An Open-label Dose Escalation and Expansion, Followed by a Phase II Study of Tulmimetostat (DZR123) and JSB462 (Luxdegalutamide) in Patients With Progressive Metastatic Castrate Resistant Prostate Cancer (mCRPC) (TulmiSTAR-01)

Official title

TulmiSTAR-01: A Two-part, Phase I Dose Escalation and Expansion Followed by a Randomized, Open-label Multicenter, Phase II Study to Assess the Safety and Efficacy of the Combination of Tulmimetostat (DZR123) and JSB462 (Luxdegalutamide) vs Standard of Care in Patients With Progressive Metastatic Castrate Resistant Prostate Cancer

Overview

This is a two-part, Phase I/II, open-label, global, multicenter study assessing the safety and efficacy of the combination of tulmimetostat (DZR123) and JSB462 (luxdegalutamide) versus standard of care in participants with progressive metastatic castrate resistant prostate cancer (mCRPC).

Detailed description

The Phase 1 study, comprised of Parts 1a and 1b, aims to assess the safety and tolerability of the combination of tulmimetostat and JSB462:

1. Part 1a is the parallel dose escalation that aims to determine the recommended dose(s) of tulmimetostat and JSB462, in combination, for further exploration. 2. Part 1b is the dose expansion/optimization that aims to determine the recommended dose of the combination for Phase II.

The purpose of the Phase II study (Part 2) is to compare the combination of tulmimetostat with JSB462 in terms of the biochemical response as assessed by PSA50 compared to the standard of care (SoC) in adult men with progressive, taxane-naive mCRPC.

Interventions

• Drug Tulmimetostat DL1 QD
  Part 1a (dose escalation): Doses of tulmimetostat beyond DL1 once a day (QD) will be opened depending on outcome of Dose Escalation Meetings (DEM(s))
• Drug Tulmimetostat DL2 QD
  Part 1a (dose escalation): Doses of tulmimetostat beyond DL1 once a day (QD) will be opened depending on outcome of Dose Escalation Meetings (DEM(s))
• Drug Tulmimetostat DL3 QD
  Part 1a (dose escalation): Doses of tulmimetostat beyond DL1 once a day (QD) will be opened depending on outcome of Dose Escalation Meetings (DEM(s))
• Drug Tulmimetostat Doses 1 or 2 QD
  Part 1b (dose expansion and optimization): tulmimetostat doses 1 or 2 QD
• Drug Tulmimetostat RP2D QD
  Part 2: tulmimetostat Recommended Phase 2 Dose (RP2D) QD
• Drug JSB462 Dose 1 QD
  JSB462 Dose 1 QD
• Drug JSB462 Dose 2 QD
  JSB462 Dose 2 QD
• Drug JSB462 QD
  The dose of JSB462 QD will be determined based on the totality of data from Part 1a
• Drug Standard of Care (SoC)
  Androgen Receptor Pathway Inhibitors (ARPI), chemotherapy or Pluvicto (AAA617) at the discretion of the investigator

Primary outcome measures

• Part 1a: Dose-limiting toxicities (DLTs) [Time frame: Up to 28 days]
• Part 1a and Part 1b: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 14 months]
• Part 1a and Part 1b: Number of Participants with dose adjustments [Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 14 months]
• Part 1a and Part 1b: Dose Intensity [Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 14 months]
• Part 1a and Part 1b: Duration of exposure to each study drug [Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 14 months]
• Part 1b and Part 2: prostate-specific antigen 50 (PSA50) at Month 6 [Time frame: Month 6]

Secondary outcome measures (12)

• Part 1a and Part 1b: Plasma concentrations of tulmimetostat and JSB462 [Time frame: Cycle 1-2: Day 1 (predose/0 hour, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours; Tulmimetostat only: 30 minutes and 3 hours). Cycle 1: Day 2 (24 hours), Days 8 and 15 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.]
• Part 2: Plasma concentrations of tulmimetostat and JSB462 [Time frame: Cycle 1 and 2: Day 1 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.]
• Part 1a and Part 1b: AUC of tulmimetostat and JSB462 [Time frame: Cycle 1-2: Day 1 (predose/0 hour, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours; Tulmimetostat only: 30 minutes and 3 hours). Cycle 1: Day 2 (24 hours), Days 8 and 15 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.]
• Part 2: AUC of tulmimetostat and JSB462 [Time frame: Cycle 1 and 2: Day 1 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.]
• Part 1a and Part 1b: Cmax of tulmimetostat and JSB462 [Time frame: Cycle 1-2: Day 1 (predose/0 hour, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours; Tulmimetostat only: 30 minutes and 3 hours). Cycle 1: Day 2 (24 hours), Days 8 and 15 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.]
• Part 2: Cmax of tulmimetostat and JSB462 [Time frame: Cycle 1 and 2: Day 1 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.]
• Part 1b and Part 2: prostate-specific antigen 50 (PSA50) at 3, 9, and 12 months [Time frame: Month 3, Month 9, Month 12]
• Part 1b and Part 2: 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 15 months]
• Part 1b and Part 2: overall survival (OS) [Time frame: From date of randomization until date of death from any cause, assessed up to approximately 15 months]
• Part 1b and Part 2: objective response (OR) [Time frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 15 months]
• Part 1b and Part 2: best overall response (BOR) [Time frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 15 months]
• Part 1b and Part 2: 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 15 months]

Eligibility criteria

Inclusion criteria

• Participant is an adult man ≥ 18 years of age.
• Participant must have histologically and/or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell features (current or prior biopsy of the prostate and/or metastatic site).
• Participant must have ≥ 1 metastatic lesion that is present on screening/baseline CT, MRI, or bone scan imaging obtained ≤ 28 days prior to start of treatment (Part 1a dose escalation) or randomization (Part 1b dose expansion and Part 2).
• Participant must have progressive mCRPC.
• Participant must have a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L).
• Prior ARPI therapy:

• Part 1a and 1b only: must have progressed on at least one prior second generation ARPI (abiraterone, enzalutamide, darolutamide, or apalutamide).
• Part 2 only: must have progressed on one prior second generation ARPI (abiraterone, enzalutamide, darolutamide, or apalutamide).
• Prior chemotherapy:

• Part 1a dose escalation only: may have received ≤ 2 prior lines of chemotherapy in CRPC setting. Note: Prior chemotherapy is permitted in the HSPC setting.
• Part 1b dose expansion/optimization only: may have received up to one prior line of chemotherapy in CRPC setting. Note: Prior chemotherapy is permitted in the HSPC setting.
• Part 2 only: Participants must be taxane-naïve in mCRPC setting; prior chemotherapy permitted in HSPC setting only

Exclusion criteria

• Previous treatment with any PRC2 inhibitor, including but not limited to EZH2 inhibitors, EZH2/1 inhibitors, or embryonic ectoderm development (EED) inhibitors.
• Previous treatment with a protein degrader compound that targets the AR.
• Known hypersensitivity or contraindication to any of the study treatment components or its excipients or to drugs of similar chemical classes.
• Treatment with any investigational agent within 28 days (or 5 half-lives, whichever is longer) prior to study entry.
• Previous treatment with radioligand therapy in the mCRPC setting, except in Part 1a where participants may have received RLT in mCRPC setting.
• Participants with evidence of mCRPC or biochemical recurrence / PSA only disease or asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy and with normal PSA for ≥ 1 year prior to study entry.
• Participants with a history of CNS metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not receiving corticosteroids for the purpose of maintaining neurologic integrity. Those with leptomeningeal disease are eligible if those areas have been treated, are stable, and no neurological impairment is present. For those with parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent radiological imaging must include evaluation of the brain with MRI (preferred) or CT with contrast.

Other protocol-defined inclusion/exclusion criteria may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 7 centers

• Sarah Cannon Research Institute — Denver
• Sarah Cannon Research Institute — Jacksonville
• Emory University — Atlanta
• Wichita Urology Group PA — Wichita
• Mass General Hospital — Boston
• Cleveland Clinic Foundation — Cleveland
• Fred Hutchinson Cancer Research Center — Seattle

Spain · 4 centers

• Novartis Investigative Site — Santiago Compostela
• Novartis Investigative Site — L'Hospitalet de Llobregat
• Novartis Investigative Site — Madrid
• Novartis Investigative Site — Madrid

Australia · 3 centers

• Novartis Investigative Site — St Leonards
• Novartis Investigative Site — Melbourne
• Novartis Investigative Site — Liverpool

Denmark · 3 centers

• Novartis Investigative Site — Herlev
• Novartis Investigative Site — Odense C
• Novartis Investigative Site — Vejle

France · 3 centers

• Novartis Investigative Site — Bordeaux
• Novartis Investigative Site — Paris
• Novartis Investigative Site — Paris

Italy · 3 centers

• Novartis Investigative Site — Milan
• Novartis Investigative Site — Padova
• Novartis Investigative Site — Orbassano

Singapore · 2 centers

• Novartis Investigative Site — Singapore
• Novartis Investigative Site — Singapore

United Kingdom · 2 centers

• Novartis Investigative Site — Sutton
• Novartis Investigative Site — London

Canada · 1 center

• Novartis Investigative Site — Halifax

China · 1 center

• Novartis Investigative Site — Beijing

Germany · 1 center

• Novartis Investigative Site — Düsseldorf

Malaysia · 1 center

• Novartis Investigative Site — Kuching

Mexico · 1 center

• Novartis Investigative Site — Tlalpan

Poland · 1 center

• Novartis Investigative Site — Poznan

Identifiers

NCT: NCT07206056 · CDZR123A12107 · 2025-521880-10-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗