Chemotherapy for Relapsed Epstein Barr Virus Associated Lymphoma

NCT ID: NCT01964755

Last Updated: 2019-09-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-04-21
• Study Completion Date: 2018-06-07

Brief 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.

Conditions

Epstein Barr Virus Associated Non Hodgkin's Lymphoma; Epstein Barr Virus Associated Hodgkin's Lymphoma; Post-Transplant Lymphoproliferative Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Chemotherapy + Antiviral-Based Therapy

Combination Chemotherapy for up to six (6) 21-day cycles and Antiviral-Based Therapy:

• Chemotherapy: Up to 6 cycles, 21 days each:

• Doxorubicin: 20 mg/m2 intravenously (IV) on Day 1 per study protocol;
• Rituximab: 375mg/m2 (optional) IV on Day 1 per study protocol;
• Methotrexate: 3.5 gm/m2 IV on Day 2 per study protocol;
• Leucovorin: 10 mg/m2 IV starting approximately 24 hours after start of Methotrexate infusion, and then 25 mg orally every 6 hours for at least 10 doses per study protocol;
• Antiviral-Based Therapy

• Zidovudine: Starting 750 mg/m2 IV on Day 2, then 1200 mg orally twice daily for 10 doses per study protocol;
• Hydroxyurea: 1,000 mg orally twice daily starting Day 2 for a total of 10 doses per study protocol.

Group Type: EXPERIMENTAL

Doxorubicin

Intervention Type: DRUG

Doxorubicin 20 mg/m2 intravenously will be administered on Day 1 in patients with systemic (non-primary CNS) lymphoma as per institutional guidelines

Methotrexate

Intervention Type: DRUG

Methotrexate administered starting on Day 2, per study protocol.

Leucovorin

Intervention Type: DRUG

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

Intervention Type: BIOLOGICAL

Hydroxyurea administered orally twice daily starting on Day 2, and continuing for a total of 10 doses, per study protocol

Zidovudine

Intervention Type: DRUG

Zidovudine administered first intravenously on Day 2, and then orally twice daily for 10 doses, per study protocol.

Rituximab

Intervention Type: DRUG

Rituximab is optional and will be administered to study participants, per study protocol.

Interventions

Doxorubicin

Doxorubicin 20 mg/m2 intravenously will be administered on Day 1 in patients with systemic (non-primary CNS) lymphoma as per institutional guidelines

Intervention Type: DRUG

Methotrexate

Methotrexate administered starting on Day 2, per study protocol.

Intervention Type: DRUG

Leucovorin

Leucovorin administered first intravenously 24 hours after start of Methotrexate infusion, then orally every 6 hours for at least 10 doses, per study protocol.

Intervention Type: DRUG

Hydroxyurea

Hydroxyurea administered orally twice daily starting on Day 2, and continuing for a total of 10 doses, per study protocol

Intervention Type: BIOLOGICAL

Zidovudine

Zidovudine administered first intravenously on Day 2, and then orally twice daily for 10 doses, per study protocol.

Intervention Type: DRUG

Rituximab

Rituximab is optional and will be administered to study participants, per study protocol.

Intervention Type: DRUG

Other Intervention Names

Adriamycin; Methotrexate sodium; Mexate; Mexate-aq; Folex; Abitrexate; Rheumatrex; Amethopterin; Leucovorin Calcium; Wellcovorin; Citrovorum Factor; Folinic Acid; 5-formyl tetrahydrofolate; LV; LCV; Hydroxycarbamide (rINN); Hydrea; Retrovir; Azidothymidine (AZT); Rituxan

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Miami

OTHER

Sponsor Role: lead

Responsible Party

Juan C. Ramos

Associate Professor of Clinical

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Juan Carlos Ramos, MD

Role: STUDY_CHAIR

University of Miami

Locations

University of Miami

Miami, Florida, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

20090166

Identifier Type: -

Identifier Source: org_study_id