Trial Information

Intergroup Trial for Children or Adolescents With B-Cell NHL or B-AL: Evaluation of Rituximab Efficacy and Safety in High Risk Patients

PRIMARY OBJECTIVES:

I. For the patients with advanced stage B-cell non-Hodgkin lymphoma (NHL)/Burkitt leukemia
(B-AL) (stage III and lactate dehydrogenase (LDH) > Nx2, any stage IV or B-AL), to test
whether adding 6 injections of rituximab to standard LMB chemotherapy regimen, improves the
event-free survival (EFS) compared with LMB chemotherapy alone. (Phase III) II. For patients
with primary mediastinal large B-cell lymphoma (PMLBL), to evaluate the EFS following
treatment with the regimen dose-adjusted (DA)-etoposide, prednisone, vincristine sulfate,
cyclophosphamide, doxorubicin hydrochloride (EPOCH), and rituximab. (Phase II)

SECONDARY OBJECTIVES:

I. To study the complete remission (CR) rate and the overall survival (OS). II. To evaluate
safety on all study arms including toxic deaths, adverse events recorded using the National
Cancer Institute (NCI)-Common Terminology Criteria (CTC) V4 (non-hematological toxicity
grade 3, infections grade 3 to 5), cardiac toxicity (CTC grade 2-5 and evolution of left
ventricular ejection fraction [LVEF] and left ventricular shortening fraction [LVSF]),
number of days with platelets transfusion, intensive-care unit admission, number of days
with red cells transfusion, and rituximab infusion reactions.

III. To study the rate of patients with immunoglobulin (Ig; G, A, and M) levels abnormally
low and lymphocyte count abnormally low at 1 year and until 5-year follow-up, to study the
need for Ig infusions, and levels of post (previous and re-) vaccination antibodies at 1
year.

IV. To study long-term (at least 5 years) risks of the use of rituximab plus chemotherapy
compared with LMB chemotherapy alone in children with advanced stage B-NHL/B-AL (all events
related [certain and probable] to therapy). (Phase III) V. To study the long-term risk of
DA-EPOCH-R regimen, especially the cardiac risk related to doxorubicin given at higher dose
than usual in children, but infused over 96 hours (i.e., evaluation of CTC grade 2-5 and
evolution of LVEF and LVSF). (Phase II)

TERTIARY OBJECTIVES:

I. To obtain data on positron emission tomography (PET)-computed tomography (CT) scan in
childhood pediatric B-cell NHL. (Exploratory) II. To evaluate the potential prognostic value
of Minimal Disseminated Disease (MDD) and Minimal Residual disease (MRD) in correlation with
outcome. (Exploratory - Phase III) III. To perform an economic study comparing the
cost-effectiveness ratio between 2 therapeutic strategies: LMB chemotherapy with versus
without rituximab. (Exploratory - Phase III) IV. To characterize the pharmacokinetics of
rituximab in combination with LMB chemotherapy in a subset of patients. (Exploratory - Phase
III)

OUTLINE: This is a multicenter study.

Phase II (patients with PMLBL): Patients receive rituximab IV on day 1; prednisone orally
(PO) twice daily (BID) or IV on day on days 1-5; etoposide IV continuously on days 1-4;
doxorubicin hydrochloride IV continuously on days 1-4; vincristine sulfate IV continuously
on days 1-4; and cyclophosphamide IV on day 5. Patients also receive filgrastim
subcutaneously (SC) once daily (QD) beginning on day 6 until blood count recovers. Treatment
repeats every 21 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

Phase III: Patients are stratified according to National Group (COG vs SFCE vs UK NCRI CCL
CSG vs AIEOP vs BSPHO vs DCOG vs SEHOP vs PPLLSG vs Hungarian Society of Pediatric
Oncologist and Pediatric Hematologist), histology (large cell vs non large cell [Burkitt,
atypical Burkitt, B-AL, or L3-AL]), and chemotherapy group (1 vs 2). Patients are assigned
to 1 of 2 treatment groups.

Group 1 (pre-phase central nervous system [CNS]-negative, cerebral spinal fluid
[CSF]-negative): Patients receive vincristine sulfate IV on day 1; cyclophosphamide IV over
15 minutes on day 1; prednisone PO BID or methylprednisolone IV on days 1-7; methotrexate
intrathecally (IT) and hydrocortisone IT on day 1. Patients are randomized to 1 of 2
treatment arms.

Arm I (R-COPADM induction therapy): Beginning 8 days later, patients receive rituximab IV on
day 1; vincristine sulfate IV on day 1; prednisone PO BID or methylprednisolone IV on days
1-5; methotrexate IV over 3 hours on day 1; leucovorin calcium PO every 6 hours on days 2-4;
cyclophosphamide IV over 15 minutes on days 2-4; doxorubicin hydrochloride over 1 hour on
day 2; and methotrexate IT and hydrocortisone IT on days 2 and 6. Treatment repeats every
18-21 days for 2 courses. Consolidation therapy (R-COPADM): Patients receive rituximab IV
on day 1; methotrexate IV over 3 hours on day 1; leucovorin calcium PO every 6 hours on days
2-4; cytarabine IV continuously on days 2-6; methotrexate IT on day 2; hydrocortisone IT on
days 2 and 7; and cytarabine IT on day 7. Treatment repeats every 21 days for 2 courses.

Arm II (COPADM induction therapy): Beginning 8 days later, patients receive vincristine
sulfate, prednisone or methylprednisolone, methotrexate, leucovorin calcium,
cyclophosphamide, doxorubicin, methotrexate IT, and hydrocortisone IT as in arm I. Treatment
repeats every 18-21 days for 2 courses.

Consolidation therapy (COPADM): Patients receive methotrexate IV over 3 hours on day 1;
leucovorin calcium PO every 6 hours on days 2-4; cytarabine IV over 12 hours on days 2-6;
methotrexate IT on day 2; hydrocortisone IT on days 2 and 7; and cytarabine IT on day 7.
Treatment repeats every 21 days for 2 courses.

Group 2 (pre-phase B-AL, CNS-negative OR CNS-positive, CSF-negative OR CSF-positive):
Patients receive vincristine sulfate IV on day 1; cyclophosphamide IV over 15 minutes on day
1; prednisone PO BID or methylprednisolone IV on days 1-7; methotrexate IT, hydrocortisone
IT, and cytarabine IT on days 1, 3, and 5; and leucovorin calcium PO BID on days 2 and 4.
Patients are randomized to 1 of 2 treatment arms.

Arm III (R-COPADM induction therapy): Patients receive rituximab IV on days -2 (course 1)
and 1; vincristine sulfate IV on day 1; prednisone PO or methylprednisolone IV on days 1-5;
high-dose methotrexate IV over 4 hours* on day 1; leucovorin calcium PO every 6 hours on
days 2-4; cyclophosphamide IV over 15 minutes on days 2-4; doxorubicin hydrochloride IV on
day 2; and methotrexate IT, hydrocortisone IT, and cytarabine IT on days 2, 4, and 6.
Treatment repeats every 21 days for 2 courses.

NOTE: *During the second course, patients with CSF-positive disease receive high-dose
methotrexate IV over 24 hours (instead of 4 hours).

Consolidation therapy (R-COPADM): Patients receive rituximab IV on day 1; hydrocortisone IT
and methotrexate IT on day 1; cytarabine IV over 12 hours on days 1-5; high-dose cytarabine
IV over 3 hours on day 2-5; and etoposide IV over 2 hours on days 2-5. If CSF-positive,
patients receive high-dose methotrexate IV over 24 hours on day 18, methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 19, and leucovorin calcium PO every 6 hours on
days 19-21. Treatment repeats every 21 days for 2 courses.

Maintenance therapy (R-COPADM): Patients receive vincristine sulfate IV on day 1; prednisone
PO or methylprednisolone IV on days 1-5; high-dose methotrexate IV over 4 hours on day 1;
leucovorin calcium PO every 6 hours on days 2-4; cyclophosphamide IV over 15 minutes on days
2-3; doxorubicin hydrochloride over 1 hour on day 2; and methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 2. Beginning 28 days later, patients receive cytarabine
subcutaneously (SC) every 12 hours on days 1-5 and etoposide IV over 90 minutes on days 1-3.

Arm IV (COPADM induction therapy): Patients receive vincristine sulfate, prednisone or
methylprednisolone, high-dose methotrexate*, leucovorin calcium, cyclophosphamide,
doxorubicin hydrochloride, and methotrexate, hydrocortisone, and cytarabine IT as in arm
III. NOTE: *Patients with CSF-positive disease receive high-dose methotrexate IV over 24
hours (instead of 4 hours).

Consolidation therapy (COPADM): Patients receive hydrocortisone and methotrexate IT,
cytarabine, high-dose cytarabine, and etoposide as in arm III consolidation therapy.

Maintenance therapy (COPADM): Patients receive vincristine sulfate, prednisone or
methylprednisolone, high-dose methotrexate*, leucovorin calcium, cyclophosphamide,
doxorubicin hydrochloride, methotrexate IT, hydrocortisone IT, cytarabine IT, cytarabine SC,
and etoposide as in arm III maintenance therapy.

NOTE: *Patients with CSF-positive disease receive high-dose methotrexate IV over 24 hours.

Blood and tumor tissue samples are collected at baseline, during, and at the completion of
study therapy for correlative studies.

After completion of study treatment, patients are followed-up for 5 years.