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

Phase 1Active Not RecruitingNCT05983198

Novartis Pharmaceuticals33 enrolled

Overview

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.

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

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Prostate Cancer

Interventions

225Ac-PSMA-R2DRUG

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

68Ga-PSMA-R2RADIATION

Kit for radiopharmaceutical preparation

68Ga-PSMA-11RADIATION

Kit for radiopharmaceutical preparation

Eligibility

Sex: MALEMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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.

Locations (9)

Mayo Clinic Rochester

Rochester, Minnesota, United States

Novartis Investigative Site

Darlinghurst, New South Wales, Australia

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Dijon, Cote D Or, France

Outcomes

Primary Outcomes

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).

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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

Data from ClinicalTrials.gov

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Novartis Investigative Site

Clermont-Ferrand, France

Novartis Investigative Site

Lyon, France

Novartis Investigative Site

Nantes, France

Novartis Investigative Site

Saint-Herblain, France

Novartis Investigative Site

Vandœuvre-lès-Nancy, France

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.

Time frame: 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)