Phase I/II Study of [225Ac]Ac-PSMA-R2 in PSMA-positive Prostate Cancer, With/Without Prior 177Lu-PSMA RLT (SatisfACtion)

SatisfACtion: Phase I/II, Open-label, Multi-center Study of [225Ac]Ac-PSMA-R2 in Men With mHSPC and Heavily Pre-treated PSMA-positive mCRPC, With/Without Prior 177Lu-labelled PSMA-targeted Radioligand Therapy

The purpose of this study is to learn if the study drug, [225Ac]Ac-PSMA-R2, is safe and tolerable, and has anti-tumor activity in treated patients.

Study Overview

• Status: Active, not recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: 225Ac-PSMA-R2; Radiation: 68Ga-PSMA-R2; Radiation: 68Ga-PSMA-11

Detailed Description

First in human (FIH) phase I/II study of 225Ac-PSMA-R2 in PSMA-positive metastatic prostate cancer across three groups: post-177Lu mCRPC, pre-177Lu mCRPC, and 177Lu-naïve mHSPC, evaluating Q6W/Q4W dosing. Dose escalation will enroll ~18-22 participants per group/schedule to define MTD/RDE, guided by safety, tolerability, PK/dosimetry, and preliminary anti-tumor activity, with possible expansion based on benefit-risk.

Enrollment and dosing for all participants in Group 1, Group 2, and Group 3 have been completed. Further enrollment has been halted, and no additional dose escalation cohorts or Phase 2 dose expansion cohorts will be opened; enrollment in this study is now considered complete. The decision to halt enrolment was not driven by any safety concerns identified in the study to date, but rather by a lowered expectation of benefit. Accordingly, the study will not proceed to Phase 2, and a recommended Phase 2 dose was not established

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • Novartis Investigative Site
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H2X 1R9
      • Novartis Investigative Site
• France
  • Clermont-Ferrand, France, 63011
    • Novartis Investigative Site
  • Lyon, France, 69373
    • Novartis Investigative Site
  • Nantes, France, 44093
    • Novartis Investigative Site
  • Saint-Herblain, France, 44805
    • Novartis Investigative Site
  • Vandœuvre-lès-Nancy, France, 54511
    • Novartis Investigative Site
  • Cote D Or
    • Dijon, Cote D Or, France, 21034
      • Novartis Investigative Site
• United States
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • BAMF Health
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Evidence of PSMA-positive disease by 68Ga-PSMA-11 PET/CT and eligible as determined by central reading
• Documented progressive mCRPC or mHSPC
• Adequate organ function
• Prior orchiectomy or ongoing ADT and should have received prior 177Lu-PSMA-RLT (Group1 dose escalation & expansion) or never received 177Lu-PSMA-RLT (Group 2 and Group 3 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
• History of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months prior to ICF signature and/or clinically active significant cardiac disease
• Diagnosis of other malignancies in the past three years expected to alter life expectancy or may interfere with disease assessment

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group-1 (mCRPC/ post-177Lu); Dose Escalation: All eligible participants with Metastatic Castration Resistant Prostate Cancer (mCRPC) who have received anti-cancer treatment (post-Androgen Receptor Pathway Inhibitors (ARPI), post-taxane based chemotherapy and heavily pre-treated and having already received prior 177Lu-labelled Prostate Specific Membrane Antigen (PSMA)-targeting Radioligand Therapy (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 who have previously received 177Lu-PSMA-RLT will be enrolled in Group 1 dose expansion.	Drug: 225Ac-PSMA-R2; PSMA-R2 is a ligand coupled with 225Ac an alpha emitting radionuclide; Radiation: 68Ga-PSMA-R2; Kit for radiopharmaceutical preparation; Radiation: 68Ga-PSMA-11; Kit for radiopharmaceutical preparation; Other Names: Locametz
Experimental: Group-2 (mCRPC/ pre-177Lu); Dose Escalation: All eligible participants with mCRPC who have received anti-cancer treatment (post-Androgen Receptor Pathway Inhibitors (ARPI), prior taxane-based chemotherapy is not required, but have never been treated with 177Lu-labelled PSMA-targeted RLT (177Lu-labelled PSMA-targeted RLT treatment naïve) 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 2.; Dose Expansion: Once RDE is determined for Group 2, participants naïve to 177Lu-labelled PSMA-targeted Radioligand Therapy (RLT) will be enrolled in Group 2 dose expansion.	Drug: 225Ac-PSMA-R2; PSMA-R2 is a ligand coupled with 225Ac an alpha emitting radionuclide; Radiation: 68Ga-PSMA-R2; Kit for radiopharmaceutical preparation; Radiation: 68Ga-PSMA-11; Kit for radiopharmaceutical preparation; Other Names: Locametz
Experimental: Group 3 (mHSPC/ pre-177Lu); Dose Escalation: All eligible participants with mHSPC (177Lu-labelled PSMA-targeted RLT treatment naïve), who are treatment naive or minimally treated with a) luteinizing hormone-releasing hormone (LHRH) agonist/antagonists or bilateral orchiectomy with or without first generation antiandrogen (e.g. bicalutamide, flutamide) b) CYP17 inhibitor or ARDT exposure. Patient in this group will start treatment with 225Ac-PSMA-R2 after group 1 and group 2 patients.; Dose Expansion: Once RDE is determined for Group 3, participants will be enrolled in Group 3 dose expansion.	Drug: 225Ac-PSMA-R2; PSMA-R2 is a ligand coupled with 225Ac an alpha emitting radionuclide; Radiation: 68Ga-PSMA-R2; Kit for radiopharmaceutical preparation; Radiation: 68Ga-PSMA-11; Kit for radiopharmaceutical preparation; Other Names: Locametz

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I Dose Escalation: Incidence and severity of DLTs during the DLT observation period	To determine the Recommended Dose for Expansion (RDE) and corresponding regimen for 225Ac-PSMA-R2 monotherapy in PSMA-positive in: Group-1 (mCRPC): Participants previously treated with 177Lu-labelled PSMA-targeted RLT (post-177Lu).; Group-2 (mCRPC): Participants not treated previously with 177Lu-labelled PSMA-targeted RLT (pre-177Lu).; Group-3 (mHSPC): Participants not treated previously with 177Lu-labelled PSMA-targeted RLT (pre-177Lu).	Up to 6 weeks after the first 225Ac-PSMA-R2 dose administration
Phase I Dose Escalation: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by group and frequency schedule	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
Phase I Dose Escalation: Tolerability	Frequency of dose interruptions, reductions, discontinuations, and dose intensity by group.	Up to 6 weeks after the first 225AC-PSMA-R2 dose administration
Phase ll Dose Expansion: Overall Response Rate (ORR)	Overall Response Rate (ORR) is defined as the proportion of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR) in soft tissue according to Prostate Cancer Working Group 3 (PCWG3) -modified RECIST v1.1 in absence of bone progression (as per PCWG3).	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I Dose Escalation: Incidence and severity of AEs and serious adverse events (SAEs)	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.	Up to 6 months after the last 225Ac-PSMA-R2 dose administration
Phase ll: Dose Expansion: Incidence and severity of AEs and serious adverse events (SAEs)	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.	Assessed up to approximately 15 months.
Phase I 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.	At day 1 of each cycle (1 cycle = up to 6 weeks)
Phase I Dose Escalation: Overall Response Rate (ORR)	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.	Assessed up to approximately 15 months.
Phase I Dose Escalation & Phase II Dose Expansion: Disease Control Rate (DCR)	Disease control rate (DCR) is defined as the proportion of participants with confirmed best overall response (BOR) of complete response (CR), partial response (PR) or stable disease (SD).	Assessed up to approximately 15 months.
Phase I Dose Escalation & Phase II Dose Expansion: Best Overall Response (BOR)	Best Overall Response (BOR) is defined as the best response recorded from the start of the treatment until disease progression.	Assessed up to approximately 15 months.
Phase I Dose Escalation & Phase II Dose Expansion: radiographic Progression Free Survival (rPFS)	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 modified RECIST 1.1 or death due to any cause.	Assessed up to approximately 15 months.
Phase I Dose Escalation & Phase II Dose Expansion: Overall Survival (OS)	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.	Assessed up to approximately 15 months.
Phase I Dose Escalation & Phase II Dose Expansion: Duration of Response (DoR)	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.	Assessed up to approximately 15 months.
Phase I Dose Escalation & Phase II Dose Expansion: Time to first Symptomatic Skeletal Event (SSE)	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.	Assessed up to approximately 15 months.
Phase I Dose Escalation & Phase II Dose Expansion: Percentage of Participants with Biochemical Response by ALP and LDH	Biochemical responses by Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH) will be measured as best percentage change from baseline	Assessed up to approximately 15 months.
Phase I Dose Escalation and Phase II Dose Expansion: Percentage of Participants with Biochemical Response by PSA	Biochemical responses as measured by Prostate Specific Antigen (PSA): PSA50 response is defined as the proportion of participants who have achieved ≥50% decrease from baseline at any time.	Assessed up to approximately 15 months.
Phase I Dose Escalation and Phase II: Dose Expansion: Pharmacokinetics characterization of 225Ac-PSMA-R2	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization.	At Cycle (C) 1 Day (D) 1 at different measurement times, and one timepoint at C1 D2, C1 D3 and C1 D4
Phase I Dose Escalation and Phase II Dose Expansion: To assess the impact of 225Ac-PSMA-R2 on participant reported outcomes	Change in heath related quality of life.	From baseline until 24 months after the end of treatment

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2023
• Primary Completion (Estimated): March 4, 2031
• Study Completion (Estimated): March 4, 2031

Study Registration Dates

• First Submitted: July 24, 2023
• First Submitted That Met QC Criteria: August 8, 2023
• First Posted (Actual): August 9, 2023

Study Record Updates

• Last Update Posted (Actual): June 29, 2026
• Last Update Submitted That Met QC Criteria: June 25, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: dose limiting toxicity; DLT; 225Ac-PSMA-R2; Escalation with Overdose Control; EWOC; pre- and post-177Lu-PSMA-RLT
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; Anticoagulants; Chelating Agents; Sequestering Agents; Calcium Chelating Agents; gallium 68 PSMA-11
• Other Study ID Numbers: CAAA802A12101; 2021-003478-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No