A Modular Phase I/II Open-label, Multicenter Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Efficacy of AZD4512 Monotherapy or in Combination With Other Anticancer Agent(s), in Participants With Relapsed/Refractory B-cell Non-Hodgkin Lymphoma (B-NHL) (Lumi-NHL)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 91
- 试验地点
- 26
- 主要终点
- Percentage of participants with dose-limiting toxicities (DLTs)
研究概览
简要总结
This is a Phase I/II open-label, global multicenter study to evaluate the safety and efficacy of AZD4512 monotherapy or in combination with other anticancer agent(s), in participants with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma (B-NHL).
详细描述
Study D9890C00001 (Lumi-NHL) is modular study designed to evaluate the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy of AZD4512 monotherapy or in combination with other anticancer agent(s), in participants with Relapsed/Refractory B-NHL. Module 1 aims to study AZD4512 monotherapy at in participants in R/R B-NHL who have been exposed to at least 2 prior lines of therapy.
Additional modules in specific B-NHL subtypes with AZD4512 as monotherapy or in combination with other anticancer agent(s) may be added in the future
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Eligible patients must be adults (≥18 years)
- •Documented histologically confirmed diagnosis of B-cell non-Hodgkin lymphoma (B-NHL) as per World Health Organization (WHO) 2022 classification. In the dose escalation phase, any B-NHL subtype is allowed (excluding some subtypes), while the backfill phase restricts inclusion to defined subtypes: large B-cell lymphomas (as defined as Diffuse large B-cell lymphoma (DLBCL), Grade 3b Follicular lymphoma (FL), high-grade B-cell lymphoma (HGBCL) NOS, DLBCL/HGBCL with MYC and BCL2 rearrangements, primary mediastinal Large B-cell lymphoma, T-cell/histiocyte-rich LBCL, and transformed indolent lymphoma) and mantle cell lymphoma.
- •Patients must have relapsed or refractory disease after at least two prior lines of systemic therapy and lack additional standard options with established benefit:
- •A)LBCL patients must have progressed after both anti-CD20 and at least one systemic chemotherapy regimen, and have considered-or be ineligible for-CAR-T, T cell engager, and stem cell transplant modalities.
- •B) Mantle cell lymphoma (MCL) patients must have had anti-CD20 and Bruton's Tyrosine Kinase (BTK) inhibitor.
- •Additional criteria include measurable disease by Lugano 2014, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and adequate organ and bone marrow function (as specified by blood counts, cardiac ejection fraction, renal and hepatic parameters, and coagulation indices).
排除标准
- •Patients are excluded if they have a diagnosis of post-transplant lymphoproliferative disease, Richter's transformation, Burkitt's lymphoma, or chronic lymphocytic leukemia (CLL)/ Small lymphocytic lymphoma (SLL), Waldenstrom Macroglobulinemia/ Lymphoplasmacytic Lymphoma, or if they have active Central nervous system (CNS) involvement from their B-NHL. Exclusion also applies to those who have received Chimeric antigen receptor-T (CAR-T) or T cell engager therapies within 90 days prior to Cycle 1 Day 1 (C1D1), any investigational drug or other systemic anticancer therapies (except low-dose corticosteroids) within 21 days or 5 half-lives, and curative radiation within 14 days (localized palliative radiotherapy is allowed).
- •Other exclusions include allogeneic Hematopoietic stem cell transplantation (HSCT) within 180 days (unless stable without active (graft-versus-host disease) GVHD for ≥2 months), autologous HSCT within 90 days (unless resolved toxicities), major surgery within 28 days, use of strong CYP3A inhibitors within 14 days or 5 half-lives before the dosing date, use of QTc-prolonging agents within 5 half-lives before the dosing date, or other malignancies within two years. Patients with unresolved ≥ Grade 2 AEs from prior therapy (except specified tolerable conditions), serious uncontrolled medical conditions, active infection within 14 days, or history/suspicion of significant interstitial lung disease/pneumonitis are also excluded.
- •Females who are pregnant or breastfeeding are not eligible.
研究组 & 干预措施
Module 1: AZD4512 Monotherapy dose escalation + backfill
In Mod 1, the efficacy and safety of AZD4512 will be evaluated in R/R B-NHL. Module 1 will consist of both dose escalation and Pharmacodynamic/safety backfills which may be used to support MTD and/or Optimal biological dose (OBD)
干预措施: AZD4512 (Drug)
结局指标
主要结局
Percentage of participants with dose-limiting toxicities (DLTs)
时间窗: Up to 4 weeks
To identify the maximum tolerated dose (MTD) and/or doses of AZD4512 for subsequent evaluation in participants with R/R B-NHL
Frequency, duration, severity of Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) and Serious Adverse Events (SAEs)
时间窗: From the first dose up to and including 30 (+7) days after the last dose of study treatment , but prior to subsequent cancer therapy
To assess the safety and tolerability of AZD4512 in participants with R/R B-NHL
Frequency of SAEs/AEs leading to discontinuation of AZD4512
时间窗: From the first dose up to and including 30 (+7) days after the last dose of study treatment , but prior to subsequent cancer therapy
To assess the safety and tolerability of AZD4512 in participants with R/R B-NHL
Number of participants with clinically significant alterations in vitals signs and abnormal laboratory parameters
时间窗: From the first dose up to and including 30 (+7) days after the last dose of study treatment , but prior to subsequent cancer therapy
To assess the safety and tolerability of AZD4512 in participants with R/R B-NHL
次要结局
- Objective response rate (ORR)(Up to 2 years)
- Complete response (CR) rate(Up to 2 years)
- Duration of response (DoR)(Up to 2 years)
- Progression-free survival (PFS)(Up to 2 years)
- Overall survival (OS)(Up to 2 years)
- Area Under plasma concentration-time Curve (AUC) of AZD4512, total antibody and total unconjugated warhead(Up to 2 years)
- Observed plasma (peak) drug concentration (Cmax) of AZD4512, total antibody and total unconjugated warhead(Up to 2 years)
- Trough concentration (Ctrough) of AZD4512, total antibody and total unconjugated warhead(Up to 2 years)
- Half life of AZD4512, total antibody and total unconjugated warhead(Up to 2 years)
- Time to reach peak or maximum observed concentration (tmax) of AZD4512, total antibody and total unconjugated warhead(Up to 2 years)
- Total clearance of AZD4512, total antibody and total unconjugated warhead(Up to 2 years)
- The number and percentage of participants who develop anti-drug antibodies (ADAs)(Up to 2 years)