Overview

This trial is active, not recruiting.

Conditions adult t acute lymphoblastic leukemia, childhood t acute lymphoblastic leukemia, stage ii adult t-cell leukemia/lymphoma, stage ii childhood lymphoblastic lymphoma, stage ii contiguous adult lymphoblastic lymphoma, stage ii non-contiguous adult lymphoblastic lymphoma, stage iii adult lymphoblastic lymphoma, stage iii adult t-cell leukemia/lymphoma, stage iii childhood lymphoblastic lymphoma, stage iv adult lymphoblastic lymphoma, stage iv adult t-cell leukemia/lymphoma, stage iv childhood lymphoblastic lymphoma, untreated adult acute lymphoblastic leukemia, untreated childhood acute lymphoblastic leukemia
Treatments asparaginase, cyclophosphamide, cytarabine, daunorubicin hydrochloride, dexamethasone, doxorubicin hydrochloride, laboratory biomarker analysis, leucovorin calcium, mercaptopurine, methotrexate, nelarabine, pegaspargase, prednisone, radiation therapy, thioguanine, vincristine sulfate
Phase phase 3
Sponsor National Cancer Institute (NCI)
Start date January 2007
End date September 2017
Trial size 1900 participants
Trial identifier NCT00408005, AALL0434, CDR0000514500, COG-AALL0434, NCI-2009-00307, U10CA098543

Summary

This randomized phase III trial is studying different combination chemotherapy regimens and their side effects and comparing how well they work in treating young patients with newly diagnosed T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. 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) may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective in treating T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Active Comparator)
Patients receive methotrexate IT on days 1, 8, 15, and 22; cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV over 15-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine sulfate IV on days 15, 22, 43 and 50; and pegaspargase IM or IV over 1-2 hours on days 15 and 43. Patients with DS also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 11-12, 15-19, and 22-26. (DS patients excluded as of 09/29/10.) Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT (1,200 cGy/dose) QD on days 15-21 and 22-28. Patients with low-risk disease do not undergo CRT.
cyclophosphamide (-)-Cyclophosphamide
Given IV
cytarabine .beta.-Cytosine arabinoside
Given IT, IV, or SC
daunorubicin hydrochloride Cerubidin
Given IV
doxorubicin hydrochloride 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
Given IV
laboratory biomarker analysis
Correlative studies
leucovorin calcium Adinepar
Given PO
mercaptopurine 3H-Purine-6-thiol
Given PO
methotrexate Abitrexate
Given IT or PO
pegaspargase L-Asparaginase with Polyethylene Glycol
Given IM or IV
prednisone .delta.1-Cortisone
Given IV or PO
radiation therapy Cancer Radiotherapy
Some patients undergo testicular and/or prophylactic cranial RT
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID on days 1-21 (for patients < 10 years of age) OR on days 1-7 and 15-21 (for patients >= 10 years of age and for patients with DS); doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6, AND day 43; methotrexate IT on days 1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. Patients with DS also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose (DS patients excluded as of 09/29/10).
cyclophosphamide (-)-Cyclophosphamide
Given IV
cytarabine .beta.-Cytosine arabinoside
Given IT, IV, or SC
dexamethasone Aacidexam
Given IV or PO
doxorubicin hydrochloride 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
Given IV
laboratory biomarker analysis
Correlative studies
leucovorin calcium Adinepar
Given PO
methotrexate Abitrexate
Given IT or PO
pegaspargase L-Asparaginase with Polyethylene Glycol
Given IM or IV
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive vincristine sulfate IV and escalating doses of methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase* IM or IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. Patients with DS also receive leucovorin calcium PO 48 and 60 hours after each methotrexate IT dose (DS patients excluded as of 09/29/10). Note: *Patients with an allergy to pegaspargase receive Erwinia asparaginase on days 2, 4, 6, 8, 10, 12, 22, 24, 26, 28, 30, and 32.
asparaginase ASP-1
Given IM or IV
laboratory biomarker analysis
Correlative studies
leucovorin calcium Adinepar
Given PO
methotrexate Abitrexate
Given IT or PO
pegaspargase L-Asparaginase with Polyethylene Glycol
Given IM or IV
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive vincristine sulfate IV on days 1, 29, and 57; dexamethasone PO BID on days 1-5, 29-33, and 57-61; mercaptopurine PO QD on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and methotrexate IT on day 1. Treatment repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 119) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL).
dexamethasone Aacidexam
Given IV or PO
laboratory biomarker analysis
Correlative studies
mercaptopurine 3H-Purine-6-thiol
Given PO
methotrexate Abitrexate
Given IT or PO
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive nelarabine IV over 60 minutes on days 1-5 and 43-47; methotrexate IT on days 15, 22, 57, and 64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV over 15-30 minutes or SC on days 8-11, 15-18, 50-53 and 57-60; mercaptopurine PO on days 8-21 and 50-63; vincristine sulfate IV on days 22, 29, 64, and 71; and pegaspargase IM or IV over 1-2 hours on days 22 and 64. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 15, 22-26, and 29-33 (DS patients excluded as of 09/29/10). (Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT QD on days 22-28 and 29-35.
cyclophosphamide (-)-Cyclophosphamide
Given IV
cytarabine .beta.-Cytosine arabinoside
Given IT, IV, or SC
daunorubicin hydrochloride Cerubidin
Given IV
doxorubicin hydrochloride 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
Given IV
laboratory biomarker analysis
Correlative studies
leucovorin calcium Adinepar
Given PO
mercaptopurine 3H-Purine-6-thiol
Given PO
methotrexate Abitrexate
Given IT or PO
nelarabine 2-Amino-6-methoxypurine arabinoside
Given IV
pegaspargase L-Asparaginase with Polyethylene Glycol
Given IM or IV
prednisone .delta.1-Cortisone
Given IV or PO
radiation therapy Cancer Radiotherapy
Some patients undergo testicular and/or prophylactic cranial RT
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive vincristine sulfate IV on days 1, 8, 15, and 50; dexamethasone IV or PO BID on days 1-21 (for patients < 10 years of age) OR on days 1-7 and 15-21 (for patients >= 10 years of age); doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6 AND day 50; methotrexate IT on days 1, 36, and 43; nelarabine IV over 60 minutes on days 29-33; cyclophosphamide IV over 30 minutes on day 36; cytarabine IV over 15-30 minutes or SC on days 36-39 and 43-46; and thioguanine PO on days 36-49.
cyclophosphamide (-)-Cyclophosphamide
Given IV
cytarabine .beta.-Cytosine arabinoside
Given IT, IV, or SC
dexamethasone Aacidexam
Given IV or PO
doxorubicin hydrochloride 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
Given IV
laboratory biomarker analysis
Correlative studies
nelarabine 2-Amino-6-methoxypurine arabinoside
Given IV
pegaspargase L-Asparaginase with Polyethylene Glycol
Given IM or IV
thioguanine 2-Amino 6MP
Given PO
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive vincristine sulfate, escalating doses of methotrexate, pegaspargase, and methotrexate IT as in arm I.
laboratory biomarker analysis
Correlative studies
leucovorin calcium Adinepar
Given PO
methotrexate Abitrexate
Given IT or PO
pegaspargase L-Asparaginase with Polyethylene Glycol
Given IM or IV
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive vincristine sulfate IV on days 1 and 57; dexamethasone PO on days 1-5 and 57-61; mercaptopurine PO QD on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; methotrexate IT on day 1; and nelarabine IV over 60 minutes on days 29-33. Treatment (that includes nelarabine) repeats every 84 days for 3 courses. Patients then receive treatment (without nelarabine) as follows: vincristine sulfate IV on days 1 and 57; dexamethasone PO on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and methotrexate IT on day 1. Treatment (without nelarabine) repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 121) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL).
dexamethasone Aacidexam
Given IV or PO
laboratory biomarker analysis
Correlative studies
mercaptopurine 3H-Purine-6-thiol
Given PO
methotrexate Abitrexate
Given IT or PO
nelarabine 2-Amino-6-methoxypurine arabinoside
Given IV
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive methotrexate, cyclophosphamide, cytarabine, mercaptopurine, vincristine sulfate, and pegaspargase as in arm I. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy as in arm I (DS patients excluded as of 09/29/10).
cyclophosphamide (-)-Cyclophosphamide
Given IV
cytarabine .beta.-Cytosine arabinoside
Given IT, IV, or SC
daunorubicin hydrochloride Cerubidin
Given IV
laboratory biomarker analysis
Correlative studies
mercaptopurine 3H-Purine-6-thiol
Given PO
methotrexate Abitrexate
Given IT or PO
pegaspargase L-Asparaginase with Polyethylene Glycol
Given IM or IV
prednisone .delta.1-Cortisone
Given IV or PO
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, methotrexate IT, cyclophosphamide, cytarabine, and thioguanine as in arm I. Patients with intermediate- or high-risk disease (CNS1 or CNS2 disease) undergo prophylactic CRT (1,200 cGy/dose) QD on days 50-54 and 57-59.
cyclophosphamide (-)-Cyclophosphamide
Given IV
cytarabine .beta.-Cytosine arabinoside
Given IT, IV, or SC
dexamethasone Aacidexam
Given IV or PO
doxorubicin hydrochloride 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
Given IV
pegaspargase L-Asparaginase with Polyethylene Glycol
Given IM or IV
thioguanine 2-Amino 6MP
Given PO
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive HDMTX IV over 24 hours and vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Beginning 42 hours after the start of HDMTX, patients also receive leucovorin calcium IV or PO once every 6 hours for 3 doses.
laboratory biomarker analysis
Correlative studies
leucovorin calcium Adinepar
Given PO
mercaptopurine 3H-Purine-6-thiol
Given PO
methotrexate Abitrexate
Given IT or PO
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive vincristine sulfate, dexamethasone, mercaptopurine, methotrexate PO, and methotrexate IT as in arm I. Treatment repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 119) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL).
dexamethasone Aacidexam
Given IV or PO
laboratory biomarker analysis
Correlative studies
mercaptopurine 3H-Purine-6-thiol
Given PO
methotrexate Abitrexate
Given IT or PO
radiation therapy Cancer Radiotherapy
Some patients undergo testicular and/or prophylactic cranial RT
(Active Comparator)
Patients receive nelarabine, methotrexate, cyclophosphamide, cytarabine, mercaptopurine, vincristine sulfate, and pegaspargase as in arm II. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy as in arm II (DS patients excluded as of 09/29/10).
cyclophosphamide (-)-Cyclophosphamide
Given IV
daunorubicin hydrochloride Cerubidin
Given IV
laboratory biomarker analysis
Correlative studies
mercaptopurine 3H-Purine-6-thiol
Given PO
methotrexate Abitrexate
Given IT or PO
nelarabine 2-Amino-6-methoxypurine arabinoside
Given IV
pegaspargase L-Asparaginase with Polyethylene Glycol
Given IM or IV
prednisone .delta.1-Cortisone
Given IV or PO
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, methotrexate IT, nelarabine, cyclophosphamide, cytarabine, and thioguanine as in arm II. Patients with intermediate- or high-risk disease (CNS 1 or CNS2 disease) undergo prophylactic CRT on days 50-54 and 57-59.
cyclophosphamide (-)-Cyclophosphamide
Given IV
cytarabine .beta.-Cytosine arabinoside
Given IT, IV, or SC
dexamethasone Aacidexam
Given IV or PO
doxorubicin hydrochloride 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
Given IV
laboratory biomarker analysis
Correlative studies
methotrexate Abitrexate
Given IT or PO
nelarabine 2-Amino-6-methoxypurine arabinoside
Given IV
pegaspargase L-Asparaginase with Polyethylene Glycol
Given IM or IV
thioguanine 2-Amino 6MP
Given PO
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive HDMTX, vincristine sulfate, mercaptopurine, methotrexate IT, and leucovorin calcium as in arm III.
laboratory biomarker analysis
Correlative studies
leucovorin calcium Adinepar
Given PO
mercaptopurine 3H-Purine-6-thiol
Given PO
methotrexate Abitrexate
Given IT or PO
vincristine sulfate Kyocristine
Given IV
(Active Comparator)
Patients receive vincristine sulfate, dexamethasone, mercaptopurine, methotrexate PO, methotrexate IT, and nelarabine as in arm II. Patients then receive treatment (without nelarabine) as follows: vincristine sulfate, dexamethasone, mercaptopurine, methotrexate PO, and methotrexate IT as in arm II. Treatment (without nelarabine) repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 121) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL).
dexamethasone Aacidexam
Given IV or PO
laboratory biomarker analysis
Correlative studies
mercaptopurine 3H-Purine-6-thiol
Given PO
methotrexate Abitrexate
Given IT or PO
nelarabine 2-Amino-6-methoxypurine arabinoside
Given IV
vincristine sulfate Kyocristine
Given IV

Primary Outcomes

Measure
Efficacy of combination chemotherapy with vs without nelarabine
time frame: Up to 10 years
Efficacy of high-dose methotrexate (with leucovorin calcium rescue) and mercaptopurine vs escalating-dose methotrexate (without leucovorin calcium rescue) and pegaspargase
time frame: Up to 10 years
Event-free survival (EFS) after initial remission
time frame: At 4 years
Incidence of toxicities of combination chemotherapy with vs without nelarabine as assessed by NCI CTCAE version 4.0
time frame: Up to 3 years
Incidence of toxicities of high-dose methotrexate (with leucovorin calcium rescue) and mercaptopurine vs escalating-dose methotrexate (without leucovorin calcium rescue) and pegaspargase
time frame: Up to 3 years
Nelarabine toxicity assessment by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
time frame: Up to week 43

Secondary Outcomes

Measure
Incidence of CNS relapse
time frame: Up to 10 years
Overall survival
time frame: Up to 10 years

Eligibility Criteria

Male or female participants from 1 year up to 30 years old.

Inclusion Criteria: - T-ALL patients must be enrolled on AALL08B1 prior to treatment and enrollment on AALL0434 - Patients must have newly diagnosed T-ALL or T-lineage lymphoblastic lymphoma (T-NHL) stage II-IV; B-lineage lymphoblastic lymphoma will not be eligible for this study; a diagnosis of T-ALL is established when leukemic blasts lack myeloperoxidase or evidence of B-lineage derivation (cluster of differentiation [CD]19/CD22/CD20), and express either surface or cytoplasmic CD3 or two or more of the antigens CD8, CD7, CD5, CD4, CD2 or CD1a; if surface CD3 is expressed on all leukemic cells, additional markers of immaturity, including transmission disequilibrium test (TdT), CD34 or CD99 will be assessed for expression; cases with uncertain expression will receive additional review within the appropriate Children's Oncology Group (COG) reference laboratory - T-NHL PATIENTS: - For T-NHL patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to T-ALL; for tissue processed by other means (i.e. paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of T-NHL defined by the submitting institution will be accepted - Prior therapy restrictions - Patients shall have had no prior cytotoxic chemotherapy with the exception of steroids and/or IT cytarabine - IT chemotherapy with cytarabine is allowed prior to registration for patient convenience; this is usually done at the time of the diagnostic bone marrow or venous line placement to avoid a second lumbar puncture; (Note: the CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment); systemic chemotherapy must begin within 72 hours of this IT therapy - Patients diagnosed as having T-NHL or T-ALL with respiratory distress or hyperleukocytosis may require steroids prior to the initiation of additional systemic therapy; they are eligible for AALL0434 and will be stratified, based on the initial complete blood count (CBC); steroid pretreatment may alter the risk group assessment; if the T-ALL patient's clinical status precludes a lumbar puncture within 48 hours of the initiation of steroid therapy, T-ALL patients CANNOT be classified as low risk and will be Intermediate or high risk based on the results of the day 29 marrow as above; patients with T-NHL who receive steroid pre-treatment will be classified as high risk; the dose and duration of previous steroid therapy should be carefully documented - For the management of airway compromise, patients who have received emergent chest irradiation up to 600 cGy will be eligible for this study - Patients with a prior seizure disorder requiring anti-convulsant therapy are not eligible to receive nelarabine; in addition, patients with pre-existing grade 2 (or greater) peripheral neurotoxicity, as determined prior to Induction treatment by the treating physician or a neurologist, are not eligible to receive nelarabine; these restrictions in eligibility are designed to prevent excessive nelarabine-induced central and peripheral neurotoxicity in at-risk patients; for the purposes of this study, this includes any patient that has received anticonvulsant therapy to prevent/treat seizures in the prior two years Exclusion Criteria: - Pregnant or lactating females are ineligible - Patients with Down syndrome are ineligible to enroll onto this study - For T-NHL patients the following additional exclusion criteria apply: - B-precursor lymphoblastic lymphoma - Morphologically unclassifiable lymphoma - Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic lymphoma - CNS3-positive or testicular involvement

Additional Information

Official title Intensified Methotrexate, Nelarabine (Compound 506U78) and Augmented BFM Therapy for Children and Young Adults With Newly Diagnosed T-cell Acute Lymphoblastic Leukemia (ALL) or T-cell Lymphoblastic Lymphoma
Principal investigator Stuart Winter
Description PRIMARY OBJECTIVES: I. To determine, through randomization, the relative safety and efficacy of the addition of nelarabine (Compound 506U78) to augmented Berlin-Frankfurt-Münster (BFM) therapy (Regimen C, Children's Cancer Group [CCG]-1961). II. To determine the relative safety and efficacy of high dose methotrexate (5 g/m^2) with leucovorin (leucovorin calcium) rescue compared to escalating methotrexate without leucovorin rescue plus pegaspargase (Capizzi I) delivered during interim maintenance. III. To gain preliminary data on the use of nelarabine in patients with high risk T-cell lymphoblastic lymphoma and its effect on long-term survival. SECONDARY OBJECTIVES: I. To determine the relative safety and efficacy of withholding radiation in patients with low risk T-cell acute lymphoblastic leukemia (T-ALL), while treating Intermediate and high risk patients with 1200 cGy of prophylactic cranial radiation. OUTLINE: INDUCTION THERAPY: (weeks 1-5) Patients receive cytarabine intrathecally (IT) on day 1; vincristine sulfate IV and daunorubicin hydrochloride IV on days 1, 8, 15, and 22; prednisone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) or IV over 1-2 hours on day 4, 5, OR 6; and methotrexate (MTX) IT on days 8 and 29*. Patients with Down syndrome (DS) also receive leucovorin calcium PO at 48 and 60 hours after each MTX dose (DS patients excluded as of 09/29/10). After completion of induction therapy, patients undergo risk assessment. Patients with M1 marrow and minimal residual disease (MRD) < 1% (defined as low- and intermediate-risk) proceed to consolidation therapy at day 36 or when blood counts recover (whichever occurs later). Patients with M2 marrow (5-25% blasts) and/or MRD >= 1% (defined as high-risk) proceed to consolidation therapy as soon as possible (i.e., they should not wait until day 36 or for blood counts to recover). Patients with M3 marrow (>= 25% blasts) (defined as induction failure) proceed to consolidation therapy as soon as possible. NOTE: *Patients with CNS3 disease also receive MTX IT on days 15 and 22. CONSOLIDATION THERAPY: (weeks 6-13) During the safety phase portion of the study, patients with low-risk or intermediate-risk disease are randomized to arms I or III. Patients with high-risk disease are randomized to arms I, II, III, or IV. (safety phase closed for accrual as of 09/29/10) During the efficacy phase portion of the study, patients with low-risk* disease are randomized to arms I and III. Patients with intermediate-risk or high-risk** disease are randomized to arms I, II, III, or IV. The safety phase ends when the first 20 high-risk patients to receive nelarabine have been evaluated. Patients with DS are nonrandomly assigned to arm I (DS patients excluded as of 09/29/10). Patients with induction failure*** are nonrandomly assigned to arm IV. NOTE: *Patients with T-cell lymphoblastic lymphoma (T-NHL) are nonrandomly assigned to arm I. NOTE: ** Patients with T-NHL are randomly assigned to arms I or II without cranial radiotherapy. NOTE: *** Patients with T-NHL are nonrandomly assigned to arm II. ARM I: Patients receive MTX IT on days 1, 8, 15, and 22*; cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV over 15-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine sulfate IV on days 15, 22, 43 and 50; and pegaspargase IM or IV over 1-2 hours on days 15 and 43. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 11-12, 15-19, and 22-26 (DS patients excluded as of 09/29/10). Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic cranial radiotherapy (CRT) (1,200 cGy/dose) once daily on days 15-21 and 22-28. Patients with low-risk disease do not undergo CRT. NOTE: *Patients with CNS3 disease omit MTX IT on days 15 and 22; patients with high-risk disease omit MTX IT on day 1 and add an extra dose at day 29. ARM II: Patients receive nelarabine IV over 60 minutes on days 1-5 and 43-47; MTX IT on days 15, 22*, 57, and 64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV over 15-30 minutes or SC on days 8-11, 15-18, 50-53 and 57-60; oral mercaptopurine on days 8-21 and 50-63; vincristine sulfate IV on days 22, 29, 64, and 71; and pegaspargase IM or IV over 1-2 hours on days 22 and 64. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 15, 22-26, and 29-33 (DS patients excluded as of 09/29/10). Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT once daily on days 22-28 and 29-35. NOTE: *Patients with CNS3 disease omit MTX IT on day 22. ARM III: Patients receive MTX, cyclophosphamide, cytarabine, mercaptopurine, vincristine sulfate, and pegaspargase as in arm I. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy as in arm I (DS patients excluded as of 09/29/10). ARM IV: Patients receive nelarabine, methotrexate, cyclophosphamide, cytarabine, mercaptopurine, vincristine sulfate, and pegaspargase as in arm II. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy as in arm II (DS patients excluded as of 09/29/10). Once blood counts recover, patients proceed to interim maintenance therapy according to their randomized/assigned arm. Patients not achieving M1 marrow by the end of consolidation therapy are removed from the study. INTERIM MAINTENANCE THERAPY (weeks 14-21 for arms I and III; weeks 17-24 for arms II and IV): ARM I: Patients* receive vincristine sulfate IV and escalating doses of methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase** IM or IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. Patients with DS also receive leucovorin calcium PO 48 and 60 hours after each methotrexate IT dose (DS patients excluded as of 09/29/10). NOTE: * Patients with T-NHL are randomized or assigned to arms I or II only. NOTE: **Patients with an allergy to pegaspargase receive Erwinia asparaginase on days 2, 4, 6, 8, 10, 12, 22, 24, 26, 28, 30, and 32. ARM II: Patients* receive vincristine sulfate, escalating doses of methotrexate, pegaspargase, and methotrexate IT as in arm I. ARM III: Patients receive high-dose methotrexate (HDMTX) IV over 24 hours and vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Beginning 42 hours after the start of HDMTX, patients also receive leucovorin calcium IV or orally once every 6 hours for 3 doses. ARM IV: Patients receive HDMTX, vincristine sulfate, mercaptopurine, methotrexate IT, and leucovorin calcium as in arm III. Once blood counts recover, patients proceed to delayed intensification therapy according to their randomized/assigned arm. DELAYED INTENSIFICATION THERAPY (weeks 22-30 for arms I and III; weeks 25-33 for arms II and IV): ARM I: Patients* receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID on days 1-21 (for patients < 10 years of age) OR on days 1-7 and 15-21 (for patients >= 10 years of age and for patients with DS); doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6, AND day 43; MTX IT on days 1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. Patients with DS also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose (DS patients excluded as of 09/29/10). NOTE: *T-NHL patients with standard-risk are nonrandomly assigned to arm I. ARM II: Patients** receive vincristine sulfate IV on days 1, 8, 15, and 50; dexamethasone IV or PO BID on days 1-21 (for patients < 10 years of age) OR on days 1-7 and 15-21 (for patients >= 10 years of age); doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6 AND day 50; methotrexate IT on days 1, 36, and 43; nelarabine IV over 60 minutes on days 29-33; cyclophosphamide IV over 30 minutes on day 36; cytarabine IV over 15-30 minutes on days 36-39 and 43-46; and thioguanine PO on days 36-49. NOTE: ** T-NHL patients with induction failure are nonrandomly assigned to arm II. ARM III: Patients receive vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, methotrexate IT, cyclophosphamide, cytarabine, and thioguanine as in arm I. Patients with intermediate- or high-risk disease (CNS1 or CNS2 disease) undergo prophylactic CRT (1,200 cGy/dose) QD on days 50-54 and 57-59. ARM IV: Patients receive vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, methotrexate IT, nelarabine, cyclophosphamide, cytarabine, and thioguanine as in arm II. Patients with intermediate- or high-risk disease (CNS 1 or CNS2 disease) undergo prophylactic CRT on days 50-54 and 57-59. All patients with CNS3 disease at diagnosis undergo CRT (1,800cGy/dose) QD on days 50-54 and 57-61. Once blood counts recover, patients proceed to maintenance therapy according to their randomized/assigned arm. MAINTENANCE THERAPY (week 31 until the end of therapy for arms I and III; weeks 34-69 for arms II and IV): ARM I: Patients* receive vincristine sulfate IV on days 1, 29, and 57; dexamethasone PO BID on days 1-5, 29-33, and 57-61; mercaptopurine PO QD on days 1-84; methotrexate PO** on days 8, 15, 22, 29*, 36, 43, 50, 57, 64, 71, and 78; and methotrexate IT on day 1. Treatment repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 119) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL). NOTE: * Patients with T-NHL and standard-risk are nonrandomly assigned to arm I. NOTE: **Patients with low-risk disease receive methotrexate IT, instead of methotrexate PO, on day 29 during the first 4 courses of therapy. ARM II: Patients*** receive vincristine sulfate IV on days 1 and 57; dexamethasone PO on days 1-5 and 57-61; mercaptopurine PO QD on days 1-84; MTX PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; methotrexate IT on day 1; and nelarabine IV over 60 minutes on days 29-33. Treatment (that includes nelarabine) repeats every 84 days for 3 courses. Patients then receive treatment (without nelarabine) as follows: vincristine sulfate IV on days 1 and 57; dexamethasone PO on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and methotrexate IT on day 1. Treatment (without nelarabine) repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 121) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL). NOTE: *** T-NHL patients with induction failure are nonrandomly assigned to arm II. ARM III: Patients receive vincristine sulfate, dexamethasone, mercaptopurine, methotrexate PO*, and methotrexate IT as in arm I. Treatment repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 119) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL). NOTE: *Patients with low-risk disease receive methotrexate IT, instead of methotrexate PO, on day 29 during the first 4 courses of therapy. ARM IV: Patients receive vincristine sulfate, dexamethasone, mercaptopurine, methotrexate PO, methotrexate IT, and nelarabine as in arm II. Patients then receive treatment (without nelarabine) as follows: vincristine sulfate, dexamethasone, mercaptopurine, methotrexate PO, and methotrexate IT as in arm II. Treatment (without nelarabine) repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 121) (for girls with T-ALL) and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL). After completion of study therapy, patients are followed periodically for at least 10 years.
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by National Cancer Institute (NCI).