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

Novartis

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Endometrial Cancer; Lymphoma, T-Cell; Ovarian Clear Cell Carcinoma; Advanced Solid Tumor; Prostatic Neoplasms, Castration-Resistant; Metastatic Castration-resistant Prostate Cancer; Mesothelioma, Malignant; Diffuse Large B Cell Lymphoma

Treatments: Drug: Enzalutamide; Drug: Tulmimetostat

Study type: Interventional

Funder types: Industry

Identifiers

NCT04104776

CDZR123A02101

CPI-0209-01

2023-508002-20-00 (Registry Identifier)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 300 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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300 participants in 10 patient groups

Phase 1

Experimental group

Description:

Eligible participants with advanced tumors will receive escalating doses of Tulmimetostat once per day orally.

Treatment:

Drug: Tulmimetostat

Phase 2 - Cohort M1 (Advanced/metastatic solid tumors or urothelial carcinoma with ARID1A mutation)

Experimental group

Description:

Eligible participants with advanced/metastatic solid tumors (excluding ovarian clear cell and endometrial carcinoma) or urothelial carcinoma, confirmed to have ARID1A mutations will receive oral Tulmimetostat once daily in 28-day treatment cycles.

Treatment:

Drug: Tulmimetostat

Phase 2 - Cohort M2 (Ovarian clear cell carcinoma with ARID1A mutation)

Experimental group

Description:

Eligible participants with advanced ovarian clear cell carcinoma, confirmed to have ARID1A mutations, who have received prior platinum-based chemotherapy will receive oral Tulmimetostat once daily in 28-day treatment cycles.

Treatment:

Drug: Tulmimetostat

Phase 2 - Cohort M3 (Endometrial carcinoma with ARID1A mutation)

Experimental group

Description:

Eligible participants with recurrent, metastatic, or unresectable endometrial carcinoma, confirmed to have ARID1A mutations, and prior platinum-based therapy will receive oral Tulmimetostat once daily in 28-day treatment cycles.

Treatment:

Drug: Tulmimetostat

Phase 2 - Cohort M4 (Relapsed/refractory lymphoma (PTCL or DLBCL))

Experimental group

Description:

Eligible participants with relapsed or refractory peripheral T-cell lymphoma (PTCL) or diffuse large B-cell lymphoma (DLBCL), including those with EZH2 hotspot mutations will receive oral Tulmimetostat once daily in 28-day treatment cycles.

Treatment:

Drug: Tulmimetostat

Phase 2 - Cohort M5 (Malignant mesothelioma with BAP1 loss)

Experimental group

Description:

Eligible participants with relapsed or refractory malignant pleural or peritoneal mesothelioma, confirmed to have BAP1 loss will receive oral Tulmimetostat once daily in 28-day treatment cycles.

Treatment:

Drug: Tulmimetostat

Phase 2 - Cohort M6 (Metastatic castration-resistant prostate cancer (mCRPC))

Experimental group

Description:

Eligible participants with mCRPC, measurable soft tissue disease, and prior treatment with at least one androgen receptor signaling inhibitor and one taxane-based chemotherapy will receive oral Tulmimetostat once daily in 28-day treatment cycles.

Treatment:

Drug: Tulmimetostat

Phase 2 - Cohort M7 (Food effect in ARID1A wildtype endometrial carcinoma)

Experimental group

Description:

Eligible participants with recurrent, advanced endometrial carcinoma that is ARID1A wildtype (no ARID1A mutation), to evaluate the effect of food on DZR123 pharmacokinetics will receive oral Tulmimetostat once daily in 28-day treatment cycles.

Treatment:

Drug: Tulmimetostat

Cohort M8 - Part 1 (Tulmimetostat + enzalutamide in mCRPC)

Experimental group

Description:

Eligible participants with mCRPC receive DZR123 in combination with enzalutamide. Part 1 is dose escalation to determine the recommended dose.

Treatment:

Drug: Tulmimetostat

Cohort M8 - Part 2 (Tulmimetostat + enzalutamide in mCRPC)

Experimental group

Description:

Eligible participants with mCRPC receive DZR123 in combination with enzalutamide. Part 2 is expansion at the selected dose to further assess safety and antitumor activity.

Treatment:

Drug: Tulmimetostat

Drug: Enzalutamide