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

NCT00854581 | Terminated Phase 4 Results DMC

• 3 other identifiers: 20070805SCCC-20070555P01CA128115-02
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (2)

• 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

• Overall Survival

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

Study Arms (4)

Induction (Up to Day 21)

EXPERIMENTAL

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; Drug: Zidovudine

Part 1 Maintenance (Up to Day 60)

EXPERIMENTAL

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; Drug: Zidovudine

Part 2A Maintenance (Up to 12 Months)

EXPERIMENTAL

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; Drug: Zidovudine

Part 2B Maintenance (Up to 12 Months)

EXPERIMENTAL

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; Drug: Valproic Acid; Drug: Zidovudine

Interventions

PEG-interferon alfa-2b BIOLOGICAL

Administered subcutaneously.

Also known as: PEG-IFN-alfa2b

Part 1 Maintenance (Up to Day 60); Part 2A Maintenance (Up to 12 Months); Part 2B Maintenance (Up to 12 Months)

Interferon alfa-2b BIOLOGICAL

Administered intravenously.

Induction (Up to Day 21)

Valproic Acid DRUG

Administered orally.

Also known as: Depakene

Part 2B Maintenance (Up to 12 Months)

Zidovudine DRUG

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

Also known as: Retrovir, AZT

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)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Miami: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

University of Miami Sylvester Comprehensive Cancer Center - Miami

Miami, Florida, 33136, United States

Location

MeSH Terms

Conditions

Lymphoma; Precancerous Conditions; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; HTLV-I Infections

Interventions

peginterferon alfa-2b; Interferon alpha-2; Valproic Acid; Zidovudine

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia; Hematologic Diseases; Deltaretrovirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Infections; Immunologic Deficiency Syndromes

Intervention Hierarchy (Ancestors)

Interferon-alpha; Interferon Type I; Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Juan Carlos Ramos MD
• Organization: University of Miami

jramos2@med.miami.edu

305-243-4909

Study Officials

• Juan Carlos Ramos, MD

  University of Miami

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Clinical

Study Record Dates

• First Submitted: February 28, 2009
• First Posted: March 3, 2009
• Study Start: November 1, 2007
• Primary Completion: June 1, 2011
• Study Completion: November 1, 2011
• Last Updated: April 17, 2018
• Results First Posted: January 6, 2015

Record last verified: 2017-12

Locations

US (1)