An International Phase 2 Study of Chemotherapy and Tyrosine Kinase Inhibitors With Blinatumomab in Patients With Newly-Diagnosed Philadelphia Chromosome-Positive or ABL-Class Philadelphia Chromosome-Like B-Cell Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 222
- 试验地点
- 266
- 主要终点
- Philadelphia chromosome-positive (Ph+) (BCR::ABL1-rearranged) 3-year event free survival (EFS)
研究概览
简要总结
This pilot trial assesses the effect of the combination of blinatumomab with dasatinib or imatinib and standard chemotherapy for treating patients with Philadelphia chromosome positive (Ph+) or ABL-class Philadelphia chromosome-like (Ph-like) B-Cell acute lymphoblastic leukemia (B-ALL). Blinatumomab is a bispecific antibody that binds to two different proteins-one on the surface of cancer cells and one on the surface of cells in the immune system. An antibody is a protein made by the immune system to help fight infections and other harmful processes/cells/molecules. Blinatumomab may bind to the cancer cell and a T cell (which plays a key role in the immune system's fighting response) at the same time. Blinatumomab may strengthen the immune system's ability to fight cancer cells by activating the body's own immune cells to destroy the tumor. Dasatinib and imatinib are in a class of medications called tyrosine kinase inhibitors. They work by blocking the action of an abnormal protein that signals cancer cells to multiply, which may help keep cancer cells from growing. Giving blinatumomab and dasatinib or imatinib in combination with standard chemotherapy may work better in treating patients with Ph+ or Ph-like ABL-class B-ALL than dasatinib or imatinib with chemotherapy.
详细描述
PRIMARY OBJECTIVES:
I. To estimate the 3-year event free survival (EFS) of children, adolescents, and young adults <25 years old with newly-diagnosed Ph+ (BCR::ABL1-rearranged) B- ALL who are treated with a modified Berlin-Frankfurt-Münster (mBFM) chemotherapy backbone that incorporates three cycles of blinatumomab without traditional consolidation chemotherapy in combination with continuous dasatinib.
II. To estimate the 3-year EFS of children, adolescents, and young adults <25 years old with newly-diagnosed ABL-class Ph-like B-ALL who are treated with a modified BFM chemotherapy backbone that incorporates three cycles of blinatumomab without traditional consolidation chemotherapy in combination with continuous imatinib for those with PDGFRB gene fusions or dasatinib for those without PDGFRB gene fusions.
III. To describe the safety and toxicity profile (infections, mucositis, neurotoxicity, cytokine release syndrome, hypogammaglobulinemia, therapy delays > 14 days, and treatment-related mortality) for patients with Ph+ or ABL-class Ph-like B-ALL treated on this novel chemo-immunotherapy backbone with continuous tyrosine kinase inhibitor (TKI).
SECONDARY OBJECTIVES:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 366 Days 至 46 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must be > 365 days and < 18 years (for AIEOP-BFM), > 365 days and < 22 years (for Children's Oncology Group [COG]) and > 365 days and < 46 years (for ALLTogether sites) at the time of enrollment
- •Newly-diagnosed Ph+ or ABL-class Ph-like B-ALL. Leukemic blasts must express CD
- •ABL-class fusions are defined as rearrangements involving the following genes predicted to be sensitive to imatinib and/or dasatinib: ABL1, ABL2, CSF1R, and PDGFRB
- •Evidence of BCR::ABL1 should be documented by a clinically-validated assay prior to study entry on day 15 from the first dose of vinCRIStine during Induction therapy. ABL-class Ph-like B-ALL gene rearrangements should be documented by a clinically-validated assay and enrolled on study by day 1 of Blinatumomab Block
- •Accepted methods of detection include fluorescence in situ hybridization (FISH) using break-apart of colocalization signal probes, singleplex or multiplex reverse-transcription polymerase chain reaction (RT-PCR), whole-transcriptome or panel-based ribonucleic acid (RNA) sequencing (e.g., Hematologic Cancer Fusion Analysis, TruSight RNA Pan-Cancer Panel or equivalent). Confirmation of 5' fusion partner genes is not required for study enrollment
- •Patients with Ph+ B-ALL must have previously started Induction therapy, which includes vinCRIStine, a corticosteroid, pegaspargase or calaspargase pegol, with or without anthracycline, and/or other standard cytotoxic chemotherapy
- •Patients with Ph+ B-ALL have not received more than 14 days of systemic Induction therapy beginning with the first Induction dose of vinCRIStine
- •Patients with ABL-class Ph-like B-ALL must have previously completed 4 or 5 weeks of multiagent Induction chemotherapy (Induction 1A)
- •Patients may have started either imatinib or dasatinib prior to study entry but should have received no more than 14 days of TKI for Ph+ B-ALL or no more than 35 days of TKI for ABL-class Ph-like B-ALL
- •Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of ≤ 2 or Karnofsky and Lansky performance scores ≥ 50%. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age
- •For pediatric patients (age 1-17 years): a glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2, as determined by one of the following methods (must be performed within 7 days prior to enrollment unless otherwise indicated):
- •Estimated GFR (eGFR) ≥ 50 mL/min/1.73 m2
- •Measured GFR ≥ 50 mL/min/1.73 m^2 (any age). If measured GFR is used, it must be performed using direct measurement with a nuclear blood sampling method or small molecule clearance method (iothalamate or other molecule per institutional standard
- •For adult patients (age 18 years or older): Creatinine clearance ≥ 30 mL/min, as estimated by the Cockcroft and Gault formula. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on body weight
- •Direct bilirubin < 2.0 mg/dL (34.2 micromoles/L) (must be performed within 7 days prior to enrollment unless otherwise indicated)
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 10 x upper limit of normal (ULN) (must be performed within 7 days prior to enrollment unless otherwise indicated)
- •* Shortening fraction of ≥ 27% by echocardiogram (must be obtained within 21 days prior to enrollment and start of protocol therapy [repeat if necessary]) OR
- •Left Ventricular Ejection fraction of ≥ 50% by radionuclide angiogram or echocardiogram (must be obtained within 21 days prior to enrollment and start of protocol therapy [repeat if necessary]) AND
- •Corrected QT Interval, QTc < 480mSec (must be obtained within 21 days prior to enrollment and start of protocol therapy [repeat if necessary])
- •Note: Repeat echocardiogram and electrocardiogram are not required if they were performed at or after initial ALL diagnosis before study enrollment
排除标准
- •Known history of chronic myeloid leukemia (CML)
- •ABL-class Ph-like B-ALL who are CNS2 or CNS3 at end of Induction phase
- •ALL developing after a previous cancer treated with cytotoxic chemotherapy
- •Active, uncontrolled infection or active systemic illness that requires ongoing vasopressor support or mechanical ventilation
- •Down syndrome (trisomy 21)
- •Pregnancy and breast feeding
- •Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A negative pregnancy test is required for female patients of childbearing potential within 7 days prior to enrollment
- •Lactating females who plan to breastfeed their infants
- •Sexually active male and female patients of reproductive potential who have not agreed to use an effective contraception method for the duration of treatment according to protocol
- •NOTE: Patients who could become pregnant or could father a child must use effective contraception during protocol treatment and for 30 days after the last dose of dasatinib or 14 days after the last dose of imatinib dose or per institutional standard of care for multiagent chemotherapy, whichever is longer
- •Prior treatment with TKIs before study entry with the exception of imatinib or dasatinib
- •Patients with congenital long QT syndrome, history of ventricular arrhythmias, or heart block
- •Patients with known Charcot-Marie-Tooth disease
- •Patients with significant central nervous system pathology that would preclude treatment with blinatumomab, including history of severe neurologic disorder or autoimmune disease with central nervous system (CNS) involvement
- •Note: Patients with a history of seizures that are well controlled on stable doses of anti-epileptic drugs are 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
- •HIV-infected patients are eligible if on effective anti-retroviral therapy that does not interact with planned study agents and with undetectable viral load within 6 months of treatment
- •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
研究组 & 干预措施
Stratum I (Ph+ ALL)
See detailed description
干预措施: Blinatumomab (Biological)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Biospecimen Collection (Procedure)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Cyclophosphamide (Drug)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Cytarabine (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Bone Marrow Biopsy (Procedure)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Dasatinib (Drug)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Prednisolone (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Radiation Therapy (Radiation)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Mercaptopurine (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Pegaspargase (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Prednisone (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Leucovorin (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Multigated Acquisition Scan (Procedure)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Biospecimen Collection (Procedure)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Prednisone (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Prednisolone (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Pegaspargase (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Radiation Therapy (Radiation)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Thioguanine (Drug)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Multigated Acquisition Scan (Procedure)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Methotrexate (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Echocardiography Test (Procedure)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Blinatumomab (Biological)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Imatinib (Drug)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Doxorubicin (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Daunorubicin (Drug)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Leucovorin (Drug)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Vincristine (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Vincristine (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Methotrexate (Drug)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Daunorubicin (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Blinatumomab (Biological)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Bone Marrow Biopsy (Procedure)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Cyclophosphamide (Drug)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Bone Marrow Biopsy (Procedure)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Calaspargase Pegol (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Echocardiography Test (Procedure)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Calaspargase Pegol (Drug)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Mercaptopurine (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Calaspargase Pegol (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Doxorubicin (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Leucovorin (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Multigated Acquisition Scan (Procedure)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Cytarabine (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Doxorubicin (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Cytarabine (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Mercaptopurine (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Methotrexate (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Dasatinib (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Daunorubicin (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Thioguanine (Drug)
Stratum III (non-PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Vincristine (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Biospecimen Collection (Procedure)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Prednisolone (Drug)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Pegaspargase (Drug)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Echocardiography Test (Procedure)
Stratum I (Ph+ ALL)
See detailed description
干预措施: Prednisone (Drug)
Stratum II (PDGFRB ABL-Class fusions)
See detailed description.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Philadelphia chromosome-positive (Ph+) (BCR::ABL1-rearranged) 3-year event free survival (EFS)
时间窗: Time from enrollment to first event, relapse, second malignancy, or death in complete remission, or last contact for those who are event-free, assessed up to 3 years
Will be assessed in children, adolescents, and young adults \<25 years old with newly-diagnosed Ph+ (BCR::ABL1-rearranged) B acute lymphoblastic leukemia (B-ALL) who are treated with a modified Berlin-Frankfurt-Münster (mBFM) chemotherapy backbone that incorporates three cycles of blinatumomab without traditional consolidation chemotherapy in combination with continuous dasatinib. Will be estimated using the Kaplan-Meier method with standard errors of Peto.
ABL-class Ph-like B-ALL 3-year event free survival (EFS)
时间窗: Time from enrollment to first event, relapse, second malignancy, or death in complete remission, or last contact for those who are event-free, assessed up to 3 years
Will be assessed in children, adolescents, and young adults \<25 years old with newly-diagnosed ABL-class Ph-like B-ALL who are treated with a modified BFM chemotherapy backbone that incorporates three cycles of blinatumomab without traditional consolidation chemotherapy in combination with continuous imatinib for those with PDGFRB gene fusions or dasatinib for those without PDGFRB gene fusions. Will be estimated using the Kaplan-Meier method with standard errors of Peto.
Incidence of adverse events
时间窗: Up to 3 years
Will assess the safety and toxicity profile (infections, mucositis, neurotoxicity, cytokine release syndrome, hypogammaglobulinemia, therapy delays \> 14 days, and treatment-related mortality) for patients with Ph+ or ABL-class Ph-like B-ALL treated on this novel chemo-immunotherapy backbone with continuous tyrosine kinase inhibitor (TKI). Will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.
次要结局
- Cumulative incidence rates of relapse(Up to 3 years)
- Treatment related mortality(Up to 3 years)
- 3-year overall survival (OS)(Time from enrollment to death from any cause or date of last contact for those who are alive, assessed up to 3 years)
- 3-year EFS(Time from enrollment to first event, relapse, second malignancy, or death in complete remission, or last contact for those who are event-free, assessed up to 3 years)
- 3-year disease free survival(Time from end of consolidation/blinatumomab block 2 (TP2) for early responders to first event (relapse, second malignancy, or death in complete remission) or last contact for those who are event-free, assessed up to 3 years)
- OS of patients with ABL-class Ph-like B-ALL(Time from enrollment to death from any cause or date of last contact for those who are alive, assessed up to 3 years)
- Rates of end of Consolidation (EOC)/timepoint 2 (TP2) minimal residual disease (MRD) negativity for patients with Ph+ B-ALL(From EOC to TP2)
- Rates of EOC/TP2 MRD negativity for patients with ABL-class Ph-like B-ALL collectively and based on their ABL-class fusion subtypes(From EOC to TP2)