Phase I/II Study of [225Ac]Ac-PSMA-R2 in PSMA-positive Prostate Cancer, With/Without Prior 177Lu-PSMA RLT
PHASE1ACTIVE_NOT_RECRUITING
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 details:
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.
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
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE1
Study ID
NCT05983198
Intervention or treatment
DRUG: 225Ac-PSMA-R2
RADIATION: 68Ga-PSMA-R2
RADIATION: 68Ga-PSMA-11
Conditions
- Prostate Cancer
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Research sites nearby
Closest Location:
Novartis Investigative Site
Select from list below to view details:
Novartis Investigative Site
Darlinghurst, New South Wales, Australia
Novartis Investigative Site
Melbourne, Victoria, Australia
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Who is running the clinical trial?
NP
Novartis Pharmaceuticals
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)
| Drug: 225Ac-PSMA-R2, Radiation: 68Ga-PSMA-R2, Radiation: 68Ga-PSMA-11 |
EXPERIMENTAL: Group-2 (mCRPC/ pre-177Lu)
| Drug: 225Ac-PSMA-R2, Radiation: 68Ga-PSMA-R2, Radiation: 68Ga-PSMA-11 |
EXPERIMENTAL: Group 3 (mHSPC/ pre-177Lu)
| Drug: 225Ac-PSMA-R2, Radiation: 68Ga-PSMA-R2, Radiation: 68Ga-PSMA-11 |
What is the study measuring?
Primary Outcome
| Measure | Description | 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
| Measure | Description | 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 RLTOther trials to consider
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