Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Contiguous Stage II Adult Lymphoblastic Lymphoma Noncontiguous Stage II Adult Lymphoblastic Lymphoma Stage II Adult T-cell Leukemia/Lymphoma Stage II Childhood 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 T-cell Adult Acute Lymphoblastic Leukemia T-cell Childhood Acute Lymphoblastic Leukemia Untreated Adult Acute Lymphoblastic Leukemia Untreated Childhood Acute Lymphoblastic Leukemia |
Drug: doxorubicin hydrochloride Drug: cytarabine Drug: daunorubicin hydrochloride Drug: prednisone Drug: pegaspargase Drug: methotrexate Drug: leucovorin calcium Drug: cyclophosphamide Drug: mercaptopurine Drug: nelarabine Drug: asparaginase Drug: dexamethasone Drug: thioguanine Drug: vincristine sulfate Radiation: radiation therapy Other: laboratory biomarker analysis |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Intensified Methotrexate, Nelarabine (Compound 506U78; IND #52611) and Augmented BFM Therapy for Children and Young Adults With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia (ALL) or T-cell Lymphoblastic Lymphoma |
- Event-free survival (EFS) after initial remission [ Time Frame: At 4 years ] [ Designated as safety issue: No ]This outcome can be modeled reasonably well by a linear decreasing hazard rate with no appreciable risk of failure after completion of year 4. EFS events include any type of relapse, death in remission or second malignant neoplasm. "Intent-to-treat" analyses (i.e. based on the regimen to which patients are initially randomized) will be the primary approach used to assess treatment efficacy.
- Nelarabine toxicity assessment by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: From week 6 to up to week 43 ] [ Designated as safety issue: Yes ]Compared directly to their randomized control not receiving nelarabine with additional examination of the comparison within the separate methotrexate regimen subsets. These comparisons will focus on grade 3 or higher non-hematologic toxicities. The overall incidence of selected neurologic toxicities will also be monitored since these represent an important target category for nelarabine toxicity.
- Safety of combination chemotherapy with vs without nelarabine as assessed by NCI CTCAE version 4.0 [ Time Frame: From week 6 to week 43 ] [ Designated as safety issue: Yes ]Futility testing boundaries will be used for the comparison of "Nelarabine" versus "No Nelarabine" to decide if stopping should occur for similarity of outcome. This will be tested with a Pampallona-Tsiatis type lower monitoring boundary when approximately 20%, 40%, 60% and 80% of the EFS event information is available.
- Efficacy of combination chemotherapy with vs without nelarabine [ Time Frame: Assessed up to 10 years ] [ Designated as safety issue: Yes ]"Intent-to-treat" analyses (i.e. based on the regimen to which patients are initially randomized) will be the primary approach used to assess treatment efficacy.
- Safety and efficacy of high-dose methotrexate (with leucovorin calcium rescue) and mercaptopurine vs escalating-dose methotrexate (without leucovorin calcium rescue) and pegaspargase [ Time Frame: At each dose level of treatment ] [ Designated as safety issue: Yes ]Analyses will be performed regularly to assess the possibility of an interaction effect (using a Cox regression likelihood ratio test) which will assess the four individual treatment regimens in the 2 x 2 design to see if a non-proportional hazards effect occurs for the combinations of the two main effect factors. Since the comparison of the methotrexate regimens utilizes a selection type analysis, no futility testing will be used for that comparison.
| Estimated Enrollment: | 1580 |
| Study Start Date: | January 2007 |
| Estimated Primary Completion Date: | September 2017 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Arm I (Consolidation chemotherapy)
Patients receive methotrexate (MTX) intrathecally (IT) on days 1, 8, 15, and 22; cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; oral mercaptopurine on days 1-14 and 29-42; vincristine IV on days 15, 22, 43 and 50; and pegaspargase intramuscularly (IM) or IV over 1-2 hours on days 15 and 43. Patients with Down syndrome (DS) also receive oral leucovorin calcium at 48 and 60 hours after each MTX 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 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.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cytarabine
Given IT, IV, or SC
Other Names:
Drug: daunorubicin hydrochloride
Given IV
Other Names:
Drug: prednisone
Given IV or orally
Other Names:
Drug: pegaspargase
Given intramuscularly or IV
Other Names:
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: leucovorin calcium
Given orally
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: mercaptopurine
Given orally
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Radiation: radiation therapy
Some patients undergo testicular and/or prophylactic cranial RT
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm II (Consolidation chemotherapy)
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 or SC on days 8-11, 15-18, 50-53 and 57-60; oral mercaptopurine on days 8-21 and 50-63; vincristine 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.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cytarabine
Given IT, IV, or SC
Other Names:
Drug: daunorubicin hydrochloride
Given IV
Other Names:
Drug: prednisone
Given IV or orally
Other Names:
Drug: pegaspargase
Given intramuscularly or IV
Other Names:
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: leucovorin calcium
Given orally
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: mercaptopurine
Given orally
Other Names:
Drug: nelarabine
Given IV
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Radiation: radiation therapy
Some patients undergo testicular and/or prophylactic cranial RT
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm III (Consolidation chemotherapy)
Patients receive MTX, cyclophosphamide, cytarabine, mercaptopurine, vincristine, 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).
|
Drug: cytarabine
Given IT, IV, or SC
Other Names:
Drug: daunorubicin hydrochloride
Given IV
Other Names:
Drug: prednisone
Given IV or orally
Other Names:
Drug: pegaspargase
Given intramuscularly or IV
Other Names:
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: mercaptopurine
Given orally
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm IV (Consolidation chemotherapy)
Patients receive nelarabine, MTX, cyclophosphamide, cytarabine, mercaptopurine, vincristine, 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).
|
Drug: daunorubicin hydrochloride
Given IV
Other Names:
Drug: prednisone
Given IV or orally
Other Names:
Drug: pegaspargase
Given intramuscularly or IV
Other Names:
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: mercaptopurine
Given orally
Other Names:
Drug: nelarabine
Given IV
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm I (Interim maintenance chemotherapy)
Patients receive vincristine IV and escalating doses of MTX IV on days 1, 11, 21, 31, and 41; pegaspargase* IM or IV over 1-2 hours on days 2 and 22; and MTX IT on days 1 and 31. Patients with DS also receive oral leucovorin calcium 48 and 60 hours after each MTX 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.] |
Drug: pegaspargase
Given intramuscularly or IV
Other Names:
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: leucovorin calcium
Given orally
Other Names:
Drug: asparaginase
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm II (Interim maintenance chemotherapy)
Patients receive vincristine, escalating doses of MTX, pegaspargase, and MTX IT as in arm I.
|
Drug: pegaspargase
Given intramuscularly or IV
Other Names:
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: leucovorin calcium
Given orally
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm III (Interim maintenance chemotherapy)
Patients receive high-dose methotrexate (HDMTX) IV over 24 hours and vincristine IV on days 1, 15, 29, and 43; oral mercaptopurine on days 1-56; and MTX 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.
|
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: leucovorin calcium
Given orally
Other Names:
Drug: mercaptopurine
Given orally
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm IV (Interim maintenance chemotherapy)
Patients receive HDMTX, vincristine, mercaptopurine, MTX IT, and leucovorin calcium as in arm III.
|
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: leucovorin calcium
Given orally
Other Names:
Drug: mercaptopurine
Given orally
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm I (Delayed intensification chemotherapy)
Patients receive vincristine IV on days 1, 8, 15, 43, and 50; dexamethasone IV or orally twice daily 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 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 or SC on days 29-32 and 36-39; and oral thioguanine on days 29-42. Patients with DS also receive oral leucovorin calcium at 48 and 60 hours after each MTX dose (DS patients excluded as of 09/29/10).
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cytarabine
Given IT, IV, or SC
Other Names:
Drug: pegaspargase
Given intramuscularly or IV
Other Names:
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: leucovorin calcium
Given orally
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: dexamethasone
Given IV or orally
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm II (Delayed intensification chemotherapy)
Patients receive vincristine IV on days 1, 8, 15, and 50; dexamethasone IV or orally twice daily 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 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; MTX 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 or SC on days 36-39 and 43-46; and oral thioguanine on days 36-49.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cytarabine
Given IT, IV, or SC
Other Names:
Drug: pegaspargase
Given intramuscularly or IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: nelarabine
Given IV
Other Names:
Drug: dexamethasone
Given IV or orally
Other Names:
Drug: thioguanine
Given orally
Other Name: 6-TG
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm III (Delayed intensification chemotherapy)
Patients receive vincristine, dexamethasone, doxorubicin hydrochloride, pegaspargase, MTX 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) once daily on days 50-54 and 57-59.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cytarabine
Given IT, IV, or SC
Other Names:
Drug: pegaspargase
Given intramuscularly or IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: dexamethasone
Given IV or orally
Other Names:
Drug: thioguanine
Given orally
Other Name: 6-TG
Drug: vincristine sulfate
Given IV
Other Names:
|
|
Active Comparator: Arm IV (Delayed intensification chemotherapy)
Patients receive vincristine, dexamethasone, doxorubicin hydrochloride, pegaspargase, MTX 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.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cytarabine
Given IT, IV, or SC
Other Names:
Drug: pegaspargase
Given intramuscularly or IV
Other Names:
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: nelarabine
Given IV
Other Names:
Drug: dexamethasone
Given IV or orally
Other Names:
Drug: thioguanine
Given orally
Other Name: 6-TG
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm I (Maintenance chemotherapy)
Patients receive vincristine IV on days 1, 29, and 57; oral dexamethasone twice daily on days 1-5, 29-33, and 57-61; oral mercaptopurine once daily on days 1-84; oral MTX on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and MTX 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).
|
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: mercaptopurine
Given orally
Other Names:
Drug: dexamethasone
Given IV or orally
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm II (Maintenance chemotherapy)
Patients receive vincristine IV on days 1 and 57; oral dexamethasone on days 1-5 and 57-61; oral mercaptopurine once daily on days 1-84; oral MTX on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; MTX 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 IV on days 1 and 57; oral dexamethasone on days 1-5, 29-33, and 57-61; oral mercaptopurine on days 1-84; oral MTX on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and MTX 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).
|
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: mercaptopurine
Given orally
Other Names:
Drug: nelarabine
Given IV
Other Names:
Drug: dexamethasone
Given IV or orally
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm III (Maintenance chemotherapy)
Patients receive vincristine, dexamethasone, mercaptopurine, oral MTX, and MTX 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).
|
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: mercaptopurine
Given orally
Other Names:
Drug: dexamethasone
Given IV or orally
Other Names:
Radiation: radiation therapy
Some patients undergo testicular and/or prophylactic cranial RT
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Active Comparator: Arm IV (Maintenance chemotherapy)
Patients receive vincristine, dexamethasone, mercaptopurine, oral MTX, MTX IT, and nelarabine as in arm II. Patients then receive treatment (without nelarabine) as follows: vincristine, dexamethasone, mercaptopurine, oral MTX, and MTX 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).
|
Drug: methotrexate
Given intrathecally or orally
Other Names:
Drug: mercaptopurine
Given orally
Other Names:
Drug: nelarabine
Given IV
Other Names:
Drug: dexamethasone
Given IV or orally
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
Show Detailed Description
Eligibility| Ages Eligible for Study: | 1 Year to 30 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Newly diagnosed with 1 of the following:
T-cell acute lymphoblastic leukemia (ALL), meeting the following criteria:
- Leukemic blasts lack myeloperoxidase or evidence of B-lineage derivation(CD19/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 TdT, CD34, or CD99 will be assessed for expression
- Concurrently enrolled on protocol COG-AALL03B1 and/or COG-AALL08B1
T-lineage lymphoblastic lymphoma (T-NHL)
Stage II-IV disease
- No B-lineage lymphoblastic lymphoma
- No morphologically unclassifiable lymphoma
- No absence of both B-cell and T-cell phenotype markers
- No CNS3-positive or testicular involvement
- No patients with ALL or T-NHL and Down syndrome
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No peripheral neurotoxicity ≥ grade 2 (for patients randomized to receive nelarabine)
- No prior seizure disorder (for patients randomized to receive nelarabine)
- Prior steroid therapy allowed
- No prior cytotoxic chemotherapy except intrathecal cytarabine
- At least 2 years since prior and no concurrent anticonvulsant therapy (for patients randomized to receive nelarabine)
- No concurrent milk or citrus products during thioguanine or mercaptopurine administration
- No concurrent intensity-modulated radiotherapy
- No concurrent nonsteroidal anti-inflammatory drugs, penicillin, or acetylsalicylic acid-containing medications for at least 3 days after high-dose methotrexate
Contacts and Locations
Show 197 Study Locations| Principal Investigator: | Stuart Winter | Children's Oncology Group |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT00408005 History of Changes |
| Other Study ID Numbers: | NCI-2009-00307, AALL0434, CDR0000514500, COG-AALL0434, U01CA98543 |
| Study First Received: | December 4, 2006 |
| Last Updated: | March 26, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Leukemia Leukemia, Lymphoid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, T-Cell Leukemia-Lymphoma, Adult T-Cell Lymphoma Lymphoma, Non-Hodgkin Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases 6-Mercaptopurine |
Cytarabine Methotrexate Thioguanine Cyclophosphamide Pegaspargase Asparaginase Daunorubicin Dexamethasone Doxorubicin Prednisone Vincristine BB 1101 Dexamethasone acetate Dexamethasone 21-phosphate Leucovorin |
ClinicalTrials.gov processed this record on June 18, 2013