Chemotherapy and HAART to Treat AIDS-related Primary Brain Lymphoma

NCT00267865 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 06005106-C-0051
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

AIDS-Related-Primary Central Nervous System Lymphoma

Keywords

Human immunodeficiency virus; Acquired immunodeficiency syndrome; High Dose Methotrexate; Methotrexate; Rituximab; CNS Lymphoma; Central Nervous System Lymphoma; AR-PCNSL; Epstein-Barr virus

Outcome Measures

Primary Outcomes (1)

• Number of Patients Alive at 2 Years Without Recurrent Brain Lymphoma or Severe Neurocognitive Defects

  Recurrent lymphoma as defined by the International Primary Central Nervous System (CNS) Lymphoma Collaborative Group for response assessment of aggressive Non-Hodgkin's Lymphoma (NHL) using fluorodeoxyglucose F 18 (18FDG-PET). Severe cognitive problems are defined as the inability to carry out normal activities with minimal difficulty and not requiring nursing care or hospitalization because of neurological impairment.

  2 years

Secondary Outcomes (5)

• Number of Participants With Serious and Non-serious Adverse Events

  Date treatment consent signed to date off study, approximately 142 months and 11 days.

• Number of Participants With Response to Treatment After Rituximab, High-Dose Methotrexate (R-HD-MTX) Induction

  At the end of 6 cycles or 12 weeks of treatment

• Estimated Percentage of Participants Overall Survival

  Time from treatment start date until date of death or date last known alive, approximately 60 months

• Median Mini Mental Status Exam (MMSE) Score in Surviving Participants After Rituximab, High-Dose Methotrexate & Leucovorin ( R-HD-MTX) Treatment

  up to 2.5 years

• Change From Baseline in Cluster of Differentiation 4 (CD4) T Cell Count at up to 2.5 Years

  Baseline and up to 2.5 years

Study Arms (1)

Rituximab, High-Dose Methotrexate & Leucovorin Treatment

EXPERIMENTAL

Induction treatment cycles with rituximab, high-dose methotrexate and leucovorin will be administered every 2 weeks for 6 cycles. Two additional consolidation cycles of high-dose methotrexate without rituximab will be administered at 4 weeks and 8 weeks following completion of the combined therapy.

Drug: Methotrexate; Drug: Rituximab; Drug: Leucovorin

Interventions

Methotrexate DRUG

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.

Also known as: Xatmep, Trexall, Otrexup (PF), Rasuvo

Rituximab, High-Dose Methotrexate & Leucovorin Treatment

Rituximab DRUG

375 mg/m\^2 intravenous (IV) day 1 of each cycle prior to administration of high-dose methotrexate

Also known as: Rituxan, MabThera

Rituximab, High-Dose Methotrexate & Leucovorin Treatment

Leucovorin DRUG

Leucovorin calcium doses will be administered orally or by short intravenous (IV) infusion over 15 minutes

Also known as: Folinic acid, citrovorum factor

Rituximab, High-Dose Methotrexate & Leucovorin Treatment

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Prior therapy for central nervous system (CNS) lymphoma
• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Levine AM. AIDS-related malignancies: the emerging epidemic. J Natl Cancer Inst. 1993 Sep 1;85(17):1382-97. doi: 10.1093/jnci/85.17.1382.

  PMID: 8350362 BACKGROUND

• 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. doi: 10.1097/00042560-199704010-00007.

  PMID: 9111477 BACKGROUND

• von Gunten CF, Von Roenn JH. Clinical aspects of human immunodeficiency virus-related lymphoma. Curr Opin Oncol. 1992 Oct;4(5):894-9. doi: 10.1097/00001622-199210000-00012.

  PMID: 1457504 BACKGROUND

• Kranick SM, Goncalves PH, Stetler-Stevenson M, Aleman K, Polizzotto MN, Little RF, Yarchoan R, Uldrick TS. Paradoxical central nervous system immune reconstitution syndrome in acquired immunodeficiency syndrome-related primary central nervous system lymphoma. Haematologica. 2015 Jan;100(1):e21-4. doi: 10.3324/haematol.2014.114736. Epub 2014 Oct 10. No abstract available.

  PMID: 25304612 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome; Epstein-Barr Virus Infections

Interventions

Methotrexate; Rituximab; Leucovorin

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Herpesviridae Infections; DNA Virus Infections; Tumor Virus Infections

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Coenzymes; Enzymes and Coenzymes

Results Point of Contact

• Title: Dr. Robert Yarchoan
• Organization: National Cancer Institute

yarchoar@nih.gov

240-760-6075

Study Officials

• Robert Yarchoan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 21, 2005
• First Posted: December 21, 2005
• Study Start: September 14, 2006
• Primary Completion: September 18, 2019
• Study Completion: September 19, 2019
• Last Updated: June 1, 2020
• Results First Posted: May 1, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)