Chemotherapy for Relapsed Epstein Barr Virus Associated Lymphoma

NCT01964755 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: 20090166
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 2

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• One-year Rate of Overall Survival

  12 months

• One-Year Rate of Failure-Free Survival (FFS)

  12 months

• Rate of Toxicity Related to Protocol Therapy

  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

  From Baseline Up to 1 Year Post-Therapy

• T-Cell Subset Levels in Peripheral Blood in Positive Participants Before, During and After Protocol Therapy

  From Baseline Up to 1 Year Post-Therapy

Study Arms (1)

Chemotherapy + Antiviral-Based Therapy

EXPERIMENTAL

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; Drug: Methotrexate; Drug: Leucovorin; Biological: Hydroxyurea; Drug: Zidovudine; Drug: Rituximab

Interventions

Doxorubicin DRUG

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

Also known as: Adriamycin

Chemotherapy + Antiviral-Based Therapy

Methotrexate DRUG

Methotrexate administered starting on Day 2, per study protocol.

Also known as: Methotrexate sodium, Mexate, Mexate-aq, Folex, Abitrexate, Rheumatrex, Amethopterin

Chemotherapy + Antiviral-Based Therapy

Leucovorin 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.

Also known as: Leucovorin Calcium, Wellcovorin, Citrovorum Factor, Folinic Acid, 5-formyl tetrahydrofolate, LV, LCV

Chemotherapy + Antiviral-Based Therapy

Hydroxyurea BIOLOGICAL

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

Also known as: Hydroxycarbamide (rINN), Hydrea

Chemotherapy + Antiviral-Based Therapy

Zidovudine DRUG

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

Also known as: Retrovir, Azidothymidine (AZT)

Chemotherapy + Antiviral-Based Therapy

Rituximab DRUG

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

Also known as: Rituxan

Chemotherapy + Antiviral-Based Therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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.
• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Miami: lead

Study Sites (2)

University of Miami

Miami, Florida, 33136, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27999, United States

Location

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Hodgkin Disease; Epstein-Barr Virus Infections

Interventions

Doxorubicin; Methotrexate; merphos; Leucovorin; Hydroxyurea; Zidovudine; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Coenzymes; Enzymes and Coenzymes; Urea; Amides; Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Juan C. Ramos MD
• Organization: University of Miami

jramos2@med.miami.edu

305-243-1326

Study Officials

• Juan Carlos Ramos, MD

  University of Miami

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Clinical

Study Record Dates

• First Submitted: October 14, 2013
• First Posted: October 17, 2013
• Study Start: April 21, 2009
• Primary Completion: June 7, 2018
• Study Completion: June 7, 2018
• Last Updated: September 23, 2019
• Results First Posted: September 23, 2019

Record last verified: 2019-08

Locations

US (2)