Phase II of Chemotherapy for Relapsed Epstein Barr Virus Associated Lymphoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by University of Miami Sylvester Comprehensive Cancer Center
Sponsor:
Information provided by (Responsible Party):
University of Miami Sylvester Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01964755
First received: October 14, 2013
Last updated: April 23, 2014
Last verified: April 2014
  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 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
Procedure: Urine Alkalization
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of Chemotherapy (Doxorubicin, Methotrexate and Leucovorin) in Combination With Antiviral-Based Therapy (Zidovudine + Hydroxyurea) for Relapsed Epstein Barr Virus Associated Lymphoma

Resource links provided by NLM:


Further study details as provided by University of Miami Sylvester Comprehensive Cancer Center:

Primary Outcome Measures:
  • Overall Survival Rate of Subjects [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    The primary objective of this phase II study is to determine the overall survival of patients with relapsed Epstein Barr Virus (EBV+) associated non-Hodgkin's and Hodgkin's lymphoma and post-transplant lymphoproliferative disease treated with high dose parenteral zidovudine (ZDV), oral hydroxyurea and combination chemotherapy with Doxorubicin, Methotrexate (MTX), and Leucovorin


Estimated Enrollment: 26
Study Start Date: April 2011
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Chemotherapy + Antiviral-Based Therapy
Doxorubicin, Methotrexate, and Leucovorin plus Zidovudine + Hydroxyurea All treatment will be administered on an inpatient basis. Treatment cycles will be given every 21-28 days, depending upon recovery from any hematologic or non-hematologic toxicity.
Drug: Doxorubicin
Doxorubicin 20 mg/m2 intravenously over approximately 3-5 min will be administered on Day 1.
Other Name: Adriamycin
Drug: Methotrexate
On Day 2 when urine output is >= 150 mL/hr for approximately four consecutive hours, urine pH is >= 7.0 and after at least 1 liter of fluids, give Methotrexate 5 gm/m2 IV in 1000 mL 0.9% sodium chloride over approximately 4 hours x 1 dose only.
Other Names:
  • Methotrexate sodium
  • MTX
  • Mexate
  • Mexate-AQ
  • Folex
  • Folex PFS
  • Abitrexate
  • Rheumatrex
  • Amethoptetrin
Drug: Leucovorin

Leucovorin 10 mg/m2 IV over 15 minutes-2 hours every 6 hours for 10 doses (see Section 4.1.8) - start approximately 24 hours after the BEGINNING of the methotrexate infusion.

Methotrexate level will be obtained approximately 48 hours after the END of the methotrexate infusion and the leucovorin dose adjusted accordingly.

Once methotrexate level is normal AND the subject has received 5 doses of intravenous zidovudine, the remaining doses of leucovorin and zidovudine may be given orally and the subject discharged from the hospital at the discretion of the investigator. Subject will be provided with a drug diary to record remaining doses taken at home: Leucovorin 25 mg every 6 hours for a total of 10 doses.

Other Names:
  • Leucovorin Calcium
  • Wellcovorin
  • Citrovorum Factor
  • Folinic Acid
  • 5-formyl tetrahydrofolate
  • LV
  • LCV
Biological: Hydroxyurea

Hydroxyurea 500 mg by mouth twice daily will begin on Day 2 and continue for a total of 10 doses.

Once methotrexate level is normal AND the subject has received 5 doses of intravenous zidovudine, the remaining doses of leucovorin and zidovudine may be given orally and the subject discharged from the hospital at the discretion of the investigator. Subject will be provided with a drug diary to record remaining doses taken at home:

Hydroxyurea 500 mg orally twice daily will be given for a total of 10 doses.

Other Names:
  • Hydroxyurea
  • Hydroxycarbamide
  • rINN
  • NSC-32065
  • SQ-1089
  • WR 83799
Drug: Zidovudine

Zidovudine 750 mg/m2 IV over approximately 1 hour twice daily will begin on Day 2 (after methotrexate) and continue for a total of 10 doses.

Once methotrexate level is normal AND the subject has received 5 doses of intravenous zidovudine, the remaining doses of leucovorin and zidovudine may be given orally and the subject discharged from the hospital at the discretion of the investigator. Subject will be provided with a drug diary to record remaining doses taken at home:

Zidovudine 1200 mg orally twice daily for a total of 10 doses.

Other Names:
  • Retrovir
  • AZT
  • ZDV
Procedure: Urine Alkalization
Urine alkalization will begin on Day 1 with normal saline or 5% dextrose with or without sodium bicarbonate.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Any stage, histologically or cytologically documented intermediate to high grade relapsed or refractory non-Hodgkin's or Hodgkin's lymphoma. Patients with relapsed/refractory monomorphic (monoclonal) post-transplant lymphoproliferative disease (PTLD) are also eligible.
  • Tumors must be positive for EBV by EBER. This may be done either on the original tumor or the biopsy of relapsed disease (if performed). Biopsy of relapsed disease is desirable but not mandatory. If stains for LMP-1 done outside are positive, EBER does not need to be done.
  • All patients must have relapsed or progressed from at least one previous standard 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, 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:

    • Absolute neutrophil count >= 1,500 cells/mm3 and platelets >= 50,000 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.
    • 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]). For bilirubin >= 3.0 mg/dL due to hepatic involvement, the initial dose of doxorubicin will be decreased by 50%.
    • 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.
  • Patients who are HIV+ are eligible.
  • Females with childbearing potential must have a negative serum pregnancy test within 72 hours 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 G-CSF are eligible, although GF therapy must be discontinued at least 24 hours prior to receiving chemotherapy.

Exclusion Criteria:

  • Concurrent active malignancies, with the exception of in situ carcinoma of the cervix, non-metastatic, non-melanomatous skin cancer, or Kaposi's sarcoma not requiring systemic chemotherapy.
  • Patients who have previously received a cumulative dose of Doxorubicin of 350 mg/m2 or greater.
  • 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.
  • Primary CNS lymphoma.
  • 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.
  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 Sylvester Comprehensive Cancer Center Recruiting
Miami, Florida, United States, 33136
Contact: Juan Carlos Ramos, MD    305-243-6611    jramos2@med.miami.edu   
Contact: University of Miami Sylvester Comprehensive Cancer Center    866-574-5124    sylvster@emergingmed.com   
Principal Investigator: Juan Carlos Ramos, MD         
Sub-Investigator: Thomas Harrington, MD         
Sub-Investigator: Peter Hosein, 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   
Sub-Investigator: Kristy Richards, PhD, MD         
Sub-Investigator: Matthew Foster, MD         
Sub-Investigator: Steven Park, MD         
Sub-Investigator: Hendrick Van Deventer, MD         
Sub-Investigator: William Wood Jr., MD         
Sub-Investigator: Peter Voorhees, MD         
Sponsors and Collaborators
University of Miami Sylvester Comprehensive Cancer Center
Investigators
Principal Investigator: Juan Carlos Ramos, MD University of Miami Sylvester Comprehensive Cancer Center
Principal Investigator: Dirk Dittmer, PhD University of North Carolina, Chapel Hill
  More Information

No publications provided

Responsible Party: University of Miami Sylvester Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01964755     History of Changes
Other Study ID Numbers: UMIAMI-20090166
Study First Received: October 14, 2013
Last Updated: April 23, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Miami Sylvester Comprehensive Cancer Center:
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
Hodgkin Disease
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antiviral Agents
Zidovudine
Doxorubicin
Liposomal doxorubicin
Hydroxyurea
Methotrexate
Formyltetrahydrofolates
Leucovorin
Tetrahydrofolates
Levoleucovorin
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex

ClinicalTrials.gov processed this record on August 28, 2014