Reduction of MTX Levels After Treatment With Reduced Glucarpidase Dose in Patients With DLBCL at Risk of CNS Involvement Who Receive Cycles of HDMTX: an Open-label, Interventional, Non-randomized, Phase 2, Pilot, Multicenter Study
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 3
- 试验地点
- 2
- 主要终点
- Proportion of patients who achieve significant change blood MTX levels (more than 95% reduction of blood MTX levels) at 6 hours after administration of Glucarpidase
研究概览
简要总结
Diffuse large B-cell lymphoma (DLBCL) is an aggressive subset of non-Hodgkin's lymphoma (NHL). Central nervous system (CNS) involvement in patients with NHL is a serious complication. The outcome of patients with CNS relapse is extremely poor, with a median survival of 4-6 months.
One approach to reduce CNS relapse in high-risk patients is the use of systemic high-dose intravenous (iv) methotrexate (HMTX) chemotherapy. Currently available methods of MTX clearance, including dialysis-based methods, have shown limited efficacy.
Glucarpidase hydrolyses MTX to inactive metabolites that are partially metabolised by the liver, thus providing an alternative route of limiting renal excretion.
The administration of Glucarpidase could prevent MTX toxicity as a whole as well as the following consequences. The aim of this study is to analyse the prophylactic effect of 2,000 units of glucarpidase administered after 12 hours of HDMTX on MTX clearance and on the incidence and severity of MTX-related toxicity.
详细描述
Glucarpidase hydrolyzes the terminal glutamate residue from MTX to inactive metabolites [4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamic acid] which are partially metabolized by the liver, thus providing an alternative route of limitation to renal excretion.
Administration of Glucarpidase cause a clinically important 99% or greater sustained MTX reduction being immediate in most patients, 87% of them experiencing a ≥ 95% reduction in serum MTX concentration at a median of 15 min post-Glucarpidase Early administration of Glucarpidase could avoid MTX toxicity as whole as well as the following consequences. The aim of this study is to analyze the prophylactic effect of 2,000 unit Glucarpidase administered after 12 hour of HDMTX on the MTX clearance and on the incidence and severity of MTX related-toxicity.
According to normal clinical practice, patients will receive for curative intent rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) by standard protocol on a 21-day cycle (a total of 6 cycles), plus 3 infusion of systemic intravenous MTX at a dose of 3 g/m2 for CNS prophylaxis (HDMTX) at cycles 1, 3 and 5.
Glucarpidase will be capped at 2,000 units per dose (in two vials of 1,000 units/vial) given as a single intravenous (IV) bolus injection over 5 minutes. Glucarpidase will be administered 12 hours following each HDMTX at cycles 1, 3 and 5.
Clinical laboratory evaluation of Hematology and Biochemistry will be conducted at each step of this study, according to the local laboratory method, to determine occurrences of adverse events (AE) or serious adverse events (SAE) following the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0).
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects aged 18-70 years
- •Patients with diagnosis of diffuse large B-cell lymphoma
- •Patients at high risk of CNS involvement (>2 extranodal sites plus an elevated LDH or /and involvement of high-risk extranodal sites including testes, paranasal sinuses, breast, liver, adrenal and renal)
- •Patients who will receive HDMTX (three cycles) into R-CHOP regimen (6 cycles) prescribed according to normal clinical practice
- •Absence of focal neurological signs
- •Absence of CNS involvement determined by cerebrospinal fluid (CSF) cytometry flow test prior to start treatment
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Absolute neutrophil count 1800-7500/µL, platelet count 130.000- 450.000/ µL, hemoglobin 13,5-18 g/dL,
- •Serum creatinine ≤1.5 x the upper limit of normal (ULN) or glomerular filtration rate (GFR) ≥60ml/min/1.73m^2
- •Total serum bilirubin ≤2 x ULN. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5 x ULN
- •Ability to understand and the willingness to sign a written informed consent document
- •In women of childbearing potential (from menarche and until becoming post-menopausal [i.e., no menses for 12 months with an alternative medical cause], unless permanently sterile) and men, use of highly effective measure of contraception (abstinence, hormonal contraception, intra-uterine device [IUD], intrauterine hormone-releasing system, [IUS], or anatomical sterility in self or partner) committed during 3 months after the last IMP administration.
排除标准
- •Malignant disease, other than those being treated in this study. Exceptions to this exclusion include malignancies that were treated curatively and have not recurred within 2 years after completion of treatment.
- •Patients suffered from cardiovascular diseases (arrhythmias, previous heart failure, thromboembolic disease)
- •Previous treatment with Glucarpidase
- •Pregnant or breastfeeding women
- •Concomitant treatment with agents which interact with methotrexate metabolism or excretion
- •Known intolerance/hypersensitivity to Glucarpidase or any of its excipients.
研究组 & 干预措施
Glucarpidase, methotrexate, R-CHOP
Glucarpidase 2000Units per dose. IV. Bolus injection over 5 minutes. Administered 12 hours following after each HDMTX cycle, for a maximum of 3 cycles.
干预措施: Glucarpidase 1000 UNT [Voraxaze] (Drug)
结局指标
主要结局
Proportion of patients who achieve significant change blood MTX levels (more than 95% reduction of blood MTX levels) at 6 hours after administration of Glucarpidase
时间窗: 6 hours
As a categorical variable: \>95% reduction of MTX (yes/no) after 6 hours after administration of 2,000 units of Glucarpidase.
次要结局
- Change blood MTX levels achieved at 15 minutes, 6 hours, 12 hours and 24 hours after administration of Glucarpidase(15min, 6 hours, 12 hours, 24 hours)
- Proportion of patients with more than 95% reduction of blood MTX levels after administration of Glucarpidase(15min, 6 hours, 12 hours, 24 hours)
- Proportion of patients who achieve clinically important reduction (CIR) in blood MTX level at 15 minutes, 6 hours, 12 hours and 24 hours after administration of Glucarpidase.(15min, 6 hours, 12 hours, 24 hours)