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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00217503

Collaborator

(none)

Enrollment

Location

Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Herpesvirus is found in the cancer cells of patients with primary effusion lymphoma. Antiviral drugs, such as zidovudine and valganciclovir, may be able to act against the herpesvirus in the cancer cells to help kill the cancer cells. Bortezomib may help the antiviral drugs kill the cancer cells. Draining the effusion removes fluid that has built up. Monoclonal antibodies, such as bevacizumab, 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. Bevacizumab may also stop the growth of cancer cells by blocking blood flow to the cancer. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with antiviral therapy followed by effusion drainage, bevacizumab, and combination chemotherapy may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving bortezomib together with antiviral therapy followed by effusion drainage, bevacizumab, and combination chemotherapy works in treating patients with primary effusion lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: bevacizumab Biological: filgrastim Biological: pegfilgrastim Drug: bortezomib Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: etoposide Drug: ganciclovir Drug: valganciclovir Drug: zidovudine	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

15 participants

Primary Purpose:

Treatment

Official Title:

Primary Effusion Lymphoma: A Pilot Trial of Bevacizumab and Modified Dose-Adjusted Infusional CDE Chemotherapy Preceded by a Brief Pre-Phase Assessment of Targeted Oncolytic Virotherapy With Bortezomib, Zidovudine and Valganciclovir

Study Start Date :

Jul 1, 2005

Actual Study Completion Date :

Jun 1, 2007

Outcome Measures

Primary Outcome Measures

Response to therapy as measured by overall, disease-free, and progression-free survival each month []

Secondary Outcome Measures

Effects of high-dose zidovudine and ganciclovir on tumor cells measured by various assays after 2 weeks of study treatment []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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