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Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma

Conditions

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

Trial Phase

Phase 3

Trial Purpose and Description

Trial 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.


Trial 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.

Participation Guidelines

Age:
1 Year - 30 Years
Gender:
Both

Eligibility Criteria


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
Sponsor:
National Cancer Institute (NCI)
Dates:
January 2007
Last Updated:
July 30, 2014
Study HIC#:

Clinicaltrials.gov ID: NCT00408005