AIDS-Related-Primary Central Nervous System Lymphoma Clinical Trial
Official title:
AIDS-Related Primary Central Nervous System Lymphoma: A Phase II Pilot Study of High-Dose Intravenous Methotrexate With Rituximab Leucovorin Rescue and Highly Active Antiretroviral Therapy
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.
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.
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