Combination Chemotherapy and Rituximab in Treating Patients With Untreated Mantle Cell Lymphoma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00433537
First received: February 8, 2007
Last updated: October 24, 2014
Last verified: January 2014
  Purpose

This phase II trial is studying how well giving rituximab together with combination chemotherapy and bortezomib works in treating patients with untreated mantle cell lymphoma. Monoclonal antibodies, such as rituximab, can block cancer 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. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving rituximab together with combination chemotherapy and bortezomib may kill more cancer cells.

Treatment consists of six agents: bortezomib (Vc), rituximab (R), cyclophosphamide (C), vincristine (V), doxorubicin (A), and dexamethasone (D) (VcR-CVAD).


Condition Intervention Phase
Contiguous Stage II Mantle Cell Lymphoma
Noncontiguous Stage II Mantle Cell Lymphoma
Stage I Mantle Cell Lymphoma
Stage III Mantle Cell Lymphoma
Stage IV Mantle Cell Lymphoma
Drug: bortezomib
Biological: rituximab
Drug: cyclophosphamide
Drug: doxorubicin hydrochloride
Drug: vincristine
Drug: dexamethasone
Biological: filgrastim
Biological: pegfilgrastim
Procedure: Autologous stem cell transplantation (ASCT)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of VcR-CVAD With Rituximab Maintenance for Untreated Mantle Cell Lymphoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Complete Response (CR) Rate [ Time Frame: Assessed after VcR-CVAD cycles 2, 4, and 6. ] [ Designated as safety issue: No ]
    Number of eligible, treated participants who achieve complete response. Response criteria are based upon the criteria from the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Complete response is defined as complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy.


Secondary Outcome Measures:
  • 2-year Progression-free Survival (PFS) [ Time Frame: Assessed every 6 months for 5 years, and then yearly thereafter. ] [ Designated as safety issue: No ]
    PFS for patients who received maintenance rituximab or ASCT after VcR-CVAD induction is defined as time from start of maintenance rituximab or ASCT to earlier of disease progression or death. Patients alive and progression-free at last follow-up were censored.

  • 3-year Overall Survival (OS) [ Time Frame: Assessed every 6 months for 5 years, and then yearly thereafter. ] [ Designated as safety issue: No ]
    OS for patients who received maintenance rituximab or ASCT after VcR-CVAD induction is defined as time from start of maintenance rituximab or ASCT to death. Patients alive at last follow-up were censored.


Enrollment: 77
Study Start Date: May 2007
Study Completion Date: June 2013
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: VcR-CVAD induction followed by maintenance rituximab

VcR-CVAD induction: Patients receive VcR-CVAD comprising bortezomib IV over 3-5 seconds on days 1 and 4; rituximab IV over 3-4 hours on day 1; doxorubicin hydrochloride IV over 48 hours on days 1 and 2; cyclophosphamide IV over 3 hours every 12 hours on days 1-3; vincristine IV over 3-5 seconds on day 3; and dexamethasone IV or orally once daily on days 1-4. Patients also receive filgrastim (G-CSF) subcutaneously (SC) or IV once daily beginning on day 5 or 6 and continuing until blood counts recover OR pegfilgrastim SC on day 5 or 6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Maintenance rituximab: Beginning 4-8 weeks after completion of induction therapy, patients receive rituximab IV over 3-4 hours once weekly for 4 weeks. Treatment repeats every 6 months for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: vincristine
Given IV
Other Names:
  • Vincristine sulfate
  • Leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: dexamethasone
Given IV
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
Biological: filgrastim
Given SC
Other Names:
  • G-CSF
  • Neupogen
Biological: pegfilgrastim
Given SC
Other Names:
  • Filgrastim SD-01
  • GCSF-SD01
  • Neulasta
  • SD-01 sustained duration G-CSF
Experimental: VcR-CVAD induction followed by ASCT

VcR-CVAD induction: Patients receive VcR-CVAD comprising bortezomib IV over 3-5 seconds on days 1 and 4; rituximab IV over 3-4 hours on day 1; doxorubicin hydrochloride IV over 48 hours on days 1 and 2; cyclophosphamide IV over 3 hours every 12 hours on days 1-3; vincristine IV over 3-5 seconds on day 3; and dexamethasone IV or orally once daily on days 1-4. Patients also receive filgrastim (G-CSF) SC or IV once daily beginning on day 5 or 6 and continuing until blood counts recover OR pegfilgrastim SC on day 5 or 6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

ASCT: After completion of induction therapy, patients who are eligible may have the option to receive consolidation therapy for autologous stem cell transplantation (off-study). These patients undergo stem cell harvest during courses 4, 5, or 6 of induction therapy.

Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: vincristine
Given IV
Other Names:
  • Vincristine sulfate
  • Leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: dexamethasone
Given IV
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
Biological: filgrastim
Given SC
Other Names:
  • G-CSF
  • Neupogen
Biological: pegfilgrastim
Given SC
Other Names:
  • Filgrastim SD-01
  • GCSF-SD01
  • Neulasta
  • SD-01 sustained duration G-CSF
Procedure: Autologous stem cell transplantation (ASCT)

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the complete response (CR) rate in patients with mantle cell lymphoma, who are treated with VcR-CVAD.

SECONDARY OBJECTIVES:

I. To evaluate the overall response rate to VcR-CVAD. II. To evaluate the progression-free survival (PFS) and overall survival (OS) of patients receiving maintenance rituximab after VcR-CVAD induction.

III. To evaluate the PFS and OS of patients who receive autologous stem cell transplantation (ASCT) after VcR-CVAD induction.

IV. To evaluate the toxicity of VcR-CVAD.

TERTIARY OBJECTIVES:

I. Evaluation of antigen expression patterns to determine or confirm possible unique expressions of MCL.

II. To evaluate the percentage of circulating mantle cell lymphoma (MCL) cells.

OUTLINE: This is a multicenter study.

Induction therapy (VcR-CVAD): Patients receive VcR-CVAD comprising bortezomib 1.3 mg/m2 IV over 3-5 seconds on days 1 and 4; rituximab 375 mg/m2 IV over 3-4 hours on day 1; doxorubicin hydrochloride 25 mg/m2/d IV over 48 hours on days 1 and 2; cyclophosphamide 300 mg/m2 IV over 3 hours every 12 hours on days 1-3; vincristine 1 mg IV over 3-5 seconds on day 3; and dexamethasone 40 mg IV or orally once daily on days 1-4. Patients also receive filgrastim (G-CSF) subcutaneously (SC) or IV once daily beginning on day 5 or 6 and continuing until blood counts recover OR pegfilgrastim SC on day 5 or 6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Maintenance therapy: Beginning 4-8 weeks after completion of induction therapy, patients receive rituximab IV over 3-4 hours once weekly for 4 weeks. Treatment repeats every 6 months for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of induction therapy, patients who are eligible may have the option to receive consolidation therapy for autologous stem cell transplantation (ASCT) (off-study). These patients undergo stem cell harvest during courses 4, 5, or 6 of induction therapy.

After completion of study treatment, patients are followed periodically for up to 10 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a histologically confirmed diagnosis of mantle cell lymphoma by demonstrating appropriate morphology plus at least one of the following on the biopsy specimen: nuclear cyclin D1+ by immunohistochemistry; t(11;14) by fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), or conventional karyotyping
  • No prior chemotherapy, immunotherapy or radiotherapy for mantle cell lymphoma; a brief course of steroids (< 14 days) for symptom relief or steroids for other indications are allowed
  • Patients must have measurable disease; CT scans at baseline are required to define the extent of measurable disease; the scans must be obtained within 6 weeks prior to registration; combined CT/PET scans may be used for the baseline and subsequent evaluations if accurate tumor measurements can be obtained from the CT component
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Absolute neutrophil count (ANC) > 1500 mm^3 (unless low count due to marrow involvement or splenomegaly)
  • Platelets > 100,000 mm^3 (unless low counts due to marrow involvement or splenomegaly)
  • Creatinine < 2 mg/dL
  • Bilirubin < 2 mg/dL (may be up to 3.0 mg/dL if due to Gilbert's disease or due to liver involvement by lymphoma)
  • Patients over the age of 45 must have a left ventricular ejection fraction (LVEF) of greater than 45% documented within 90 days prior to registration
  • Patients must be tested for Hepatitis B surface antigen (HBs Ag) within 4 weeks prior to registration NOTE: HBs Ag positive patients are not excluded but will have more stringent monitoring of liver function tests

Exclusion Criteria:

  • Known HIV disease; an HIV test is not required for entry on study but is required if the patient is perceived to be at risk; patients with a history of intravenous drug use or any other behavior with an increased risk for HIV infection should be tested for exposure to the HIV virus; patients with known HIV are excluded since the immunocompromised state of patients with HIV infection or the concomitant use of highly active antiretroviral therapy (HAART) may result in more extensive dose modifications than intended for the intensive therapeutic regimen used in this study
  • Pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; women of childbearing potential and sexually active males must use an accepted and effective method of contraception
  • Grade 2 or higher baseline peripheral neuropathy
  • Known hypersensitivity to boron or mannitol
  • History of prior malignancy unless at least one of the following conditions are met:

    • Malignancy was in-situ
    • Malignancy was treated surgically or with local radiation therapy with curative intent and the patient has been disease free for > 3 years
    • Any adjuvant hormonal therapy must have been discontinued > 3 months prior to registration
  • Known central nervous system (CNS) involvement
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00433537

Locations
United States, Massachusetts
Eastern Cooperative Oncology Group
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Investigators
Study Chair: Brad Kahl Eastern Cooperative Oncology Group
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00433537     History of Changes
Other Study ID Numbers: NCI-2012-02966, NCI-2012-02966, E1405, E1405, E1405, U10CA021115
Study First Received: February 8, 2007
Results First Received: October 24, 2014
Last Updated: October 24, 2014
Health Authority: United States: Food and Drug Administration
United States: Federal Government

Additional relevant MeSH terms:
Lymphoma, Mantle-Cell
Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
BB 1101
Bortezomib
Cyclophosphamide
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Doxorubicin
Lenograstim
Liposomal doxorubicin
Rituximab
Vincristine
Adjuvants, Immunologic
Alkylating Agents
Anti-Inflammatory Agents
Antibiotics, Antineoplastic
Antiemetics
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Hormonal
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on October 29, 2014