Clinical trial protocol: A randomized phase 2 trial of FLEXible and extended dosing of 177Lu-PSMA-617 Molecular Radioligand Therapy (FLEX-MRT)

Introduction: The U.S. Food and Drug Administration (FDA) approved ¹⁷⁷Lu-PSMA-617 radioligand therapy (RLT) for patients with progressive metastatic castration-resistant prostate cancer (mCRPC) after taxane-based chemotherapy with a fixed dosing schedule: Six cycles of 7.4 GBq administered in six-week intervals. Yet, some patients may need more treatment cycles whereas others who experience a complete or almost complete response before cycle #06 may benefit from a treatment holiday. A more flexible and extended dosing schedule of ¹⁷⁷Lu-PSMA RLT may be beneficial in patients with mCRPC. However, no prospective data on such extended or abbreviated treatment schedule are available. In this randomized trial, we aim to determine the efficacy of ¹⁷⁷Lu-PSMA-617 RLT administered up to 12 treatment cycles using a flexible dosing schedule including potential "treatment holiday" periods in men with mCRPC compared to the standard fixed dosing schedule.

Methods: This is an investigator initiated prospective phase 2, open-label, randomized, controlled, parallel group, single-center trial. The aim is to assess the 2-year survival rate in mCRPC patients treated with a flexible dosing schedule of ¹⁷⁷Lu-PSMA therapy up to 12 cycles in comparison to the fixed dosing schedule of 6 cycles. Patients with progressive mCRPC post-ARSI, post taxane-based chemotherapy are eligible by PSMA positron emission tomography (PET) VISION trial criteria. Exclusion criteria include prior ¹⁷⁷Lu-PSMA-617 therapy and less than 6 weeks since the last myelosuppressive therapy. We hypothesized 2-year survival rates of 55% in the investigational group and 30% in the control group. A two-sided log rank test with an overall sample size of 90 subjects (45 in the control group and 45 in the treatment group) achieves 80.3% power at a 0.050 significance level to detect a hazard ratio of 0.4966. Patients will be randomized in a 1:1 ratio: The investigational arm is treated with up to 12 cycles including potential "treatment holidays" depending on the treatment response (n=45); the control arm receives 6 cycles every 6 weeks (n=45). Imaging response to ¹⁷⁷Lu-PSMA RLT is assessed using ¹⁷⁷Lu-PSMA-617 SPECT/CT 24 h after each cycle and using PSMA PET/CT during treatment holidays (every 12 weeks), respectively. In the investigational arm, RLT will be re-started after a treatment holiday period if the patient experiences a ≥25% PSA progression and an imaging progression according to the Response Evaluation Criteria in PSMA PET/CT (RECIP). Primary endpoint is the 2-year survival rate. Survival is calculated from the date of the first cycle of ¹⁷⁷Lu-PSMA-617 therapy. Secondary endpoints include safety by Common Terminology Criteria for Adverse Events (CTCAE) and dosimetry, and determination of overall and progression-free survival (evidence of progression as defined by either radiographic progression, PSA progression, clinical progression, or death from any cause, whichever occurs first). An overview of the study protocol is given in Figure 1.

The FLEX-MRT trial has been approved by the FDA (IND #168362), and the UCLA IRB (#23-000931). Start of enrollment is planned for January 2024. The study will last for 48 months of which subject accrual (entry) occurs in the first 12 months.

Results: n/a (Trials in Progress track)

Conclusions: The randomized FLEX-MRT trial aims to generate evidence for an individualized treatment strategy using a flexible and extended dosing schedule of ¹⁷⁷Lu-PSMA RLT in patients with advanced mCRPC.

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