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

The primary objective of this study is divided into two phases. In Phase I, the aim is to determine the Recommended Dose(s) for Expansion of tulmimetostat when administered in combination with darolutamide and in combination with abiraterone in patients with metastatic hormone-sensitive prostate cancer. In Phase II, the primary objective is to determine the improvement in biochemical response rate of tulmimetostat in combination with darolutamide compared to darolutamide alone. This evaluation is clinically relevant for establishing optimal dosing regimens and assessing the potential therapeutic benefit of adding tulmimetostat to standard androgen receptor pathway inhibitor therapy in this patient population.

The secondary objectives include:

• Phase I: To characterize the pharmacokinetics of tulmimetostat, darolutamide, and abiraterone in combination therapies.

• Phase II: To assess the efficacy of tulmimetostat at one or more dose levels in combination with darolutamide, compared to darolutamide alone.

• Phase II: To evaluate the safety and tolerability of tulmimetostat at one or more doses in combination with darolutamide compared to darolutamide alone.

• Phase II: To further characterize the pharmacokinetics of tulmimetostat and darolutamide in combination therapy.

• Phase II: To evaluate the time to first symptomatic skeletal event at one or more tulmimetostat doses in combination with darolutamide compared to darolutamide alone.

This clinical trial enrolled a total of **95 participants**, all of whom were **adult men** aged **18 years and older** diagnosed with **metastatic hormone-sensitive prostate cancer**. The study population consisted of patients with either de novo or recurrent disease, excluding those with neuroendocrine or small cell features, and required at least one documented metastatic lesion in bone, soft tissue, visceral regions, or both. Participants were required to have **castrate levels of testosterone** (≤ 50 ng/dL or ≤ 1.7 nM) and an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 to 2, indicating relatively preserved functional capacity. Adequate bone marrow and organ function were mandatory for enrollment. All participants had initiated **androgen deprivation therapy (ADT)** at least one month but no more than 24 months prior to study entry and were required to continue ADT throughout the treatment period. Prior use of taxane-based therapy was permitted, provided participants had not progressed on such treatment, with Phase II limiting enrollment to 25% of participants with prior taxane exposure. Previous treatment with **androgen receptor pathway inhibitors (ARPI)** such as abiraterone, enzalutamide, darolutamide, or apalutamide was allowed under specific conditions, including any duration of prior ARPI use in biochemical recurrence or curative treatment settings, and up to six months of prior ARPI use in metastatic hormone-sensitive prostate cancer for Phase II participants, though those currently receiving darolutamide were excluded. Prior prostate-directed radiation or surgical intervention was permitted, with radiation required to be completed before study entry and surgery at least two weeks prior to enrollment.

This is a two-part clinical trial consisting of a **Phase I dose escalation** study followed by an open-label, **randomized Phase II dose expansion** study. The trial evaluates **tulmimetostat** (DZR123) administered as **film-coated tablets** via the **oral route** in combination with either **darolutamide** or **abiraterone** in patients with **metastatic hormone-sensitive prostate cancer**. The study design incorporates multiple treatment arms to assess safety, tolerability, and efficacy of the investigational medicinal product in combination regimens. **Gonadotropin releasing hormone analogues** and **glucocorticoids** are utilized as auxiliary medicinal products to support the treatment protocol. The trial is classified as a **Category 2** clinical trial and represents an integrated phase 1-2 study design.

The Phase I component aims to determine the **Recommended Dose(s) for Expansion** (RDE) of tulmimetostat when combined with darolutamide and when combined with abiraterone. The primary endpoints for Phase I include assessment of **dose-limiting toxicities** (DLTs) during the first 28 days of combination treatment, evaluation of the type, frequency, and severity of **adverse events** according to **CTCAE version 5.0**, and monitoring of notable values in laboratory parameters, vital signs, and **electrocardiograms**. Tolerability is assessed through documentation of dose interruptions, dose reductions, drug discontinuations, dose intensity, and duration of exposure to study treatment. Secondary endpoints for Phase I include determination of **plasma concentrations** of tulmimetostat, darolutamide, and abiraterone, along with derived **pharmacokinetic parameters** including **area under the curve** (AUC) and **maximum plasma concentration** (Cmax).

The Phase II component is designed to determine the improvement in **biochemical response rate** (BCR) of tulmimetostat in combination with darolutamide compared to darolutamide alone. The primary endpoint for Phase II is defined as BCR, specifically **prostate-specific antigen** (PSA) decline to less than 0.2 ng/mL at 6 months, confirmed by a second PSA measurement at least 3 weeks later. Secondary endpoints for Phase II include **radiographic progression-free survival** (rPFS), **overall survival** (OS), **objective response** (OR), **best overall response** (BOR), **duration of response** (DOR), PSA50 and biochemical response of less than 0.1 ng/mL, and time to **castration-resistant prostate cancer** (CRPC). Additional secondary endpoints encompass safety and tolerability assessments including type, frequency, and severity of treatment-emergent and treatment-related adverse events, plasma concentrations of tulmimetostat and darolutamide, and **time to first symptomatic skeletal event** (TTSSE). 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.

The principal inclusion criteria require adult men aged 18 years or older with de novo or recurrent metastatic hormone-sensitive prostate cancer without neuroendocrine or small cell features, with at least one documented metastatic lesion located in bone, soft tissue/visceral region, or both. Participants must have castrate levels of testosterone, defined as 50 ng/dL or less (1.7 nM or less). An **Eastern Cooperative Oncology Group** (ECOG) **performance status** of 0 to 2 is required along with adequate bone marrow and organ function. Participants must have started **androgen deprivation therapy** (ADT) at least 1 month but no more than 24 months before study entry and be willing to continue ADT during treatment. Prior taxane use for metastatic hormone-sensitive prostate cancer is permitted with specific limitations: participants may have received, but not progressed on, one prior taxane-based therapy, and in Phase II, prior taxane use is limited to 25 percent of participants. Prior use of **androgen receptor pathway inhibitors** (ARPI) including abiraterone, enzalutamide, darolutamide, or apalutamide is allowed in both Phase I and Phase II with specific conditions. Prior ARPI use in biochemical recurrence or curative treatment is allowed for any duration, provided therapy was discontinued and the participant had no evidence of conventional imaging positive metastatic disease at that time. For prior ARPI use in metastatic hormone-sensitive prostate cancer, Phase I allows use for any duration, while Phase II permits prior exposure to ARPI for 6 months or less, with participants currently using darolutamide being ineligible. Prior prostate-directed radiation or surgical intervention is permitted, with radiation required to be completed before study entry and surgery completed at least 2 weeks prior.

The estimated recruitment start date for the trial is February 26, 2026, with an estimated end date of May 14, 2032, indicating an overall trial duration of approximately 6 years. The duration of individual participant involvement will vary depending on treatment response, tolerability, and disease progression. Participants may be withdrawn from the study based on conditions including disease progression, unacceptable toxicity, dose-limiting toxicities requiring discontinuation, participant withdrawal of consent, or investigator decision based on safety or medical considerations.

The experimental medicinal product tulmimetostat (also known as CPI-0209 or DZR123) is administered as a film-coated tablet via the oral route. Tulmimetostat is a chemical substance with the systematic chemical name (2R)-7-chloro-2-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]-2,4-dimethyl-N-{[6-methyl-4-(methylsulfanyl)-2-oxo-1,2-dihydropyridin-3-yl]methyl}-2H-1,3-benzodioxole-5-carboxamide. The product is supplied by Novartis Pharma AG. In the Phase I portion of the trial, the study aims to determine the Recommended Dose for Expansion of tulmimetostat when administered in combination with darolutamide and when administered in combination with abiraterone. In the Phase II portion, tulmimetostat is evaluated in combination with darolutamide.

Darolutamide is utilized as both a test and comparator medicinal product in this trial. Darolutamide is supplied as a film-coated tablet administered via the oral route. The product is a chemical substance that will be relabeled as it is supplied via Fisher. In the Phase I portion, darolutamide is administered in combination with tulmimetostat to establish the recommended dosing regimen. In the Phase II portion, darolutamide serves as both a combination partner with tulmimetostat in one treatment arm and as a monotherapy comparator in the control arm.

Abiraterone is employed as a test medicinal product in combination with tulmimetostat during the Phase I portion of the trial. Abiraterone is available in two pharmaceutical forms: film-coated tablet and tablet, both administered via the oral route. This chemical substance will be relabeled as it is supplied via Fisher. The combination of abiraterone with tulmimetostat is evaluated during the dose escalation phase to determine the Recommended Dose for Expansion.

Glucocorticoids (ATC code H02AB) are utilized as auxiliary medicinal products in this trial. These products are administered via the oral route. The glucocorticoids will be relabeled as they are supplied via Fisher. These products represent a therapeutic class rather than a single specific substance.

Gonadotropin releasing hormone analogues (ATC code L02AE) serve as auxiliary medicinal products in the trial. These products undergo relabeling and are included as part of the treatment regimen. Due to the diversity of the ATC level selected, the specific medicinal product characteristics vary within this therapeutic class.

Efficacy will be assessed through distinct endpoints for each phase of the trial. In Phase I, efficacy evaluation focuses on safety and tolerability, with primary endpoints including dose-limiting toxicities during the first 28 days of combination treatment, type, frequency, and severity of adverse events per Common Terminology Criteria for Adverse Events version 5.0, and notable values in laboratory parameters, vital signs, and electrocardiograms. Tolerability will be measured through dose interruptions, dose reductions, drug discontinuations, dose intensity, and duration of exposure to study treatment. In Phase II, the primary efficacy endpoint is biochemical response rate defined as prostate-specific antigen decline to less than 0.2 ng/mL at 6 months, confirmed by a second prostate-specific antigen measurement at least 3 weeks later.

Secondary efficacy endpoints in Phase II include radiographic progression-free survival, overall survival, objective response, best overall response, duration of response, prostate-specific antigen decline of 50 percent or more, biochemical response of less than 0.1 ng/mL, and time to castration-resistant prostate cancer. Additional secondary endpoints assess time to first symptomatic skeletal event, 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. Phase I secondary endpoints include plasma concentrations of tulmimetostat, darolutamide, and abiraterone, and derived pharmacokinetic parameters including area under the curve and maximum plasma concentration. Phase II also includes assessment of plasma concentrations of tulmimetostat and darolutamide as secondary endpoints.