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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Lymphoma, Precancerous/Nonmalignant Condition

Intervention / Treatment
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* Biological: PEG-interferon alfa-2b
* Biological: Interferon alfa-2b
* Drug: Valproic Acid
* Drug: Zidovudine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction (Up to Day 21)<br>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<br>* Administered intravenously.<br>Drug: Zidovudine<br>* Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).<br>* Other names: AZT;|
| Experimental: Part 1 Maintenance (Up to Day 60)<br>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<br>* Administered subcutaneously.<br>* Other names: PEG-IFN-alfa2b;Drug: Zidovudine<br>* Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).<br>* Other names: AZT;|
| Experimental: Part 2A Maintenance (Up to 12 Months)<br>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<br>* Administered subcutaneously.<br>* Other names: PEG-IFN-alfa2b;Drug: Zidovudine<br>* Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).<br>* Other names: AZT;|
| Experimental: Part 2B Maintenance (Up to 12 Months)<br>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<br>* Administered subcutaneously.<br>* Other names: PEG-IFN-alfa2b;Drug: Valproic Acid<br>* Administered orally.<br>* Other names: Depakene;Drug: Zidovudine<br>* Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).<br>* Other names: AZT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Achieving Clinical Response to Protocol Therapy Who Lack IRF-4 and/or c-Rel Expression. | 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. | Up to 12 months post-initiation of protocol therapy | 
| Presence of Minimal Residual Disease at 3 and 6 Months of Maintained Remission and at 1 Year Post Initiation of Therapy | 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, 6 and 12 months. | 
| Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | 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. | At time of relapse or disease progression, assessed up to 12 months | 
| Number of Participants Exhibiting NF-kB Inhibition Upon Treatment With AZT in Vivo | 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. | During 48 hours of first AZT therapy | 
| The Effect of Valproic Acid Therapy on Persistence of Clonal Disease in Patients Who Achieve Clinical Remission | 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 | 3, 6 and 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure-free Survival (FFS) | 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. | From date of treatment initiation until date of documented disease progression, relapse after response, or death from any cause, assessed up to 5 years | 
| Overall Survival | 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. | From date of treatment initiation until date of death, assessed up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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