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

Condition(s) targeted: Lymphoma; Precancerous/Nonmalignant Condition

Intervention: PEG-interferon alfa-2b (Biological); Interferon alfa-2b (Biological); Valproic Acid (Drug); Zidovudine (Drug); Molecular Evaluation/Analysis of Malignant Clones of ATLL (Genetic); NF-kB Inhibition (Genetic)

Phase: Phase 1/Phase 2

Status: Terminated

Sponsored by: University of Miami

Official(s) and/or principal investigator(s):
Juan Carlos Ramos, MD, Principal Investigator, Affiliation: University of Miami Sylvester Comprehensive Cancer Center

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.

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 design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

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.

Presence of Minimal Residual Disease at 3 and 6 Months of Maintained Remission and at 1 Year Post Initiation of Therapy

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 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.

Number of Patients Who Achieved Complete Response or Partial Response According to Molecular Response Criteria

Secondary outcome:

Failure-free Survival

Overall Survival

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

University of Miami Sylvester Comprehensive Cancer Center - Miami, Miami, Florida 33136, United States

Clinical trial summary from the National Cancer Institute's PDQ® database

Related publications:

Tsukasaki K, Hermine O, Bazarbachi A, Ratner L, Ramos JC, Harrington W Jr, O'Mahony D, Janik JE, Bittencourt AL, Taylor GP, Yamaguchi K, Utsunomiya A, Tobinai K, Watanabe T. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. J Clin Oncol. 2009 Jan 20;27(3):453-9. doi: 10.1200/JCO.2008.18.2428. Epub 2008 Dec 8.

Starting date: November 2007
Last updated: December 22, 2014