PET Imaging Study of 64Cu-GRIP B for Patients Receiving CD19-directed CAR-T Therapy

Phase 1

Recruiting

• Conditions: Non Hodgkin Lymphoma
• Interventions: Drug: 64Cu-GRIP B; Procedure: Positron Emission Tomography (PET); Procedure: Optional tumor biopsy

• Registration Number: NCT06522932
• Lead Sponsor: C. Babis Andreadis

Brief Summary

This is a phase I/Ib imaging study of granzyme B, 64-copper granzyme targeting restricted interaction peptide specific to family member B (64Cu-GRIP B) Positron Emission Tomography (PET) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL) receiving CD19-directed Chimeric antigen receptor T cells (CAR-T) therapy. The proposed study represents the first-ever lymphoma patient imaging studies with 64Cu-GRIP B PET. The tracer is designed to detect extracellular granzyme B as it is secreted by activated immune cells in the tumor microenvironment, which may highlight tumors that will exhibit a durable response to Cluster of Differentiation 19 (CD19)-directed CAR T-cell therapy.

Detailed Description

Primary Objectives:

1. To establish the feasibility of granzyme B detection with 64Cu-GRIP B PET in participants with relapsed/refractory NHL receiving CD19-directed CAR-T cell therapy in both cohorts.

Secondary Objectives:

1. To descriptively report the patterns of intra-tumoral uptake of 64Cu-GRIP B on whole body PET, including by site of disease, uptake by tumor type, inter-tumoral and inter-participant heterogeneity, and tumor-to-background signal in participants with participants with NHL.

2. To descriptively report the number of lesions identified on 64Cu-GRIP B PET compared with conventional imaging in participants with NHL.

3. To assess the safety of 64Cu-GRIP B in participants with NHL undergoing CAR-T cell therapy.

Participants will be initially enrolled in Cohort 1. Based on the interim analysis, enrollment will begin in Cohort 2. An optional research biopsy will be collected after the post-therapy scan and participants will be followed for 12 months after the end of the study intervention.

Study Timeline

• Study First Submitted: 2024-07-22
• Study First Submitted QC: 2024-07-22
• Study First Posted: 2024-07-26
• Study Start: 2024-10-23
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-15
• Last Update Posted: 2024-11-19
• Primary Completion: 2027-01-31
• Study Completion: 2027-01-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 32

Inclusion Criteria

1. Disease characteristics, as defined by:

   1. Histologically-confirmed relapsed/refractory non-Hodgkin lymphoma with at least one prior line of therapy.
   2. Planned treatment with a commercially available CD19 targeting CAR-T cell product .

2. Willing to undergo post-treatment tumor biopsies and has safely accessible soft tissue lesion.

3. Age >= 18 years.

4. Ability to understand and the willingness to sign a written informed consent document.

5. Eastern Cooperative Oncology Group (ECOG) performance status <2 (Karnofsky >60%).

6. Demonstrates adequate organ function as defined below:

   1. Absolute neutrophil count >=1,500/microliter (mcL)
   2. Platelets ≥100,000/mcL
   3. Total bilirubin within normal institutional limits, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits.
   4. Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) <=3 X institutional upper limit of normal.
   5. Alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) <=3 X institutional upper limit of normal
   6. Creatinine <= 1.5 x within institutional upper limit of normal OR creatinine clearance Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2, calculated using the Cockcroft-Gault equation, unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2.

7. Human immunodeficiency virus (HIV)-infected individuals on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial.

8. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

9. Individuals with a history of hepatitis C virus (HCV) infection must have been treated and cured. Individuals with HCV infection who are currently on treatment are eligible if an undetectable HCV viral load is demonstrated.

10. Individuals with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.

11. Individuals with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.

12. Individuals with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. The effects of 64Cu-GRIP B on the developing human fetus are unknown. For this reason, participants of childbearing potential must agree to use adequate contraception: all participants should use barrier protection for the duration of study participation and for one month after last administration of study intervention. Should a participant become pregnant or suspect they are pregnant while they or their partner are participating in this study, they should inform their treating physician immediately. Male participants treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and one month after last administration of study treatment.

Exclusion Criteria

1. Any condition that, in the opinion of the Principal Investigator, would impair the participant's ability to comply with study procedures.
2. Pregnant participants are excluded from this study because the effects of 64Cu-GRIP B on the developing human fetus are unknown. There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the nursing parent with 64Cu-GRIP B, breastfeeding should be discontinued if the nursing parent receives 64Cu-GRIP B.
3. Hypersensitivity to 64Cu-GRIP B or any of its excipients.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 2: Expansion Phase 64Cu-GRIP B PET imaging	64Cu-GRIP B	Participants with NHL will undergo 64Cu-GRIP B PET before and after CD19-directed CAR-T therapy with one of the three time points chosen based on 64Cu-GRIP B uptake determined in Cohort 1. An optional soft tissue biopsy will be collected following the post-treatment PET. Participants will be followed up for 12 months after the final PET scan.
Cohort 2: Expansion Phase 64Cu-GRIP B PET imaging	Positron Emission Tomography (PET)	Participants with NHL will undergo 64Cu-GRIP B PET before and after CD19-directed CAR-T therapy with one of the three time points chosen based on 64Cu-GRIP B uptake determined in Cohort 1. An optional soft tissue biopsy will be collected following the post-treatment PET. Participants will be followed up for 12 months after the final PET scan.
Cohort 2: Expansion Phase 64Cu-GRIP B PET imaging	Optional tumor biopsy	Participants with NHL will undergo 64Cu-GRIP B PET before and after CD19-directed CAR-T therapy with one of the three time points chosen based on 64Cu-GRIP B uptake determined in Cohort 1. An optional soft tissue biopsy will be collected following the post-treatment PET. Participants will be followed up for 12 months after the final PET scan.
Cohort 1: 64Cu-GRIP B PET imaging	Positron Emission Tomography (PET)	Participants with NHL will undergo 64Cu-GRIP B PET before and after CD19-directed CAR-T therapy. Three participants will undergo post-treatment 64Cu-GRIP B PET at the Day 8 time point, three participants will undergo post-treatment 64Cu-GRIP B PET at the Day 15 (+/- 3) time point, and three participants will undergo post-treatment 64Cu-GRIP B PET Day 22 (+/- 3) time point. An optional soft tissue biopsy will be collected following the post-treatment PET. Participants will be followed up for 12 months after the final PET scan.
Cohort 1: 64Cu-GRIP B PET imaging	Optional tumor biopsy	Participants with NHL will undergo 64Cu-GRIP B PET before and after CD19-directed CAR-T therapy. Three participants will undergo post-treatment 64Cu-GRIP B PET at the Day 8 time point, three participants will undergo post-treatment 64Cu-GRIP B PET at the Day 15 (+/- 3) time point, and three participants will undergo post-treatment 64Cu-GRIP B PET Day 22 (+/- 3) time point. An optional soft tissue biopsy will be collected following the post-treatment PET. Participants will be followed up for 12 months after the final PET scan.
Cohort 1: 64Cu-GRIP B PET imaging	64Cu-GRIP B	Participants with NHL will undergo 64Cu-GRIP B PET before and after CD19-directed CAR-T therapy. Three participants will undergo post-treatment 64Cu-GRIP B PET at the Day 8 time point, three participants will undergo post-treatment 64Cu-GRIP B PET at the Day 15 (+/- 3) time point, and three participants will undergo post-treatment 64Cu-GRIP B PET Day 22 (+/- 3) time point. An optional soft tissue biopsy will be collected following the post-treatment PET. Participants will be followed up for 12 months after the final PET scan.

Primary Outcome Measures

Name	Time	Method
Proportion of positive tumors at the post-CAR-T scan	From prior to CAR-T to Day 22 following CAR-T cell, approximately 32 days total	The proportion of known lesions with detectable radiotracer uptake on conventional imaging will be reported along with 95% binomial exact confidence intervals. Tumors will be defined as positive if they are focally avid with maximum standardized uptake value (SUVmax) \>1.5 fold above adjacent background.

Secondary Outcome Measures

Name	Time	Method
Frequency and severity of treatment-emergent adverse events	Up to 13 months	Frequency and severity of treatment adverse events following 64Cu-GRIP B injection classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v 5.0).
Mean SUVmax by disease site	From prior to CAR-T to Day 22 following CAR-T cell, approximately 32 days total	The mean/sd (median and range, if normality assumption does not hold) for intra-tumoral SUVmax within lesions will be descriptively reported, to assess for intra-tumoral heterogeneity and differences in uptake by site of disease.
Overall Mean SUVmax by cohort	From prior to CAR-T to Day 22 following CAR-T cell, approximately 32 days total	The mean/sd (median and range, if normality assumption does not hold) for inter-participant SUVmax within lesions will be descriptively reported, to assess for inter-participant heterogeneity and differences in uptake.
Percent of lymphoma lesions detected	From prior to CAR-T to Day 22 following CAR-T cell, approximately 32 days total	The percentage of lesions detected on conventional imaging that are detected on baseline 64Cu-GRIP B PET will be descriptively reported.

Trial Locations

Locations (1)

University of California, San Francisco; 🇺🇸 San Francisco, California, United States