A Phase 2 Multicenter Study of the Combination Zanubrutinib, Bendamustine, and Rituximab in Previously Untreated Waldenström Macroglobulinemia (ZEBRA Trial)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 65
- 试验地点
- 9
- 主要终点
- Very Good Partial Response (VGPR) or Better Response Rate
研究概览
简要总结
The purpose of this study is to determine the very good partial response (VGPR) or better rate in participants with Waldenström macroglobulinemia (WM).
The names of the study drugs involved in this study are as follows: zanubrutinib, bendamustine, and rituximab.
详细描述
This is multi-center phase 2 of zanubrutinib, bendamustine, and rituximab (ZBR) in previously untreated Waldenström macroglobulinemia (WM).
A phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.
The U.S. Food and Drug Administration (FDA) has not approved bendamustine and rituximab for your specific disease, but it has been approved for other uses.
The U.S. FDA has approved zanubrutinib as a treatment option for your disease.
The combination of zanubrutinib, bendamustine, and rituximab is not approved regimen for Waldenström macroglobulinemia (WM) and is investigational in this study.
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
- •Clinicopathological diagnosis of waldenström macroglobulinemia (WM) per the second international workshop on waldenström macroglobulinemia (IWWM2) criteria
- •Presence of any MYD88 and CXCR4 mutation status, including MYD88 L265P mutation plus CXCR4 wild type, MYD88 L265P mutation plus CXCR4 mutation, or MYD88 wild type
- •Meeting criteria for treatment per IWWM2 criteria. At least one of the following:
- •Constitutional Symptoms (at least one of the following)
- •Recurrent fever
- •Night sweats
- •Weight loss
- •Progressive or symptomatic lymphadenopathy or splenomegaly
- •Hemoglobin ≤ 10 g/dL
- •Platelet count ≤ 100 k/uL
- •Hyperviscosity syndrome
- •Symptomatic peripheral neuropathy
- •Systemic amyloidosis
- •Renal insufficiency
- •Symptomatic cryoglobulinemia or cold agglutinemia
- •Treatment naive; must have not received any prior systemic therapy for WM
- •Participants with suspected or symptomatic hyperviscosity (e.g. nosebleeds, headaches, blurred vision) must undergo plasmapheresis prior to treatment initiation.
- •Adults age ≥18
- •ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
- •Women of childbearing potential: Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or practice complete abstinence1 from heterosexual intercourse during treatment and for at least 1 week after the last dose of zanubrutinib or at least 12 months after the last dose of rituximab, whichever is later. FCBP must be referred to a qualified provider of contraceptive methods if needed. Also, FCBP must have a pregnancy check with a negative serum pregnancy test obtained 28 days prior to and confirmed by C1D
- •Men must agree to use a condom during sexual contact with a female of childbearing potential (FCBP) even if they have had a successful vasectomy 1) while participating in the study; and 2) for at least 1 week following the last dose of zanubrutinib.
- •Participants must meet the following organ and marrow function as defined below:
- •Absolute neutrophil count ≥500/mcL believed to be caused by WM bone marrow involvement. Growth factors are not permitted <14 days prior to C1D
- •Platelets ≥30,000/mcL believed to be caused by WM bone marrow involvement. Platelet transfusions are not permitted <14 days prior to C1D
- •Hemoglobin ≥ 7 g/dL. RBC transfusions are not permitted <14 days prior to C1D
- •Total bilirubin ≤ 1.5 X institutional ULN, or ≤3 x institutional ULN with documented liver metastases and/or Gilbert's Disease
- •AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal, or ≤5 X institutional ULN with documented liver metastases
- •Creatinine clearance ≥30 mL/min using the Cockcroft-Gault formula
- •Able to adhere to the study visit schedule and other protocol requirements.
- •Ability to understand and the willingness to sign a written informed consent document.
排除标准
- •Any serious medical condition, laboratory abnormality, uncontrolled intercurrent illness, or psychiatric illness/social condition that would prevent the participant from signing the informed consent form
- •Female participants who are pregnant, breastfeeding, or planning to become pregnant or breastfeed while enrolled in this study
- •Participants with known CNS involvement by WM
- •Participants with known history of Human Immunodeficiency Virus (HIV)
- •Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
- •Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (antiHBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before enrollment. Patients who are hepatitis B PCR positive will be excluded.
- •Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before enrollment. Patients who are hepatitis C RNA positive will be excluded.
- •Concurrent systemic immunosuppressant therapy. Systemic steroids at doses <20mg prednisone per day are permitted.
- •Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura).
- •Concurrent administration of warfarin or warfarin derivatives.
- •Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
- •Active uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the Investigator and the Sponsor makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required. Active uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the Investigator and the Sponsor makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required.
- •Major surgery within 4 weeks of first dose of study drug.
- •History of severe bleeding disorder such as hemophilia A, hemophilia B, or history of spontaneous bleeding requiring blood transfusion or other medical intervention. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
- •Participants with inability to swallow pills.
- •Inability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of the study participation.
- •Any uncontrolled or significant cardiovascular disease defined as:
- •Unstable angina within 3 months before screening, or
- •History of myocardial infarction within 6 months prior to planned start of zanubrutinib, or
- •Previously documented left ventricular ejection fraction (LVEF) by any method of ≤ 45% in the 12 months prior to planned start of zanubrutinib; assessment of LVEF via echocardiogram or multigated acquisition (MUGA) scan during Screening should be performed in selected patients as medically indicated, or
- •Any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or
- •Uncontrolled or symptomatic arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
- •Participants with a known hypersensitivity to any of the excipients of Zanubrutinib, Rituximab, or Bendamustine.
- •Participants with a history of non-compliance to medical regimens, which will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs.
- •Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancers.
- •Severe or debilitating pulmonary disease.
- •Ongoing alcohol or drug addiction or any psychiatric condition(s) which would compromise ability to comply with study procedures.
- •Ongoing use of a strong CYP3A inducer.
研究组 & 干预措施
Zanubrutinib + Bendamustine + Rituximab
Zanubrutinib will be taken orally once daily on days 1-28 of cycles 1-15.
Bendamustine will be given by intravenous infusion over about 10 to 60 minutes on days 1 and 2 of cycles 1 to 4.
Rituximab will be given by intravenous infusion over about 30 minutes on day 1 of cycles 1 to 4.
Drug diaries will be provided to participants to document information about the study treatment being taken.
干预措施: Zanubrutinib (Drug)
Zanubrutinib + Bendamustine + Rituximab
Zanubrutinib will be taken orally once daily on days 1-28 of cycles 1-15.
Bendamustine will be given by intravenous infusion over about 10 to 60 minutes on days 1 and 2 of cycles 1 to 4.
Rituximab will be given by intravenous infusion over about 30 minutes on day 1 of cycles 1 to 4.
Drug diaries will be provided to participants to document information about the study treatment being taken.
干预措施: Bendamustine (Drug)
Zanubrutinib + Bendamustine + Rituximab
Zanubrutinib will be taken orally once daily on days 1-28 of cycles 1-15.
Bendamustine will be given by intravenous infusion over about 10 to 60 minutes on days 1 and 2 of cycles 1 to 4.
Rituximab will be given by intravenous infusion over about 30 minutes on day 1 of cycles 1 to 4.
Drug diaries will be provided to participants to document information about the study treatment being taken.
干预措施: Rituximab (Drug)
结局指标
主要结局
Very Good Partial Response (VGPR) or Better Response Rate
时间窗: Day 1 to 5 years post treatment
Assessed using 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM11) criteria. All participants will be gauged for very good partial response (VGPR) rate or better.
次要结局
- Median time to Next Treatment(From Day 1 until date of next line of therapy is first documented, assessed up to 5 years post treatment)
- Overall Survival(From Day 1 until date of first documented disease progression or date of death from any cause, whichever came first, assessed up to 5 years post treatment)
- Overall Response Rate(Day 1 to 5 years post treatment)
- Major Response Rate(Day 1 to 5 years post treatment)
- Progression-Free Survival(From Day 1 until date of first documented disease progression or date of death from any cause, whichever came first, assessed up to 5 years post treatment)
- Median Time to Response(Day 1 to 5 years post treatment)
- Treatment Related Adverse Events(Day 1 to 5 years post treatment)
- Complete Response Rate(Day 1 to 5 years post treatment)
- Median Time to Major Response(From Day 1 until date of major response is first documented, assessed up to 5 years post treatment)
研究者
Andrew R. Branagan, M.D., Ph.D.
Principal Investigator
Massachusetts General Hospital