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

Novartis

Status and phase: Active, not recruiting; Phase 1

Conditions: Prostate Cancer

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

Study type: Interventional

Funder types: Industry

Identifiers

NCT05983198

CAAA802A12101

2021-003478-30 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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

Enrollment: 33 patients

Sex: Male

Ages: 18 to 100 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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33 participants in 3 patient groups

Group-1 (mCRPC/ post-177Lu)

Experimental group

Description:

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.

Treatment:

Drug: 225Ac-PSMA-R2

Radiation: 68Ga-PSMA-11

Radiation: 68Ga-PSMA-R2

Group-2 (mCRPC/ pre-177Lu)

Experimental group

Description:

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.

Treatment:

Drug: 225Ac-PSMA-R2

Radiation: 68Ga-PSMA-11

Radiation: 68Ga-PSMA-R2

Group 3 (mHSPC/ pre-177Lu)

Experimental group

Description:

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.

Treatment:

Drug: 225Ac-PSMA-R2

Radiation: 68Ga-PSMA-11

Radiation: 68Ga-PSMA-R2