RecruitingInterventionalPhase 1/Phase 2

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

NCT ID: NCT07190300Sponsor: Novartis PharmaceuticalsLast updated: 2026-06-09

Summary

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).

Detailed description

The study consists of two phases: 1. 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 the groups. Participants in both Group A and Group B will continue androgen deprivation therapy (ADT) to maintain castrate testosterone levels (\< 50 ng/dL or \< 1.7 nmol/L), with the ADT modality determined by the investigator based on local guidelines. In Group B, abiraterone will be co-administered with an oral corticosteroid (prednisone or prednisolone) as per local prescribing information. 2. The Phase II part is a randomized, open-label, multicenter dose-expansion study designed to further evaluate the recommended dose(s) of tulmimetostat in combination with darolutamide and provide proof-of-concept for its efficacy and safety. Participants in Phase II will be randomized to receive either tulmimetostat plus darolutamide or darolutamide alone. Eligible participants include those with de novo or recurrent mHSPC who have not previously received prior radioligand therapy but may have prior exposure to taxane-based chemotherapy and/or androgen receptor pathway inhibitors (ARPI, excluding darolutamide). This study aims to explore tulmimetostat-based combinations as potential therapeutic 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.

Arms & interventions

DrugTulmimetostat
Doses of tulmimetostat beyond DL1 once a day (QD) will be opened depending on outcome of Dose Escalation Meetings (DEM(s))
DrugDarolutamide
600 mg is administered orally BID
DrugAbiraterone
1000 mg is administered orally QD

Outcome measures

Primary

Phase I (Group A and Group B): Dose-limiting toxicities (DLTs)
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).
Time frame: Up to 28 days
Phase I (Group A and Group B): Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.
Time frame: From date of randomization till 30 days safety fup, 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 adjustments (reductions, interruption, or permanent discontinuation) will be summarized by treatment arm.
Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months
Phase I (Group A and Group B): Dose Intensity
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
Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months
Phase I (Group A and Group B): Duration of exposure to each study drug
Duration of exposure (in months) to each study drug will be summarized by means of descriptive statistics
Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months
Phase II (Group A): Prostate-Specific Antigen (PSA) response rate of < 0.2 ng/mL
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.
Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months

Secondary

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.
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.
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.
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.
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.
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.
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
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
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
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
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
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
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
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
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
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
Phase II (Group A): Dose Intensity
Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months
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
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.
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.
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.
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.
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.
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.
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.

Eligibility criteria

Sex: MaleAge: 18 Years and olderHealthy volunteers: No

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: 1. 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 2. 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