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NCT Number: NCT07190300

TulmiSTAR-02: A Phase I/II Open-label Study of Tulmimetostat in Combination With Darolutamide vs. Darolutamide, and Tulmimetostat With Abiraterone in Patients With Metastatic Hormone-sensitive Prostate Cancer (mHSPC)

The purpose of the study is to evaluate the safety, tolerability, and efficacy of the two different treatment combinations of tulmimetostat in participants with de novo or recurrent Metastatic Hormone-Sensitive Prostate Cancer (mHSPC).

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Key information

Conditions

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) Bulbo-Spinal Atrophy, X-Linked Central Nervous System Diseases Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Genetic Diseases, X-Linked Heredodegenerative Disorders, Nervous System Motor Neuron Disease Muscular Atrophy, Spinal Nervous System Diseases Neurodegenerative Diseases Neuromuscular Diseases Spinal Cord Diseases

Age range

18 year and older

Sex eligibility

Male

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Novartis Investigative Site, Camperdown, New South Wales, Australia

Loading trial locations.

About this study

The study consists of two phases:

  • Phase I:

The Phase I part includes two groups: Part 1 will assess the combination of tulmimetostat with darolutamide (Group A), and Part 2 will assess tulmimetostat with abiraterone (Group B). The primary objective of Phase I is to determine the recommended dose escalations (RDEs) for each combination, with enrollment using a staggered approach between groups.

Participants in both groups will continue androgen deprivation therapy (ADT) to maintain castrate testosterone levels (<50 ng/dL or <1.7 nmol/L), as determined by the investigator based on local guidelines. In Group B, abiraterone will be administered with an oral corticosteroid (prednisone or prednisolone) per local prescribing information.

  • Phase II:

Phase II is a randomized, open-label, multicenter dose-expansion study to further evaluate the recommended dose(s) of tulmimetostat in combination with darolutamide and provide proof-of-concept for efficacy and safety. Participants will be randomized to receive tulmimetostat plus darolutamide or darolutamide alone.

Eligible participants include those with metastatic hormone-sensitive prostate cancer (mHSPC) who are either de novo or recurrent, without prior radioligand therapy, but who may have received prior taxane-based chemotherapy and/or androgen receptor pathway inhibitors (ARPIs), excluding darolutamide. The study evaluates tulmimetostat-based combinations as potential treatment options for men with mHSPC.

The study for each participant consists of a screening period, a study treatment period followed by a post treatment long-term follow-up.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Key Inclusion Criteria:

  • Adult men ≥ 18 years old with de novo or recurrent mHSPC (without neuroendocrine or small cell features). The tumor lesion(s) may be located in the bone, soft tissue/visceral region, or both.
  • Participants must have castrate levels of testosterone, i.e., ≤ 50 ng/dL (≤ 1.7 nM).
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
  • Adequate bone marrow and organ function
  • Prior ADT: Participants must have started ADT at least 1 month (at least 28 days) but no more than 12 months before study entry and be willing to continue ADT during treatment
  • Prior taxane use for mHSPC is permitted:

~ Phase I and II: Participants may have received, but not progressed on, one prior taxane-based therapy. Phase II: Limited to 25% participants with prior taxane use.

  • Prior ARPI is allowed in both Phase I and Phase II:
  • Prior ARPI use in biochemical recurrence (BCR) or curative treatment is allowed for any duration, provided therapy was discontinued and participant had no evidence of conventional imaging positive metastatic disease at that time
  • Prior ARPI use in mHSPC is permitted but not mandated. - If participants meet all study eligibility criteria, they are required to stop their prior ARPI after providing informed consent and remain off ARPI until Cycle 1 Day 1, when study treatment is initiated.
  • Phase I: Allowed for any duration.
  • Phase II: Allowed prior exposure to ARPI is ≤4 months.
  • Phase II: Participants with ongoing use of darolutamide are not eligible. Participants with ongoing ARPI are eligible for a switch from their ongoing ARPI therapy if they have not progressed to CRPC disease, and meet any of the criteria, indicative of suboptimal biochemical response, or intolerability, as assessed by the Investigator.
  • Other permitted prior local therapy for mHSPC:
  • Phase I and II: Prior prostate-directed radiation or surgical intervention. Radiation must be completed before study entry; surgery at least 2 weeks prior.

Key Exclusion Criteria:

  • 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 the start of study treatment.
  • Participants who have not received ARPI treatment for mHSPC and present with PSA levels of ≤0.5 ng/mL or those with prior/ongoing ARPI treatment presenting with PSA levels of ≤ 0.2 ng/mL prior to treatment assignment/randomization.
  • Participants with CNS metastases are excluded unless:
  • they have received prior therapy (e.g. surgery, radiotherapy, gamma knife), are neurologically stable and asymptomatic.
  • they are not receiving corticosteroid for the purpose of maintaining neurologic integrity and have baseline and subsequent radiological imaging of the brain.
  • Concurrent use of first-generation anti-androgens (like bicalutamide). Prior use of a first-generation anti-androgen drug in the context of ADT initiation with a GNRH analog is allowed, provided it was administered for ≤14 days and the last dose was administered ≥7 days from the study entry.
  • Systemic ketoconazole is used as antineoplastic treatment for prostate cancer.
  • Previous exposure to radioligand therapy.
  • Treatment with any investigational agent within 28 days (or 5 half-lives, whichever is longer) prior to study entry.
  • Previous treatment with any Polycomb Repressive Complex 2 (PRC2) inhibitor, including but not limited to Enhancer of Zeste Homolog 2 (EZH2) inhibitors, EZH2/1 inhibitors, or embryonic ectoderm development (EED) inhibitors.
  • Herbal products that may decrease PSA levels within 4 weeks prior to the start of study drug treatment and while on study.
  • Participants taking prohibited medication(s) (e.g., strong CYP3A4 inducers or strong or moderate CYP3A4 inhibitors that cannot be stopped within 7 days or 5 half-lives (whichever is longer) prior to study treatment and for the duration of the study treatment or prohibited herbal product(s) that cannot be stopped 7 days prior to study treatment.

Other inclusion/exclusion criteria may apply

Treatment and study plan

Tulmimetostat

Drug

Doses of tulmimetostat beyond DL1 once a day (QD) will be opened depending on outcome of Dose Escalation Meetings (DEM(s))

Other names: DZR123

Darolutamide

Drug

600 mg is administered orally BID

Abiraterone

Drug

1000 mg is administered orally QD

Primary outcomes

  1. Phase I (Group A and Group B): Dose-limiting toxicities (DLTs)

    Time frame: Up to 28 days

    A dose-limiting toxicity is defined as an adverse event or abnormal laboratory value, not clearly due to underlying disease or extraneous causes, that occurs within the first 28 days of treatment with tulmimetostat 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. For the purpose of dose-escalation decisions, DLTs will be considered and included in the Bayesian Logistic Regression Model (BLRM).

  2. Phase I (Group A and Group B): 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 79 months

    The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.

  3. Phase I (Group A and Group B): Number of Participants with dose adjustments

    Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months

    The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) will be summarized by treatment arm.

  4. Phase I (Group A and Group B): Dose Intensity

    Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months

    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) will be summarized by means of descriptive statistics

  5. Phase I (Group A and Group B): Duration of exposure to each study drug

    Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months

    Duration of exposure (in months) to each study drug will be summarized by means of descriptive statistics

  6. Phase II (Group A): Prostate-Specific Antigen (PSA) response rate of < 0.2 ng/mL

    Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months

    Prostate-Specific Antigen (PSA) response rate is defined as proportion of participants who achieved a decline in PSA to < 0.2 ng/mL at month 6 months, confirmed by a second PSA measurement ≥ 3 weeks later.

Secondary outcomes

  1. Phase I (Group A): Plasma concentrations of Tulmimetostat and Darolutamide

    Time frame: Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    Tulmimetostat and Darolutamide pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

  2. Phase I (Group A): AUC of Tulmimetostat and Darolutamide

    Time frame: Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) will be listed and summarized using descriptive statistics.

  3. Phase I (Group A): Cmax of Tulmimetostat and Darolutamide

    Time frame: Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

  4. Phase I (Group B): Plasma concentrations of Tulmimetostat and Abiraterone

    Time frame: Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours), Day 2 (0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    Tulmimetostat and Abiraterone pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

  5. Phase I (Group B): AUC of Tulmimetostat and Abiraterone

    Time frame: Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours), Day 2 (0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) will be listed and summarized using descriptive statistics.

  6. Phase I (Group B): Cmax of Tulmimetostat and Abiraterone

    Time frame: Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours), Day 2 (0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

  7. Phase II (Group A): 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 79 months

    Radiographic progression free survival (rPFS) is defined as the time between randomization and the first occurrence of disease progression as per PCWG3-modified RECIST v1.1 or death due to any cause

  8. Phase II (Group A):Overall survival (OS)

    Time frame: From date of randomization until date of death from any cause, assessed up to approximately 79 months

    Overall survival (OS) is defined as the time between randomization to date of death due to any cause

  9. Phase II (Group A): Objective response (OR)

    Time frame: From date of randomization until date of confirmed Complete Response (CR) or Partial Response (PR), assessed up to approximately 79 months

    Objective response (OR) is defined as a confirmed Complete Response (CR) or Partial Response (PR) per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST 1.1 as assessed by the Investigator

  10. Phase II (Group A): 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 79 months

    Best Overall response (BOR) is defined as the best response per PCWG3-modified RECIST 1.1 as assessed by the Investigator from the start of the treatment until disease progression/recurrence

  11. Phase II (Group A): 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 79 months

    Duration of response (DOR) defined as time between first documented CR/PR and disease progression per PCWG3-modified RECIST 1.1 as assessed by the Investigator or death due to any cause

  12. Phase II (Group A): Prostate-Specific Antigen 50 (PSA50)

    Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months

    Prostate-Specific Antigen 50 (PSA50) is defined as a ≥ 50% decrease in PSA levels from baseline at any timepoint, confirmed by a second PSA measurement ≥ 3 weeks without any PSA progression in between

  13. Phase II (Group A): Prostate-Specific Antigen (PSA) Response of <0.1 ng/mL

    Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months

    Prostate-Specific Antigen (PSA) Response of <0.1 ng/mL is defined as PSA level < 0.1 ng/mL at any timepoint during the trial from randomization

  14. Phase II (Group A): Time to castration-resistant prostate cancer (CRPC)

    Time frame: From date of randomization until date of PSA progression, radiological progression by bone lesions, or radiological progression by soft tissue and visceral lesions, whichever comes first, assessed up to approximately 79 months

    Time to castration-resistant prostate cancer (CRPC) is defined as the time from randomization to the first occurrence of one of the following events: PSA progression, radiological progression by bone lesions, or radiological progression by soft tissue and visceral lesions

  15. Phase II (Group A): 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 79 months

    The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.

  16. Phase II (Group A): Number of Participants with dose adjustments

    Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months

    The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) will be summarized by treatment arm.

  17. Phase II (Group A): Dose Intensity

    Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months

    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) will be summarized by means of descriptive statistics

  18. Phase II (Group A): Duration of exposure to each study drug

    Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months

    Duration of exposure to each study drug will be summarized by means of descriptive statistics

  19. Phase II (Group A): Plasma concentrations of Tulmimetostat and Darolutamide

    Time frame: Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    In selected number of participants receiving Tulmimetostat and Darolutamide combination therapy in Phase II, or in selected number of participants if only one dose level of Tulmimetostat is evaluated in combination with Darolutamide in Phase II, Tulmimetostat and Darolutamide pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

  20. Phase II (Group A): AUC of Tulmimetostat and Darolutamide

    Time frame: Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    In selected number of participants receiving tulmimetostat and darolutamide combination therapy in Phase II, or in selected number of participants if only one dose level of tulmimetostat is evaluated in combination with darolutamide in Phase II, venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) will be listed and summarized using descriptive statistics.

  21. Phase II (Group A): Cmax of Tulmimetostat and Darolutamide

    Time frame: Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    In selected number of participants receiving tulmimetostat and darolutamide combination therapy in Phase II, or in selected number of participants if only one dose level of tulmimetostat is evaluated in combination with darolutamide in Phase II, venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

  22. Phase II (Group A): Plasma concentrations of Tulmimetostat

    Time frame: Cycle 1-2: Day 1 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    Tulmimetostat pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

  23. Phase II (Group A): AUC of Tulmimetostat

    Time frame: Cycle 1-2: Day 1 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) will be listed and summarized using descriptive statistics.

  24. Phase II (Group A): Cmax of Tulmimetostat

    Time frame: Cycle 1-2: Day 1 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

  25. Phase II (Group A): 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 79 months.

    Time to first symptomatic skeletal event (TTSSE) is defined as the time from randomization to the first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first

Study contacts

Contact information is provided by the study sponsor or research team.

Novartis Pharmaceuticals

CONTACT

[email protected]

1-888-669-6682

Novartis Pharmaceuticals

CONTACT

[email protected]

+41613241111

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Registry information

Official study title

TulmiSTAR-02: A Two-part Phase I Dose Escalation Study of Tulmimetostat (DZR123) in Combination With Darolutamide or Abiraterone Followed by Open-label, Randomized, Phase II Dose Expansion Study to Assess the Safety and Efficacy of Tulmimetostat in Combination With Darolutamide Versus Darolutamide Alone in Patients With Metastatic Hormone-sensitive Prostate Cancer

Acronym: TulmiSTAR-02

Important dates

Study start
2026
Primary completion
2032
Study completion
2032
First posted
Sep 24, 2025
Registry last updated
Jun 23, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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