Efficacy of First Line Bortezomib, Rituximab, Ibrutinib (B-RI) for Patients With Treatment Naive Waldenström's Macroglobulinemia
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 53
- 试验地点
- 12
- 主要终点
- 1 year progression free survival
研究概览
简要总结
In Waldenström macroglobulinemia (WM) conventional chemotherapy induces only low complete remission (CR) rates and responses of short duration compared to other indolent lymphomas. Thus innovative approaches are needed which combine excellent activity and tolerability in patients with WM, who are mostly of advanced age. The immunochemotherapy DRC (dexamethasone, rituximab, cyclophosphamide) was shown to be highly effective in patients with WM without inducing major hematological toxicities. On the other hand the proteasome inhibitor bortezomib showed substantial activity as a single agent in WM with only very few side effects when given in a weekly schedule. Recent data confirmed high activity with low toxicity for ibrutinib in relapsed WM patients as single agent therapy. Based on these observations it is the aim of this study to investigate the efficacy and toxicity of the chemotherapy-free combination bortezomib, rituximab, ibrutinib (B-RI) in treatment naïve WM patient.
详细描述
In Waldenström's macroglobulinemia (WM) conventional chemotherapy induces only low complete remission (CR) rates and responses of short duration compared to other indolent lymphomas. Thus innovative approaches are needed which combine excellent activity and tolerability in patients with WM, who are mostly of advanced age. Today, chemotherapy in combination with the anti-cluster of differentiation (CD) 20 antibody rituximab is still the backbone of treatment in patients with WM and is recommended as first line in national and international treatment guidelines. With the approval of Ibrutinib by the European Medicines Agency (EMA) 2015 for patients with relapsed WM or for patients not eligible for chemotherapy with treatment naïve WM treatment landscape has changed in this lymphoma subtype and there is an urgent need to evaluate to which extent chemotherapy-free approaches add clinical benefit to the patient. The treatment in the "European Consortium for Waldenström's Macroglobulinemia" (ECWM)-2 trial will test, whether the chemotherapy-free approach, which is given orally (ibrutinib) and subcutaneously (bortezomib and rituximab from cycle 2 onwards) (B-RI) will approach the efficacy of chemotherapy containing treatment concepts, but avoids chemotherapy associated toxicity. From the perspective of single agent ibrutinib, this regimen tests whether ibrutinib can be further optimized by adding rituximab and bortezomib. The combination of rituximab and ibrutinib was tested in comparison to rituximab/placebo in a large international phase III trial on behalf of the European Consortium for Waldenström's Macroglobulinemia in relapsed and first line WM, and results were recently published: in this trial no unexpected toxicity of the combination ibrutinib/rituximab was reported. Furthermore, ibrutinib/rituximab was significantly superior to rituximab/placebo with regard to response rates and PFS. From the perspective of the established rituximab/bortezomib regimen, the combination of B-RI will evaluate whether adding ibrutinib to this combination will add any benefit for the patient.
To this end, the aim of the study is to assess the toxicity and efficacy of B-RI in an exploratory phase II trial.
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
- 未提供
排除标准
- •Prior systemic treatment of the WM (plasmapheresis and short - term administration of corticosteroids < 4 weeks administered at a dose equivalent to < 20 mg/day prednisone is allowed)
- •Patient with hypersensitivity to Bortezomib
- •Patient with hypersensitivity to MabThera
- •Patient with hypersensitivity to Ibrutinib
- •Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
- •Uncontrolled viral infection
- •Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.
- •Congenital or acquired severe immunodeficiency not attributed to lymphoma (clinical appearance: recurrent infections, necessity of immunoglobulin substitution therapy, patients after transplantation)
- •Known interstitial lung disease
- •Prior allergic reaction or severe anaphylactic reaction related to humanized or murine monoclonal antibody.
- •Central Nervous System involvement by lymphoma
- •Prior history of malignancies unless the subject has been free of the disease for ≥ 5 years. Exceptions include the following:
- •Basal cell carcinoma of the skin,
- •Squamous cell carcinoma of the skin,
- •Carcinoma in situ of the cervix,
- •Carcinoma in situ of the breast,
- •Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b).
- •Uncontrolled illness including, but not limited to:
- •Uncontrolled diabetes mellitus (as indicated by metabolic derangements and/or severe diabetes mellitus related uncontrolled organ complications)
- •Chronic symptomatic congestive heart failure (Class New York Heart Association (NYHA) III or IV).
- •Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months
- •Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia.
- •Known pericardial disease
- •acute diffuse infiltrative pulmonary and pericardial disease
- •Subjects with ≥ Grade 2 neuropathy.
- •Recent major surgery (within 4 weeks prior to study inclusion)
- •History of stroke or intracranial haemorrhage within 6 months prior to study inclusion
- •Women who are pregnant as well as women who are breast-feeding and do not consent to discontinue breast-feeding.
- •Participation in another clinical trial within four weeks prior to study inclusion
- •No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician about study participation
- •St. John's Wort with Ibrutinib
- •Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon).
- •Requires treatment with strong cytochrome P (CYP) 3A inhibitors.
- •Vaccinated with live, attenuated vaccines within 4 weeks prior to study inclusion.
- •Person of legal age who is incapable of comprehending the nature, significance and implications of the clinical trial and of determining his/her will in the light of these facts
研究组 & 干预措施
Bortezomib-Rituximab-Ibrutinib
Cycle 1:
Rituximab: 375 mg/m2 intravenously (i.v) day 1; Bortezomib:1.6 mg/ m2 subcutanously (SC) day 1,8,15; Ibrutinib: 420 mg orally (p.o.) day 1-28;
Cycle 2-6 Rituximab: 1400 mg absolute SC day 1; Bortezomib:1.6 mg/ m2 SC day 1,8,15; Ibrutinib: 420 mg p.o. day 1-28;
Maintenance I (1 cycle = 56 days):
Ibrutinib 420 mg p.o. daily, until evidence of progressive disease or no longer tolerated by the subject (for a maximum of 10 years); Rituximab 1400 mg absolute SC day 1, every second month for 24 months (month 7-30);
Maintenance II (1 cycle = 84 days):
Ibrutinib 420 mg p.o. daily, until evidence of progressive disease or no longer tolerated by the subject (for a maximum of 10 years);
干预措施: Ibrutinib / Bortezomib / Rituximab (Drug)
结局指标
主要结局
1 year progression free survival
时间窗: 1 year
The primary endpoint is the rate of 1 year progression free survival (1YPFS).
次要结局
- Time to best response(up to 10 years)
- Progression Free Survival (PFS)(up to 10 years)
- Response rate(6 months)
- Safety Analysis(up to 10 years)
- Time to first response(up to 10 years)
- Time to Treatment failure (TTF)(up to 10 years)
- Remission duration (RD)(up to 10 years)
- Overall survival (OS)(up to 10 years)
- Best response(up to 10 years)
- Cause specific survival (CSS)(up to 10 years)
研究者
Christian Buske
Prof. Dr. med.
University of Ulm