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)

Novartis

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

Treatments: Drug: Abiraterone; Drug: Tulmimetostat; Drug: Darolutamide

Study type: Interventional

Funder types: Industry

Identifiers

NCT07190300

2025-521873-15-00 (Registry Identifier)

CDZR123C12101

Details and patient eligibility

About

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).

Full 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.

Enrollment: 181 estimated patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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 but no more than 24 months before study entry and be willing to continue ADT during treatment

• Prior taxane use for mHSPC:

  ~ 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 (abiraterone, enzalutamide, darolutamide, or apalutamide) 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

     • Phase I: Allowed for any duration.
     • Phase II: Allowed prior exposure to ARPI is ≤6 months. Participants with ongoing use of darolutamide are not eligible.

     Note: Participants are required to stop their prior ARPI after providing their consent to join this study. 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 with PSA levels of ≤ 0.2 ng/mL at the start of study treatment.

• 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.
  • Participants with epidural disease, canal disease, or prior spinal cord involvement are excluded unless these areas have been treated, are stable, and the participant is not neurologically impaired.

• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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181 participants in 5 patient groups

Phase I: Group A (part 1)

Experimental group

Description:

Tulmimetostat oral (PO) once a day (QD) escalating doses + Darolutamide 600 mg twice a day (BID)

Treatment:

Drug: Darolutamide

Drug: Tulmimetostat

Phase I: Group B (part 2)

Experimental group

Description:

Tulmimetostat PO QD escalating doses + Abiraterone 1000 mg PO QD

Treatment:

Drug: Tulmimetostat

Drug: Abiraterone

Phase II: Arm 1

Experimental group

Description:

Tulmimetostat dose 1 PO + Darolutamide 600 mg PO BID

Treatment:

Drug: Darolutamide

Drug: Tulmimetostat

Phase II: Arm 2

Experimental group

Description:

Tulmimetostat dose 2 PO + Darolutamide 600 mg PO BID

Treatment:

Drug: Darolutamide

Drug: Tulmimetostat

Phase II: Arm 3

Active Comparator group

Description:

Darolutamide 600 mg PO BID

Treatment:

Drug: Darolutamide