A Phase 3 Randomized Study of Loncastuximab Tesirine Combined With Rituximab Versus Immunochemotherapy in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (LOTIS-5)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 440
- 试验地点
- 249
- 主要终点
- Progression-free Survival (PFS)
研究概览
简要总结
The purpose of this study is to evaluate the efficacy of loncastuximab tesirine (ADCT-402) combined with rituximab compared to standard immunochemotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Male or female participant aged 18 years or older
- •Pathologic diagnosis of DLBCL, as defined by the 2016 World Health Organization classification (including participants with DLBCL transformed from indolent lymphoma), or high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
- •Relapsed (disease that has recurred following a response) or refractory (disease that failed to respond to prior therapy) disease following at least one multi-agent systemic treatment regimen [For China only: Adequate first line anti-DLBCL therapy is defined as having received at least 4 cycles of multiagent systemic treatment regimen containing rituximab and anthracycline, unless the participants are intolerant to the regimen, or had disease progression during the treatment. If disease progression occurred during the treatment period, then the disease is considered refractory where the number of treatment cycles will not be specified. For participants who are ineligible for anthracycline, anthracycline is not required.]
- •Not considered by the investigator to be a candidate for stem cell transplantation based on performance status, advanced age, and/or significant medical comorbidities such as organ dysfunction
- •Measurable disease as defined by the 2014 Lugano Classification as assessed by positron-emission tomography (PET)- computed tomography (CT) or by CT or magnetic resonance imaging (MRI) if tumor is not fluorodeoxyglucose (FDG)-avid on screening PET-CT
- •Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or minimum 10 freshly cut unstained slides if block is not available) Note: Any biopsy since initial diagnosis is acceptable, but if several samples are available, the most recent sample is preferred [For China only: This inclusion criterion is not applicable]
- •ECOG performance status 0-2
- •Adequate organ function as defined by screening laboratory values within the following parameters:
- •Absolute neutrophil count ≥1000/μL (off growth factors for at least 72 hours)
- •Platelet count ≥100000/μL without transfusion within the past 2 weeks
- •ALT, AST, and GGT ≤2.5 × the upper limit of normal (ULN)
- •Total bilirubin ≤1.5 × ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 × ULN)
- •Calculated creatinine clearance ≥30 mL/min by the Cockcroft and Gault equation
- •Note: A laboratory assessment may be repeated a maximum of two times during the Screening period to confirm eligibility.
- •Negative beta-human chorionic gonadotropin (β-hCG) pregnancy test within 7 days prior to start of study drug (Cycle 1 Day 1) for women of childbearing potential
- •Women of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 12 months after the last dose of study treatment. Men with female partners who are of childbearing potential must agree to use a condom when sexually active or practice total abstinence from the time of giving informed consent until at least 7 months after the participant receives his last dose of study treatment.
排除标准
- •Previous treatment with loncastuximab tesirine
- •Previous treatment with R-GemOx
- •Known history of hypersensitivity to a CD19 antibody, loncastumiximab tesirine (including SG3249) or any of its excipients, or history of positive serum human ADA to a CD19 antibody
- •Pathologic diagnosis of Burkitt lymphoma
- •Active second primary malignancy other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor's medical monitor and Investigator agree and document should not be exclusionary
- •Autologous transplant within 30 days prior to start of study drug (Cycle 1 Day 1)
- •Allogeneic transplant within 60 days prior to start of study drug (Cycle 1 Day 1)
- •Active graft-versus-host disease
- •Post-transplantation lymphoproliferative disorders
- •Active autoimmune disease, including motor neuropathy considered of autoimmune origin and other central nervous system (CNS) autoimmune disease
- •Human immunodeficiency virus (HIV) seropositive with any of the following:
- •CD4+ T-cell (CD4+) counts <350 cells/μL
- •Acquired immunodeficiency syndrome-defining opportunistic infection within 12 months prior to screening
- •Not on anti-retroviral therapy, or on anti-retroviral therapy for <4 weeks at the time of screening
- •HIV viral load ≥400 copies/mL
- •Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy or with detectable HBV viral load
- •Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load
- •History of Stevens-Johnson syndrome or toxic epidermal necrolysis
- •Lymphoma with active CNS involvement, including leptomeningeal disease
- •Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath)
- •Breastfeeding or pregnant
- •Uncontrolled hypertension (blood pressure ≥160/100 mm Hg repeatedly), unstable angina, congestive heart failure (greater than New York Heart Association class II), electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial infarction within 6 months prior to screening, uncontrolled atrial or ventricular cardiac arrhythmia, poorly controlled diabetes, severe chronic pulmonary disease, or other serious medical condition which is likely to significantly impair the participant's ability to tolerate the study treatment
- •Major surgery within 4 weeks prior to start of study drug (Cycle 1 Day 1); radiotherapy, chemotherapy or other antineoplastic therapy within 14 days prior to start of study drug (Cycle 1 Day 1), except shorter if approved by the Sponsor
- •Use of any other experimental medication within 14 days or 5 half-lives prior to start of study drug (Cycle 1 Day 1)
- •Received live vaccine within 4 weeks of Cycle 1 Day 1
- •Failure to recover to ≤Grade 1 (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) from acute non-hematologic toxicity (except alopecia) due to previous therapy prior to screening
- •Congenital long QT syndrome or a corrected QTcF interval of ≥480 ms at screening (unless secondary to pacemaker or bundle branch block)
- •Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgment, make the participant inappropriate for study participation or put the participant at risk
- •Known history of hypersensitivity to oxaliplatin or other platinum-based drugs, or gemcitabine, or rituximab, or any of their excipients
研究组 & 干预措施
Part 1: Loncastuximab Tesirine + Rituximab (Lonca-R)
Part 1 consists of a non-randomized safety run-in period evaluating the study drug for the first 20 participants.
Participants will receive Lonca-R on Day 1 of each cycle for up to 8 cycles, where 1 cycle is 3 weeks. Lonca-R will be administered via an intravenous infusion of loncastuximab tesirine 150 µg/kg + rituximab 375 mg/m^2 Q3W for 2 cycles, then loncastuximab tesirine 75 µg/kg + rituximab 375 mg/m^2 Q3W for up to 6 additional cycles.
干预措施: Loncastuximab Tesirine (Drug)
Part 1: Loncastuximab Tesirine + Rituximab (Lonca-R)
Part 1 consists of a non-randomized safety run-in period evaluating the study drug for the first 20 participants.
Participants will receive Lonca-R on Day 1 of each cycle for up to 8 cycles, where 1 cycle is 3 weeks. Lonca-R will be administered via an intravenous infusion of loncastuximab tesirine 150 µg/kg + rituximab 375 mg/m^2 Q3W for 2 cycles, then loncastuximab tesirine 75 µg/kg + rituximab 375 mg/m^2 Q3W for up to 6 additional cycles.
干预措施: Rituximab (Drug)
Part 2: Loncastuximab Tesirine + Rituximab (Lonca-R)
Randomized participants will receive Lonca-R on Day 1 of each cycle for up to 8 cycles, where 1 cycle is 3 weeks. Lonca-R will be administered via an intravenous infusion of loncastuximab tesirine 150 µg/kg + rituximab 375 mg/m^2 every Q3W for 2 cycles, then loncastuximab tesirine 75 µg/kg + rituximab 375 mg/m^2 Q3W for up to 6 additional cycles.
干预措施: Loncastuximab Tesirine (Drug)
Part 2: Standard Immunochemotherapy (R-GemOx)
Randomized participants will receive R-GemOx consisting of rituximab, gemcitabine and oxaliplatin as a standard immunochemotherapy treatment on Day 1 or Day 2 of each cycle for up to 8 cycles, where 1 Cycle is 2 weeks. R-GemOx will be administered via an intravenous infusion of rituximab 375 mg/m^2 + gemcitabine 1000 mg/m^2 + oxaliplatin 100 mg/m^2 every 2 weeks (Q2W) for up to 8 cycles.
干预措施: Gemcitabine (Drug)
Part 2: Loncastuximab Tesirine + Rituximab (Lonca-R)
Randomized participants will receive Lonca-R on Day 1 of each cycle for up to 8 cycles, where 1 cycle is 3 weeks. Lonca-R will be administered via an intravenous infusion of loncastuximab tesirine 150 µg/kg + rituximab 375 mg/m^2 every Q3W for 2 cycles, then loncastuximab tesirine 75 µg/kg + rituximab 375 mg/m^2 Q3W for up to 6 additional cycles.
干预措施: Rituximab (Drug)
Part 2: Standard Immunochemotherapy (R-GemOx)
Randomized participants will receive R-GemOx consisting of rituximab, gemcitabine and oxaliplatin as a standard immunochemotherapy treatment on Day 1 or Day 2 of each cycle for up to 8 cycles, where 1 Cycle is 2 weeks. R-GemOx will be administered via an intravenous infusion of rituximab 375 mg/m^2 + gemcitabine 1000 mg/m^2 + oxaliplatin 100 mg/m^2 every 2 weeks (Q2W) for up to 8 cycles.
干预措施: Rituximab (Drug)
Part 2: Standard Immunochemotherapy (R-GemOx)
Randomized participants will receive R-GemOx consisting of rituximab, gemcitabine and oxaliplatin as a standard immunochemotherapy treatment on Day 1 or Day 2 of each cycle for up to 8 cycles, where 1 Cycle is 2 weeks. R-GemOx will be administered via an intravenous infusion of rituximab 375 mg/m^2 + gemcitabine 1000 mg/m^2 + oxaliplatin 100 mg/m^2 every 2 weeks (Q2W) for up to 8 cycles.
干预措施: Oxaliplatin (Drug)
结局指标
主要结局
Progression-free Survival (PFS)
时间窗: Up to 4 years
次要结局
- Overall Survival (OS)(Up to 4 years)
- Overall Response Rate (ORR)(Up to 4 years)
- Complete Response Rate (CRR)(Up to 4 years)
- Duration of Response (DOR)(Up to 4 years)
- Number of Participants Who Experience At Least One Serious Adverse Event (SAE)(Up to 4 years)
- Number of Participants Who Experience At Least One Treatment-Emergent Adverse Event (TEAE)(Day 1 up to a maximum of Week 39)
- Number of Participants Who Experience a Clinically Significant Change From Baseline in Physical Examinations(Day 1 up to a maximum of Week 25)
- Number of Participants Who Experience a Clinically Significant Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status(Day 1 up to a maximum of Week 25)
- Number of Participants Who Experience a Clinically Significant Change From Baseline in Electrocardiogram (ECG) Results(Day 1 up to a maximum of Week 25)
- Average Concentration of Loncastuximab Tesirine Before Infusion(Day 1 of Cycles 1 through 6 (each cycle is 3 weeks))
- Number of Participants Who Experience a Clinically Significant Change From Baseline in Clinical Laboratory Results(Day 1 up to a maximum of Week 25)
- Average Concentration of Loncastuximab Tesirine at the End of Infusion(Day 1 of Cycles 1 through 6 (each cycle is 3 weeks))
- Number of Participants Who Experience a Clinically Significant Change From Baseline in Vital Sign Measurements(Day 1 up to a maximum of Week 25)
- Number of Participants With Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine(Day 1 up to a maximum of Week 25)
- Part 2: Change from Baseline in Health-Related Quality of Life (HRQoL) as Measured by the Lymphoma Subscale of Functional Assessment of Cancer Therapy- Lymphoma (LymS of FACT-Lym)(Baseline up to a maximum of Week 25)
- Part 2: Change from Baseline in Health-Related Quality of Life (HRQoL) as Measured by GP5 Item of the Functional Assessment of Cancer Therapy- Lymphoma (FACT-Lym)(Baseline up to a maximum of Week 25)
- Part 2: Change from Baseline in Health-Related Quality of Life (HRQoL) as Measured by EuroQol-5 Dimensions-5 Levels (EQ-5D-5L)(Baseline to up to 4 years)
- Part 2: Change from Baseline in Health-Related Quality of Life (HRQoL) as Measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire -Core 30 (EORTC QLQ-C30)(Baseline up to a maximum of Week 25)