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

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 ⁶⁸Ga-PSMA-11 used for PET/CT scans in patients with primary, recurrent, or suspected recurrent PC.

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 ⁶⁸Ga-PSMA-11, were excluded from this study.

A single intravenous dose of ⁶⁸Ga-PSMA-11 2.0 MBq/kg (± 10%) was administered using the ⁶⁸Ga-PSMA-11 injection kit provided by Telix Pharmaceuticals and ⁶⁸Ge/⁶⁸Ga generator AX001 (Fig. 1). Briefly, gallium (⁶⁸Ga) 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.

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 ⁶⁸Ga-PSMA-11.

Image reconstruction parameters were optimized to ensure image quality and quantitative accuracy. A Pool Phantom was used to encapsulate ⁶⁸Ga, 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 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 ⁶⁸Ga-PSMA-11. Laboratory tests were performed on venous blood samples collected prior to dosing and 120 min and 7 days after administration.

Following ⁶⁸Ga-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 Hitachi-Aloka DCM-200 was used to analyze blood and urine samples.

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 ⁶⁸Ga-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.

Pharmacokinetic parameters, including area under the blood concentration–time curve (AUC), clearance (CL), elimination phase volume of distribution (V_z), and elimination half-life (T¹/_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.

Five patients (50%) experienced a total of 6 adverse events: 66.7% (2/3 patients) in Cohort 1, 50.0% (2/4 patients) in Cohort 2, and 33.3% (1/3 patients) in Cohort 3 (Table 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 ⁶⁸Ga-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.

Estimated absorbed doses in major organs/tissues are given in Table 3. The estimated whole body effective dose (mean ± SD) was 2.524 × 10^–2 ± 2.546 × 10^–3 mSv/MBq.

Blood concentrations for individual patients from 2 to 120 min after ⁶⁸Ga-PSMA-11 administration are shown in Fig. 3. Time to maximum concentration (mean ± SD: 1.16 × 10^–4 ± 1.3 × 10^–5% ID/mL) in whole blood was 2.15 ± 0.33 min. Individual blood concentrations ranged from 9.16 to 20.16 kBq/mL at 2 min and decreased to 1.38 to 4.69 kBq/mL by 120 min.

Pharmacokinetic parameters (mean ± SD, n = 9) were as follows: T¹/_2z, 94.16 ± 9.04 min; AUC from dose administration to last measurable concentration (AUC_last), 2.828 × 10^–3 ± 3.18 × 10^–4 min × % ID/mL; AUC from dose administration until elimination from the body (AUC_inf), 4.803 × 10^–3 ± 7.77 × 10^–4 min × %ID/mL; Vz, 28.64268 ± 3.15303 L; and CL, 213.01 ± 33.67 mL/minute.