Evaluation of 68Ga-PSMA-11 PET/CT: a Phase 1 clinical study in Japanese patients with primary, recurrent, or suspected recurrent prostate cancer

Background Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals allow whole-body imaging to detect prostate cancer (PC). Positron emission tomography imaging using gallium-68 (68Ga)-PSMA-11 has been shown to have a favorable safety and tolerability profile and high diagnostic performance. The study evaluates the safety and pharmacokinetics of 68Ga-PSMA-11 in Japanese patients with primary, recurrent, or suspected recurrent prostate cancer. Methods This single arm study enrolled Japanese patients with primary PC (n = 3), suspected recurrent PC following radical prostatectomy (n = 4), or suspected recurrent PC following radical radiotherapy (n = 3). All patients received a single intravenous dose of 68Ga-PSMA-11 2.0 MBq/kg (±10%) followed by PSMA PET imaging and safety and pharmacokinetic evaluations. Based on the blood concentrations of 68Ga-PSMA-11 and the radioactivity distribution rate in each organ/tissue, the absorbed doses in major organs/tissues and the whole-body effective dose were calculated by the Medical Internal Radiation Dose method. Results Ten patients were enrolled. Mean age was 73.3 ± 4.8 years, and median prostate-specific antigen was 8.250 ng/mL. Five patients (50%) experienced a total of 6 adverse events, and no grade ≥ 2 adverse events or serious adverse events were reported. No clinically significant changes in vital signs, haematology parameters, or blood chemistry or ECG abnormalities were observed. The estimated whole body effective dose of 68Ga-PSMA-11 (mean ± standard deviation) was 2.524 × 10–2 ± 2.546 × 10–3 mSv/MBq. Time to maximum concentration (1.16 × 10–4 ± 1.3 × 10–5% ID/mL) in whole blood was 2.15 ± 0.33 min. Conclusions 68Ga-PSMA-11 has a favourable safety and tolerability profile in Japanese patients with primary, recurrent, or suspected recurrent prostate cancer, which is comparable to previous observations in other populations.


Introduction
Prostate cancer (PC) has increasing significance: it is the second most frequent cancer diagnosis in patients and the fifth leading cause of cancer death worldwide [1].In Japan, the incidence of PC has been growing rapidly over the past decades.The age-standardized incidence rate rose from 7.1 in 1975 to 58.7 per 100,000 in 2014 [2].PC remains the sixth major cause of death in Japanese patients [2] and was the leading cancer-related cause of death in 2020 [3].
Imaging of the prostate-specific membrane antigen (PSMA) has become an important tool for managing patients with PC, and PSMA positron emission imaging (PET) is now part of the diagnostic flowchart for PC in international guidelines [4].In primary PC, PSMA PET has shown superiority to cross-sectional imaging for the detection of pelvic lymph nodes and distant metastases.In PC recurrence, higher detection rates have been observed for PSMA PET than for any other available imaging techniques, especially at low prostate-specific antigen (PSA) values [4].
We aimed to evaluate the safety of 68 Ga-PSMA-11, administered using the injection kit for PET/CT imaging in a sample of Japanese patients with primary, recurrent, or suspected recurrent PC.

Study design
This was a single-centre, open-label, prospective phase I study approved by the Institutional Review Board of Kanazawa University Hospital and registered with the Japanese Registry of Clinical Trials (identifier: JRCT2041200110).The study was conducted in accordance with the ethical standards of the Declaration of Helsinki and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice.All patients provided written informed consent for participation in the study.The objectives of the study were to evaluate the safety and pharmacokinetics of 68 Ga-PSMA-11 used for PET/CT scans in patients with primary, recurrent, or suspected recurrent PC.

Patient population
Japanese males (> 20 years of age) with primary, recurrent, or suspected recurrent PC were divided into 3 investigative cohorts (Fig. 1).Cohort 1 included patients with histologically confirmed untreated high-risk PC or advanced PC (N1 or M1).Cohort 2 included patients with histologically confirmed PC, treated with radical prostatectomy at initial onset, who then had recurrent disease in a local or metastatic lesion and an increase in blood PSA concentration from baseline and suspected recurrence on imaging (such as bone scintigraphy, CT, magnetic resonance imaging (MRI), and fluorodeoxyglucose-PET). Cohort 3 included patients with histologically confirmed PC at the initial onset, treated with radical radiotherapy (external irradiation, interstitial irradiation, or its combination) who then had confirmed recurrent PC in a locally recurrent or metastatic lesion, an increase in blood PSA concentration from baseline and suspected recurrence on imaging.All patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 within 28 days prior to study enrolment and agree to use proper contraception until 90 days after investigational drug administration.Patients with an active second cancer, virus infections or other infections or conditions necessitating treatment during the study period or with previous exposure to 68 Ga-PSMA-11, were excluded from this study.

Ga-PSMA-11 administration
A single intravenous dose of 68 Ga-PSMA-11 2.0 MBq/ kg (± 10%) was administered using the 68 Ga-PSMA-11 injection kit provided by Telix Pharmaceuticals and 68 Ge/ 68 Ga generator AX001 (Fig. 1).Briefly, gallium ( 68 Ga) chloride and 25 µg of PSMA-11 reconstituted with acetate buffer were transferred into a sterile vacuumed vial.Quality control was performed according to the manufacturer's recommendations by visual examination, pH testing, and instant thin layer chromatography. 68Ga-PSMA-11 was administered within 28 days of trial registration.

PSMA PET imaging
PET/CT imaging was performed using a Philips Vereos PET-CT system (serial no: 9000105).The imaging protocol was designed to capture a comprehensive head-to-toe assessment, spanning approximately 17-18 bed positions per patient.Patients were scanned in each bed position for 180 s.The temporal acquisition points were set at 5, 60, and 120 min following administration of 68 Ga-PSMA-11.
Image reconstruction parameters were optimized to ensure image quality and quantitative accuracy.A Pool Phantom was used to encapsulate 68 Ga, and then the uniformity of the radiotracer distribution and a standardized uptake value of 1 were validated.The reconstruction algorithm utilized was Ordered Subset Expectation Maximization combined with Time-of-Flight information.The specific settings for the reconstruction were as follows: 2 iterations, 11 subsets, and a 3 mm Gaussian filter.Attenuation correction was performed using CT-based attenuation correction, while scatter correction was achieved through the Single Scatter Simulation method.The reconstructed images had a voxel size of 2 × 2x2 mm in the X, Y, and Z dimensions.
The field of view for PET imaging was set to 567 mm and for CT-AC was set to 600 mm.

Safety assessment
Safety and tolerability assessment was based on physical examination, vital signs, haematology, serum chemistry, urinalysis, 12-lead electrocardiograms, MRI, CT, PSMA PET together with subjective findings and ECOG PS at predefined time intervals.Adverse events were defined as any untoward medical occurrence (including an abnormal laboratory value), whether or not related to the investigational drug.Adverse reactions were defined as adverse events for which a causal relationship with the investigational drug could not be ruled out.All adverse events and adverse reactions were graded according to Common Terminology Criteria for Adverse Events (CTCAE version 5).
Adverse events were collected from drug administration through Day 7 follow-up.Vital signs and subjective and objective symptoms were assessed prior to study entry and at 30, 60, 120 min and 7 days after administration of 68 Ga-PSMA-11.Laboratory tests were performed on venous blood samples collected prior to dosing and 120 min and 7 days after administration.

Pharmacokinetics
Following 68 Ga-PSMA-11 administration, blood samples were collected at 2, 5, 30, 60, and 120 min for pharmacokinetic and blood radioactivity evaluation.Urine samples for pharmacokinetic and radioactivity evaluation were collected at 60 and 120 min post-administration, and the well-counter

Dosimetry
The effective dose (mSv/MBq) in the whole body and the absorbed dose (mGy/MBq) in each organ were evaluated.The effective dose in the whole body was calculated based on the estimated absorbed doses of 68 Ga-PSMA-11 in major organs/tissues using tissue weighting factors as described in the International Commission on Radiological Protection Publication 103 using the Medical Internal Radiation Dose method [9].Phoenix Winnonlin was used to calculate dosimetry, and OLINDA2 was used to calculate absorbed and effective doses.

Statistical analysis
Pharmacokinetic parameters, including area under the blood concentration-time curve (AUC), clearance (CL), elimination phase volume of distribution (V z ), and elimination half-life (T 1 / 2z ) were calculated.Grade ≥ 3 safety events (and ≥ Grade 2 for adverse events other than laboratory values) were summarised using descriptive statistics.Absorbed and effective dose estimates were calculated by the medical internal radiation dose method and means, medians, and standard deviations (SD) are reported.

Results
In total, ten male patients were included (n = 3, n = 4, and n = 3 in Cohorts 1, 2, and 3, respectively).Cohort 1 included patients with untreated high-risk PC or advanced PC (N1 or M1).Cohort 2 included patients with suspected recurrent PC following radical prostatectomy.Cohort 3 included patients with suspected recurrent PC following radical radiotherapy (external irradiation, interstitial irradiation, or its combination).All patients underwent dosing with 68 Ga-PSMA-11 followed by PET imaging.Representative PET/CT images are depicted in Fig. 2.
These included one occurrence each of injection site haemorrhage, injection site pain, injection site discomfort, amylase increased, neck pain, and dysuria.No Grade ≥ 2 adverse events or serious adverse events were observed in any patient.The events of injection site pain, injection site discomfort, and dysuria were also considered to be adverse reactions (adverse events that may be related to experimental treatment).One patient each reported increased amylase, neck pain, and dysuria.The dysuria event was determined to be related to 68 Ga-PSMA-11, while amylase and neck pain events were determined to not be related.Adverse reactions were reported by 30.0%(3/10 patients) overall, 33.3% (1/3 patients) in Cohort 1, 25.0% (1/4 patients) in Cohort 2, and 33.3% (1/3 patients) in Cohort 3.
No clinically significant changes in vital signs, haematology parameters, or blood chemistry, were observed throughout the study.No electrocardiogram abnormalities were observed for any patient.

Discussion
Accurate diagnostic imaging is crucial for detecting local recurrence or metastatic lesions in patients with prostate cancer [10].Conventional imaging, such as CT, MRI, or bone scintigraphy, has been historically used to determine the extent of lymph node involvement and presence of metastases [10].However, conventional imaging is limited in specificity and positivity [11][12][13][14][15], potentially subjecting patients to unnecessary harmful and costly procedures [16].PSMA-targeted radiopharmaceuticals allow whole-body imaging for the detection of PC spread, and their increased sensitivity and specificity make them ideally suited for front-line imaging [17].They are also associated with higher detection rates compared with other agents used in PC imaging [18].Globally, PSMA PET is an emerging standard of care in PC imaging [4,6,19] with several products either approved or in development worldwide.
68 Ga-PSMA-11 has been used in clinical practice outside Japan for approximately four years and the updated Society of Nuclear Medicine & Molecular Imaging Appropriate Use Criteria include 68 Ga-PSMA-11 PET/CT as an alternative to standard bone and soft tissue imaging [20].Since its development in 2012 [21], the 68 Ga-PSMA-11 injection kit has been widely used in PET/CT imaging of prostate cancer and evaluated in many clinical studies, and a vast amount of clinical data have been obtained worldwide in prospective studies, retrospective studies, the phase 3 VISION study, and investigator-initiated clinical trials [7,8,[22][23][24][25][26][27].Due to the widely available clinical data already available in healthy volunteers, this study sought to confirm the favourable safety and tolerability of 68 Ga-PSMA-11 in the Japanese patient population compared to other populations [6,7].As in studies in other populations, no serious adverse events were observed in any cohorts in this trial.A purification step is not required for 68 Ga-PSMA-11, unlike other radiolabelling methods for PSMA, enabling rapid radiolabelling at room temperature with high radiochemical purity and production consistency, suited to the hospital radio-pharmacy setting.A commercially available 68 Ga-based PSMA PET imaging kit has been approved in Canada, New Zealand, and Australia.In the United States, the Food and Drug Administration has approved for patients with suspected metastasis who are candidates for initial definitive therapy, patients with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level, and for selection of patients with metastatic prostate cancer, for whom lutetium-177 ( 177 Lu) vipivotide tetraxetan PSMAdirected therapy is indicated [28].
This trial also confirmed the blood concentrations of 68 Ga-PSMA-11 and its pharmacokinetic parameters, as well as the estimated exposure dose of 68 Ga-PSMA-11 in the organs/tissues and whole body in Japanese men.In addition, the time-course of blood drug concentration and the distribution of radioactivity in the Japanese population observed in this clinical trial were similar to those in the non-Japanese population observed in overseas clinical trials [6,7].Recently, results from two phase 1/2 trials exploring 18 F-PSMA-1007 PET/CT imaging for Japanese patients with prostate cancer have been published [29,30].Direct comparison of radiotracer performance is challenging and has not been studied in a large, prospective trial with lesion validation [31].However, of available radiotracers, 68 Ga-PSMA-11 has the most real-world evidence and studied most in clinical trials [31].Interpretation of bone lesions, largely due to unspecific uptake, is more difficult on imaging acquired with 18 F-labelled radiotracers than with 68 Ga-PSMA-11 [32][33][34][35]. 18F-PSMA-1007 imaging has been shown to have significantly higher rates of nonspecific uptake, or equivocal bone lesions, than 68 Ga-PSMA-11 imaging [36].
A recent comprehensive review has suggested that, from an imaging point of view, 68 Ga-PSMA-11 PET/CT is unquestionably one of the most useful tools for the therapeutic management of patients with PC in the clinical setting in 2020 and foreseeable future [5].Our trial results demonstrate that 68 Ga-PSMA-11 has a favourable safety and tolerability profile for Japanese patients.

Conclusion
68 Ga-PSMA-11 has a favourable safety and tolerability profile in Japanese patients with primary, recurrent, or suspected recurrent prostate cancer.The time-course of blood drug concentration and the distribution of radioactivity in the Japanese population are comparable to previous observations in other populations.
Acknowledgements The authors wish to thank the patients who participated in the trial.The authors also wish to thank investigators Tomo Hiromasa, Takafumi Yamase, Yi Kunita, Norihito Amatani, Kazuyoshi Shigehara, Takahiro Nohara, Yasuhito Imai, and Hisayuki Ogura for their contributions.Medical writing support, under the direction of the authors, was provided by Clare Gurton, Jacobson Medical Writing, Inc, Jess Roetman, and Stefanie Martina, and was funded by Telix Pharmaceuticals, in accordance with Good Publication Practice 2022 guidelines.
Authors contribution All authors contributed to the study conception and design, participated in writing the manuscript, and approved the final manuscript for submission.
Funding Open Access funding provided by Kanazawa University.This study was funded by Telix Pharmaceuticals.

Data availability
The datasets used and/or analyzed during the current study are available for the corresponding author on reasonable request.

Declarations
Conflict of interest The authors declare that they have no conflict of interest.permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

3
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not Table Estimated absorbed doses of 68 Ga-PSMA-11 in major organs MBq megabecquerel, mGy milli-gray, SD standard deviation Target Organ (n = 10) Estimated absorbed dose of 68 Ga-PSMA-11, .6 × 10 -2 ± 6.040 × 10 -3 Lungs 2.045 × 10 -2 2.117 × 10 -2 ± 4.202 × 10 -3 Pancreas 1.550 × 10 -2 1.645 × 10 -2 ± 3.131 × 10 -3 Prostate 1.185 × 10 -2 1.207 × 10 -2 ± 1.537 × 10 -

Table 1
Demographics and baseline characteristics by patientPSA prostate-specific antigen, TNM tumour, lymph nodes, metastasis Union for International Cancer Control staging system, T0 no local PCa lesion due to hormone therapy or radiation therapy, Tx no prostate due to radical prostatectomy