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)

NCT07190300 | Recruiting Phase 1 FDA Drug

• 3 other identifiers: CDZR123C121012025-521873-15-002025
• Study Type: interventional
• Target: 181
• Locations: 14 countries
• Sites: 31

Brief Summary

The purpose of this study is to evaluate the safety, tolerability, and efficacy of two different treatment combinations of tulmimetostat in participants with de novo or recurrent metastatic hormone-sensitive prostate cancer (mHSPC). Phase I aims to determine the recommended dose(s) for expansion (RDE) of tulmimetostat in combination with darolutamide or abiraterone. Phase II is designed to further evaluate the efficacy and safety of tulmimetostat in combination with darolutamide compared with darolutamide alone in participants with mHSPC.

Conditions

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

Keywords

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC); Enhancer of Zeste Homolog 2 (EZH2); Androgen Receptor (AR); Androgen Receptor Pathway Inhibitors (ARPIs); Prostate-Specific Antigen (PSA); PSA Response Rate; TulmiSTAR-02; Tulmimetostat (DZR123); Darolutamide; Abiraterone

Outcome Measures

Primary Outcomes (6)

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

  A dose-limiting toxicity was defined as an adverse event or abnormal laboratory value that was not clearly attributable to the underlying disease or an extraneous cause, occurred during the first 28 days of treatment with tulmimetostat, and met the protocol-defined dose-limiting toxicity criteria. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dose-limiting toxicities were included in the Bayesian Logistic Regression Model used to support dose-escalation decisions.

  From the first dose of study treatment through the end of Cycle 1, up to 28 days

• Phase I (Group A and Group B): Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)

  The incidence, type, frequency, seriousness, and severity of adverse events and serious adverse events will be summarized. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

  From the first dose of study treatment through the 30-day safety follow-up, assessed up to approximately 79 months

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

  The number of participants with dose reductions, dose interruptions, or permanent discontinuations, including the reasons for the dose adjustments, will be summarized by treatment group and dose cohort.

  From the first dose of study treatment through the 30-day safety follow-up, assessed up to approximately 79 months

• Phase I (Group A and Group B): Dose Intensity

  Dose intensity, calculated as the actual cumulative dose received divided by the actual duration of exposure, and relative dose intensity, calculated as the dose intensity divided by the planned dose intensity, will be summarized using descriptive statistics for each study drug.

  From the first dose of study treatment through the 30-day safety follow-up, assessed up to approximately 79 months

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

  The duration of exposure, in months, to each study drug will be summarized using descriptive statistics by treatment group and dose cohort.

  From the first dose of study treatment through the 30-day safety follow-up, assessed up to approximately 79 months

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

  Prostate-Specific Antigen (PSA) response rate is defined as the proportion of participants who achieved a prostate-specific antigen level below 0.2 ng/mL at Month 6, confirmed by a second prostate-specific antigen assessment performed at least 3 weeks later.

  At Month 6, with confirmation by a second prostate-specific antigen assessment performed at least 3 weeks later

Secondary Outcomes (21)

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

  Cycles 1 and 2, Day 1: 0, 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose; Cycle 1, Day 2: 0 and 24 hours post-dose for tulmimetostat; Cycle 1, Days 8 and 15: 0 and 2 hours post-dose; Cycles 3 to 5, Day 1: pre-dose. Each cycle is 28 days

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

  Cycles 1 and 2, Day 1: 0, 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose; Cycle 1, Day 2: 0 and 24 hours post-dose for tulmimetostat; Cycle 1, Days 8 and 15: 0 and 2 hours post-dose; Cycles 3 to 5, Day 1: pre-dose. Each cycle is 28 days

• Phase I (Group A): Maximum Observed Plasma Concentration (Cmax) of Tulmimetostat and Darolutamide

  Cycles 1 and 2, Day 1: 0, 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose; Cycle 1, Day 2: 0 and 24 hours post-dose for tulmimetostat; Cycle 1, Days 8 and 15: 0 and 2 hours post-dose; Cycles 3 to 5, Day 1: pre-dose. Each cycle is 28 days

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

  Cycles 1 and 2, Day 1: 0, 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose; Day 2: 0 and 24 hours post-dose; Days 8 and 15: 0 and 2 hours post-dose; Cycles 3 to 5, Day 1: pre-dose. Each cycle is 28 days.

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

  Cycles 1 and 2, Day 1: 0, 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose; Day 2: 0 and 24 hours post-dose; Days 8 and 15: 0 and 2 hours post-dose; Cycles 3 to 5, Day 1: pre-dose. Each cycle is 28 days.

Study Arms (5)

Phase I: Group A (part 1)

EXPERIMENTAL

Tulmimetostat administered orally once daily (QD) at escalating dose levels in combination with darolutamide 600 mg orally twice daily (BID). Participants will continue androgen deprivation therapy (ADT) throughout the study.

Drug: Tulmimetostat; Drug: Darolutamide; Drug: Androgen Deprivation Therapy (ADT)

Phase I: Group B (part 2)

EXPERIMENTAL

Tulmimetostat administered orally once daily (QD) at escalating dose levels in combination with abiraterone 1000 mg orally once daily (QD). Participants will continue androgen deprivation therapy (ADT). Abiraterone will be administered with prednisone/prednisolone according to local prescribing information.

Drug: Tulmimetostat; Drug: Abiraterone; Drug: Prednisone/Prednisolone; Drug: Androgen Deprivation Therapy (ADT)

Phase II: Arm 1

EXPERIMENTAL

Tulmimetostat Dose 1 orally once daily (QD) in combination with darolutamide 600 mg orally twice daily (BID). Participants will continue androgen deprivation therapy (ADT).

Drug: Tulmimetostat; Drug: Darolutamide; Drug: Androgen Deprivation Therapy (ADT)

Phase II: Arm 2 (Optional)

EXPERIMENTAL

Tulmimetostat Dose 2 orally once daily (QD) in combination with darolutamide 600 mg orally twice daily (BID). Participants will continue androgen deprivation therapy (ADT). This arm will be included if two recommended dose(s) for expansion are selected from Phase I.

Drug: Tulmimetostat; Drug: Darolutamide; Drug: Androgen Deprivation Therapy (ADT)

Phase II: Arm 3 (Control)

ACTIVE COMPARATOR

Darolutamide 600 mg orally twice daily (BID). Participants will continue androgen deprivation therapy (ADT).

Drug: Darolutamide; Drug: Androgen Deprivation Therapy (ADT)

Interventions

Tulmimetostat DRUG

Tulmimetostat is an oral dual EZH1/EZH2 inhibitor administered once daily. In Phase I, escalating dose levels will be evaluated in combination with darolutamide or abiraterone. In Phase II, one or two dose levels selected from Phase I will be evaluated in combination with darolutamide.

Also known as: DZR123

Phase I: Group A (part 1); Phase I: Group B (part 2); Phase II: Arm 1; Phase II: Arm 2 (Optional)

Darolutamide DRUG

Darolutamide 600 mg administered orally twice daily (BID).

Phase I: Group A (part 1); Phase II: Arm 1; Phase II: Arm 2 (Optional); Phase II: Arm 3 (Control)

Abiraterone DRUG

Abiraterone 1000 mg administered orally once daily (QD) in combination with prednisone/prednisolone according to local prescribing information.

Phase I: Group B (part 2)

Prednisone/Prednisolone DRUG

Oral corticosteroid administered with abiraterone in Phase I Group B according to local prescribing information.

Phase I: Group B (part 2)

Androgen Deprivation Therapy (ADT) DRUG

Background therapy consisting of a gonadotropin-releasing hormone (GnRH) agonist/antagonist or prior orchiectomy to maintain castrate testosterone levels (\<50 ng/dL \[\<1.7 nmol/L\]). All participants will continue ADT throughout study participation.

Phase I: Group A (part 1); Phase I: Group B (part 2); Phase II: Arm 1; Phase II: Arm 2 (Optional); Phase II: Arm 3 (Control)

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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. 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:
• Evidence of insufficient PSA control or suboptimal PSA response, defined as PSA ≥ 0.2 ng/mL after 6-12 months ADT and no more than 4 months of current ARPI therapy in mHSPC with declining or stable PSA trend. Eligibility based on biochemical progression should be supported by objective evidence (e.g. PSA results).

You may not qualify if:

• 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.
• Have a history of a concurrent or second malignancy except for adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 3 years. Participants with a history of leukemia/lymphoma and/or MDS are not eligible.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (31)

Univ of Alabama at Birmingham

Birmingham, Alabama, 35294-3300, United States

RECRUITING

Uni Of Iowa Hospitals And Clinics

Iowa City, Iowa, 52242, United States

RECRUITING

University of Kansas Cancer Center

Westwood, Kansas, 66205, United States

RECRUITING

Wichita Urology Group PA

Wichita, Kansas, 67226, United States

RECRUITING

Duke University Medical Center

Durham, North Carolina, 27710, United States

RECRUITING

Medical University of South Carolina MUSC

Charleston, South Carolina, 29425, United States

RECRUITING

Carolina Urologic Research Center

Myrtle Beach, South Carolina, 29572, United States

RECRUITING

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

RECRUITING

Novartis Investigative Site

Camperdown, New South Wales, 2050, Australia

WITHDRAWN

Novartis Investigative Site

Wollongong, New South Wales, 2500, Australia

RECRUITING

Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, 90610-001, Brazil

RECRUITING

Novartis Investigative Site

Montreal, Quebec, H2X 1R9, Canada

RECRUITING

Novartis Investigative Site

Guangzhou, 510060, China

RECRUITING

Novartis Investigative Site

Créteil, 94010, France

RECRUITING

Novartis Investigative Site

Lille, 59020, France

RECRUITING

Novartis Investigative Site

Nantes, 44093, France

RECRUITING

Novartis Investigative Site

Jena, Thuringia, 07740, Germany

RECRUITING

Novartis Investigative Site

Essen, 45147, Germany

RECRUITING

Novartis Investigative Site

Hong Kong, 999077, Hong Kong

RECRUITING

Novartis Investigative Site

Budapest, 1083, Hungary

RECRUITING

Novartis Investigative Site

Budapest, 1122, Hungary

RECRUITING

Novartis Investigative Site

Szeged, 6725, Hungary

RECRUITING

Novartis Investigative Site

Rozzano, MI, 20089, Italy

RECRUITING

Novartis Investigative Site

Verona, VR, 37134, Italy

RECRUITING

Novartis Investigative Site

Seoul, 05505, South Korea

RECRUITING

Novartis Investigative Site

Seoul, 06591, South Korea

RECRUITING

Novartis Investigative Site

Madrid, 28034, Spain

RECRUITING

Novartis Investigative Site

Madrid, 28040, Spain

RECRUITING

Novartis Investigative Site

Madrid, 28222, Spain

RECRUITING

Novartis Investigative Site

Ankara, Sihhiye Altindag, 06230, Turkey (Türkiye)

RECRUITING

Novartis Investigative Site

London, W1G 6AD, United Kingdom

RECRUITING

MeSH Terms

Conditions

Bulbo-Spinal Atrophy, X-Linked

Interventions

darolutamide; abiraterone; Prednisone; Prednisolone; Androgen Antagonists

Condition Hierarchy (Ancestors)

Muscular Atrophy, Spinal; Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Motor Neuron Disease; Neuromuscular Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienetriols; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Central Study Contacts

Novartis Pharmaceuticals

CONTACT

1-888-669-6682; novartis.email@novartis.com

Novartis Pharmaceuticals

CONTACT

+41613241111; novartis.email@novartis.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Phase I is an open-label, parallel dose-escalation study comprising two treatment groups: Group A (tulmimetostat + darolutamide) and Group B (tulmimetostat + abiraterone). Phase II is a randomized, open-label, multicenter dose-expansion study evaluating one or two dose levels of tulmimetostat in combination with darolutamide versus darolutamide alone.

Study Record Dates

• First Submitted: September 16, 2025
• First Posted: September 24, 2025
• Study Start: January 13, 2026
• Primary Completion (Estimated): August 2, 2032
• Study Completion (Estimated): August 2, 2032
• Last Updated: September 29, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will share

Locations

AU (2); HK (1); KR (2); CA (1); BR (1); CN (1); ES (3); US (8); TU (1); DE (2); IT (2); HU (3); FR (3); GB (1)