PHASE 1B/PHASE 3 MULTICENTER STUDY OF AVELUMAB (MSB0010718C) IN COMBINATION REGIMENS THAT INCLUDE AN IMMUNE AGONIST, EPIGENETIC MODULATOR, CD20 ANTAGONIST AND/OR CONVENTIONAL CHEMOTHERAPY IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) JAVELIN DLBCL
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 29
- 试验地点
- 29
- 主要终点
- Objective Response Rate (ORR) as Assessed by Investigator Per Lugano Response Classification Criteria
研究概览
简要总结
Study B9991011 is a multi-center, international, randomized, open label, 2 component (Phase 1b followed by Phase 3), parallel-arm study of avelumab in combination with various agents for the treatment of Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL).
详细描述
The target study population of this Phase 1b/3 registrational study is patients with R/R DLBCL who have completed at least 2 (but not more than 4) lines of prior rituximab-containing multi-agent chemotherapy, and/or in whom autologous stem cell transplant (ASCT) has failed, or who are not candidates for ASCT or who are not eligible for intensive chemotherapy. Patients who are ineligible for intensive second line chemotherapy must have received at least one prior rituximab-containing combination chemotherapy regimen. The study will assess the safety, efficacy, pharmacokinetics (PK), immunogenicity of the 3 avelumab-based combination regimens tested, and collect patient reported outcome (PRO) data.
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
- •Any of the following as defined by the WHO, 2016 lymphoid neoplasm classifications and histologically confirmed:
- •Diffuse large B-cell lymphoma (DLBCL), Not Otherwise Specified (NOS): Germinal center B-cell type (GCB), Activated B-cell type (ABC)
- •High-grade B-cell lymphoma (HGBCL) NOS
- •HGBCL with MYC and BCL2 and/or BCL6 rearrangements
- •T-cell histocyte-rich large B-cell lymphoma
- •EBV+ DLBCL, NOS
- •HHV8+ DLBCL, NOS
- •Relapsed or refractory disease following at least 2 lines (and a maximum of 4 lines) of prior rituximab containing multi-agent chemotherapy which may include an autologous stem cell transplantation unless patients are not considered suitable for intensive second-line chemotherapy or autologous stem cell transplantation. Patients who are ineligible for intensive second line chemotherapy,must have received at least one prior rituximab-containing combination chemotherapy regimen. Patients who are ineligible for intensive second line chemotherapy, must have received at least one prior rituximab-containing combination chemotherapy regimen.
- •Baseline measurable disease with at least 1 bi dimensional lesion with longest diameter (LDi) >1.5cm on CT scan which is FDG avid on PET scan.
- •A biopsy (archived or Screening/recent) will be collected at Screening.
- •At least 18years of age (or ≥20 years in Japan).
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or
排除标准
- •Active central nervous system (CNS) lymphoma.
- •Prior organ transplantation including prior allogeneic SCT.
- •Prior therapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab, tremelimumab or any other antibody, or drug specifically targeting T cell co stimulatory or immune checkpoint pathways).
研究组 & 干预措施
Phase 1b Arm C
avelumab/rituximab/bendamustine
干预措施: Bendamustine (Drug)
Phase 1b Arm A
avelumab/utomilumab/rituximab
干预措施: Avelumab (Biological)
Phase 1b Arm A
avelumab/utomilumab/rituximab
干预措施: Utomilumab (Biological)
Phase 1b Arm A
avelumab/utomilumab/rituximab
干预措施: Rituximab (Biological)
Phase 1b Arm B
avelumab/utomilumab/azacitidine
干预措施: Avelumab (Biological)
Phase 1b Arm B
avelumab/utomilumab/azacitidine
干预措施: Utomilumab (Biological)
Phase 1b Arm B
avelumab/utomilumab/azacitidine
干预措施: Azacitidine (Other)
Phase 1b Arm C
avelumab/rituximab/bendamustine
干预措施: Avelumab (Biological)
Phase 1b Arm C
avelumab/rituximab/bendamustine
干预措施: Rituximab (Biological)
Phase 3 Arm D (selected from Phase 1b)
Selected regimen from Phase 1b component which may be i) avelumab/utomilumab/rituximab OR ii) avelumab/rituximab/azacitidine OR iii) avelumab/rituximab/bendamustine
干预措施: Avelumab (Biological)
Phase 3 Arm D (selected from Phase 1b)
Selected regimen from Phase 1b component which may be i) avelumab/utomilumab/rituximab OR ii) avelumab/rituximab/azacitidine OR iii) avelumab/rituximab/bendamustine
干预措施: Utomilumab (Biological)
Phase 3 Arm D (selected from Phase 1b)
Selected regimen from Phase 1b component which may be i) avelumab/utomilumab/rituximab OR ii) avelumab/rituximab/azacitidine OR iii) avelumab/rituximab/bendamustine
干预措施: Rituximab (Biological)
Phase 3 Arm D (selected from Phase 1b)
Selected regimen from Phase 1b component which may be i) avelumab/utomilumab/rituximab OR ii) avelumab/rituximab/azacitidine OR iii) avelumab/rituximab/bendamustine
干预措施: Azacitidine (Other)
Phase 3 Arm D (selected from Phase 1b)
Selected regimen from Phase 1b component which may be i) avelumab/utomilumab/rituximab OR ii) avelumab/rituximab/azacitidine OR iii) avelumab/rituximab/bendamustine
干预措施: Bendamustine (Drug)
Phase 3 Arm E
Investigator's Choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin
干预措施: Rituximab (Biological)
Phase 3 Arm E
Investigator's Choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin
干预措施: Bendamustine (Drug)
Phase 3 Arm E
Investigator's Choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin
干预措施: Gemcitabine (Drug)
Phase 3 Arm E
Investigator's Choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin
干预措施: Oxaliplatin (Drug)
结局指标
主要结局
Objective Response Rate (ORR) as Assessed by Investigator Per Lugano Response Classification Criteria
时间窗: Randomization until date of PD, start of new anticancer therapy, discontinuation from study or death due to any cause, whichever occurred first (maximum up to 36 months)
ORR was defined as percentage of participants with complete response (CR) or partial response (PR), as assessed by investigator per lugano response classification criteria. CR was defined as a score of 1 (no uptake above background), 2 (uptake less than or equal to \[\<=\] mediastinum), or 3 (uptake less than \[\<\] mediastinum but \<=liver) with or without a residual mass on PET 5-point scale (5-PS), for lymph nodes and extralymphatic sites; no new lesions; no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. PR was defined as \>=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a \>=50% decrease in sum of products of diameters (SPD) of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease.
Number of Participants With Dose Limiting Toxicities (DLT)
时间窗: Day 1 Cycle 1 up to 4 Weeks
AEs occurring in first 4 weeks of treatment,attributable to 1 of study drugs. Hematology:1)Grade 4 neutropenia,2)Grade \>=3 febrile neutropenia with single temperature of \>38.3 degrees Celsius (C)/sustained temperature of \>=38.0 degrees C for more than 1 hour with/without associated sepsis,3)Grade \>=3 neutropenic infection,4)Grade 4 thrombocytopenia/Grade 3 thrombocytopenia with clinically significant bleeding,5)Grade 4 anemia 6)Any grade \>=3 non-hematology toxicity except:transient Grade 3 flu like symptoms/fever controlled with standard medical management;transient Grade 3 fatigue,localized skin reactions/headache that resolves to Grade \<=1;Grade 3 nausea,vomiting/diarrhea resolved to Grade \<=1 in ˂72 hours after initiation of adequate medical management;Grade 3 skin toxicity resolved to Grade \<=1 in ˂7 days;tumor flare;Single laboratory values that are out of normal range,that have no clinical correlate and resolve to Grade \<=1 within 7 days with adequate medical management.
次要结局
- Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor and Immune Cells as Assessed by Immunohistochemistry (IHC) at Baseline(Screening (prior to first dose of study treatment))
- Number of Participants With Neutralizing Antibodies (nAb) Against Utomilumab by Never and Ever Positive Status(From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months))
- Progression-Free Survival (PFS) as Assessed by the Investigator Per Lugano Response Classification Criteria(From the date of randomization to progression of disease, study discontinuation, censoring date or death due to any cause, whichever occurred first (up to 36 months))
- Overall Survival(From the date of randomization to discontinuation from the study or death, whichever occurred first (maximum up to 36 months))
- Number of Participants With Anti-Drug Antibodies (ADA) Against Utomilumab by Never and Ever Positive Status(From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months))
- Number of Participants With Neutralizing Antibodies (nAb) Against Rituximab by Never and Ever Positive Status(From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months))
- Number of Participants With Laboratory Abnormalities As Per National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03(From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months))
- Number of Participants With Electrocardiogram (ECG) Abnormalities(From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months))
- Number of Participants With Anti-Drug Antibodies (ADA) Against Rituximab by Never and Ever Positive Status(From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months))
- Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status(From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months))
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Greater Than or Equal to (>=) Grade 3, As Per National Cancer Institute Common Terminology Criteria For Adverse Events (NCI-CTCAE), Version 4.03(From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months))
- Disease Control Rate as Assessed by the Investigator Per Lugano Response Classification Criteria(From the date of randomization to the first documentation of PD, study discontinuation, start of new anti-cancer therapy or death due to any cause, whichever occurred first (maximum up to 36 months))
- Duration of Response (DOR) as Assessed by Investigator Per Lugano Response Classification Criteria(First response (CR or PR) to date of PD, start of new anti-cancer therapy, discontinuation from the study, censoring date or death due to any cause, whichever occurred first (maximum up to 36 months))
- Time to Tumor Response (TTR) as Assessed by Investigator Per Lugano Response Classification Criteria(From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to 36 months))
- Concentration Verses Time Summary of Avelumab(1 hour Post dose Day 2 Cycle 1, 144 hour Post dose Day 8 of Cycle 1, 0 hour Post dose Day 16 of Cycle 1, Day 1 of Cycle 4 and Cycle 6)
- Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status(Baseline: 2 hours pre-dose of first dose of avelumab, Post baseline: post first dose up to up to 30 Days after the end of treatment (maximum up to 36 months))
- Number of Participants With Minimal Residual Disease Burden (MRD) Positive, Negative and Not Evaluable (NE) Status(Baseline, Day 1 of Cycle 3, 6, 9, 12 and 18)