• Response of bortezomib (part I) [ Designated as safety issue: No ]
• Toxicity and maximum tolerated dose (MTD) of bortezomib with concurrent etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) (part II) [ Designated as safety issue: Yes ]
• Response of bortezomib and EPOCH (part II) [ Designated as safety issue: No ]

• Response of bortezomib (part I)
• Toxicity and maximum tolerated dose (MTD) of bortezomib with concurrent etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) (part II)
• Response of bortezomib and EPOCH (part II)

• Biological effect of bortezomib as measured by microarray and immunohistochemistry (IHC) during biopsy (part I) [ Designated as safety issue: No ]
• Markers of drug resistance on response identified at baseline [ Designated as safety issue: No ]

• Biological effect of bortezomib as measured by microarray and immunohistochemistry (IHC) during biopsy (part I)
• Markers of drug resistance on response identified at baseline

RATIONALE: Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Combining bortezomib with combination chemotherapy may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of bortezomib when given together with combination chemotherapy and to see how well they work compared to bortezomib alone in treating patients with relapsed or refractory large B-cell lymphoma.

OBJECTIVES:

• Determine the response rate of patients with relapsed or refractory diffuse large B-cell lymphoma within the activated and germinal center B cell-like molecular subtypes treated with bortezomib alone or with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH).
• Determine the maximum tolerated dose of bortezomib administered in combination with EPOCH in patients who do not achieve a complete remission or progress with bortezomib alone.
• Determine the toxicity of this combination regimen in these patients.
• Determine the biological effect of bortezomib on tumor biopsies, including bcl-2 and NF-kappa B, using DNA microarray profiling and immunohistochemistry in these patients.
• Correlate markers of drug resistance (bcl-2, MIB-1, and p53) with response in patients treated with this combination regimen.

OUTLINE: This is a 2-part study. Part II is a dose-escalation study of bortezomib. Patients who require an immediate treatment response for medical reasons only receive therapy in part II.

• Part I (Bortezomib alone): Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 3 weeks. Patients who are candidates for autologous or allogeneic stem cell transplantation may receive up to 6 courses. Patients with progressive or stable disease after 2 courses may proceed to therapy in part II. Patients in complete remission may be referred for transplantation. Patients who are not candidates for transplantation but who have stable or responding disease may receive bortezomib for up to 1 year. Patients with disease progression after any course may proceed to therapy in part II.
• Part II (EPOCH and bortezomib): Patients receive EPOCH comprising etoposide IV, doxorubicin IV, and vincristine IV continuously on days 1-4; cyclophosphamide IV over 15 minutes on day 5; and oral prednisone twice daily on days 1-5. Patients also receive bortezomib IV over 3-5 seconds on days 1 and 4 and filgrastim (G-CSF) subcutaneously beginning on day 6 and continuing until blood counts recover. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceeding that at which no more than 1 of 6 patients experience dose-limiting toxicity.

Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

• Drug: bortezomib
• Drug: cyclophosphamide
• Drug: doxorubicin hydrochloride
• Drug: etoposide
• Drug: prednisone
• Drug: vincristine sulfate

DISEASE CHARACTERISTICS:

• Histologically confirmed relapsed or refractory large B-cell lymphoma of 1 of the following subtypes:

  • Diffuse
  • Mediastinal (thymic)
  • Transformed
  • Follicular grade IIIB
  • Intravascular
• Tumor tissue available for biopsy
• Prior anthracycline-based treatment required
• No active CNS lymphoma

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count at least 1,000/mm^3*
• Platelet count at least 50,000/mm^3* NOTE: *Unless impairment due to organ involvement by lymphoma

Hepatic

• Bilirubin less than 2 mg/dL (5 mg/dL in patients with Gilbert's syndrome [defined by greater than 80% unconjugated])*
• AST less than 5 times upper limit of normal*
• Hepatitis B surface antigen negative NOTE: *Unless impairment due to organ involvement by lymphoma

Renal

• Creatinine no greater than 1.5 mg/dL* OR
• Creatinine clearance greater than 60 mL/min* NOTE: *Unless impairment due to organ involvement by lymphoma

Cardiovascular

• Cardiac ejection fraction at least 40%*
• No symptomatic cardiac disease* NOTE: *For patients receiving EPOCH chemotherapy

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• More than 4 weeks since prior systemic cytotoxic therapy
• More than 4 weeks since prior experimental therapy