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

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. The study is divided into Phase 1 and Phase 2.

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 are enrolled to receive escalating doses of DZR123 (also known as Tulmimetostat, CPI-0209) as monotherapy. The primary objective of this phase is to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of DZR123. Dose escalation proceeds until the maximum tolerated dose or a suitable recommended Phase 2 dose is identified based on cumulative safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data. Patients are non-randomized in this phase.

Phase 2: Dose Expansion and Optimization (Monotherapy and Combination) Phase 2 is designed to further evaluate the safety, tolerability, and antitumor activity of DZR123 in disease-specific cohorts, as well as to explore dose optimization and combination strategies.

\~ Cohorts M1-M6: Disease-Specific Monotherapy Patients are enrolled into six disease-specific cohorts (M1-M6), each defined by tumor type and/or molecular characteristics (for example, adenine-thymine-rich interactive domain-containing protein 1A \[ARID1A\] mutation, BRCA1 associated protein-1 \[BAP1\] loss, or metastatic castration-resistant prostate cancer \[mCRPC\]).

Enrollment in Cohorts M1, M2, M3, M5, and M6 follows a Simon's two-stage design: ten patients are enrolled in Stage 1, and if at least one response is observed, up to nineteen additional patients may be enrolled in Stage 2 (for a maximum of twenty-nine per cohort).

Cohort M4 (lymphoma) enrolls up to twenty patients in a single stage and does not proceed to Stage 2.

Patients in these cohorts are non-randomized.

\~ Dose Optimization in Cohorts M2 and M3 For ovarian clear cell carcinoma (Cohort M2) and endometrial carcinoma (Cohort M3), dose optimization is conducted in Stage 2 after the initial Simon's two-stage expansion.

In Stage 2a, approximately twenty patients per cohort are randomized 1:1 to receive either 200 milligrams or 300 milligrams of DZR123 once daily.

If protocol-defined criteria are met, Stage 2b is opened to enroll an additional ten patients in one or both dose arms, for a potential total of up to forty patients per cohort.

Randomization is used only in these dose optimization stages.

\~ Cohort M7: Food Effect in ARID1A Wildtype Endometrial Carcinoma This cohort evaluates the effect of a high-fat, high-calorie meal on the pharmacokinetics of DZR123 in patients with ARID1A wildtype endometrial carcinoma.

Approximately twenty patients are enrolled and receive a single dose of DZR123 with a standardized meal, followed by continued dosing in the fasted state.

Patients are non-randomized.

\~ Cohort M8: Combination with Enzalutamide in Metastatic Castration-Resistant Prostate Cancer

Cohort M8 is divided into two parts:

* Part 1 (Dose Escalation): Patients with metastatic castration-resistant prostate cancer receive escalating doses of DZR123 in combination with enzalutamide (160 milligrams once daily) to determine the recommended Phase 2 dose for the combination. Dose escalation is guided by a Bayesian logistic regression model (BLRM) with escalation with overdose control (EWOC).
* Part 2 (Dose Expansion): After the recommended Phase 2 dose is established, approximately 40 additional patients are randomized to receive the combination at the selected dose to further evaluate safety, tolerability, and preliminary antitumor activity.

Patients are non-randomized.