Bortezomib and Antiviral Therapy Followed By Effusion Drainage, Bevacizumab, and Combination Chemotherapy in Treating Patients With Primary Effusion Lymphoma

OBJECTIVES:

Primary

• Determine the complete response rate in patients with previously untreated primary effusion lymphoma treated with effusion drainage and bevacizumab in combination with chemotherapy comprising cyclophosphamide, doxorubicin, and etoposide.

Secondary

• Determine the overall survival, disease-free survival, and progression-free survival of patients treated with this regimen.
• Determine the toxicity of this regimen in previously treated or untreated patients.
• Determine, preliminarily, the biologic effects of targeted oncolytic virotherapy comprising bortezomib, zidovudine, and valganciclovir in these patients.

OUTLINE: This is a 2-part, pilot study.

Patients who are HIV-positive receive highly-active antiretroviral therapy during study treatment.

• Part 1 (targeted oncolytic virotherapy)*: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, and 8, zidovudine IV over 1 hour twice daily on days 1-10, and oral valganciclovir (or ganciclovir IV) twice daily on days 1-14. One day after completion of zidovudine, patients begin treatment in part 2.

NOTE: *Part 1 treatment may be omitted in patients who are acutely ill with primary effusion lymphoma at study entry AND a 10- to 14-day delay of starting part 2 treatment may pose a hazard to the patient.

• Part 2

• Effusion drainage: Patients undergo effusion drainage prior to each course of bevacizumab* and chemotherapy. The drainage tube may remain in place to allow for continuous drainage of effusion during treatment with bevacizumab* and chemotherapy.
• Bevacizumab* plus cyclophosphamide, doxorubicin, and etoposide (iCDE): Patients receive bevacizumab* IV over 30-90 minutes on days 1 and 6, cyclophosphamide, doxorubicin, and etoposide IV continuously over 96 hours beginning on day 1 and continuing until day 5, and filgrastim (G-CSF) subcutaneously (SC) daily beginning on day 6 and continuing until day 19 or until blood counts recover OR pegfilgrastim SC on day 6.

NOTE: *Patients may receive iCDE without bevacizumab if they meet any exclusion criteria for receiving bevacizumab.

Treatment with bevacizumab and iCDE repeats every 21 days for 4-8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving complete response (CR) receive 2 additional courses beyond CR.

After completion of study treatment, patients are followed monthly for 6 months, every 2 months for 6 months, every 3 months for 1 year, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 15 patients will be accrued for this study within 2.5 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed primary effusion lymphoma (PEL) involving a body cavity

• Kaposi's sarcoma associated-herpesvirus
• Any anatomic site or distribution of involvement allowed
• HIV infection allowed
• Previously treated or untreated disease
• No mass lesions in the brain (for patients receiving bevacizumab during study treatment)

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-3* NOTE: *ECOG 4 allowed if due to a mechanical effect of the PEL that can be corrected by effusion drainage resulting in improved performance status to ECOG 3 or better

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count > 1,000/mm^3
• Platelet count > 75,000/mm^3
• No active bleeding or coagulopathy (for patients receiving bevacizumab during study treatment)

Hepatic

• AST and ALT < 3 times upper limit of normal (ULN) (6 times ULN if due to hyperalimentation)
• Bilirubin < 2.0 mg/dL OR
• Total bilirubin ≤ 4.5 mg/dL AND direct bilirubin < 0.4 mg/dL (for patients with Gilbert's syndrome or receiving protease-inhibitor therapy)

Renal

• Creatinine ≤ 1.5 mg/dL OR
• Creatinine clearance > 50 mL/min

Cardiovascular

• Patients receiving bevacizumab during study treatment must meet the following criteria:

• No deep venous or arterial thrombosis within the past 6 months
• No uncontrolled hypertension (i.e., systolic blood pressure [BP] > 160 mm Hg or diastolic BP > 95 mm Hg)
• No unstable angina
• No New York Heart Association class II-IV congestive heart failure
• No cardiac arrhythmia requiring medication
• No clinically significant peripheral artery disease
• No peripheral vascular disease ≥ grade 2
• No prior myocardial infarction
• No transient ischemic attack or cerebral vascular accident within the past 6 months
• No other clinically significant cardiovascular disease

Neurologic

• Patients receiving bevacizumab during study treatment must meet the following criteria:

• No uncontrolled seizure disorder
• No CNS bleeding within the past 6 months
• No other substantial CNS disease

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other malignancy requiring treatment that would preclude study treatment, including, but not limited to, any of the following:

• Life-threatening Kaposi's sarcoma
• Non-resectable lung cancer
• Acute leukemia
• No grade IV organ dysfunction unrelated to PEL
• No infection requiring chronic systemic therapy that would preclude study treatment (except HIV, hepatitis B, or hepatitis C), including, but not limited to, any of the following:

• Invasive aspergillosis
• End-organ cytomegalovirus (CMV)

• CMV retinitis (e.g., ocular implants not requiring systemic therapy) allowed if controlled with local therapy
• No other condition or circumstance that would preclude study participation
• No gastrointestinal bleeding within the past 6 months (for patients receiving bevacizumab during study treatment)
• No pathological condition that would confer a high risk for bleeding (for patients receiving bevacizumab during study treatment)

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No live virus vaccines (e.g., vaccinia or rotavirus) or bacterial vaccines during and for 3 months after completion of study treatment

Chemotherapy

• No prior cumulative anthracycline dose > 450 mg/m^2 (unless cardiac ejection fraction normal)

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No concurrent chronic daily aspirin ≥ 325 mg/day or nonsteroidal medication that interferes with platelet function (for patients receiving bevacizumab during study treatment)
• No concurrent therapeutic anticoagulation (INR > 1.5) unless patient is on full-dose warfarin (for patients receiving bevacizumab during study treatment)

• Full-dose anticoagulants allowed provided both of the following criteria are met:

• INR normal
• On a stable dose of warfarin or low-molecular weight heparin