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

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.

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.