Bortezomib, Doxorubicin Hydrochloride Liposome, and Rituximab in Treating Patients With Diffuse Large B-Cell Lymphoma That Has Relapsed or Not Responded to Treatment

Study Overview
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Brief Summary
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RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Drugs used in chemotherapy, such as doxorubicin hydrochloride liposome, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer cell 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 cell-killing substances to them. Giving bortezomib together with doxorubicin hydrochloride liposome and rituximab may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving bortezomib together with doxorubicin hydrochloride liposome and rituximab works in treating patients with diffuse large B-Cell lymphoma that has relapsed or not responded to treatment.

Detailed Description
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OBJECTIVES: Primary To determine the overall objective response rate (i.e., complete and partial response) in patients with relapsed or refractory, CD20-positive, diffuse large B-cell lymphoma treated with bortezomib, pegylated liposomal doxorubicin hydrochloride, and rituximab. Secondary To assess the toxicity/safety profile associated with this regimen. To conduct correlative translational research studies. OUTLINE: Patients receive bortezomib IV on days 1, 4, 8, and 11, pegylated liposomal doxorubicin hydrochloride IV on day 11, and rituximab IV on day 8. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Tissue and blood samples are collected periodically for correlative studies. Samples are analyzed for expression of CD11b/CD18, CD32, CD 33, CD62, CD64, CD69, and CD56 by flow cytometric analysis of neutrophils, NK cells, and monocytes; antibody-dependent cellular and complement-mediated cytotoxicity; and genotypic analysis of polymorphisms by PCR. Autologous neoplastic B-cells derived from tissue samples are used for genetic and protein profiling. After completion of study therapy, patients are followed periodically for 4 years.

Official Title
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A Phase II Study of VDR (VELCADE™, DOXIL® and RITUXAN™) in Relapsed/Refractory Diffuse Large B-cell Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: bortezomib
* Drug: pegylated liposomal doxorubicin hydrochloride
* Genetic: gene expression analysis
* Genetic: polymerase chain reaction
* Genetic: polymorphism analysis
* Genetic: proteomic profiling
* Other: flow cytometry
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of CD20-positive diffuse large B-cell lymphoma, including any of the following morphological variants: Centroblastic Immunoblastic T-cell/histiocyte-rich Anaplastic Mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Relapsed or refractory disease Measurable disease, defined as tumor size 2 cm² Must have received ≥ 1 prior standard chemotherapy regimen No Burkitt or precursor B-lymphoblastic lymphoma No brain involvement or evidence of CNS lymphoma PATIENT CHARACTERISTICS: Karnofsky performance status (PS) 70-100% OR ECOG PS 0-2 Life expectancy ≥ 12 weeks Absolute neutrophil count ≥ 1,500/μL* Platelet count ≥ 100,000/μL* Creatinine < 2.5 mg/dL OR > 40 mL/min* Hemoglobin > 8.0 g/dL* AST/ALT < 2 times upper limit of normal (ULN) (< 3 times ULN with liver involvement)* Alkaline phosphatase < 2 times ULN (< 3 times ULN with liver involvement)* Total bilirubin < 2 times ULN (< 3 times ULN with liver involvement or Gilbert disease)* NOTE: *Unless attributable to non-Hodgkin lymphoma LVEF ≥ 50% by MUGA scan or ECHO Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after completion of therapy No HIV positivity No hepatitis B positivity Peripheral neuropathy < grade 2 as defined by NCI CTCAE v 3.0 No history of uncontrolled orthostatic hypotension None of the following cardiac conditions: Myocardial infarction within the past 6 months New York Heart Association class II-IV congestive heart failure Uncontrolled angina Severe uncontrolled ventricular arrhythmias Clinically significant pericardial disease ECG evidence of acute ischemic or active conduction system abnormalities No hypersensitivity to bortezomib, boron, or mannitol No history of allergic reactions to compounds containing boron, mannitol, bortezomib, conventional formulation of doxorubicin hydrochloride, or the components of pegylated liposomal doxorubicin hydrochloride No uncontrolled intercurrent illness including, but not limited to, any of the following: Ongoing or active infection Poorly controlled hypertension Diabetes mellitus Serious medical or psychiatric conditions that would interfere with adherence to or completion of this study No other primary malignancy except squamous cell or basal cell carcinoma of the skin, in situ carcinoma of the cervix, superficial bladder carcinoma, or previously treated localized prostate cancer with normal PSA levels and disease-free for ≥ 5 years PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from significant toxicity associated with prior surgery, radiotherapy, chemotherapy, or immunotherapy Prior rituximab or other monoclonal immunotherapy allowed More than 4 weeks since prior investigational drugs More than 4 weeks since prior chemotherapy More than 4 weeks since prior major surgery, other than diagnostic surgery No prior doxorubicin hydrochloride (or equivalent) anthracycline treatment exceeding 400 mg/m² No concurrent corticosteroids, except to control a transient inflammatory reaction (i.e., skin rash or hives) Concurrent non-steroidal hormones administered for non-lymphoma related conditions (e.g., insulin for diabetes) allowed No concurrent radiotherapy No other concurrent antitumor or chemotherapeutic agents No other concurrent investigational agents

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: rituximab|Given IV|
|Drug: bortezomib|Given IV|
|Drug: pegylated liposomal doxorubicin hydrochloride|Given IV|
|Genetic: gene expression analysis|Correlative Study|
|Genetic: polymerase chain reaction|Correlative Study|
|Genetic: polymorphism analysis|Correlative Study|
|Genetic: proteomic profiling|Correlative Study|
|Other: flow cytometry|Correlative Study|
|Other: laboratory biomarker analysis|Correlative Study|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor Efficacy in Terms of Overall, Complete, and Partial Response Rates and Time to Progression at Weeks 9 and 21 |  | at weeks 9 and 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult diffuse large cell lymphoma, recurrent adult immunoblastic large cell lymphoma, anaplastic large cell lymphoma