Neoadjuvant Lu-PSMA Radioligand Therapy and Ipilimumab in Men With Very High-risk Prostate Cancer

A randomized, open-label Phase I/II study of neoadjuvant treatment with \[177Lu\]Lu-PSMA-617 radioligandtherapy (LuPSMA) with or without Ipilimumab in participants with very high-risk prostate cancer who are candidates for Radical Prostatectomy. The study will be initiated by a safety cohort regarding the \[177Lu\]Lu- PSMA-617 dose including 6 to 12 patients, who will receive combination therapy with \[177Lu\]Lu-PSMA-617 and Ipilimumab. The Safety-Run-In-Phase follows a "none of three or one of six patients experienced intolerable events" approach per dose level. That is: The first 3 patients will receive 4 courses of ipilimumab (3 mg/kg) and 2 courses of 3.7 GBq \[177Lu\]Lu-PSMA-617. If no more than one of these patients develop grade 4 adverse reactions (ARs) without recovery within 3 weeks, another 3 patients will receive the same dosage. If no grade 4 AEs are observed in this second set of patients, we will enroll an additional 3 patients to increase the \[177Lu\]LuPSMA 617 dose to 7.4 GBq. If no more than one of those patients develop grade 4 ARs without recovery within 3 weeks back to grade ≤1 or to baseline values, another 3 patients will receive the same increased dosage. Provided that these patients do not develop grade 4 ARs, randomization of patients will be started. If the "none of three or one of six patients experienced intolerable events" approach per dose level is not passed the study will be terminated at this point. 46 patients with newly diagnosed very high-risk prostate cancer will be randomly assigned in a 1:1 ratio (Ipilimumab + \[177Lu\]Lu-PSMA- 617 vs. \[177Lu\]Lu-PSMA-617 alone) to receive 2 cycles of 7,4 GBq \[177Lu\]Lu-PSMA-617 with or without 4 cycles of concomitant Ipilimumab 3mg/kg prior to prostatectomy. Radioligandtherapy will be given at 6 weeks intervals while ipilimumab will be given every 3 weeks. For application of ipilimumab and \[177Lu\]Lu-PSMA-617 within one cycle (week 1 and 7), \[177Lu\]Lu-PSMA-617 is administered on day 1 and ipilimumab on day 3. ADT will be applied to all patients during the neoadjuvant treatment phase.