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)

Official 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

Overview

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. 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. 2. 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.

Interventions

• Drug Tulmimetostat
  Doses of tulmimetostat beyond DL1 once a day (QD) will be opened depending on outcome of Dose Escalation Meetings (DEM(s))
• Drug Darolutamide
  600 mg is administered orally BID
• Drug Abiraterone
  1000 mg is administered orally QD

Primary outcome measures

• Phase I (Group A and Group B): Dose-limiting toxicities (DLTs) [Time frame: Up to 28 days]
• 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]
• 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]
• 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]
• 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]
• 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]

Secondary outcome measures (12)

• 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]

Eligibility criteria

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.

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 8 centers

• Univ of Alabama at Birmingham — Birmingham
• Uni Of Iowa Hospitals And Clinics — Iowa City
• University of Kansas Cancer Center — Westwood
• Wichita Urology Group PA — Wichita
• Duke University Medical Center — Durham
• Medical University of South Carolina MUSC — Charleston
• Carolina Urologic Research Center — Myrtle Beach
• Huntsman Cancer Institute — Salt Lake City

France · 3 centers

• Novartis Investigative Site — Créteil
• Novartis Investigative Site — Lille
• Novartis Investigative Site — Nantes

Hungary · 3 centers

• Novartis Investigative Site — Budapest
• Novartis Investigative Site — Budapest
• Novartis Investigative Site — Szeged

Spain · 3 centers

• Novartis Investigative Site — Madrid
• Novartis Investigative Site — Madrid
• Novartis Investigative Site — Madrid

Australia · 2 centers

• Novartis Investigative Site — Camperdown
• Novartis Investigative Site — Wollongong

Germany · 2 centers

• Novartis Investigative Site — Jena
• Novartis Investigative Site — Essen

Italy · 2 centers

• Novartis Investigative Site — Rozzano
• Novartis Investigative Site — Verona

South Korea · 2 centers

• Novartis Investigative Site — Seoul
• Novartis Investigative Site — Seoul

Brazil · 1 center

• Novartis Investigative Site — Porto Alegre

Canada · 1 center

• Novartis Investigative Site — Montreal

China · 1 center

• Novartis Investigative Site — Guangzhou

Hong Kong · 1 center

• Novartis Investigative Site — Hong Kong

Turkey (Türkiye) · 1 center

• Novartis Investigative Site — Ankara

United Kingdom · 1 center

• Novartis Investigative Site — London

Identifiers

NCT: NCT07190300 · CDZR123C12101 · 2025-521873-15-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗