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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

Phase 2
18 Years
Open (Enrolling)
AIDS-Related Primary Central Nervous System Lymphoma, HIV

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Trial Information

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

Background: 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 CD20+ tumors, and occur
once the CD4+ cells have fallen to below 50 cells/mm3 . Highly active antiretroviral therapy
(HAART) can result in immune reconstitution that decreases the risk of AR-PCNSL. However, a
subset of HIV-infected patients still develop 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. Secondary objectives include evaluation
of safety and toxicities associated with R-HD-MTX plus HAART in patients with AR-PCNSL as
well as estimating the complete response rate, progression-free, disease-free, overall
survivals and long-term neurocognitive outcomes. Additionally, this study will assess
overall survival, progression-free survival, and longterm neurocognitive outcomes in
patients with AR-PCNSL in who HD-MTX is contraindicated and are therefore treated with
radiation-sparing therapy consisting of dose-modified, dose-dense rituximab combined with
HAART but no HD-MTX.

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.

Inclusion Criteria


Positive HIV serology (previous records acceptable)

- Diagnosis of Primary Central Nervous System Lymphoma

- Confirmed histopathologic diagnosis by 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 AR-PCNSL

- Positive brain FDG-PET and

- EBV detected in the CSF using PCR

- Age 18 years or greater

- 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


- Prior therapy for 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

- 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

- Refusal to adhere to 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


- 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.

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

The number of patients alive at 2 years without recurrent brain lymphoma or severe neurocognitive defects

Safety Issue:


Principal Investigator

Robert Yarchoan, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

December 2005

Completion Date:

December 2014

Related Keywords:

  • AIDS-Related Primary Central Nervous System Lymphoma
  • HIV
  • HIV
  • EBV
  • Brain
  • Tumor
  • Immunosuppression
  • AIDS-Related-Primary Central Nervous System Lymphoma
  • High Dose Methotrexate
  • Rituximab
  • Highly Active Antiretroviral Therapy
  • AIDS Related-Primary Central Nervous System Lymphoma
  • Acquired Immunodeficiency Syndrome
  • Lymphoma



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