64Cu-GRIP B in Patients With Advanced Genitourinary Malignancies

A First-in-Human, Phase I/II PET Imaging Study of 64Cu-GRIP B, a Radiotracer Targeting Granzyme B, in Patients With Advanced Genitourinary Malignancies

This is a first-in-human phase I/II imaging study of 64Cu-GRIP B PET in patients with advanced genitourinary (GU) malignancies. 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 regress on treatment with immunomodulatory therapies. The study population is focused on genitourinary malignancies, including renal cell and urothelial cancer, two tumor types with high mutational burden and tumor infiltrating lymphocytes compared to other tumor types, and have a predictable response rate at the population level to immune checkpoint inhibitors.

PRIMARY OBJECTIVES: Cohort A: To determine safety, dosimetry, and pharmacokinetics of 64Cu-GRIP B PET in patients with metastatic GU malignancy (renal, urothelial, or prostate) Cohort B and C: To determine the mean percent change in both tumor maximum standardized uptake value (SUVmax), and ratio of SUVmax/blood standardized uptake value average (SUVave) on 64Cu-GRIP B PET in patients with participants with metastatic renal cell carcinoma (RCC) and urothelial carcinoma (UC) (Cohort B) or metastatic castrate-resistant prostate cancer (mCRPC) (Cohort C). SECONDARY OBJECTIVES: To determine the safety and average organ dosimetry of 64Cu-GRIP B PET in patients with participants with metastatic RCC and UC (Cohort B) or mCRPC (Cohort C). 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-patient heterogeneity, and tumor-to-background signal at baseline and at the time of progression (Cohorts B and C) in participants with metastatic RCC and UC (Cohort B) or mCRPC (Cohort C). To descriptively report Grade >= 2 immune-related adverse event(s) in patients with metastatic RCC and UC (Cohort B) who have 64Cu-GRIP B PET performed within 14 days of onset of event. To descriptively report the number of lesions identified on 64Cu-GRIP B PET compared with conventional imaging in patients with metastatic RCC and UC (Cohort B) or mCRPC (Cohort C). To determine whether baseline uptake on 64Cu-GRIP B PET is associated with subsequent clinical outcomes, including objective response, progression-free survival, response defined as decrease > 50% from baseline (PSA50), and immune-related adverse events (irAE) in participants with metastatic RCC and UC (Cohort B) or mCRPC (Cohort C). OUTLINE: A total of 6 participants will be enrolled in Cohort A, initially. Successful completion of the feasibility portion of the study (Cohort A) will provide the necessary preliminary data to support subsequent enrollment in Cohorts B and C. All participants will receive 64Cu-GRIP B PET at baseline. For participants in Cohorts B & C, another PET scan will be performed 8 weeks following initiation of checkpoint inhibitor treatment, and at disease progression. Participants will be followed for up to 2 years for longitudinal endpoints.

Six participants with metastatic GU malignancy (renal, urothelial, or prostate) (3 males, 3 females), dosimetry calculation will be performed by obtaining whole body (vertex to thighs) PET images up to five time points from 0.5 to 24 hours post 64Cu-GRIP B injections An additional intravenous line will be placed in the contra-lateral arm to collect blood for this group.

Participants with renal cell and urothelial carcinoma will have longitudinal imaging performed prior to treatment outside of this study with anti-programmed death-1 (PD-1)/anti-PD-1 ligand 1 (PD-L1) blockade (with or without concomitant anti-CTLA4 treatment), after 8 weeks of checkpoint blockade, and again at the time of disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Participants with metastatic castration resistant prostate cancer (mCRPC)) will have longitudinal imaging performed prior to treatment outside of this study, 8 weeks following initiation of treatment outside of this study, and at the time of disease progression by Prostate Cancer Working Group 3 (PCWG3) criteria.

For Cohort A, the frequency and severity of adverse events following 64Cu-GRIP B injection will be descriptively reported, using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

For Cohort A, the tracer kinetics is measured in the organs and total-body, and the % of injected activity for each time point will be recorded for participants in Cohort A. This information is used as input for organ and whole-body effective dose calculation using Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM). This will provide the data of whole-body effective dose (millisievert (mSv)/megabecquerels (MBq)), and organ doses.

Pharmacokinetic (PK) parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the time it takes for a drug to reach the maximum concentration (Cmax) after administration of a drug that needs to be absorbed.

PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the maximum concentration (Cmax) after administration of a drug that needs to be absorbed.

PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the area under the concentration-time curve (AUC) from hour 0 to the last measurable concentration (AUC0-t; min*unit/mL)

PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the AUC extrapolated to infinity (AUC0-∞; min*unit/mL)

PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the volume of plasma which is completely cleared of a substance per minute (mL/min).

PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute the apparent terminal elimination rate constant.

PK parameters for participants in Cohort A derived from plasma will be calculated using a non-compartmental approach with a log-linear terminal assumption for up to a possible 5 time points. A custom software package or a commercial software package like Phoenix WinNonlin will be used to compute apparent terminal elimination half-life (t1/2; min).

For Cohort B and C, descriptive statistics will be used to summarize the change in SUVmax from baseline to 8 weeks at lesion level for participants in Cohorts B & C.

For Cohort B and C, descriptive statistics will be used to summarize the change in the ratio of SUVmax/SUVave from baseline to 8 weeks at lesion level for participants in Cohorts B & C.

For Cohort B and C, the frequency and severity of adverse events following 64Cu-GRIP B injection will be descriptively reported

The mead/sd (median and range, if normality assumption does not hold) for intra-tumoral SUVmax within metastatic lesions will be descriptively reported, to assess for intra-tumoral heterogeneity and differences in uptake by site of disease

The percentage of metastatic lesions detected on conventional imaging that are also detected on baseline 64Cu-GRIP B PET will be descriptively reported

For the subset of patients in Cohort B experiencing Grade ≥ 2 immune-related adverse event who have 64Cu-GRIP B PET performed within 14 days of onset of event, the mean change from baseline in involved organ site(s) uptake on PET will be descriptively reported along with sd (or median with range) at lesion-level

For the subset of patients in Cohort B experiencing Grade >= 2 immune-related adverse event who have 64Cu-GRIP B PET performed within 14 days of onset of event, the mean change from baseline in involved organ site(s) uptake on PET will be descriptively reported along with sd (or median with range) at patient-level

For Cohort B and C, to analyze the association between the baseline in SUVmax and with subsequent response by RECIST 1.1 for Cohort B and modified RECIST 1.1/PCWG3 criteria, metastatic lesions will be segregated based on objective response by RECIST 1.1 criteria on follow up conventional imaging.

To assess the association between the baseline SUVmax with progression-free survival, defined as the time from date of initiation of checkpoint inhibition to subsequent progression by Prostate Cancer Clinical Trials Working Group 3 (PCWG3)/RECIST criteria, the patient cohort will be dichotomized above and below the median PFS,

To assess the association between the baseline in SUVmax with the patient cohort will be dichotomized into PSA50 vs. non-PSA50 reporters using linear mixed models

To assess the association between the baseline in SUVmax with the patient cohort will be dichotomized into irAE vs. non-irAE reporters using linear mixed models

Inclusion Criteria: Disease characteristics by cohort, as defined by: Cohort A: Histologically-confirmed metastatic solid tumor malignancy (3 Male, 3 Female) Locally advanced or metastatic disease on conventional imaging Cohort B: Histologically-confirmed metastatic renal cell carcinoma (any histologic sub-type) or urothelial carcinoma Locally advanced or metastatic disease on conventional imaging Cohort C: Histologically-confirmed prostate adenocarcinoma Metastatic castration resistant prostate cancer by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria Planned treatment with immune checkpoint inhibitor (Cohorts B and C only) Willing to undergo paired tumor biopsies and has safely accessible bone or soft tissue lesion (Cohorts B and C only) The subject is able and willing to comply with study procedures and provide signed and dated informed consent. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Age 18 years or older at the time of study entry. Adequate organ function, as defined by: Serum creatinine <= 1.5 x upper limit of normal (ULN) or estimated creatinine clearance > 60 mL/min Total bilirubin <= 1.5 x ULN (< 3 x ULN in patients with documented or suspected Gilbert's). Hemoglobin >= 8.0 g/dL Platelet count >= 75,000/microliter Absolute neutrophil count ≥ 1000/microliter Patients must not be pregnant or breast feeding. Women of childbearing potential are required to obtain a negative pregnancy test within 14 days of PET Imaging scan. Effective contraception (men and women) must be used in subjects of child-bearing potential. Exclusion Criteria: Patients who because of age, general medical or psychiatric condition, or physiologic status cannot give valid informed consent. Any condition that, in the opinion of the Principal Investigator, would impair the patient's ability to comply with study procedures. Is currently pregnant or breastfeeding.