A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Comparing the Efficacy and Safety of Polatuzumab Vedotin in Combination With Rituximab and CHP (R-CHP) Versus Rituximab and CHOP (R-CHOP) in Previously Untreated Patients With Diffuse Large B-Cell Lymphoma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,000
- 试验地点
- 407
- 主要终点
- Progression-Free Survival (PFS) as Assessed by the Investigator, Using the Lugano Response Criteria for Malignant Lymphoma
研究概览
简要总结
This Phase III, randomized, double-blind, placebo-controlled study will compare the efficacy, safety, and pharmacokinetics of polatuzumab vedotin plus R-CHP versus R-CHOP in participants with previously untreated diffuse large B-cell lymphoma (DLBCL).
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Previously untreated participants with cluster of differentiation 20 (CD20)-positive DLBCL, including one of the following diagnoses by 2016 World Health Organization (WHO) classification of lymphoid neoplasms: DLBCL, not otherwise specified (NOS) including germinal center B-cell type, activated B-cell type; T-cell/histiocyte-rich large B-cell lymphoma; Epstein-Barr virus-positive DLBCL, NOS; anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma; human herpesvirus-8 (HHV8)-positive DLBCL, NOS; High-grade B-cell lymphoma with MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements (double-hit or triple-hit lymphoma); High-grade B-cell lymphoma, NOS
- •Availability of archival or freshly collected tumor tissue before study enrolment
- •International Prognostic Index (IPI) score of 2-5
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- •Life expectancy greater than or equal to (>/=)12 months
- •Left ventricular ejection fraction (LVEF) >/= 50 percent (%) on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)
- •Adequate hematologic function
- •Female participants: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods and refrain from donating eggs.
- •Male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom and agreement to refrain from donating sperm.
排除标准
- •History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
- •Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines
- •Prior organ transplantation
- •Current Grade greater than (>) 1 peripheral neuropathy by clinical examination
- •Demyelinating form of Charcot-Marie-Tooth disease
- •History of indolent lymphoma
- •History of follicular lymphoma grade 3B
- •B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (grey-zone lymphoma)
- •Primary mediastinal (thymic) large B-cell lymphoma
- •Burkitt lymphoma
- •Prior treatment with cytotoxic drugs within 5 years of screening for any condition (example [e.g.], cancer, rheumatoid arthritis) or prior use of any anti-CD20 antibody
- •Prior use of any monoclonal antibody within 3 months of the start of Cycle 1
- •Prior therapy for DLBCL, with the exception of nodal biopsy
- •Corticosteroid use >30 mg/day of prednisone or equivalent, for purposes other than lymphoma symptom control
- •Participants with central nervous system (CNS) lymphoma (primary or secondary involvement), primary effusion DLBCL, and primary cutaneous DLBCL
- •Vaccination with live vaccines within 28 days prior to the start of Cycle 1
- •Any investigational therapy within 28 days prior to the start of Cycle 1
- •History of other malignancy that could affect compliance with the protocol or interpretation of results
- •Evidence of significant, uncontrolled, concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or pulmonary disease
- •Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis
- •History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree heart block, or evidence of prior myocardial infarction
- •Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or significant infections within 2 weeks before the start of Cycle 1
- •Clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis
- •Prior radiotherapy to the mediastinal/pericardial region
- •Participants with suspected active or latent tuberculosis
- •Positive test results for chronic hepatitis B and hepatitis C infection
- •Known history of human immunodeficiency virus (HIV) seropositive status
- •Positive results for the human T-lymphotrophic 1 virus (HTLV-1)
- •Participants with a history of progressive multifocal leukoencephalopathy
研究组 & 干预措施
R-CHP plus Vincristine Placebo plus Polatuzumab Vedotin
Participants will receive polatuzumab vedotin 1.8 milligrams per kilogram (mg/kg) intravenously (IV), placebo for vincristine IV, rituximab 375 milligrams per square meter (mg/m^2) IV, cyclophosphamide 750 mg/m^2 IV, and doxorubicin 50 mg/m^2 IV on Day 1 and prednisone 100 milligrams per day (mg/day) orally (PO) on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Rituximab (Drug)
R-CHP plus Vincristine Placebo plus Polatuzumab Vedotin
Participants will receive polatuzumab vedotin 1.8 milligrams per kilogram (mg/kg) intravenously (IV), placebo for vincristine IV, rituximab 375 milligrams per square meter (mg/m^2) IV, cyclophosphamide 750 mg/m^2 IV, and doxorubicin 50 mg/m^2 IV on Day 1 and prednisone 100 milligrams per day (mg/day) orally (PO) on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Vincristine Placebo (Drug)
R-CHP plus Vincristine Placebo plus Polatuzumab Vedotin
Participants will receive polatuzumab vedotin 1.8 milligrams per kilogram (mg/kg) intravenously (IV), placebo for vincristine IV, rituximab 375 milligrams per square meter (mg/m^2) IV, cyclophosphamide 750 mg/m^2 IV, and doxorubicin 50 mg/m^2 IV on Day 1 and prednisone 100 milligrams per day (mg/day) orally (PO) on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Doxorubicin (Drug)
R-CHOP plus Polatuzumab Vedotin Placebo
Participants will receive placebo for polatuzumab vedotin, rituximab 375 mg/m^2 IV, cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV (maximum 2 milligrams per dose [mg/dose]) on Day 1 and prednisone 100 mg/day PO on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Polatuzumab vedotin Placebo (Drug)
R-CHOP plus Polatuzumab Vedotin Placebo
Participants will receive placebo for polatuzumab vedotin, rituximab 375 mg/m^2 IV, cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV (maximum 2 milligrams per dose [mg/dose]) on Day 1 and prednisone 100 mg/day PO on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Prednisone (Drug)
R-CHP plus Vincristine Placebo plus Polatuzumab Vedotin
Participants will receive polatuzumab vedotin 1.8 milligrams per kilogram (mg/kg) intravenously (IV), placebo for vincristine IV, rituximab 375 milligrams per square meter (mg/m^2) IV, cyclophosphamide 750 mg/m^2 IV, and doxorubicin 50 mg/m^2 IV on Day 1 and prednisone 100 milligrams per day (mg/day) orally (PO) on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Polatuzumab Vedotin (Drug)
R-CHP plus Vincristine Placebo plus Polatuzumab Vedotin
Participants will receive polatuzumab vedotin 1.8 milligrams per kilogram (mg/kg) intravenously (IV), placebo for vincristine IV, rituximab 375 milligrams per square meter (mg/m^2) IV, cyclophosphamide 750 mg/m^2 IV, and doxorubicin 50 mg/m^2 IV on Day 1 and prednisone 100 milligrams per day (mg/day) orally (PO) on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Cyclophosphamide (Drug)
R-CHP plus Vincristine Placebo plus Polatuzumab Vedotin
Participants will receive polatuzumab vedotin 1.8 milligrams per kilogram (mg/kg) intravenously (IV), placebo for vincristine IV, rituximab 375 milligrams per square meter (mg/m^2) IV, cyclophosphamide 750 mg/m^2 IV, and doxorubicin 50 mg/m^2 IV on Day 1 and prednisone 100 milligrams per day (mg/day) orally (PO) on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Prednisone (Drug)
R-CHOP plus Polatuzumab Vedotin Placebo
Participants will receive placebo for polatuzumab vedotin, rituximab 375 mg/m^2 IV, cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV (maximum 2 milligrams per dose [mg/dose]) on Day 1 and prednisone 100 mg/day PO on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Rituximab (Drug)
R-CHOP plus Polatuzumab Vedotin Placebo
Participants will receive placebo for polatuzumab vedotin, rituximab 375 mg/m^2 IV, cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV (maximum 2 milligrams per dose [mg/dose]) on Day 1 and prednisone 100 mg/day PO on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Cyclophosphamide (Drug)
R-CHOP plus Polatuzumab Vedotin Placebo
Participants will receive placebo for polatuzumab vedotin, rituximab 375 mg/m^2 IV, cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV (maximum 2 milligrams per dose [mg/dose]) on Day 1 and prednisone 100 mg/day PO on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Doxorubicin (Drug)
R-CHOP plus Polatuzumab Vedotin Placebo
Participants will receive placebo for polatuzumab vedotin, rituximab 375 mg/m^2 IV, cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV (maximum 2 milligrams per dose [mg/dose]) on Day 1 and prednisone 100 mg/day PO on Days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m^2 IV will be administered as monotherapy in Cycles 7 and 8.
干预措施: Vincristine (Drug)
结局指标
主要结局
Progression-Free Survival (PFS) as Assessed by the Investigator, Using the Lugano Response Criteria for Malignant Lymphoma
时间窗: From randomization to the first occurrence of disease progression or relapse, or death from any cause, whichever occurs earlier (up to 38 months)
次要结局
- Percentage of Participants With Complete Response (CR) as Assessed by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) by Blinded Independent Central Review (BICR)(End of treatment visit (6-8 weeks after last dose on Day 1 of Cycle 8 [Cycle length=21 days] [up to Week 32]))
- Event-Free Survival-Efficacy (EFSeff) as Assessed by the Investigator, Using the Lugano Response Criteria for Malignant Lymphoma(From randomization to first occurrence of disease progression/relapse;or death from any cause;or other primary efficacy reason that leads to initiation of any non-protocol specified antilymphoma treatment(NALT);or residual disease(up to approx 65 months))
- Percentage of Participants Who are Progression Free as Assessed by the Investigator, Using the Lugano Response Criteria for Malignant Lymphoma(24 months after enrollment (up to approximately 65 months))
- Overall Survival(From randomization until death from any cause (up to approximately 65 months))
- Percentage of Participants With CR as Assessed by FDG-PET by Investigator(End of treatment visit (6-8 weeks after last dose on Day 1 of Cycle 8 [Cycle length=21 days] [up to Week 32]))
- Disease-Free Survival (DFS) as Assessed by the Investigator, Using the Lugano Response Criteria for Malignant Lymphoma(From the date of first occurrence of a documented CR to the date of relapse or death from any cause (up to approximately 65 months))
- Duration of Response as Assessed by the Investigator, Using the Lugano Response Criteria for Malignant Lymphoma(From the date of first occurrence of a documented CR or partial response (PR) to the date of progression, relapse, or death from any cause (up to approximately 65 months))
- Event-Free Survival-All Causes (EFSall) as Assessed by the Investigator, Using the Lugano Response Criteria for Malignant Lymphoma(From randomization to disease progression or relapse, or death from any cause, or initiation of any NALT (up to approximately 65 months))
- Time to Deterioration in European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) Physical Functioning and Fatigue(Day 1 of Cycles 1, 2, 3 and 5 (Cycle length=21 days); treatment completion visit (TCV)/early treatment termination visit (ETTV) (up to approximately 32 weeks); post-treatment follow-up (FU) visit (up to approximately 65 months))
- Time to Deterioration in Functional Assessment of Cancer Therapy-Lymphoma Lymphoma Subscale (FACT-Lym LymS)(Day 1 of Cycles 1, 2, 3 and 5 (Cycle length=21 days); TCV/ETTV (up to approximately 32 weeks); post-treatment FU visit (up to approximately 65 months))
- Percentage of Participants Achieving Meaningful Improvement in EORTC QLQ-C30 Physical Functioning and Fatigue(Day 1 of Cycles 1, 2, 3 and 5 (Cycle length=21 days); TCV/ETTV (up to approximately 32 weeks); post-treatment FU visit (up to approximately 65 months))
- Percentage of Participants Achieving Meaningful Improvement in FACT-Lym LymS(Day 1 of Cycles 1, 2, 3 and 5 (Cycle length=21 days); TCV/ETTV (up to approximately 32 weeks); post-treatment FU visit (up to approximately 65 months))
- EORTC QLQ-C30 Treatment-Related Symptoms Score(Day 1 of Cycles 1, 2, 3 and 5 (Cycle length=21 days); TCV/ETTV (up to approximately 32 weeks); post-treatment FU visit (up to approximately 65 months))
- Functional Assessment of Cancer Treatment/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) Peripheral Neuropathy Score(Day 1 of Cycles 1-8 (Cycle length=21 days); TCV/ETTV (up to approximately 32 weeks); post-treatment FU visit (up to approximately 65 months))
- Percentage of Participants With adverse Events (AEs)(From randomization to the end of study (up to approximately 65 months))
- Serum Concentration of Total Polatuzumab Vedotin(Pre-infusion (0 hour [hr]), 0.5 hr post-infusion (infusion duration=90 minutes [min]) on Day 1 of Cycle 1 and 4 (Cycle length=21 days); TCV/ETTV (up to approximately 32 weeks); post-treatment FU visit (up to approximately 65 months))
- Plasma Concentration of Polatuzumab Vedotin Conjugate (Antibody-Conjugated Mono-Methyl Auristatin E [acMMAE])(0.5 hr post-infusion (infusion duration=90 min) on Day 1 of Cycle 1 and 4 (Cycle length=21 days); TCV/ETTV (up to approximately 32 weeks); post-treatment FU visit (up to approximately 65 months))
- Plasma Concentration of Polatuzumab Vedotin Unconjugated MMAE(0.5 hr post-infusion (infusion duration=90 min) on Day 1 of Cycle 1 and 4 (Cycle length=21 days); TCV/ETTV (up to approximately 32 weeks); post-treatment FU visit (up to approximately 65 months))
- Percentage of Participants With Anti-Drug Antibody (ADA) to Polatuzumab Vedotin(Pre-infusion (0 hr) on Day 1 of Cycle 1 and 4 (Cycle length=21 days); TCV/ETTV (up to approximately 32 weeks); post-treatment FU visit (up to approximately 65 months))