Granzyme B PET Imaging for Cancer Response Prediction

Overseen By Colin G Miller, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Cytosite Biopharma Inc.

Must be taking: Checkpoint inhibitors

Must not be taking: Systemic steroids, Immunosuppressive agents

Disqualifiers: Brain metastases, Inflammatory disease, others

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

Compensation: Varies

Number of Visits: 1

Duration: 2 cycles of treatment

30 Participants Needed

Trial Summary

What is the purpose of this trial?

First in Human Safety of \[68Ga\]-NOTA-hGZP PET Imaging in subjects with cancer undergoing treatment with a checkpoint inhibitor either as a monotherapy of in combination I-O therapy

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

The trial does not specify if you need to stop your current medications, but you cannot be on systemic steroids or immunosuppressive agents unless they are below certain doses. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment [68Ga]-NOTA-hGZP for cancer response prediction?

Research shows that PET imaging with granzyme B-targeted radiotracers, like 68Ga-grazytracer, can effectively predict tumor responses to immunotherapy by identifying active immune cells in tumors. This method has been shown to distinguish between patients who respond to treatment and those who do not, suggesting its potential usefulness in assessing cancer treatment responses. ^{1 2 3 4 5}

How does Granzyme B PET Imaging differ from other cancer treatments?

Granzyme B PET Imaging is unique because it uses a special imaging technique to predict how well a cancer patient will respond to immunotherapy by detecting granzyme B, a protein released by immune cells. This approach allows for early assessment of treatment effectiveness, helping to distinguish between patients who will benefit from immunotherapy and those who will not, unlike traditional imaging methods. ^{1 2 3 4 5}

Research Team

Colin G Miller, PhD

Principal Investigator

CytoSite Bio Inc.

Eligibility Criteria

Adults with metastatic cancer eligible for checkpoint inhibitor therapy (PD-1, PD-L1, CTLA-4, LAG-3 inhibitors) can join. They must have a life expectancy over 6 months, at least one sizable tumor lesion, and be able to consent. Excluded are those with unresolved prior treatment side effects, brain metastases, allergies to trial drugs or similar compounds, current steroid/immunosuppressant use (with exceptions), recent investigational drug use or previous checkpoint inhibitors.

Inclusion Criteria

eGRF eGFR < 45 mL/min/1.73 m2

I am not able to become pregnant or have a negative pregnancy test.

My metastatic cancer will be treated with specific immune therapy drugs.

Exclusion Criteria

I am allergic to certain drugs similar to [68Ga]-NOTA-hGZP or pembrolizumab.

I am on low-dose steroids but do not have an active autoimmune disease.

I haven't taken any experimental drugs or treatments in the last 90 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a mass dose of 40 μg or less of [68Ga]-NOTA-hGZP and undergo PET and CT scans to evaluate the safety and predict the clinical response to checkpoint inhibitor therapy

2 cycles of treatment

1 visit (in-person) for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in physical examination findings, vital signs, blood chemistry, and ECG

up to 6 months

Extension

Evaluate the correlation of [68Ga]-NOTA-hGZP accumulation in tumor foci to 6-month outcome and assess treatment response in individual lesions

6 months

Treatment Details

Interventions

• [68Ga]-NOTA-hGZP

Trial Overview The trial is testing the safety of a new PET imaging drug [68Ga]-NOTA-hGZP in humans. It aims to see if this drug can predict how well patients respond to immunotherapy using checkpoint inhibitors. This is a single-arm study where all participants receive the same intervention.

Participant Groups

Group I: Single Arm Experimental Treatment 1 Intervention

All participants will receive a mass dose of 40 μg or less of \[68Ga\]-NOTA-hGZP (radioactivity dose of 3 mCi to 8 mCi) and have a PET and CT scan.

Who Is Running the Clinical Trial?

Cytosite Biopharma Inc.

Lead Sponsor

Trials

2

Recruited

40+

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

University of Alabama at Birmingham

Collaborator

Trials

1,677

Recruited

2,458,000+

Chang Gung Memorial Hospital

Collaborator

Trials

1,117

Recruited

490,000+

Findings from Research

The study developed novel SPECT imaging probes, [111 In]IDT and [111 In]IDAT, which effectively target granzyme B, a promising biomarker for enhancing immune checkpoint inhibitor treatments.

In experiments with tumor-bearing mice, these probes demonstrated moderate accumulation in tumors, correlating with granzyme B expression, suggesting their potential utility in monitoring treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and evaluation of 111 In-labeled tetrapeptide-based compounds as single-photon emission computed tomography imaging probes targeting granzyme B. Kazuta, N., Watanabe, H., Ono, M.[2023]

The PET imaging technique using the granzyme B-targeted radiotracer 68Ga-grazytracer can effectively predict tumor responses to immunotherapy, showing better sensitivity in distinguishing responders from nonresponders compared to traditional methods.

In a preliminary clinical trial with 5 patients, 68Ga-grazytracer was safe with no adverse events reported, and its PET results correlated well with clinical responses to immunotherapy, suggesting its potential for improving patient stratification and early response assessment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy. Zhou, H., Wang, Y., Xu, H., et al.[2022]

Granzyme B has been identified as a promising early biomarker for predicting responses to cancer immunotherapy, with preclinical studies showing that PET imaging can effectively distinguish between tumor responders and nonresponders in mice.

In human melanoma patients undergoing checkpoint inhibitor therapy, significant differences in granzyme B expression were found between responders and nonresponders, indicating its potential for clinical application as a predictive biomarker.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response. Larimer, BM., Wehrenberg-Klee, E., Dubois, F., et al.[2021]

Granzyme B PET imaging using the targeted peptide GZP is a highly sensitive and specific method for early assessment of response to cancer immunotherapy, showing 93% sensitivity and 94% negative predictive value in predicting treatment outcomes.

The study demonstrated that GZP PET imaging can effectively compare the efficacy of different checkpoint inhibitor regimens, revealing that sequential dosing of PD-1 and CTLA-4 therapies is as effective as concurrent administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effectiveness of Checkpoint Inhibitor Combinations and Administration Timing Can Be Measured by Granzyme B PET Imaging. Larimer, BM., Bloch, E., Nesti, S., et al.[2020]

A new imaging technology, using a specially engineered peptide called GRIP B, allows researchers to measure the activity of granzyme B (GZMB) in living organisms, providing insights into its biological functions in real-time.

In mouse cancer models, this method successfully detected GZMB activity in tumors and lymphoid tissues, indicating its potential role in immune responses, especially when combined with immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo Measurement of Granzyme Proteolysis from Activated Immune Cells with PET. Zhao, N., Bardine, C., Lourenço, AL., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Synthesis and evaluation of 111 In-labeled tetrapeptide-based compounds as single-photon emission computed tomography imaging probes targeting granzyme B. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

The Effectiveness of Checkpoint Inhibitor Combinations and Administration Timing Can Be Measured by Granzyme B PET Imaging. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

In Vivo Measurement of Granzyme Proteolysis from Activated Immune Cells with PET. [2023]