This site became the new ClinicalTrials.gov on June 19th. Learn more.
Show more
ClinicalTrials.gov Menu IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu IMPORTANT: Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu
Give us feedback

Phase II of Chemotherapy for Relapsed Epstein Barr Virus Associated Lymphoma

This study is currently recruiting participants.
See Contacts and Locations
Verified April 2017 by Juan C. Ramos, University of Miami
Sponsor:
Information provided by (Responsible Party):
Juan C. Ramos, University of Miami
ClinicalTrials.gov Identifier:
NCT01964755
First received: October 14, 2013
Last updated: April 5, 2017
Last verified: April 2017
  Purpose
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.

Condition Intervention 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
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Juan C. Ramos, University of Miami:

Primary Outcome Measures:
  • Rate of Complete Response to Protocol Therapy [ Time Frame: Through Duration of Protocol Therapy, Up to six 21-day cycles (+/- 7 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 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.


Secondary Outcome Measures:
  • Rate of Overall Survival [ Time Frame: Up to 12 months ]
    Rate of overall survival of study participants. 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).

  • Rate of Failure-Free Survival (FFS) [ Time Frame: Up to 12 months ]
    Rate of failure-free survival of study participants. 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.

  • 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 Before, During and After Protocol Therapy [ Time Frame: From Baseline Up to 1 Year Post-Therapy ]
    Measurement of T-cell subset levels 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 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/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.


Estimated Enrollment: 26
Actual Study Start Date: April 21, 2009
Estimated Study Completion Date: April 2019
Estimated Primary Completion Date: April 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: Doxorubicin
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
Drug: Methotrexate
Methotrexate administered starting on Day 2, per study protocol.
Other Names:
  • Methotrexate sodium
  • Mexate
  • Mexate-aq
  • Folex
  • Abitrexate
  • Rheumatrex
  • Amethopterin
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.
Other Names:
  • Leucovorin Calcium
  • Wellcovorin
  • Citrovorum Factor
  • Folinic Acid
  • 5-formyl tetrahydrofolate
  • LV
  • LCV
Biological: Hydroxyurea
Hydroxyurea administered orally twice daily starting on Day 2, and continuing for a total of 10 doses, per study protocol
Other Names:
  • Hydroxycarbamide (rINN)
  • Hydrea
Drug: Zidovudine
Zidovudine administered first intravenously on Day 2, and then orally twice daily for 10 doses, per study protocol.
Other Names:
  • Retrovir
  • Azidothymidine (AZT)
Drug: Rituximab
Rituximab is optional and will be administered to study participants, per study protocol.
Other Name: Rituxan

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01964755

Locations
United States, Florida
University of Miami Recruiting
Miami, Florida, United States, 33136
Contact: Juan Carlos Ramos, MD    305-243-6611    jramos2@med.miami.edu   
Principal Investigator: Juan Carlos Ramos, MD         
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27999
Contact: Dirk Dittmer, PhD    919-966-7960    ddittmer@med.unc.edu   
Principal Investigator: Dirk Dittmer, PhD         
Sponsors and Collaborators
University of Miami
Investigators
Study Chair: Juan Carlos Ramos, MD University of Miami
  More Information

Responsible Party: Juan C. Ramos, Associate Professor of Clinical, University of Miami
ClinicalTrials.gov Identifier: NCT01964755     History of Changes
Other Study ID Numbers: 20090166
Study First Received: October 14, 2013
Last Updated: April 5, 2017

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

Keywords provided by Juan C. Ramos, University of Miami:
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

Additional relevant MeSH terms:
Virus Diseases
Lymphoma
Lymphoma, Non-Hodgkin
Hodgkin Disease
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Liposomal doxorubicin
Rituximab
Methotrexate
Doxorubicin
Hydroxyurea
Zidovudine
Antiviral Agents
Leucovorin
Levoleucovorin
Tetrahydrofolates
Formyltetrahydrofolates
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on July 26, 2017