Dasatinib and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This phase II/III trial is studying the side effects and how well giving dasatinib together with combination chemotherapy works in treating young patients with newly diagnosed acute lymphoblastic leukemia (ALL). Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving dasatinib together with combination chemotherapy may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the feasibility and toxicity of an intensified chemotherapeutic regimen that incorporates dasatinib for treatment of children, adolescents, and young adults (up to age 30) with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). II. To determine whether the intensification of tyrosine kinase inhibition through the addition of dasatinib in Induction (Days 15-28) and substitution of dasatinib for imatinib during post-Induction therapy, in the context of intensive cytotoxic therapy (according to AALL0031) and a good early response to therapy, will lead to a 3-year event-free survival (EFS) of at least 60% in patients with Ph+ ALL. SECONDARY OBJECTIVES: I. To determine whether the addition of dasatinib during Induction therapy (Days 15-28) will decrease levels of minimal residual disease (MRD) present at end of Induction therapy as compared with COG AALL0031. II. To determine whether early intensified tyrosine kinase inhibitor (TKI) therapy will lower end-Consolidation MRD levels as compared to patients on COG AALL0031 that received imatinib in Consolidation Blocks 1 and 2 (Cohorts 3-5). III. To determine the overall 3-year EFS rate for the whole cohort of Standard- and High-Risk patients treated with dasatinib. IV. To determine the long-term effects of dasatinib on growth, development, and bone metabolism. V. To assess BCR-ABL mutation status at time of diagnosis and progression/relapse. OUTLINE: This is a multicenter study. Patients are stratified according to risk (standard risk vs high risk) at the end of consolidation therapy. INDUCTION THERAPY (weeks 1-4): Patients receive initial induction therapy on days 1-14 prior to beginning the study. Patients then receive vincristine intravenously (IV) and daunorubicin hydrochloride* IV over 15 minutes on days 15 and 22; dasatinib orally (PO) once daily (QD) and prednisone PO (or methylprednisolone IV) twice daily (BID) on days 15-28; methotrexate intrathecally (IT) on day 29; and some patients receive methotrexate, hydrocortisone, and cytarabine IT on days 15 and 22. After completion of induction therapy, patients undergo bone marrow aspiration for evaluation of disease. Patients with M1 bone marrow and minimal residual disease (MRD) < 1% (standard-risk disease) proceed to block 1 consolidation therapy 1 week after completion of induction therapy or when blood counts recover (whichever occurs later). Patients with M2 or M3 bone marrow or MRD >= 1% (high-risk disease) proceed immediately to block 1 consolidation therapy, regardless of blood counts. Patients with clinically evident or biopsy-proven testicular leukemia at diagnosis that persists at the end of induction therapy undergo 12 fractions of testicular radiotherapy beginning within 4 days prior to starting block 1 consolidation therapy. NOTE: *Patients who receive initial induction therapy on a DFCI Childhood ALL Consortium trial do not receive daunorubicin hydrochloride during induction therapy on this study. CONSOLIDATION THERAPY: BLOCK 1 CONSOLIDATION THERAPY: (weeks 6-8) Patients receive etoposide IV over 1 hour and ifosfamide IV over 1 hour on days 1-5, dasatinib PO on days 1-14 OR on days 1-21, and some patients receive methotrexate, hydrocortisone, and cytarabine IT on days 8 and 15. Patients also receive filgrastim (G-CSF) subcutaneously (SC) or IV QD beginning on day 6 and continuing until blood counts recover. After completion of block 1 consolidation therapy, patients proceed to block 2 consolidation therapy. BLOCK 2 CONSOLIDATION THERAPY: (weeks 9-11) Patients receive high-dose methotrexate IV continuously over 24 hours on day 1; leucovorin calcium PO or IV every 6 hours for 3 doses on days 2-3; methotrexate, hydrocortisone, and cytarabine IT on day 1; cytarabine IV over 3 hours every 12 hours for 4 doses on days 2 and 3; and dasatinib PO on days 1-14 OR on days 1-21. Patients also receive G-CSF SC or IV QD beginning on day 4 and continuing until blood counts recover. After completion of block 2 consolidation therapy and recovery of blood counts, patients undergo bone marrow aspiration for evaluation of disease. Patients with MRD < 0.01% (standard-risk disease) with a matched related donor and who are willing to undergo hematopoietic stem cell transplantation (HSCT) proceed to HSCT off study. Standard-risk patients without a suitable donor or those who elect not to undergo HSCT proceed to post-consolidation therapy. Patients with MRD >= 0.01% (high-risk disease) with a matched related or unrelated donor proceed to HSCT off study. High-risk patients without a suitable donor proceed to post-consolidation therapy. POST-CONSOLIDATION THERAPY: REINDUCTION BLOCK 1 THERAPY: (weeks 12-14) Patients receive vincristine IV on days 1, 8, and 15; daunorubicin hydrochloride IV over 15 minutes on days 1 and 2; cyclophosphamide IV over 1 hour every 12 hours for 4 doses on days 3 and 4; pegaspargase intramuscularly (IM) on day 4; methotrexate, hydrocortisone, and cytarabine IT on days 1 and 15; dexamethasone PO or IV BID on days 1-7 and 15-21; and dasatinib PO on days 1-14 OR on days 1-21. Patients also receive G-CSF SC or IV QD beginning on day 5 and continuing until blood counts recover. After completion of reinduction block 1 therapy, patients proceed to intensification block 1 therapy. INTENSIFICATION BLOCK 1 THERAPY: (weeks 15-23) Patients receive high-dose methotrexate IV continuously over 24 hours on day 1; leucovorin calcium PO or IV every 6 hours for 3 doses on days 2-3; methotrexate, hydrocortisone, and cytarabine IT on days 1 and 22; etoposide IV over 1 hour and cyclophosphamide IV over 1 hour on days 22-26; cytarabine IV over 3 hours every 12 hours for 4 doses on days 43 and 44; asparaginase IM on day 44; and dasatinib PO on days 1-14, 22-35, and 43-56 OR on days 1-63. Patients also receive G-CSF SC or IV QD beginning on day 27 and continuing until blood counts recover. After completion of intensification block 1 therapy, patients proceed to reinduction block 2 therapy. REINDUCTION BLOCK 2 THERAPY: (weeks 24-26) Patients receive reinduction block 2 therapy as per reinduction block 1 therapy. After completion of reinduction block 2 therapy, patients proceed to intensification block 2 therapy. INTENSIFICATION BLOCK 2 THERAPY: (weeks 27-35) Patients receive intensification block 2 therapy as per intensification block 1 therapy. After completion of intensification block 2 therapy, patients proceed to maintenance therapy. MAINTENANCE THERAPY: MAINTENANCE COURSES 1-4: (weeks 36-67) Patients receive high-dose methotrexate IV continuously over 24 hours on day 1; leucovorin calcium PO or IV every 6 hours for 3 doses on days 2-3; methotrexate, hydrocortisone, and cytarabine IT and vincristine IV on days 1 and 29; prednisone PO or IV BID on days 1-5 and 29-33; mercaptopurine PO on days 8-28; methotrexate PO on days 8, 15, and 22; etoposide IV over 1 hour and cyclophosphamide IV over 1 hour on days 29-33; and dasatinib PO on days 1-14 and 29-42 OR on days 1-56. Patients also receive G-CSF SC or IV QD beginning on day 34 and continuing until blood counts recover. Courses repeat every 56 days. After completion of maintenance courses 1-4, patients proceed to maintenance course 5. MAINTENANCE COURSE 5: (weeks 68-75) Patients receive vincristine IV on days 1 and 29; prednisone PO or IV BID on maintenance courses 6-12. MAINTENANCE COURSES 6-12: (weeks 76-131) Patients receive vincristine IV on days 1 and 29; prednisone PO or IV BID on days 1-5 and 29-33; mercaptopurine PO on days 1-56; methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, and 50; and dasatinib PO on days 1-14 and 29-42 OR on days 1-56. Courses repeat every 56 days. Patients long-term growth, development, and bone metabolism are assessed after completion of study therapy and then annually for 5 years. After completion of study therapy, patients are followed up periodically for up to 10 years.

Official Title
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Intensified Tyrosine Kinase Inhibitor Therapy (Dasatinib NSC# 732517) in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (ALL)

Conditions
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Acute Lymphoblastic Leukemia, Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, Childhood B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1

Intervention / Treatment
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* Drug: Asparaginase
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dasatinib
* Drug: Daunorubicin Hydrochloride
* Drug: Dexamethasone
* Drug: Etoposide
* Biological: Filgrastim
* Drug: Hydrocortisone Sodium Succinate
* Drug: Ifosfamide
* Other: Laboratory Biomarker Analysis
* Drug: Leucovorin Calcium
* Drug: Mercaptopurine
* Drug: Methotrexate
* Drug: Methylprednisolone
* Drug: Pegaspargase
* Drug: Prednisone
* Radiation: Radiation Therapy
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed acute lymphoblastic leukemia (ALL) Definitive evidence of BCR-ABL fusion (Philadelphia chromosome positive [PH+]) from an approved Children's Oncology Group (COG) cytogenetics laboratory Meets one of the following criteria: Concurrent enrollment on Clusters of Orthologous Groups (COG)-AALL03B1 (or a successor trial) AND COG-AALL0232, COG-AALL0331, COG-AALL0434 or other front-line COG ALL clinical trial Concurrent enrollment on COG-AALL03B1 (or a successor trial) AND scheduled to receive a 3 or 4-drug standard induction regimen Concurrent enrollment on a Dana-Farber Cancer Institute (DFCI) Childhood ALL Consortium trial (or scheduled to be treated as per a DFCI Childhood ALL Consortium induction regimen) All patients must have definitive evidence of BCR-ABL fusion from an approved COG cytogenetics laboratory; patients may NOT have received Day 15 of Induction chemotherapy (or day 18 vincristine if enrolled on a DFCI Childhood ALL Consortium trial) prior to enrollment on AALL0622 Patients must have a performance status of 0, 1 or 2 at completion of two weeks of Induction; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 or maximum serum creatinine based on age and gender as follows: 0.4 mg/dL (for patients 1 to 5 months of age) 0.5 mg/dL (for patients 6 to 11 months of age) 0.6 mg/dL (for patients 1 year of age) 0.8 mg/dL (for patients 2 to 5 years of age) 1.0 mg/dL (for patients 6 to 9 years of age) 1.2 mg/dL (for patients 10 to 12 years of age) 1.5 mg/dL (males) or 1.4 mg/dL (females) (for patients 13 to 15 years of age) 1.7 mg/dL (males) or 1.4 mg/dL (females) (for patients >= 16 years of age) Total bilirubin =< 1.5 times upper limit of normal (ULN) for age Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 times ULN for age Shortening fraction >= 27% by echocardiogram or ejection fraction >= 50% by gated radionuclide study No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% at sea level if there is clinical indication for determination Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled; however, drugs that induce CYP3A4/5 (carbamazepine, oxcarbazepine, phenytoin, primidone, phenobarbital) should be avoided Patients will start AALL0622 therapy on day 15 of induction therapy (or day 18 if enrolled on a DFCI Childhood ALL Consortium trial); patients must have received the first 2 weeks of Induction therapy Exclusion Criteria: Females of childbearing potential must have a negative pregnancy test; patients of childbearing potential must agree to use an effective birth control method Female patients who are lactating must agree to stop breast-feeding Patients with Down syndrome Patients with any clinically significant cardiovascular disease including the following: Myocardial infarction or ventricular tachyarrhythmia within 6 months Ejection fraction less than institutional normal Major conduction abnormality (unless a cardiac pacemaker is present)

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 30 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor therapy and chemotherapy)<br>See Detailed Description | Drug: Asparaginase<br>* Given IT<br>* Other names: Spectrila;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cytarabine<br>* Given IT or IV<br>* Other names: WR-28453;Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Drug: Dexamethasone<br>* Given IV or PO<br>* Other names: ZoDex;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Biological: Filgrastim<br>* Given IV or SC<br>* Other names: Tevagrastim;Drug: Hydrocortisone Sodium Succinate<br>* Given IT<br>* Other names: Solu-Glyc;Drug: Ifosfamide<br>* Given IV<br>* Other names: Z-4942;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Leucovorin Calcium<br>* Given IV or PO<br>* Other names: Wellcovorin;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IT, PO, or IV<br>* Other names: WR-19039;Drug: Methylprednisolone<br>* Given IV<br>* Other names: Wyacort;Drug: Pegaspargase<br>* Given IM<br>* Other names: Polyethylene Glycol-L-Asparaginase;Drug: Prednisone<br>* Given PO or IV<br>* Other names: SK-Prednisone;Radiation: Radiation Therapy<br>* Some patients undergo cranial RT<br>* Other names: Therapy, Radiation;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival (EFS) of Patients With Standard-risk Disease Treated With Dasatinib in Combination With Intensified Chemotherapy | Event-Free Survival (EFS) curves will be constructed using the Kaplan-Meier life table method with standard errors computed using the method of Peto and Peto. A 1-sided 95% confidence interval for EFS will be constructed. | At 3 years | 
| Feasibility and Toxicity of an Intensified Chemotherapeutic Regimen Incorporating Dasatinib for Treatment of Children and Adolescents With Ph+ ALL Assessed by Examining Adverse Events | Number of patients in safety cohort with dose limiting toxicity (DLT)(including treatment delay) | Weeks 3 through 23 of treatment (From week 3 Induction through Intensification Block 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Contribution of Dasatinib on Minimal Residual Disease (MRD) After Induction Therapy | Percent of patients MRD Positive (MRD > 0.01%) at End of Induction. | At the end of induction therapy (at 5 weeks) | 
| Percent of Patients MRD Positive (MRD > 0.01%) at End of Consolidation | A 1-sample Z-test of proportions (alpha=5%, 1-sided test) will be used. | At end of consolidation (at 11 weeks) | 
| Overall EFS Rate for the Combined Cohort of Standard- and High-Risk Patients (Who Receive the Final Chosen Dose of Dasatinib) | An event is defined as: Induction failure, relapse at any site, secondary malignancy, or death. | From the time entry on study to first event or date of last follow-up, assessed up to 7 years |