A Phase 3 Trial Investigating Blinatumomab (NSC# 765986) in Combination With Chemotherapy in Patients With Newly Diagnosed Standard Risk or Down Syndrome B-Lymphoblastic Leukemia (B-ALL) and the Treatment of Patients With Localized B-Lymphoblastic Lymphoma (B-LLy)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 6,720
- 试验地点
- 398
- 主要终点
- DFS in boys in the SR-favorable subset of SR B-ALL with or without Down syndrome (DS)
研究概览
简要总结
This phase III trial studies how well blinatumomab works in combination with chemotherapy in treating patients with newly diagnosed, standard risk B-lymphoblastic leukemia or B-lymphoblastic lymphoma with or without Down syndrome. Monoclonal antibodies, such as blinatumomab, may induce changes in the body's immune system and may interfere with the ability of cancer cells to grow and spread. Chemotherapy drugs, such as vincristine, dexamethasone, prednisone, prednisolone, pegaspargase, methotrexate, cytarabine, mercaptopurine, doxorubicin, cyclophosphamide, and thioguanine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Leucovorin decreases the toxic effects of methotrexate. Giving monoclonal antibody therapy with chemotherapy may kill more cancer cells. Giving blinatumomab and combination chemotherapy may work better than combination chemotherapy alone in treating patients with B-ALL. This trial also assigns patients into different chemotherapy treatment regimens based on risk (the chance of cancer returning after treatment). Treating patients with chemotherapy based on risk may help doctors decide which patients can best benefit from which chemotherapy treatment regimens.
详细描述
PRIMARY OBJECTIVES:
I. To determine in a randomized manner if the addition of 2 cycles of blinatumomab to standard therapy improves disease-free survival (DFS) in patients with standard risk (SR) B-ALL and higher risk features (SR-High), and patients with standard-risk average (SR-Avg) B-ALL who are negative for minimal residual disease (MRD) by flow cytometry but have detectable or indeterminate MRD as measured by high-throughput sequencing (HTS) at end of induction (EOI).
II. To confirm that boys in the standard-risk favorable (SR-Fav) subset of B-ALL, with or without Down syndrome (DS), will maintain a 5-year DFS of greater than 93% when treated with a standard chemotherapy regimen with a treatment duration of 2 years from the start of interim maintenance I (IM1).
SECONDARY OBJECTIVES:
I. To describe the DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of IM1, regardless of sex.
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
- 365 Days 至 31 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to treatment and enrollment on AALL
- •APEC 14B1 is not a requirement for B-LLy patients. B-LLy patients may directly enroll on AALL
- •Age at diagnosis:
- •Patients must be >= 365 days and < 10 years of age (B-ALL patients without DS).
- •Patients must be >= 365 days and =< 31 years of age (B-ALL patients with DS).
- •Patients must be >= 365 days and =< 31 years of age (B-LLy patients with or without DS).
- •B-ALL patients without DS must have an initial white blood cell count < 50,000/uL (performed within 7 days prior to enrollment).
- •B-ALL patients with DS are eligible regardless of the presenting white blood cell count (WBC) (performed within 7 days prior to enrollment).
- •Patient has newly diagnosed B-cell ALL, with or without Down syndrome: > 25% blasts on a bone marrow (BM) aspirate;
- •OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis can be established by a pathologic diagnosis of B-ALL on a BM biopsy;
- •OR a complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells;
- •OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without Down syndrome.
- •Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e., paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted (diagnostic biopsy for B-LLy must be performed within 14 days prior to enrollment).
- •All patients and/or their parents or legal guardians 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
- •Patient must not have secondary ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior history of transient myeloproliferative disease (TMD) are not considered to have had a prior malignancy. They would therefore be eligible whether or not the TMD was treated with cytarabine.
- •With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B ALL or B LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL
- •For patients receiving steroid pretreatment, the following additional exclusion criteria apply:
- •Non-DS B-ALL patients must not have received steroids for more than 24 hours in the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to initiation of the steroids.
- •DS and non-DS B-LLy patients must not have received > 48 hours of oral or IV steroids within 4 weeks of diagnosis.
- •Patients who have received > 72 hours of hydroxyurea within 1 week (7 days) prior to the start of systemic protocol therapy.
- •B-ALL patients who do not have sufficient diagnostic bone marrow submitted for APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted containing > 1,000/uL circulating leukemia cells.
- •Patient must not have acute undifferentiated leukemia (AUL).
- •Non-DS B-ALL patients with central nervous system [CNS]3 leukemia (CNS status must be known prior to enrollment).
- •Note: DS patients with CNS3 disease are eligible but will be assigned to the DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment.
- •Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular disease are eligible but will be assigned to the DS-High B-ALL arm).
- •For LLy patients, the following additional exclusion criteria apply:
- •T-Lymphoblastic Lymphoma.
- •Morphologically unclassifiable lymphoma.
- •Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic lymphoma.
- •CNS positive disease or testicular involvement.
- •M2 (5% - 25% blasts) or M3 (> 25% blasts) marrow.
- •Patients with known Charcot-Marie-Tooth disease.
- •Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL, regardless of blast immunophenotype.
- •Patients requiring radiation at diagnosis.
- •Female 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.
- •Lactating females who plan to breastfeed their infants.
- •Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.
研究组 & 干预措施
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Thioguanine (Drug)
B-LLy
See detailed description.
干预措施: Mercaptopurine Oral Suspension (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Pegaspargase (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Asparaginase Erwinia chrysanthemi (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Cytarabine (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Dexamethasone (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Cyclophosphamide (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Cytarabine (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Dexamethasone (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Leucovorin Calcium (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Mercaptopurine (Drug)
B-LLy
See detailed description.
干预措施: Cyclophosphamide (Drug)
B-LLy
See detailed description.
干预措施: Cytarabine (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Blinatumomab (Biological)
DS B-ALL
See detailed description.
干预措施: Asparaginase Erwinia chrysanthemi (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Asparaginase Erwinia chrysanthemi (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Asparaginase Erwinia chrysanthemi (Drug)
DS B-ALL
See detailed description.
干预措施: Radiation Therapy (Radiation)
B-LLy
See detailed description.
干预措施: Vincristine Sulfate (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Mercaptopurine Oral Suspension (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Prednisolone (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Prednisone (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Asparaginase Erwinia chrysanthemi (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Blinatumomab (Biological)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Cytarabine (Drug)
DS B-ALL
See detailed description.
干预措施: Pegaspargase (Drug)
DS B-ALL
See detailed description.
干预措施: Methotrexate (Drug)
DS B-ALL
See detailed description.
干预措施: Mercaptopurine (Drug)
DS B-ALL
See detailed description.
干预措施: Thioguanine (Drug)
DS B-ALL
See detailed description.
干预措施: Vincristine Sulfate (Drug)
B-LLy
See detailed description.
干预措施: Asparaginase Erwinia chrysanthemi (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Leucovorin Calcium (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Mercaptopurine Oral Suspension (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Methotrexate (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Thioguanine (Drug)
DS B-ALL
See detailed description.
干预措施: Dexamethasone (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Mercaptopurine (Drug)
DS B-ALL
See detailed description.
干预措施: Doxorubicin Hydrochloride (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Dexamethasone (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Mercaptopurine (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Cyclophosphamide (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Methotrexate (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Asparaginase Erwinia chrysanthemi (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Cytarabine (Drug)
B-LLy
See detailed description.
干预措施: Thioguanine (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Vincristine Sulfate (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Cyclophosphamide (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Dexamethasone (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Thioguanine (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Pegaspargase (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Methotrexate (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Doxorubicin Hydrochloride (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Mercaptopurine (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Prednisolone (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Prednisone (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Vincristine Sulfate (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Leucovorin Calcium (Drug)
B-LLy
See detailed description.
干预措施: Leucovorin Calcium (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Leucovorin Calcium (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Blinatumomab (Biological)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Methotrexate (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Pegaspargase (Drug)
NCI SR or HR DS B-ALL
See detailed description.
干预措施: Leucovorin Calcium (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Mercaptopurine Oral Suspension (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Mercaptopurine Oral Suspension (Drug)
DS B-ALL
See detailed description.
干预措施: Leucovorin Calcium (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Mercaptopurine Oral Suspension (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Pegaspargase (Drug)
Arm C (SR-High Control)
Arm C: See detailed description.
干预措施: Pegaspargase (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Prednisolone (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Prednisone (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Thioguanine (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Cyclophosphamide (Drug)
DS B-ALL
See detailed description.
干预措施: Cyclophosphamide (Drug)
B-LLy
See detailed description.
干预措施: Mercaptopurine (Drug)
B-LLy
See detailed description.
干预措施: Methotrexate (Drug)
B-LLy
See detailed description.
干预措施: Pegaspargase (Drug)
B-LLy
See detailed description.
干预措施: Prednisone (Drug)
B-LLy
See detailed description.
干预措施: Prednisolone (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Vincristine Sulfate (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Mercaptopurine (Drug)
DS B-ALL
See detailed description.
干预措施: Mercaptopurine Oral Suspension (Drug)
B-LLy
See detailed description.
干预措施: Dexamethasone (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Vincristine Sulfate (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Doxorubicin Hydrochloride (Drug)
DS B-ALL
See detailed description.
干预措施: Cytarabine (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Vincristine Sulfate (Drug)
B-LLy
See detailed description.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm A (SR-Avg control)
Arm A: See detailed description.
干预措施: Prednisone (Drug)
Arm B (SR-Avg experimental)
Arm B: See detailed description.
干预措施: Dexamethasone (Drug)
Arm D (SR-High experimental)
Arm D See detailed description.
干预措施: Methotrexate (Drug)
结局指标
主要结局
DFS in boys in the SR-favorable subset of SR B-ALL with or without Down syndrome (DS)
时间窗: 5.1 years
DFS is calculated as the time from end of induction to first event (relapse, second malignancy, remission death) or censored at date of last contact. A five year DFS estimate and two-sided 80% confidence interval will be calculated.
Disease free survival (DFS) in randomization eligible patients with higher risk features (SR-High) or standard risk average (SR-Avg) B-ALL patients based on randomization with addition of blinatumomab
时间窗: 5.3 years
Will be assessed in SR-High patients and SR-Avg B-ALL patients who are negative for MRD by flow cytometry but have detectable or indeterminate MRD as measured by high throughput sequencing (HTS) at end of induction (EOI), and patients with double trisomy of chromosomes 4 and 10 (DT) with MRD (flow) 0.01% - \< 0.1%. DFS is calculated as the time from randomization at the end of consolidation to first event (relapse, second malignancy, remission death) or censored at date of last contact. Five year DFS estimates will be calculated from the point of randomization for both groups. Two-sided 95% confidence intervals will be calculated.
次要结局
- DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of interim maintenance (IM)1, regardless of sex(5.1 years)
- Treatment-related mortality in Down syndrome high risk (DS-high) patients after replacement of intensive elements of standard chemotherapy (omission of anthracyclines in induction, omission of the second month of DI) with 3 cycles of blinatumomab(2.3 years)
- Caregiver burden as measured by the Mean Total score from the Care of My Child with Cancer questionnaire among a subset of children enrolled in the HMH and neurocognitive outcome study(1 year)
- Caregiver burden as measured by the At-Work Productivity Loss summary score from the Caregiver Work Limitations questionnaire among a subset of children enrolled in the HMH and neurocognitive outcome study(1 year)
- BM using HTS MRD vs. BM by flow cytometry at EOC in patients who were Day 29 MRD positive by flow cytometry(1 year)
- DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated with a standard chemotherapy regimen(5.1 years)
- DFS of DS-High B-ALL patients when intensive elements of chemotherapy are replaced with 3 cycles of blinatumomab(5.3 years)
- DFS of patients with localized B-lymphoblastic lymphoma (B-LLy) receiving standard risk acute lymphoblastic leukemia therapy(5 years)
- Change in neurocognitive functioning from baseline to end-of-therapy between children from poor (defined as presence of household material hardship [HMH], including either food, housing or energy insecurity) and non-poor families (absence of HMH)(3.3 years)
- Peripheral blood (PB) samples using HTS MRD vs. bone marrow (BM) results at EOI(1 year)