Risk-Stratified Randomized Phase III Testing of Blinatumomab (NSC#765986) in First Relapse of Childhood B-Lymphoblastic Leukemia (B-ALL)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 669
- 试验地点
- 339
- 主要终点
- Disease Free Survival (DFS) of High-risk (HR) and Intermediate-risk (IR) Relapse Patients
研究概览
简要总结
This randomized phase III trial studies how well blinatumomab works compared with standard combination chemotherapy in treating patients with B-cell acute lymphoblastic leukemia that has returned after a period of improvement (relapsed). Immunotherapy with blinatumomab may allow the body's immune system to attack and destroy some types of leukemia cells. It is not yet known whether blinatumomab is more effective than standard combination chemotherapy in treating relapsed B-cell acute lymphoblastic leukemia.
详细描述
PRIMARY OBJECTIVES:
I. To compare disease free survival (DFS) of high-risk (HR) and intermediate-risk (IR) relapse B-cell acute lymphoblastic leukemia (B-ALL) patients who are randomized following induction block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR randomization) as a part of a treatment regimen prior to allogeneic bone marrow transplantation. (Closed to enrollment effective September 18, 2019) II. To compare the DFS of low risk (LR) relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR randomization). (Closed to enrollment effective September 30, 2019)
SECONDARY OBJECTIVES:
I. To compare overall survival (OS) of HR and IR relapse B-ALL patients who are randomized following induction block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR randomization). (Closed to enrollment effective September 18, 2019) II. To compare OS of LR relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR randomization).
EXPLORATORY OBJECTIVES:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 31 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients >= 1 year and < 31 years of age at the time of relapse will be eligible
- •First relapse of B-ALL, allowable sites of disease include isolated bone marrow, combined bone marrow and CNS and/or testicular, and isolated CNS and/or testicular; extramedullary sites are limited to the CNS and testicles
- •No waiting period for patients who relapse while receiving standard maintenance therapy
- •Patients who relapse on frontline therapy in phases other than maintenance must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
- •Cytotoxic therapy: at least 14 days since the completion of cytotoxic therapy with the exception of hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy, or maintenance chemotherapy, or intrathecal chemotherapy (methotrexate strongly preferred) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status
- •Biologic (anti-neoplastic) agent: at least 7 days since the completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
- •Stem cell transplant or rescue: patient has not had a prior stem cell transplant or rescue
- •Patient has not had prior treatment with blinatumomab
- •With the exception of intrathecal chemotherapy (methotrexate strongly preferred; cytarabine is permissible) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status, patient has not received prior relapse-directed therapy (i.e., this protocol is intended as the INITIAL treatment of first relapse)
- •Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
- •Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
- •1 to < 2 years: =< 0.6 mg/dL
- •2 to < 6 years: =< 0.8 mg/dL
- •6 to < 10 years: =< 1 mg/dL
- •10 to < 13 years: =< 1.2 mg/dL
- •13 to < 16 years: =< 1.5 mg/dL (males) and =< 1.4 mg/dL (females)
- •>= 16 years: =< 1.7 mg/dL (males) and =< 1.4 mg/dL (females)
- •Direct bilirubin < 3.0 mg/dL
- •Shortening fraction of >= 27% by echocardiogram, or
- •Ejection fraction of >= 50% by radionuclide angiogram
- •All patients and/or their parent or legal guardian must sign a written informed consent
- •All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
排除标准
- •Patients with Philadelphia chromosome positive/breakpoint cluster region protein (BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL1)+ ALL are not eligible
- •Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia are not eligible
- •Patients with T-lymphoblastic leukemia (T-ALL)/lymphoblastic lymphoma (T-LL) are not eligible
- •Patients with B-lymphoblastic lymphoma (B-LL) are not eligible
- •Patients with known optic nerve and/or retinal involvement are not eligible; patients who are presenting with visual disturbances should have an ophthalmologic exam and, if indicated, a magnetic resonance imaging (MRI) to determine optic nerve or retinal involvement
- •Patients known to have one of the following concomitant genetic syndromes: Down syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome
- •Patients with known human immunodeficiency virus (HIV) infection
- •Patients with known allergy to mitoxantrone, cytarabine, or both etoposide and etoposide phosphate (Etopophos)
- •Lactating females who plan to breastfeed
- •Patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential
- •Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
- •Patients with pre-existing significant central nervous system pathology that would preclude treatment with blinatumomab, including: history of severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination/movement disorder, or autoimmune disease with CNS involvement are not eligible; patients with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not eligible; (patients with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic deficits have resolved)
- •Patients with uncontrolled seizure disorder are not eligible; (patients with seizure disorders that do not require antiepileptic drugs, or are well controlled with stable doses of antiepileptic drugs remain eligible)
研究组 & 干预措施
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Cyclophosphamide (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Therapeutic Hydrocortisone (Drug)
Arm B (HR and IR blinatumomab)
Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT.
干预措施: Dexamethasone (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Vincristine (Drug)
Arm B (HR and IR blinatumomab)
Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT.
干预措施: Cytarabine (Drug)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Pegaspargase (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Cytarabine (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Etoposide (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Methotrexate (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Leucovorin Calcium (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Mitoxantrone Hydrochloride (Drug)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Leucovorin Calcium (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Leucovorin Calcium (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Pharmacological Study (Other)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Etoposide (Drug)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Methotrexate (Drug)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Mercaptopurine (Drug)
Arm B (HR and IR blinatumomab)
Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT.
干预措施: Therapeutic Hydrocortisone (Drug)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Dexamethasone (Drug)
Arm B (HR and IR blinatumomab)
Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT.
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Asparaginase (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Blinatumomab (Biological)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Therapeutic Hydrocortisone (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Dexamethasone (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Radiation Therapy (Radiation)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Mercaptopurine (Drug)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Cytarabine (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Pegaspargase (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Cytarabine (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Cyclophosphamide (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Mitoxantrone (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Pegaspargase (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Asparaginase (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Methotrexate (Drug)
Arm B (HR and IR blinatumomab)
Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT.
干预措施: Pharmacological Study (Other)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Pharmacological Study (Other)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Vincristine Sulfate (Drug)
Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
干预措施: Therapeutic Hydrocortisone (Drug)
Arm B (HR and IR blinatumomab)
Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT.
干预措施: Blinatumomab (Biological)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Radiation Therapy (Radiation)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Dexamethasone (Drug)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Vincristine (Drug)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Vincristine Sulfate (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Cyclophosphamide (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Pharmacological Study (Other)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Vincristine Sulfate (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Vincristine (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Etoposide (Drug)
Arm B (HR and IR blinatumomab)
Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT.
干预措施: Methotrexate (Drug)
Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
干预措施: Thioguanine (Drug)
Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
干预措施: Thioguanine (Drug)
结局指标
主要结局
Disease Free Survival (DFS) of High-risk (HR) and Intermediate-risk (IR) Relapse Patients
时间窗: Up to 2 years from date of randomization
DFS rates of HR and IR relapse B-ALL patients who are randomized following Induction Block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR Randomization). DFS is calculated as the time from randomization to date of first event (treatment failure, relapse, second malignancy, remission death) or date of last contact. Two-year DFS estimates will be calculated from date of randomization for both Arm A and Arm B. Two-sided 95% confidence intervals will be calculated.
Disease Free Survival (DFS) of Low Risk (LR) Relapse Patients
时间窗: Up to 3 years from date of randomization
DFS rates of LR relapse B-ALL patients who are randomized following Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR Randomization). DFS is calculated as the time from randomization to date of first event (relapse, second malignancy, remission death) or date of last contact. Three-year DFS estimates will be calculated from date of randomization for both Arm C and Arm D. Two-sided 95% confidence intervals will be calculated.
次要结局
- Overall Survival (OS) of HR and IR Relapse Patients(Up to 2 years from date of randomization)
- Overall Survival (OS) of LR Relapse Patients(Up to 3 years from date of randomization)