Clinical Trials /

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

NCT02737046

Description:

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

Related Conditions:
  • Adult T-Cell Leukemia/Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Belinostat Therapy With Zidovudine for Adult T-Cell Leukemia-Lymphoma
  • Official Title: A Phase II Trial of Belinostat as Consolidation Therapy With Zidovudine for Adult T-Cell Leukemia-Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 20150567
  • NCT ID: NCT02737046

Conditions

  • Adult T-cell Leukemia-Lymphoma
  • ATLL

Interventions

DrugSynonymsArms
BelinostatPXD101, Beleodaq®Belinostat + Zidovudine
ZidovudineAZTBelinostat + Zidovudine
Interferon-Alfa-2bIFN-α-2bBelinostat + Zidovudine
Pegylated Interferon-Alfa-2bPEG-IFN-α-2bBelinostat + Zidovudine

Purpose

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

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' 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 NF-κB, and increases apoptosis in the presence
      of AZT.
    

Trial Arms

NameTypeDescriptionInterventions
Belinostat + ZidovudineExperimentalBelinostat + 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)
  • Belinostat
  • Zidovudine
  • Interferon-Alfa-2b
  • Pegylated Interferon-Alfa-2b

Eligibility 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 zidovudine/interferon -alfa therapy (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 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.

          6. 18 years of age or older.

          7. Karnofsky performance status (KPS) ≥ 50% or Eastern Cooperative Oncology Group (ECOG)
             performance status ≤ 2

          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. New York Heart Association (NYHA) Class 3 or 4 heart disease as per Appendix D.

         10. Ejection fraction < 50%

         11. Psychological, familial, sociological or geographical conditions likely in the
             judgment of the Investigator(s) to interfere or limit compliance with study
             requirements/treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of Participants achieving Complete Molecular Response (CMR)
Time Frame:Up to 12 Months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Rate of Participants Achieving Clinical Response
Time Frame:Up to 12 months
Safety Issue:
Description: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.
Measure:Rate of Failure-Free Survival (FFS)
Time Frame:Up to 12 months
Safety Issue:
Description: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.
Measure:Rate of Overall Survival (OS)
Time Frame:Up to 12 months
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Miami

Trial Keywords

  • Adult T-cell Leukemia-Lymphoma
  • ATLL

Last Updated

April 5, 2017