Low-Dose or High-Dose Vincristine and Combination Chemotherapy in Treating Young Patients With Relapsed B-Cell Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This randomized phase III trial is studying low-dose vincristine to see how well it works compared with high-dose vincristine when given together with different combination chemotherapy regimens in treating young patients with intermediate-risk relapsed B-cell acute lymphoblastic leukemia. 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 more than one drug (combination chemotherapy) and giving the drugs in different ways and different doses may kill more cancer cells..

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the efficacy of an intensive chemotherapy regimen (based on POG-9412) for pediatric patients with intermediate-risk relapsed B-precursor acute lymphoblastic leukemia. SECONDARY OBJECTIVES: I. To determine levels of minimal residual disease (MRD) present at the end of the first & third blocks of Induction and determine if higher MRD levels at these times identify patients at higher risk of relapse who might be candidates for alternative therapies in future trials. II. To determine whether common polymorphisms in candidate genes are associated with the frequency of vincristine adverse effects (peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion [SIADH], or constipation) and with anti-leukemic response (level of end-Induction MRD). III. Compare, descriptively, the outcomes of patients treated with combination chemotherapy vs those treated with matched sibling-related donor hematopoietic stem cell transplantation (for those with eligible donors). IV. To use deoxyribonucleic acid (DNA) arrays to characterize patterns of gene expression that predict treatment failure, and to compare gene expression profiles at the time of relapse with those at initial diagnosis to gain an understanding of the pathways that may be involved in disease resistance. OUTLINE: This is a multicenter, randomized study. Patients are randomized to 1 of 2 treatment regimens (randomization closed as of 09/2010). INDUCTION THERAPY 1 (WEEKS 1-5): Regimen A: Patients receive low-dose vincristine intravenously (IV) on days 1, 8, 15, and 22; prednisone orally (PO) 3 times daily (TID) on days 1-28; doxorubicin hydrochloride IV over 15 minutes on day 1; pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22; cytarabine intrathecally (IT) on day 1; and methotrexate IT* on days 15 and 29. Regimen B: (closed to accrual as of 09/2010)***: Patients receive high-dose vincristine IV on days 1, 8, 15, and 22 and prednisone, doxorubicin hydrochloride, pegaspargase, cytarabine, and methotrexate* as in Regimen A. NOTE: *Central nervous system (CNS)-positive patients do not receive methotrexate IT. In both arms, CNS-positive patients receive intrathecal triple therapy (ITT) comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1, 8, 15, 22, and 29. CNS-positive patients not achieving remission after induction therapy 1 receive one additional dose of ITT on day 36. Patients in both arms then proceed to induction therapy 2**. NOTE: **Patients who are CNS-positive at relapse receive induction therapy 3 BEFORE induction therapy 2. NOTE: ***Patients already enrolled on Regimen B are crossover to Regimen A. INDUCTION THERAPY 2 (WEEKS 6-10 or 7-11): Once blood counts recover, all patients receive etoposide phosphate IV over = 1 hour and cyclophosphamide IV over 1 hour on days 1-5; high-dose methotrexate IV continuously over 24 hours on day 22; leucovorin calcium IV or PO beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; and methotrexate IT* on days 1 and 22. Patients also receive filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 6 and continuing until blood counts recover. NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 22. Patients with testicular-relapse with persistent testicular disease at the end of induction therapy 1 undergo testicular radiotherapy once daily (QD), 5 days a week, for 12 days during induction therapy 2**. NOTE: **Radiotherapy should be completed before beginning high-dose methotrexate (week 9) chemotherapy. All patients then proceed to induction therapy 3. INDUCTION THERAPY 3 (WEEKS 11-15 or 12-16): All patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9, and asparaginase IM on days 2 and 9. Patients also receive G-CSF IV or SC beginning on day 10 and continuing until blood counts recover. Patients with a suitable HLA-matched related donor are removed from study and proceed to stem cell transplantation. Patients without a suitable HLA-matched related donor proceed to intensification therapy 1 (as per their randomized regimen in induction therapy 1). INTENSIFICATION THERAPY 1 (WEEKS 16-27 or 17-28): Regimen A: Patients receive low-dose vincristine IV and high-dose methotrexate IV continuously over 24 hours on day 1; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 2-6; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 8; and methotrexate IT* on day 15. Treatment repeats every 21 days for 4 courses (with the exception of IT methotrexate which repeats for only 3 courses). Regimen B: Patients receive high-dose vincristine IV on day 1 and high-dose methotrexate, leucovorin calcium, mercaptopurine, etoposide phosphate, cyclophosphamide, and methotrexate IT* as in Regimen A. (closed to accrual as of 09/2010) NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 15. ITT repeats every 3 weeks for 3 courses. NOTE: ** Patients already enrolled on Regimen B are crossover to Regimen A. Patients in both regimens then proceed to reinduction therapy (as per their randomized regimen in induction therapy 1). REINDUCTION THERAPY (WEEKS 28-32 or 29-33): Regimen A: Patients receive low-dose vincristine IV and doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15, oral dexamethasone twice daily on days 1-7 and 15-21, pegaspargase IM on days 2 and 15, and methotrexate IT* on days 1 and 28. Regimen B: Patients receive high-dose vincristine IV on days 1, 8, and 15 and doxorubicin hydrochloride, dexamethasone, pegaspargase, and methotrexate IT* as in Regimen A. (closed to accrual as of 09/2010) NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 28. NOTE: ** Patients already enrolled on Regimen B are crossover to Regimen A. Patients in both regimens then proceed to intensification therapy 2 (as per their randomized regimen in induction therapy 1). INTENSIFICATION THERAPY 2 (WEEKS 33-56 or 34-57): Regimen A: Once blood counts recover, patients receive high-dose cytarabine IV over 3 hours on days 1 and 2; pegaspargase IM on day 2; low-dose vincristine IV on days 22 and 29; high-dose methotrexate IV on day 22; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 23-27; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 29; and methotrexate IT* on day 36. Patients also receive G-CSF IV or SC beginning on day 3 and continuing until blood counts recover. Treatment repeats every 42 days for 4 courses (with the exception of IT methotrexate which only repeats for 3 courses). Regimen B: Patients receive high-dose cytarabine, high-dose methotrexate, leucovorin calcium, pegaspargase, mercaptopurine, etoposide phosphate, cyclophosphamide, methotrexate IT*, and G-CSF as in Regimen A. Patients also receive high-dose vincristine IV on days 22 and 29. NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 36. Treatment repeats every 6 weeks for 3 courses. Patients in both regimens then proceed to maintenance therapy (as per their randomized regimen in induction therapy 1). MAINTENANCE THERAPY (week 57-106 or 58-107): Regimen A: Patients receive methotrexate IT on day 1* and then PO on days 8, 15, 22, 29, and 36; mercaptopurine PO QD on days 1-42; dexamethasone PO twice daily (BID) on days 1-5; and low-dose vincristine IV and cyclophosphamide IV over 1 hour on days 43, 50, 57, and 64. Treatment repeats every 70 days for 5 courses. Regimen B: Patients receive methotrexate*, mercaptopurine, dexamethasone, and cyclophosphamide as in Regimen A. Patients also receive high-dose vincristine IV on days 43, 50, 57, and 64. NOTE: *CNS-positive patients receive methotrexate IT on day 1, instead of oral methotrexate. Beginning in week 1 of the first maintenance therapy course, patients with CNS relapse undergo cranial radiotherapy QD, 5 days a week, for 10 days. Patients with CNS relapse do not receive any IT therapy during maintenance therapy. After completion of study therapy, patients are followed periodically for 5 years.

Official Title
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Intensive Treatment for Intermediate-Risk Relapse of Childhood B-precursor Acute Lymphoblastic Leukemia (ALL): A Randomized Trial of Vincristine Strategies

Conditions
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B-cell Childhood Acute Lymphoblastic Leukemia, L1 Childhood Acute Lymphoblastic Leukemia, L2 Childhood Acute Lymphoblastic Leukemia, Intermediate Risk Recurrent Childhood Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: vincristine sulfate
* Drug: prednisone
* Drug: doxorubicin hydrochloride
* Drug: pegaspargase
* Drug: cytarabine
* Drug: methotrexate
* Drug: dexamethasone
* Drug: etoposide
* Drug: cyclophosphamide
* Drug: leucovorin calcium
* Biological: filgrastim
* Drug: asparaginase
* Drug: mercaptopurine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute lymphoblastic leukemia (ALL) Bone marrow with > 25% L1 or L2 lymphoblasts (M3 marrow) Patients with > 25% L3 marrow lymphoblasts and/or evidence of c-myc translocation are not eligible (considered Burkitt's or mature B-cell leukemia) Intermediate-risk relapsed disease, meeting 1 of the following criteria: Bone marrow relapse ≥ 36 months after initial diagnosis (defined as M3 marrow after previous remission from ALL) Combined bone marrow and extramedullary (CNS* and/or testicular**) relapse ≥ 36 months after initial diagnosis Isolated extramedullary (CNS* and/or testicular**) relapse < 18 months after initial diagnosis The following subtypes are not allowed: T-lineage ALL Mature B-cell (Burkitt's) leukemia (defined as L3 morphology and/or evidence of c-myc translocation) Philadelphia-chromosome positive disease No Down syndrome (trisomy 21) Shortening fraction >= 27% by echocardiogram OR ejection fraction >= 50% by radionuclide angiogram Bilirubin < 3.0 mg/dL Not pregnant Fertile patients must use effective contraception No history of peripheral neuropathy >= grade 3 within the past month No toxicity (i.e. peripheral neuropathy) >= grade 3 attributable to vincristine within the past month At least 5 days since prior intrathecal chemotherapy No prior hematopoietic stem cell or marrow transplantation No prior cranial radiotherapy > 1200 cGy (for patients with CNS relapse) No concurrent stem cell transplant No concurrent alternative therapy No concurrent itraconazole in patients receiving vincristine No concurrent intensity-modulated radiotherapy

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 29 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: Regimen A: Standard vincristine dosing<br>See detailed description. | Drug: vincristine sulfate<br>* Given IV<br>* Other names: Vincasar PFS;Drug: prednisone<br>* Given PO<br>* Other names: Deltra;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: Adriamycin RDF;Drug: pegaspargase<br>* Given IM<br>* Other names: PEG-L-asparaginase;Drug: cytarabine<br>* Given IT or IV<br>* Other names: cytosine arabinoside;Drug: methotrexate<br>* Given IT or IV<br>* Other names: MTX;Drug: dexamethasone<br>* Given PO<br>* Other names: DXM;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: leucovorin calcium<br>* Given IV or PO<br>* Other names: LV;Biological: filgrastim<br>* Given IV or SC<br>* Other names: Neupogen;Drug: asparaginase<br>* Given IM<br>* Other names: L-ASP;Drug: mercaptopurine<br>* Given PO<br>* Other names: MP;|
| Experimental: Arm B: Randomized High Dose Vincristine regimen<br>See detailed description. Closed to accrual as of 09/2010). | Drug: vincristine sulfate<br>* Given IV<br>* Other names: Vincasar PFS;Drug: prednisone<br>* Given PO<br>* Other names: Deltra;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: Adriamycin RDF;Drug: pegaspargase<br>* Given IM<br>* Other names: PEG-L-asparaginase;Drug: cytarabine<br>* Given IT or IV<br>* Other names: cytosine arabinoside;Drug: methotrexate<br>* Given IT or IV<br>* Other names: MTX;Drug: dexamethasone<br>* Given PO<br>* Other names: DXM;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: leucovorin calcium<br>* Given IV or PO<br>* Other names: LV;Biological: filgrastim<br>* Given IV or SC<br>* Other names: Neupogen;Drug: asparaginase<br>* Given IM<br>* Other names: L-ASP;Drug: mercaptopurine<br>* Given PO<br>* Other names: MP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival. EFS | Percentage of patients who were event free at 3 years among those on Standard VCR dosing who did not undergo Hematopoietic Stem Cell Transplant (SCT). | 3 years after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and Severity of Adverse Effects | Percentage of patients who developed at least 1 episode of grade 2 to 4 neuropathy. | Up to 107 weeks | 
| Gene Expression Profile | Percent of unfavorable gene expression profile of early versus late marrow relapse. | Up to 36 months | 
| Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1 | Percentage of patients who had minimal residual disease (MRD) < 0.01% among those with isolated BM or combined BM relapse >= 36 months and had successful MRD determinations at End Block 1 | End of Block 1 (35 days) of Induction therapy | 
| Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3 | Percentage of patients who had minimal residual disease (MRD) < 0.01% among those with isolated BM or combined BM relapse >= 36 months and had successful MRD determinations at End Block 3. | End of Block 3 (105 days) of Induction therapy | 
| Event Free Survival (EFS) | Percentage of patients who were event free at 3 years among those with isolated BM or combined BM relapse >= 36 months. | 3 years | 
| Adjusted Event Free Survival | Adjusted percentage of patients who were event free at 3 years. For patients who received matched donor SCT, EFS was adjusted to start from the actual SCT date. For patients who did not undergo SCT, EFS was adjusted to start from median time to SCT based on patients who received matched related SCT (where patients who had events prior to SCT date were excluded from the calculation of median time to SCT). | 3 years |