A Phase Ib/II Open-label Study of AMO959 With Lutetium (177Lu) Vipivotide Tetraxetan (AAA617) in Combination With ARPI in Adult Participants With PSMA-positive mCRPC

A Phase Ib/II Open-label, Multi-center Study of AMO959 With Lutetium (177Lu) Vipivotide Tetraxetan (AAA617) in Combination With an Androgen Receptor Pathway Inhibitor (ARPI) in Adult Participants With PSMA-positive Metastatic Castration Resistant Prostate Cancer (mCRPC)

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.

Study Overview

• Status: Recruiting
• Conditions: PSMA-positive Metastatic Castration Resistant Prostate Cancer (mCRPC) With Prior Exposure to One Prior ARPI Who Are Candidates for Taxane-based Chemotherapy
• Intervention / Treatment: Drug: AMO959; Radiation: AAA617; Drug: Enzalutamide; Drug: Abiraterone

Detailed Description

This study will consist of two phases:

1. The escalation phase (Ib) will consist of provisionally three dose level cohorts of 3-6 participants investigating the safety, tolerability, and to determine the recommended dose for expansion (RDE) of AMO959 with standard dose of AAA617 +/- ARPI (abiraterone or enzalutamide). Initially AMO959 monotherapy will be administered, and then AMO959 will be given along with AAA617 in the same participants. Dose escalation meetings (DEMs) will occur when all participants in a dose level cohort have completed the DLT evaluation period or have experienced a DLT prior to the end of the evaluation period.
2. The Phase II will follow with 25 participants per arm randomized in a 1:1:1 ratio treated at the RDE(s) of AMO959 along with AAA617 and ARPI (abiraterone or enzalutamide) and AAA617 and ARPI (abiraterone or enzalutamide).

• Study Type: Interventional
• Enrollment (Estimated): 123
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111; Email: novartis.email@novartis.com

Study Locations

• Australia
  • Victoria
    • Malvern, Victoria, Australia, 3144
      • Recruiting
      • Novartis Investigative Site
    • Melbourne, Victoria, Australia, 3004
      • Recruiting
      • Novartis Investigative Site
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Recruiting
      • Novartis Investigative Site
• France
  • Bordeaux, France, 33076
    • Recruiting
    • Novartis Investigative Site
  • Clermont-Ferrand, France, 63011
    • Recruiting
    • Novartis Investigative Site
  • Nantes, France, 44093
    • Recruiting
    • Novartis Investigative Site
  • Villejuif, France, 94800
    • Recruiting
    • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Recruiting
    • Novartis Investigative Site
  • München, Germany, 80377
    • Recruiting
    • Novartis Investigative Site
• Italy
  • Naples, Italy, 80131
    • Recruiting
    • Novartis Investigative Site
  • FE
    • Cona, FE, Italy, 44124
      • Recruiting
      • Novartis Investigative Site
  • MI
    • Milan, MI, Italy, 20133
      • Recruiting
      • Novartis Investigative Site
• Japan
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8648
      • Recruiting
      • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08036
    • Recruiting
    • Novartis Investigative Site
  • Madrid, Spain, 28041
    • Recruiting
    • Novartis Investigative Site
  • Andalusia
    • Granada, Andalusia, Spain, 18014
      • Recruiting
      • Novartis Investigative Site
• United States
  • Texas
    • El Paso, Texas, United States, 79912
      • Recruiting
      • Rio Grande Urology
      • Principal Investigator: Jameson T Mendel
      • Contact: Paola Delgado; Email: pdelgado@riograndeurology.com
  • Utah
    • Murray, Utah, United States, 84107
      • Recruiting
      • Utah Intermountain Medical Center
      • Principal Investigator: Dustin Boothe
      • Contact: Preston Mayer; Phone Number: 801-507-9333; Email: preston.mayer@imail.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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:

  • Serum/plasma PSA progression is defined as 2 increases in PSA measured at least 1 week apart. The minimal start value is 2.0 ng/mL; 1.0 ng/mL is the minimal starting value if confirmed rise in PSA is the only indication of progression as per PCWG3 guidelines.
  • Soft-tissue progression defined PCWG3-modified RECIST v1.1 (Eisenhauer et al 2009, Scher et al 2016).
  • Progression of bone disease: 2 new lesions; only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria Scher et al 2016).

Key Exclusion Criteria:

• Concurrent local (radiation therapy to the prostate with curative intent or other prostate antineoplastic ablative procedures) or systemic (hormonal ablation, chemotherapy, immunotherapy, , RLTs) antineoplastic treatments, or within 28 days of enrollment (Phase Ib) or randomization (Phase II)
• Prior treatment with any RLT or PSMA-targeted agents (approved or investigational)
• Any other investigational agents within 28 days prior to first dose of any study treatment
• Concurrent serious medical conditions that may interfere with study procedures or followup
• Participants with a history of CNS metastases must have received therapy (surgery, whole brain radiation therapy, stereotactic radiosurgery) and be neurologically stable, asymptomatic, and not taking corticosteroids for the purpose of maintaining neurologic integrity.

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1b: Doublet; Participants will receive AMO959 BID for first 14 days followed by AAA617+AMO959 every 6 weeks for a maximum of 6 cycles.	Drug: AMO959; DNA Damage Response inhibitor; Other Names: BY1298; BY101298; Radiation: AAA617; PSMA-targeted radiopharmaceutical; Other Names: Pluvicto [177Lu]Lu-PSMA-617
Experimental: Phase 1b: Triplet; 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.	Drug: AMO959; DNA Damage Response inhibitor; Other Names: BY1298; BY101298; Radiation: AAA617; PSMA-targeted radiopharmaceutical; Other Names: Pluvicto [177Lu]Lu-PSMA-617; Drug: Enzalutamide; Androgen receptor pathway inhibitor; Drug: Abiraterone; Androgen receptor pathway inhibitor
Experimental: Phase 1b: Food Effect; 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.	Drug: AMO959; DNA Damage Response inhibitor; Other Names: BY1298; BY101298; Radiation: AAA617; PSMA-targeted radiopharmaceutical; Other Names: Pluvicto [177Lu]Lu-PSMA-617
Experimental: Phase II: Arm 1; 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.	Drug: AMO959; DNA Damage Response inhibitor; Other Names: BY1298; BY101298; Radiation: AAA617; PSMA-targeted radiopharmaceutical; Other Names: Pluvicto [177Lu]Lu-PSMA-617; Drug: Enzalutamide; Androgen receptor pathway inhibitor; Drug: Abiraterone; Androgen receptor pathway inhibitor
Experimental: Phase II: Arm 2; 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.	Drug: AMO959; DNA Damage Response inhibitor; Other Names: BY1298; BY101298; Radiation: AAA617; PSMA-targeted radiopharmaceutical; Other Names: Pluvicto [177Lu]Lu-PSMA-617; Drug: Enzalutamide; Androgen receptor pathway inhibitor; Drug: Abiraterone; Androgen receptor pathway inhibitor
Experimental: Phase II: Arm 3; Participants will receive AAA617 every 6 weeks for a maximum of 6 cycles, with ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.	Radiation: AAA617; PSMA-targeted radiopharmaceutical; Other Names: Pluvicto [177Lu]Lu-PSMA-617; Drug: Enzalutamide; Androgen receptor pathway inhibitor; Drug: Abiraterone; Androgen receptor pathway inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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
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

Secondary Outcome Measures

Outcome Measure	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
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.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2025
• Primary Completion (Estimated): July 10, 2028
• Study Completion (Estimated): September 13, 2029

Study Registration Dates

• First Submitted: November 7, 2025
• First Submitted That Met QC Criteria: November 7, 2025
• First Posted (Actual): November 12, 2025

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: dose escalation; Lutetium (177Lu) vipivotide tetraxetan; Androgen Receptor Pathway Inhibitor (ARPI); PSMA-positive metastatic castration resistant prostate cancer; AMO959
• Additional Relevant MeSH Terms: Pluvicto; abiraterone; enzalutamide
• Other Study ID Numbers: CAMO959A12103; 2025-521859-23-00 (Registry Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No