International Phase 3 Trial in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Testing Imatinib in Combination With Two Different Cytotoxic Chemotherapy Backbones
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 352
- 试验地点
- 412
- 主要终点
- Disease free survival (DFS) of Randomized Arms (standard risk [SR] Philadelphia chromosome [Ph+] acute lymphoblastic leukemia [ALL] patients)
研究概览
简要总结
This randomized phase III trial studies how well imatinib mesylate works in combination with two different chemotherapy regimens in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (ALL). Imatinib mesylate has been shown to improve outcomes in children and adolescents with Philadelphia chromosome positive (Ph+) ALL when given with strong chemotherapy, but the combination has many side effects. This trial is testing whether a different chemotherapy regimen may work as well as the stronger one but have fewer side effects when given with imatinib. The trial is also testing how well the combination of chemotherapy and imatinib works in another group of patients with a type of ALL that is similar to Ph+ ALL. This type of ALL is called "ABL-class fusion positive ALL", and because it is similar to Ph+ ALL, is thought it will respond well to the combination of agents used to treat Ph+ ALL.
详细描述
PRIMARY OBJECTIVE:
I. To compare disease-free survival (DFS) of standard risk (SR) pediatric Philadelphia chromosome (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib) combined with either a high-risk Children's Oncology Group (COG) ALL chemotherapy backbone or the more intensive European (Es)PhALL chemotherapy backbone.
SECONDARY OBJECTIVES:
I. To compare DFS of SR pediatric Ph+ and ABL-class fusion positive ALL patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone.
II. To determine the feasibility of administration of imatinib after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk (HR) Ph+ ALL patients.
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 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •For patients enrolled on APEC14B1 prior to enrollment on AALL1631, the required diagnostic bone marrow sample has been fulfilled
- •For patients who have not previously enrolled on APEC14B1 prior to enrollment on AALL1631, a baseline diagnostic sample (or peripheral blood sample with blasts if marrow sample unavailable) must be available to develop an MRD probe
- •In addition, laboratory reports detailing evidence of BCR::ABL1 fusion or ABL-class fusion must be submitted for rapid central review within 72 hours of study enrollment
- •>= 1 year (365 days) and =< 21 years at ALL diagnosis
- •Ph+ (BCR::ABL1 fusion): newly diagnosed de novo ALL (B-ALL or T-ALL) or mixed phenotypic acute leukemia (MPAL meeting 2016 World Health Organization [WHO] definition) with definitive evidence of BCR::ABL1 fusion by karyotype, fluorescence in situ hybridization (FISH) and/or molecular methodologies
- •ABL-class fusion: newly diagnosed B-ALL with definitive evidence of ABL-class fusions. ABL-class fusions are defined as those involving the following genes: ABL1, ABL2, CSF1R, PDGFRB, PDGFRA. Methods of detection include fluorescence in-situ hybridization ([FISH], e.g. using break-apart or colocalization signals probes), multiplex or singleplex reverse-transcription polymerase chain reaction (RT-PCR), whole transcriptome or panel-based RNA-sequencing (e.g. TruSight RNA Pan-Cancer Panel; Illumina, San Diego, California [CA], United States of America [USA] or similar)
- •Ph+ patients must have previously started Induction therapy, which includes vincristine, a corticosteroid, pegaspargase, with or without anthracycline, and/or other standard cytotoxic chemotherapy
- •Ph+ patients have not received more than 14 days of multiagent Induction therapy beginning with the first dose of vinCRIStine
- •Ph+ patients may have started imatinib prior to study entry but have not received more than 14 days of imatinib
- •ABL-class fusion patients must have previously completed the 4 or 5 weeks of multiagent Induction chemotherapy (Induction IA phase)
- •ABL-class fusion patients may have started imatinib during Induction IA, at the same time of or after the first vinCRIStine dose
- •Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2
- •Direct bilirubin =< 2.0 mg/dL
- •Shortening fraction of >= 27% by echocardiogram
- •Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram
- •Corrected QT interval, QTc < 480 msec
- •Note: Repeat echocardiogram and electrocardiogram are not required if they were performed at or after initial ALL diagnosis, before study enrollment
- •Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or serum creatinine within normal limits based on age/gender, as follows:
- •1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
- •2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
- •6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
- •10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
- •13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
- •>= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
排除标准
- •Known history of chronic myelogenous leukemia (CML)
- •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
- •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 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 treatment according to protocol
- •Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart block
- •Prior treatment with dasatinib, or any TKI other than imatinib
研究组 & 干预措施
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Questionnaire Administration (Other)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Prednisolone (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Methylprednisolone (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Vincristine Sulfate (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Questionnaire Administration (Other)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Cytarabine (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Daunorubicin Hydrochloride (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Dexamethasone (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Dexrazoxane Hydrochloride (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Methylprednisolone (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Pegaspargase (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Prednisolone (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Dexrazoxane Hydrochloride (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Doxorubicin (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Etoposide (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Filgrastim (Biological)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Imatinib Mesylate (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Leucovorin Calcium (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Levoleucovorin (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Mercaptopurine (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Methotrexate (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Methylprednisolone (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Thioguanine (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Methotrexate (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Thioguanine (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Levoleucovorin (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Leucovorin Calcium (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Doxorubicin (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Ifosfamide (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Pegaspargase (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Cyclophosphamide (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Dexamethasone (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Dexrazoxane Hydrochloride (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Mercaptopurine (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Questionnaire Administration (Other)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Thioguanine (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Dexamethasone (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Ifosfamide (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Pegaspargase (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Prednisolone (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Therapeutic Hydrocortisone (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Mercaptopurine (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Calaspargase Pegol (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Cyclophosphamide (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Cytarabine (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Doxorubicin (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Imatinib Mesylate (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Laboratory Biomarker Analysis (Other)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Leucovorin Calcium (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Levoleucovorin (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Calaspargase Pegol (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Methotrexate (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Cyclophosphamide (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Vincristine Sulfate (Drug)
Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
干预措施: Calaspargase Pegol (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Laboratory Biomarker Analysis (Other)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Filgrastim (Biological)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Therapeutic Hydrocortisone (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Imatinib Mesylate (Drug)
Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
干预措施: Etoposide (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Laboratory Biomarker Analysis (Other)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Cytarabine (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Daunorubicin Hydrochloride (Drug)
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
干预措施: Vincristine Sulfate (Drug)
结局指标
主要结局
Disease free survival (DFS) of Randomized Arms (standard risk [SR] Philadelphia chromosome [Ph+] acute lymphoblastic leukemia [ALL] patients)
时间窗: Up to 3 years
Three-year DFS and 95% confidence intervals (CI) of SR Ph+ ALL patients treated continuous imatinib mesylate with high risk Children's Oncology Group (COG)-ALL chemotherapy backbone or more intensive European (Es)PhALL chemotherapy backbone.
次要结局
- DFS on Randomized Arms (SR Ph+ ALL and ABL-class fusion positive patients)(Up to 3 years)
- Feasibility of post hematopoietic stem cell transplantation (HSCT) imatinib mesylate administration after allogenic HSCT in high risk Ph+ ALL patients(Up to 2 years)
- Event free survival (EFS) of high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission, and post-HSCT imatinib mesylate(Up to 3 years)
- Incidence of grade 3 or higher infections in standard risk Ph+ ALL patients in the two randomized arms(Up to 3 years)
- EFS of all Ph+ patients(Up to 3 years)
- Overall survival (OS) of all Ph+ patients(Up to 3 years)
- OS of SR Ph+ patients(Up to 3 years)
- OS of SR Ph+ patients by randomization group(Up to 3 years)
- OS of high risk Ph+ patients(Up to 3 years)
- EFS of all eligibility ABL-class fusion positive ALL patients(Up to 3 years)
- OS of all eligibility ABL-class fusion positive ALL patients(Up to 3 years)