Chemotherapy and HAART to Treat AIDS-related Primary Brain Lymphoma
Condition: AIDS-Related-Primary Central Nervous System Lymphoma
MeSH terms: Lymphoma
Intervention: Methotrexate; Rituximab; Leucovorin
Intervention description: 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
Intervention MeSH terms: Leucovorin; Rituximab; Methotrexate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Human immunodeficiency virus; Acquired immunodeficiency syndrome; High Dose Methotrexate; Methotrexate; Rituximab; CNS Lymphoma; Central Nervous System Lymphoma; AR-PCNSL; Epstein-Barr virus

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Positive human immunodeficiency virus (HIV) serology (previous records acceptable)

          -  Diagnosis of Primary Central Nervous System Lymphoma

          -  Confirmed histopathologic diagnosis by National Cancer Institute (NCI) Laboratory of
             Pathology

          -  If tissue diagnosis is not feasible for any reason, such as undue risk to the patient
             to acquire tissue diagnosis, the following will be accepted as confirmed Acquired
             immunodeficiency syndrome-related primary central nervous system lymphoma (AR-PCNSL)
             diagnosis:

          -  Positive brain fluro-2-deoxy-d-glucose positron emission tomography (FDG-PET) and

          -  Epstein Barr Virus (EBV) detected in the cerebrospinal fluid (CSF) using polymerase
             chain reaction (PCR)

          -  Age 18 years or greater

          -  Eastern Cooperative Oncology Group (ECOG) performance less than or equal to 0-4

          -  Ability to understand and willing to provide informed consent

          -  If patient unable to understand informed consent, a previously designated durable
             power of attorney for healthcare or an individual with legal authority may substitute
             in this capacity

          -  Assignment of a durable power of attorney for healthcare if not already done

        EXCLUSION CRITERIA:

          -  Prior therapy for central nervous system (CNS) lymphoma

          -  Steroids not an exclusion

          -  Evidence of lymphoma outside of the central nervous system

          -  Ocular involvement will not exclude

          -  Multidrug resistant HIV not amenable to long-term suppression based on either or both:

          -  Clinical history of poor adherence to multiple antiretroviral drugs deemed sufficient
             to render effective HIV control unattainable;

          -  HIV mutational analysis (genotyping and/or phenotyping) that reveals high-level
             resistance to more than 1 class of anti-HIV drugs such that a combination regimen
             comprised of agents from at least two drug classes can not be devised to suppress HIV
             long-term.

          -  Refusal to adhere to highly active antiretroviral therapy (HAART)

          -  Concurrent malignancy other than Kaposi sarcoma, resectable squamous cell or basal
             cell skin cancer, or T1 anal cancer amenable to surgical resection.

          -  Heart failure, Class IV by New York Heart Association criteria

          -  Chronic Liver Disease, Child-Pugh class B or C

        Pregnancy

          -  Refusal to practice contraception during chemotherapy.

          -  Any condition or set of circumstances that the Principal Investigator or Protocol
             Chair interprets as creating undue risk to the patient by participating on this study
             or would make the patient unlikely to comply with the study.