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

Phase 4

Terminated

Conditions: Lymphoma
Precancerous/Nonmalignant Condition

Interventions: Biological: PEG-interferon alfa-2b
Biological: Interferon alfa-2b
Drug: Zidovudine
Drug: Valproic Acid

Registration Number: NCT00854581

Lead Sponsor: 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 13

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 2A Maintenance (Up to 12 Months)	PEG-interferon alfa-2b	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
Part 2B Maintenance (Up to 12 Months)	PEG-interferon alfa-2b	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
Part 1 Maintenance (Up to Day 60)	PEG-interferon alfa-2b	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.
Induction (Up to Day 21)	Interferon alfa-2b	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
Induction (Up to Day 21)	Zidovudine	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
Part 1 Maintenance (Up to Day 60)	Zidovudine	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.
Part 2A Maintenance (Up to 12 Months)	Zidovudine	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
Part 2B Maintenance (Up to 12 Months)	Valproic Acid	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
Part 2B Maintenance (Up to 12 Months)	Zidovudine	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

Primary Outcome Measures

Name	Time	Method
Number of Participants Exhibiting NF-kB Inhibition Upon Treatment With AZT in Vivo	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.
Number of Patients Achieving Clinical Response to Protocol Therapy Who Lack IRF-4 and/or c-Rel Expression.	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.
Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants	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.
The Effect of Valproic Acid Therapy on Persistence of Clonal Disease in Patients Who Achieve Clinical Remission	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
Presence of Minimal Residual Disease at 3 and 6 Months of Maintained Remission and at 1 Year Post Initiation of Therapy	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.

Secondary Outcome Measures

Name	Time	Method
Failure-free Survival (FFS)	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.
Overall Survival	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.