Trial Information

Randomized Phase III Study for the Treatment of Newly Diagnosed Disseminated Lymphoblastic Lymphoma or Localized Lymphoblastic Lymphoma

OBJECTIVES:

- Compare the event-free survival and overall survival of children or adolescents with
newly diagnosed disseminated stage III or IV lymphoblastic lymphoma treated with 4
chemotherapy regimens*.

- Determine whether treatment with a regimen without methotrexate maintains the same
disease-free survival as NHL/BFM 90 in these patients.

- Determine whether intensification with anthracycline and cyclophosphamide improves
disease-free survival in these patients.

- Collect outcome data on uniformly treated patients with localized disease or
CNS-positive disease.

- Determine whether rapid reduction in tumor volume by chest radiography and CT scan is
predictive of improved outcome in patients treated with these regimens.

- Determine the prevalence of bone marrow involvement at presentation in these patients.

- Determine whether peripheral blood can replace bone marrow in the initial staging of
these patients.

- Determine the clinical significance of bone marrow and peripheral blood involvement in
these patients.

NOTE: *All patients as of 4/2006 receive treatment on Arm III regimen only

OUTLINE: Patients are stratified by disease characteristics (disseminated lymphoblastic
lymphoma vs localized lymphoblastic lymphoma [localized lymphoblastic lymphoma is closed to
accrual as of 10/2005]) and age. Patients with CNS negative disseminated lymphoblastic
lymphoma are randomized to 1 of 4 treatment arms*. Patients with testicular involvement at
diagnosis are nonrandomly assigned to arm IV and do not receive testicular radiotherapy.
Patients with localized lymphoblastic lymphoma (closed to accrual as of 10/2005) are not
randomized.

NOTE: *All patients as of 4/2006 receive treatment on Arm III only

- Localized lymphoblastic lymphoma (closed to accrual as of 10/2005):

- Induction (5 weeks): Patients receive vincristine IV and daunorubicin IV over 15
minutes to 2 hours on days 0, 7, 14, and 21; oral prednisone on days 0-27; and
asparaginase intramuscularly (IM) on days 3, 5, and 7 and then 3 times a week for
9 doses (during days 8-21). Patients also receive methotrexate intrathecally (IT)
on days 7 and 28 and cytarabine IT on day 0.

- Consolidation (5 weeks): Patients receive methotrexate IT on days 0, 7, 14, and 21
followed by cyclophosphamide IV over 1 hour on days 0 and 14; cytarabine IV on
days 0-3, 7-10, 14-17, and 21-24; oral mercaptopurine on days 0-27; and oral
prednisone over 10 days.

- Interim maintenance (8 weeks): Patients receive methotrexate IT on days 0 and 28;
oral mercaptopurine on days 0-41; and oral methotrexate on days 7, 14, 21, and 35.

- Delayed intensification (7 weeks): Patients receive vincristine IV and doxorubicin
IV over 15 minutes to 2 hours on days 0, 7, and 14; asparaginase IM on day 3 and
then 3 times a week for 6 doses; oral dexamethasone on days 0-30; cyclophosphamide
IV over 1 hour on day 28; and cytarabine IV or SC on days 28-31 and 35-38.
Patients also receive oral thioguanine on days 28-41 and methotrexate IT on days
28 and 35.

- Maintenance (84 day course): Patients receive vincristine IV on days 0, 28, and
56; oral prednisone on days 0-4, 28-32, and 56-60; oral methotrexate on days 7,
14, 21, 28, 35, 42, 49, 56, 63, 70, and 77; oral mercaptopurine on days 0-83; and
methotrexate IT on day 0.

- Disseminated lymphoblastic lymphoma:

- Arm I (closed to accrual as of 4/2006): Patients receive same induction,
consolidation, and interim maintenance therapy schedule as localized lymphoblastic
lymphoma patients.

- Delayed intensification (7 weeks): Patients receive vincristine IV and
doxorubicin IV over 15 minutes to 2 hours on days 0, 7, 14, and 21;
asparaginase IM on day 3 and then 3 times a week for 6 doses; and oral
dexamethasone on days 0-28. Patients also receive cyclophosphamide IV over 1
hour on day 35; cytarabine IV or SC on days 35-38 and 42-45; oral thioguanine
on days 35-48; and methotrexate IT on days 35 and 42.

- Maintenance (84 day course): Patients receive same therapy as localized
lymphoblastic lymphoma patients, except methotrexate IT is administered on
day 0 and 28 (for first 4 courses).

- Arm II (closed to accrual as of 4/2006): Patients receive consolidation, interim
maintenance, and maintenance therapy as in arm I.

- Induction (5 weeks): Patients receive vincristine IV on days 0, 7, 14, and
21; daunorubicin IV over 48 hours on days 0-2; oral prednisone on days 0-27;
and asparaginase IM on days 3, 5, and 7 and then 3 times a week for 9 doses
(during days 8-21). Patients also receive methotrexate IT on days 7 and 28;
cyclophosphamide IV over 1 hour on day 2; and cytarabine IT on day 0.

- Delayed intensification (7 weeks): Patients receive vincristine IV on days 0,
7, 14, 21; daunorubicin IV over 48 hours on days 0-2; asparaginase IM on day
3 and then 3 times a week for 6 doses; and oral dexamethasone on days 0-28.
Patients also receive cyclophosphamide IV over 1 hour on days 2 and 35;
cytarabine IV or SC on days 35-38 and 42-45; oral thioguanine on days 35-48;
and methotrexate IT on days 35 and 42.

- Arm III:

- Induction (5 weeks): Patients receive vincristine IV and daunorubicin IV over
1 hour on days 0, 7, 14, and 21 and oral prednisone on days 0-37. Patients
also receive asparaginase IM on day 11 and then 3 times a week for 9 doses;
methotrexate IT on days 7 and 28; and cytarabine IT on day 0.

- Consolidation (5 weeks): Patients receive methotrexate IT and
cyclophosphamide IV over 1 hour on days 0 and 14; cytarabine IV or SC on days
0-3, 7-10, 14-17, and 21-24; oral mercaptopurine on days 0-27; and oral
prednisone over 10 days.

- Interim maintenance (9 weeks): Patients receive methotrexate IT and IV on
days 7, 21, 35, and 49; oral mercaptopurine on days 0-55; and leucovorin
calcium IV at 42, 48, and 54 hours after methotrexate IV.

- Delayed intensification (10 weeks): Patients receive vincristine IV and
doxorubicin IV over 1 hour on days 0, 7, 14, and 21; asparaginase IM on day 3
and then 3 times a week for 6 doses; and oral dexamethasone on days 0-29.
Patients also receive cyclophosphamide IV over 1 hour on day 35; cytarabine
IV on days 35-38 and 42-45; oral thioguanine on days 35-48; and methotrexate
IT on days 35 and 42.

- Maintenance (84 day courses): Patients receive vincristine IV on days 0, 28,
and 56; oral prednisone on days 0-4, 28-32, and 56-60; oral methotrexate on
days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77; and oral mercaptopurine
on days 0-83.

- Arm IV (closed to accrual as of 4/2006): Patients receive consolidation and
interim maintenance therapy as in arm III.

- Induction: Patients receive vincristine IV on days 0, 7, 14, and 21;
daunorubicin IV over 48 hours on days 0-2; oral prednisone on days 0-37;
asparaginase IM on day 11 and then 3 times a week for 9 doses; methotrexate
IT on days 7, 14, 21, and 28; cyclophosphamide IV on day 2; and cytarabine IT
on day 0.

- Delayed intensification (10 weeks): Patients receive vincristine IV on days
7, 14, 21, and 28; daunorubicin IV over 48 hours on days 0-2; asparaginase IM
on day 3 and then 3 times a week for 6 doses; and oral dexamethasone on days
0-29. Patients also receive cyclophosphamide IV over 1 hour on days 2 and 35;
cytarabine IV on days 35-38 and 42-45; oral thioguanine on days 35-48; and
methotrexate IT on days 35 and 42.

- Maintenance (84 day courses): Patients receive therapy as in arm III.
Patients who are over 1 year of age and have CNS disease at diagnosis undergo
cranial radiotherapy once daily 5 days a week beginning on day 0. Patients
over 2 years of age undergo radiotherapy over 11-14 days (6-9 days for 1-2
years of age).

Patients are followed monthly for one year, every 3 months for 1 year, every 6 months for
1.5 years, and then annually thereafter.

PROJECTED ACCRUAL: Approximately 250-400 patients will be accrued for this study within 5
years.