A Phase I/II Study of [ 177 Lu]Lu-HTK03170 with Personalized Dosimetry in Patients with Metastatic Castration-Resistant Prostate Cancer: Clinical Trial Protocol

Prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals, such as the novel [¹⁷⁷Lu]Lu-HTK03170, present a promising therapeutic option for metastatic castration-resistant prostate cancer (mCRPC). [¹⁷⁷Lu]Lu-HTK03170, being used in humans for the first time in this trial, was specifically designed to improve tumor specificity and minimize off-target toxicity, addressing the limitations of existing PSMA radiopharmaceutical therapies. This phase I/II clinical trial aims to evaluate the safety, dosimetry, and efficacy of [¹⁷⁷Lu]Lu-HTK03170 in patients with PSMA-positive mCRPC who have progressed on androgen receptor pathway inhibitors with or without taxane chemotherapy. Methods: This first-in-human, open-label, single-center phase I/II trial is designed to assess the safety and efficacy of [¹⁷⁷Lu]Lu-HTK03170. Phase I follows a traditional 3 + 3 dose-escalation design to determine the maximum tolerated injected activity of the first injection of [¹⁷⁷Lu]Lu-HTK03170, followed by personalized dosimetry to calculate the activity of each subsequent injection. Dose-limiting toxicities will be used to guide dose adjustments, with personalized dosimetry used to monitor absorbed doses to critical organs. Up to 18 patients are expected to be enrolled in phase I. Phase II, using a Simon 2-stage design, will evaluate the treatment's efficacy, with approximately 32 patients expected to enroll. Each participant will receive up to 7 treatment cycles administered every 8 wk. In phase I, the primary endpoints include determining the maximum tolerated injected activity and safety profile, which will be assessed by the occurrence of dose-limiting toxicities and the measurement of absorbed doses to normal organs. In phase II, the primary endpoint is the objective response rate as defined by RECIST 1.1. Secondary endpoints include prostate-specific antigen response rate, progression-free survival, overall survival, time to symptomatic skeletal events, and quality of life. Exploratory endpoints include evaluating circulating tumor DNA/RNA as potential biomarkers for treatment response. Conclusion: This ongoing first-in-human trial aims to establish the safety, dosimetry, and preliminary efficacy of [¹⁷⁷Lu]Lu-HTK03170 in patients with PSMA-positive mCRPC. The results of this study will inform the clinical development of [¹⁷⁷Lu]Lu-HTK03170 as a potential treatment option for mCRPC.