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Belinostat Therapy With Zidovudine for Adult T-Cell Leukemia-Lymphoma

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ClinicalTrials.gov Identifier: NCT02737046
Recruitment Status : Recruiting
First Posted : April 13, 2016
Last Update Posted : June 5, 2019
Sponsor:
Information provided by (Responsible Party):
Juan C. Ramos, University of Miami

Brief Summary:
The investigators propose to use Belinostat in combination with AZT as consolidation therapy for the treatment of ATLL.

Condition or disease Intervention/treatment Phase
Adult T-cell Leukemia-Lymphoma ATLL Drug: Belinostat Drug: Zidovudine Drug: Interferon-Alfa-2b Drug: Pegylated Interferon-Alfa-2b Phase 2

Detailed Description:

ATLL is an aggressive malignancy caused by HTLV-1. ATLL cannot be cured by conventional chemotherapy thus urging the development of new therapeutic strategies. HDAC inhibitors are broadly active anti-neoplastic agents that can be exploited for the treatment of ATLL as it has been demonstrated that pharmacologic inhibition of HDACs promotes acetylation of nucleosomes and chromatin unwinding at the HTLV-1 5' long terminal repeat (LTR), which results in transcription of the viral genome.

Belinostat, a potent pan HDAC inhibitor, causes H3 subunit acetylation and induces HTLV-1 Tax expression in cultured ATLL cells resulting in dose-dependent apoptosis. Further, Belinostat blocks constitutive expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and increases apoptosis in the presence of AZT.

  • This is an open-label, single arm, phase II study of zidovudine (AZT) and Belinostat, as consolidation therapy with optional interferon-alfa-2b (IFN-alfa-2b) or pegylated interferon-alfa-2b (PEG-IFN-alfa-2b). For subjects receiving interferon therapy at baseline, the corresponding interferon, IFN-alfa-2b at 5 million IU daily or PEG-IFN-alfa-2b at 1.5 μg/kg once weekly, may be continued. Subjects will receive up to 8 cycles of Belinostat combined with AZT (as consolidation) followed by AZT-based maintenance therapy (± IFN-alfa) for at least 6 more months.
  • Subjects will be restaged at the end of Belinostat Cycle 3(-7 days), Belinostat Cycle 8(-14 days), end of Month 9(≤14 days) and end of Month 12 (≤14 days) post-Belinostat during AZT-based maintenance treatment. Subjects who have progression of disease at any of these time points will be taken off study treatment. At the end of Cycle 3 (of Belinostat), subjects who achieve a molecular complete response or maintain a clinical stable response may continue on the study.
  • At the end of Cycle 8 (i.e. completion of Belinostat), subjects who achieve or maintain a complete molecular response (CMR) with no evidence of minimal residual disease (MRD) will continue to receive AZT (±IFN-alfa). Subjects with MRD with no clinical evidence of disease progression nor clinical evidence of ATLL may also continue to receive AZT (± IFN-alfa) OR be removed from treatment at the discretion of the Investigator.
  • At the end of Month 9, subjects who maintain/achieve CR with no evidence of MRD will continue to receive AZT (± IFN-alfa) for 3 more months, to Month 12. Those with MRD (without clinical evidence of disease progression or clinical evidence of ATLL) may also continue to receive AZT (± IFN-alfa) for 3 more months to Month 12 OR be removed from the study at the discretion of the Investigator.
  • Up to 20 subjects are expected to be enrolled. Correlative evaluations will also be performed at specified visits.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Belinostat as Consolidation Therapy With Zidovudine for Adult T-Cell Leukemia-Lymphoma
Actual Study Start Date : December 12, 2016
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : November 2021


Arm Intervention/treatment
Experimental: Belinostat + Zidovudine
Belinostat + Zidovudine (AZT) in combination as consolidation therapy, followed by standard zidovudine (AZT)-based maintenance therapy with optional Interferon-Alfa-2b (IFNalfa-2b) or Pegylated Interferon-Alfa-2b (PEG-IFN-alfa-2b)
Drug: Belinostat
Belinostat will be administered as 1,000 mg/m2 IV infusion over 30 minutes on Days 1- 5 every 21 days (Exception as per FDA-approved Package Insert: In patients known to be homozygous for the UGT1A1*28 allele, the starting belinostat dose must be 750mg/m2) for up to 8 cycles.
Other Names:
  • PXD101
  • Beleodaq®

Drug: Zidovudine
Zidovudine shall be administered in the outpatient setting as 300 mg tablets orally (PO), three times daily (TID) for 21 days on cycles 1 to 8, followed by maintenance therapy (+/- IFN-alfa) up to the end of Month 12.
Other Name: AZT

Drug: Interferon-Alfa-2b
OPTIONAL: For subjects receiving interferon therapy at baseline, continue Interferon alfa-2b 5 million IU daily or pegylated interferon alfa-2b 1.5 μg/kg once weekly, subcutaneously (SQ) for up to 12 months.
Other Name: IFN-α-2b

Drug: Pegylated Interferon-Alfa-2b
OPTIONAL: For subjects receiving interferon therapy at baseline, continue Interferon alfa-2b 5 million IU daily or pegylated interferon alfa-2b 1.5 μg/kg once weekly, subcutaneously (SQ) for up to 12 months.
Other Name: PEG-IFN-α-2b




Primary Outcome Measures :
  1. Rate of Participants achieving Complete Molecular Response (CMR) [ Time Frame: From End of Cycle 3 to End of Maintenance Therapy, Up to 12 Months ]
    Rate of participants achieving Complete Molecular Response after receiving protocol therapy. Complete Molecular Response (CMR) is defined as no evidence of disease at any body sites AND the disappearance of malignant clone(s), as proven by negative T-cell receptor gene rearrangement studies of peripheral blood DNA. Molecular response will be evaluated based upon T-cell clonality studies to be conducted while subjects are on Belinostat, and while subjects are receiving AZT-based maintenance treatment (after Belinostat completion).

  2. Rate of Participants Experiencing Treatment-Related Toxicity [ Time Frame: Up to 30 Days after the last dose of protocol therapy ]
    To determine the safety of adding Belinostat to AZT-based regimen as consolidation therapy for ATLL. Rate of participants experiencing adverse events/toxicities related to protocol therapy.

  3. Proportion of Participants with Minimal Residual Disease (MRD) [ Time Frame: From End of Cycle 3 to End of Maintenance Therapy, Up to 12 Months ]
    The proportion of subjects with minimal residual disease (MRD) will also be reported. Minimal Residual Disease (MRD) is defined as the presence of malignant clone(s) as determined by negative T-cell receptor gene rearrangement studies of peripheral blood DNA.


Secondary Outcome Measures :
  1. Rate of Participants Achieving Clinical Response [ Time Frame: Up to 12 months ]

    Rate of participants achieving complete response (CR) or partial response (PR) to protocol therapy. Response is assessed on the basis of clinical, radiologic, molecular and pathologic (i.e.

    bone marrow) criteria.


  2. Rate of Failure-Free Survival (FFS) [ Time Frame: Up to 12 months ]
    Rate of Failure-Free Survival in participants receiving protocol therapy. FFS is defined as the time from study treatment initiation until documented disease progression, relapse after response or death (by any cause, in the absence of progression). In the failure-free subjects, FFS will be censored at the last documented date of failure-free status.

  3. Rate of Overall Survival (OS) [ Time Frame: Up to 12 months ]
    Rate of overall survival (OS) in participants receiving protocol therapy. OS is defined as the elapsed time from study treatment initiation to death or date of censoring. Subjects alive or those lost to follow-up will be censored at the last date known to be alive.

  4. Investigation of whether Belinostat disrupts HTLV-1 latency in vivo [ Time Frame: Baseline, at the end of Cycles 3 and 8 (each cycle is 21 days), and end of Months 9 and 12 of protocol therapy. About 13 months ]
    Serial blood samples will be collected from participants for immunologic assays as well as molecular evaluations and analysis of ATLL and HTLV-1 clones. Investigators will report the proportion of patients exhibiting a cytotoxic T-cell response upon treatment with belinostat in vivo, or specific molecular alterations from correlative studies, and correlate with response using two-sample t-test.

  5. Determination of whether Belinostat provokes an immune or cytotoxic T-cell response load in vivo [ Time Frame: Baseline, at the end of Cycles 3 and 8 (each cycle is 21 days), and end of Months 9 and 12 of protocol therapy. About 13 months. ]
    Serial blood samples will be collected from participants for immunologic assays as well as molecular evaluations and analysis of ATLL and HTLV-1 clones. Investigators will report the proportion of patients exhibiting a cytotoxic T-cell response upon treatment with belinostat in vivo, or specific molecular alterations from correlative studies, and correlate with response using two-sample t-test.

  6. Determination of impact of belinostat/AZT (+/- IFNα) on HTLV-1 proviral load as a measure of HTLV-1 infected reservoirs in vivo. [ Time Frame: Baseline, at the end of Cycles 1, 3 and 8 (each cycle is 21 days); and End of Months 9 and 12 of protocol therapy. About 13 months ]
    Serial blood samples will be collected from participants for immunologic assays as well as molecular evaluations and analysis of ATLL and HTLV-1 clones. Investigators will report the proportion of patients exhibiting a cytotoxic T-cell response upon treatment with belinostat in vivo, or specific molecular alterations from correlative studies, and correlate with response using two-sample t-test.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically or cytologically documented adult T-cell leukemia/lymphoma (ATLL) with the following characteristics:

    • any stage of disease,
    • aggressive leukemic types (unfavorable chronic or acute)
    • initial absolute lymphocytosis ≥ 4.0 cells/mm3 upon initial disease presentation, and
    • documented presence of ATLL cells in peripheral blood by either morphology, histology, flow cytometry or gene rearrangement studies
  2. One of the following: Received prior AZT/IFNα therapy for ≥2 weeks and achieved at least partial hematological response defined as > 50% reduction in absolute lymphocyte count) without evidence of new disease lesions or disease progression (defined as 50% increase in measurable disease from nadir as in section 14.5 if imaging is performed) at the time of enrollment; OR; Received chemotherapy for ≥ 2 weeks duration, followed by at least a partial hematologic response ((defined as > 50% reduction in absolute lymphocyte count), and without evidence of new disease lesions or disease progression (defined as 50% increase in absolute lymphocyte count or measurable disease from nadir as specified in section 14.5 if imaging is performed) at the time of enrollment.
  3. Presence of residual ATLL based on morphology, histology, flow cytometry, or T-cell clonality in peripheral blood at the time of enrollment.
  4. Documented Human T-cell lymphotropic virus type 1 (HTLV-1) infection: Documentation may be serologic assay (ELISA) confirmed by Western blot or polymerase chain reaction (PCR).
  5. Measurable or evaluable disease, including presence of molecular disease as evidence by T-cell clonality detected by gene rearrangement studies.
  6. 18 years of age or older.
  7. Karnofsky performance status (KPS) ≥ 50% or Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3
  8. Patients must have adequate end organ and bone marrow function as defined below:

    • absolute neutrophil count (ANC)≥ 1,000 cells/mm3 [Exception: Unless cytopenias are secondary to ATLL]
    • platelets (PLT) ≥ 50,000 cells/mm3 [Exception: Unless cytopenias are secondary to ATLL]
    • Adequate hepatic function:

      • transaminase ≤ 2.5 the institutional upper limit of normal (ULN),
      • total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN), [Exception: Unless secondary to hepatic infiltration with lymphoma. If the elevated bilirubin is felt to be secondary to Indinavir or Atazavinir therapy (or anti-HIV medications), patients will be allowed to enroll.]
    • Creatinine clearance (CrCl) ≥ 40 mL/min, [Exception: Unless secondary to renal involvement by lymphoma.]
  9. Patients who are human immunodeficiency virus positive (HIV+) are also eligible.
  10. Females of childbearing potential (CBP) must have a negative serum pregnancy test within one week of enrollment. Women should avoid pregnancy while receiving study treatment. Males and females must agree to use adequate birth control during participation in this trial and for 3 months after completing therapy.
  11. Patients receiving erythropoietin or Granulocyte-colony stimulating factor (G-CSF) from baseline are eligible.
  12. Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

  1. Patients with progressive disease (after previous chemotherapy or AZT/IFNα) at the time of enrollment.
  2. Patients with lymphomatous, chronic leukemia with favorable features, or smoldering type ATLL (for definition of ATLL subtypes see Appendix H).
  3. Patients receiving any other investigational agents within 14 days prior to initiation of study therapy. (Exception: Patients actively receiving IFN-alfa-2b or PEG-IFN-alfa-2b are permitted).
  4. Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that are likely in the judgment of the Investigator(s) to interfere or limit compliance with study requirements/treatment.
  5. Pregnant or breast-feeding women.
  6. Known hypersensitivity to histone deacetylases (HDACs), zidovudine, belinostat or any component of the formulation(s).
  7. Autoimmune or viral hepatitis or decompensated liver disease unless due to lymphoma.
  8. 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.
  9. Known New York Heart Association (NYHA) Class 3 or 4 heart disease as per Appendix D.
  10. Known ejection fraction < 45% or institutional limit of normal range
  11. Psychological, familial, sociological or geographical conditions likely in the judgment of the Investigator(s) to interfere or limit compliance with study requirements/treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02737046


Locations
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United States, Florida
University of Miami Recruiting
Miami, Florida, United States, 33136
Contact: Juan C Ramos, MD    305-243-6611    jramos2@med.miami.edu   
Principal Investigator: Juan C Ramos, MD         
Sponsors and Collaborators
University of Miami
Investigators
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Principal Investigator: Juan C Ramos, MD University of Miami

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Responsible Party: Juan C. Ramos, Associate Professor, University of Miami
ClinicalTrials.gov Identifier: NCT02737046     History of Changes
Other Study ID Numbers: 20150567
First Posted: April 13, 2016    Key Record Dates
Last Update Posted: June 5, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Juan C. Ramos, University of Miami:
Adult T-cell Leukemia-Lymphoma
ATLL
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, Lymphoid
Interferons
Interferon-alpha
Interferon alpha-2
Zidovudine
Peginterferon alfa-2b
Belinostat
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Anti-Retroviral Agents
Anti-HIV Agents
Histone Deacetylase Inhibitors