A Phase I/II, Open-label, Multi-center Study of [225Ac]Ac-PSMA-R2 in Men With PSMA-positive Prostate Cancer With or Without Prior 177Lu-PSMA Radioligand Therapy.

A Phase I/II, Open-label, Multi-center Study of [225Ac]Ac-PSMA-R2 in Men With PSMA-positive Prostate Cancer With or Without Prior 177Lu-PSMA Radioligand Therapy.

SatisfACtion: A Phase I/II, Open-label, Multi-center Study of [225Ac]Ac-PSMA-R2 in Men With Heavily Pre-treated PSMA Positive Metastatic Castration Resistant Prostate Cancer (mCRPC) With or Without Prior 177Lu-labelled PSMA-targeted Radioligand Therapy.

The purpose of the study is to characterize the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of 225Ac-PSMA-R2 in male adult participants with metastatic castration-resistant prostate cancer (mCRPC) previously treated with androgen receptor pathway inhibitors in post-177Lu and pre-177Lu settings.

This is an open label, phase I/II, multi-center study which contains two treatment groups (Group 1 and Group 2). Each group has a dose escalation part, once the Maximum Tolerated Dose/Recommended Dose for Expansion (MTD/RDE) is determined in each of the dose escalation parts, the study will continue with an expansion part in the respective group. The dose escalation parts will establish the MTD/RDE of the 225Ac-PSMA-R2 guided by the well-established Bayesian Logistic Regression Model (BLRM) method. The adaptive BLRM will be guided by the Escalation with Overdose Control (EWOC) principle to control the risk of DLT in future participants on study. Dose escalation decisions will be performed by the Investigators and Novartis during dose escalation meetings (DEMs) based on safety and tolerability information (BLRM summaries of DLT risk) along with PK and preliminary efficacy information. The dose expansion parts will assess the anti-tumor activity (Overall Response Rate (ORR) by Prostate Cancer Working Group 3 (PCWG3) modified RECIST 1.1 and Prostate Specific Antigen 50 (PSA50) response rate) as well as further assess the safety, tolerability, and PK of 225Ac-PSMA-R2.

225Ac-PSMA-R2, dose limiting toxicity, DLT, Escalation with Overdose Control, EWOC, pre- and post-177Lu-PSMA-RLT, pre- and post-177Lu-PSMA-617

Dose Escalation: All eligible participants with mCRPC heavily pre-treated and refractory to 177Lu-labelled PSMA-targeting RLT will receive the starting dose of 7 Megabecquerel (MBq) of 225Ac-PSMA-R2 to determine the Maximum Tolerated Dose/Recommended Dose for Expansion (MTD/RDE) of Group 1. Dose Expansion: Once RDE is determined for Group-1, participants being non/partial responders to 177Lu-labelled PSMA-targeted RLT or requiring re-treatment/re-challenge after 177Lu-labelled PSMA-targeted RLT treatment will be enrolled in Group 1 dose expansion.

Dose Escalation: All eligible participants with mCRPC who have received previous treatment with Androgen Receptor Pathway Inhibitors (ARPI) or Computed Tomography (CT) but have never been treated with 177Lu-labelled PSMA-targeted RLT (177Lu-labelled PSMA-targeted RLT treatment naïve) will receive one level higher than the RDE of Group 1 as the starting dose of 225Ac-PSMA-R2 in order to determine the MTD/RDE of Group 2. Dose Expansion: Once RDE is determined for Group 2, participants naïve to 177Lu-labelled PSMA-targeted RLT with high volume soft tissue and visceral disease and in participants with diffuse bone metastasis will be enrolled in Group 2 dose expansion. Alternatively, if the RDE1 is not determined, Group 2 will begin the evaluation for the dose escalation at the dose of 7 MBq of 225Ac-PSMA-R2 upon Novartis decision. The early starting of Group 2 will be supported by emerging safety and preliminary efficacy data from Group 1 dose escalation.

Dose Escalation: Incidence and severity of Dose Limiting Toxicity (DLTs) during the first cycle of treatment

To determine the Recommended Dose for Expansion (RDE) and corresponding regimen for 225Ac-PSMA-R2 monotherapy in PSMA-positive mCRPC in: Group-1: Participants previously treated with 177Lu-labelled PSMA-targeted RLT (post-177Lu). Group-2: Participants not treated previously with 177Lu-labelled PSMA-targeted RLT (pre-177Lu).

Dose Escalation: Incidence and severity of AEs and serious adverse events (SAEs) during the first cycle of treatment.

The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

Overall Response Rate (ORR) is defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR) in soft tissue, as per BICR and according to Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1, in the absence of bone progression as per PCWG3. CR and PR must be confirmed by repeat assessments that should be performed not less than 4 weeks after the criteria for response are first met.

From date of the first administration of 225Ac-PSMA-R2 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 15 months

Dose Expansion: Percentage of participants achieving prostate-specific antigen (PSA) response 50 (PSA50)

PSA50 response rate is defined as the proportion of participants who have achieved >= 50% decrease in PSA from baseline confirmed by a second PSA measurement >= 4 weeks.

From date of the first administration of 225Ac-PSMA-R2 till 30 days safety follow-up, assessed up to approximately 15 months

The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

From date of the first administration of 225Ac-PSMA-R2 till 30 days safety follow-up, assessed up to approximately 15 months

Dose Escalation & Dose Expansion: Frequency of dose interruptions, reductions, discontinuations, and dose intensity by treatment.

Tolerability of study drug will be assessed by summarizing the number of and the reasons for dose delays and dose reductions. Dose intensity will also be tabulated by treatment group.

Overall Response Rate (ORR) is defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR) in soft tissue, as per BICR and according to Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1, in the absence of bone progression as per PCWG3. CR and PR must be confirmed by repeat assessments that should be performed not less than 4 weeks after the criteria for response are first met.

From date of the first administration of 225Ac-PSMA-R2 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 15 months

Disease control rate (DCR) is defined as the proportion of participants with best overall response (BOR) of complete response (CR), partial response (PR) or stable disease (SD), as per central and local review and according to PCWG3-modified RECIST v1.1.

From date of the first administration of 225Ac-PSMA-R2 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 15 months

Best Overall Response (BOR) is defined to derive Overall Response Rate (ORR) and includes complete response (CR) or partial response (PR). BOR is determined from the sequence of overall responses.

From date of the first administration of 225Ac-PSMA-R2 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 15 months

Radiographic progression free survival (rPFS) is defined as the time (in months) from the date of the first administration of 225Ac-PSMA-R2 to the date of radiographic progression as outlined in PCWG3 guideline or death due to any cause.

From date of the first administration of 225Ac-PSMA-R2 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 15 months

Overall survival (OS) is defined as the time (in months) from the date of the first administration of 225Ac-PSMA-R2 to the date of death due to any cause. If a participant is not known to have died, then OS will be censored at the latest date the participant was known to be alive (on or before the cut-off date).

From date of the first administration of 225Ac-PSMA-R2 until date of death from any cause, assessed up to approximately 15 months

Duration of response (DOR) is defined as the time (in months) from the date of the first documented response (CR or PR) to the date of first documented progression according to PCWG3-modified RECIST v1.1 or death due to any cause, among participants with a confirmed response.

From the date of the first documented response (CR or PR) to the date of first documented progression or death due to any cause, assessed up to approximately 15 months

Time to a first symptomatic skeletal event (SSE) is defined as the time (in months) from the first administration of 225Ac-PSMA-R2 to the date of SSE or death due to any cause. SSE date is date of the first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain, or death due to any cause, whichever comes first.

From the date of the first administration of 225Ac-PSMA-R2 until the date of SSE or date of death from any cause, whichever comes first, assessed up to approximately 15 months

Biochemical responses as measured by Prostate Specific Antigen (PSA), Alkaline Phosphatase (ALP), Lactate Dehydrogenase (LDH).

From date of the first administration of 225Ac-PSMA-R2 till 30 days safety follow-up, assessed up to approximately 15 months

Dose Escalation: Area under the serum concentration-time cure from time zero to the time of last quantifiable concentration (AUClast) of 225Ac-PSMA-R2 during the first cycle of treatment

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Dose Escalation: Area under the plasma concentration-time curve from time zero to infinity (AUCinf) of 225Ac-PSMA-R2 during the first cycle of treatment

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Dose Escalation: Maximum plasma concentration (Cmax) of 225Ac-PSMA-R2 during the first cycle of treatment

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Dose Escalation: Total systemic clearance for intravenous administration (CL) of 225Ac-PSMA-R2 during the first cycle of treatment

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Dose Escalation: Time of observed drug concentration occurrence (Tmax) of 225Ac-PSMA-R2 during the first cycle of treatment

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Dose Escalation: Volume of distribution during the terminal phase following intravenous elimination (Vz) of 225Ac-PSMA-R2 during the first cycle of treatment

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Dose Escalation: Terminal elimination half-life (T1/2) of 225Ac-PSMA-R2 during the first cycle of treatment

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T1/2 will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Dose Expansion: Area under the serum concentration-time cure from time zero to the time of last quantifiable concentration (AUClast) of 225Ac-PSMA-R2

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Dose Expansion: Area under the plasma concentration-time curve from time zero to infinity (AUCinf) of 225Ac-PSMA-R2

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Dose Expansion: Volume of distribution during the terminal phase following intravenous elimination (Vz) of 225Ac-PSMA-R2

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T1/2 will be listed and summarized using descriptive statistics.

Cycle (C) 1 Day (D) 1 (Pre-dose (before start of infusion), Mid-infusion, Just before or at the end of infusion, Post-dose (5 minutes (min), 15 min, 30 min, 1 hour (hr), 2 hr, 4 hr, 8 hr)), C1 D2 (24 hr), C1 D3 (48 hr), C1 D4 (72 hr). Cycle = 6 weeks

Key Inclusion Criteria: Evidence of PSMA-positive disease by 68Ga-PSMA-R2 PET/CT and eligible as determined by central reading Documented progressive mCRPC Adequate organ function (bone marrow reserve, hepatic, renal) Prior orchiectomy and/or ongoing ARPI and taxane-based chemotherapy and should have received prior 177Lu-PSMA-RLT (Group1 dose escalation & expansion) or never received 177Lu-PSMA-RLT (Group 2 dose escalation & expansion). Key Exclusion Criteria: Any other investigational agents within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy Any systemic anti-cancer therapy within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy Uncontrolled pain or incompatibility that may result in participant's lack of ability to comply with imaging procedures History of CNS metastases and symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression Uncontrolled cardiovascular history Diagnosis of other malignancies expected to alter life expectancy or may interfere with disease assessment Other protocol-defined inclusion/exclusion criteria may apply.