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

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.