Combination Chemotherapy and Rituximab in Treating Young Patients With Recurrent or Refractory Non-Hodgkin's Lymphoma or Acute Lymphoblastic Leukemia

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Terminated

CT.gov ID

NCT00058461

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

This phase II trial is studying how well rituximab together with ifosfamide, carboplatin, and etoposide works in treating young patients with recurrent or refractory non-Hodgkin's lymphoma or acute lymphoblastic leukemia. Chemotherapy drugs, such as ifosfamide, carboplatin, and etoposide, work in different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining ifosfamide, carboplatin, and etoposide with rituximab may kill more cancer cells.

Condition or Disease	Intervention/Treatment	Phase
B-cell Childhood Acute Lymphoblastic Leukemia Childhood Burkitt Lymphoma Childhood Diffuse Large Cell Lymphoma Childhood Immunoblastic Large Cell Lymphoma L3 Childhood Acute Lymphoblastic Leukemia Recurrent Childhood Acute Lymphoblastic Leukemia Recurrent Childhood Large Cell Lymphoma Recurrent Childhood Lymphoblastic Lymphoma Recurrent Childhood Small Noncleaved Cell Lymphoma	Drug: ifosfamide Drug: etoposide Biological: rituximab Drug: carboplatin Biological: filgrastim Drug: methotrexate Drug: cytarabine Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

Determine the response of pediatric patients with relapsed or refractory B-cell non-Hodgkin's lymphoma or acute lymphoblastic leukemia treated with ifosfamide, carboplatin, and etoposide combined with rituximab.
Determine the relapse-free survival rate of patients treated with this regimen.
Determine the toxicity profile of this regimen in these patients, specifically the frequency of therapy delays between courses due to prolonged grade IV hematologic toxicity.

SECONDARY OBJECTIVES:

Determine whether this regimen plus filgrastim (G-CSF) will result in mobilization of greater than 2 X 10^6/kg peripheral blood stem cells (CD34+ cells, PBSC) in at least 80% of patients for whom peripheral stem cell collection is performed.
Determine the time course of engraftment for patients who undergo peripheral stem cell transplantation after collection of stem cells using this mobilization regimen.

OUTLINE: This is a multicenter study. Patients are stratified by disease (B-cell large cell lymphoma or atypical precursor B-cell lymphoblastic lymphoma vs small non-cleaved cell lymphoma or B-cell acute lymphoblastic leukemia).

Patients receive ifosfamide IV over 2 hours and etoposide IV over 1 hour on days 3-5, rituximab IV on days 1 and 3, and carboplatin IV over 1 hour on day 3. Patients receive filgrastim (G-CSF) subcutaneously once daily beginning on day 6 and continuing until blood counts recover. Patients also receive intrathecal (IT) chemotherapy comprising methotrexate and cytarabine. Patients with B-cell large cell lymphoma and negative CSF cytology receive IT chemotherapy on day 3 of the first course only. Patients with small non-cleaved cell lymphoma or B-cell acute lymphoblastic leukemia and negative CSF cytology receive IT chemotherapy on day 3. All patients with positive CSF cytology receive IT chemotherapy on days 3, 10, and 17 of the first and second courses. Treatment repeats every 23 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 42-82 patients (21-41 per disease stratum) will be accrued for this study within 2-4 years.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

82 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Study of Rituximab (IND #7028) and Ifosfamide, Carboplatin and Etoposide (ICE) Chemotherapy in Children With Recurrent/Refractory B-cell (CD20+) Non-Hodgkin Lymphoma and B-cell Acute Lymphoblastic Leukemia

Study Start Date :

Nov 1, 2003

Actual Primary Completion Date :

Mar 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (chemotherapy, rituximab) Patients receive ifosfamide IV over 2 hours and etoposide IV over 1 hour on days 3-5, rituximab IV on days 1 and 3, and carboplatin IV over 1 hour on day 3. Patients receive filgrastim (G-CSF) subcutaneously once daily beginning on day 6 and continuing until blood counts recover. Patients also receive intrathecal (IT) chemotherapy comprising methotrexate and cytarabine. Patients with B-cell large cell lymphoma and negative CSF cytology receive IT chemotherapy on day 3 of the first course only. Patients with small non-cleaved cell lymphoma or B-cell acute lymphoblastic leukemia and negative CSF cytology receive IT chemotherapy on day 3. All patients with positive CSF cytology receive IT chemotherapy on days 3, 10, and 17 of the first and second courses. Treatment repeats every 23 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.	Drug: ifosfamide Given IV Drug: etoposide Given IV Biological: rituximab Given IV Drug: carboplatin Given IV Biological: filgrastim Given SC Drug: methotrexate Given IT Drug: cytarabine Given IT Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy, rituximab)

Drug: ifosfamide

Given IV

Drug: etoposide

Given IV

Biological: rituximab

Given IV

Drug: carboplatin

Given IV

Biological: filgrastim

Given SC

Drug: methotrexate

Given IT

Drug: cytarabine

Given IT

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

Response rate determined by physical exam and appropriate imaging studies [Up to 3 years]
Response rates and confidence intervals will be constructed according to the method of Chang and O'Brien.
Relapse-free survival rate [Up to 3 years]
Estimated by the Kaplan-Meier method.
Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) [Up to 3 years]

Secondary Outcome Measures

CD34 cells mobilization by flow cytometry [At the completion of 2 courses of treatment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed B-cell non-Hodgkin's lymphoma OR acute lymphoblastic leukemia
CD20+ (confirmed by flow cytometry of tumor tissue, involved marrow, or CD20 immunostaining)
The following histologies are generally CD20+ and are eligible:
Diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, or follicular lymphoma, grade III (rare), documented by flow cytometry or appropriate immunohistochemistry, any stage
Burkitt's lymphoma or atypical Burkitt's/Burkitt-like lymphoma, any stage
B-cell acute lymphoblastic leukemia, with FABL3 morphology and/or demonstration of surface immunoglobin by flow cytometry
Atypical precursor B-cell lymphoblastic lymphoma or other unusual histologies that are CD20+
Measurable disease by clinical, radiographic, or histologic criteria
Must be in first or later recurrence or have disease that is primarily refractory to conventional therapy
No isolated CNS disease
Performance status - ECOG 0-2
At least 2 months
Absolute neutrophil count ≥ 1,000/mm^3*
Platelet count ≥ 100,000/mm^3 (transfusion independent)*
Hemoglobin ≥ 10.0 g/dL (RBC transfusion allowed)*
Bilirubin ≤ 1.5 times normal
ALT < 2.5 times normal
No chronic renal insufficiency
Renal insufficiency allowed provided it is secondary to tumor lysis syndrome
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 3 months after study treatment
HIV negative
No active uncontrolled infection
Seizure disorder allowed if well controlled with anticonvulsants
No CNS toxicity greater than grade II
At least 24 hours since prior growth factor(s)
At least 60 days since prior biologic (antineoplastic) therapy
Prior stem cell transplantation allowed provided the following criteria are met:
More than 60 days since transplantation
Hematopoietic lab value requirements are met (See Hematopoietic)
No evidence of graft-versus-host disease (if post-allogeneic transplantation)
Prior monoclonal antibody therapy allowed (including rituximab)
No other concurrent immunomodulating agents
More than 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas)
No other concurrent chemotherapy
No concurrent steroids (except for rituximab infusion-related symptoms)
At least 2 weeks since prior local palliative radiotherapy (small port)
At least 6 weeks since prior substantial bone marrow radiotherapy
At least 6 months since prior craniospinal radiotherapy or radiotherapy to 50% or more of the pelvis
Concurrent radiotherapy to localized painful, airway-compromising, or other acute organ-threatening lesions allowed provided at least 1 measurable lesion is not irradiated
Recovered from prior therapy
No concurrent participation in another phase II study