PET Imaging for Sickle Cell Crisis

Overseen By Jude Jonassaint, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Enrico Novelli

Must be taking: Hydroxyurea, L-glutamine

Disqualifiers: Active malignancy, Pregnancy, Chronic transfusion, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to observe events during a sickle cell crisis, a painful occurrence caused by blocked blood vessels. Researchers use PET scans with Cu-64-LLP2A, an experimental imaging agent, to identify biomarkers indicating these blockages. This could enhance treatment and aid in developing better drugs for sickle cell disease. Individuals with sickle cell disease who have experienced at least two crises requiring medical care in the past year may be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to experience this new imaging approach.

Do I need to stop my current medications for the trial?

If you are taking hydroxyurea, L-glutamine, crizanlizumab, voxelotor, or erythropoietin stimulating agents, you must continue taking them at the same dose and schedule during the study. The protocol does not specify about other medications.

What prior data suggests that this PET imaging method is safe for SCD patients?

Research has shown that Cu-64-LLP2A, the treatment under study in this trial, is safe for humans. Studies have found that this substance, used for PET scans, is well-tolerated, with radiation levels within safe limits. Earlier human studies reported no serious side effects. This is encouraging for prospective participants, suggesting the treatment is likely safe to use. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using Cu-64]-LLP2A for sickle cell crisis because it offers a new way to understand the disease's impact on the body. Unlike traditional treatments that focus on managing pain and complications, this approach uses a radiotracer to provide detailed PET imaging. This imaging can help pinpoint the exact timing and severity of a sickle cell crisis, potentially leading to more personalized and effective care strategies. By visualizing the crisis in real-time, clinicians can gain insights into the disease that were previously out of reach.

What evidence suggests that this PET imaging method is effective for identifying vaso-occlusion in sickle cell disease?

Research has shown that Cu-64-LLP2A is a promising tool for imaging vaso-occlusive crises (VOC) in sickle cell disease (SCD). This trial will evaluate Cu-64-LLP2A's effectiveness in identifying potential VOC sites in the body. Studies in mice have demonstrated its ability to detect hyper-adhesion, a key factor in VOC, suggesting it could help locate these blockages in people with SCD. By making VOC visible, this method could improve patient care and support the development of new treatments. Participants in this trial will receive injections of the radiotracer and undergo PET scans to determine the optimal timing for imaging during a sickle cell crisis. ^{1 2 3 6 7}

Who Is on the Research Team?

Enrico Novelli, MD, MS

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for adults with Sickle Cell Disease who've had at least 2 blood vessel blockage crises in the past year. They must be on stable doses of certain medications like hydroxyurea for 12 weeks before and during the study. People with cancer, pregnant or breastfeeding women, and those on regular blood transfusions or another drug trial recently can't join.

Inclusion Criteria

I have been on my current medication for sickle cell disease for at least 12 weeks and plan to continue it during the study.

Experienced at least 2 VOCs leading to healthcare visit within the 12 months prior to screening visit as determined by medical history.

I have been diagnosed with Sickle Cell Disease through specific blood tests.

Exclusion Criteria

Received active treatment on another investigational trial within 30 days (or 5 half-lives of that agent, whichever is greater) prior to screening visit or plans to participate in another investigational drug trial

I currently have cancer.

Current pregnancy or breast feeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline PET Imaging

Participants receive an injection of the radiotracer and undergo PET scans to establish baseline measurements

1 day

1 visit (in-person)

VOC PET Imaging

Participants receive another injection of the radiotracer during a sickle cell crisis and undergo PET scans to measure tracer uptake during VOC

Up to 5 days

1 visit (in-person)

Optional Follow-up PET Imaging

Participants may receive an optional injection and perform another PET scan 12 months after the sickle cell crisis if there were technical problems with previous scans

12 months after VOC

Follow-up

Participants are monitored for safety and effectiveness after PET imaging

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Cu-64]-LLP2A

Trial Overview Researchers are testing a new way to see blood vessel blockages using PET scans and a tracer called Cu-64]-LLP2A in people with Sickle Cell Disease. This could improve patient care by predicting these painful crises and aiding future drug development.

How Is the Trial Designed?

Group I: Scan at Determined Optimal Timepoint Experimental Treatment 2 Interventions

Group B participants will receive an injection of the radiotracer and undergo only one PET scan during a baseline state. Participants will receive another injection of the radiotracer during a sickle cell crisis and have one PET scan. Receive an optional injection and perform another PET scan 12 months after your sickle cell crisis if there were technical problems the previous scans.

Group II: Finding Optimal Scan Timing Experimental Treatment 2 Interventions

Group A will receive two PET scans after the radiotracer injection to learn the best timing of the scan for the rest of the people in the study during participant's baseline state. Participants will receive another injection of the radiotracer during a sickle cell crisis and have one PET scan. Receive an optional injection and perform another PET scan 12 months after your sickle cell crisis if there were technical problems the previous scans.

Who Is Running the Clinical Trial?

Enrico Novelli

Lead Sponsor

Trials

2

Recruited

50+

Enrico M Novelli

Lead Sponsor

Trials

2

Recruited

50+

The Pittsburgh Foundation

Collaborator

Trials

8

Recruited

470+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

In a study involving 23 patients with urological malignancies, the PET tracer copper-64(II)dichloride (64Cu(II)Cl2) demonstrated higher uptake in cancerous tissues compared to healthy tissues, indicating its potential effectiveness in detecting urological cancers.

64Cu(II)Cl2 was found to be safe, with no drug-related adverse effects reported, and showed high detection rates for prostate and bladder cancers (85.7%) and penile cancer (83.3%), suggesting it is a reliable imaging tool for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of the 64Cu(II)Cl2 PET/CT for Urological Malignancies: Phase IIa Clinical Study. Mascia, M., Villano, C., De Francesco, V., et al.[2023]

The bifunctional chelates 3p-C-NE3TA and 3p-C-NOTA demonstrated rapid and efficient binding with copper-64 (64Cu), making them promising candidates for targeted PET imaging in cancer diagnosis and staging.

Both chelates showed excellent stability in human serum for up to 2 days and outperformed the commonly used C-DOTA in terms of stability against EDTA challenges, indicating their potential for reliable imaging applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Promising bifunctional chelators for copper 64-PET imaging: practical (64)Cu radiolabeling and high in vitro and in vivo complex stability. Wu, N., Kang, CS., Sin, I., et al.[2022]

64-copper (64Cu) positron emission tomography (PET) is a powerful imaging tool that allows researchers to visualize and track copper metabolism in the body, which is crucial for understanding disorders like Wilson disease and Menke's disease.

This technique not only aids in diagnosing Wilson disease but also has applications in other fields such as cancer and stroke research, highlighting its versatility in medical imaging and treatment evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Positron Emission Tomography Using 64-Copper as a Tracer for the Study of Copper-Related Disorders. Emilie Munk, D., Teicher Kirk, F., Vendelbo, M., et al.[2023]

The 64Cu PET imaging agent developed shows significant ability to penetrate the blood-brain barrier and specifically bind to beta-amyloid aggregates, which are associated with Alzheimer's disease.

This imaging agent successfully differentiates between amyloid plaque presence in the brains of 5xFAD mice and wild-type mice, indicating its potential for effective in vivo imaging of Alzheimer's pathology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of a multivalent bifunctional chelator for diagnostic 64Cu PET imaging in Alzheimer's disease. Cho, HJ., Huynh, TT., Rogers, BE., et al.[2021]

Copper-64 ((64)Cu) has a longer half-life of 12.7 hours compared to traditional PET radioisotopes like (11)C and (18)F, making it more practical for drug discovery and development (D3) applications.

Recent advancements in the production of (64)Cu suggest that it can be commercially produced more widely, offering a cost-effective alternative for researchers who want to utilize PET imaging without the need for expensive radiochemistry infrastructure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular imaging with copper-64 in the drug discovery and development arena. Smith, SV.[2013]

Copper-64 was successfully produced with high yield and purity, allowing for the effective preparation of [(64)Cu]-PTSM, which is crucial for its use in medical applications.

In fibrosarcoma-bearing mice, [(64)Cu]-PTSM demonstrated significant tumor accumulation, indicating its potential for targeted imaging and therapy in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Production and tumour uptake of [64Cu]Pyruvaldehyde-bis (N4-methylthiosemicarbazone) for PET and/or therapeutic purposes. Jalilian, AR., Rowshanfarzad, P., Kamrani, YY., et al.[2016]

The monobody E1, labeled with 64Cu, shows high uptake and retention in hEphA2-expressing prostate cancer cells, indicating its potential as a targeted imaging agent.

In PC3 xenograft mice, 64Cu-NOTA-E1 allowed for effective tumor visualization via PET imaging, with significant tumor uptake observed at 24 hours post-injection and minimal background activity in other tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Production of 64Cu-labeled monobody for imaging of human EphA2-expressing tumors. Pyo, A., You, SH., Sik Kim, H., et al.[2021]

This study successfully produced clinical-grade Copper-64 ([64Cu]CuCl2) using a research reactor, demonstrating its potential for PET imaging in cancer patients, specifically prostate cancer and glioblastoma.

Toxicity studies in Wistar rats indicated that the doses of Copper in the radiopharmaceutical are negligible, ensuring safety for human use, while clinical PET scans showed effective uptake in cancerous tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reactor produced [64Cu]CuCl2 as a PET radiopharmaceutical for cancer imaging: from radiochemistry laboratory to nuclear medicine clinic. Chakravarty, R., Shetty, P., Nair, KVV., et al.[2021]

A new method for producing high specific activity Copper-64 (64Cu) using a cyclotron has been developed, achieving over 200 mCi of radioactivity and a specific activity of 5.6 GBq/μmoL, which is crucial for biomedical applications.

The produced 64Cu was successfully incorporated into a modified monoclonal antibody (DOTA-rituximab) for micro-PET imaging, demonstrating its potential for effective imaging in medical diagnostics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Establishing Reliable Cu-64 Production Process: From Target Plating to Molecular Specific Tumor Micro-PET Imaging. Xie, Q., Zhu, H., Wang, F., et al.[2018]

The study successfully developed a standardized automated synthesis process for the copper-64 radioisotope tracer [64Cu][Cu(ATSM)], which is important for both PET imaging and targeted radiotherapy in cancer treatment.

The synthesized [64Cu][Cu(ATSM)] demonstrated high radiochemical purity (>99%) and maintained its quality for at least 20 hours, indicating its potential for reliable use in clinical settings for imaging tumor hypoxia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of an automated production process of [64 Cu][Cu (ATSM)] for positron emission tomography imaging and theranostic applications. Liu, T., Redalen, KR., Karlsen, M.[2022]

The newly synthesized bifunctional ligand p-SCN-PhPr-NE3TA effectively binds Cu(II) ions, even in the presence of competing Fe(III), making it a strong candidate for use in radiopharmaceuticals.

In vivo studies in mice showed that the (64)Cu-NE3TA-PEG4-LLP2A conjugate had high tumor uptake and low background signal, indicating its potential for effective PET imaging in cancer diagnostics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Bifunctional Chelator p-SCN-PhPr-NE3TA for Copper-64: Synthesis, Peptidomimetic Conjugation, Radiolabeling, and Evaluation for PET Imaging. Gai, Y., Sun, L., Hui, W., et al.[2018]

Citations

1. withpower.com withpower.com/trial/phase-1-anemia-sickle-cell-7-2021-efa60

PET Imaging for Sickle Cell Crisis The specific compound Cu-64-LLP2A has demonstrated high tumor uptake and favorable performance in imaging studies, suggesting its potential effectiveness for ...

2. researchgate.net researchgate.net/publication/344166690_Integrin_VLA-4_as_a_PET_imaging_biomarker_of_hyper-adhesion_in_transgenic_sickle_mice

(PDF) Integrin VLA-4 as a PET imaging biomarker of hyper ... Currently, [ 64 Cu]Cu-LLP2A is also being evaluated as a diagnostic tool for the vaso-occlusive crisis in sickle cell disease (NCT04925492; ref. 35) , and LLP2A ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9902845/

First-in-Humans Evaluation of Safety and Dosimetry ... In our future 64Cu-LLP2A-PET imaging trials, we plan to incorporate a systems biology approach to integrate longitudinal clinical data with the imaging results.

4. researchgate.net researchgate.net/figure/Experimental-design-and-representative-PET-CT-scans-A-SCD-and-non-SCD-mice-were-imaged_fig1_344166690

Experimental design and representative PET/CT scans. (A) ... Another recently published study demonstrated the use of [ 64 Cu] Cu-LLP2A as a PET imaging agent to detect VLA4mediated hyper adhesion in transgenic sickle ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36008121/

First-in-Humans Evaluation of Safety and Dosimetry of 64Cu ... 64 Cu-LLP2A is a VLA4-targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM.

6. profiles.wustl.edu profiles.wustl.edu/en/publications/first-in-human-evaluation-of-safety-and-dosimetry-of-sup64supcu-l

First-in-Human Evaluation of Safety and Dosimetry of >64> ... Dive into the research topics of 'First-in-Human Evaluation of Safety and Dosimetry of 64Cu-LLP2A for PET Imaging'. Together they form a unique ...

7. researchgate.net researchgate.net/publication/380177551_Albumin-Binding_Lutetium-177-Labeled_LLP2A_Derivatives_as_Theranostics_for_Melanoma

Albumin-Binding Lutetium-177-Labeled LLP2A Derivatives ... Conclusion: 64Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans. ... In sickle cell disease (SCD), very late antigen-4 (VLA-4 or ...