First-in-human study of ¹⁷⁷ Lu-JH020002 in patients with metastatic castration-resistant prostate cancer.

5055 Background: 177 Lu-JH020002 is a novel radioligand therapy that delivers beta-particle radiation to PSMA-expressing tumor cells and the surrounding microenvironment, demonstrating high affinity and antitumor activity in preclinical studies. JH020002-01C is an ongoing, multicenter, open-label phase I/II study investigating the safety, tolerability, pharmacokinetics, dosimetry and preliminary antitumor activity of 177 Lu-JH020002 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Here, we reported the preliminary safety and efficacy results of phase I. Methods: Eligible pts for phase I had mCRPC, were refractory to or had progressed following at least one androgen receptor pathway inhibitor (ARPI) and chemotherapy, and had at least one PSMA-positive tumoral lesion (PET imaging). Pts received an intravenous dose of 177 Lu-JH020002 at the beginning of each 6-week cycle, up to a maximum of 6 cycles. Dose escalation and determination of the maximum tolerated dose (MTD) in phase I were based on an accelerated titration and 3+3 dose-escalation design, including 5 dose cohorts. The primary objective of phase I is to evaluate the safety and tolerability of 177 Lu-JH020002 and determine the recommended phase 2 dose. Secondary objectives are dosimetry, pharmacokinetics, efficacy and safety. Tumor response is assessed per PCWG3 criteria. Results: As of Jan 22, 2025, 12 pts received 177 Lu-JH020002 with a median cumulative dose of 18.06 GBq. 91.7% pts with bone, 33.3% nodal, 8.3% peritoneal metastases. 100% with ≥1 prior ARPI therapy, 50% ≥ 1 prior chemo regimen, 16.7% 223 Ra, 33.3% PARPi. No DLT was reported and MTD was not reached. The most common treatment related adverse events (TRAEs) were Grade1-2. No grade 4/5 AEs were reported. TRAEs of note were hematologic TRAEs, including lymphocyte count decreased (91.7%), platelet count decreased (50.0%), anaemia (66.7%) and white blood cell count decreased (16.7%). With follow-up ongoing, across cohorts 2-5, 63.6% with ≥ 50% PSA decline; 27.3% with ≥ 90% PSA decline. Seven pts were evaluated per PCWG3. None of them had progressive disease, and all of them remain under treatment follow-up. Among all pts, 1 was with measurable disease and had a partial response. Conclusions: 177 Lu-JH020002 exhibited excellent antitumor activity in heavily pre-treated pts with mCRPC. Toxicity was well tolerated and generally manageable. Further clinical trials are under planning. Clinical trial information: NCT06139575 . Exposure and clinical activity (cohorts 2~5, at doses ≥ 3.70 GBq). Parameter,median (range) or n (%) 3.70 GBq 5.90 GBq 7.40 GBq 8.88 GBq Total No. of patients 2 3 3 3 11 Cumulative dose (GBq) 11.20(4.2-18.2) 24.58 (5.4-35.2) 22.8(22.1-29.1) 17.29 (17.28-17.9) 18.21 (4.2-35.2) PSA decline 2 (100) 2 (66.7) 3 (100) 2 (66.7) 9 (81.8) ≥ 50% PSA decline 1 (50) 2 (66.7) 2 (66.7) 2 (66.7) 7 (63.6)