PET Imaging Study of 89Zr-DFO-YS5

A First-in-Human, Pilot PET Imaging Study of 89Zr-DFO-YS5, an immunoPET Agent for Detecting CD46 Positive Malignancy in Men With Prostate Cancer

CD46 is an exciting new therapeutic target in prostate cancer, with the antibody drug conjugate FOR46 under investigation in phase I clinical trials. The hypothesis of the study is that CD46 expression, measured via our novel imaging biomarker, is a characteristic feature of mCRPC, and particularly common in the most lethal forms of the disease including adenocarcinoma and Small-cell neuroendocrine carcinoma (SCNC). These data will provide crucial information about the feasibility of targeting cluster of differentiation 46 (CD46) in mCRPC, will be used guide the development of novel therapeutic and theranostic agents, to help develop treatments that improve outcomes for men with the most lethal forms of prostate cancer.

This single center imaging study involves one microdose of the imaging agent, followed by whole body PET imaging. Imaging data will be acquired in up to four PET studies to determine tumor and normal tissue uptake and dosimetry. PRIMARY OBJECTIVES: To determine the optimal time point for imaging (based on analyzing the 4 scans of all participants using 89Zr-DFO-YS5 PET post-injection. (Cohort A) To determine the optimal antibody dose for imaging using 89Zr-DFO-YS5 PET. (Cohort B). To determine the sensitivity of metastatic lesion detection in mCRPC using 89Zr-DFO-YS5 PET as compared with conventional imaging.(Cohorts C & D) SECONDARY OBJECTIVES: To determine the safety of 89Zr-DFO-YS5. To determine average organ uptake of 89Zr-DFO-YS5 (Cohort C & D). To descriptively report the patterns of intra-tumoral uptake of 89Zr-DFO-YS5 on whole body PET, including by site of disease, uptake by tumor type, inter-tumoral and inter-patient heterogeneity, and tumor-to-background signal (Cohorts C & D). ARMS: Cohort A: PET imaging data will be acquired up to four times to determine tumor and normal tissue uptake and dosimetry. The optimized scan time will be used for imaging in Cohorts B and C. Cohort B: A dose of cold, non-radiolabeled antibody administered will be varied to determine the optimal antibody dose for image quality. The optimized antibody dose will be used in Cohort C and D. Participants will be followed for an additional 4-5 weeks after dose administration to assess for adverse events. Participants have the option to receive a repeat scan at the time of disease progression. Cohort C: PET imaging will be acquired at the optimal time point and optimal antibody dose determined in Cohorts A & B. Participants in Cohort C have the option to receive a repeat scan at the time of disease progression. Cohort D: PET imaging will be acquired at four time points using the antibody to enable calculation of tumor and organ dosimetry. This cohort enrolls concurrently with Cohort C. All participants will be followed for up to 5 weeks after their first scan to assess for adverse events

Participants receive one dose of 89Zr-DFO-YS5 up to 3 millicurie (mCi), and undergo a whole body PET performed at 1-4 hours, approximately 20-28 hours, 48-96 hours, and 120-168 hours post injection for up to 4 scans total. The optimized scan time will be used for imaging in cohorts B and C.

Participants receive either a 20mg or 50mg dose of YS5 prior to imaging and administration of one dose of up to 3 millicurie (mCi) 89Zr-DFO-YS5 and then complete a single whole body PET scan at the optimal time determined in Cohort A. The optimal dose of unmodified YS5 antibody will be used in the following cohorts C & D. Participants have the option to receive a repeat 89Zr-DFO-YS5 PET at the time of disease progression.

Participants receive optimal dose of YS5 antibody prior to imaging and administration of one dose of up to 3 millicurie (mCi) 89Zr-DFO-YS5 and then complete a single whole body PET scan at the optimal time determined in Cohort A. Participants have the option to receive a repeat 89Zr-DFO-YS5 PET at the time of disease progression.

Participants will receive optimal dose of YS5 prior to imaging and administration of one dose of up to 3 millicurie (mCi) 89Zr-DFO-YS5 and then complete a series of whole body PET scans performed at 1-4 hours, approximately 20-28 hours, 48-96 hours, and 120-168 hours post injection for up to 4 scans total. Participants in have the option to receive a repeat 89Zr-DFO-YS5 PET at the time of disease progression.

For Cohort A, the optimal time point will be selected based on optimal maximun Standardized uptake value (SUVmax) of metastatic lesions, and ratio of SUVmax to blood pool. Due to the limited samples, the investigator will use all available lesions without considering the location of the lesions or the possible intra-correlation of the lesions from the same participant.

For Cohort B, the optimal dose of antibody will be selected based on the optimal SUVmax of metastatic lesions, and ratio of SUVmax to blood pool. Due to the limited samples, the investigator will use all available lesions without considering the location of the lesions or the possible intra-correlation of the lesions from the same participant.

Proportion of participants with metastatic lesions accurately detected in mCRPC using 89Zr-DFO-YS5 PET (sensitivity) (Cohort C & D)

Sensitivity is the probability that a test will indicate disease among those with the actual disease: True Positive / (True Positive + False Negative). Lesions will be graded on a semi-quantitative scale ranging from 1-5 as is common for 89Zr-antibody human imaging studies (1 = no uptake, 2 = probably no uptake, 3 = equivocal, 4 = probably positive, 5 = definitely positive). Using as a cut-off to 4 or 5 on the semi-quantitative scale, the sensitivity of 89Zr-DFO-YS5 PET will be descriptively reported on a lesion-per-lesion basis, using as reference standard staging scans including CT or MRI of the chest/abdomen/pelvis and whole body bone scan. The sensitivity estimate will be based on lesion level without considering the location of the lesions or the possible intra-correlation of the lesions from the same patient.

The median and range of SUVmax across all metastatic lesions per participant will be descriptively reported using mediastinal blood pool and normal organ as background uptake values will be reported with range of SUVmax.

The average SUVmax-ave across all metastatic lesions per participant will be descriptively reported using mediastinal blood pool and normal organ as background uptake values for all cohorts will be reported with 95% confidence intervals

The frequency and severity of adverse events following Zr-DFO-YS5 injection will be descriptively reported, using CTCAE version 5.0

The median and range for intra-tumoral SUVmax within metastatic lesions will be descriptively reported

The median and range for intra-tumoral SUVmax within metastatic lesions will be descriptively reported

The median and range for intra-tumoral SUVmax within metastatic lesions will be descriptively reported to assess for Inter-tumoral heterogeneity.

The median and range for intra-tumoral SUVmax within metastatic lesions will be descriptively reported to assess for Inter-participant heterogeneity

The median and range for intra-tumoral SUVmax within metastatic lesions will be descriptively reported

Inclusion Criteria: Participants must have histologically or cytologically confirmed metastatic, castration resistant prostate cancer (mCRPC). Age >=18 years Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky >60%). Demonstrates adequate organ function as defined below: Total bilirubin <1.5 X upper limit of normal (ULN). Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase (SGOT)) <= 3 X institutional upper limit of normal (ULN). Alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase (SGPT)) <= 3 X institutional ULN. Creatinine clearance >= 60 mL/min, calculated using the Cockcroft-Gault equation. Ability to understand a written informed consent document, and the willingness to sign it. 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. 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. Patients who have received the same antibody (YS5) earlier as part of therapy or detection.