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RecruitingInterventionalPhase 1/Phase 2

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)

NCT ID: NCT07226986Sponsor: Novartis PharmaceuticalsLast updated: 2026-06-16

Summary

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.

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).

Arms & interventions

  • DrugAMO959

    DNA Damage Response inhibitor

  • RadiationAAA617

    PSMA-targeted radiopharmaceutical

  • DrugEnzalutamide

    Androgen receptor pathway inhibitor

  • DrugAbiraterone

    Androgen receptor pathway inhibitor

Outcome measures

Primary

  • 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.

    Time frame: 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.

    Time frame: 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).

    Time frame: 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).

    Time frame: 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.

    Time frame: 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.

    Time frame: From date of start of study treatment, assessed up to approximately 24 months

Secondary

  • Prostate Specific Antigen 90 (PSA90) response

    Time frame: From date of start of study treatment, assessed up to approximately 24 months

  • Phase Ib: Prostate Specific Antigen 50 (PSA50) response

    Time frame: From date of start of study treatment, assessed up to approximately 24 months

  • Phase Ib and Phase II: Radiographic progression-free survival (rPFS)

    Time frame: 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)

    Time frame: 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)

    Time frame: 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)

    Time frame: From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months

  • Overall Survival (OS)

    Time frame: From date of start of study, assessed up to approximately 45 months

  • Phase II: Time to soft tissue progression (TTSTP)

    Time frame: From date of start of study randomization, assessed up to approximately 24 months

  • Phase Ib: Plasma concentrations of AMO959

    Time frame: Throughout run-in periods and first cycle with AAA617, assessed up to 6 months

  • Phase Ib: Plasma concentrations of AAA617

    Time frame: Throughout treatment periods with AAA617, assessed up to 6 months

  • Phase Ib: Time activity curves (TACs) for AAA617

    Time frame: Throughout treatment periods with AAA617, assessed up to 6 months

  • Phase Ib: Absorbed radiation doses in selected organs and tumor lesions for AAA617

    Time frame: Throughout treatment periods with AAA617, assessed up to 6 months

  • Phase II: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Time frame: From date of start of study treatment, assessed up to approximately 45 months

  • Phase II: Number of Participants with dose adjustments

    Time frame: From date of start of study treatment, assessed up to approximately 24 months

  • Phase II: Dose Intensity

    Time frame: From date of start of study treatment, assessed up to approximately 24 months

  • Phase II: Duration of exposure to each study drug

    Time frame: 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)

    Time frame: 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)

    Time frame: 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 frame: From date of start of study, assessed up to approximately 45 months.

  • Phase II: Time to first symptomatic skeletal event (TTSSE)

    Time frame: From date of start of study randomization, assessed up to approximately 24 months.

Eligibility criteria

Sex: MaleAge: 18 Years and olderHealthy volunteers: No
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 locations (2)

Rio Grande Urology

El Paso, Texas, 79912

Recruiting
Paola Delgado · Contact
pdelgado@riograndeurology.com
Jameson T Mendel · Principal Investigator

Utah Intermountain Medical Center

Murray, Utah, 84107

Recruiting
Preston Mayer · Contact
801-507-9333preston.mayer@imail.org
Dustin Boothe · Principal Investigator