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

Inclusion Criteria

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