TulmiSTAR-01: A phase I/II dose optimization study of tulmimetostat in combination with luxdegalutamide versus standard of care (SOC) in patients (pts) with progressive metastatic castrate-resistant prostate cancer (mCRPC).

Abstract

TPS301 Background: Prostate cancer is the second leading cause of cancer death in men, and mCRPC remains difficult to treat due to acquired resistance to androgen receptor pathway inhibitors (ARPIs). Preclinical studies implicate enhancer of zeste homolog 2 (EZH2) in mediating resistance to ARPIs. Combining AR directed treatment with EZH2 inhibition could potentially overcome resistance. Tulmimetostat is an investigational, novel, oral, next-generation dual inhibitor of EZH2/EZH1. Luxdegalutamide is a proteolysis targeting chimera (PROTAC) AR degrader, demonstrated preliminary evidence of clinical activity. This phase I/II study evaluates the combination of tulmimetostat and luxdegalutamide in pts with progressive mCRPC (NCT07206056). Methods: This two-part, multicenter, open-label, global, phase I/II study will enroll ~188 male pts (≥18 years) with ECOG performance status 0-2, and life expectancy ≥6 months. Study details are described in the table below. In the phase I, pts may have received prior chemotherapy (CT) in the mCRPC setting, while in phase II, pts must be taxane-naïve (allowed in hormone-sensitive setting only). Phase I, part Ib will randomize pts to doses selected in part Ia, and pts will be stratified by prior CT. Phase II will evaluate tulmimetostat at the RP2D plus luxdegalutamide at 100 mg or 300 mg QD vs SOC. The time-to-event efficacy endpoints will be analyzed using Kaplan–Meier estimates. Dose escalation will be guided by Bayesian logistic regression model with overdose control. Clinical trial information: NCT07206056 . Phase Parts Treatment R N Objectives I Ia: Parallel dose escalation Tulmimetostat QD + luxdegalutamide (100 or 300 mg) - Primary: RDE, safety, tolerability Secondary: PK Ib: Dose expansion and optimization Tulmimetostat (RDE(s) from Part 1a) QD + luxdegalutamide (100 or 300 mg QD) 1:1 88 Primary: Safety, tolerability, RP2D, PSA50 at 6 mo at the RDEs Secondary: PK, rPFS, OS, OR, BOR, DOR, TTSSE II Tulmimetostat RP2D QD + luxdegalutamide (100 or 300 mg QD) vs SOC* (control arm) 1:1 100 Primary: PSA50 at 6 mo Secondary: Safety, tolerability, PK, PSA50 at 3, 9 and 12 mo, rPFS, OS, ORR, BOR, DOR, TTSSE *Choice of ARPI, chemotherapy or lutetium ( 177 Lu) vipivotide tetraxetan. BOR, best overall response; mo, months; DOR, duration of response; QD, once a daily; ORR, objective radiographic response; OS, overall survival; PK, pharmacokinetics, PSA, prostate-specific antigen; RDE, recommended dose for expansion; rPFS, radiographic progression-free survival; R, randomization; RP2D, recommended phase II dose; SOC, standard of care; TTSSE, time to first symptomatic skeletal event.