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A Pilot Study To Determine The Toxicity Of The Addition Of Rituximab To The Induction And Consolidation Phases And The Addition Of Rasburicase To The Reduction Phase In Children With Newly Diagnosed Advanced B-Cell Leukemia/Lymphoma Treated With LMB/FAB Therapy


Phase 2
1 Year
29 Years
Not Enrolling
Both
Childhood Burkitt Lymphoma, Childhood Diffuse Large Cell Lymphoma, Childhood Immunoblastic Large Cell Lymphoma, Stage I Childhood Large Cell Lymphoma, Stage I Childhood Small Noncleaved Cell Lymphoma, Stage II Childhood Large Cell Lymphoma, Stage II Childhood Small Noncleaved Cell Lymphoma, Stage III Childhood Large Cell Lymphoma, Stage III Childhood Small Noncleaved Cell Lymphoma, Stage IV Childhood Large Cell Lymphoma, Stage IV Childhood Small Noncleaved Cell Lymphoma, Untreated Childhood Acute Lymphoblastic Leukemia

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Trial Information

A Pilot Study To Determine The Toxicity Of The Addition Of Rituximab To The Induction And Consolidation Phases And The Addition Of Rasburicase To The Reduction Phase In Children With Newly Diagnosed Advanced B-Cell Leukemia/Lymphoma Treated With LMB/FAB Therapy


OBJECTIVES:

I. Determine the toxicity of the addition of rituximab to induction chemotherapy comprising
vincristine, methylprednisolone, methotrexate, leucovorin calcium, cyclophosphamide, and
doxorubicin (COPADM) [COMRAP] and to consolidation chemotherapy in children with newly
diagnosed FAB prognostic group B or group C leukemia or lymphoma treated with LMB/FAB
therapy.

II. Determine the toxicity of the addition of rasburicase to the reduction phase comprising
cyclophosphamide, vincristine, prednisone or methylprednisolone, methotrexate, and
leucovorin calcium (COP-R) in these patients.

III. Determine the incidence of tumor lysis syndrome, renal complications, and the use of
assisted renal support (i.e., dialysis or hemofiltration) during the COP-R reduction phase
and the first induction phase of COPADM or COMRAP in these patients.

IV. Determine the response rate of patients treated with COMRAP incorporated into LMB/FAB
therapy.

V. Assess minimal residual disease in patients before and during COMRAP therapy incorporated
into LMB/FAB therapy.

OUTLINE: This is a multicenter study. Patients are stratified according to FAB prognostic
group (B vs C) and treated by group classification.

FAB GROUP B

TREATMENT I (first 6 patients):

REDUCTION THERAPY: Patients receive the COP-R regimen comprising cyclophosphamide IV over 15
minutes, vincristine IV, and methotrexate and hydrocortisone intrathecally (IT) on day 0;
rasburicase* IV over 30 minutes every 12 hours on days 0 and 1 and then once daily on days
2-4 (patients exhibiting hyperuricemia and clinical suspicion of B-cell non-Hodgkin's
lymphoma or B-cell acute lymphocytic leukemia also receive rasburicase on days -3, -2, and
-1); leucovorin calcium IV or orally every 12 hours on days 1 and 3; and prednisone (PRED)
or methylprednisolone (MePRDL) IV (or orally) on days 0-6. Patients too critical to proceed
may receive another course of reduction therapy.

NOTE: *Patients with G6PD deficiency do not receive rasburicase during reduction therapy.

INDUCTION THERAPY: Patients with less than 20% tumor reduction follow the group C induction
phase (described below). Patients with at least 20% tumor reduction receive 1 course of the
COPADM regimen: vincristine IV and methotrexate IV over 4 hours on day 0; PRED or MePRDL IV
(or orally) on days 0-7; leucovorin calcium IV or orally every 6 hours for 12 doses on days
1-3; doxorubicin IV over 30-60 minutes on day 1; cyclophosphamide IV over 15 minutes every
12 hours on days 1-3; methotrexate IT and hydrocortisone IT on days 1 and 5; and filgrastim
(G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts recover.

Patients receive the second part of induction therapy when peripheral blood counts have
recovered but no fewer than 16 days after the first part of induction therapy. Patients
receive 1 course of the COMRAP regimen comprising rituximab IV on days -2 and 0 with COPADM
as in the first part of induction therapy.

CONSOLIDATION THERAPY: Patients receive the CYM-RM regimen comprising rituximab IV and
methotrexate IV over 4 hours on day 0; leucovorin calcium IV or orally every 6 hours for 12
doses on days 1-3; cytarabine IV over 24 hours daily on days 1-5; hydrocortisone IT on days
1 and 6; methotrexate IT on day 1; and cytarabine IT on day 6.

After full recovery from consolidation therapy, patients with any residual masses undergo
surgical excision or biopsy. Patients with histology positive for tumor (even if completely
resected) proceed to Group C consolidation therapy (described below). Patients with
histology negative for tumor proceed to Group B maintenance therapy.

MAINTENANCE THERAPY: Patients receive the COPADM regimen comprising vincristine IV and
methotrexate IV over 4 hours on day 0; PRED or MePRDL IV (or orally) on days 0-7;
doxorubicin IV over 30-60 minutes, and cyclophosphamide IV over 30 minutes on days 1 and 2;
methotrexate IT and hydrocortisone IT on day 1; and leucovorin calcium IV or orally every 6
hours on days 1-3 (12 doses).

TREATMENT II (44 patients):

REDUCTION THERAPY: Patients receive the COP-R regimen as in treatment I.

INDUCTION THERAPY: Patients receive 2 courses of the COMRAP regimen as in the second
induction of treatment I.

CONSOLIDATION THERAPY: Patients receive the CYM-RM regimen as in treatment I.

MAINTENANCE THERAPY: Patients receive the COPADM regimen as in treatment I.

FAB GROUP C:

TREATMENT I (first 3 patients):

REDUCTION THERAPY: Patients receive the COP-R regimen as in group B treatment I, with the
addition of triple intrathecal therapy (TIT) comprising methotrexate, hydrocortisone, and
cytarabine on days 0, 2, and 4.

INDUCTION THERAPY: Patients receive 2 courses of the COPADM regimen as in group B treatment
I, with the addition of TIT on days 1, 3, and 5. Patients in group C who have biopsy-proven
disease after induction therapy are off protocol therapy and treated at the discretion of
the investigator.

CONSOLIDATION THERAPY:

CNS-POSITIVE DISEASE: Patients receive 2 courses of the CYVE-RM regimen comprising rituximab
IV and methotrexate and hydrocortisone IT on day 0; cytarabine IV over 12 hours on days 0-4;
high-dose cytarabine IV over 3 hours and etoposide IV over 2 hours on days 1-4; and G-CSF SC
on days 6-20. During the first course, patients also receive HD-MTX IV over 4 hours on day
17; TIT on day 18; and leucovorin calcium IV or orally every 6 hours on days 18-21 (12
doses).

CNS-NEGATIVE DISEASE: Patients receive the CYVE-RM regimen without intrathecal therapy,
HD-MTX, or leucovorin calcium.

After full recovery from consolidation therapy, patients with any residual masses undergo
surgical excision or biopsy. Patients who do not achieve complete remission after
consolidation therapy are considered treatment failures.

MAINTENANCE THERAPY (each course lasts 28 days):

COURSE M1: Patients receive vincristine IV and high-dose methotrexate IV over 4 hours on
day 0; PRED or MePRDL IV (or orally) on days 0-7; doxorubicin IV over 30-60 minutes and TIT
on day 1; cyclophosphamide IV over 30 minutes on days 1 and 2; and leucovorin calcium IV or
orally every 6 hours on days 1-4 (12 doses).

COURSE M2: Patients receive etoposide IV over 90 minutes on days 0-2 and cytarabine SC every
12 hours on days 0-4.

COURSE M3: Patients receive vincristine IV on day 0; cyclophosphamide IV over 30 minutes on
days 0 and 1; PRED or MePRDL IV (or orally) twice daily on days 0-7; and doxorubicin IV over
30-60 minutes on day 0 (after first dose of cyclophosphamide).

COURSE M4: Patients receive etoposide and cytarabine as in course M2.

TREATMENT II (37 patients):

REDUCTION THERAPY: Patients receive 2 courses of the COP-R regimen as in group C treatment
I.

INDUCTION THERAPY: Patients receive the COMRAP regimen comprising rituximab IV, vincristine
IV, and HD-MTX IV over 4 hours on day 0; PRED or MePRDL IV (or orally) on days 0-7;
leucovorin calcium IV or orally and cyclophosphamide IV over 15 minutes on days 1-3;
doxorubicin IV over 30-60 minutes on day 1; TIT on days 1, 3, and 5; and G-CSF SC on days
6-20.

CONSOLIDATION THERAPY: CNS-positive disease: Patients receive the CYVE-RM regimen plus
HD-MTX as in group C treatment I. Patients then receive CYVE-RM for a second course.

CNS-NEGATIVE DISEASE: Patients receive CYVE-RM regimen as in group C treatment I.

MAINTENANCE THERAPY: Patients receive maintenance therapy as in group C treatment I.

Patients are followed every 3-6 months for 1 year and then every 6 months for up to 5 years


Inclusion Criteria:



- Newly diagnosed mature B-lineage (CD20-positive) leukemia or lymphoma by the REAL
classification of 1 of the following subtypes:

- Diffuse large cell lymphoma

- Burkitt's lymphoma

- High-grade B-cell lymphoma (Burkitt-like)

- No B-cell anaplastic large cell Ki-1 positive lymphomas and B-lymphoblastic lymphomas

- One of the following FAB prognostic groups:

- Group B (intermediate risk)

- Group C (high risk)

- Bone marrow involvement with at least 25% blasts and/or CNS involvement
meeting 1 or more of the following criteria:

- Any L3 blasts in cerebrospinal fluid

- Cranial nerve palsy (if not explained by extracranial tumor)

- Clinical spinal cord compression

- Isolated intracerebral mass

- Parameningeal extension (cranial and/or spinal)

- Hepatitis B status known

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 6 months after study
participation

- No known history of congenital immune deficiency and/or laboratory evidence of
acquired immune deficiency

- No known G6PD deficiency (if receiving rasburicase)

- No prior malignancies treated with systemic chemotherapy with alkylator or
anthracycline therapy

- No prior chemotherapy

- At least 1 week since prior steroids except emergency steroids initiated within 72
hours of study entry

- No prior radiotherapy except emergency radiotherapy initiated within 72 hours of
study entry

- No concurrent radiotherapy

- No prior solid organ transplantation

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity rate of rituximab using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0

Outcome Description:

Two events are of particular interest, the incidence of grade ≥ 3 stomatitis and any occurrence of a toxic death. For the implementation of the toxic death rate stopping rule, a death must be possibly, probably or definitely attributable to rituximab and/or chemotherapy to be considered a toxic death.

Outcome Time Frame:

Up to 1 year

Safety Issue:

Yes

Principal Investigator

Mitchell Cairo

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

ANHL01P1

NCT ID:

NCT00057811

Start Date:

June 2004

Completion Date:

Related Keywords:

  • Childhood Burkitt Lymphoma
  • Childhood Diffuse Large Cell Lymphoma
  • Childhood Immunoblastic Large Cell Lymphoma
  • Stage I Childhood Large Cell Lymphoma
  • Stage I Childhood Small Noncleaved Cell Lymphoma
  • Stage II Childhood Large Cell Lymphoma
  • Stage II Childhood Small Noncleaved Cell Lymphoma
  • Stage III Childhood Large Cell Lymphoma
  • Stage III Childhood Small Noncleaved Cell Lymphoma
  • Stage IV Childhood Large Cell Lymphoma
  • Stage IV Childhood Small Noncleaved Cell Lymphoma
  • Untreated Childhood Acute Lymphoblastic Leukemia
  • Burkitt Lymphoma
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphoma, Large-Cell, Immunoblastic

Name

Location

Children's Oncology GroupArcadia, California  91006-3776