A Study Comparing the Combination of Dasatinib and Chemotherapy Treatment With or Without Blinatumomab for Children, Adolescents, and Young Adults With Philadelphia Chromosome Positive (Ph+) or Philadelphia Chromosome-Like (Ph-Like) ABL-Class B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Study Overview
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Brief Summary
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This phase III trial compares the effect of the combination of blinatumomab with dasatinib and standard chemotherapy versus dasatinib and standard chemotherapy for treating patients with Philadelphia chromosome positive (PH+) or Philadelphia chromosome-like (Ph-Like) ABL-class 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 is in a class of medications called tyrosine kinase inhibitors. It works 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 in combination with standard chemotherapy may work better in treating patients with PH+ or Ph-Like ABL-class B-ALL compared to dasatinib and chemotherapy alone.

Detailed Description
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PRIMARY OBJECTIVE: I. To compare the 4-year event free survival (EFS) of children, adolescents, and young adults with Ph+ (BCR:ABL1-rearranged) and Ph-like ABL-class B- ALL who are randomized post-Induction to receive continuous dasatinib and the modified augmented Berlin-Frankfurt-Munster (mBFM) chemotherapy backbone (Arm A) versus continuous dasatinib and a chemotherapy backbone that incorporates three cycles of blinatumomab (Arm B) without traditional consolidation chemotherapy. SECONDARY OBJECTIVES: I. To compare the 4-year and long-term overall survival (OS) of all patients with Ph+ and Ph-like ABL-class B-ALL between randomized arms. I. To compare post-induction/pre-maintenance toxicities (infections, mucositis, neurotoxicity, cytokine release syndrome, therapy delays > 14 days, and treatment-related mortality) between patients on the randomized study arms. I. To compare end of consolidation (EOC)/timepoint 2 (TP2) minimal residual disease (MRD) negativity at the 1x10^-4 or 0.01% threshold between patients on the randomized study arms. EXPLORATORY OBJECTIVES: I. To describe rates of end of induction (EOI)/timepoint 1 (TP1) bone marrow MRD negativity with the introduction of dasatinib by induction day 15 for Ph+ and Ph-like ABL-class B-ALL patients as a whole cohort and as separate groups. II. To describe EFS, disease-free survival (DFS), and overall survival (OS) of Ph+ and Ph-like ABL-class B-ALL patients separately and compared to historical controls. III. To describe the outcomes of patients with Ph+ and Ph-like ABL-class B-ALL who are removed from protocol therapy due to consolidation failure. IV. To describe the percentage of patients with Ph+ and Ph-like ABL-class B-ALL who continue tyrosine kinase inhibitors (TKI) beyond protocol-prescribed therapy and their outcomes. V. To describe the prognostic significance of MRD by next-generation sequencing (NGS) at end of induction and end of consolidation. VI. To describe the clinical characteristics and outcomes of patients with chronic myeloid leukemia (CML)-like biology. VII. To describe the immune function of Ph+ and Ph-like ABL-class B-ALL patients between the two randomized arms and correlate with treatment response. VIII. To describe the dasatinib levels in the plasma and cerebrospinal fluid of children with Ph+ and Ph-like ABL-class B-ALL and correlate with outcome. IX. To describe the impact of dasatinib and high-dose methotrexate interaction and identify clinical and biologic factors influencing methotrexate clearance. OUTLINE: INDUCTION PART I: All patients receive dasatinib orally (PO) or nasogastrically (NG) once daily (QD) days 1-14 per standard of care (SOC). Patients are randomized to 1 of 2 arms. ARM I: INDUCTION PART II: Patients receive dasatinib PO or NG QD on days 15-29, daunorubicin intravenously (IV) over 15 minutes on days 15 and 22, prednisolone or prednisone PO twice daily (BID) on days 1-28, vincristine IV on days 15 and 22, methotrexate intrathecally (IT) on days 15, 22, and 29, and cytarabine IT on days 18 and 25 for 2 weeks on study. CONSOLIDATION PART I: Patients receive dasatinib PO or NG QD on days 1-28, cyclophosphamide IV over 30-60 minutes on day 1, cytarabine IV over 30 minutes on says 1-4 and 8-11, mercaptopurine PO QD on days 1-14, methotrexate IT on days 1, 8, 15 and 22, pegaspargase IV or calaspargase pegol IV over 1-2 hours on day 15, and vincristine IV on days 1 and 22 over 4 weeks on study. CONSOLIDATION PART II: Patients receive dasatinib PO or NG QD on day 29 until the end of consolidation, cyclophosphamide IV over 30-60 minutes on day 29, cytarabine IV over 30 minutes on days 29-32 and 36-39, mercaptopurine PO QD on days 29-42, methotrexate IT on days 1, 8, 15 and 22, pegaspargase IV or calaspargase pegol IV over 1-2 hours on day 43, and vincristine IV on days 43 and 50 over 4 weeks on study. INTERIM MAINTENANCE I: Patients receive dasatinib PO or NG QD until the end of interim maintenance I, mercaptopurine PO QD on days 1-56, vincristine IV on days 8, 22, 36, and 50, methotrexate IT on days 8 and 36, high-dose methotrexate IV over 24 hours on days 8, 22, 36 and 50, and leucovorin PO or IV on days 10, 11, 24, 25, 38, 39, 52 and 53 over 9 weeks on study. DELAYED INTENSIFICATION PART I: Patients receive dasatinib PO or NG QD on days 1-28, methotrexate IT on day 1, dexamethasone PO or IV on days 1-7 and 15-21, doxorubicin IV over 15 minutes on days 1, 8, and 15, vincristine IV on days 1, 8, and 15, and pegaspargase IV or calaspargase pegol IV over 1-2 hours on day 4 over 9 weeks on study. DELAYED INTENSIFICATION PART II: Patients receive dasatinib PO or NG QD on day 29 until the end of delayed intensification part II, cyclophosphamide IV over 60 minutes on day 29, cytarabine IV over 30 minutes on days 29-32 and 36-39, methotrexate IT on days 29 and 36, thioguanine PO on days 29-42, pegaspargase IV or calaspargase pegol on day 43 and vincristine IV on days 43 and 50 over 9 weeks on study. INTERIM MAINTENANCE PART II: Patients receive dasatinib PO or NG QD on day 1 until the end of interim maintenance part II, methotrexate IV on days 1, 11, 21, 31, and 41, vincristine IV on 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV or calaspargase pegol IV over 1-2 hours on days 2, 22 and 23 over 9 weeks on study. MAINTENANCE: Patients receive dasatinib PO or NG QD on days 1-84, methotrexate IT on days 1 and 29, dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84, vincristine IV on days 1, 29 and 57, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 on study. Cycles repeat every 12 weeks for 2 years in the absence of disease progression or unacceptable toxicity. ARM II: INDUCTION PART II: Patients receive dasatinib PO or NG QD on days 15-29, daunorubicin intravenously (IV) over 15 minutes on days 15 and 22, prednisolone or prednisone PO BID on days 1-28, vincristine IV on days 15 and 22 methotrexate IT on days 15, 22, and 29 and cytarabine IT on days 18 and 25 over 2 weeks on study. BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on days 1 and 8, blinatumomab IV on days 1-28, dasatinib PO or NG on days 1-35, and methotrexate IT on days 1 and 15 over 5 weeks on study. Patients may undergo radiation therapy in 12 QD fractions. BLINATUMOMAB BLOCK II: Patients receive dexamethasone PO or IV on day 1, blinatumomab IV on days 1-28, dasatinib PO or NG on days 1-35, and methotrexate IT on days 1 and 15 over 5 weeks on study. INTERIM MAINTENANCE I: Patients receive dasatinib PO or NG QD until the end of interim maintenance I, mercaptopurine PO QD on days 1-56, vincristine IV on days 8, 22, 36, and 50, methotrexate IT on days 8 and 36, high-dose methotrexate IV over 24 hours on days 8, 22, 36 and 50, and leucovorin PO or IV on days 10, 11, 24, 25, 38, 39, 52 and 53 over 9 weeks on study. BLINATUMOMAB BLOCK III: Patients receive blinatumomab IV on days 1-28, dasatinib PO or NG on days 1-35, and methotrexate IT on day 1 over 9 weeks on study. DELAYED INTENSIFICATION PART I: Patients receive dasatinib PO or NG QD on days 1-28, methotrexate IT on day 1, dexamethasone PO or IV on days 1-7 and 15-21, doxorubicin IV over 15 minutes on days 1, 8, and 15, vincristine IV on days 1, 8, and 15, and pegaspargase IV or calaspargase pegol IV over 1-2 hours on day 4 over 9 weeks on study. DELAYED INTENSIFICATION PART II: Patients receive dasatinib PO or NG QD on day 29 until the end of delayed intensification part II, cyclophosphamide IV over 60 minutes on day 29, cytarabine IV over 30 minutes on days 29-32 and 36-39, methotrexate IT on days 29 and 36, thioguanine PO on days 29-42, pegaspargase IV or calaspargase pegol over 1-2 hours on day 43 and vincristine IV on days 43 and 50 over 9 weeks on study. INTERIM MAINTENANCE II: Patients receive dasatinib PO or NG QD until the end of interim maintenance II, methotrexate IV over 15 minutes on days 1, 11, 21, 31, and 41, vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV or calaspargase pegol IV over 1-2 hours on days 2 and 23 over 9 weeks on study. All patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening. Patients also undergo blood and cerebrospinal fluid (CSF) sample collection and bone marrow biopsy throughout the study and as clinically indicated on study. MAINTENANCE: Patients receive dasatinib PO or NG QD on days 1-84, methotrexate IT on days 1 and 29, dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84, vincristine IV on days 1, 29 and 57, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 on study. Cycles repeat every 12 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

Official Title
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A Randomized International Phase 3 Trial of Imatinib and Chemotherapy With or Without Blinatumomab in Patients With Newly-Diagnosed Philadelphia Chromosome-Positive or Philadelphia Chromosome-Like ABL-Class B-Cell Acute Lymphoblastic Leukemia

Conditions
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B Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Biological: Blinatumomab
* Procedure: Bone Marrow Biopsy
* Drug: Calaspargase Pegol
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dasatinib
* Drug: Daunorubicin
* Drug: Doxorubicin
* Procedure: Echocardiography
* Drug: Leucovorin
* Drug: Mercaptopurine
* Drug: Methotrexate
* Procedure: Multigated Acquisition Scan
* Drug: Pegaspargase
* Drug: Prednisolone
* Drug: Prednisone
* Radiation: Radiation Therapy
* Drug: Thioguanine
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be > 365 days and < 18 years (for AIEOP-BFM), > 365 days and < 22 years (for COG) and > 365 days and < 46 years (for ALLTogether sites) at the time of enrollment Newly-diagnosed Ph+ or Ph-like ABL-class B-ALL. Leukemic blasts must express CD19. ABL-class fusions are defined as those involving the following genes predicted to be sensitive to dasatinib: ABL1, ABL2, CSF1R, KIT, PDGFRA, and PDGFRB Evidence of ABL-class fusions including 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. 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., TruSight RNA Pan-Cancer Panel, Illumina, San Diego, CA, USA or equivalent). Confirmation of 5' fusion partner genes is not required for study enrollment Patients 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 have not received more than 14 days of systemic Induction therapy beginning with the first Induction dose of vincristine Patients may have started dasatinib prior to study entry but cannot have received more than 14 days of dasatinib 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 (performed within 7 days prior to enrollment unless otherwise indicated): Estimated GFR (eGFR) ≥ 50 mL/min/1.73 m^2 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) (within 7 days prior to enrollment unless otherwise indicated) Shortening fraction of ≥ 27% by echocardiogram or Left Ventricular Ejection fraction of ≥ 50% by radionuclide angiogram or echocardiogram AND Corrected QT Interval, QTc < 480mSec (within 7 days prior to enrollment unless otherwise indicated) Note: Repeat echocardiogram and electrocardiogram are not required if they were performed at or after initial ALL diagnosis before study enrollment. (within 7 days prior to enrollment unless otherwise indicated) Exclusion Criteria: Known history of chronic myeloid 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 (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: Females of reproductive potential must use effective contraception during protocol treatment and for 30 days after the last dasatinib dose or per institutional standard of care for multiagent chemotherapy, whichever is longer Patients with congenital long QT syndrome, history of ventricular arrhythmias, or heart block Prior treatment with any TKI other than dasatinib 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 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 Human immunodeficiency virus (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

Ages Eligible for Study
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Minimum Age: 366 Days
Maximum Age: 46 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (dasatinib, standard chemo)<br>See detailed description. | Procedure: Biospecimen Collection<br>* Undergo blood and CSF sample collection<br>* Other names: Specimen Collection;Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Drug: Calaspargase Pegol<br>* Receive IV<br>* Other names: Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase;Drug: Cyclophosphamide<br>* Receive IV<br>* Other names: WR-138719;Drug: Cytarabine<br>* Receive IV<br>* Other names: WR-28453;Drug: Dasatinib<br>* Receive PO or NG<br>* Other names: Sprycel;Drug: Daunorubicin<br>* Receive IV<br>* Other names: Rubomycin C;Drug: Doxorubicin<br>* Receive IV<br>* Other names: Hydroxyldaunorubicin;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Leucovorin<br>* Receive PO or IV<br>* Other names: Folinic acid;Drug: Mercaptopurine<br>* Receive PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Receive IT or IV<br>* Other names: WR-19039;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Pegaspargase<br>* Receive IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Drug: Prednisolone<br>* Receive PO<br>* Other names: Sterane;Drug: Prednisone<br>* Receive PO<br>* Other names: SK-Prednisone;Drug: Vincristine<br>* Receive IV<br>* Other names: Vincrystine;|
| Experimental: Arm II (blinatumomab)<br>See detailed description. | Procedure: Biospecimen Collection<br>* Undergo blood and CSF sample collection<br>* Other names: Specimen Collection;Biological: Blinatumomab<br>* Receive IV<br>* Other names: MT103;Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Drug: Calaspargase Pegol<br>* Receive IV<br>* Other names: Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase;Drug: Cyclophosphamide<br>* Receive IV<br>* Other names: WR-138719;Drug: Cytarabine<br>* Receive IV<br>* Other names: WR-28453;Drug: Dasatinib<br>* Receive PO or NG<br>* Other names: Sprycel;Drug: Daunorubicin<br>* Receive IV<br>* Other names: Rubomycin C;Drug: Doxorubicin<br>* Receive IV<br>* Other names: Hydroxyldaunorubicin;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Leucovorin<br>* Receive PO or IV<br>* Other names: Folinic acid;Drug: Mercaptopurine<br>* Receive PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Receive IT or IV<br>* Other names: WR-19039;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Pegaspargase<br>* Receive IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Drug: Prednisolone<br>* Receive PO<br>* Other names: Sterane;Drug: Prednisone<br>* Receive PO<br>* Other names: SK-Prednisone;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Drug: Thioguanine<br>* Receive PO<br>* Other names: X 27;Drug: Vincristine<br>* Receive IV<br>* Other names: Vincrystine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival | Will be assessed in children, adolescents, and young adults with Philadelphia chromosome-positive (Ph+) and Ph-like ABL-class B-acute lymphoblastic leukemia (ALL) who are randomized post-Induction to receive continuous dasatinib and the modified augmented Berlin-Frankfurt-Münster (mBFM) chemotherapy backbone (Arm A) versus continuous dasatinib and a chemotherapy backbone that incorporates 3 cycles of blinatumomab (Arm B). Will be estimated using the Kaplan-Meier method with standard errors of Peto. | Time from randomization at the end of Induction to first event, relapse, second malignancy, or death in complete remission, or last contact for those who are event-free, assessed up to 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Will be compared in all patients with Ph+ and Ph-like ABL-class B-ALL between randomized arms. Will be estimated using the Kaplan-Meier method with standard errors of Peto. | Time from randomization to death from any cause or date of last contact for those who are alive, assessed up to 6 years | 
| Incidence of adverse events | Will be compared post-Induction/pre-maintenance and include infections, mucositis, neurotoxicity, cytokine release syndrome, therapy delays > 14 days, and treatment-related mortality between randomized arms. Will be assessed for all patients and the rates compared between the randomized arms (Arm A vs Arm B). Incidence and severity of potential cytokine release syndrome and neurotoxicity will be evaluated during the blinatumomab-containing cycles, specifically in patients on Arm B. In addition, there is concern regarding toxicities due to the use of benzyl alcohol in the infusion bags for blinatumomab. Hence the occurrence of metabolic acidosis related to benzyl alcohol will be closely observed on Arm B, and the rates will be summarized.Will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5. | Up to 6 years | 
| Minimal residual disease (MRD) negativity | Will be monitored on the two randomized arms; they will be summarized and reviewed at the time of each biannual reporting to the Childrens Oncology Group Data and Safety Monitoring Committee. | At end of consolidation (EOC)/timepoint 2 (TP2) |