An Open-label Dose Escalation and Expansion, Followed by a Phase II Study of Tulmimetostat (DZR123) and JSB462 (Luxdegalutamide) in Patients With Progressive Metastatic Castrate Resistant Prostate Cancer (mCRPC) (TulmiSTAR-01)

Phase 2RecruitingNCT07206056

Novartis Pharmaceuticals188 enrolled

Overview

This is a two-part, Phase I/II, open-label, global, multicenter study assessing the safety and efficacy of the combination of tulmimetostat (DZR123) and JSB462 (luxdegalutamide) versus standard of care in participants with progressive metastatic castrate resistant prostate cancer (mCRPC).

The Phase 1 study, comprised of Parts 1a and 1b, aims to assess the safety and tolerability of the combination of tulmimetostat and JSB462: 1. Part 1a is the parallel dose escalation that aims to determine the recommended dose(s) of tulmimetostat and JSB462, in combination, for further exploration. 2. Part 1b is the dose expansion/optimization that aims to determine the recommended dose of the combination for Phase II. The purpose of the Phase II study (Part 2) is to compare the combination of tulmimetostat with JSB462 in terms of the biochemical response as assessed by PSA50 compared to the standard of care (SoC) in adult men with progressive, taxane-naive mCRPC.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

188

Conditions

Progressive Metastatic Castrate Resistant Prostate Cancer

Interventions

Tulmimetostat DL1 QDDRUG

Part 1a (dose escalation): Doses of tulmimetostat beyond DL1 once a day (QD) will be opened depending on outcome of Dose Escalation Meetings (DEM(s))

Tulmimetostat DL2 QDDRUG

Part 1a (dose escalation): Doses of tulmimetostat beyond DL1 once a day (QD) will be opened depending on outcome of Dose Escalation Meetings (DEM(s))

Tulmimetostat DL3 QDDRUG

Part 1a (dose escalation): Doses of tulmimetostat beyond DL1 once a day (QD) will be opened depending on outcome of Dose Escalation Meetings (DEM(s))

Tulmimetostat Doses 1 or 2 QDDRUG

Part 1b (dose expansion and optimization): tulmimetostat doses 1 or 2 QD

Tulmimetostat RP2D QDDRUG

Part 2: tulmimetostat Recommended Phase 2 Dose (RP2D) QD

JSB462 Dose 1 QDDRUG

JSB462 Dose 1 QD

JSB462 Dose 2 QDDRUG

JSB462 Dose 2 QD

JSB462 QDDRUG

The dose of JSB462 QD will be determined based on the totality of data from Part 1a

Standard of Care (SoC)DRUG

Androgen Receptor Pathway Inhibitors (ARPI), chemotherapy or Pluvicto (AAA617) at the discretion of the investigator

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * Participant is an adult man ≥ 18 years of age. * Participant must have histologically and/or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell features (current or prior biopsy of the prostate and/or metastatic site). * Participant must have ≥ 1 metastatic lesion that is present on screening/baseline CT, MRI, or bone scan imaging obtained ≤ 28 days prior to start of treatment (Part 1a dose escalation) or randomization (Part 1b dose expansion and Part 2). * Participant must have progressive mCRPC. * Participant must have a castrate level of serum/plasma testosterone (\< 50 ng/dL or \< 1.7 nmol/L). * Prior ARPI therapy: * Part 1a and 1b only: must have progressed on at least one prior second generation ARPI (abiraterone, enzalutamide, darolutamide, or apalutamide). * Part 2 only: must have progressed on one prior second generation ARPI (abiraterone, enzalutamide, darolutamide, or apalutamide). * Prior chemotherapy: * Part 1a dose escalation only: may have received ≤ 2 prior lines of chemotherapy in CRPC setting. Note: Prior chemotherapy is permitted in the HSPC setting. * Part 1b dose expansion/optimization only: may have received up to one prior line of chemotherapy in CRPC setting. Note: Prior chemotherapy is permitted in the HSPC setting. * Part 2 only: Participants must be taxane-naïve in mCRPC setting; prior chemotherapy permitted in HSPC setting only Key Exclusion Criteria: * Previous treatment with any PRC2 inhibitor, including but not limited to EZH2 inhibitors, EZH2/1 inhibitors, or embryonic ectoderm development (EED) inhibitors. * Previous treatment with a protein degrader compound that targets the AR. * Known hypersensitivity or contraindication to any of the study treatment components or its excipients or to drugs of similar chemical classes. * Treatment with any investigational agent within 28 days (or 5 half-lives, whichever is longer) prior to study entry. * Previous treatment with radioligand therapy in the mCRPC setting, except in Part 1a where participants may have received RLT in mCRPC setting. * 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 study entry. * Participants with a history of CNS metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not receiving corticosteroids for the purpose of maintaining neurologic integrity. Those with leptomeningeal disease are eligible if those areas have been treated, are stable, and no neurological impairment is present. For those with parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent radiological imaging must include evaluation of the brain with MRI (preferred) or CT with contrast. Other protocol-defined inclusion/exclusion criteria may apply.

Locations (27)

Sarah Cannon Research Institute

Denver, Colorado, United States

RECRUITING

Sarah Cannon Research Institute

Jacksonville, Florida, United States

RECRUITING

Wichita Urology Group PA

Wichita, Kansas, United States

RECRUITING

Mass General Hospital

Boston, Massachusetts, United States

RECRUITING

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

RECRUITING

Novartis Investigative Site

St Leonards, New South Wales, Australia

RECRUITING

Novartis Investigative Site

Melbourne, Victoria, Australia

RECRUITING

Novartis Investigative Site

Liverpool, Australia

RECRUITING

Novartis Investigative Site

Halifax, Nova Scotia, Canada

RECRUITING

Novartis Investigative Site

Beijing, China

RECRUITING

...and 17 more locations

Outcomes

Primary Outcomes

Part 1a: Dose-limiting toxicities (DLTs)

A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness/injury, or concomitant medications that occurs within the first 28 days of treatment with tulmimetostat and JSB462 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

Part 1a and Part 1b: 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 14 months

Part 1a and Part 1b: 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 14 months

Part 1a and Part 1b: 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 14 months

Part 1a and Part 1b: Duration of exposure to each study drug

The duration of exposure (in months) to Tulmimetostat and JSB462 (Part 1a and Part 1b) will be summarized by means of descriptive statistics

Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 14 months

Part 1b and Part 2: prostate-specific antigen 50 (PSA50) at Month 6

PSA50 is defined as a PSA reduction of at least 50% from baseline at 6 months confirmed by a second PSA measurement ≥ 3 weeks later.

Time frame: Month 6

Secondary Outcomes

Part 1a and Part 1b: Plasma concentrations of tulmimetostat and JSB462

Tulmimetostat and JSB462 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 (predose/0 hour, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours; Tulmimetostat only: 30 minutes and 3 hours). Cycle 1: Day 2 (24 hours), Days 8 and 15 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.

Part 2: Plasma concentrations of tulmimetostat and JSB462

Tulmimetostat and JSB462 pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

Time frame: Cycle 1 and 2: Day 1 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.

Part 1a and Part 1b: AUC of tulmimetostat and JSB462

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) and Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) will be listed and summarized using descriptive statistics.

Part 2: AUC of tulmimetostat and JSB462

Time frame: Cycle 1 and 2: Day 1 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.

Part 1a and Part 1b: Cmax of tulmimetostat and JSB462

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

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

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Part 2: Cmax of tulmimetostat and JSB462

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 and 2: Day 1 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.

Part 1b and Part 2: prostate-specific antigen 50 (PSA50) at 3, 9, and 12 months

PSA50 is defined as a PSA reduction of at least 50% from baseline at 3, 9, and 12 months confirmed by a second PSA measurement ≥ 3 weeks later.

Time frame: Month 3, Month 9, Month 12

Part 1b and Part 2: radiographic progression free survival (rPFS)

rPFS is defined as 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 15 months

Part 1b and Part 2: overall survival (OS)

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 15 months

Part 1b and Part 2: objective response (OR)

OR is defined as a confirmed complete response (CR) or partial response (PR) per PCWG3-modified RECIST 1.1 as assessed by the investigator

Time frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 15 months

Part 1b and Part 2: best overall response (BOR)

BOR is defined as the best response 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 progression or date of death from any cause, whichever come first, assessed up to approximately 15 months

Part 1b and Part 2: duration of response (DOR)

DOR is defined as time between first documented CR/PR and disease progression or death due to any cause per PCWG3-modified RECIST 1.1 as assessed by the investigator

Time frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 15 months

Part 1b and Part 2: time to first symptomatic skeletal event (TTSSE)

TTSSE is defined as 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 15 months.

Part 2: 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 15 months

Part 2: 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 15 months

Part 2: Dose Intensity

Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 15 months

Part 2: Duration of exposure to each study drug

The duration of exposure (in months) to Tulmimetostat and JSB462 / Standard of Care (SoC) of investigator's choice (Part 2) will be summarized within each strata by means of descriptive statistics

Time frame: From date of randomization till 30 days safety fup, assessed up to approximately 15 months