Five Eleven Pharma, Inc.

Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and radioligand therapy (RLT) of prostate cancer. Two novel PSMA-targeting radionuclide therapy agents, [¹⁷⁷Lu]Lu-P17-087, and its albumin binder modified derivative, [¹⁷⁷Lu]Lu-P17-088, were evaluated in metastatic castration-resistant prostate cancer (mCRPC) patients. The primary endpoint was dosimetry evaluation, the second endpoint was radiation toxicity assessment (CTCAE 5.0) and PSA response (PCWG3).

Patients with PSMA-positive tumors were enrolled after [⁶⁸Ga]Ga-PSMA-11 PET/CT scan. Five mCRPC patients received [¹⁷⁷Lu]Lu-P17-087 and four other patients received [¹⁷⁷Lu]Lu-P17-088 (1.2 GBq/patient). Multiple whole body planar scintigraphy was performed at 1.5, 4, 24, 48, 72, 120 and 168 h after injection and one SPECT/CT imaging was performed at 24 h post-injection for each patient. Dosimetry evaluation was compared in both patient groups.

Patients showed no major clinical side-effects under this low dose treatment. As expected [¹⁷⁷Lu]Lu-P17-088 with longer blood circulation (due to its albumin binding) exhibited higher effective doses than [¹⁷⁷Lu]Lu-P17-087 (0.151 ± 0.036 vs. 0.056 ± 0.019 mGy/MBq, P = 0.001). Similarly, red marrow received 0.119 ± 0.068 and 0.048 ± 0.020 mGy/MBq, while kidney doses were 0.119 ± 0.068 and 0.046 ± 0.022 mGy/MBq, respectively. [¹⁷⁷Lu]Lu-P17-087 demonstrated excellent tumor uptake and faster kinetics; while [¹⁷⁷Lu]Lu-P17-088 displayed a slower washout and higher average dose (7.75 ± 4.18 vs. 4.72 ± 2.29 mGy/MBq, P = 0.018). After administration of [¹⁷⁷Lu]Lu-P17-087 and [¹⁷⁷Lu]Lu-P17-088, 3/5 and 3/4 patients showed reducing PSA values, respectively.

[¹⁷⁷Lu]Lu-P17-088 and [¹⁷⁷Lu]Lu-P17-087 displayed different pharmacokinetics but excellent PSMA-targeting dose delivery in mCRPC patients. These two agents are promising RLT agents for personalized treatment of mCRPC. Further studies with increased dose and frequency of RLT are warranted to evaluate the potential therapeutic efficacy.

¹⁷⁷Lu-P17-087/¹⁷⁷Lu-P17-088 in Patients with Metastatic Castration-resistant Prostate Cancer (NCT05603559, Registered at 25 October, 2022). URL OF REGISTRY: https://classic.

gov/ct2/show/NCT05603559 .

This paper discusses the optimization of pharmacokinetic modelling and alternate simplified quantification method for [¹⁸F]AlF-P16-093, a novel tracer for in vivo imaging of prostate cancer.

Dynamic PET/CT scans were conducted on eight primary prostate cancer patients, followed by a whole-body scan at 60 min post-injection. Time-activity curves (TACs) were obtained by drawing volumes of interest for primary prostatic and metastatic lesions. Optimal kinetic modelling involved evaluating three compartmental models (1T2K, 2T3K, and 2T4K) accounting for fractional blood volume (V_b). The simplified quantification method was then determined based on the correlation between the static uptake measure and total distribution volume (V_t) obtained from the optimal pharmacokinetic analysis.

In total, 17 intraprostatic lesions, 10 lymph nodes, and 36 osseous metastases were evaluated. Visually, the contrast of the tumor increased and showed the steepest incline within the first few minutes, whereas background activity decreased over time. Full pharmacokinetic analysis revealed that a reversible two-compartmental (2T4K) model is the preferred kinetic model for the given tracer. The kinetic parameters K₁, k₃, V_b, and V_t were all significantly higher in lesions when compared with normal tissue (P < 0.01). Several simplified protocols were tested for approximating comprehensive dynamic quantification in tumors, with image-based SURmean (the ratio of tumor SUVmean to blood SUVmean) within the 28-34 min window found to be sufficient for approximating the total distribution V_t values (R² = 0.949, P < 0.01). Both V_t and SURmean correlated significantly with the total serum prostate-specific antigen (tPSA) levels (P < 0.01).

This study introduced an optimized pharmacokinetic modelling approach and a simplified acquisition method for [¹⁸F]AlF-P16-093, a novel PSMA-targeted radioligand, highlighting the feasibility of utilizing one static PET imaging (between 30 and 60 min) for the diagnosis of prostate cancer. Note that the image-derived input function in this study may not reflect the true corrected plasma input function, therefore the interpretation of the associated kinetic parameter estimates should be done with caution.

This is a first-in-human study to evaluate the radiation dosimetry of a new prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical, [¹⁸F]AlF-P16-093, and also initial investigation of its ability to detect PSMA-positive tumors using PET scans in a cohort of prostate cancer (PCa) patients.

The [¹⁸F]AlF-P16-093 was automatically synthesized with a GE TRACERlab. A total of 23 patients with histopathologically proven PCa were prospectively enrolled. Dosimetry and biodistribution study investigations were carried out on a subset of six (6) PCa patients, involving multiple time-point scanning. The mean absorbed doses were estimated with PMOD and OLINDA software.

[¹⁸F]AlF-P16-093 was successfully synthesized, and radiochemical purity was > 95%, and average labeling yield was 36.5 ± 8.3% (decay correction, n = 12). The highest tracer uptake was observed in the kidneys, spleen, and liver, contributing to an effective dose of 16.8 ± 1.3 μSv/MBq, which was ~ 30% lower than that of [⁶⁸Ga]Ga-P16-093. All subjects tolerated the PET examination well, and no reportable side-effects were observed. The PSMA-positive tumors displayed rapid uptake, and they were all detectable within 10 min, and no additional lesions were observed in the following multi-time points scanning. Each patient had at least one detectable tumor lesion, and a total of 356 tumor lesions were observed, including intraprostatic, lymph node metastases, bone metastases, and other soft tissue metastases.

We report herein a streamlined method for high yield synthesis of [¹⁸F]AlF-P16-093. Preliminary study in PCa patients has demonstrated its safety and acceptable radiation dosimetry. The initial diagnostic study indicated that [¹⁸F]AlF-P16-093 PET/CT is efficacious and potentially useful for a widespread application in the diagnosis of PCa patients.