Chemotherapy for Relapsed Epstein Barr Virus Associated Lymphoma
Condition: Epstein Barr Virus Associated Non Hodgkin's Lymphoma; Epstein Barr Virus Associated Hodgkin's Lymphoma; Post-Transplant Lymphoproliferative Disease
MeSH terms: Virus Diseases; Epstein-Barr Virus Infections; Lymphoma; Lymphoma, Non-Hodgkin; Hodgkin Disease; Lymphoproliferative Disorders
Intervention: Doxorubicin; Methotrexate; Leucovorin; Hydroxyurea; Zidovudine; Rituximab
Intervention description: Doxorubicin 20 mg/m2 intravenously will be administered on Day 1 in patients with systemic (non-primary CNS) lymphoma as per institutional guidelines; Methotrexate administered starting on Day 2, per study protocol.; Leucovorin administered first intravenously 24 hours after start of Methotrexate infusion, then orally every 6 hours for at least 10 doses, per study protocol.; Hydroxyurea administered orally twice daily starting on Day 2, and continuing for a total of 10 doses, per study protocol; Zidovudine administered first intravenously on Day 2, and then orally twice daily for 10 doses, per study protocol.; Rituximab is optional and will be administered to study participants, per study protocol.
Intervention MeSH terms: Leucovorin; Tetrahydrofolates; Formyltetrahydrofolates; Zidovudine; Rituximab; Doxorubicin; Methotrexate; Hydroxyurea; Levoleucovorin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: EBV+; NHL; HL; Non Hodgkin's Lymphoma; Hodgkin's Lymphoma; Epstein Barr Virus; Epstein Barr Virus Associated Non Hodgkin's Lymphoma; Epstein Barr Virus Associated Hodgkin's Lymphoma; Post-Transplant Lymphoproliferative Disease

Summary:

      By combining a variety of agents that potentiate Zidovudine (ZDV), the investigators hope to
      induce remission in this generally fatal disease. Most therapies for aggressive B cell
      lymphomas are based upon intensive chemotherapeutic regimens, expensive modalities (bone
      marrow transplant, Rituximab), or experimental approaches (gene therapy, cytotoxic T cell
      infusion) that are difficult to implement in heavily pre-treated patients. Therapy for
      relapsed aggressive B cell lymphomas is very poor. Even curable lymphomas such as Burkitt
      Lymphoma (BL) and Hodgkin lymphoma are extremely difficult to treat in relapse and/or after
      stem cell transplant failure. The investigators propose a novel therapeutic approach that
      exploits the presence of Epstein-Barr virus (EBV) in lymphomas; antiviral mediated
      suppression of NF-kB and disruption of viral latency.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Any stage, histologically or cytologically documented intermediate to high grade
             relapsed or refractory EBV+ non-Hodgkin's (NHL) or Hodgkin's lymphoma (HL), or any
             treated or untreated patients with EBV+ lymphoma involving CNS. Patients with relapsed
             or refractory monomorphic (monoclonal) post-transplant lymphoproliferative disease
             (PTLD) are also eligible.

          2. Patients who are HIV+ or negative. Documentation of HIV infection can be done at any
             time prior to study entry. Documentation may be serologic (positive ELISA and positive
             Western blot), molecular (positive HIV viral RNA), or other federally approved
             licensed HIV test. Prior documentation of HIV seropositivity is acceptable.

          3. Tumors must be positive for EBV. This may be done either by Epstein-Barr virus-encoded
             small RNA (EBER) stain on the original tumor or the biopsy of relapsed disease (if
             performed). Biopsy of relapsed disease is desirable but not mandatory. If stains for
             Epstein-Barr virus latent membrane protein 1 (LMP1) done outside are positive, EBER
             does not need to be done.

          4. All patients, except those who have CNS involvement, must have relapsed or progressed
             from at least one previous chemotherapy based regimen.

          5. Measurable or non-measurable tumor parameter(s). Non-measurable tumor parameter(s) is
             defined as not having bi-dimensional measurements (e.g., gastric or marrow
             involvement), but can be followed for response by other diagnostic tests such as
             gallium scan, Positron emission tomography (PET) imaging and/or bone marrow biopsy.

          6. Age ≥ 18 years.

          7. Karnofsky performance status (KPS) ≥ 50%/Eastern Cooperative Oncology Group (ECOG)
             Performance Score 0, 1, 2.

          8. Patients must have adequate end organ and bone marrow function as defined below:

               -  8.1 Absolute neutrophil count ≥ 1,500 cells/mm3 and platelets ≥ 75,000 cells/dL
                  unless cytopenias are secondary to lymphomatous involvement of bone marrow or due
                  to HIV-related thrombocytopenia. All patients must be off colony stimulating
                  factor therapy at least 24 hours prior to institution of Cycle 1 chemotherapy.

               -  8.2 Adequate hepatic function: Serum glutamic-oxaloacetic transaminase (SGOT) ≤ 5
                  times the upper limit of normal. Total bilirubin ≤ 2.0 mg/dL (unless elevated
                  secondary to lymphomatous involvement of liver or biliary system or due to other
                  HIV medications [e.g., indinavir, tenofovir or atazanavir]). Patients who are
                  negative for Hepatitis B, or if infected with Hepatitis B, receiving
                  anti-Hepatitis B therapy are eligible. All subjects will be required to be
                  screened for Hepatitis B and C. Per Infectious Diseases Society of America (IDSA)
                  and American Association for the Study of Liver Diseases (AASD) guidelines, those
                  subjects that show no immunity, defined by the lack of Hepatitis B surface
                  antibody, and show evidence of chronic infection (i.e. HBsAg+, HBcore+, HBsAB-)
                  will be required to be on anti-Hepatitis B therapy, during the study, in order to
                  be eligible. Patients will be permitted to enroll in the study provided liver
                  function tests meet criteria listed above, and there is no evidence of cirrhosis.
                  The exact Hepatitis B therapy will be at the discretion of the infection disease
                  specialist or investigator. However all patients who present with acute hepatitis
                  B or show normal transaminases and are HBsAg+ and IgM+ for Hepatitis core antigen
                  will not be eligible for trial enrollment. Subjects who are Hepatitis C antibody
                  positive, with or without a positive Hepatitis C RNA level, will be permitted to
                  enroll in the study provided liver function tests meet criteria listed above, and
                  have no evidence of cirrhosis. Patients diagnosed with Hepatitis C less than 6
                  months from trial enrollment, will be considered to have Acute Hepatitis C and
                  will be excluded from study unless Hep C viral load is undetectable.

               -  8.3 Creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 60 mL/min unless due to
                  renal involvement by lymphoma.

          9. Concurrent radiation, with or without steroids, for emergency conditions secondary to
             lymphoma (CNS tumor, cord compression, etc.) will be permitted.

         10. Females with childbearing potential must have a negative serum pregnancy test within 7
             days prior of entering into the study. Men and women must agree to use adequate birth
             control if conception is possible during the study. Women must avoid pregnancy and men
             avoid fathering children while in the study and for 6 months following the last study
             drug treatment.

         11. Able to give consent.

         12. Patients already receiving erythropoietin or Granulocyte-colony stimulating factor
             (G-CSF) are eligible, although G-CSF therapy must be discontinued at least 24 hours
             prior to receiving chemotherapy.

         13. The maximum cumulative dose of doxorubicin allowed is 450 mg/m2. Patients who have
             previously received doxorubicin with a cumulative dose of 350 mg/m2 or greater are
             eligible but MAY NOT receive doxorubicin under protocol.

        Exclusion Criteria:

          1. Concurrent active malignancies, with the exception of in situ carcinoma of the cervix,
             non-metastatic, non-melanomatous skin cancer, or Kaposi sarcoma not requiring systemic
             chemotherapy.

          2. Myocardial infarction (MI) within 6 months prior to study entry, New York Heart
             Association (NYHA) Class II or greater heart failure, uncontrolled angina, severe,
             uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or
             electrocardiograph evidence of acute ischemic or active conduction system
             abnormalities.

          3. Left Ventricular Ejection Fraction (LVEF) that is less than the lower institutional
             limits of normal as assessed by Multiple Gated Acquisition (MUGA) scan or
             echocardiogram within 6 weeks prior to registration.

          4. Subjects with viral hepatitis who do not meet the criteria listed on (8.2) will be not
             be eligible. All patients who present with acute hepatitis B including those with
             normal transaminases who are HBsAg+ and IgM + for hepatitis core antigen will not be
             eligible. Subjects who are Hepatitis B core antibody positive are eligible only if
             they start or are on prophylactic therapy. A hepatitis B viral load should be
             confirmed negative on all patients who are hepatitis B core antibody positive, but
             hepatitis B antigen negative. Patients refusing to take any anti-hepatitis B therapy
             during study will also be excluded. Patients diagnosed with Hepatitis C are eligible
             if they meet criteria listed on (8.2).

          5. Psychological, familial, sociological or geographical conditions that do not permit
             treatment and/or medical follow-up required to comply with the study protocol.

          6. Patients may not be receiving any other investigational agents.

          7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements. Patients with mycobacterium avium will not be excluded.

          8. Pregnant or breast-feeding women.