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
18 Years
N/A
Both
Lymphoma, Precancerous/Nonmalignant Condition
Trial Information
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
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.
Inclusion 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
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
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.
Outcome Time Frame:
For responders we will report median time to relapse (duration of remission) and relapse-free rate at 6 and 12 months.
Safety Issue:
No
Principal Investigator
Juan Carlos Ramos, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
University of Miami Sylvester Comprehensive Cancer Center
Authority:
United States: Food and Drug Administration
Study ID:
EPROST-20070805
NCT ID:
NCT00854581
Start Date:
November 2007
Completion Date:
November 2014
Related Keywords:
- Lymphoma
- Precancerous/Nonmalignant Condition
- 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
- Leukemia
- Leukemia, T-Cell
- Leukemia-Lymphoma, Adult T-Cell
- Lymphoma
- Precancerous Conditions
Name | Location |
|---|---|
| University of Miami Sylvester Comprehensive Cancer Center - Miami | Miami, Florida 33136 |
