Chemotherapy for Relapsed Epstein Barr Virus Associated Lymphoma

Study Overview
=================
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.

Official Title
-----------------
Phase II Study of Chemotherapy (Doxorubicin, Methotrexate and Leucovorin) in Combination With Antiviral-Based Therapy (Zidovudine + Hydroxyurea) for AIDS, Immunocompromised, or Immunocompetent Patients With Relapsed or CNS Positive Epstein Barr Virus Associated Lymphoma

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

Intervention / Treatment
-----------------
* Drug: Doxorubicin
* Drug: Methotrexate
* Drug: Leucovorin
* Biological: Hydroxyurea
* Drug: Zidovudine
* Drug: Rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. 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. 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. All patients, except those who have CNS involvement, must have relapsed or progressed from at least one previous chemotherapy based regimen. 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. Age ≥ 18 years. Karnofsky performance status (KPS) ≥ 50%/Eastern Cooperative Oncology Group (ECOG) Performance Score 0, 1, 2. 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. Concurrent radiation, with or without steroids, for emergency conditions secondary to lymphoma (CNS tumor, cord compression, etc.) will be permitted. 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. Able to give consent. 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. 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: 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. 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. 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. 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). Psychological, familial, sociological or geographical conditions that do not permit treatment and/or medical follow-up required to comply with the study protocol. Patients may not be receiving any other investigational agents. 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. Pregnant or breast-feeding women.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemotherapy + Antiviral-Based Therapy<br>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. | Drug: Doxorubicin<br>* Doxorubicin 20 mg/m2 intravenously will be administered on Day 1 in patients with systemic (non-primary CNS) lymphoma as per institutional guidelines<br>* Other names: Adriamycin;Drug: Methotrexate<br>* Methotrexate administered starting on Day 2, per study protocol.<br>* Other names: Amethopterin;Drug: Leucovorin<br>* Leucovorin administered first intravenously 24 hours after start of Methotrexate infusion, then orally every 6 hours for at least 10 doses, per study protocol.<br>* Other names: LCV;Biological: Hydroxyurea<br>* Hydroxyurea administered orally twice daily starting on Day 2, and continuing for a total of 10 doses, per study protocol<br>* Other names: Hydrea;Drug: Zidovudine<br>* Zidovudine administered first intravenously on Day 2, and then orally twice daily for 10 doses, per study protocol.<br>* Other names: Azidothymidine (AZT);Drug: Rituximab<br>* Rituximab is optional and will be administered to study participants, per study protocol.<br>* Other names: Rituxan;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Complete Response to Protocol Therapy | Complete Response (CR) rate in study participants to protocol therapy. Response will be assessed via CT Scan and bone marrow aspirate/biopsy, if applicable. Complete response criteria include: Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities definitely assignable to Non Hodgkin's Lymphoma (NHL); All lymph nodes and tumor masses disappeared or regressed to normal size (≤ 1.5 cm in their greatest transverse diameters for nodes > 1.5 cm before therapy); Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter (GTD) before treatment must have decreased to ≤ 1 cm in their GTD after treatment, or by more than 75% bin the sum of the products of the greatest diameters (SPD); No new sites of disease. | About 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year Rate of Overall Survival | Rate of overall survival of study participants at one year since initiation of protocol therapy. Overall survival (OS) will be measured from the date of initiation of study treatment until date of death from any cause. In the absence of death, the follow-up will be censored at date of last contact (censored observation). Kaplan-Meier estimate of overall survival at one-year. | 12 months | 
| One-Year Rate of Failure-Free Survival (FFS) | Rate of failure-free survival of study participants one-year after start of protocol therapy. Failure-free survival (FFS) will be measured from the date of treatment initiation until date of documented disease progression, relapse after response, or death from any cause. For patients alive and free of relapse or progression, follow-up time will be censored at the last documented date of failure-free status. Kaplan-Meier estimate of failure-free survival at one-year. | 12 months | 
| Rate of Toxicity Related to Protocol Therapy | Rate of adverse events, serious adverse events or other toxicities related to protocol therapy in study participants. | Through Duration of Protocol Therapy, Up to six 21-day cycles (+/- 7 days) | 
| HIV Viral Load in Positive Subjects Before, During and After Protocol Therapy | Measurement of HIV Viral Load in positive subjects before, during and after protocol therapy to assess the effect of protocol therapy on immune reconstitution or exhaustion. | From Baseline Up to 1 Year Post-Therapy | 
| T-Cell Subset Levels in Peripheral Blood in Positive Participants Before, During and After Protocol Therapy | Measurement of T-cell subset levels (CD4, CD8) in peripheral blood before, during and after protocol therapy to assess the effect of protocol therapy on immune re-constitution or exhaustion. | From Baseline Up to 1 Year Post-Therapy | 
| EBV Viral Load in Peripheral Blood Before, During and After Protocol Therapy | Measurement of Epstein Barr Virus (EBV) viral load in peripheral blood in study participants before, after treatment, and during surveillance in order to correlate the presence of with tumor load and disease status. | From Baseline Up to 1 year Post-Therapy | 
| EBV Reactivation in Circulating Peripheral Blood Memory B-cells Before and After Protocol Therapy. | Measurement of EBV reactivation in circulating peripheral blood memory B-cells before and after treatment with chemotherapy/Zidovudine (ZDV) in order to assess the drug effect on EBV latency. | From Baseline Up to 1 year Post-Therapy | 
| Baseline Tumor EBV Gene Expression Profile in Study Participants | Determine baseline tumor EBV gene expression profile to assess viral thymidine kinases. (BXLF1/vTK and BGLF4/PK), EBV latency pattern (I, II or III) and lytic phase. | Baseline | 
| Measurement of Immune Activation Markers and Inflammation in Peripheral Blood | Measurement of immune activation markers and inflammation in peripheral blood in response to treatment and EBV reactivation. | Through Duration of Response to Protocol Therapy Until Disease Progression, Up to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
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