detectable 19F MRI signal at the site of injection
This process will involve testing if the number of PBMC at the site of injection can be visualized and quantified following injection. Signal produced by labeled cells is linearly related to the number of cells. In vivo quantification has been demonstrated in animal modes, but not in a clinical setting to date.
If necessary, specific imaging parameters will be adjusted to optimize for clinical anatomical and 19F cell tracking imaging.
Measured: 1hr post injection
Number of patients with detectable 19F MRI signal at local lymph nodes
PBMC are required to migrate to the lymph node for optimum therapeutic effect. Here the investigators will determine if 19F-MRI contains the necessary imaging sensitivity to detect migration.
Measured: 24 hours post injection
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Oct 2016 (estimated)
- Study startJul 2019 (estimated)
- Primary completionJun 2022 (estimated)
- Study completionDec 2022 (estimated)
Why it stopped: Lack of funding
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Adverse Reaction to Diagnostic Agents and Kits NosStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gregory A. Dekaban
- Sponsor type
- University, hospital or other
- Collaborators
- Western University, Canada, Ontario Institute for Cancer Research
- Responsible party
- Sponsor-investigator, Gregory A. Dekaban, Western University, Canada
- Investigators
- Gregory A Dekaban, PhD, Principal investigator, Robarts Research Institte - Western UniverstiyPaula J Foster, PhD, Principal investigator, Robarts Research Institte - Western UniverstiySowmya Vuswanathan, PhD, Principal investigator, University Health Network - University of TorontoJoseph Chin, MD, Study chair, London Health Research Institute - Western UniversityMichael Rieder, MD PhD, Study chair, Robarts Research Institte - Western UniversityGary Brahm, MD, Study chair, London Health Research InstituteDoreen Matsui, MD, Study chair, Western UniversityGeorge Dresser, MD, Study chair, Western University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02921373
- Sponsor's protocol ID
- CS-PBMC-2015-001
- Acronym
- TRACK
- Status last verified
- Jul 2024
- First submitted
- 27 Sep 2016
- Last updated
- 24 Jul 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: Only group data will be presented
Study at a glance
From the registry record, last updated by the sponsor on 24 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Study Evaluating the Feasibility of Using Fluorine-19 Cell Sense to Image Human Peripheral Blood Mononuclear Cells In Vivo
- ClinicalTrials.gov ID
- NCT02921373
- Acronym / sponsor ID
- TRACK / CS-PBMC-2015-001
- Keywords
- perfluorocarbon imaging, peripheral blood mononuclear cells, cancer immunotherapy, prostate cancer, MRI
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Lack of funding
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Gregory A. DekabanUniversity, hospital or other
- Collaborators
- Western University, Canada, Ontario Institute for Cancer Research
- Study start
- Jul 2019 (estimated)
- Primary completion
- Jun 2022 (estimated)
- Study completion
- Dec 2022 (estimated)
- First posted
- 3 Oct 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Cell-based therapies in the form of stem cell-based or immune cell-based therapies are becoming important treatment options that are either approved for clinical use or are showing promise in clinical trials. One of the issues regarding cell-based therapies is that, once the cells are injected into a subject, there is no easy way to track where they go, assess whether adequate numbers of cells arrive at the intended therapeutic target and for how long they persist at a given location. To address this issue non-invasive imaging methods have been developed using magnetic resonance imaging (MRI). When used with an appropriate cell labelling contrast agent, Cellular MRI can track cells non-invasively in vivo. Detection of cells is accomplished with an inert imaging agent containing the MRI sensitive fluorine-19 (19F) nuclei. The objective of this study is to demonstrate that 19F-MRI is safe to use in humans so that it can subsequently be used to track cell-based immunotherapies in future clinical trials. The long term goal is to be able to quantify immune cell migration to secondary lymphoid tissues and potentially to tumors and correlate to therapeutic outcomes.
Detailed description
Background: None of the currently available Good Manufacturing Practices (GMP)-grade MRI cell labelling agents are approved for use in Canada. There is one iron oxide nanoparticle GMP grade preparation that is commercially available but it is not suitable for labelling the immune cell populations the investigators are interested in tracking in vivo. The investigators have, instead, chosen to develop the commercially available, GMP-grade 19F-based perfluorocarbon, known as Cell Sense, for the purpose of tracking immune cell-based vaccine therapies in vivo. This agent has been successful used in a phase I clinical trial in United States and is approved for a second trial current recruiting, under the oversight of the FDA.
The cell tracing agent Cell Sense (CS-1000) is an inert, non-metabolizable tracer. As CS-1000 is taken-up and incorporated into the cell traditional pharmacodynamic and pharmacokinetic analyses in animals and humans are not appropriate, as adsorption and biodistribution will vary with cell type, and therefore have not been done. In vitro studies of toxicity towards various cell types did not yield evidence of adverse effects on various cell functions. Cell Sense also was shown to be non-mutagenic using the Ames and Forward thymidine kinase (TK) assays. Some limited skin irritation was observed when >2,500 fold more Cell Sense than expected to be maximally injected into humans was injected intradermally into rats.
Examples of MRI cell tracking labels include superparamagnetic iron oxide nanoparticles and 19F-containing compounds such as perfluorocarbons. The advantage of using cellular MRI to track cells is that a non-radioactive tracer is used that is suitable for longitudinal studies. MRI offers 3D imaging with exquisite soft tissue contrast. The additional advantage of using 19F over iron-based agents is that 19F is a positive, easily quantifiable contrast cell labelling agent. Furthermore, there is no 19F-background MRI signal in humans whereas MRI involving iron can be confounded by different imaging artifacts and it is a negative contrast agent that is difficult to accurately quantify. The investigators are particularly interested in whether immune cells arrive in secondary lymphoid organs such as lymph nodes.
Study Design:
Open label, dose escalating, single centre, phase I study that will accrue (a) 6 healthy adults and (b) 6 prostate cancer patients.
Three healthy adults and three prostate cancer patients will be enrolled into the first cohort. Whole blood (150 ml) will be obtained by venipuncture. After processing of the blood to obtain peripheral blood mononuclear cells (PBMC), half of the PBMC will be treated with Cell Sense for 8-24 hours. Given the robustness of our data using 5 donors during dry runs, the investigators do not propose to compare labeled vs unlabeled cells as release criteria. However, the investigators will be collecting this data for information and research purposes. Three million (3 x 106) Cell Sense labeled autologous PBMC will be administered intradermally to the cohort 1 subjects. The three healthy adults and the 3 prostate cancer subjects will be tested concurrently.
If no grade 2 or higher adverse events are observed with the 1st cohort, concurrent enrolment will proceed to recruit a second set of 3 healthy adult subjects and the second set of 3 prostate cancer patients. The second cohort of subjects will be subjected to the same design but with an escalation of the dose to 2-3 x 107 Cell Sense-labeled autologous PBMC administered intradermally.
Endpoints:
Primary Endpoints:
Determine the feasibility of using Cell Sense to detect and monitor the migration of PBMC in humans
Secondary Endpoints:
- Confirm and further optimize the 19F Cell Sense detection and Hydrogen- 1 (1H) anatomical imaging parameters for imaging using the 19F/1H dual coil.
- Determine if Cell Sense-labeled PBMC migration to the draining lymph node can be detected.
- Determine if the lymph nodes in the area of interest imaged change in size on the injected side compared to the contralateral side.
- Quantify the number of Cell Sense-labeled PBMC detected.
- Evaluate safety parameters (toxicity) as defined by:
- adverse events.
- serious adverse events.
- changes in laboratory determination and vital sign parameters as assessed by medical history, physical examination and clinical laboratory tests.
The following categories will be used to grade any adverse events:
- Grade 1: does not interfere with daily activity,
- Grade 2: interferes with daily activity, no treatment required, except paracetamol,
- Grade 3: prevents daily activity or requires treatment.
- Grade 4: Life-threatening
NIH and FDA (or CTCAE v 4.0) guidelines will be used to determine the severity of adverse events
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Prostate Cancer Patients | Experimental | Biological: 19F Cell Sense-labeled PBMC, Device: MRIUp to 6 Male prostate cancer patients with metastatic, castration resistant prostate cancer will be enrolled. 19F Cell Sense-labeled PBMC (3 million cells) will be injected intradermally into the upper thigh of each participant above the inguinal lymph node. MRI will be used to image the administration site. |
| Healthy Volunteers | Experimental | Biological: 19F Cell Sense-labeled PBMC, Device: MRIUp to 6 male or female healthy volunteers will be enrolled. 19F Cell Sense-labeled PBMC (3 million cells) will be injected intradermally into the upper thigh of each participant above the inguinal lymph node. MRI will be used to image the administration site. |
Who may qualify
- Ages
- 40 to 85 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Men diagnosed with confirmed adenocarcinoma of the prostate
- No history of skin hypersensitivities or allergies.
- Normal liver functions as defined by alanine aminotransferase (ALT) (3-36 U/L) and aspirate aminotransferase (AST) levels (10-34 U/L)
- Normal kidney function by monitoring urea (2.5-8.0 ηmol/L) and creatine (70-120 μmol/L [for males]) concentrations.
- Normal complete blood count with differential
Key exclusion criteria (7 listed)
- Contraindication to venipuncture and donation of 100-160 mL of blood
- Active infection (not limited to HIV, HTLV1\&2, Hep A, B, C, syphilis)
- Participants are on active chemotherapy (not including castrate hormone therapy), radiation therapy or immunosuppressive therapy (i.e. steroid use, anti-transplant rejection drugs, depleting antibodies)
- Participants who are unable to have an MRI scan (e.g. history of head or eye injury involving metal fragments, implanted electrical device (such as a cardiac pacemaker), conductive implants or devices such as skin patches, body piercing or tattoos containing metallic inks, severe heart disease (including susceptibility to heart rhythm abnormalities), claustrophobia, etc.)
- Participants with known allergies to phenol red, β-lactams and β-lactam derivative
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 19F Cell Sense-labeled PBMCPeripheral blood mononuclear cells (PBMC) will be isolated from patient whole blood samples and labeled in a GMP facility with GMP grade 19F Cell Sense imaging agent. These cells will be re-administered to the patient prior to imaging. | Biological | Healthy Volunteers, Prostate Cancer Patients |
| MRIParticipants will undergo Magnetic Resonance Imaging (MRI) at 1 hour and 24 hours following PBMC administration | Device | Healthy Volunteers, Prostate Cancer Patients |
Primary outcome
Number of participants with treatment-related adverse effects as assessed by CTCAE v4.0
Time frame: 12 months
2 secondary outcomes
Number of patients with detectable 19F MRI signal at the site of injection
Time frame: 1hr post injection
Number of patients with detectable 19F MRI signal at local lymph nodes
Time frame: 24 hours post injection
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jul 2024.
- Individual participant dataSharing planned: No. Only group data will be presented
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gregory A Dekaban, PhD principal investigator
Robarts Research Institte - Western Universtiy
Paula J Foster, PhD principal investigator
Robarts Research Institte - Western Universtiy
Sowmya Vuswanathan, PhD principal investigator
University Health Network - University of Toronto
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing 19F Cell Sense-labeled PBMC and MRI in people with Adverse Reaction to Diagnostic Agents and Kits Nos, run by Gregory A. Dekaban at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 24 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of participants with treatment-related adverse effects as assessed by CTCAE v4.0 (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jul 2024.