Chemotherapy for Relapsed Epstein Barr Virus Associated Lymphoma
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|ClinicalTrials.gov Identifier: NCT01964755|
Recruitment Status : Terminated (Investigator Decision)
First Posted : October 17, 2013
Results First Posted : September 23, 2019
Last Update Posted : September 23, 2019
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|Condition or disease||Intervention/treatment||Phase|
|Epstein Barr Virus Associated Non Hodgkin's Lymphoma Epstein Barr Virus Associated Hodgkin's Lymphoma Post-Transplant Lymphoproliferative Disease||Drug: Doxorubicin Drug: Methotrexate Drug: Leucovorin Biological: Hydroxyurea Drug: Zidovudine Drug: Rituximab||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||6 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Actual Study Start Date :||April 21, 2009|
|Actual Primary Completion Date :||June 7, 2018|
|Actual Study Completion Date :||June 7, 2018|
Experimental: Chemotherapy + Antiviral-Based Therapy
Combination Chemotherapy for up to six (6) 21-day cycles and Antiviral-Based Therapy:
Doxorubicin 20 mg/m2 intravenously will be administered on Day 1 in patients with systemic (non-primary CNS) lymphoma as per institutional guidelines
Other Name: Adriamycin
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.
Other Name: Rituxan
- Rate of Complete Response to Protocol Therapy [ Time Frame: About 21 days ]
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.
- One-year Rate of Overall Survival [ Time Frame: 12 months ]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.
- One-Year Rate of Failure-Free Survival (FFS) [ Time Frame: 12 months ]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.
- Rate of Toxicity Related to Protocol Therapy [ Time Frame: Through Duration of Protocol Therapy, Up to six 21-day cycles (+/- 7 days) ]Rate of adverse events, serious adverse events or other toxicities related to protocol therapy in study participants.
- HIV Viral Load in Positive Subjects Before, During and After Protocol Therapy [ Time Frame: From Baseline Up to 1 Year Post-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.
- T-Cell Subset Levels in Peripheral Blood in Positive Participants Before, During and After Protocol Therapy [ Time Frame: From Baseline Up to 1 Year Post-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.
- EBV Viral Load in Peripheral Blood Before, During and After Protocol Therapy [ Time Frame: From Baseline Up to 1 year Post-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.
- EBV Reactivation in Circulating Peripheral Blood Memory B-cells Before and After Protocol Therapy. [ Time Frame: From Baseline Up to 1 year Post-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.
- Baseline Tumor EBV Gene Expression Profile in Study Participants [ Time Frame: Baseline ]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.
- Measurement of Immune Activation Markers and Inflammation in Peripheral Blood [ Time Frame: Through Duration of Response to Protocol Therapy Until Disease Progression, Up to 5 years ]Measurement of immune activation markers and inflammation in peripheral blood in response to treatment and EBV reactivation.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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.
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01964755
|United States, Florida|
|University of Miami|
|Miami, Florida, United States, 33136|
|United States, North Carolina|
|University of North Carolina at Chapel Hill|
|Chapel Hill, North Carolina, United States, 27999|
|Study Chair:||Juan Carlos Ramos, MD||University of Miami|
Documents provided by Juan C. Ramos, University of Miami:
|Responsible Party:||Juan C. Ramos, Associate Professor of Clinical, University of Miami|
|Other Study ID Numbers:||
|First Posted:||October 17, 2013 Key Record Dates|
|Results First Posted:||September 23, 2019|
|Last Update Posted:||September 23, 2019|
|Last Verified:||August 2019|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
|Product Manufactured in and Exported from the U.S.:||No|
Non 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
Epstein-Barr Virus Infections
Neoplasms by Histologic Type
Immune System Diseases
DNA Virus Infections
Tumor Virus Infections
Antineoplastic Agents, Immunological
Physiological Effects of Drugs