This is a four-part study evaluating the safety and efficacy of a PSMA-directed radioantibody (rosopatamab tetraxetan, conjugated to either In-111 or Ac-225). Part 1 will consist of one administration of In-111-rosopatamab tetraxetan to characterize the biodistribution of the radioantibody to target organs and prostate cancer lesions. Participants then will be enrolled into either Part 2 (Dose Optimization) or Part 3 (Dose Escalation and Expansion) depending on their prior treatment history. Part 4 will be an extended regimen in dose escalation and expansion. Participants qualifying for Part 2 will be randomized to receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle (dose administration on Day 1 and Day 15) at either 45 or 60 kBq/Kg. Participants qualifying for Part 3 must have received prior Lu-177-PSMA-radioligand therapy and will receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle at 45, 55, or 60 kBq/Kg. Dose limiting toxicities (DLTs) will be monitored in Part 3 to determine the recommended phase 2 dose (RP2D), and the study may enroll additional participants to be treated with the RP2D dose level. Participants qualifying for Part 4 will initially receive two doses (dose administration on Day 1 and Day 15) at the dose level selected in Part 2, followed by a single third dose of Ac-225 rosopatamab tetraxetan administered approximately 12 weeks after completion of the Part 2 fractionated dosing regimen. The starting dose level for Part 4 will be 22 kBq/kg (or fixed activity equivalent). Dose limiting toxicities (DLTs) will be monitored following administration of the third dose in Part 4 to determine the recommended phase 2 dose (RP2D) of a third dose of Ac-225 rosopatamab tetraxetan. Participants enrolled into any part will attend study visits which will include blood samples, electrocardiogram (ECG), radiographic imaging, and physical examinations along with other assessments.
Serum PSA progression as defined by PCWG3 (rising PSA consisting of two consecutive increases measured at least 3 weeks apart, of a rise of >25%, and with an absolute rise of 2.0 ng/mL.
Soft tissue progression defined as a ≥20% increase in the sum of the diameter (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest sum of the diameter since the previous treatment was started or the appearance of one or more new lesions by CT/magnetic resonance imaging (MRI)
Progression of bone disease defined by PCWG3 as evaluable disease or new bone lesions by bone scan
Identification of new soft tissue or bone lesions on PSMA PET imaging
Superscans by nuclear medicine/99mTc bone scan
A known malignancy that is progressing or has required active treatment within the past 3 years other than CRPC, which is expected to alter life expectancy or may interfere with CRPC disease assessment
Prior platinum-based chemotherapy
Prior PARP inhibitors (e.g., olaparib or rucaparib)
Sequential
In-111 rosopatamab tetraxetan
Biological/VaccineA single dose of 148 ± 37 MBq In-111 rosopatamab tetraxetan will be administered as an IV infusion over a period of 10 minutes.
45 kBq/kg Ac-225 rosopatamab tetraxetan
Biological/Vaccine45 kBq/kg Ac-225 rosopatamab tetraxetan will be administered as an IV infusion over a period of 10 minutes. Doses will be given two weeks apart for a total of two doses.
45 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan
Biological/Vaccine45 kBq/kg Ac-225 rosopatamab tetraxetan will be administered as an IV infusion over a period of 10 minutes. Doses will be given two weeks apart for a total of two doses.
60 kBq/kg Ac-225 rosopatamab tetraxetan
Biological/Vaccine60 kBq/kg Ac-225 rosopatamab tetraxetan will be administered as an IV infusion over a period of 10 minutes. Doses will be given two weeks apart for a total of two doses.
Single dose 22 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan
Biological/Vaccine22 kBq/kg Ac-225 rosopatamab tetraxetan will be administered as an IV infusion over a period of 10 minutes. A single dose will be given.
Single dose 34 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan
Biological/Vaccine34 kBq/kg Ac-225 rosopatamab tetraxetan will be administered as an IV infusion over a period of 10 minutes. A single dose will be given.
Single dose 45 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan
Biological/Vaccine45 kBq/kg Ac-225 rosopatamab tetraxetan will be administered as an IV infusion over a period of 10 minutes. A single dose will be given.
55 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan
Biological/Vaccine55 kBq/kg Ac-225 rosopatamab tetraxetan will be administered as an IV infusion over a period of 10 minutes. Doses will be given two weeks apart for a total of two doses.
60 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan
Biological/Vaccine60 kBq/kg Ac-225 rosopatamab tetraxetan will be administered as an IV infusion over a period of 10 minutes. Doses will be given two weeks apart for a total of two doses.
Part 1: Visual evaluation on whole body planar scans (days 1 and 4) with comparison to reference scans for the presence of radiolabeled rosopatamab textraxetan in organs of interest (e.g., liver, circulation, spleen) to determine biodistribution
Part 2: Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) overall, by severity, and leading to discontinuation of study intervention
Part 2: Proportion of participants who achieve a greater than or equal to 50% decline in prostate-specific antigen (PSA50)
Part 3: Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) overall, by severity, and leading to discontinuation of study intervention
Part 2: Determine the clearance of rosopatamab tetraxetan and Ac-225 rosopatamab tetraxetan via measurement of whole blood and serum levels at specified serial timepoints
Part 2: Radioactivity levels of Ac-225 rosopatamab tetraxetan
Part 2: Radiation dosimetry of Ac-225 rosopatamab tetraxetan: Absorbed radiation dose (expressed as Gy/MBq) in normal organs
Part 2: Biochemical progression-free survival (bPFS) as assessed by the Prostate Cancer Working Group 3 (PCWG3)
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