Chemotherapy and HAART to Treat AIDS-related Primary Brain Lymphoma
Condition: AIDS-Related-Primary Central Nervous System Lymphoma
MeSH terms: Lymphoma
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will investigate the use of chemotherapy plus highly active antiretroviral therapy
      (HAART) in patients with Acquired Immunodeficiency Syndrome (AIDS)-related primary brain
      lymphoma. None of the drugs used in this study are experimental, but chemotherapy plus HAART
      has not been established as a standard treatment in patients with AIDS. The chemotherapy
      regimen used in this study (see below) was chosen because it may be less toxic to immune
      cells called T-lymphocytes than most drug treatments for lymphoma.

      People with AIDS 18 and older and have primary brain lymphoma may be eligible for this study.
      Candidates are screened with a medical history and physical examination, magnetic resonance
      imaging (MRI), computed tomography (CT) and positron emission tomography (PET) scans,
      cerebrospinal fluid studies, brain biopsy at tumor sites, if possible, electrocardiogram and
      blood tests.

      Participants undergo six 2-week "induction treatment" cycles of HAART plus chemotherapy with
      methotrexate, rituximab and leucovorin, followed by two 4-week "consolidation" treatment
      cycles using HAART, methotrexate and leucovorin, and then HAART alone. Rituximab is given by
      intravenous (intravenous (IV), through a vein) day 1 of each cycle. Also on day 1 IV fluids
      are given to lower acidity in the urine to protect the kidneys from the methotrexate. On day
      2, methotrexate is infused through a vein over 4 hours. Starting 24 hours after initiation of
      the methotrexate infusion, leucovorin is given every 3 to 6 hours (first IV and then possibly
      by mouth) until the drug decreases to a target level in the blood. HAART is begun as soon as
      possible. The specific HAART regimen for each patient is determined individually. All
      patients are hospitalized the first week of every 2-week treatment cycle for safety
      monitoring. In addition to HAART and chemotherapy, patients undergo the following tests and
      procedures:

        -  Intellectual functioning: Before starting treatment, patients are tested for their
           ability to understand basic concepts and coordination in order to be able to evaluate
           how the brain lymphoma affects thinking and concentration. After the lymphoma appears to
           have resolved, more formal and intensive tests are done. The intensive tests are
           repeated each year, and shorter, interim tests are done about every 6 months. Also, a
           specialist periodically monitors patients' understanding of HAART and the importance of
           this therapy.

        -  Blood tests: Blood is drawn every day during hospitalizations to measure methotrexate
           levels and to evaluate kidney and liver function and blood counts. Blood is also drawn
           before starting therapy, when the lymphoma disappears, 6 months after completing
           treatment, and any time it appears that the lymphoma may have recurred to test for
           Epstein-Barr virus (EBV), a virus that is almost always present in AIDS-related primary
           brain lymphoma.

        -  Imaging tests: Patients undergo magnetic resonance imaging (MRI) and positron emission
           tomography (PET) scans periodically to monitor the effects of treatment on the lymphoma.
           MRI scans are done after the 2nd, 4th, 6th, and 8th treatments, then every 2 months for
           three times, every 3 months for six times, every 6 months for four times, and then every
           year for 5 years, or sooner if there is a concern about the brain. PET scans are done
           after the first cycle, after the MRI suggests the lymphoma is gone, and then yearly.

        -  Lumbar puncture (spinal tap): This test is done to look for EBV in the cerebrospinal
           fluid (CSF). Under local anesthetic, a needle is inserted in the space between the bones
           in the lower back where the CSF circulates below the spinal cord and a small amount of
           fluid is collected through the needle. This test is done at the same times as the blood
           tests for EBV.

        -  Eye examinations: Patients' eyes are examined periodically because brain lymphoma can
           sometimes spread to the eye and because some people with AIDS-related primary brain
           lymphoma are at risk of certain eye infections.
    

Detailed description: 
      Background: Acquired Immunodeficiency Syndrome (AIDS)-related primary central nervous system
      lymphoma (AR-PCNSL) is an Epstein-Barr virus (EBV)-driven lymphoproliferative process that
      typically results in death within a few months. Essentially all of the cases are
      immunoblastic cluster of differentiation 20 (CD20+) tumors, and occur once the cluster of
      differentiation 4 (CD4+) cells have fallen to below 50 cells/mm^3. Highly active
      antiretroviral therapy (HAART) can result in immune reconstitution that decreases the risk of
      AR-PCNSL. However, a subset of human immunodeficiency virus (HIV)-infected patients still
      develops ARPCNSL, often because they are unaware that they are HIV infected, or they do not
      take HAART. Treatment options for such patients are limited. In the non-AIDS setting,
      chemotherapy has become the standard of care for primary central nervous system lymphoma
      (PCNSL) and late neurocognitive decline consequent to radiotherapy can be avoided by such
      approaches. In the pre-HAART era, AR-PCNSL was generally treated with whole brain
      radiotherapy, however death due to recurrent lymphoma or to other AIDS complications occurred
      prior to the potential manifestations of late occurring radiation-related neurotoxicity.
      Radiation-sparing approaches have not been studied in AR-PCNSL in the HAART era, where
      advances in antiretroviral therapy have made curative intent chemotherapy feasible for most
      patients with HIV infection.

      Objectives: The primary objective of this study is to estimate the fraction of patients with
      AR-PCNSL receiving experimental treatment consisting of HAART, combined with rituximab,
      high-dose methotrexate and leucovorin (R-HD-MTX) who are alive and without recurrent lymphoma
      or severe cognitive problems at two years. .

      Eligibility: HIV-infected, age 18 years or older, AR-PCSNL that has not previously been
      treated, and be able to give informed consent or have a durable power of attorney who can
      provide informed consent, HIV profile that makes them likely to respond to HAART. There are a
      number of other specific inclusion and exclusion criteria, in part to exclude patients who
      would be unlikely to tolerate the therapy.

      Design: Phase II pilot study investigating R-HD-MTX given with leucovorin rescue and HAART as
      a treatment for AR-PCNSL. Evaluation will include quantitative measurement of lymphocyte
      subsets, quantitative polymerase chain reaction (PCR) of HIV and EBV viral loads (including
      both blood and cerebrospinal fluid in the case of EBV) to assess immune response and
      anti-viral effects. Tumor evaluation with brain magnetic resonance imaging (MRI) and brain
      fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET scans) will be used for
      staging and response assessment. Longitudinal neuropsychologic testing after complete
      responses are documented will serve to evaluate neurocognitive parameters post therapy.

      a separate cohort for additional secondary endpoints.
    

Intervention name(s): Methotrexate; Rituximab; Leucovorin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 6000 mg/m^2 will be administered by intravenous infusion over 4 hours after confirming that the recipient patients urine pH is within the range greater than or equal to 7 to less than or equal to 8, and urine output is greater than or equal to 100 mL/hour.; 375 mg/m^2 intravenous (IV) day 1 of each cycle prior to administration of high-dose methotrexate; Leucovorin calcium doses will be administered orally or by short intravenous (IV) infusion over 15 minutes
Other intervention name(s): Xatmep; Trexall; Otrexup (PF); Rasuvo; Rituxan; MabThera; Folinic acid; citrovorum factor
Intervention MeSH terms: Leucovorin; Rituximab; Methotrexate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Human immunodeficiency virus; Acquired immunodeficiency syndrome; High Dose Methotrexate; Methotrexate; Rituximab; CNS Lymphoma; Central Nervous System Lymphoma; AR-PCNSL; Epstein-Barr virus