Zidovudine, Interferon Alfa-2b, and PEG-Interferon Alfa-2b in Treating Patients With Human T-Cell Lymphotropic Virus Type 1-Associated Adult T-Cell Leukemia/Lymphoma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
University of Miami Sylvester Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00854581
First received: February 28, 2009
Last updated: June 20, 2014
Last verified: June 2014
  Purpose

RATIONALE: Human T-cell lymphotropic virus type 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 Intervention
Lymphoma
Precancerous/Nonmalignant Condition
Biological: PEG-interferon alfa-2b
Biological: Interferon alfa-2b
Drug: Valproic Acid
Drug: Zidovudine
Genetic: Molecular Evaluation/Analysis of Malignant Clones of ATLL
Genetic: NF-kB Inhibition

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • To investigate whether the lack of IRF-4 and/or c-Rel is associated with response (CR or PR) to Zidovudine (AZT) and IFN alpha-2b therapy. [ Time Frame: For responders we will report median time to relapse (duration of remission) and relapse-free rate at 6 and 12 months. ] [ Designated as safety issue: No ]
  • Presence of minimal residual disease at 3 and 6 months of maintained remission and at 1 year post initiation of therapy [ Time Frame: 3 and 6 months of maintained remission and at 1 year post initiation of therapy ] [ Designated as safety issue: No ]
  • To analyze clones from patients who relapse to determine whether antiviral escape is associated with expression of IRF-4, c-Rel or other molecular events (p53, p16 mutations) including expansion of novel clones. [ Time Frame: 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. ] [ Designated as safety issue: No ]
  • To investigate whether AZT functions as an inhibitor of NF-kB in vivo by analyzing serially collected leukemic samples during the first 48 hours of treatment with AZT only. [ Time Frame: we will report the proportion of tumors exhibiting NF-kB inhibition upon treatment with AZT in vivo and correlate with response using two-sample t-test. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Failure-free survival [ Time Frame: measured from the date of treatment initiation until date of documented disease progression, relapse after response, or death from any cause. ] [ Designated as safety issue: No ]
    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.

  • Overall survival [ Time Frame: Measured from the date of initiation of study treatment until date of death from any cause. ] [ Designated as safety issue: No ]
    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).


Enrollment: 13
Study Start Date: November 2007
Estimated Study Completion Date: November 2014
Estimated Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Zidovudine + Interferon alfa-2b + PEG Interferon alfa-2b Biological: PEG-interferon alfa-2b
PEG-IFN-alfa2b 1.5 ug/kg SQ weekly.
Other Name: PEG-IFN-alfa2b
Biological: Interferon alfa-2b
Days 3 - 14: Interferon Alpha-2b 5 10 million units IV twice daily.
Drug: Valproic Acid
Patients will be started on one capsule (250 mg) with water twice daily.
Other Name: Depakene
Drug: Zidovudine
Days 1-2: (0-48 hours) Zidovudine (AZT) 1.5 grams intravenously (IV) twice daily. Days 3-14: Zidovudine (AZT) 1.5 grams IV twice daily and Interferon Alpha-2b 5 10 million units IV twice daily. Subsequent doses dependent on patient response.
Other Names:
  • Retrovir
  • AZT
Genetic: Molecular Evaluation/Analysis of Malignant Clones of ATLL
Blood Sample - Baseline/Pre-Treatment, Day 60, End of Month 12, Disease Progession
Genetic: NF-kB Inhibition
Blood Sample - Baseline/Pre-Treatment, Induction,

Detailed Description:

OBJECTIVES:

Primary

  • To investigate whether the lack of IRF-4 and/or c-Rel is associated with response (complete response or partial response) to zidovudine, recombinant interferon alfa-2b, and PEG-interferon alfa-2b therapy in patients with human T-cell lymphotropic virus type 1-associated adult T-cell leukemia/lymphoma (ATLL).
  • To analyze, in responders, the presence of any remaining detectable clones of ATLL (minimal residual disease) at 3 and 6 months of maintained remission on antivirals and at one-year post-initiation of therapy in order to determine whether this represents persistence of the original tumor clone or another variant.
  • To analyze clones from patients who relapse to determine whether antiviral escape is associated with expression of IRF-4, c-Rel, or other molecular events (p53, p16 mutations) including expansion of novel clones.
  • To investigate whether zidovudine functions as an inhibitor of NF-κB in vivo by analyzing serially collected leukemic samples during the first 48 hours of treatment with zidovudine alone.
  • To determine the effect of valproic acid therapy on persistent clonal disease in patients in complete or stable partial remission.

Secondary

  • To determine the failure-free survival and overall survival of these patients.

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.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Histologically or cytologically confirmed diagnosis of adult T-cell leukemia/lymphoma

    • Any stage disease
    • Leukemic types only (smoldering, chronic, or acute)
  • Tumors must be CD3 positive (> 50% cells express CD3)
  • Documented human T-cell lymphotropic virus type 1 (HTLV-1) infection by serologic assay (ELISA, western blot) and confirmed to be HTLV-1 rather than HTLV-2 by differential western blot or PCR
  • Measurable or evaluable disease

PATIENT CHARACTERISTICS:

  • Karnofsky performance status 50-100%
  • ANC ≥ 1,500/mm^3
  • Platelet count ≥ 50,000/mm^3 unless cytopenias are secondary to adult T-cell leukemia/lymphoma
  • Transaminases ≤ 7 times upper limit of normal unless secondary to hepatic infiltration with lymphoma
  • Total bilirubin < 2.0 mg/dL unless secondary to hepatic infiltration with lymphoma (if secondary to indinavir or atazanavir therapy, patients are eligible provided total bilirubin ≤ 3.5 mg/dL and that direct bilirubin is normal)
  • Creatinine < 2.0 mg/dL
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during study treatment
  • No grade 3 or 4 cardiac failure
  • Ejection fraction ≥ 50%
  • No concurrent uncontrolled illness including, but not limited to, any of the following:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness or social situations that would limit compliance with study requirements
  • No concurrent active malignancy except for in situ carcinoma of the cervix; non-metastatic, non-melanomatous skin cancer; or Kaposi's sarcoma not requiring systemic chemotherapy
  • No autoimmune or viral hepatitis or decompensated liver disease unless due to lymphoma
  • No hypersensitivity to recombinant interferon alfa-2b, PEG-interferon alfa-2b, zidovudine, or any component of the formulation
  • No psychological, familial, sociological, or geographical conditions precluding study treatment and/or medical follow-up
  • HIV positivity allowed

PRIOR CONCURRENT THERAPY:

  • Patients already receiving erythropoietin or filgrastim (G-CSF) allowed
  • Concurrent antiretroviral therapy in HIV-positive patients allowed
  • No prior zidovudine and/or interferon
  • No other concurrent investigational agents
  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: NCT00854581

Locations
United States, Florida
University of Miami Sylvester Comprehensive Cancer Center - Miami
Miami, Florida, United States, 33136
Sponsors and Collaborators
University of Miami Sylvester Comprehensive Cancer Center
Investigators
Principal Investigator: Juan Carlos Ramos, MD University of Miami Sylvester Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: University of Miami Sylvester Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00854581     History of Changes
Other Study ID Numbers: UMIAMI-20070805, SCCC-2007055
Study First Received: February 28, 2009
Last Updated: June 20, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Miami Sylvester Comprehensive Cancer Center:
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:
Leukemia
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Lymphoma
Precancerous Conditions
Neoplasms by Histologic Type
Neoplasms
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Interferon-alpha
Interferons
Zidovudine
Peginterferon alfa-2b
Valproic Acid
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Anticonvulsants
Central Nervous System Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Antimanic Agents

ClinicalTrials.gov processed this record on August 26, 2014