Chemotherapy and HAART to Treat AIDS-related Primary Brain Lymphoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT00267865
First received: December 21, 2005
Last updated: March 14, 2014
Last verified: October 2013
  Purpose

This study will investigate the use of chemotherapy plus highly active antiretroviral therapy (HAART) in patients with 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, MRI, CT and 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 (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.

Condition Intervention Phase
AIDS-Related Primary Central Nervous System Lymphoma
HIV
Drug: Methotrexate
Biological: rituximab
Procedure: antiviral therapy
Drug: leucovorin calcium
Phase 2

Study Type: Interventional
Study Design: Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • The number of patients alive at 2 years without recurrent brain lymphoma or severe neurocognitive defects [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To assess overall survival, progression-free survival, and long-term 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-de...
  • To assess overall survival and long-term neurocognitive outcomes in patients with ARPCNSL who receive Radiation Sparing Best Available Care , consisting of HAART and any additional first or second line radiation-sparing approaches.

Estimated Enrollment: 28
Study Start Date: December 2005
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Methotrexate
    N/A
    Biological: rituximab
    N/A
    Procedure: antiviral therapy
    N/A
    Drug: leucovorin calcium
    N/A
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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 diagnosis:
  • 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

EXCLUSION CRITERIA:

  • 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 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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00267865

Contacts
Contact: Karen Aleman, R.N. (301) 496-8959 alemank@mail.nih.gov
Contact: Robert Yarchoan, M.D. (301) 496-0328 robert.yarchoan@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Robert Yarchoan, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT00267865     History of Changes
Obsolete Identifiers: NCT00304044
Other Study ID Numbers: 060051, 06-C-0051
Study First Received: December 21, 2005
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
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
AR-PCNSL

Additional relevant MeSH terms:
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Methotrexate
Levoleucovorin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Nucleic Acid Synthesis Inhibitors
Antidotes
Protective Agents

ClinicalTrials.gov processed this record on October 02, 2014