First-in-human Study of 225Ac-PSMA-Trillium (BAY 3563254) in Participants With Advanced Metastatic Castration-resistant Prostate Cancer (mCRPC)

Inclusion Criteria:

• mCRPC with pathological confirmation of adenocarcinoma without small-cell orneuroendocrine features.

• Documented progressive mCRPC per PCWG3, defined when at least one of the followingcriteria is met:

• PSA progression (defined as 2 consecutive increases over a previous referencevalue obtained at a minimum of 1-week intervals, with a minimum starting valueof 1.0 ng/mL)

• Radiological progression in soft-tissue lesions according to PCWG3 modificationof RECIST v1.1 criteria

• Progression of bone disease (defined as ≥ 2 new bone lesions according to PCWG3bone scan criteria)

• Previous treatment with at least 1 novel androgen axis drug (NAAD) (e.g.,enzalutamide, apalutamide, darolutamide and/or abiraterone).

• Prior orchiectomy and/or ongoing androgen deprivation therapy and a castrate levelof serum testosterone (<50 ng/dL or <1.7 nmol/L).

• Prior taxane treatment:

• Dose Escalation: Participants must either have had prior treatment with atleast 1 but no more than 2 taxane regimens, or been deemed ineligible for orrefused taxane therapy on consultation with their physician

• Dose Expansion Group A: Participants must have had prior treatment with atleast 1 but no more than 2 taxane regimens, in the castration-resistant setting

• Dose Expansion Group B: Participants must not have received any taxane regimenssince becoming castration-resistant

• Dose Expansion Group C: Participants must either have had prior treatment withat least 1 but no more than 2 taxane regimens, or been deemed ineligible for orrefused taxane therapy on consultation with their physician

• Prior treatment with an established Lu-PSMA therapy (i.e., dose activity and cyclescomparable to approved treatments) is required for participants in Dose ExpansionGroup C only. More specifically, to qualify for this expansion group, participantsmust meet all of the following criteria:

• Received a minimum of two cycles of Lu-PSMA

• Not discontinued Lu-PSMA treatment due to intolerance; and • Not achieved aPSA50 or partial /complete response on radiographic assessment during thecourse of 7Lu-PSMA treatment..

• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.

• Adequate bone marrow, hepatic, and renal function, as assessed by the followinglaboratory requirements within 30 days before start of study intervention, asindicated below. Note that blood transfusions (red blood cells or platelets) andadministration of G-CSF or GM-CSF are prohibited within 21 days prior to screeningfor the below bone marrow-related parameters.

• Hemoglobin ≥9.0 g/dL

• Absolute neutrophil count (ANC) ≥1500/mm^3

• Platelet count ≥100,000/mm^3

• Total bilirubin ≤1.5 x the Upper limit of normal (ULN), or ≤3×ULN if theparticipant has a confirmed history of Gilbert's syndrome (note thatparticipants with Gilbert's syndrome should be carefully evaluated for otherliver-related disorders that may impact their suitability for this study).

• Alanine transaminase (ALT) and Aspartate transaminase (AST) ˂2.5 x ULN (≤5 xULN for participants with liver involvement)

• Participants on a stable dose of anticoagulation therapy are allowed toparticipate if they have no sign of bleeding or clotting, and prothrombin timeinternational normalized ratio (PT/INR) and activated partial thromboplastintime (aPTT) test results are acceptable at the Investigator's discretion

• Estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m^2, according tothe Modified Diet in Renal Disease (MDRD) abbreviated formula and serumcreatinine ≤1.5 x ULN

• Participants must have at least one PSMA-positive (prostate-specific membraneantigen) distant metastatic lesion on the screening PSMA PET/CT scan using thestudy-designated PSMA PET tracers, as determined by the site Investigator. Foreligibility purposes, a PSMA-positive lesion must have activity greater than theliver by visual assessment of the screening PSMA PET/CT. A PSMA-positive metastaticlesion should not correspond to a normal tissue structure or benign lesion.

Exclusion Criteria:

• Participants who have any of the following tumor lesions which are PSMA negative ANDmeet the size criteria below are excluded as determined by the site Investigator. APSMA-negative lesion for eligibility purposes must have activity equal to or lessthan the liver by visual assessment of the screening PSMA PET/CT scan using thestudy-designated PSMA PET/CT tracers. A PSMA-negative metastatic lesion should notcorrespond to a normal tissue structure or benign lesion.

• a. Any single or multiple lymph node(s) ≥2.5 cm in the short axis.

• b. Any solid organ metastasis (e.g., lung, liver, adrenal glands, etc.) that is ≥1 cm in the short axis.

• c. Any bone metastasis with a soft tissue component ≥ 1 cm in short axis withthe soft tissue component being PSMA-negative. PSMA-negative osseous metastaseswithout a soft tissue component do not exclude a participant.

• d. Predominantly necrotic lesions with greater than 1 cm of enhancing tissue oncontrast-enhanced computed tomography / magnetic resonance imaging (CT/MRI).

• Prior systemic anticancer therapy including chemotherapy, NAAD, biologic therapy,immunotherapy, or investigational therapies within 4 weeks of the start of studytreatment, except luteinizing hormone-releasing hormone (LHRH) orgonadotropin-releasing hormone (GnRH). Start of study treatment is allowed inshorter timeframes if 5 half-lives of the prior drug(s) have elapsed.

• Prior radiopharmaceutical treatment using actinium-225.

Other prior radiopharmaceutical treatments:

• Dose escalation and Dose expansion Groups A and B: Prior treatment with aradiopharmaceutical is prohibited, with the following exception: Prior treatmentwith radium-223 dichloride more than 3 months before the start of study interventionis permitted.

• Dose expansion Group C: Prior treatment with a radiopharmaceutical is prohibitedwith the following exceptions: Prior treatment with radium-223 dichloride more than 3 months before the start of study intervention is permitted; and prior treatmentwith Lu PSMA more than 6 weeks before the start of study intervention is required.Note: Participants who have discontinued Lu-PSMA treatment due to intolerance orloss of initial response are excluded from Group C.

• Prior definitive therapy (radiotherapy or surgery) completed less than 6 weeksbefore the start of study intervention. Note that palliative radiotherapy completedless than 6 weeks before the start of study intervention will be allowed if: (i) nomore than 10% of the participants' bone marrow is irradiated, (ii) it does notencompass all potential target/measurable lesions for participants in doseexpansion.

• Toxic effects of Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade ≥2 from prior anticancer therapy not yet stabilized or where significantpost-treatment toxicities have been observed. Chronic toxic effects of CTCAE Grade ≤2 from prior anticancer therapy where no further resolution is expected do notrequire exclusion with agreement between the Investigator and Sponsor (e.g.,chemotherapy-induced neuropathy, fatigue, alopecia, anorexia, etc.).