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

PHASE1PHASE2RECRUITING

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.

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Study details:

The study contains three groups (Group 1, Group 2, and Group 3). Each group has a dose escalation part at a specific dosing schedule followed by a dose expansion part. The dose escalation parts in each group within each dosing schedule will establish the maximum tolerated dose or the recommended dose for expansion (MTDs/RDEs) of the 225Ac-PSMA-R2.

Dose escalation decisions will be made by the Investigators and Novartis during dose escalation meetings (DEMs) based on safety and tolerability information. The dose expansion parts in each group group/dosing schedule will assess the anti-tumor activity in the mHSPC and mCRPC populations.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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)

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

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: Male

Things to know

Study dates

Study start: 2023-11-07

Primary completion: 2027-06-08

Study completion finish: 2027-12-15

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT05983198

Intervention or treatment

DRUG: 225Ac-PSMA-R2

RADIATION: 68Ga-PSMA-R2

RADIATION: 68Ga-PSMA-11

Conditions

• Prostate Cancer

Condition: Prostate Cancer
DRUG: 225Ac-PSMA-R2 and other drugs
Darlinghurst, New South Wales, Australia
Sponsor: Novartis Pharmaceuticals

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Find a site

Closest Location:

Novartis Investigative Site

Research sites nearby

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Novartis Investigative Site
Darlinghurst, New South Wales, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Group-1 (mCRPC/ post-177Lu) 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 PSMA-R2 is a ligand coupled with 225Ac an alpha emitting radionuclide
EXPERIMENTAL: Group-2 (mCRPC/ pre-177Lu) 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 PSMA-R2 is a ligand coupled with 225Ac an alpha emitting radionuclide
EXPERIMENTAL: Group 3 (mHSPC/ pre-177Lu) 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 PSMA-R2 is a ligand coupled with 225Ac an alpha emitting radionuclide

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
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 outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
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
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.
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)
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.
Dose Escalation & 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.
Dose Escalation & 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.
Dose Escalation & 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.
Dose Escalation & 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.
Dose Escalation & 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.
Dose Escalation & 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.
Dose Escalation & 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.
Dose Escalation and 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.
Dose Escalation and 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
Dose escalation and 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

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References

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