Prostate Cancer
Conditions
Keywords
225Ac-PSMA-R2, dose limiting toxicity, DLT, Escalation with Overdose Control, EWOC, pre- and post-177Lu-PSMA-RLT
Brief summary
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.
Detailed 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
Interventions
DRUG225Ac-PSMA-R2
PSMA-R2 is a ligand coupled with 225Ac an alpha emitting radionuclide
RADIATION68Ga-PSMA-R2
Kit for radiopharmaceutical preparation
RADIATION68Ga-PSMA-11
Kit for radiopharmaceutical preparation
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I Dose Escalation: Incidence and severity of DLTs during the DLT observation period | Up to 6 weeks after the first 225Ac-PSMA-R2 dose administration | 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). |
| Phase I Dose Escalation: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by group and frequency schedule | From date of the first administration of 225Ac-PSMA-R2 till 30 days safety follow-up, assessed up to approximately 15 months | 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. |
| Phase I Dose Escalation: Tolerability | Up to 6 weeks after the first 225AC-PSMA-R2 dose administration | Frequency of dose interruptions, reductions, discontinuations, and dose intensity by group. |
| Phase ll Dose Expansion: Overall Response Rate (ORR) | 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 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase I Dose Escalation: Incidence and severity of AEs and serious adverse events (SAEs) | Up to 6 months after the last 225Ac-PSMA-R2 dose administration | 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. |
| Phase ll: Dose Expansion: Incidence and severity of AEs and serious adverse events (SAEs) | Assessed up to approximately 15 months. | 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. |
| Phase I 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) | 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. |
| Phase I Dose Escalation: Overall Response Rate (ORR) | Assessed up to approximately 15 months. | 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. |
| Phase I Dose Escalation & Phase II Dose Expansion: Disease Control Rate (DCR) | Assessed up to approximately 15 months. | 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). |
| Phase I Dose Escalation & Phase II Dose Expansion: Best Overall Response (BOR) | Assessed up to approximately 15 months. | Best Overall Response (BOR) is defined as the best response recorded from the start of the treatment until disease progression. |
| Phase I Dose Escalation & Phase II Dose Expansion: radiographic Progression Free Survival (rPFS) | Assessed up to approximately 15 months. | 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. |
| Phase I Dose Escalation & Phase II Dose Expansion: Overall Survival (OS) | Assessed up to approximately 15 months. | 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. |
| Phase I Dose Escalation & Phase II Dose Expansion: Duration of Response (DoR) | Assessed up to approximately 15 months. | 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. |
| Phase I Dose Escalation & Phase II Dose Expansion: Time to first Symptomatic Skeletal Event (SSE) | Assessed up to approximately 15 months. | 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. |
| Phase I Dose Escalation & Phase II Dose Expansion: Percentage of Participants with Biochemical Response by ALP and LDH | Assessed up to approximately 15 months. | Biochemical responses by Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH) will be measured as best percentage change from baseline |
| Phase I Dose Escalation and Phase II Dose Expansion: Percentage of Participants with Biochemical Response by PSA | Assessed up to approximately 15 months. | 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. |
| Phase I Dose Escalation and Phase II: Dose Expansion: Pharmacokinetics characterization of 225Ac-PSMA-R2 | At Cycle (C) 1 Day (D) 1 at different measurement times, and one timepoint at C1 D2, C1 D3 and C1 D4 | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. |
| Phase I Dose Escalation and Phase II Dose Expansion: To assess the impact of 225Ac-PSMA-R2 on participant reported outcomes | From baseline until 24 months after the end of treatment | Change in heath related quality of life. |
Countries
Australia, Canada, France, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Outcome results
None listed