A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas

Overview

The purpose of this open-label, first-in-human (FIH) trial is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of DZR123 (Tulmimetostat, CPI-0209), both as monotherapy and in combination with enzalutamide, in patients with advanced solid tumors and lymphomas.

This study consists of Phase 1 dose-escalation and Phase 2 dose-expansion cohorts designed to characterize DZR123 across multiple tumor-specific populations and to identify dose levels for further clinical development. Phase 2 includes disease-specific monotherapy cohorts, dose-optimization cohorts, a food-effect cohort, and a combination cohort evaluating DZR123 with enzalutamide in metastatic castration-resistant prostate cancer. The study also includes long-term follow-up to monitor survival and the occurrence of second primary malignancies, with assessments conducted approximately every 3 months for the first 3 years and every 6 months thereafter. Phase 1: Dose Escalation (Monotherapy) The initial phase of the study consists of a dose-escalation period using a traditional 3+3 design. Adult patients with advanced, relapsed, or refractory solid tumors or lymphomas receive escalating doses of DZR123 as monotherapy. The primary objective of this phase is to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of DZR123. Dose-escalation decisions are based on safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary antitumor activity data. Patients are not randomized during this phase. Phase 2: Dose Expansion and Optimization Phase 2 further evaluates the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of DZR123 in disease-specific cohorts and explores dose optimization and combination therapy approaches. Cohorts M1-M6: Disease-Specific Monotherapy Patients are enrolled into disease-specific cohorts defined by tumor type and/or molecular characteristics, including adenine-thymine-rich interactive domain-containing protein 1A (ARID1A) mutations, BRCA1-associated protein 1 (BAP1) loss, lymphoma subtypes, and metastatic castration-resistant prostate cancer (mCRPC). Cohorts M1, M5, and M6 use a Simon's two-stage design in which 10 patients are enrolled in Stage 1; if at least 1 response is observed, up to 19 additional patients are enrolled in Stage 2. Cohorts M2 and M3 also begin with a Simon's two-stage design and subsequently transition into dose-optimization stages. Cohort M4 enrolls approximately 20 patients with lymphoma in a single stage without further expansion. Patients are not randomized except during dose-optimization stages in Cohorts M2 and M3. Dose Optimization in Cohorts M2 and M3 For ovarian clear cell carcinoma (Cohort M2) and endometrial carcinoma (Cohort M3), dose optimization is conducted after initial cohort expansion. In Stage 2a, participants are randomized 1:1 to receive DZR123 200 mg or 300 mg once daily. Depending on predefined efficacy and safety criteria, Stage 2b may enroll additional participants in one or both dose groups to further evaluate the optimal dose for future clinical development. Cohort M7: Food-Effect Evaluation Cohort M7 evaluates the effect of a high-fat, high-calorie meal on the pharmacokinetics of DZR123 in patients with ARID1A wild-type endometrial carcinoma. Approximately 20 participants receive a single dose of DZR123 with a standardized meal on Cycle 1 Day 1, followed by continued DZR123 administration. Results from this cohort may inform future administration instructions regarding food intake in subsequent DZR123 studies and cohorts. Cohort M8: DZR123 in Combination With Enzalutamide Cohort M8 evaluates DZR123 in combination with enzalutamide in participants with metastatic castration-resistant prostate cancer and consists of two parts. * Part 1 (Dose Escalation): Participants receive escalating doses of DZR123 in combination with enzalutamide 160 mg once daily. Dose escalation is guided by a Bayesian logistic regression model (BLRM) using the Escalation With Overdose Control (EWOC) principle to determine the RP2D for the combination. Approximately 30 participants are enrolled. A 7-day enzalutamide run-in period may be used prior to combination treatment. * Part 2 (Dose Expansion): Following selection of the RP2D, approximately 40 additional participants receive DZR123 at the selected dose in combination with enzalutamide to further evaluate safety, tolerability, PK, PD, and antitumor activity. Amendment 15 increased the planned enrollment in Part 2 from approximately 15 to approximately 40 participants and revised the primary efficacy assessment to focus on prostate-specific antigen response. The study includes safety monitoring throughout treatment and follow-up, including collection of adverse events, laboratory assessments, tumor evaluations, and dedicated surveillance for second primary malignancies associated with EZH1/2 inhibition.