A Phase 1/1b, Open-label Multi-center Two-part Study of SETD2 Inhibitor EZM0414 in Subjects With Relapsed/Refractory Multiple Myeloma and Relapsed/Refractory Diffuse Large B Cell Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 13
- 试验地点
- 8
- 主要终点
- Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
研究概览
简要总结
This study will include participants with relapsed/refractory (R/R) Multiple Myeloma (MM). MM is a type of cancer of the blood. This study will also include participants with relapsed/refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL).
DLBCL is also a type of cancer of the blood. They are referred to as 'relapsed' when the disease has come back after treatment and 'refractory' when treatment no longer works. The study has 2 main parts, called phase 1 and phase 1b. The main objective of both parts will be to evaluate the safety and tolerability of the study drug, called EZM0414.
The main objective of phase 1b will also be to determine the effectiveness of EZM0414. During phase 1 six dose levels will be tested to obtain the most tolerated dose. Participants will receive study drug at the assigned dose level every 28 days. During phase 1b participants will receive study drug at the maximum tolerated dose in 28-day cycles.
详细描述
The first part of the study will be a Phase 1 dose-escalation designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of EZM0414 in subjects with R/R MM and R/R DLBCL.
Six dose levels starting at 100 mg, then 200 mg, 300 mg, 400 mg, 600 mg, and 900 mg as well as an optional step-down dose of 75 mg (if needed) will be tested. The second part of the study is the Phase 1b dose expansion at the MTD designed to evaluate safety and efficacy in subjects with R/R DLBCL and R/R MM with or without select genetic translocation.
Dose expansion will enroll subjects in 3 cohorts: Cohort 1 for R/R MM subjects with t(4;14), Cohort 2 for R/R MM subjects without t(4;14), and Cohort 3 for subjects with R/R DLBCL.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Voluntarily provide signed informed consent after review of verbal and written material about the trial and agree to abide with protocol requirements. All study related activities must be carried out after written consent is obtained.
- •Subjects must be ≥18 years of age at the time of signing the ICF (Informed Consent Form).
- •Subjects must have an Eastern Cooperative Oncology Group (ECOG) status of 0 -
- •For MM, subjects must have measurable disease by IMWG (International Myeloma Working Group) 2016 criteria
- •For DLBCL, subjects must have measurable disease by Lugano criteria
- •Females must not be breastfeeding or pregnant at screening
- •Females of childbearing potential must not have had unprotected sexual intercourse while participating in this study
- •Male subjects must either practice complete abstinence or agree to use a latex or synthetic condom, even with a successful vasectomy, during study treatment and for 30 days after the final dose of study treatment
排除标准
- •Subjects with plasma cell leukemia defined as a plasma cell count >2000/mm
- •Subjects with Waldenstrom's macroglobulinemia or smoldering MM.
- •Subjects who had prior treatment with SETD2 or NSD2 inhibitor.
- •Subjects with active acute or chronic systemic infection requiring systemic treatment, including COVID-
- •Has cardiovascular impairment
- •Prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 480 msec or history of long QT syndrome.
- •Known left ventricular ejection fraction (LVEF) < 50% by either echocardiogram (ECHO) or multigated acquisition (MUGA).
- •Prior major surgery within 4 weeks of treatment start.
- •Known hypersensitivity to components of the investigational product.
- •Subjects who have received treatment with any unapproved drug product within 4 weeks prior to screening.
- •Current participation in any other interventional clinical study except for follow up.
- •Subjects with a history of or active malignancy other than disease under study
- •Underlying medical/social conditions that in PI opinion will place the subject in significant risk and affect the interpretation of toxicity and adverse events assessments.
- •Inability to take oral medication or known gastrointestinal (GI) disease, GI procedure or medical condition that could interfere with the oral absorption or tolerance of the study drug
研究组 & 干预措施
Open-label EZM0414
Participants will receive EZM0414 in continuous 28-day cycles. EZM0414 will be administered orally once daily (QD) without food.
Participants who receive EZM0414 at Maximum tolerated dose (MTD) and do not have Dose limiting toxicities (DLT) in the dose escalation part of the study will be rolled over to a cohort of this dose expansion part.
Cohort 1 for R/R MM Participants. Cohort 2 for R/R MM Participants. Cohort 3 for Participants with R/R DLBCL.
干预措施: EZM0414 (Drug)
结局指标
主要结局
Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
时间窗: From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment (Day 57), up to approximately 87 days
An adverse event was any untoward medical occurrence in a participant or clinical investigation participant administered a medicinal product and which does not necessarily had a causal relationship with this treatment. A serious adverse event was any untoward medical occurrence that at any dose, resulted in death, was life-threatening, required in-subject hospitalization or prolongation of hospitalization, resulted in persistent or significant disability or incapacity, or resulted in a congenital abnormality or birth defect, was an important medical event. A TEAE was an AE that started or worsened in severity on or after the date of the first dose of the study treatment through 30 days after the end of treatment.
Part 1: Number of Participants With Dose-limiting Toxicities (DLTs)
时间窗: From first dose of study treatment (Cycle 1 Day 1) up to end of the Cycle 1 (Cycle 1 Day 28), maximum of 28 days
According to National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0, DLT was defined as any of following AE that occurred in Part 1 during first cycle of study treatment: grade (G)4 neutropenia lasting \>5 days; G3 febrile neutropenia; G3 thrombocytopenia with clinically significant bleeding; G4 thrombocytopenia; G4 anemia unexplained by underlying disease; any other non-hematological toxicity ≥3 except: alopecia, G3 nausea/vomiting or diarrhea for \<3 days with supportive care, G3 fatigue for \<1 week, G3 or higher isolated electrolyte abnormalities for up to 3 days, not clinically complicated, and resolved spontaneously, or responded to conventional medical interventions; G3 or higher amylase/lipase elevation without symptoms of pancreatitis; G3 tumor lysis syndrome for up to 3 days, not clinically complicated, and resolved spontaneously, or responded to conventional medical interventions; and any participant meeting Hy's law criteria.
Part 2: Objective Response Rate (ORR)
时间窗: Tumour assessments were planned to be performed at Screening (within 28 days before start of study treatment) or Cycle 1 Day 1 (pre-dose) up to end of the study, approximately 23 months
ORR was planned to be assessed in Part 2. ORR was defined as percentage of responders as assessed by Investigator per International Myeloma Working Group (IMWG) 2016 guidelines for MM (complete response \[CR\], stringent CR \[sCR\], partial response \[PR\], very good PR \[VGPR\]) or Lugano 2014 guidelines for DLBCL (CR+PR). Per IMWG response criteria, CR: negative immunofixation on serum and urine; disappearance of soft tissue plasmacytomas; \<5% plasma cells in bone marrow(BM); sCR: CR + normal free light chain (FLC) ratio; absence of BM clonal cells by immunohistochemistry; VGPR: serum and urine M-protein (MP) detected by immunofixation but not on electrophoresis or ≥90% reduction in serum MP + urine MP\<100 mg/24 hours (h) or ≥90% decrease in sum of maximal perpendicular diameter (SPD) compared to baseline in soft tissue plasmacytoma; PR: ≥50% reduction of serum MP and reduction in 24 h urinary M-protein by ≥90% or to \<200 mg/24 h; ≥50% reduction in size (SPD) of soft tissue plasmacytomas.
次要结局
- Part 2: Progression-free Survival (PFS)(Tumour assessments were planned to be performed at Screening (within 28 days before start of study treatment) or Cycle 1 Day 1 (pre-dose) up to end of the study, approximately 23 months)
- Part 2: Disease Control Rate (DCR)(Tumour assessments were planned to be performed at Screening (within 28 days before start of study treatment) or Cycle 1 Day 1 (pre-dose) up to end of the study, approximately 23 months)
- Part 2: Duration of Response (DOR)(Tumour assessments were planned to be performed at Screening (within 28 days before start of study treatment) or Cycle 1 Day 1 (pre-dose) up to end of the study, approximately 23 months)