A Phase 1/2 Study of DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 300
- 试验地点
- 198
- 主要终点
- Cohort M8 Part 2: Prostate-Specific Antigen 50 (PSA50) Response
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Cohort M8 - Part 1 (Tulmimetostat + enzalutamide in mCRPC)
Eligible participants with mCRPC receive DZR123 in combination with enzalutamide. Part 1 is dose escalation to determine the recommended dose.
干预措施: Tulmimetostat (Drug)
Cohort M8 - Part 2 (Tulmimetostat + enzalutamide in mCRPC)
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.
干预措施: Enzalutamide (Drug)
Phase 1
Eligible participants with advanced tumors will receive escalating doses of Tulmimetostat once per day orally.
干预措施: Tulmimetostat (Drug)
Phase 2 - Cohort M3 (Endometrial carcinoma with ARID1A mutation)
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.
干预措施: Tulmimetostat (Drug)
Phase 2 - Cohort M4 (Relapsed/refractory lymphoma (PTCL or DLBCL))
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.
干预措施: Tulmimetostat (Drug)
Phase 2 - Cohort M5 (Malignant mesothelioma with BAP1 loss)
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.
干预措施: Tulmimetostat (Drug)
Phase 2 - Cohort M7 (Food effect in ARID1A wildtype endometrial carcinoma)
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.
干预措施: Tulmimetostat (Drug)
Phase 2 - Cohort M2 (Ovarian clear cell carcinoma with ARID1A mutation)
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.
干预措施: Tulmimetostat (Drug)
Phase 2 - Cohort M1 (Advanced/metastatic solid tumors or urothelial carcinoma with ARID1A mutation)
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.
干预措施: Tulmimetostat (Drug)
Phase 2 - Cohort M6 (Metastatic castration-resistant prostate cancer (mCRPC))
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.
干预措施: Tulmimetostat (Drug)
Cohort M8 - Part 2 (Tulmimetostat + enzalutamide in mCRPC)
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.
干预措施: Tulmimetostat (Drug)
结局指标
主要结局
Cohort M8 Part 2: Prostate-Specific Antigen 50 (PSA50) Response
时间窗: 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)
时间窗: 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.
Tulmimetostat Monotherapy Phase 2: Overall response rate (ORR)
时间窗: 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)
时间窗: 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: Overall response rate (ORR)
时间窗: 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) per Investigator assessment based on Prostate Cancer Clinical Trials Working Group 3 (PCWG3)
次要结局
- Tulmimetostat Monotherapy (Phase 1 & 2) and Cohort M8 (Parts 1 & 2): Incidence Rate of Adverse Events (AEs)(Up to 18 months)
- Tulmimetostat Monotherapy (Phase 1 & 2), Cohort M7 and Cohort M8 (Parts 1 & 2): Maximum observed plasma concentration (Cmax)(Up to 18 months)
- Tulmimetostat Monotherapy (Phase 1 & 2), Cohort M7 and Cohort M8 (Parts 1 & 2): Time of maximum observed plasma concentration (Tmax)(Up to 18 months)
- 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)
- 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)
- Tulmimetostat Monotherapy (Phase 1 & 2) and Cohort M7: Terminal elimination half-life (T1/2)(Up to 18 months)
- 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)
- Tulmimetostat Monotherapy (Phase 1) and Cohort M8 (Part 1): Objective Response Rate (ORR)(Up to 30 months)
- Tulmimetostat Monotherapy (Phase 1 & 2): ORR per Gynecologic Cancer Intergroup (GCIG)(Up to 30 months)
- Tulmimetostat Monotherapy (Phase 1): ORR per Prostate Cancer Clinical Trials Working Group 3 (PCWG3)(Up to 30 months)
- Tulmimetostat Monotherapy (Phase 1 & 2) and Cohort M8 (Part 2): Progression-free survival (PFS)(Up to 30 months)
- Tulmimetostat Monotherapy (Phase 1 & 2) and Cohort M8 (Parts 1 & 2): Duration of response (DOR)(Up to 30 months)
- Tulmimetostat Monotherapy (Phase 1 & 2): Time to response (TTR)(Up to 30 months)
- Tulmimetostat Monotherapy (Phase 1 & 2) and Cohort M8 (Part 1): Disease Control Rate (DCR)(Up to 30 months)
- Tulmimetostat Monotherapy (Phase 2) and Cohort M8 (Part 2): Overall survival (OS)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 1: Time to response (TTR)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 1: Maximum observed plasma concentration (Cmax)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 1: Time of maximum observed plasma concentration (Tmax)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 1: Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-last)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 1: Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-Inf)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 1: Incidence Rate of AEs(Up to 18 months)
- Tulmimetostat Monotherapy Phase 1: Terminal elimination half-life (T1/2)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 1: Plasma concentrations prior to the next dose-trough (Cmin)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 1: Gene expression in blood cells(Up to 18 months)
- Tulmimetostat Monotherapy Phase 1: H3K27me3(Up to 18 months)
- Tulmimetostat Monotherapy Phase 1: Objective Response Rate (ORR)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 1: ORR per Gynecologic Cancer Intergroup (GCIG)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 1: ORR per Prostate Cancer Clinical Trials Working Group 3 (PCWG3)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 1: Progression-free survival (PFS)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 1: Duration of response (DOR)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 1: Disease Control Rate (DCR)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 2: Progression-free survival (PFS)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 2: Time-to-progression (TTP)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 2: Duration of response (DOR)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 2: Time to response (TTR)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 2: Disease Control Rate (DCR)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 2: ORR per Gynecologic Cancer Intergroup (GCIG)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 2: Overall survival (OS)(Up to 30 months)
- Tulmimetostat Monotherapy Phase 2: Incidence Rate of AEs(Up to 18 months)
- Tulmimetostat Monotherapy Phase 2: Maximum observed plasma concentration (Cmax)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 2: Time of maximum observed plasma concentration (Tmax)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 2: Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-last)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 2: Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-Inf)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 2: Terminal elimination half-life (T1/2)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 2: Plasma concentrations prior to the next dose-trough (Cmin)(Up to 18 months)
- Tulmimetostat Monotherapy Phase 2: Gene expression in blood cells(Up to 18 months)
- Tulmimetostat Monotherapy Phase 2: H3K27me3(Up to 18 months)
- Cohort M7: Maximum observed plasma concentration (Cmax)(Up to 18 months)
- Cohort M7: Time of maximum observed plasma concentration (Tmax)(Up to 18 months)
- Cohort M7: Terminal elimination half-life (T1/2)(Up to 18 months)
- Cohort M7: Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-last)(Up to 18 months)
- Cohort M7: Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-Inf)(Up to 18 months)
- Cohort M7: Plasma concentrations prior to the next dose-trough (Cmin)(Up to 18 months)
- Cohort M8 Part 1: Incidence Rate of AEs(Up to 18 months)
- Cohort M8 Part 1: Maximum observed plasma concentration (Cmax)(Up to 18 months)
- Cohort M8 Part 1: Time of maximum observed plasma concentration (Tmax)(Up to 18 months)
- Cohort M8 Part 1: Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-last)(Up to 18 months)
- Cohort M8 Part 1: Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-Inf)(Up to 18 months)
- Cohort M8 Part 1: Plasma concentrations prior to the next dose-trough (Cmin)(Up to 18 months)
- Cohort M8 Part 1: Gene expression in blood cells(Up to 18 months)
- Cohort M8 Part 1: H3K27me3(Up to 18 months)
- Cohort M8 Part 1: Objective Response Rate (ORR)(Up to 30 months)
- Cohort M8 Part 1: Duration of response (DOR)(Up to 30 months)
- Cohort M8 Part 2: Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-last)(Up to 18 months)
- Cohort M8 Part 1: Disease Control Rate (DCR)(Up to 30 months)
- Cohort M8 Part 1: Prostate-Specific Antigen 50 (PSA50) Response(Up to 18 months)
- Cohort M8 Part 1: Number of participants experiencing Dose-limiting toxicities (DLTs)(DLTs assessed during Cycle 1 (cycle = 28 days))
- Cohort M8 Part 2: Incidence Rate of AEs(Up to 18 months)
- Cohort M8 Part 2: Maximum observed plasma concentration (Cmax)(Up to 18 months)
- Cohort M8 Part 2: Time of maximum observed plasma concentration (Tmax)(Up to 18 months)
- Cohort M8 Part 2: Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-Inf)(Up to 18 months)
- Cohort M8 Part 2: Plasma concentrations prior to the next dose-trough (Cmin)(Up to 18 months)
- Cohort M8 Part 2: Gene expression in blood cells(Up to 18 months)
- Cohort M8 Part 2: H3K27me3(Up to 18 months)
- Cohort M8 Part 2: Duration of response (DOR)(Up to 30 months)
- Cohort M8 Part 2: Progression-free survival (PFS)(Up to 30 months)
- Cohort M8 Part 2: Prostate-Specific Antigen 50 (PSA50) Response(Up to 18 months)
- Cohort M8 Part 2: Time to Prostate-Specific Antigen (PSA) Progression(Up to 18 months)
- Cohort M8 Part 2: Overall survival (OS)(Up to 30 months)