68Ga-PSMA-R2 in Patients With Biochemical Relapse (BR) and Metastatic Prostate Cancer (mPCa)

Study Overview
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Brief Summary
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This was an open-label, multicenter, single dose, Phase I/II study to evaluate the safety and tolerability of a single administration of 3 mega Becquerel (MBq)/kg, but not less than 150 MBq and not more than 250 MBq, of 68^Ga-PSMA-R2 in adult male patients with biochemical relapse (BR) and metastatic prostate cancer (mPCa).

Detailed Description
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This study consisted of 2 parts. During the first part (Phase I) of the study, 6 subjects with biochemically recurrent prostate cancer (PCa) received the investigational product (IP) and remained at the site for approximately 6 hours post-administration in order to assess the PK, biodistribution versus time, and dosimetry for critical organs. Subjects received a single dose of 3 MBq/kg, (>=150 and =<250 MBq), of 68^Ga-PSMA-R2 intravenously. Serial blood and urine samples were collected for PK characterization and dosimetry and whole-body PET/CT were acquired at selected time points (0 to 4 hours) to determine organ and tumor absorbed doses. Safety assessments were conducted after IP administration on Day 1, and during follow-up on Days 7 and 28. In the second part of the study (Phase II), 2 groups of 12 subjects were enrolled (subjects with PCa in biochemical recurrence [PCa-BR], and subjects with prostate cancer in the metastatic stage [mPCa]). Based on the preliminary data analysis from the Phase I part of the study provided sufficient dosimetry data, all subjects underwent the whole body PET/CT imaging optimized for time (up to 2 time points) according to the data analysis from the Phase I part of the study. This study was comprised of 4 clinical visits and conducted in 3 study periods: screening, administration/imaging, and safety follow-up period.

Official Title
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A Phase 1/2 Open-label, Multi-center, Safety and Tolerability Study of a Single Dose of 68Ga-PSMA-R2 in Patients With Biochemical Relapse (BR) and Metastatic Prostate Cancer (mPCa)

Conditions
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Prostate Cancer Metastatic

Intervention / Treatment
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* Drug: [68Ga]-PSMA-R2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males 18 years or older. Signed and dated written informed consent by the subject prior to any study-specific procedures. Histologically confirmed adenocarcinoma of the prostate, defined as follows: Biochemical recurrence: defined as PSA is ≥0.2 ng/mL after radical prostatectomy or PSA nadir plus 2 ng/mL after radiation therapy with corresponding CT/MRI or bone scan revealing absence of local recurrence or metastatic lesions. OR Metastatic disease: defined as both, castration-sensitive or castration-resistant mPCa (presence of at least 1 metastatic lymph node, visceral metastasis and/or bone metastasis). At least 2 weeks must have elapsed between last anticancer treatment administration and the administration of the imaging product, 68Ga-PSMA-R2. Prior major surgery must be at least 12 weeks prior to study entry. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, with a life expectancy ≥6 months. Adequate bone marrow reserve and organ function as demonstrated by complete blood count, and biochemistry in blood and urine at Screening: Hemoglobin (Hb): >8 g/dL Platelet count of >50.000/mm3 Serum creatinine <1.5*upper limit normal (ULN) or estimated glomerular filtration rate (eGFR) >50 mL/min based upon The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. For male subjects with partners of childbearing potential, agreement to use barrier contraceptive method (condom) and to continue its use for 28 days after IP administration. Exclusion Criteria: Pathological finding consistent with small cell, neuroendocrine carcinoma of the prostate or any other histologies different than adenocarcinoma. Administered a radioisotope =<10 physical half-lives prior to the day of PET/CT. Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, or need of indwelling/condom catheters. Uncontrolled pain or incompatibility that results in subject's lack of compliance with imaging procedures. Other known coexisting malignancies except non-melanoma skin or low grade superficial bladder cancer unless definitively treated and proven no evidence of recurrence for 5 years. Subject with known incompatibility to CT scans. Any evidence of severe or uncontrolled systemic or psychiatric diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the subject to participate in the study or which would jeopardize compliance with the protocol, or active infection including human immunodeficiency virus (HIV) and untreated hepatitis B, hepatitis C. Screening for chronic conditions was not required. Subjects who have received any investigational agent within the last 28 days were excluded from participation in this study. Any acute toxicity due to prior chemotherapy and/or radiotherapy that has not resolved according to the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Studies. Known allergy, hypersensitivity, or intolerance to the IP or its excipients. Subject unlikely to comply with study procedures, restrictions and requirements and judged by the investigator to be unsuitable for study participation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase I: characterize PK and dosimetry Phase II: diagnostic potential in 2 groups Prostate Cancer in biochemical relapse, and Metastatic Prostate Cancer
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Biochemically Recurrent Prostate Cancer (PCa-BR) (Phase I)<br>All eligible participants received recommended dose of [68Ga]-PSMA-R2 of 3 Mega Becquerel (MBq)/Kg (+/- 10%) [but not more than 250 and not less than 150 MBq]. | Drug: [68Ga]-PSMA-R2<br>* radio-labelled PSMA ligand<br>|
| Experimental: Biochemically Recurrent Prostate Cancer (PCa-BR) (Phase II)<br>All eligible participants received recommended dose of [68Ga]-PSMA-R2 of 3 Mega Becquerel (MBq)/Kg (+/- 10%) [but not more than 250 and not less than 150 MBq]. | Drug: [68Ga]-PSMA-R2<br>* radio-labelled PSMA ligand<br>|
| Experimental: Metastatic Prostate Cancer (mPCa) (Phase II)<br>All eligible participants received recommended dose of [68Ga]-PSMA-R2 of 3 Mega Becquerel (MBq)/Kg (+/- 10%) [but not more than 250 and not less than 150 MBq]. | Drug: [68Ga]-PSMA-R2<br>* radio-labelled PSMA ligand<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events | Treatment-emergent adverse events (TEAEs) were collected from first dosing (single administration, Day 1) up to last follow-up visit or until the event has resolved to baseline grade or better or the event was assessed stable by the investigator or the patient was lost to follow-up or withdrew consent. The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed. | dosing through 28 days post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Decay Corrected Tissue Time-activity Curves (TACs) From 68Ga-PSMA-R2 PET/CT Images in Normal Organs | PET/CT scans were performed at approximately 20 to 30 min and at 1, 2, 3 to 4 hours postinjection. Time activity curves (TACs) for various organs (Brain, Heart Wall, Kidney, Lacrimal Gland, Liver, Lungs, Salivary Gland, Spleen and Thyroid) were produced as decay-corrected tissue of injected activity (mSv/MBq) per organ. Only descriptive analysis performed. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 (20-30 min post-injection, 1 hour, 2 hours and 3-4 hours post-injection) | 
| Phase I: Urinary Excretion of [68Ga]-PSMA-R2 | Urine samples were collected (up to 6 hours after dosing) for activity-based pharmacokinetics characterization. The apparent systemic clearance for the analyte in urine (Cl) was summarized with descriptive statistics. | 0 to 6 hours post-dose | 
| Phase I: Half-life of 68Ga-PSMA-R2 in Blood | Serial blood samples were collected (up to 6 hours after dosing) for activity-based pharmacokinetics characterization. The half-life (T^1/2) for the analyte in blood was summarized with descriptive statistics. | 0 to 6 hours post-dose | 
| Phase I: Non-decay Corrected Tissue Time-activity Curves (TACs) From 68Ga-PSMA-R2 PET/CT Images in Normal Organs | PET/CT scans were performed at approximately 20 to 30 min and at 1, 2, 3 to 4 hours postinjection. Time activity curves (TACs) for the various organs were produced as non-decay-corrected fraction of injected activity (mSv/MBq) per organ. Only descriptive analysis performed. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 (20-30 min post-injection, 1 hour, 2 hours and 3-4 hours post-injection) | 
| Phase I: Residence Times in Normal Organs | Residence times of radiation in normal organs were summarized with descriptive statistics. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 | 
| Phase I: Absorbed Dose of 68Ga-PSMA-R2 | Absorbed radiation dose of 68Ga-PSMA-R2 in target organs were summarized with descriptive statistics. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 | 
| Phase I: Whole-body Dose of 68Ga-PSMA-R2 | The whole-body dose of 68Ga-PSMA-R2 was summarized with descriptive statistics. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 | 
| Phase I: Effective Dose of 68Ga-PSMA-R2 | The effective dose of 68Ga-PSMA-R2 was summarized with descriptive statistics. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 | 
| Standard Uptake Value (SUV) Mean and Max in Lesions Detected by PET Scans by Timepoint | Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The SUVmean and SUVmax (g/mL) of each lesion were calculated and reported by lesion location with summary statistics at all imaging time points. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection) | 
| Tumor to Background Ratio (TBR) of Lesions Detected by PET Scans by Timepoint | Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The lesion Tumor to Background Ratio (TBR) was defined as SUVmax(lesion) / SUVmean(gluteal or thigh) was calculated and reported by lesion location with summary statistics at all imaging time points. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection) | 
| Standard Uptake Value (SUV) Mean and Max in Lesions Detected by PET Scans and Also Detected by Conventional Scans by Timepoint | Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The SUVmean and SUVmax (g/mL) of each lesion were calculated and reported by lesion location with summary statistics at all imaging time points. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection) | 
| Tumor to Background Ratio (TBR) of Lesions Detected by PET Scans and Also Detected by Conventional Scans by Timepoint | Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The lesion Tumor to Background Ratio (TBR) was defined as SUVmax(lesion) / SUVmean(gluteal or thigh) was calculated and reported by lesion location with summary statistics at all imaging time points. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection) | 
| Standard Uptake Value (SUV) Mean and Max in Lesions Detected by PET Scans and Not Detected by Conventional Scans by Timepoint | Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The SUVmean and SUVmax (g/mL) of each lesion were calculated and reported by lesion location with summary statistics at all imaging time points. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection) | 
| Tumor to Background Ratio (TBR) of Lesions Detected by PET Scans and Not Detected by Conventional Scans by Timepoint | Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The lesion Tumor to Background Ratio (TBR) was defined as SUVmax(lesion) / SUVmean(gluteal or thigh) was calculated and reported by lesion location with summary statistics at all imaging time points. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection) | 
| Patient Level Agreement of 68Ga-PSMA-R2 PET Imaging Relative to Conventional Techniques in Prostate Cancer Patients | The subject-level positive percent agreement, negative percent agreement, and overall percent agreement was calculated based on the number of subjects with at least 1 positive lesion detected by conventional scan or at least 1 positive lesion detected by PET scan. These percent agreements were calculated as follows: Positive percent agreement: a/(a+c) × 100 Negative percent agreement: d/(b+d) × 100 Overall percent agreement: (a+d)/(a+b+c+d) × 100 Where: a = number of subjects with at least 1 positive lesion detected by conventional scan and at least 1 positive lesion detected by PET scan b = number of subjects with at least 1 positive lesion detected by PET scan that was not correlated with conventional scan c = number of subjects with at least 1 positive lesion detected by conventional scan that was not correlated with PET scan d = number of subjects with no lesions detected by conventional scan or PET scan. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection) | 
| Burden of Tumor Lesions Measured by 68Ga-PSMA-R2 PET (1hr) Scan Compared With Standard Imaging Modality, by Location (Overall) | The differences of number of positive lesions, number of positive lesions detected by PET scan and/or conventional scan and the location of positive lesions were summarized with descriptive statistics. | 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour post-injection) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostatic Neoplasms, Cancer of Prostate, Cancer of the Prostate, Neoplasms, Prostate, Prostate Cancer, Prostatic Cancer, Genital Neoplasms, Male, Urogenital Neoplasms, Neoplasms by Site, Neoplasms, Genital Diseases, Male, Prostatic Diseases, PSMA, Prostate-specific membrane antigen, Gallium radioisotope 68, 68Ga-PSMA-R2, 68Ga-PSMA ligand