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)

Phase 2RecruitingNCT07190300

Novartis Pharmaceuticals155 enrolled

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Interventions

TulmimetostatDRUG

Doses of tulmimetostat beyond DL1 once a day (QD) will be opened depending on outcome of Dose Escalation Meetings (DEM(s))

DarolutamideDRUG

600 mg is administered orally BID

AbirateroneDRUG

abiraterone 1000 mg is administered orally QD

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (10)

Wichita Urology Group PA

Wichita, Kansas, United States

RECRUITING

Carolina Urologic Research Center

Myrtle Beach, South Carolina, United States

RECRUITING

Novartis Investigative Site

Wollongong, New South Wales, Australia

RECRUITING

Novartis Investigative Site

Guangzhou, China

RECRUITING

Novartis Investigative Site

Hong Kong, Hong Kong

RECRUITING

Novartis Investigative Site

Seoul, South Korea

RECRUITING

Novartis Investigative Site

Seoul, South Korea

RECRUITING

Novartis Investigative Site

Majadahonda, Madrid, Spain

RECRUITING

Novartis Investigative Site

Madrid, Spain

RECRUITING

Novartis Investigative Site

Madrid, Spain

RECRUITING

Outcomes

Primary Outcomes

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): Biochemical Response Rate (BCR)

Biochemical Response Rate (BCR) is defined as prostate-specific antigen (PSA) decline to \< 0.2 ng/mL at 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 Outcomes

Phase I (Group A): Plasma concentrations of Tulmimetostat and Darolutamide

Tulmimetostat and Darolutamide pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

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

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) will be listed and summarized using descriptive statistics.

Phase I (Group A): Cmax of Tulmimetostat and Darolutamide

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

Phase I (Group B): Plasma concentrations of Tulmimetostat and Abiraterone

Tulmimetostat and Abiraterone pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

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.

Central Contacts

Novartis Pharmaceuticals

CONTACT

1-888-669-6682 novartis.email@novartis.com

Novartis Pharmaceuticals

CONTACT

+41613241111 novartis.email@novartis.com

Data from ClinicalTrials.gov

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Phase I (Group B): AUC of Tulmimetostat and Abiraterone

Phase I (Group B): Cmax of Tulmimetostat and Abiraterone

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

Phase II (Group A): Radiographic progression free survival (rPFS)

Radiographic progression free survival (rPFS) is defined as the time between randomization and the first occurrence of disease progression as per PCWG3-modified RECIST v1.1 or death due to any cause

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)

Overall survival (OS) is defined as the time between randomization to date of death due to any cause

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)

Objective response (OR) is defined as a confirmed Complete Response (CR) or Partial Response (PR) per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST 1.1 as assessed by the Investigator

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)

Best Overall response (BOR) is defined as the best response per PCWG3-modified RECIST 1.1 as assessed by the Investigator from the start of the treatment until disease progression/recurrence

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)

Duration of response (DOR) defined as time between first documented CR/PR and disease progression per PCWG3-modified RECIST 1.1 as assessed by the Investigator or death due to any cause

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)

Prostate-Specific Antigen 50 (PSA50) is defined as a ≥ 50% decrease in PSA levels from baseline at any timepoint, confirmed by a second PSA measurement ≥ 3 weeks without any PSA progression in between

Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 79 months

Phase II (Group A): Biochemical Response of <0.1 ng/mL

Biochemical Response of \<0.1 ng/mL is defined as PSA level \< 0.1 ng/mL at any timepoint during the trial from randomization

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 to castration-resistant prostate cancer (CRPC) is defined as the time from randomization to the first occurrence of one of the following events: PSA progression, radiological progression by bone lesions, or radiological progression by soft tissue and visceral lesions

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)

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 II (Group A): 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 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

Duration of exposure 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): Plasma concentrations of Tulmimetostat and Darolutamide

In selected number of participants receiving Tulmimetostat and Darolutamide combination therapy in Phase II, or in selected number of participants if only one dose level of Tulmimetostat is evaluated in combination with Darolutamide in Phase II, Tulmimetostat and Darolutamide pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

Phase II (Group A): AUC of Tulmimetostat and Darolutamide

In selected number of participants receiving tulmimetostat and darolutamide combination therapy in Phase II, or in selected number of participants if only one dose level of tulmimetostat is evaluated in combination with darolutamide in Phase II, venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) will be listed and summarized using descriptive statistics.

Phase II (Group A): Cmax of Tulmimetostat and Darolutamide

Phase II (Group A): Plasma concentrations of Tulmimetostat

Tulmimetostat pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

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

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

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 to first symptomatic skeletal event (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

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.

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)

Overview

Conditions

Interventions

Eligibility

Locations (10)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts