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.

Key Inclusion Criteria:

All Patients:

• Adults aged ≥18 years with life expectancy ≥12 weeks
• ECOG performance status 0-1
• Adequate recovery from prior therapy-related toxicities (Grade ≤1, with exceptions)
• Adequate bone marrow, renal, and hepatic function per protocol-defined thresholds
• Willingness to provide tumor tissue and blood samples for biomarker analyses
• Agreement to protocol-specified contraception requirements
• Signed informed consent prior to study procedures

Disease-Specific Inclusion Criteria:

Phase 1 (Dose Escalation):

• Histologically or cytologically confirmed locally advanced or metastatic solid tumors or lymphoma
• Disease refractory to standard therapy or with no available effective standard treatment
• For prostate cancer: castrate testosterone levels maintained throughout the study

Phase 2 (Disease-Specific Cohorts):

• M1: ARID1A mutant urothelial carcinoma or other ARID1A mutant solid tumors (with cohort specific prior therapy and RECIST 1.1 measurable disease requirements)
• M2: ARID1A mutant ovarian clear cell carcinoma after prior platinum-based therapy (and bevacizumab unless contraindicated)
• M3: ARID1A mutant recurrent/metastatic endometrial carcinoma after platinum therapy and appropriate immunotherapy
• M4: Relapsed/refractory peripheral T cell lymphoma or diffuse large B cell lymphoma, transplant-ineligible, with measurable disease
• M5: Relapsed/refractory pleural or peritoneal mesothelioma with documented BAP1 loss
• M6: Metastatic castration-resistant prostate cancer (mCRPC) with documented progression after AR targeted therapy and taxane chemotherapy
• M7: ARID1A wild type endometrial carcinoma (exploratory food-effect cohort)
• M8: mCRPC treated with DZR123 in combination with enzalutamide, with cohort specific requirements for prior androgen receptor pathway inhibitor and chemotherapy exposure

Key Exclusion Criteria:

All Patients:

Medical Conditions:

• Prior solid organ or allogeneic hematopoietic cell transplant
• Active or untreated symptomatic CNS metastases (with limited exceptions)
• Clinically significant cardiovascular disease, including uncontrolled arrhythmias or prolonged QTc
• Active interstitial lung disease or pneumonitis
• Uncontrolled infections or significant gastrointestinal disorders affecting absorption
• Active HIV or hepatitis B/C infection
• Concurrent malignancy requiring active treatment (with protocol-defined exceptions)
• Pregnancy, breastfeeding, or inability to comply with protocol requirements

Prior or Concomitant Therapy:

• Recent anticancer therapy within protocol-defined washout periods
• Prior EZH2 inhibitor treatment
• Recent radiation or liver-directed therapies outside allowed windows
• Use of strong CYP3A4/5 inhibitors or inducers

Additional Cohort-Specific Exclusions:

• M6 (mCRPC): Bone-only disease, unstable bone lesions, PSA-lowering herbal products, recent prohibited prostate cancer therapies
• M8 (Combination): PSA-only disease, prior investigational androgen receptor pathway inhibitors, significant seizure risk, extensive prior bone marrow irradiation, active inflammatory gastrointestinal disease

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com