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| ID | Type | Description | Link |
|---|---|---|---|
| 2025-521859-23-00 | Registry Identifier | EU CT Number |
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The purpose of this phase Ib/II study is to (a) in Phase Ib evaluate the safety, tolerability, and pharmacokinetics (PK) of AMO959 when given in combination with lutetium (177Lu) vipivotide tetraxetan (also known as [177Lu]Lu-PSMA-617 or 177Lu-PSMA-617 and hereafter referred to as AAA617) with an androgen receptor pathway inhibitor (ARPI) in participants with metastatic castration resistant prostate cancer (mCRPC) who have failed one prior ARPI and with or without prior taxane exposure, and (b) in Phase II evaluate the preliminary efficacy of AMO959 in combination with AAA617 and ARPI in participants with mCRPC who have failed one prior ARPI, but who have not yet been exposed to taxane treatment.
This study will consist of two phases:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Phase 1b: Doublet | Experimental | Participants will receive AMO959 BID for first 14 days followed by AAA617+AMO959 every 6 weeks for a maximum of 6 cycles. |
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| Phase 1b: Triplet | Experimental | Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide) administered continuously starting on day 1. |
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| Phase 1b: Food Effect | Experimental | Participants will receive a single dose of AMO959 on Day 1 (fed), followed by 2-day washout, then AMO959 BID (fasted) for 14 days followed by 2-day washout and AAA617+AMO959 (fasted) every 6 weeks for a maximum of 6 cycles. |
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| Phase II: Arm 1 | Experimental | Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide administered continuously starting on day 1. |
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| Phase II: Arm 2 |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AMO959 | Drug | DNA Damage Response inhibitor |
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| Measure | Description | Time Frame |
|---|---|---|
| Phase Ib: Incidence rate of Dose-limiting toxicities (DLTs) | Incidence of dose limiting toxicities (DLTs) with AMO959 in combination with AAA617 +/- ARPI A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness/injury, or concomitant medications that occurs within the evaluation period and meets any of the criteria specified in the protocol. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5.0 will be used for all grading. | Up to 42 days after the first AAA617 dose administration |
| Phase Ib: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of adverse events by type, frequency, and severity, as graded by the NCI CTCAE version 5.0. | From date of start of study treatment, assessed up to approximately 45 months |
| Phase Ib: Number of Participants with dose adjustments | The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation). | From date of start of study treatment, assessed up to approximately 24 months |
| Phase Ib: Dose Intensity | Dose intensity (computed as the ratio of actual cumulative dose received and actual duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity). | From date of start of study treatment, assessed up to approximately 24 months |
| Phase Ib: Duration of exposure to each study drug | Duration of exposure (in months) to each study drug. | From date of start of study treatment, assessed up to approximately 24 months |
| Measure | Description | Time Frame |
|---|---|---|
| Prostate Specific Antigen 90 (PSA90) response | PSA90 response is defined as the proportion of participants who have achieved a ≥ 90% decrease in PSA from baseline at any time during the treatment period prior to start of new anti-cancer therapy that is confirmed by a second PSA measurement ≥4 weeks later. | From date of start of study treatment, assessed up to approximately 24 months |
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Key Inclusion Criteria:
Signed informed consent must be obtained prior to participation in the study.
Participants must be adults ≥ 18 years of age.
Participants must have an ECOG performance status of 0 to 2.
Participants must have histologically confirmed adenocarcinoma of the prostate. Participants with other histology (e.g. neuroendocrine, intraductal subtype) are not eligible.
Phase Ib: Prior exposure of up to 1 line of taxane-based chemotherapy is permissible. Phase II: Participants must not have received taxane-based chemotherapy in mCRPC setting (allowed in mHSPC setting).
Participants must have PSMA-PET positive disease assessed by using a PSMA imaging agent that is approved as per protocol and are eligible as determined by the sponsor's central reading rules.
Castration level of testosterone (< 50 ng/dL), and/or use of concomitant ADT
Participant must have been diagnosed with mCRPC with documented progressive disease while on treatment with ARPI in mHSPC or earlier setting as their last treatment (and did not progress on more than one ARPI), based on at least 1 of the following criteria:
Key Exclusion Criteria:
Other protocol-defined inclusion/exclusion criteria may apply.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Novartis Pharmaceuticals | Contact | 1-888-669-6682 | novartis.email@novartis.com | |
| Novartis Pharmaceuticals | Contact | +41613241111 | novartis.email@novartis.com |
| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| VA Greater LA Healthcare System | Recruiting | Los Angeles | California | 90073 | United States |
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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| Experimental |
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide) administered continuously starting on day 1. |
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| Phase II: Arm 3 | Experimental | Participants will receive AAA617 every 6 weeks for a maximum of 6 cycles, with ARPI (abiraterone or enzalutamide) administered continuously starting on day 1. |
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| AAA617 | Radiation | PSMA-targeted radiopharmaceutical |
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| Enzalutamide | Drug | Androgen receptor pathway inhibitor |
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| Abiraterone | Drug | Androgen receptor pathway inhibitor |
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| Phase II: Biochemical Response (PSA50) | Biochemical response (PSA50), defined as the proportion of participants who achieved a ≥ 50% decrease in PSA from baseline at any time during the treatment period prior to start of new anti-cancer therapy that is confirmed by a second PSA measurement ≥ 4 weeks later. | From date of start of study treatment, assessed up to approximately 24 months |
| Phase Ib: Prostate Specific Antigen 50 (PSA50) response | PSA50 response is defined as the proportion of participants who have achieved a ≥ 50% decrease in PSA from baseline at any time during the treatment period prior to the start of new anti-cancer therapy, confirmed by a second PSA measurement ≥4 weeks later. | From date of start of study treatment, assessed up to approximately 24 months |
| Phase Ib and Phase II: Radiographic progression-free survival (rPFS) | Radiographic progression- free survival (rPFS) is defined as the time from the date of start of study treatment (Phase Ib) / randomization (Phase II) to the date of first documented radiographic disease progression using conventional imaging and Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 criteria (Scher et al 2016) or death due to any cause, whichever occurs first. | From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months |
| Phase Ib and Phase II: Overall Response Rate (ORR) | Overall Response Rate (ORR) is defined as the proportion of participants with best overall response (BOR) of confirmed complete response (CR) or partial response (PR) in soft tissue based on tumor response data and according to PCWG3-modified RECIST v1.1, in the absence of bone progression as per PCWG3. | From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months |
| Phase Ib and Phase II: Disease control rate (DCR) | Disease control rate (DCR) is defined as the proportion of participants with a BOR of confirmed CR or PR, stable disease (SD) or Non-CR/Non- progressive disease (PD) in soft tissue based on tumor response data and according to PCWG3-modified RECIST v1.1, in the absence of bone progression as per PCWG3. | From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months |
| Phase Ib and Phase II: Duration of Response (DoR) | Duration of Response (DoR) is defined as the duration of time between the date of first documented response (CR or PR) according to PCWG3- modified RECIST v1.1, in the absence of bone progression as per PCWG3, based on tumor response data and the date of first documented radiographic progression in soft tissue or death due to any cause, whichever occurs first. | From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months |
| Overall Survival (OS) | Overall Survival (OS) is defined as the time from the date of start of study treatment (Phase Ib) / randomization (Phase II) to the date of death due to any cause. | From date of start of study, assessed up to approximately 45 months |
| Phase II: Time to soft tissue progression (TTSTP) | Time to soft tissue progression (TTSTP) is defined as time from randomization to the date of first documented radiographic soft tissue progression per PCWG3-modified RECIST v1.1. | From date of start of study randomization, assessed up to approximately 24 months |
| Phase Ib: Plasma concentrations of AMO959 | AMO959 pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms | Throughout run-in periods and first cycle with AAA617, assessed up to 6 months |
| Phase Ib: Plasma concentrations of AAA617 | AAA617 pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms | Throughout treatment periods with AAA617, assessed up to 6 months |
| Phase Ib: Time activity curves (TACs) for AAA617 | Time Activity Curves (TAC) will be generated by plotting concentrations against time. | Throughout treatment periods with AAA617, assessed up to 6 months |
| Phase Ib: Absorbed radiation doses in selected organs and tumor lesions for AAA617 | The organ absorbed radiation dose and effective radiation dose will be evaluated. | Throughout treatment periods with AAA617, assessed up to 6 months |
| Phase II: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of adverse events by type, frequency, and severity, as graded by the NCI CTCAE version 5.0. | From date of start of study treatment, assessed up to approximately 45 months |
| Phase II: Number of Participants with dose adjustments | The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation). | From date of start of study treatment, assessed up to approximately 24 months |
| Phase II: Dose Intensity | Dose intensity (computed as the ratio of actual cumulative dose received and actual duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity). | From date of start of study treatment, assessed up to approximately 24 months |
| Phase II: Duration of exposure to each study drug | Duration of exposure (in months) to each study drug. | From date of start of study treatment, assessed up to approximately 24 months |
| Phase II: Radiographic Progression Free Survival (rPFS) by Positron Emission Tomography (PET) (rPFS-PET) | Radiographic Progression Free Survival (rPFS) by Positron Emission Tomography (PET) (rPFS- PET) is defined as the time from the date of randomization to first documented radiographic disease progression (an increase in PSMA-positive tumor volume ≥ 20% from baseline and new PSMA-positive malignant lesions) using PSMA PET/CT imaging (Seifert et al 2023, Gafita et al 2023) or death due to any cause, whichever occurs first. | From date of start of study randomization, assessed up to approximately 24 months |
| Phase II: Change from baseline in FACT-P Prostate Cancer Subscale (PCS) | Change from baseline in FACT-P PCS refers to the difference in a patient's score on the Prostate Cancer Subscale (PCS) of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire between the start of a study (baseline) and subsequent time points. | From date of start of study, assessed up to approximately 45 months. |
| Phase II: Time to worsening on the Brief Pain Inventory - Short Form (BPI-SF) | Time to worsening on the Worst Pain defined as the time from the date of randomization to the first occurrence of worsening on the Brief Pain Inventory - Short Form (BPI-SF) Worst Pain item of at least 30% increase from baseline or a minimum of 2 points increase from baseline or death due to any cause, whichever occurs first. | From date of start of study, assessed up to approximately 45 months. |
| Phase II: Time to first symptomatic skeletal event (TTSSE) | Time to first symptomatic skeletal event (TTSSE) is defined as the time from the date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, or requirement for radiation therapy to relieve bone pain, or death due to any cause, whichever occurs first. | From date of start of study randomization, assessed up to approximately 24 months. |
| Rio Grande Urology | Recruiting | El Paso | Texas | 79912 | United States |
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| Utah Intermountain Medical Center | Recruiting | Murray | Utah | 84107 | United States |
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| Novartis Investigative Site | Recruiting | Malvern | Victoria | 3144 | Australia |
| Novartis Investigative Site | Recruiting | Melbourne | Victoria | 3004 | Australia |
| Novartis Investigative Site | Recruiting | Murdoch | Western Australia | 6150 | Australia |
| Novartis Investigative Site | Recruiting | Bordeaux | 33076 | France |
| Novartis Investigative Site | Recruiting | Clermont-Ferrand | 63011 | France |
| Novartis Investigative Site | Recruiting | Nantes | 44093 | France |
| Novartis Investigative Site | Recruiting | Villejuif | 94800 | France |
| Novartis Investigative Site | Recruiting | Dresden | Saxony | 01307 | Germany |
| Novartis Investigative Site | Recruiting | Essen | 45147 | Germany |
| Novartis Investigative Site | Recruiting | München | 80377 | Germany |
| Novartis Investigative Site | Recruiting | Cona | FE | 44124 | Italy |
| Novartis Investigative Site | Recruiting | Milan | MI | 20133 | Italy |
| Novartis Investigative Site | Recruiting | Naples | 80131 | Italy |
| Novartis Investigative Site | Recruiting | Sapporo | Hokkaido | 060-8648 | Japan |
| Novartis Investigative Site | Recruiting | Granada | Andalusia | 18014 | Spain |
| Novartis Investigative Site | Recruiting | L'Hospitalet de Llobregat | Barcelona | 08907 | Spain |
| Novartis Investigative Site | Recruiting | Barcelona | 08036 | Spain |
| Novartis Investigative Site | Recruiting | Madrid | 28041 | Spain |
| ID | Term |
|---|---|
| C000610110 | Pluvicto |
| C540278 | enzalutamide |
| C089740 | abiraterone |
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