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Zidovudine, Interferon Alfa-2b, PEG-Interferon Alfa-2b in Patients With HTLV-I Associated Adult T-Cell Leukemia/Lymphoma

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ClinicalTrials.gov Identifier: NCT00854581
Recruitment Status : Terminated (Investigator Decision)
First Posted : March 3, 2009
Results First Posted : January 6, 2015
Last Update Posted : April 17, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Juan C. Ramos, University of Miami

Brief Summary:

RATIONALE: Human T-cell lymphotropic virus type 1 (HTLV-1) can cause cancer. Zidovudine is an antiviral drug that acts against the human T-cell lymphotropic virus type 1. Giving zidovudine, interferon alfa-2b, and PEG-interferon alfa-2b together may stimulate the immune system and slow down or keep the cancer cell from growing.

PURPOSE: This clinical trial is studying how well giving zidovudine together with interferon alfa-2b and PEG-interferon alfa-2b works in treating patients with human T-cell lymphotropic virus type 1-associated adult T-cell leukemia/lymphoma.


Condition or disease Intervention/treatment Phase
Lymphoma Precancerous/Nonmalignant Condition Biological: PEG-interferon alfa-2b Biological: Interferon alfa-2b Drug: Valproic Acid Drug: Zidovudine Phase 4

Detailed Description:

OUTLINE: This is a multicenter study.

  • Induction therapy: Patients receive zidovudine IV twice daily on days 1-14, and recombinant interferon alfa-2b IV twice daily on days 3-14. Patients achieving clinical complete response (CR) proceed to part 1 maintenance therapy; patients achieving partial response (PR) receive another 7 days of zidovudine and recombinant interferon alfa-2b and then proceed to part 1 maintenance therapy.
  • Part 1 maintenance therapy: Patients receive oral zidovudine twice daily and PEG-interferon alfa-2b subcutaneously (SC) once weekly, beginning on day 14 or 21 and continue to day 60. Patients are evaluated after completion of part 1 maintenance therapy and proceed to part 2 maintenance therapy.
  • Part 2 maintenance therapy: Patients achieving CR with undetectable clonal disease proceed to group A; patients achieving CR with minimal residual disease (by PCR) or PR proceed to group B.

    • Group A: Patients receive oral zidovudine twice daily and PEG-interferon alfa-2b SC once weekly. Treatment continues in the absence of disease progression or unacceptable toxicity.
    • Group B: Patients receive oral zidovudine twice daily and PEG-interferon alfa-2b SC once weekly for 12 weeks and undergo reevaluation. Patients in continued CR with minimal residual disease or stable PR receive oral valproic acid twice daily, PEG-interferon alfa-2b SC once weekly, and oral zidovudine twice daily for 6 months. At that point (month 9) patients with no detectable clonal disease continue their previous treatment, while patients with minimal residual disease receive PEG-interferon alfa-2b SC and oral zidovudine twice daily in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline, days 1 and 2, and months 3, 6, and 12 for protein, genomic DNA, and RNA analysis. Baseline molecular characteristics of the tumor and tumor response to treatment is assessed.

After completion of study treatment, patients are followed every 3 months for 1 year.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective Study of the Molecular Characteristics of Sensitive and Resistant Disease in Patients With HTLV-I Associated Adult T Cell Leukemia Treated With Zidovudine (AZT) Plus Interferon Alpha-2b
Study Start Date : November 2007
Actual Primary Completion Date : June 2011
Actual Study Completion Date : November 2011


Arm Intervention/treatment
Experimental: Induction (Up to Day 21)

For one cycle, up to Day 21. All participants are enrolled to induction therapy phase, then move to the maintenance therapy phase if they achieve complete response (PR) or partial response (PR). Participants who achieve a clinical CR at Day 14 response assessment will go on to Part 1 maintenance therapy. Patients who achieve a PR will receive 7 more days of induction therapy and then go on to Part 1 Maintenance Therapy.:

  • Zidovudine:

    • Days 1-2: 1.5 grams intravenously (IV) twice daily
    • Days 3-21: 1.5 grams IV twice daily
  • Interferon alfa-2b (IFN):

    • 5 10 million units (mu) intravenously twice daily
Biological: Interferon alfa-2b
Administered intravenously.

Drug: Zidovudine
Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).
Other Names:
  • Retrovir
  • AZT

Experimental: Part 1 Maintenance (Up to Day 60)

From Treatment Day 14 or 21 to start of Month 3 (Day 60). Study participants move on to Part 1 Maintenance Therapy only if they achieve complete response (CR) or partial response (PR) after induction therapy. Restaging and molecular evaluation of disease at start of Month 3:

  • Zidovudine: 600 mg orally twice daily in all phases of Maintenance Therapy
  • PEG-Interferon alfa-2b: 1.5 ug/kg subcutaneously (SQ) once weekly
  • Participants then proceed to Part 2 maintenance.
Biological: PEG-interferon alfa-2b
Administered subcutaneously.
Other Name: PEG-IFN-alfa2b

Drug: Zidovudine
Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).
Other Names:
  • Retrovir
  • AZT

Experimental: Part 2A Maintenance (Up to 12 Months)

Participants achieving a CR with undetectable clonal disease. Participants will receive therapy for as long as response is maintained:

  • Zidovudine: 600 mg orally twice daily
  • PEG-Interferon alfa-2b: 1.5 ug/kg subcutaneously (SQ) once weekly
Biological: PEG-interferon alfa-2b
Administered subcutaneously.
Other Name: PEG-IFN-alfa2b

Drug: Zidovudine
Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).
Other Names:
  • Retrovir
  • AZT

Experimental: Part 2B Maintenance (Up to 12 Months)

Participants achieving a CR with minimal residual disease (by multiplex PCR) or PR in Part 1:

  • Zidovudine: 600 mg or 300 mg orally twice daily, per protocol
  • PEG-Interferon alfa-2b: 1.5 ug/kg subcutaneously (SQ) once weekly, per protocol
  • Valproic acid, 250 mg orally twice daily, per protocol
Biological: PEG-interferon alfa-2b
Administered subcutaneously.
Other Name: PEG-IFN-alfa2b

Drug: Valproic Acid
Administered orally.
Other Name: Depakene

Drug: Zidovudine
Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).
Other Names:
  • Retrovir
  • AZT




Primary Outcome Measures :
  1. Number of Patients Achieving Clinical Response to Protocol Therapy Who Lack IRF-4 and/or c-Rel Expression. [ Time Frame: Up to 12 months post-initiation of protocol therapy ]

    Number of patients achieving clinical response (complete response (CR) + partial response (PR)) who lack interferon regulatory factor 4 (IRF-4) or c-Rel biomarker expression. Treatment response was assessed according to the International Consensus Review's adult T-cell leukemia/lymphoma (ATLL) consensus report by Tsukasaki et al published in the Journal of Clinical Oncology (JCO) in 2009.

    For imaging, Cheson criteria was used to assess response:

    • Complete response (CR): Disappearance of all clinical, microscopic, and radiographic evidence of disease. All lymph nodes regressed to normal size (≤ 1.5 cm), and previously involved nodes that were 1.1 to 1.5 cm decreased to ≤ 1.0 cm. In addition, abnormally elevated peripheral blood absolute lymphocyte count (ALC) < 4 x 10^9 /L.
    • Partial response (PR): ≥ 50% reduction in measurable disease and abnormal lymphocyte count in peripheral blood.
    • CR or PR had to persist for a period of at least 4 weeks.

  2. Presence of Minimal Residual Disease at 3 and 6 Months of Maintained Remission and at 1 Year Post Initiation of Therapy [ Time Frame: 3, 6 and 12 months. ]

    Number of participants achieving complete response (CR) with minimal residual disease at 3, 6 and 12 months post-initiation of protocol therapy. Treatment response was assessed according to the International Consensus Review's adult T-cell leukemia/lymphoma (ATLL) consensus report by Tsukasaki et al published in the Journal of Clinical Oncology (JCO) in 2009.

    For imaging, Cheson criteria was used to assess response:

    • Complete response (CR): Disappearance of all clinical, microscopic, and radiographic evidence of disease. All lymph nodes regressed to normal size (≤ 1.5 cm), and previously involved nodes that were 1.1 to 1.5 cm decreased to ≤ 1.0 cm. In addition, abnormally elevated peripheral blood absolute lymphocyte count (ALC) < 4 x 10^9 /L.
    • Partial response (PR): ≥ 50% reduction in measurable disease and abnormal lymphocyte count in peripheral blood.
    • CR or PR had to persist for a period of at least 4 weeks.

  3. Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants [ Time Frame: At time of relapse or disease progression, assessed up to 12 months ]
    Expressions of c-Rel, IRF-4 or other molecular events (p53, p16 mutations) including expansion of novel clones obtained at time of relapse will be compared to baseline data using paired t-test.

  4. Number of Participants Exhibiting NF-kB Inhibition Upon Treatment With AZT in Vivo [ Time Frame: During 48 hours of first AZT therapy ]
    Number of patients exhibiting NF-kb inhibition upon treatment with AZT in vivo. Investigation of whether AZT functions as an inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in vivo by analyzing serially collected leukemic samples during the first 48 hours of treatment with AZT only. The investigators will report the number of participants exhibiting NF-kB inhibition upon treatment with AZT in vivo and correlate with response using two-sample t-test.

  5. The Effect of Valproic Acid Therapy on Persistence of Clonal Disease in Patients Who Achieve Clinical Remission [ Time Frame: 3, 6 and 12 months. ]
    Number of participants achieving a molecular remission after starting valproic acid as evidenced by disappearance of T-cell clonality as measured by gene rearrangement studies using multiplex PCR


Secondary Outcome Measures :
  1. Failure-free Survival (FFS) [ Time Frame: From date of treatment initiation until date of documented disease progression, relapse after response, or death from any cause, assessed up to 5 years ]
    Failure-free survival is the elapsed time from the date of initiation of study treatment 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 was censored at the last documented date of failure-free status.

  2. Overall Survival [ Time Frame: From date of treatment initiation until date of death, assessed up to 5 years ]
    Overall survival (OS) is the elapsed time from the date of initiation of study treatment until date of death from any cause. In the absence of death, the follow-up was censored at date of last contact.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Any stage, histologically or cytological documented adult T-cell leukemia/lymphoma (ATLL), leukemic types only (smoldering, chronic or acute). See Appendix I for definitions of the clinical subtypes.
  • Patients who have received prior treatment, including zidovudine and/or IFN, are eligible, provided that zidovudine/IFN therapy did not result in progressive disease.
  • Documented HTLV-I infection: documentation may be serologic assay (ELISA, Western blot) and confirmed to be HTLV-I rather than HTLV-2 by differential Western blot (e.g., Genelabs Diagnostics HTLV Blot 2.4) or PCR.
  • Measurable or evaluable disease.
  • Age 18 or older.
  • Karnofsky performance status ≥ 50%.
  • Patients must have adequate end organ and bone marrow function as defined below:

    • Absolute neutrophil count ≥ 1,000 cells/mm3 and platelets ≥ 50,000 cells/mm3 unless cytopenias are secondary to ATLL.
    • Adequate hepatic function: (transaminase ≤ 7 times the upper limit of normal, total bilirubin < 2.0), unless secondary to hepatic infiltration with lymphoma. If the elevated bilirubin is felt to be secondary to Indinavir or Atazavinir therapy (anti-HIV medications), patients will be allowed to enroll on protocol if the total bilirubin is ≤ 3.5 mg/dl provided that the direct bilirubin is normal.
    • Creatinine < 2.0 unless due to lymphomatous infiltration.
  • Patients who are HIV+ are also eligible.
  • Females with childbearing potential must have a negative serum pregnancy test within 72 hours of entering into the study. Males and females 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.
  • Able to give consent.
  • Patients already receiving erythropoietin or granulocyte-colony stimulating factor (G-CSF) are eligible.

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.
  • Grade 3 or 4 cardiac failure and/or ejection fraction < 50%.
  • 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.
  • Pregnant or breast-feeding women.
  • Hypersensitivity to interferon alpha-2b, peginterferon alpha-2b, zidovudine or any component of the formulation
  • Autoimmune or viral hepatitis or decompensated liver disease unless due to lymphoma.

Information from the National Library of Medicine

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): NCT00854581


Locations
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United States, Florida
University of Miami Sylvester Comprehensive Cancer Center - Miami
Miami, Florida, United States, 33136
Sponsors and Collaborators
University of Miami
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Juan Carlos Ramos, MD University of Miami

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Responsible Party: Juan C. Ramos, Associate Professor of Clinical, University of Miami
ClinicalTrials.gov Identifier: NCT00854581     History of Changes
Other Study ID Numbers: 20070805
SCCC-2007055 ( Other Identifier: UM/Sylvester Comprehensive Cancer Center )
5P01CA128115-02 ( U.S. NIH Grant/Contract )
First Posted: March 3, 2009    Key Record Dates
Results First Posted: January 6, 2015
Last Update Posted: April 17, 2018
Last Verified: December 2017
Keywords provided by Juan C. Ramos, University of Miami:
recurrent adult T-cell leukemia/lymphoma
stage I adult T-cell leukemia/lymphoma
stage II adult T-cell leukemia/lymphoma
stage III adult T-cell leukemia/lymphoma
stage IV adult T-cell leukemia/lymphoma
HTLV-1 infection
Additional relevant MeSH terms:
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Leukemia-Lymphoma, Adult T-Cell
Psychotropic Drugs
Lymphoma
Leukemia
Leukemia, T-Cell
Precancerous Conditions
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, Lymphoid
Interferons
Interferon-alpha
Interferon alpha-2
Zidovudine
Peginterferon alfa-2b
Valproic Acid
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Anti-Retroviral Agents