Advanced Solid Tumor, Diffuse Large B Cell Lymphoma, Endometrial Cancer, Lymphoma, T-Cell, Mesothelioma, Malignant, Metastatic Castration-resistant Prostate Cancer, Ovarian Clear Cell Carcinoma, Prostatic Neoplasms, Castration-Resistant
Conditions
Keywords
Tulmimetostat, DZR123, Lymphoma, Large B-Cell, Diffuse, Lymphoma, B-cell, Lymphoma, T-cell, Lymphoma, Non-Hodgkin, Lymphoma, Neoplasms by Site, Neoplasms by Histologic Type, Neoplasms, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Diseases, Topoisomerase Inhibitors, Molecular Mechanisms of Pharmacological Action, Antineoplastic Agents, Endometrial Cancer, Ovarian Clear Cell Carcinoma, Food effect, Adenine-thymine (AT)-rich interactive domain-containing protein 1A (ARID1A), ARID1A wildtype (ARID1A WT) endometrial carcinoma, Metastatic castration-resistant prostate cancer (mCRPC)
Brief summary
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.
Detailed 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.
Interventions
DRUGTulmimetostat
Tulmimetostat dosed once per day orally in 28 day cycles
DRUGEnzalutamide
Enzalutamide dosed once per day orally in 28 day cycles
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tulmimetostat Monotherapy Phase 2: Overall response rate (ORR) | Up to 30 months | ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) based on RECIST 1.1 or applicable response criteria |
| Cohort M8 Part 1: Frequency of Dose-limiting toxicities (DLTs) | DLTs assessed during Cycle 1 (cycle = 28 days) | The maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of Tulmimetostat in combination with enzalutamide in patients with castration-resistant prostate cancer (mCRPC) with measurable soft tissue disease. |
| Cohort M8 Part 2: Prostate-Specific Antigen 50 (PSA50) Response | Up to 30 months | Prostate-Specific Antigen 50 (PSA50) is defined as a ≥ 50% decrease in PSA levels from baseline at any timepoint, confirmed by a second PSA measurement ≥ 3 weeks without any PSA progression in between |
| Tulmimetostat Monotherapy Phase 1: Frequency of Dose-limiting toxicities (DLTs) | DLTs assessed during Cycle 1 (cycle = 28 days) | The maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of Tulmimetostat as monotherapy in patients with advanced tumors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tulmimetostat Monotherapy (Phase 1) and Cohort M8 (Part 1): Objective Response Rate (ORR) | Up to 30 months | ORR defined as proportion of patients with a best overall response of complete response (CR) or partial response (PR), per Investigator assessment based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1 or applicable response criteria) |
| Tulmimetostat Monotherapy (Phase 1 & 2): ORR per Gynecologic Cancer Intergroup (GCIG) | Up to 30 months | ORR per Gynecologic Cancer Intergroup (GCIG)-defined CA-125 response criteria (ovarian cancer patients) |
| Tulmimetostat Monotherapy (Phase 1): ORR per Prostate Cancer Clinical Trials Working Group 3 (PCWG3) | Up to 30 months | ORR per Prostate Cancer Clinical Trials Working Group 3 (PCWG3) (in Phase 1 prostate cancer patients only) |
| Tulmimetostat Monotherapy (Phase 1 & 2) and Cohort M8 (Part 2): Progression-free survival (PFS) | Up to 30 months | PFS defined as the time from first dose to confirmed disease progression or death |
| Tulmimetostat Monotherapy (Phase 1 & 2) and Cohort M8 (Parts 1 & 2): Duration of response (DOR) | Up to 30 months | DOR defined as the time from the date of first response to the date of confirmed disease progression |
| Tulmimetostat Monotherapy (Phase 1 & 2): Time to response (TTR) | Up to 30 months | TTR defined as the time from first dose to date of first response |
| Tulmimetostat Monotherapy (Phase 1 & 2) and Cohort M8 (Part 1): Disease Control Rate (DCR) | Up to 30 months | DCR defined as the proportion of patients with a best overall response of CR, PR, or stable disease (SD) |
| Tulmimetostat Monotherapy Phase 2: Time-to-progression (TTP) | Up to 30 months | TTP defined as duration from the start of treatment until the disease progression |
| Tulmimetostat Monotherapy (Phase 2) and Cohort M8 (Part 2): Overall survival (OS) | Up to 30 months | OS defined as the time from first dose to death |
| Cohort M8 Part 1: Prostate-Specific Antigen 50 (PSA50) Response | Up to 18 months | PSA50 response defined as PSA decline by \>=50% from baseline |
| Cohort M8 Part 1: Number of participants experiencing Dose-limiting toxicities (DLTs) | DLTs assessed during Cycle 1 (cycle = 28 days) | To establish dose-toxicity relationship between Tulmimetostat and enzalutamide combination |
| Cohort M8 Part 2: Time to Prostate-Specific Antigen (PSA) Progression | Up to 18 months | Time to PSA progression defined as the time from first dose to PSA progression |
| Tulmimetostat Monotherapy (Phase 1 & 2), Cohort M7 and Cohort M8 (Parts 1 & 2): Maximum observed plasma concentration (Cmax) | Up to 18 months | Venous whole blood samples will be collected for pharmacokinetics characterization. Cmax of Tulmimetostat will be listed and summarized using descriptive statistics. |
| Tulmimetostat Monotherapy (Phase 1 & 2), Cohort M7 and Cohort M8 (Parts 1 & 2): Time of maximum observed plasma concentration (Tmax) | Up to 18 months | Venous whole blood samples will be collected for pharmacokinetics characterization. Tmax of Tulmimetostat will be listed and summarized using descriptive statistics. |
| Tulmimetostat Monotherapy (Phase 1 & 2), Cohort M7 and Cohort M8 (Parts 1 & 2): Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-last) | Up to 18 months | Venous whole blood samples will be collected for pharmacokinetics characterization. AUC0-last of Tulmimetostat will be listed and summarized using descriptive statistics. |
| Tulmimetostat Monotherapy (Phase 1 & 2) and Cohort M8 (Parts 1 & 2): Incidence Rate of Adverse Events (AEs) | Up to 18 months | Number of Participants With Adverse Events (AEs) |
| Tulmimetostat Monotherapy (Phase 1 & 2), Cohort M7 and Cohort M8 (Parts 1 & 2): Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-Inf) | Up to 18 months | Venous whole blood samples will be collected for pharmacokinetics characterization. AUC0-Inf of Tulmimetostat will be listed and summarized using descriptive statistics. |
| Tulmimetostat Monotherapy (Phase 1 & 2) and Cohort M7: Terminal elimination half-life (T1/2) | Up to 18 months | Venous whole blood samples will be collected for pharmacokinetics characterization. T 1/2 of Tulmimetostat will be listed and summarized using descriptive statistics. |
| Tulmimetostat Monotherapy (Phase 1 & 2), Cohort M7 and Cohort M8 (Parts 1 & 2): Plasma concentrations prior to the next dose-trough (Cmin) | Up to 18 months | Venous whole blood samples will be collected for pharmacokinetics characterization. Cmin of Tulmimetostat will be listed and summarized using descriptive statistics. |
Countries
France, Italy, Poland, South Korea, Spain, United Kingdom, United States
Contacts
CONTACTNovartis Pharmaceuticals
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Outcome results
None listed