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

Primary Purpose

Lymphoma, Precancerous/Nonmalignant Condition

Status

Terminated

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

PEG-interferon alfa-2b

Interferon alfa-2b

Valproic Acid

Zidovudine

About this trial

This is an interventional treatment trial for Lymphoma focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University of Miami Sylvester Comprehensive Cancer Center - Miami

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Induction (Up to Day 21)

Part 1 Maintenance (Up to Day 60)

Part 2A Maintenance (Up to 12 Months)

Part 2B Maintenance (Up to 12 Months)

Arm Description

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

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.

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

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

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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

Secondary Outcome Measures

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.

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.

Full Information

NCT ID

NCT00854581

First Posted

February 28, 2009

Last Updated

March 19, 2018

Sponsor

University of Miami

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00854581

Brief Title

Zidovudine, Interferon Alfa-2b, PEG-Interferon Alfa-2b in Patients With HTLV-I 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 Type

Interventional

2. Study Status

Record Verification Date

December 2017

Overall Recruitment Status

Terminated

Why Stopped

Investigator Decision

Study Start Date

November 2007 (undefined)

Primary Completion Date

June 2011 (Actual)

Study Completion Date

November 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Miami

Collaborators

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Lymphoma, Precancerous/Nonmalignant Condition

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

13 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Induction (Up to Day 21)

Arm Type

Experimental

Arm Description

Arm Title

Part 1 Maintenance (Up to Day 60)

Arm Type

Experimental

Arm Description

Arm Title

Part 2A Maintenance (Up to 12 Months)

Arm Type

Experimental

Arm Description

Arm Title

Part 2B Maintenance (Up to 12 Months)

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

PEG-interferon alfa-2b

Other Intervention Name(s)

PEG-IFN-alfa2b

Intervention Description

Administered subcutaneously.

Intervention Type

Biological

Intervention Name(s)

Interferon alfa-2b

Intervention Description

Administered intravenously.

Intervention Type

Drug

Intervention Name(s)

Valproic Acid

Other Intervention Name(s)

Depakene

Intervention Description

Administered orally.

Intervention Type

Drug

Intervention Name(s)

Zidovudine

Other Intervention Name(s)

Retrovir, AZT

Intervention Description

Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).

Primary Outcome Measure Information:

Title

Number of Patients Achieving Clinical Response to Protocol Therapy Who Lack IRF-4 and/or c-Rel Expression.

Description

Time Frame

Up to 12 months post-initiation of protocol therapy

Title

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

Description

Time Frame

3, 6 and 12 months.

Title

Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants

Description

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.

Time Frame

At time of relapse or disease progression, assessed up to 12 months

Title

Number of Participants Exhibiting NF-kB Inhibition Upon Treatment With AZT in Vivo

Description

Time Frame

During 48 hours of first AZT therapy

Title

The Effect of Valproic Acid Therapy on Persistence of Clonal Disease in Patients Who Achieve Clinical Remission

Description

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

Time Frame

3, 6 and 12 months.

Secondary Outcome Measure Information:

Title

Failure-free Survival (FFS)

Description

Time Frame

From date of treatment initiation until date of documented disease progression, relapse after response, or death from any cause, assessed up to 5 years

Title

Overall Survival

Description

Time Frame

From date of treatment initiation until date of death, assessed up to 5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Juan Carlos Ramos, MD

Organizational Affiliation

University of Miami

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Miami Sylvester Comprehensive Cancer Center - Miami

City

Miami

State/Province

Florida

ZIP/Postal Code

33136

Country

United States

12. IPD Sharing Statement

Learn more about this trial

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

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