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)
Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)
Investigational drug(s) / intervention(s)
TulmimetostatDarolutamideAbiraterone
Tulmimetostat: Doses of tulmimetostat beyond DL1 once a day (QD) will be opened depending on outcome of Dose Escalation Meetings (DEM(s))
Darolutamide: 600 mg is administered orally BID
Abiraterone: 1000 mg is administered orally QD
Study 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).
Eligibility
Sex
MALE
Min age
18 Years
Max age
—
Healthy 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
Primary outcome measure(s)
Phase I (Group A and Group B): Dose-limiting toxicities (DLTs) — Up to 28 days 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).
Phase I (Group A and Group B): Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) — From date of randomization till 30 days safety fup, assessed up to approximately 79 months The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.
Phase I (Group A and Group B): Number of Participants with dose adjustments — From date of randomization till 30 days safety fup, assessed up to approximately 79 months The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) will be summarized by treatment arm.
Phase I (Group A and Group B): Dose Intensity — From date of randomization till 30 days safety fup, assessed up to approximately 79 months 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
Phase I (Group A and Group B): Duration of exposure to each study drug — From date of randomization till 30 days safety fup, assessed up to approximately 79 months Duration of exposure (in months) to each study drug will be summarized by means of descriptive statistics
Phase II (Group A): Prostate-Specific Antigen (PSA) response rate of < 0.2 ng/mL — From date of randomization till 30 days safety fup, assessed up to approximately 79 months 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.
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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