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.

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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.

View Eligibility Criteria

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

Study is for people with:

Non Hodgkin Lymphoma

Phase:

Phase 1

Estimated Enrollment:

23

Study ID:

NCT00598169

Recruitment Status:

Completed

Sponsor:

AIDS Malignancy Consortium

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There are 17 Locations for this study

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Rebecca and John Moores UCSD Cancer Center
La Jolla California, 92093, United States
USC/Norris Comprehensive Cancer Center and Hospital
Los Angeles California, 90089, United States
UCLA Clinical AIDS Research and Education (CARE) Center
Los Angeles California, 90095, United States
University of California at Davis Center for Aids Research and Education Services
Sacramento California, 95814, United States
University of Miami Sylvester Comprehensive Cancer Center - Miami
Miami Florida, 33136, United States
Emory Winship Cancer Institute
Atlanta Georgia, 30322, United States
Cancer Research Center of Hawaii
Honolulu Hawaii, 96813, United States
Northwestern Cancer Center
Chicago Illinois, 60611, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore Maryland, 21231, United States
Beth Israel Deaconess Medical Center
Boston Massachusetts, 02215, United States
Montefiore Medical Center
Bronx New York, 10467, United States
Memorial Sloan-Kettering Cancer Center
New York New York, 10065, United States
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
Columbus Ohio, 43210, United States
Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia
Philadelphia Pennsylvania, 19106, United States
Thomas Street Health Center
Houston Texas, 77009, United States
Baylor College of Medicine
Houston Texas, 77030, United States
Virginia Mason Medical Center
Seattle Washington, 98101, United States

How clear is this clinincal trial information?

Study is for people with:

Non Hodgkin Lymphoma

Phase:

Phase 1

Estimated Enrollment:

23

Study ID:

NCT00598169

Recruitment Status:

Completed

Sponsor:


AIDS Malignancy Consortium

How clear is this clinincal trial information?

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