Bortezomib, Ifosfamide, Carboplatin, and Etoposide, With or Without Rituximab, in Treating Patients With Relapsed or Refractory AIDS-Related Non-Hodgkin Lymphoma
Condition: Lymphoma
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin
Study type: Interventional
Phase: Phase 1

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.
    

Detailed 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.
    

Intervention name(s): rituximab; bortezomib; carboplatin; dexamethasone; etoposide; ifosfamide; polymerase chain reaction; western blotting
Intervention type(s): Biological; Drug; Drug; Drug; Drug; Drug; Genetic; Genetic
Intervention description(s): 375mg/m2 on Day 1; Part A: Velcade Day 1 and Day 8 of a 28-day cycle, with inter-subject dose escalation over four dose levels: 0.7 mg/m2, 1 mg/m2, 1.3 mg/m2 and 1.5 mg/m2 Part B: Velcade on Days 1 and 8 of a 21-day cycle.; Carboplatin will be dosed to an AUC=5, calculated using the Calvert formula (5 x [creatinine clearance + 25]; the maximum dose of carboplatin is 750 mg.
Part A: AUC=5 (maximum 750 mg) IV administered on Day 9. Part B: AUC=5 (maximum 750 mg) IV administered on Day 2.; Part A: 20 mg IV on Days 8-10. Part B: 20 mg IV on Days 1-3 and on Day 8.; Part A: 100 mg/m2 IV Days 8-10. Part B: 100 mg/m2 IV daily on Days 1 to 3.; Part A: 5000 mg/m2 mixed with an equal amount of Mesna as a 24 hour continuous IV infusion on Day 9.
Part B: 5000 mg/m2 mixed with an equal dose of Mesna administered via continuous infusion for 24 hours beginning on Day 2.; Correlate EBV/HHV-8 viral load changes with lymphoma response. HIV and EBV/HHV-8 viral loads will be assessed on baseline, day 2, 4, and 8 of week 1 of Part A.; Peripheral blood mononuclear cells will be collected at Day 1 prior to chemotherapy, Day 2, 4 and 8 (prior to chemotherapy) then weekly during Part A, just prior to each additional cycle of Part B and at treatment completion. Western blot using antibody specific for APOBEC3G and antibody against actin for internal control will be used to quantify APOBEC3G levels. Changes at will be compared with baseline using a paired t-test.
Intervention MeSH terms: Dexamethasone; Rituximab; Carboplatin; Etoposide; Bortezomib; Ifosfamide
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: AIDS-related diffuse large cell lymphoma; AIDS-related diffuse mixed cell lymphoma; AIDS-related diffuse small cleaved cell lymphoma; AIDS-related immunoblastic large cell lymphoma; AIDS-related lymphoblastic lymphoma; AIDS-related peripheral/systemic lymphoma; AIDS-related primary CNS lymphoma; AIDS-related small noncleaved cell lymphoma