Non Hodgkin Lymphoma Clinical Trial
Bortezomib, Ifosfamide, Carboplatin, and Etoposide, With or Without Rituximab, in Treating Patients With Relapsed or Refractory AIDS-Related Non-Hodgkin Lymphoma
Summary
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 dexamethasone, ifosfamide, carboplatin, and etoposide, 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 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. It is not yet known whether giving bortezomib together with combination chemotherapy is more effective with or without rituximab in treating AIDS-related non-Hodgkin lymphoma.
PURPOSE: This clinical trial is studying giving bortezomib together with dexamethasone, ifosfamide, carboplatin, and etoposide to see how well it works with or without rituximab in treating patients with relapsed or refractory AIDS-related non-Hodgkin lymphoma.
Full Description
OBJECTIVES:
Primary
Evaluate the safety and overall lymphoma response rate of bortezomib in combination with ifosfamide, carboplatin, and etoposide (ICE) with or without rituximab in patients with Epstein-Barr Virus (EBV)- and/or human herpes virus-8 (HHV-8)- positive relapsed or refractory HIV-associated non-Hodgkin lymphoma (NHL).
Secondary
Evaluate the impact of bortezomib alone and in combination with rituximab) and ICE ([R] ICE) on serum HIV viral loads and APOBEC3G levels.
Estimate the impact of bortezomib alone and in combination with (R)ICE on EBV and HHV-8 lytic activation using serum viral loads.
Estimate the median response duration and 1 year overall survival rate of patients treated with this regimen.
Evaluate the safety of bortezomib alone in patients with relapsed or refractory AIDS-associated lymphomas.
Correlate EBV/HHV-8 viral load changes with lymphoma response.
Compare the above outcomes to a parallel protocol employing ICE with or without rituximab in patients with EBV/HHV-8-negative AIDS-NHL to assess whether bortezomib has additional effects beyond (R)ICE alone.
OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are assigned to 1 of 2 treatment groups.
CD20-negative patients
Part A: Patients receive bortezomib IV over 3-5 seconds on days 1 and 8, dexamethasone IV and etoposide IV over 2 hours on days 8-10, and ifosfamide IV continuously over 24-hours and carboplatin IV over 2 hours on day 9. Treatment repeats every 28 days until the maximum tolerated dose (MTD) is determined. Patients who tolerate the MTD of bortezomib may move on to part B.
Part B: Patients receive bortezomib IV over 3-5 seconds at the MTD on days 1 and 8, dexamethasone IV on days 1-3 and 8, etoposide IV over 2 hours on days 1-3, and ifosfamide IV continuously over 24-hours and carboplatin IV over 2 hours on day 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Some patients may undergo hematopoietic stem cell transplantation (HSCT).
CD20-positive patients
Part A: Patients receive bortezomib, dexamethasone, etoposide, ifosfamide, and carboplatin as in the CD20-negative patients part A group.
Part B: Patients receive rituximab IV on day 1. Patients also receive bortezomib, dexamethasone, etoposide, ifosfamide, and carboplatin as in the CD20-negative patients part B group. Some patients may undergo HSCT.
Patients undergo blood sample collection periodically for correlative studies. Samples are analyzed for the effects of bortezomib on viral activation and replication via Taqman polymerase chain reaction (PCR), and for quantification of APOBEC3G levels via western blot. Similar studies are performed on the BCLB-1 EBV containing lines, as well as Daudi and other EBV-transformed B-lymphocyte lines via quantitative viral DNA PCR.
Patients complete the Functional Assessment of Cancer Therapy/GOG-Neurotoxicity Questionnaire, v4.0 at day 8 and week 4 of Part A and at least once per course of Part B for assessment of neuropathic pain and/or peripheral neuropathy.
After completion of study treatment, patients achieving complete response (CR) are followed at 2-4 weeks and then every 3 months for 1 year. Patients not achieving CR at completion of study treatment and declining further antineoplastic treatment are followed at 2-4 weeks and then every 3 months for 1 year.
Eligibility Criteria
DISEASE CHARACTERISTICS:
Histologically or cytologically confirmed relapsed or refractory HIV-associated non-Hodgkin lymphoma (NHL)
Must have histologic or cytologic documentation of prior AIDS-associated NHL (i.e., at time of diagnosis) for clinically relapsed and/or refractory disease for which biopsy is not feasible
Must have documented HIV seropositivity
Must have documentation of Epstein-Barr Virus (EBV)- and/or human herpes virus-8 (HHV-8)- positive infection within the lymphoma (i.e., LMP-1, LANA expression, or positive Epstein-Barr-encoded RNAs [EBERs])
PATIENT CHARACTERISTICS:
Inclusion criteria:
ECOG performance status (PS) 0-2 OR Karnofsky PS 50-100%
Life expectancy > 2 months
ANC ≥ 1,000/mm³* (growth factor support allowed)
Hemoglobin ≥ 8.0 g/dL* (growth factor support allowed)
Platelet count ≥ 100,000/mm³
Total bilirubin ≤ 1.5 mg/dL
AST/ALT ≤ 2.5 times institutional upper limit of normal (ULN)
Serum creatinine ≤ ULN
Creatinine clearance ≥ 50 mL/min
Negative pregnancy test
Not pregnant or nursing
Fertile patients must use effective contraception NOTE: *Patients with lymphomatous involvement of the bone unable to meet hematologic criteria are allowed
Exclusion criteria:
Peripheral neuropathy ≥ grade 2
Uncontrolled intercurrent illness including, but not limited to, any of the following:
Ongoing or active infection
Opportunistic infections controlled by antimicrobial or suppressive therapy allowed, unless the investigator judges the infection likely to become life-threatening in the setting of multi-agent chemotherapy
Symptomatic congestive heart failure
Unstable angina pectoris
NYHA class III or IV heat failure
Myocardial infarction within the past 6 months
Uncontrolled angina
Severe uncontrolled ventricular or other cardiac arrhythmias
Acute ischemia or active conduction system abnormalities by ECG
Serious psychiatric or medical illness, that would interfere with study compliance
Social situations that would interfere with study compliance
Acute active HIV-associated opportunistic infection requiring antibiotic treatment
Mycobacterium avium or candidiasis allowed unless concurrent therapy with moderate-to-strong CYP3A4 inducers or inhibitors is required
Chronic myelosuppressive agent therapy allowed provided hematologic criteria are met
Hypersensitivity to compounds of similar chemical or biological composition to bortezomib, boron, mannitol, ifosfamide, carboplatin, or etoposide
Concurrent malignancy except carcinoma in situ of the cervix, in situ anal cancer, nonmetastatic nonmelanoma skin cancer, or Kaposi's sarcoma not requiring systemic chemotherapy
Active hepatitis B infection (hepatitis B surface antigen-positive), unless 1 of the following criteria are met:
Able to start dual anti-hepatitis B adefovir and telbivudine therapy prior to study
Receiving dual anti-hepatitis B therapy for at least 12 weeks prior to study with either agent active against HIV (i.e., entecavir, tenofovir, lamivudine, or emtricitabine)
Concurrent grapefruit juice/fruit or green tea
PRIOR CONCURRENT THERAPY:
See Disease Characteristics
Recovered from prior adverse effects due to agents administered more than 3 weeks earlier
Glucocorticoid therapy within the past 3 weeks allowed
More than 3 weeks since prior chemotherapy
More than 2 weeks since prior radiotherapy
More than 14 days since prior and no other concurrent investigational agents (other than bortezomib)
No concurrent moderate-to-strong CYP3A4 inducers or inhibitors other than protease inhibitors
Concurrent stable (at least 12 weeks) antiretroviral regimen allowed
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There are 17 Locations for this study
La Jolla California, 92093, United States
Los Angeles California, 90089, United States
Los Angeles California, 90095, United States
Sacramento California, 95814, United States
Miami Florida, 33136, United States
Atlanta Georgia, 30322, United States
Honolulu Hawaii, 96813, United States
Chicago Illinois, 60611, United States
Baltimore Maryland, 21231, United States
Boston Massachusetts, 02215, United States
Bronx New York, 10467, United States
New York New York, 10065, United States
Columbus Ohio, 43210, United States
Philadelphia Pennsylvania, 19106, United States
Houston Texas, 77009, United States
Houston Texas, 77030, United States
Seattle Washington, 98101, United States
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