Trial record 1 of 1 for:    NCT01595048
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Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III-IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia

This study is currently recruiting participants.
Verified February 2014 by Children's Oncology Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT01595048
First received: May 8, 2012
Last updated: February 5, 2014
Last verified: February 2014

May 8, 2012
February 5, 2014
June 2012
December 2020   (final data collection date for primary outcome measure)
EFS [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
Will be estimated with the Kaplan Meier method. The 95% confidence intervals (95% CI) of the actuarial rates will be calculated with the Rothman method.
EFS at 3 years [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01595048 on ClinicalTrials.gov Archive Site
  • Survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Estimated by the Kaplan-Meier method and the 95% confidence intervals (95% CI) of the actuarial rates calculated by the Rothman method.
  • Complete remission rate compared between arms by logistic regression [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Compared between arms by logistic regression.
  • Acute and long-term toxicity as assessed by the National Cancer Institute Common Terminology Criteria version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
  • Immune reconstitution as assessed by Ig (G, A, and M) levels and lymphocyte counts [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
  • Survival estimated by the Kaplan-Meier method and the 95% confidence intervals (95% CI) of the actuarial rates calculated by the Rothman method [ Designated as safety issue: No ]
  • Complete remission rate compared between arms by logistic regression [ Designated as safety issue: No ]
  • Acute and long-term toxicity as assessed by the National Cancer Institute Common Terminology Criteria version 4.0 [ Designated as safety issue: Yes ]
  • Immune reconstitution as assessed by Ig (G, A, and M) levels and lymphocyte counts [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III-IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia
Intergroup Trial for Children or Adolescents With B-Cell NHL or B-AL: Evaluation of Rituximab Efficacy and Safety in High Risk Patients

This randomized phase II/III trial studies how well giving combination chemotherapy with or without rituximab works in treating younger patients with stage III or stage IV non-Hodgkin lymphoma or B-cell acute leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibody, such as rituximab, can block cancer cells growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known whether giving combination chemotherapy together with rituximab is more effective in treating patients with non-Hodgkin lymphoma or B-cell acute leukemia.

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.

Interventional
Phase 2
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • B-cell Childhood Acute Lymphoblastic Leukemia
  • Childhood Diffuse Large Cell Lymphoma
  • L3 Childhood Acute Lymphoblastic Leukemia
  • Stage III Childhood Large Cell Lymphoma
  • Stage IV Childhood Large Cell Lymphoma
  • Untreated Childhood Acute Lymphoblastic Leukemia
  • Biological: rituximab
    Given IV
    Other Names:
    • IDEC-C2B8
    • IDEC-C2B8 monoclonal antibody
    • Mabthera
    • MOAB IDEC-C2B8
    • Rituxan
  • Drug: prednisone
    Given PO or IV
    Other Names:
    • DeCortin
    • Deltra
  • Drug: etoposide
    Given IV
    Other Names:
    • EPEG
    • VP-16
    • VP-16-213
  • Drug: doxorubicin hydrochloride
    Given IV
    Other Names:
    • ADM
    • ADR
    • Adria
    • Adriamycin PFS
    • Adriamycin RDF
  • Drug: cytarabine
    Given IV
    Other Names:
    • ARA-C
    • arabinofuranosylcytosine
    • arabinosylcytosine
    • Cytosar-U
    • cytosine arabinoside
  • Drug: vincristine sulfate
    Given IV
    Other Names:
    • leurocristine sulfate
    • VCR
    • Vincasar PFS
  • Drug: cyclophosphamide
    Given IV
    Other Names:
    • CPM
    • CTX
    • Cytoxan
    • Endoxan
    • Endoxana
  • Drug: methotrexate
    Given IT
    Other Names:
    • amethopterin
    • Folex
    • methylaminopterin
    • Mexate
    • MTX
  • Drug: methylprednisolone
    Given IV
    Other Names:
    • Depo-Medrol
    • Medrol
    • MePRDL
    • Solu-Medrol
    • Wyacort
  • Drug: leucovorin calcium
    Given PO
    Other Names:
    • CF
    • CFR
    • LV
  • Drug: therapeutic hydrocortisone
    Given IT
    Other Names:
    • Aeroseb-HC
    • Barseb HC
    • Cetacort
    • Cort-Dome
    • Cortef
  • Experimental: Arm I
    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, therapeutic hydrocortisone IT on days 2 and 6 and etoposide. Treatment repeats every 18-21 days for 2 courses.
    Interventions:
    • Biological: rituximab
    • Drug: prednisone
    • Drug: etoposide
    • Drug: doxorubicin hydrochloride
    • Drug: vincristine sulfate
    • Drug: cyclophosphamide
    • Drug: methotrexate
    • Drug: methylprednisolone
    • Drug: leucovorin calcium
    • Drug: therapeutic hydrocortisone
  • Experimental: Arm II
    Beginning 8 days later, patients receive vincristine sulfate, prednisone or methylprednisolone, methotrexate, leucovorin calcium, cyclophosphamide, doxorubicin, methotrexate IT, therapeutic hydrocortisone IT as in arm I and etoposide. Treatment repeats every 18-21 days for 2 courses.
    Interventions:
    • Drug: prednisone
    • Drug: etoposide
    • Drug: doxorubicin hydrochloride
    • Drug: vincristine sulfate
    • Drug: cyclophosphamide
    • Drug: methotrexate
    • Drug: methylprednisolone
    • Drug: leucovorin calcium
    • Drug: therapeutic hydrocortisone
  • Experimental: Arm III
    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, therapeutic hydrocortisone IT, and cytarabine IT on days 2, 4, and 6. Treatment repeats every 21 days for 2 courses.
    Interventions:
    • Biological: rituximab
    • Drug: prednisone
    • Drug: doxorubicin hydrochloride
    • Drug: cytarabine
    • Drug: vincristine sulfate
    • Drug: cyclophosphamide
    • Drug: methotrexate
    • Drug: methylprednisolone
    • Drug: therapeutic hydrocortisone
  • Experimental: Arm IV
    Patients receive vincristine sulfate, prednisone or methylprednisolone, high-dose methotrexate, leucovorin calcium, cyclophosphamide, doxorubicin hydrochloride, and methotrexate, therapeutic hydrocortisone, cytarabine IT as in arm III and etoposide.
    Interventions:
    • Drug: prednisone
    • Drug: doxorubicin hydrochloride
    • Drug: cytarabine
    • Drug: vincristine sulfate
    • Drug: cyclophosphamide
    • Drug: methotrexate
    • Drug: methylprednisolone
    • Drug: leucovorin calcium
    • Drug: therapeutic hydrocortisone
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
640
Not Provided
December 2020   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically or cytologically proven B-cell malignancies; Burkitt leukemia or B-cell acute leukemia (B-AL) (Burkitt leukemia = L3-AL), or diffuse large B-cell non-Hodgkin lymphoma (NHL), or aggressive mature B-cell NHL not otherwise specified or specifiable (phase III)

    • Stage III with elevated LDH level (B-high) [LDH > twice the institutional upper limit of the adult normal values (> Nx2)], any stage IV, or B-AL (phase III)
  • Histologically or cytologically proven primary mediastinal large B-cell lymphoma (PMLBL) (phase II)

    • No central nervous system (CNS) involvement
  • No follicular lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, or nodular marginal zone lymphoma
  • Tumor cell negative for CD20 (absence of result due to technical problems in the presence of other characteristics suggestive of BL/DLBCL, including genetic and phenotypic features, is not an exclusion criteria)
  • Males and females of reproductive potential must agree to use an effective contraceptive method during the treatment, and after the end of treatment: 12 months for women and 5 months for men
  • Able to comply with scheduled follow-up and with management of toxicity
  • Signed informed consent from patients and/or their parents or legal guardians
  • No patients with congenital immunodeficiency, chromosomal breakage syndrome, prior organ transplantation, previous malignancy of any type, or known positive human immunodeficiency virus (HIV) serology
  • Not pregnant or nursing
  • No severe active viral infection, especially hepatitis B virus (HBV)

    • Severe infection (such as sepsis, pneumonia, etc.) should be clinically controlled at the time of randomization
  • No HBV carrier status or positive serology; a patient is considered as HBV carrier or to have (had) HBV infection by any of the following criteria:

    • Unimmunized and hepatitis B surface antigen (HBsAg) and/or anti-HBs antibody and/or anti-hepatitis B core (HBc)-antibody positive
    • Immunized and HBsAg and/or anti-HBc antibody positive
    • For the Phase III trial, a patient without a known history of HBV could be randomized in the study if the serology results are not available at the time of the randomization; however, if the serology results are positive or not available at day 6 (the first day to receive rituximab, if so randomized), the patient must be withdrawn from the study whatever the allocated treatment arm; for the phase II trial, the hepatitis B serology results must be available before registration
  • No patients who, for any reason, are not able to comply with the national legislation
  • No past or current anti-cancer treatment except corticosteroids for less than one week
  • No participation in another investigational drug clinical trial
  • No prior exposure to rituximab
Both
up to 18 Years
No
Not Provided
United States,   Australia,   Canada
 
NCT01595048
ANHL1131, NCI-2012-01963, CDR0000732604, U10CA098543, COG-ANHL1131
Yes
Children's Oncology Group
Children's Oncology Group
National Cancer Institute (NCI)
Principal Investigator: Thomas Gross Children's Oncology Group
Children's Oncology Group
February 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP