Phase 2 Study Evaluating the Safety, Tolerability and Efficacy of Allogeneic Donor Lymphocyte Infusions Combined With Blinatumomab in Patients With Treatment-Resistant Mixed Chimerism or Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia After Allogeneic Stem Cell Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Safety and tolerability of combined DLI and blinatumomab treatment in subjects with treatment-resistant MC or MRD of CD19+ B-precursor ALL after allogeneic SCT
研究概览
简要总结
This phase 2 study is designed to evaluate the safety, tolerability and efficacy of allogeneic donor lymphocyte infusions (DLI) combined with the bispecific T cell engager blinatumomab in B-precursor ALL patients who have mixed chimerism (MC) or are MRD-positive after allogeneic SCT and are refractory to at least one MRD- or MC-targeted therapy (i.e. blinatumomab, DLI, tyrosine kinase inhibitors or other agents).
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
- •Adult patients with CD19+ B-precursor ALL (as determined by immunophenotyping) in hCR (defined as having less than 5% blasts in bone marrow) after allogeneic SCT.
- •One, or a combination of the following documented after an interval of at least 2 weeks since cessation of the most recent leukemia-targeting therapy (i.e. chemotherapy, immunotherapy or cellular therapy, except for intrathecal prophylaxis):
- •Positivity for CD19+ MRD (molecular failure or molecular relapse), defined as presence of MRD at a level of ≥10^-4 according to an assay with a minimum sensitivity of 10^-
- •Donor chimerism <90%, as determined by analysis of host and donor STRs in bone marrow sample engraftment analysis.
- •At least one previous line of treatment for MRD-positivity and/or reduced donor chimerism (i.e. blinatumomab, DLI, TKI or other agents) after allogeneic SCT.
- •For those with BCR/ABL-positive B-precursor ALL only: persistence of MRD and/or MC following at least one ≥ second generation TKI (dasatinib, nilotinib, bosutinib, ponatinib) OR intolerance to second generation TKI and intolerance to or persistence of MRD and/or MC following imatinib mesylate.
- •Availability of allogeneic donor lymphocytes from the subject's donor (at least 2 x 10^8 T cells/kg).
- •Subject has provided written informed consent prior to initiation of any study-specific activities/procedures.
- •Subject has provided informed consent to be followed up in the GMALL-Registry.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤
- •Renal function as follows: serum creatinine < 2.0 mg/dL and estimated glomerular filtration rate > 30 mL/min.
- •Hepatic function as follows:
- •Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN)
- •Alkaline phosphatase (ALP) < 3.0 x ULN
- •Bilirubin ≤ 2.0 x ULN (unless considered due to Gilbert's syndrome or hemolysis)
- •For female subjects only: Women of child-bearing age have to use a reliable method of contraception.
排除标准
- •Eligibility for treatment with blinatumomab ALONE or other antibody-based treatment approaches (e.g. inotuzumab ozogamicin), as considered by the treating physician.
- •Eligibility for standard chemotherapy, as considered by the treating physician.
- •Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, retinoid therapy, or investigational agent) within 14 days or 5 half-lives (whichever is longer) prior to baseline MRD and/or chimerism assessment.
- •Treatment with systemic immune modulators including, but not limited to, non-topical systemic corticosteroids, cyclosporine, and tacrolimus within 2 weeks before enrollment.
- •Any grade of GvHD currently requiring treatment.
- •Clinically relevant central nervous system (CNS) pathology requiring treatment (e.g., unstable epilepsy).
- •Evidence of current CNS involvement by ALL.
研究组 & 干预措施
DLI-TARGET
14d screening period: methotrexate, cytarabine, dexamethasone infusion i.th.
Cycle 1 (all patients): d1-28: blinatumomab continuous infusion i.v., d4: allogeneic donor lymphocyte single infusion i.v., d29: methotrexate, cytarabine, dexamethasone infusion i.th.
Cycle 2 (only patients with toxicity ≤ grade 2 CTCAE in cycle 1): d43-d70: blinatumomab continuous infusion i.v., d46: allogeneic donor lymphocyte single infusion i.v., d71: methotrexate, cytarabine, dexamethasone infusion i.th.
干预措施: Blinatumomab in combination with donor lymphocyte infusion (Drug)
结局指标
主要结局
Safety and tolerability of combined DLI and blinatumomab treatment in subjects with treatment-resistant MC or MRD of CD19+ B-precursor ALL after allogeneic SCT
时间窗: 18 weeks
Subject incidence and grade of adverse events (AEs) including graft-versus-host disease (GvHD). The intensity of (S)AEs will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.
次要结局
- Efficacy of a combined treatment of DLI and blinatumomab to induce a complete MRD/chimerism response(18 weeks)
- Duration of the response and survival after combined treatment of DLI and blinatumomab(18 weeks)
研究者
Christian Schmidt, MD
Deputy Principal Investigator
Ludwig-Maximilians - University of Munich