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

NCT05983198 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: CAAA802A121012021-003478-30
• Study Type: interventional
• Target: 33
• Locations: 4 countries
• Sites: 11

Brief Summary

This is an open label, phase I/II, multi-center study in adult participants with metastatic hormone sensitive prostate cancer (mHSPC) and with metastatic castration resistant prostate cancer (mCRPC) who have received prior anti-cancer treatment and have a positive 68Ga-PSMA-11 PET scan. 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.

Conditions

Prostate Cancer

Keywords

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

Outcome Measures

Primary Outcomes (4)

• 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

• 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

• 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

• 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 Outcomes (14)

• Dose Escalation: Incidence and severity of AEs and serious adverse events (SAEs)

  Up to 6 months after the last 225Ac-PSMA-R2 dose administration

• Dose Expansion: Incidence and severity of AEs and serious adverse events (SAEs)

  Assessed up to approximately 15 months.

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

  At day 1 of each cycle (1 cycle = up to 6 weeks)

• Dose Escalation: Overall Response Rate (ORR)

  Assessed up to approximately 15 months.

• Dose Escalation & Dose Expansion: Disease Control Rate (DCR)

  Assessed up to approximately 15 months.

Study Arms (3)

Group-1 (mCRPC/ post-177Lu)

EXPERIMENTAL

1. 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. 2. 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; Radiation: 68Ga-PSMA-R2; Radiation: 68Ga-PSMA-11

Group-2 (mCRPC/ pre-177Lu)

EXPERIMENTAL

1. 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. 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; Radiation: 68Ga-PSMA-R2; Radiation: 68Ga-PSMA-11

Group 3 (mHSPC/ pre-177Lu)

EXPERIMENTAL

1. 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. 2. Dose Expansion: Once RDE is determined for Group 3, participants will be enrolled in Group 3 dose expansion.

Drug: 225Ac-PSMA-R2; Radiation: 68Ga-PSMA-R2; Radiation: 68Ga-PSMA-11

Interventions

68Ga-PSMA-R2 RADIATION

Kit for radiopharmaceutical preparation

Group 3 (mHSPC/ pre-177Lu); Group-1 (mCRPC/ post-177Lu); Group-2 (mCRPC/ pre-177Lu)

68Ga-PSMA-11 RADIATION

Kit for radiopharmaceutical preparation

Also known as: Locametz

Group 3 (mHSPC/ pre-177Lu); Group-1 (mCRPC/ post-177Lu); Group-2 (mCRPC/ pre-177Lu)

225Ac-PSMA-R2 DRUG

PSMA-R2 is a ligand coupled with 225Ac an alpha emitting radionuclide

Group 3 (mHSPC/ pre-177Lu); Group-1 (mCRPC/ post-177Lu); Group-2 (mCRPC/ pre-177Lu)

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (11)

BAMF Health

Grand Rapids, Michigan, 49503, United States

Location

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

Location

Novartis Investigative Site

Darlinghurst, New South Wales, 2010, Australia

Location

Novartis Investigative Site

Montreal, Quebec, H2X 1R9, Canada

Location

Novartis Investigative Site

Montreal, Quebec, H3T 1E2, Canada

Location

Novartis Investigative Site

Dijon, Cote D Or, 21034, France

Location

Novartis Investigative Site

Clermont-Ferrand, 63011, France

Location

Novartis Investigative Site

Lyon, 69373, France

Location

Novartis Investigative Site

Nantes, 44093, France

Location

Novartis Investigative Site

Saint-Herblain, 44805, France

Location

Novartis Investigative Site

Vandœuvre-lès-Nancy, 54511, France

Location

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

gallium 68 PSMA-11

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 24, 2023
• First Posted: August 9, 2023
• Study Start: November 7, 2023
• Primary Completion (Estimated): November 19, 2026
• Study Completion (Estimated): November 5, 2029
• Last Updated: April 29, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2); AU (1); FR (6); US (2)