Daratumumab for Minimal Residual Disease Eradication in T-Acute Lymphoblastic Leukemia - A Phase 2 Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- MRD negativity
研究概览
简要总结
T-ALL (T-acute lymphoblastic leukemia) is an aggressive blood cancer, wherein patients who are MRD positive after two courses of induction chemotherapy have poor outcomes. This goal of this study is to determine if Daratumumab can make such T-ALL patients MRD negative.
The main questions this study aims to answer are -
- Whether MRD Positive T-ALL patients can become MRD negative after two doses of daratumumab?
- Whether MRD Positive T-ALL patients can become MRD negative after four doses of daratumumab?
- Whether addition of daratumumab can affect the risk of progression or death at 1-year?
- Whether daratumumab is safe to use?
Newly diagnosed patients of T-ALL who are MRD positive after two courses of induction chemotherapy will be eligible to receive daratumumab. These patients will receive two doses of weekly intravenous daratumumab at standard dose (16mg/kg), and will undergo repeat evaluation of MRD from bone marrow one week after the second dose of daratumumab. Patients who become MRD negative will continue chemotherapy as per institutional policy. Those who remain MRD positive will be eligible to receive two additional doses, and will undergo another bone marrow MRD testing one week after the fourth dose. Irrespective of the results after the fourth dose, patients will be continued on chemotherapy as per institutional policy.
详细描述
Hypothesis - Daratumumab will increase the MRD negative CR rate in newly diagnosed T-ALL who are MRD positive after two-cycles of induction chemotherapy.
Rationale of dosing Daratumumab being a monoclonal antibody primarily depends on its target mediated clearance. In myeloma, dose finding studies of daratumumab showed that the drug at a dose of 16mg per kg was able to saturate all the receptors due to which a lower clearance and higher trough concentrations were observed. On the other hand, a lower dose of 8 mg/kg demonstrated higher clearance due to lack of complete target engagement / saturation. Hence, 16 mg/kg was the approved dose. In accordance with the above concept, daratumumab has been used in multiple indications apart from myeloma viz. PRCA post-transplant, Extranodal NK/T lymphoma, Blastic Plasmacytoid Dendritic Cell Neoplasm, at the myeloma approved dose of 16 mg/kg. Moreover, from its phenomenon of indirect coombs test positivity, it is evident that daratumumab binds CD38 antigen on RBCs, even though the expression of CD38 on RBCs is low. Its ability to bind to CD38 antigen across cell lineages, further supports that the same dose will be valid for T-ALL.
Method - T-ALL adult patients (on modified BFM-90 induction chemotherapy or any other pediatric inspired protocol) who are MRD positive by flow cytometry (≥0.01%) at end of phase 1a induction, will undergo a bone marrow-minimal residual disease (BM-MRD) testing at the end of phase 1b induction (or after 2 phases of induction of any pediatric inspired protocol), at count recovery (ANC>1000/cumm, Platelet >75,000/cumm).
Multicolor flow-cytometry for MRD will be performed using a 13-color T-MRD panel in Dx FLEX flow-cytometer (Beckman Coulter). The analysis will be performed with Kaluza version 2.0 software.
T-ALL patients in CR-1 who are MRD positive i.e., ≥0.01% on flow-cytometry at the end of phase 1b induction (two phases of chemotherapy) and CD38 positive (expression on >=20% blasts) will be eligible for the 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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults ≥18 - ≤65 years of age
- •Baseline diagnosis of T-ALL, including ETP-ALL
- •MRD positive (≥0.01%) disease (by flow-cytometry) assessed on BM after two phases of induction chemotherapy in CR-1
- •CD38 positive
- •Eastern cooperative oncology group (ECOG) performance status ≤2
- •Acceptable liver functions, as specified below:
- •Total bilirubin <2 times upper limit of normal (ULN); Aspartate transaminase (AST;SGOT), alanine transaminase (ALT;SGPT) <3 ULN
- •Subject ready to sign an informed consent form
- •Patients with baseline CSF cytology positive, but who have cleared CSF by either modality (cytology or flow cytometry)
排除标准
- •T-LBL (T-lymphoblastic lymphoma) without BM involvement
- •Patients with persistently positive CSF cytology after two phases of induction or baseline testicular involvement
- •Patients with symptomatic obstructive airway disease, as per assessing clinician
- •Presence of an active systemic infection, as per assessing clinician
- •New York Heart Association (NYHA) Class III or IV cardiac disease, or left ventricular ejection fraction <40%
- •Human immunodeficiency virus (HIV) positive.
- •Pregnant or breastfeeding female
- •HBsAg positive or HBV-DNA positivity
研究组 & 干预措施
Single Arm
This will be a single arm, open-label, prospective, interventional phase 2 study. T-ALL patients who are MRD positive post two courses of induction therapy (as per pediatric inspired protocol) will be eligible for this study
干预措施: Daratumumab Injection (Drug)
结局指标
主要结局
MRD negativity
时间窗: "week 3 after Daratumumab initiation"
To determine the MRD negativity rates after two doses of weekly intravenous daratumumab as a single agent for MRD positive T-ALL
次要结局
- To determine cumulative incidence of MRD negativity("Upto week 5 after Daratumumab initiation")
- Progression free survival("1-year after initiation of daratumumab")
- Adverse events("From day of initiation of daratumumab till four weeks after the last dose of daratumumab")