Bortezomib After Combination Chemotherapy, Rituximab, and an Autologous Stem Cell Transplant in Treating Patients With Mantle Cell Lymphoma

NCT ID: NCT00310037

Last Updated: 2025-10-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 151 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-06-30
• Study Completion Date: 2022-06-30

Brief Summary

This randomized phase II trial studies how well bortezomib works when given after combination chemotherapy, rituximab, and an autologous stem cell transplant in treating patients with mantle cell lymphoma. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. 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. Giving more than one drug (combination chemotherapy) together with an autologous stem cell transplant may allow more chemotherapy to be given so that more cancer cells are killed. 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. Giving bortezomib after combination chemotherapy, monoclonal antibody therapy, and an autologous stem cell transplant may kill any remaining cancer cells or keep the cancer from coming back.

Detailed Description

Objectives

Primary Objective:

To determine the 18-month progression-free survival (PFS) in patients with previously untreated mantle cell lymphoma who are treated with aggressive chemo-immunotherapy and autologous stem cell transplant followed by randomization to either maintenance or consolidation bortezomib therapy

Secondary Objectives:

• To determine the toxicity profiles of maintenance and consolidation bortezomib by evaluating the number of patients able to complete all maintenance or consolidation therapy
• To determine the complete response rate to intensive chemo-immunotherapy plus maintenance or consolidation bortezomib
• To determine time to progression and overall survival using these two treatment regimens

Correlative/Other Pre-Specified Objectives:

• To determine the importance of p53 mutation or deletion on patient outcome with respect to CR rate, PFS, and OS
• To determine the importance of Ki67, cyclin D1, phosphohistone 3, p27, p21, p16, and PARP p85 expression in pre-treatment tumor biopsies with respect to CR rate, PFS, and OS
• To determine the relationship between proliferation signature and clinical outcome using quantitative real-time RT-PCR
• To evaluate the importance of quantitative cyclin D1 expression and expression of cyclin D1 isoforms in predicting clinical outcome using quantitative real-time RT-PCR
• To evaluate the prognostic significance of microRNAs in mantle cell lymphoma using microRNA arras
• To explore the correlation of selected microRNA polymorphisms with gene target expression with clinical outcomes such as response, PFS, and OS
• To determine changes in gene expression profile from diagnosis to relapse samples to identify genes differentially silenced or over-expressed with disease recurrence
• To determine the importance of early PCR negativity (following Treatment 2) using bcl-1/IgH junction and/or IgH chain gene rearrangement with respect to maintained PFS and the success of maintenance or consolidation therapy to converting patients to PCR negative status

OUTLINE OF INTERVENTIONS:

CHEMOIMMUNOTHERAPY: Patients receive chemoimmunotherapy comprising rituximab* intravenously (IV) over 4-6 hours on day 1, methotrexate (MTX) IV over 4 hours on day 2, cyclophosphamide IV over 2 hours, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 3, and prednisone orally (PO) on days 3-7. Beginning 24 hours after completion of MTX, patients receive leucovorin calcium IV every 6 hours until blood levels of MTX are in a safe range. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily (QD) beginning on day 3 and continuing until blood counts recover. Beginning no sooner than day 22, but no later that day 29 of the first course, patients receive a second course of chemoimmunotherapy as above. Patients with > 15% persistent bone marrow involvement may receive a third course of chemoimmunotherapy. Patients are restaged and those with progressive disease are removed from therapy.

NOTE: *During the first course of chemoimmunotherapy, patients receive rituximab only if the number of circulating mantle cells is =< 10,000/mm^3, otherwise, rituximab is omitted during the first course of chemoimmunotherapy.

HIGH-DOSE CONSOLIDATION CHEMOIMMUNOTHERAPY AND PERIPHERAL BLOOD STEM CELL (PBSC) COLLECTION: Approximately 4 weeks after completion of chemoimmunotherapy, patients receive high-dose consolidation chemoimmunotherapy comprising cytarabine IV over 2 hours and etoposide phosphate IV continuously on days 1-4, and rituximab IV over 4-6 hours on days 5 and 12 OR 6 and 13. Beginning on day 14 and continuing until completion of PBSC collection, patients receive G-CSF SC QD. Once blood counts recover, patients undergo 1-3 leukapheresis procedures for collection of PBSCs on days 22-25.

HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS PBSC TRANSPLANTATION (PBSCT): Beginning 4-6 weeks after completion of leukapheresis, patients receive carmustine IV over 2 hours on day -6, etoposide phosphate IV over 4 hours on day -4, and cyclophosphamide IV over 2 hours on day -2. Patients undergo autologous PBSCT on day 0. Patients also receive G-CSF SC QD beginning on day 4 and continuing until blood counts recover.

POST-TRANSPLANTATION IMMUNOTHERAPY: Approximately 5 weeks after autologous PBSCT, patients receive rituximab IV over 4-6 hours once weekly for 2 weeks. Approximately 4 weeks after completion of post-transplantation immunotherapy, patients proceed to maintenance therapy or consolidation therapy with bortezomib as described in the Arms section.

After completion of study treatment, patients are followed every 2 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

Conditions

Mantle Cell Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A maintenance therapy

Patients receive bortezomib 1.6 mg/m\^2 IV on days 1, 8, 15, and 22 once daily for 4 weeks. There will be a 4 week rest period. One cycle is a total of 8 weeks. A total of 10 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

bortezomib

Intervention Type: DRUG

Given IV

Arm B consolidation therapy

Patients receive bortezomib 1.3 mg/m\^2 IV on days 1, 4, 8, and 11 once daily for 3 weeks. One cycle is a total of 3 weeks. A total of 4 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

bortezomib

Intervention Type: DRUG

Given IV

Interventions

bortezomib

Given IV

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• A diagnosis based on peripheral blood or bone marrow is allowed. If the diagnosis is based only on blood, in addition to the immunophenotype and molecular confirmation above, a peripheral blood smear must be available for central pathology review. If the diagnosis is based on a bone marrow biopsy, the tissue block should be submitted.
• Note: Failure to submit pathology materials within 60 days of patient registration will be considered a major protocol violation.

B. Extent of Disease:

• Stage I-IV. Patients with nodular histology mantle cell lymphoma must have Ann Arbor stage III or IV disease to be eligible. Patients with mantle zone histology will not be eligible because of their relatively favorable prognosis. Patients with other mantle cell histologies are eligible regardless of stage.
• No active CNS disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma. A lumbar puncture demonstrating mantle cell lymphoma at the time of registration to this study is not an exclusion for study enrollment.

2. Prior Treatment:

A. Patients must be previously untreated or have received no more than one prior cycle of chemotherapy and/or rituximab treatment.

B. No prior radiation therapy for mantle cell lymphoma.

C. ≥ 2 weeks since major surgery.

D. ≥ 3 weeks since prior chemotherapy.

3. Age Eligibility: Age ≥ 18 years and < 70 years

4. Murine Products Hypersensitivity Eligibility: No known hypersensitivity to murine products.

5. Use of Systemic Corticosteroids Eligibility: No medical condition requiring chronic use of systemic corticosteroids.

6. Eligibility Criteria on HIV Infection: No HIV infection. Patients with a history of intravenous drug abuse or any behavior associated with an increased risk of HIV infection should be tested for exposure to the HIV virus. Patients who test positive or who are known to be infected are not eligible due to an increased risk of infection with this regimen. An HIV test is not required for entry on this protocol, but is required if the patient is perceived to be at risk.

7. Non-pregnant and non-nursing: Non-pregnant and non-nursing. Treatment under this protocol would expose an unborn child to significant risks. Women and men of reproductive potential should agree to use an effective means of birth control.

8. HepBSAg or HepC Ab Eligibility: Patients who test positive for HepBSAg or HepC Ab are eligible provided all of the following criteria are met:

A. bilirubin ≤ 2 x upper limit of normal; AND

B. AST ≤ 3 x upper limit of normal; AND

C. liver biopsy demonstrates ≤ grade 2 fibrosis and no cirrhosis.

Hepatitis B surface Ag(+) patients will be treated with lamivudine (3TC) throughout protocol therapy and for 6-12 months thereafter.

9. Secondary Malignancy Eligibility: Patients with a "currently active" second malignancy, other than non-melanoma skin cancers are not eligible. This includes Waldenstrom's Macroglobulinemia, since such patents have experienced transient increases in IgM following initiation of rituximab, with the potential for hyperviscosity syndrome requiring plasmapheresis. Patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, and are considered by their physician to be at less than 30% risk of relapse.

10. Initial Required Laboratory Values:

• LVEF by MUGA or ECHO ≥ 45%
• Creatinine ≤ 2.0 mg/dL
• Total Bilirubin ≤ 2.0 mg/dL (Unless attributable to Gilbert's Disease)
• u-HCG or serum HCG Negative (If patient of childbearing potential).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 69 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

Alliance for Clinical Trials in Oncology

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lawrence D. Kaplan, MD

Role: STUDY_CHAIR

University of California, San Francisco

Locations

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, United States

Illinois CancerCare - Bloomington

Bloomington, Illinois, United States

St. Joseph Medical Center

Bloomington, Illinois, United States

Graham Hospital

Canton, Illinois, United States

Illinois CancerCare - Canton

Canton, Illinois, United States

Illinois CancerCare - Carthage

Carthage, Illinois, United States

Memorial Hospital

Carthage, Illinois, United States

University of Chicago Cancer Research Center

Chicago, Illinois, United States

Eureka Community Hospital

Eureka, Illinois, United States

Illinois CancerCare - Eureka

Eureka, Illinois, United States

Galesburg Clinic, PC

Galesburg, Illinois, United States

Illinois CancerCare - Galesburg

Galesburg, Illinois, United States

Illinois CancerCare - Havana

Havana, Illinois, United States

Mason District Hospital

Havana, Illinois, United States

Illinois CancerCare - Kewanee Clinic

Kewanee, Illinois, United States

Illinois CancerCare - Macomb

Macomb, Illinois, United States

McDonough District Hospital

Macomb, Illinois, United States

Illinois CancerCare - Monmouth

Monmouth, Illinois, United States

OSF Holy Family Medical Center

Monmouth, Illinois, United States

BroMenn Regional Medical Center

Normal, Illinois, United States

Community Cancer Center

Normal, Illinois, United States

Illinois CancerCare - Community Cancer Center

Normal, Illinois, United States

Community Hospital of Ottawa

Ottawa, Illinois, United States

Oncology Hematology Associates of Central Illinois, PC - Ottawa

Ottawa, Illinois, United States

Illinois CancerCare - Pekin

Pekin, Illinois, United States

Proctor Hospital

Peoria, Illinois, United States

CCOP - Illinois Oncology Research Association

Peoria, Illinois, United States

Oncology Hematology Associates of Central Illinois, PC - Peoria

Peoria, Illinois, United States

Methodist Medical Center of Illinois

Peoria, Illinois, United States

OSF St. Francis Medical Center

Peoria, Illinois, United States

Illinois CancerCare - Peru

Peru, Illinois, United States

Illinois Valley Community Hospital

Peru, Illinois, United States

Illinois CancerCare - Princeton

Princeton, Illinois, United States

Perry Memorial Hospital

Princeton, Illinois, United States

Illinois CancerCare - Spring Valley

Spring Valley, Illinois, United States

Dana-Farber/Brigham and Women's Cancer Center

Boston, Massachusetts, United States

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute

Boston, Massachusetts, United States

Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis

St Louis, Missouri, United States

Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

Monter Cancer Center of the North Shore-LIJ Health System

Lake Success, New York, United States

CCOP - North Shore University Hospital

Manhasset, New York, United States

Don Monti Comprehensive Cancer Center at North Shore University Hospital

Manhasset, New York, United States

Long Island Jewish Medical Center

New Hyde Park, New York, United States

SUNY Upstate Medical University Hospital

Syracuse, New York, United States

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, United States

Wake Forest University Comprehensive Cancer Center

Winston-Salem, North Carolina, United States

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

Countries

United States

Other Identifiers

CDR0000466167

Identifier Type: OTHER

Identifier Source: secondary_id

CALGB-50403

Identifier Type: -

Identifier Source: org_study_id