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A Study of JSB462 (Luxdegalutamide) Plus Lutetium (177Lu) Vipivotide Tetraxetan in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)

Clinicaltrials.gov ID: NCT07047118
db-list-check Status RECRUITING
b-loader Phase PHASE2
b-people Age ≥ 18 Years
b-bullseye-arrow Enrollments 130

Conditions

Prostatic Cancer, Castration-Resistant

Drugs

JSB462, AAA617

Summary

This Phase II study aims to evaluate the efficacy and safety of the combination of JSB462 (also known as luxdegalutamide) at 100 mg and 300 mg QD doses + lutetium (177Lu) vipivotide tetraxetan (hereafter referred as AAA617) compared with AAA617 (control) in participants with metastatic Castration Resistant Prostate Cancer (mCRPC) with prior exposure to at least 1 Androgen Receptor Pathway Inhibitor (ARPI) and 0-2 taxane regimens and to select the recommended dose of the combination for phase III. Towards that end, the totality of the efficacy, safety, tolerability and pharmacokinetic (PK) data from participants randomized in the study will be evaluated.

Detailed Description

The study consists of a screening period, a randomization period, a treatment period, a post-treatment safety follow-up followed by a long-term follow-up period.

JSB462 administration starts at day 1 of randomization, whereas AAA617 administration starts at day 1 of treatment period. Participants in arm 1 and arm 2 will therefore receive JSB462 during the 14-day randomization period before first administration of AAA617.

* JSB462 is administered orally, daily and continuously (100 mg or 300 mg once a day (QD)) until disease progression per Prostate Cancer Working Group (PCWG) 3-modified Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision.
* AAA617 will be administered at 7.4 gigabecquerel (GBq) intravenously every 6 weeks for up to 6 doses, unless there is disease progression per PCWG3-modified RECIST v1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision.

During the post-treatment follow up period:

* Safety follow-Up: After discontinuation of study treatment, all participants will be followed for at least 1 safety follow-up visit (30 days [+/- 7 days] after end of treatment visit). Subsequent lines of therapy may be administered according to investigator’s discretion after treatment discontinuation.
* Long-term follow-up: Starts after the Safety follow-up period and lasts until the end of study. Safety, efficacy and survival information may be collected from the participants during this period.

Locations

2 locations Found with status Recruiting

Status

  • RECRUITING

Contact Person

Study Director

  • Novartis Pharmaceuticals

Status

  • RECRUITING

Contact Person

Study Director

  • Novartis Pharmaceuticals

Eligibility Criteria

Key Inclusion Criteria:

* Adult male participants with histologically and/or cytologically confirmed adenocarcinoma of the prostate. Participants with mixed histology (neuroendocrine) are not eligible.
* An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) grade ≤2.
* At least 1 bone or visceral metastatic lesion present on baseline CT, MRI, or bone scan imaging obtained ≤28 days prior to initiation of study treatment.
* Participants must be [68Ga]Ga-PSMA-11 PET/CT scan positive and eligible as determined by the sponsor's central reader.
* Participant must have prior exposure to at least one second generation ARPI in the metastatic/advanced setting.
* Previous treatment with a maximum of 2 taxane regimens is allowed.
* Participants eligible for PARPi and/or immune checkpoint inhibitor (per local testing and according to investigator's judgement) are eligible to participate if they have previous exposure to this(these) therapy(ies).

Key Exclusion Criteria:

* Prior treatment with any RLT (approved or investigational) is not allowed
* Prior treatment with a protein degrader compound that targets AR is not allowed

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

Arm 1

EXPERIMENTAL

JSB462 100 mg QD + AAA617 7.4 GBq Q6W

  • DRUG:

    JSB462

    Description:

    Administered orally, daily and continuously (100 mg or 300 mg QD) until disease progression per PCWG3-modified RECIST v1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision

  • DRUG:

    AAA617

    Description:

    administered at 7.4 GBq intravenously every 6 weeks for up to 6 doses, unless there is disease progression per PCWG3-modified RECIST v1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision

Arm 2

EXPERIMENTAL

JSB462 300 mg QD + AAA617 7.4 GBq Q6W

  • DRUG:

    JSB462

    Description:

    Administered orally, daily and continuously (100 mg or 300 mg QD) until disease progression per PCWG3-modified RECIST v1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision

  • DRUG:

    AAA617

    Description:

    administered at 7.4 GBq intravenously every 6 weeks for up to 6 doses, unless there is disease progression per PCWG3-modified RECIST v1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision

Arm 3

ACTIVE_COMPARATOR

AAA617 7.4 GBq Q6W

  • DRUG:

    AAA617

    Description:

    administered at 7.4 GBq intravenously every 6 weeks for up to 6 doses, unless there is disease progression per PCWG3-modified RECIST v1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision

Outcome Measures

Primary Outcome Measures

Prostate Specific Antigen 50 (PSA50) Rate

Time Frame: From date of randomization till 30 days safety fup, assessed up to approximately 30 months

Incidence rate of adverse events (AEs)

Time Frame: From date of randomization till 30 days safety fup, assessed up to approximately 30 months

Number of participants with dose adjustments

Time Frame: From date of randomization till 30 days safety fup, assessed up to approximately 30 months

Duration of exposure to study treatment

Time Frame: From date of randomization till 30 days safety fup, assessed up to approximately 30 months

Secondary Outcome Measures

Radiographic Progression Free Survival (rPFS)

Time Frame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 41 months

Overall Survival (OS)

Time Frame: From date of randomization until date of death from any cause, assessed up to approximately 41 months

Incidence rate of adverse events (AEs)

Time Frame: From date of randomization until date of death from any cause, assessed up to approximately 41 months

Overall Response Rate (ORR)

Time Frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 41 months

Disease Control Rate (DCR)

Time Frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 41 months

Duration of Response (DOR)

Time Frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 41 months

Time to Response (TTR)

Time Frame: From date of randomization until date of first documented Complete Response (CR) or Partial Response (PR), assessed up to approximately 41 months

Time to soft tissue progression (TTSTP)

Time Frame: From date of randomization until date of soft tissue radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 41 months

Prostate Specific Antigen 90 (PSA90) Rate

Time Frame: From date of randomization till 30 days safety fup, assessed up to approximately 30 months

Prostate Specific Antigen 30 (PSA30) Rate

Time Frame: From date of randomization till 30 days safety fup, assessed up to approximately 30 months

Prostate Specific Antigen 0 (PSA0) Rate

Time Frame: From date of randomization till 30 days safety fup, assessed up to approximately 30 months

Duration of biochemical response (DBR)

Time Frame: From date of date of first PSA50 response until date of PSA progression or death from any cause, assessed up to approximately 41 months

Time to first symptomatic skeletal event (TTSSE)

Time Frame: From randomization until the first occurrence of a new symptomatic bone fracture, spinal cord compression, tumor-related orthopedic surgery, radiation therapy for bone pain, or death, assessed up to 41 months.

Plasma concentrations of JSB462 and plasma concentrations of its metabolite ARV-767

Time Frame: Day 1 of Cycles 1 and 2: Pre-dose/0hour and Post-dose 4hour +/- 1hour. Day 1 of Cycles 3 to 6: Pre-dose/0hour. End of Treatment Visit (EOT): through study treatment discontinuation, an average of 24 months. 1 cycle = 28 days.

Concentrations of AAA617 in blood over time and PK parameters from blood radioactivity data

Time Frame: Cycle 1: Day 1 (pre-dose/0hour, end of infusion (EOI), 1hour u00b115minutes, 4hours u00b130minutes), Day 2 (24hours u00b12hours), Day 3 (48hours u00b12hours), Day 8 (168hours u00b112hours).Cycles 3 & 5: Day 1 (pre-dose/0hour, EOI), Day 3 (48hours u00b12hours). 1 cycle=6 weeks.

Area under the AAA617 concentration-time curve from time zero to the time of last quantifiable concentration (AUClast)

Time Frame: Cycle 1: Day 1 (pre-dose/0hour, end of infusion (EOI), 1hour u00b115minutes, 4hours u00b130minutes), Day 2 (24hours u00b12hours), Day 3 (48hours u00b12hours), Day 8 (168hours u00b112hours).Cycles 3 & 5: Day 1 (pre-dose/0hour, EOI), Day 3 (48hours u00b12hours). 1 cycle=6 weeks.

Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) of AAA617

Time Frame: Cycle 1: Day 1 (pre-dose/0hour, end of infusion (EOI), 1hour u00b115minutes, 4hours u00b130minutes), Day 2 (24hours u00b12hours), Day 3 (48hours u00b12hours), Day 8 (168hours u00b112hours).Cycles 3 & 5: Day 1 (pre-dose/0hour, EOI), Day 3 (48hours u00b12hours). 1 cycle=6 weeks.

Observed maximum blood concentration (Cmax) of AAA617

Time Frame: Cycle 1: Day 1 (pre-dose/0hour, end of infusion (EOI), 1hour u00b115minutes, 4hours u00b130minutes), Day 2 (24hours u00b12hours), Day 3 (48hours u00b12hours), Day 8 (168hours u00b112hours).Cycles 3 & 5: Day 1 (pre-dose/0hour, EOI), Day 3 (48hours u00b12hours). 1 cycle=6 weeks.

Time of maximum observed blood concentration occurrence (Tmax) of AAA617

Time Frame: Cycle 1: Day 1 (pre-dose/0hour, end of infusion (EOI), 1hour u00b115minutes, 4hours u00b130minutes), Day 2 (24hours u00b12hours), Day 3 (48hours u00b12hours), Day 8 (168hours u00b112hours).Cycles 3 & 5: Day 1 (pre-dose/0hour, EOI), Day 3 (48hours u00b12hours). 1 cycle=6 weeks.

Terminal elimination half-life (T1/2) of AAA617

Time Frame: Cycle 1: Day 1 (pre-dose/0hour, end of infusion (EOI), 1hour u00b115minutes, 4hours u00b130minutes), Day 2 (24hours u00b12hours), Day 3 (48hours u00b12hours), Day 8 (168hours u00b112hours).Cycles 3 & 5: Day 1 (pre-dose/0hour, EOI), Day 3 (48hours u00b12hours). 1 cycle=6 weeks.

Total systemic clearance for intravenous administration (CL) of AAA617

Time Frame: Cycle 1: Day 1 (pre-dose/0hour, end of infusion (EOI), 1hour u00b115minutes, 4hours u00b130minutes), Day 2 (24hours u00b12hours), Day 3 (48hours u00b12hours), Day 8 (168hours u00b112hours).Cycles 3 & 5: Day 1 (pre-dose/0hour, EOI), Day 3 (48hours u00b12hours). 1 cycle=6 weeks.

Volume of distribution during the terminal phase following intravenous elimination (Vz) of AAA617

Time Frame: Cycle 1: Day 1 (pre-dose/0hour, end of infusion (EOI), 1hour u00b115minutes, 4hours u00b130minutes), Day 2 (24hours u00b12hours), Day 3 (48hours u00b12hours), Day 8 (168hours u00b112hours).Cycles 3 & 5: Day 1 (pre-dose/0hour, EOI), Day 3 (48hours u00b12hours). 1 cycle=6 weeks.

Radiation absorbed doses in organs and tumors for AAA617

Time Frame: Cycle 1: Day 1 (1-4 hours), Day 2 (24 hours u00b16 hours), Day 3 (48 hours u00b16 hours), Day 8 (168 hours u00b124 hours). Cycle 3: Day 1 (1-4 hours), Day 3 (48 hours u00b16 hours). Cycle 5b (fit patients): Day 1 (1-4 hours), Day 3 (48 hours u00b16 hours). 1 cycle=6 weeks.

Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Time Frame: From date of randomization until date of death from any cause, assessed up to approximately 41 months

Timeline

  • Last Updated
    August 13, 2025
  • Start Date
    July 2, 2025
  • Today
    October 17, 2025
  • Completion Date ( Estimated )
    December 11, 2028

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