Protocol Number: 06-C-0051

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

Number:

06-C-0051

Summary:

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.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility 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 SPECT thallium and

-EBV detected in the CSF using PCR

-Age 18 years or greater

-ECOG performance less than or equal to 3

-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.

-On HAART for 6 or more months with immunological failure as defined by HIV suppression less than 50 but poor recovery of CD4 cells remaining less than 70/mm(3).

-Refusal to adhere to HAART

-Evidence of other opportunistic diseases or complications of HIV infection that would make the protocol therapy infeasible to administer

-Examples include, but are not limited to:

-Aggressive symptomatic Kaposi's sarcoma requiring systemic therapy

-Systemic and/or CNS-invasive fungal infection

-Laboratory abnormalities that make the protocol therapy unsafe to administer:

-PT and or PTT greater than 120% of control unless due to presence of lupus anticoagulant

-ANC less than 1,000 cells/mm(3)

-Platelet count less than 50,000/mm(3)

-ALT and/or AST greater than 2 X upper limit of normal

-Bilirubin greater than 2 X upper limit of normal unless due to protease inhibitor therapy

-Creatinine greater than 1.5 mg/dL unless estimated or measured creatinine clearance is 60 ml/min or greater

-If the calculated creatinine clearance is less than 100 mL/min, a measured creatinine clearance should be obtained.

-Patients with Class III or higher New York Heart Association Classification of Congestive Heart Failure unresponsive to treatment that would make hydration infeasible.

-Hypersensitivity to murine proteins or any component of rituximab

-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.

Special Instructions:

Currently Not Provided

Keywords:

HIV

EBV

Brain

Tumor

Immunosuppression

Recruitment Keyword(s):

HIV

AIDS Related-Primary Central Nervous System Lymphoma

AR-PCNSL

Condition(s):

AIDS-Related Primary Central Nervous System Lymphoma

HIV

Investigational Drug(s):

None

Investigational Device(s):

None

Intervention(s):

Drug: Methotrexate

:

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Levine AM. AIDS-related malignancies: the emerging epidemic.J Natl Cancer Inst. 1993 Sep 1;85(17):1382-97. Review.

Goplen AK, Dunlop O, Liestol K, Lingjaerde OC, Bruun JN, Maehlen J. The impact of primary central nervous system lymphoma in AIDS patients: a population-based autopsy study from Oslo. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Apr 1;14(4):351-4.

von Gunten CF, Von Roenn JH. Clinical aspects of human immunodeficiency virus-related lymphoma. Curr Opin Oncol. 1992 Oct;4(5):894-9. Review.

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