A Phase II Trial of Belinostat as Consolidation Therapy With Zidovudine for Adult T-Cell Leukemia-Lymphoma
Phase: PHASE2
Conditions: Adult T-cell Leukemia-Lymphoma, ATLL
Sponsor: University of Miami

1
EProst # 20150567
A Phase II Trial of Belinostat as Consolidation Therapy with Zidovudine for 
Adult T-Cell Leukemia-Lymphoma (ATLL)
VERSION #
9.0
VERSION DATE
4 December, 2025
NCT#
NCT02737046
PRINCIPAL INVESTIGATOR (PI)
Juan Carlos Ramos, MD
Professor of Clinical Medicine
Division of Hematology
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Confidentiality Statement: The information contained in this document, especially unpublished 
data, is confidential property.  The information in this document may not be disclosed to others 
unless federal or state law or regulations require such disclosure.  Subject to the foregoing, this 
information may be disclosed only to those persons involved in the study who have a need to 
know, with the obligation not to further disseminate this information.
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CONTACT INFORMATION
PRINCIPAL 
INVESTIGATOR
Juan Carlos Ramos, MD
Professor of Clinical Medicine
SUB-
INVESTIGATOR(S)
Thomas Harrington, MD Assistant
Professor of Clinical Medicine
 
Georgios Pongas, MD
Assistant Professor of Clinical Medicine
 
STATISTICIAN
Isildinha M. Reis, DrPH
Research Professor 
COLLABORATOR(S)
Jennifer Chapman, 
M.D.
UMH Department 
of Pathology
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Hilda B. Ye, Ph.D.
Department of 
Cell Biology
Albert Einstein 
College of 
Medicine, NY
Anne Van den 
Broeke
University of 
Liege, Belgium
CLINICAL TRIAL 
MANAGEMENT
Clinical Research Services (CRS)
 
FUNDING SOURCE
University of Miami
Miller School of Medicine
Sylvester Comprehensive Cancer Center (SCCC)
Regulatory Sponsor
Juan Carlos Ramos, MD
Funding Source(s)
Sylvester Comprehensive Cancer Center
Investigational Agent(s)
Acrotech Bioharma:
Belinostat (Beleodaq®)
Other Agent(s)
Commercial Supplies: 
Zidovudine (AZT or Retrovir®)
IFN-alfa-2b (Intron A®)
PEG-IFN-alfa-2b (Pegintron®)
IND Status
IND #: Exempt
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Spectrum IND #:070789
Participating 
Sites/Institutions – if 
multicenter study 
coordinated by UM/SCCC
PI’s name
Site’s role
Choose an item.
Choose an item.
Choose an item.
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INVESTIGATOR AGREEMENT
I confirm that I have read this protocol, I understand it, and I will work according to this 
protocol and to the ethical principles stated in the latest version of the Declaration of 
Helsinki, the applicable ICH guidelines for good clinical practices, and the applicable 
federal, state, and local laws, rules, and regulations relating to the conduct of the protocol.
I have read and understand the information in the Investigators’ Brochure (and/or other such 
pertinent safety information) regarding the risks and potential benefits.
I agree to inform all those who assist/collaborate with me in the conduct of this study of 
their responsibilities and obligations.
Once the protocol has been reviewed and approved by the Institutional Review Board (IRB) 
I understand that any change(s) made during the course of the study must also (first) be 
approved by the IRB prior to implementation, except when such modification is made to 
remove any immediate hazard(s) to the subject(s).
I certify that I and the study staff responsible have received the requisite training to conduct 
this research protocol.
I agree to maintain adequate and accurate records in accordance with the University of 
Miami policies, federal, state and local laws and regulations.
I agree to maintain the confidentiality of all information received and/or developed in 
connection with this protocol.
eProst Number:
Protocol Version Number: 9.0
Protocol Version Date: 
4 December, 2025
Signature of Investigator:
Date:
Name of Investigator (printed):
Institution:
TABLE OF CONTENTS
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CONTACT INFORMATION .........................................................................................................3
TABLE OF CONTENTS ................................................................................................................6
ABBREVIATIONS & DEFINITIONS .........................................................................................11
PROTOCOL SYNOPSIS ..............................................................................................................12
PROTOCOL SCHEMA.................................................................................................................17
1.0
BACKGROUND ................................................................................................................18
1.1
Study Disease..................................................................................................................18
1.2
HTLV-1 Endemic Regions and Affected Populations....................................................18
1.3
Treatment of ATLL.........................................................................................................18
1.4
HDAC Inhibitors in ATLL .............................................................................................19
1.5
Clinical Experience with HDAC Inhibitors in ATLL.....................................................20
1.6
Investigational Agent: Belinostat....................................................................................21
1.7
Preclinical Efficacy of Belinostat in ATLL ....................................................................22
.........................................................................................................................................23
1.8
Study Rationale...............................................................................................................23
1.9
Correlative Studies..........................................................................................................25
2.0
OBJECTIVES.....................................................................................................................26
2.1
Primary Objectives..........................................................................................................26
2.2
Secondary Objectives......................................................................................................26
2.3
Exploratory Objectives ...................................................................................................26
3.0
ENDPOINTS ......................................................................................................................26
3.1
Primary endpoints ...........................................................................................................26
3.2
Secondary endpoints .......................................................................................................27
3.3
Exploratory endpoints.....................................................................................................28
4.0
SUBJECT RECRUITMENT & SCREENING ..................................................................28
5.0
PATIENT SELECTION.....................................................................................................28
5.1
Inclusion Criteria.............................................................................................................28
5.2
Exclusion Criteria ...........................................................................................................29
6.0
Enrollment Procedures........................................................................................................30
6.1
Cancellation Guidelines ..................................................................................................30
6.2
Emergency Registration..................................................................................................30
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7.0
STUDY DESIGN ...............................................................................................................31
8.0
TREATMENT PLAN.........................................................................................................31
8.1
Zidovudine (AZT)...........................................................................................................32
8.2
Belinostat ........................................................................................................................32
8.3
Interferon alfa-2b (IFN-α-2b) or pegylated interferon alfa-2b (PEG-IFN-α-2b) or other 
forms of IFN-alfa that become commercially available to replace existing preparations or 
those preferred by patient’s insurance. .....................................................................................32
8.4
Lymphodepletion therapy: A one-time administration of standard low dose 
cyclophosphamide (up to 375 mg/m2) will be permitted during cycle 1 after Day 5 belinostat to 
treat any increase in absolute lymphocyte count, which may occur transiently during cycle 1 
after belinostat, possibly due to re-activation of HTLV-1, based on early trial observations. ..33
8.5
Treatment Schema...........................................................................................................34
8.6
Treatment Dispensation, Compliance and Accountability .............................................35
8.7
Supportive Care Guidelines ............................................................................................36
8.8
Duration of Treatment.....................................................................................................36
8.9
Duration of Follow-Up....................................................................................................36
9.0
TREATMENT/ DOSE MODIFICATIONS.......................................................................37
9.1
Dose Modification Guidelines ........................................................................................37
10.0
TREATMENT DISCONTINUATION ..............................................................................39
11.0
SCHEDULE OF CLINICAL & LABORATORY EVALUATIONS................................40
11.1
Pre-Treatment Evaluations (Screening)..........................................................................40
11.2
Evaluations on Treatment ...............................................................................................42

Complete physical examination: includes neurologic examination, careful measurement of 
all palpable peripheral lymph nodes and measurement of other sites of disease present on 
physical examination including skin. Palpable lymph nodes or masses should be measured in at 
least two dimensions......................................................................................................................42

ECOG or Karnofsky performance score (Appendix C) .........................................................42

Vital signs (HR, BP, RR, and oral temp) ...............................................................................42

Weight ....................................................................................................................................42

ECOG or Karnofsky performance score (Appendix C) .........................................................43
11.3
Off-Treatment Evaluations (Early Discontinuation not due to disease progression, End 
of Treatment or EOT visit).........................................................................................................45
11.4
Follow-up Evaluations ....................................................................................................46
11.5
Calendar of Clinical and Laboratory Evaluations...........................................................46
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12.0
SCHEDULE OF CORRELATIVE EVALUATIONS .......................................................49
12.1
Pre-Treatment Specimen Collection (Screening) ...........................................................49
12.2
On Treatment Specimen Collection................................................................................49
12.3
Off-Treatment Specimen Collection (End of Treatment or EOT visit)..........................50
12.4
Calendar of Specimen Collection for Correlative Studies..............................................50
13.0
MEASUREMENT OF EFFECT ........................................................................................51
13.1
Response Assessment .....................................................................................................51
13.2
Complete Response (CR)................................................................................................52
13.3
Partial Response (PR) .....................................................................................................53
13.4
Stable Disease (SD) ........................................................................................................53
13.5
Progressive Disease (PD, non-responders) .....................................................................53
13.6
Recurrent Disease ...........................................................................................................54
13.7
Time to Response............................................................................................................54
13.8
Time to progression ........................................................................................................54
14.0
ADVERSE EVENTS..........................................................................................................54
14.1
Purpose............................................................................................................................54
14.2
Adverse Event.................................................................................................................55
14.3
Serious Adverse Events (see also Appendix A)..............................................................56
14.4
Adverse Event Collection Period....................................................................................56
14.5
Adverse Event Reporting Requirements.........................................................................57
14.6
Expedited Adverse Event Reporting Requirements........................................................58
15.0
STATISTICAL CONSIDERATIONS ...............................................................................58
15.1
Overview.........................................................................................................................58
15.2
Definitions.......................................................................................................................58
15.3
Sample Size.....................................................................................................................59
15.4
Statistical Analyses .........................................................................................................60
16.0
DATA REPORTING..........................................................................................................61
16.1
Data and Safety Monitoring............................................................................................61
16.2
Early Stopping Rules (for Interim Monitoring of Toxicity) ...........................................61
16.3
Interim Review of Safety Data (Role of the Research Team) ........................................62
16.4
Study Termination...........................................................................................................63
17.0
STUDY MONITORING ....................................................................................................63
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18.0
INVESTIGATOR RESPONSIBILITIES...........................................................................63
18.1
Investigator Responsibility/Performance........................................................................63
18.2
Confidentiality ................................................................................................................63
18.3
Informed Consent and Permission to Use Protected Health Information.......................64
18.4
Source Documentation and Investigator Files ................................................................64
18.5
Recording and Processing of Data..................................................................................64
18.6
Non-Protocol Research ...................................................................................................65
18.7
Ethics...............................................................................................................................65
18.8
Essential documents for the conduct of a clinical trial ...................................................65
APPENDIX A: EXPEDITED ADVERSE EVENT (AE) REPORTING REQUIREMENTS......69
APPENDIX B: PERFORMANCE STATUS SCALES ................................................................69
APPENDIX C: NYHA CLASSIFICATION OF HEART DISEASE...........................................71
APPENDIX D: INFORMATION ON POSSIBLE DRUG INTERACTIONS.............................72
APPENDIX E: IMMUNOLOGIC ASSAYS ................................................................................74
APPENDIX F: MOLECULAR EVALUATION/ ANALYSIS OF ATLL AND HTLV-
1+CLONES....................................................................................................................................75
APPENDIX G: DEFINITION OF CLINICAL SUBTYPES OF ATLL.......................................77
APPENDIX H: PATIENT DOSING DIARY ...............................................................................78
APPENDIX I: BIOBANKING CONSIDERATIONS ..................................................................80
APPENDIX J: AGENTS (DRUG FORMULATION AND PROCUREMENT)..........................83
APPENDIX K: AGENTS (DRUG FORMULATION AND PROCUREMENT) ........................84
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ABBREVIATIONS & DEFINITIONS
Term
Abbreviation
Definition
Failure-free Survival 
FFS
The length of time from the start of treatment 
for a disease until documented disease 
progression, relapse after response or death 
from any cause. 
Overall Survival
OS
The length of time from either the date of 
diagnosis or the start of treatment for a disease, 
that patients diagnosed with the disease are still 
alive.
Progression-Free Survival
PFS
The length of time during and after the 
treatment of a disease that a patient lives with 
the disease but it does not get worse.
Time to Progression
TTP
The length of time from the date of the start of 
treatment for a disease until the disease starts to 
get worse or spread to other parts of the body.
Reference: National Cancer Institute (NCI) Dictionary of Cancer 
Termshttp://www.cancer.gov/dictionary
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PROTOCOL SYNOPSIS
Protocol Title
A phase II trial of belinostat as consolidation therapy with zidovudine for 
adult T-cell leukemia-lymphoma (ATLL).
Targeted 
Patient 
Population
• Presence of residual ATLL based on morphology, histology, flow cytometry 
or morphology, or T-cell clonality by gene rearrangement studies in peripheral 
blood (at the time of enrollment)
AND
• Treatment with prior chemotherapy or other antineoplastic agents ≥ 2 weeks 
prior to enrollment with the exception of dose-reduced vincristine/and or 
cyclophosphamide, or high dose steroids, administered for cytoreductive 
purpose. (Note: Continuation of zidovudine and interferon therapy is allowed)
Study Design
This is an open-label, single arm, phase II study using belinostat/AZT in 
combination as consolidation therapy followed by standard zidovudine 
(AZT)-based maintenance therapy with optional interferon-alfa-2b (IFN-alfa-
2b) or pegylated interferon-alfa-2b (PEG-IFN-alfa-2b) during the study. For 
subjects receiving interferon therapy at baseline, the corresponding 
commercially available interferon, for example IFN-alfa-2b at 5 million IU 
daily or PEG-IFN-alfa-2b at 1.5 μg/kg once weekly (rounded up to the closest 
commercially available individual vial/syringe preparation), or newer forms of 
pegylated interferon that become available at the recommended package insert 
doses, may be continued. Subjects will receive 8 cycles of belinostat treatment 
combined with AZT (± IFN-alfa or PEG-IFN-alfa). Thereafter subjects may 
receive additional AZT (± IFN-alfa) for 6 more months, depending on 
response assessments.
Treatment 
Schema (see 
also Section 
8.6.1 for 
Concurrent 
Medications/ 
Measures)
Regimen Description
Agent
Premedication; 
Precautions
Dose
Route Schedule
Cycle 
Length
BelinostatA
see Appendix E
1,000 
mg/m2(or 750 
mg/m2B)
IV 30 
min 
Days 1-5 
x 
8 cycles
21 
days
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Zidovudine 
(AZT)A
see Appendix I
300mg tablet
PO
Three 
times 
daily, or 
continue 
dose given 
prior to 
enrollment
(OPTIONAL) 
IFN-alfa-2b 
or
(for subjects 
already 
receiving IFN)
5 million IU
SQ
Once 
daily
PEG-IFN-
alfa-2b
(for subjects 
already 
receiving PEG-
IFN)
1.5 μg/kg 
(rounded up 
to the closest 
commercially 
available 
dosing 
preparation), 
or dose 
recommended 
by package 
insert for 
pegylated 
interferon 
substitutes 
that become 
commercially 
available
SQ 
Once 
weekly
A Zidovudine must be administered (for patients who are AZT-experienced, as 
well as for patients who are AZT-naïve) at least 24-hours prior to the first 
dose (i.e. 24-hours before C1D1) of belinostat
BAs per FDA-approved Package Insert: In patients known to be homozygous 
for the UGT1A1*28 allele, the starting belinostat dose must be 750mg/m2
Duration of 
Treatment
Approximately six months of belinostat/AZT (+/-IFN-alfa-2b) with an 
additional six months of maintenance AZT (+/-IFN-alfa-2b) for at least 1 year 
of treatment on-study. After this, subjects who enter a complete molecular 
response (CMR) may stop maintenance AZT (+/-IFN-alfa-2b) or continue 
standard maintenance AZT +/- IFN-alfa-2b at the discretion of the treating 
physician. Those with molecular evidence of residual disease may continue 
standard maintenance AZT +/- IFN-alfa-2b at the discretion of the treating 
physician, or be removed from the study at the discretion of the treating 
physician.
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Follow-up 
Required Post-
Treatment
All subjects will be followed at approximately 30-days (+/-7 days) after the 
last dose of study treatment.
Subjects who complete one year [i.e. 8 cycles of belinostat/AZT plus 6 
months of AZT (±IFN-alfa-2b) maintenance] of study treatment will be 
followed every 3 months (+/-2 weeks) for a at least one year (up to month 24), 
with response assessment at months 18 and 24 (+/- 1 month). Survival data 
will be collected up to 5 years in all subjects. Those who stop therapy under 
protocol early and remain on the study will continue to be followed every 3 
months (+/-2 weeks) for a at least one year, and for failure-free survival for at 
least 12 months or until they receive a new different treatment, whichever 
occurs first; they may continue all protocol study-related assessments until 
disease progression or until initiation of new different treatment after being 
removed from the study .
Objectives
Primary Objectives:

To determine the complete molecular response (CMR) rate after adding 
belinostat as consolidation therapy for ATLL during AZT-based 
maintenance treatment.

To determine the safety of adding belinostat to AZT-based regimen as 
consolidation therapy for ATLL.
Secondary Objectives:

To evaluate the clinical response rates, minimum 1-year failure-free and 
overall survivals

To investigate whether belinostat disrupts HTLV-1 latency load in vivo

To determine whether belinostat provokes an immune or cytotoxic T-cell 
response in vivo

To determine the impact of belinostat/AZT (+/- IFNα) on HTLV-1 proviral 
load, a measure of HTLV-1 infected reservoirs, and clonal abundance in 
vivo.
Exploratory Objectives:

To study the molecular effects of belinostat on ATLL cells in vivo, 
including on histone acetylation, expression of HTLV-1 genes, including 
Tax and HTLV-1 basic zipper factor (HBZ), and cellular genes and 
proteins that can be affected. To bank available baseline ATLL specimens 
in order to perform genomic studies including next generation RNA and 
exome sequencing, or future technologies that become available, which 
may help identify putative biomarkers that can predict treatment response 
and disease outcome.
Expected 
Number of 
Subjects
A minimum of 10 (as long as primary end point is reached) or maximum of 
20
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Expected 
Number of 
Centers
Sylvester Comprehensive Cancer Center
Note: SCCC is inclusive of the constituent satellite sites.
Expected 
Duration of the 
Protocol
Expected time to complete accrual is 5 years.  Expected time to study 
completion is approximately 6 years from date of first enrollment.
Inclusion 
Criteria
1. Histologically or cytologically documented adult T-cell 
leukemia/lymphoma (ATLL) with the following characteristics (for 
definition of ATLL subtypes see Appendix H):

Any stage of disease

Aggressive types (except smoldering or chronic type with favorable 
features, i.e. normal LDH)

Documented presence of ATLL cells in peripheral blood by either 
morphology, histology, flow cytometry or gene rearrangement studies 
Received chemotherapy or antineoplastic drug treatment ≥ 2 weeks prior to 
enrollment with the exception of dose-reduced vincristine/and or 
cyclophosphamide, or high dose steroids, administered for cytoreductive 
purpose. (Note: Continuation of zidovudine and interferon therapy is 
allowed.)
2. Presence of residual ATLL in peripheral blood either by morphology, 
histology, flow cytometry or gene rearrangement studies (T-cell clonality) 
during screening prior to enrollment.
3. Documented HTLV-1 infection: Documentation may be serologic assay 
(ELISA) confirmed by Western blot or polymerase chain reaction (PCR). 
4. Measurable or evaluable clinical or molecular disease, which may only be 
detected by flow cytometry or T-cell clonality (gene rearrangement 
studies).
5. 18 years of age or older.
6. Karnofsky performance status (KPS) ≥ 50% or ECOG performance status 
≤ 3 (See Appendix C)
7. 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 x the institutional 
upper limit of normal, total bilirubin ≤ 1.5 x institutional upper limit of 
normal, [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 
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allowed to enroll.] Creatinine clearance (CrCl) ≥ 40 mL/min, unless 
secondary to renal involvement by lymphoma.
8. Patients who are human immunodeficiency virus positive (HIV+) are also 
eligible.
9. 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 methods of birth control during participation in this trial 
and for 3 months after completing therapy.
10. Patients receiving erythropoietin or G-CSF from baseline are eligible.
11. Ability to understand and willingness to sign a written informed consent 
document.
Exclusion 
Criteria
1. Patients with chronic leukemia with favorable features (normal LDH 
level), or smoldering type ATLL (for definition of ATLL subtypes see 
Appendix H).
2. Patients receiving any other investigational agents within 14 days prior to 
initiation of study therapy.  (Exception: Patients actively receiving IFN-
alfa-2b, PEG-IFN-alfa-2b, or similar commercially available substitutes 
are permitted).
3. 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. 
4. Pregnant or breast-feeding women.
5. Known hypersensitivity to histone deacetylases (HDACs), zidovudine, 
belinostat or any other component(s) of the formulation(s).
6.  Acute hepatitis or decompensated liver disease, unless due to lymphoma. 
Chronic hepatitis will be required to be on prophylactic treatment during 
the study if provided liver function test meet criteria listed above without 
evidence of cirrhosis induced by viral hepatitis, to be eligible.
7. 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.
8. Known NYHA Class 3 or 4 heart disease as per Appendix D.
9. Known history of cardiomyopathy with ejection fraction < 45% (or lower 
limit of institutional normal value) or uncontrolled arrhythmia.
10. Psychological, familial, sociological or geographical conditions likely in 
the judgment of the Investigator(s) to interfere or limit compliance with 
study requirements/treatment.
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17
PROTOCOL SCHEMA
Abbreviations: CR=Complete Response; MRD=Minimal Residual Disease; PR=Partial Response; PD=Progressive Disease
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18
1.0 BACKGROUND
1.1
Study Disease
Adult T-cell leukemia-lymphoma (ATLL) was first described as a distinct clinical entity in 
1979 and its association with the human T-cell leukemia virus type 1 (HTLV-1) was reported 
shortly thereafter (1). ATLL can present in multiple forms and is generally sub-classified 
into four subtypes (2). Lymphoma and acute ATLL are the two most aggressive variants 
where patients usually present with a high tumor burden and hypercalcemia. The chronic and 
smoldering forms of ATLL have a more indolent course, although they often progress to the 
more malignant forms of the disease (3).
Therapies available for ATLL, particularly for acute and lymphoma subtypes have 
demonstrated low clinical benefit. A large published retrospective series, which included 
over 800 Japanese patients with ATLL, show that the median survival times for acute and 
lymphomatous types were 6.2 and 10.2 months respectively regardless of treatment (2). With 
some of the most intensive chemotherapy regimens, complete response rates of ~35% or 
more have been reported (4, 5). Allogeneic bone marrow transplantation, including reduced-
intensity regimens, has been successful in a number of ATLL patients although severe 
immunodeficiency due to both the underlying disease and preparatory regimens poses a 
serious risk (6, 7). Even after stem cell transplant, the majority of patients succumb to their 
disease.
Newly developed investigational therapies include the use of monoclonal antibodies 
targeting T-cell receptor molecules, such as Tac (CD25) and CCR4 (8, 9). However, a benefit 
of adding these drugs in combination with chemotherapy has yet to be proven in randomized 
studies. Such agents are also expensive and not widely available in regions where HTLV-1 
is endemic, such as the Caribbean and South America.
1.2
HTLV-1 Endemic Regions and Affected Populations
HTLV-1 affects about 10-20 million people worldwide and is endemic in southwest Japan, 
sub-Saharan Africa, the Caribbean, and parts of South America, particularly Brazil and Peru 
(11). Miami in Florida (USA), due to its close proximity to the Caribbean, has a large 
population of immigrants from HTLV-1 endemic areas. African-American patients are also 
frequently diagnosed with ATLL at our institution (10). The University of Miami (UM) and 
affiliated hospitals represent outstanding resources for the study of HTLV-1 related diseases 
(12). ATLL patients are also frequently encountered in New York City (13).
1.3
Treatment of ATLL
1.3.1
Chemotherapy
ATLL is considered generally chemotherapy resistant, and the long-term outcome of 
patients with this disease is dismal. Clinical trials performed in the U.S. using standard 
aggressive chemotherapy have only yielded modest results. A phase II trial of 15 patients 
with aggressive ATLL treated with CHOP (cyclophosphamide, doxorubicin, vincristine 
and prednisone) in combination with daclizumab (a humanized anti-CD25 monoclonal 
antibody) resulted in OS of 10 months (14). Another phase II trial using EPOCH 
(etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) followed by AZT 
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plus interferon-alfa-2b (IFNα) as maintenance showed that a significant number of subjects 
progressed early during their treatment, and all patients eventually relapsed (15). At UM, 
we have recently completed the largest retrospective study of ATLL cases in the U.S. 
history to this date (12), and we have not observed any cures in any patients treated with 
conventional chemotherapy at our institution.
In Japan, a randomized phase III study of 188 patients demonstrated a trend to overall 
survival advantage favoring the ranimustine-containing chemotherapy regimen VCAP-
AMP-VECP over intensive CHOP (16). The complete response (CR) rate was higher in 
the VCAP-AMP-VECP arm as compared to biweekly CHOP (40% v 25%, respectively; 
p=0.020). Progression-free survival (PFS) at 1 year was 28% in the VCAP-AMP-VECP 
arm compared with 16% in the CHOP arm (p= 0.100, two-sided p = 0.200). Overall 
survival (OS) at 3 years was 24% in the VCAP-AMP-VECP arm and 13% in the CHOP 
arm (p= 0.085, two-sided P = 0.169). However, the VCAP-AMP-VECP was significantly 
more toxic resulting in universal neutropenia and 3 treatment-related deaths.
1.3.2
Zidovudine (AZT) Plus Interferon (IFNα) Therapy
Several phase II studies carried out outside of Japan, including at our center, have 
demonstrated that AZT/IFNα as induction followed by maintenance therapy can be 
efficacious as first line treatment in patients with leukemia-type ATLL (17-21). High 
response rates were noted in chemotherapy naïve with some patients achieving very 
prolonged responses. A recent meta-analysis suggests AZT/IFNα therapy may be superior 
to conventional chemotherapy for acute and chronic leukemic type ATLL in terms of 
overall survival (22). AZT/IFNα can have a major impact in extending survival in a subset 
of ATLL patients. At UM, we have observed that patients with aggressive ATLL who 
achieved a CR after AZT/IFNα therapy (n=16) had a significantly longer progression-free 
survival (PFS), as compared to those achieving a CR after conventional chemotherapy 
(n=35) (PFS= 48 months vs. 11 months respectively, p=0.003) (12). However, CR rate 
using AZT/IFNα was 24% in acute type ATLL and not significantly effective in 
lymphomatous type ATLL. The results of an international meta-analysis on AZT/IFNα as 
first-line therapy which were presented at the 13th International Conference on Human 
Retrovirology: HTLV and at the 49th Annual Meeting of the American Society of 
Hematology, showed strong promise as an option for the treatment of leukemic types of 
ATLL (23).  AZT/IFNα is now considered an acceptable first-line therapy option for ATLL 
per the latest National Comprehensive Cancer Network (NCCN) recommendation 
guidelines.
In summary, while chemotherapy or AZT-IFN can be effective in some patients with 
ATLL, response rates are suboptimal, and patients usually relapse and succumb to their 
disease. Therefore, new therapeutic approaches and strategies are urgently needed to treat 
ATLL.
1.4 HDAC Inhibitors in ATLL
HDAC inhibitors are broadly active agents in cancer treatment. Currently, three HDAC 
inhibitors (vorinostat/SAHA, romidepsin, and belinostat) are FDA-approved and clinically 
available for the treatment of relapsed cutaneous or peripheral T-cell lymphoma (PTCL). 
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The mechanism of action of HDAC inhibitors in activating the HTLV-1 promoter has been 
elucidated. Virtually all ATLL cells contain clonally integrated HTLV-1 provirus. The 
HTLV-1 promoter is regulated by histone deacetylases; histone acetylation results in 
HTLV-1 promoter activation (24). The HTLV-1 promoter is trans-activated by the HTLV-
1 protein Tax through binding of CREB and p300/CBP at the 5’LTR (25). Tax binding to 
p300/CBP promotes its histone acetyl transferase (HAT) activity resulting in chromatin 
unwinding and transcription of the viral genome (26). The p300/CBP-mediated HAT 
activity is countered by HDAC1, and by the HTLV-1 basic leucine zipper factor (HBZ), 
which binds CREB and p300/CBP thus displacing Tax (24, 25). The HBZ gene is 
transcribed from the 3’ end of the proviral genome, and unlike Tax, it is the only viral gene 
consistently expressed in ATLL (25). Overall, the effect of HDAC inhibitors is to promote 
the activation of the HTLV-1 provirus and expression of the viral genome.
1.5
Clinical Experience with HDAC Inhibitors in ATLL
The dual anti-neoplastic and HTLV-1 transcriptional activating role of HDAC inhibitors 
can be exploited in the treatment of ATLL. Selective induction of HTLV might allow the 
immune response under antiretroviral treatment (AZT) to clear HTLV-1 infection (27). A 
similar approach using the old generation HDAC inhibitor (HDI) valproic acid (VPA) in 
combination with AZT has been utilized in a primate (baboon) model infected with simian 
T-cell leukemia virus I (STLV-1), which is highly homologous and related to HTLV-1, to 
eradicate virus infected cells (28). 
1.5.1
Prospective Study using an HDAC Inhibitor in ATLL: University of Miami
We have recently conducted a pilot trial for aggressive ATLL incorporating the old 
generation HDAC inhibitor valproic acid (VPA) during AZT/IFNα maintenance therapy 
entitled “Prospective Study of the Molecular Characteristics of Sensitive and Resistant 
Disease in Patients with HTLV-1 Associated Adult T Cell Leukemia Treated with 
Zidovudine (AZT) Plus Interferon alpha-2b”. This study was designed to add VPA to 
AZT/IFN-α maintenance therapy after successful induction. We hypothesized that through 
HDAC inhibition, VPA would reactivate HTLV-I thus leading to an immune response 
against HTLV-1 and infected cells, thereby effectively eradicating blood circulating ATLL 
clones that normally persist after AZT/IFN-α (27). The interim results of this study were 
updated at the 2013 International Conference on HTLV-1 and Related Viruses conference 
(Montreal, Canada) (12), and the 2014 HTLV-1 European Research Network Conference 
(Rome, Italy). Results of this study have been reported at ClinicalTrials.gov (study 
identifier: NCT01964755). Thirteen subjects were accrued on this study (10 acute types, 
and 3 lymphomatous types with circulating ATLL cells). Of 12 subjects with evaluable 
responses, 3 patients received VPA that was added at Day 60 during maintenance therapy 
using AZT and pegylated-IFN; VPA was given for a maximum of 6 months. ACR was 
achieved in 4 patients, 2 of which received had achieved a partial response to AZT/IFN-α 
prior to starting VPA. One patient relapsed shortly after beginning VPA, while the addition 
of VPA resulted in clinical complete remission and decrease of HTLV-1 proviral load over 
time in two ATLL subjects, and a molecular remission in one subject (ATLL-84) based on 
disappearance of signal indicative of T-cell receptor gene rearrangement on serial 
multiplex PCR studies at months 6, 9, and 12 (Figure 1). This patient continued to be in 
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clinical remission for 4 years. In past experience we had not observed such effect in long-
term survivors treated with AZT/IFNα therapy alone (21).
Overall these data support the innovative notion that targeting ATLL with HDAC 
inhibitors under anti-retroviral therapy (i.e. AZT) treatment may eliminate ATLL clones 
and HTLV-1 infected reservoirs in vivo.
1.6
Investigational Agent: Belinostat
Belinostat is a pan-HDAC inhibitor that recently obtained accelerated approval in the U.S. 
for the treatment of relapsed/refractory PTCL based on efficacy and duration of response 
(29). The largest safety analysis of belinostat to date was conducted in the BELIEF trial 
(30). In this study, 120 evaluable patients with relapsed or refractory PTCL with platelets 
≥ 50,000/µL who had received a median of 2 prior therapies were treated with belinostat 
intravenously at 1000 mg/m2 on days 1-5 of a 3-week cycle schedule for a median of 2 
cycles. The overall response rate was 26% (CR = 10%; PR = 16%). The median time to 
response was 5.6 weeks, the median duration of response was 8.3 months, and the longest 
duration of response was 29.4 months. The most common grade ¾ adverse events were 
thrombocytopenia and neutropenia (13%), anemia (10%), dyspnea (6%), pneumonia (6%), 
and fatigue (5%). The authors concluded that belinostat was well tolerated in patients with 
Figure 1. Hematologic and molecular 
response of ATLL patient to AZT/IFN-α
therapy with valproic acid (VPA). Shows 
WBC plot over time and combined 
multiplex PCR analyses for acute ATLL 
patient (ATLL-84) during AZT/IFN-α 
therapy. Multiplex PCR studies were 
performed utilizing two sets of reaction 
primers including those specific to the V
1-8, 
V
9 and consensus J
1 and J
2 regions of β-
chain TCR genes (peaks on the right) or 
alternate J
1 and J
2 regions (peaks on the left) 
at the indicated dates (month/year). VPA 
was started on Day 60 (indicated by arrow 
on WBC plot). Positive and negative control 
multiplex 
PCR 
experiments 
using 
a 
monoclonal T-cell line and polyclonal T-
cells as indicated were performed on the 
same dates of the experiments indicated by 
the corresponding arrows ()



+ controls
- controls
Figure 1
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platelet counts less than 100,000/μL. Progressive disease was observed in 64% of patients, 
which was the major cause for drug discontinuation.
Belinostat is also active in other hematologic malignancies and in solid tumors. As of May, 
2015, a total of 34 clinical trials using belinostat alone or in combination with other 
chemotherapies were listed in ClinicalTrials.gov. At University of Miami, one patient with 
refractory ATLL was treated with intravenous belinostat at 1000 mg/m2 on days 1-5 with 
daily oral AZT at a maximum dose of 600 mg twice daily. After four 3-week cycles, this 
patient tolerated treatment well and had an objective response in skin disease (unpublished 
data). The patient experienced no side effects to belinostat/AZT and no hematologic 
toxicity was observed. Based on this experience, belinostat appeared to be clinically safe 
in combination with the antiviral drug zidovudine.
1.7
Preclinical Efficacy of Belinostat in ATLL
ATLL is challenging to study in part due to the lack of suitable pre-clinical models. A 
well-known in vitro phenomenon is that ATLL cells express Tax immediately upon 
culture. Tax protein exerts wide cellular effects driving malignant growth in T-cells 
resulting in genetic instability and transformation through the interaction with pleotropic 
transcription factors such as NF-B (31-33). However, Tax is not significantly expressed 
in primary ATLL tumors, which often harbor a defective provirus (33). Unfortunately, 
most published work describing the biology of ATLL and drug therapeutic pre-clinical 
studies involve Tax+ cell lines and animal models (34). 
We tested the in vitro effects of belinostat on ATLL cells using a patient-derived low-
passage cell line (JEA) established from patient ATLL-84 in our laboratory. We found that 
belinostat caused H3 subunit acetylation in JEA cells (low Tax-expressing) inducing the 
expression of high levels of Tax, resulting in cell death using concentrations within the 
nanoMolar range that are well below those achievable in patients in a dose-dependent 
manner (Figure 2 A-C). Further, belinostat blocked the expression of the HTLV-1 basic 
zip factor (HBZ), which is transcribed from the 3’ end of the proviral genome, and 
therefore not subject to 5’LTR promoter regulation (Figure 3). Unlike Tax, HBZ the only 
viral gene consistently expressed in ATLL, and it is thought to play a major pathogenic 
role in ATLL, and to drive the propagation of latently infected reservoirs in patients (25). 
The belinostat-induced apoptosis was augmented by increasing doses of AZT that can be 
achieved in patients after oral administration (Figure 4). In JEA cells, the combination of 
IFN 2b, AZT, and belinostast separately, resulted in higher cell death (Figure 5A). 
However, an interesting observation we have made is that IFN may diminish the killing 
effects of bellinostat in long-established, interferon-resistant ATLL-derived cell lines and 
freshly isolated leukemic cells (ATLL-151 shown in Figure 5B). Based on these data and 
concepts, we proposed the use of belinostat with AZT for the treatment of ATLL after 
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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 (Figure 2). Further, belinostat blocks 
HBZ, a key viral protein that is essential for propagation of HTLV-1 infected clones and 
increases apoptosis in the presence of AZT (Figures 3, 4, and 5).
We propose to use belinostat in combination with AZT as consolidation therapy for the 
treatment of ATLL. Patients will receive standard maintenance AZT-based therapy (35). 
Patients who are receiving interferon-alfa 2b (IFN-α) or other similar forms of IFN-alfa 
available at baseline and demonstrate to have derived clinical benefit may continue the 
drug. As our pre-clinical data suggest that IFN-α decrease the killing effect of HDAC 
inhibitors in some cell lines and primary fresh ATLL isolates from patient samples 
(Figure 5), patients who have not received IFN-α pre-study will receive AZT only along 
with belinostat. 
Patients’ blood samples will be assessed for minimal residual disease (MRD) by T-cell 
clonality studies (multiplex PCR) and HTLV-1 proviral loads before, during, and after 
belinostat treatment using assays available at our collaborating laboratories. 
Table 1: UM laboratories participating in correlative studies
Investigator/ Collaborator 
Laboratory
Correlative Studie(s)
Hilda B. Ye,
, PhD
Immunologic and cytotoxic T-cell assays
Anne Van den Broeke, PhD
Clonal abundance studies
Jennifer Chapman, MD
Immunophenotyping studies on ATLL tumors, and 
TCR Gene Rearrangement(s) via multiplex PCR
Juan Carlos Ramos, MD
HTLV-1 proviral loads and reactivation, molecular 
evaluations of belinostat in ATLL
Correlative studies will include measuring HTLV-1 reactivation in peripheral blood T-
cells, assessing the cytotoxic T-cell response in vivo, and investigating the molecular 
effects of belinostat in ATLL cells in vivo. The clinicians involved in this study have a 
track record in treating ATLL and well-established clinics where patients will be 
followed closely. In this way, alternative therapies can be quickly offered to non-
responders (i.e. intensive chemotherapy, targeted therapies, or allogeneic bone marrow 
transplant when feasible). The study will be initiated at the University of Miami first and 
may be expanded to committed domestic sites in New York City and international sites 
contingent upon available funding in the future. An average of 8-15 new ATLL cases are 
encountered at the University of Miami (based on trend over last 5 years). Similar number 
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of ATLL cases are encountered at Memorial West Hospital (Pembroke Pines, FL) and in 
New York City Hospitals (i.e. Weil Cornell Medical College-affiliated Columbia 
Presbyterian Hospital, and Albert Einstein/Montefiore Medical Center). With the 
participation of any of these collaborating sites in the future, we expect to exceed accrual 
goals under strict eligibility criteria.
1.9
Correlative Studies
1.9.1
Eradication of ATLL clones and HTLV-1 infected reservoirs
We hypothesize that adding belinostat under anti-retroviral control will result in eradication of 
ATLL and HTLV-1 infected reservoirs. To test this hypothesis, patients will be assessed for 
minimal residual disease (MRD) at specified times during treatment (after cycles 3 and 8), and at 
the end of months 9, 12 using multiplex PCR for T-cell receptor gene rearrangements as used 
previously (36). Matching DNA samples will be preserved for measuring HTLV-1 proviral loads 
using single molecule droplet-based digital PCR before belinostat, during treatment (Day 15, after 
cycles 3 and 8), and at the end of months 9 and 12.
1.9.2
Evaluation of HTLV-1 reactivation and cytotoxic T-cell immune response in vivo
We hypothesize that through HDAC inhibition belinostat will reactivate HTLV-1 provirus in 
ATLL cells and infected T-cell reservoirs in subjects. The HTLV-1 protein Tax is highly 
immunogenic. Therefore, HTLV-1 reactivation should provoke a potent cytotoxic T-cell response 
against ATLL cells and other virus harboring cell reservoirs. To confirm this biological effect in 
vivo, CD4+ T-cell enriched peripheral blood mononuclear cells (PBMC’s) will be isolated before 
and within 48-72 hours after belinostat treatment initiation. Expression of HTLV-1 genes (Tax, 
gag, Pol) will be determined by single molecule droplet based digital RT-PCR. Cytotoxic T-cell 
lymphocyte (CTL) assays using isolated CD4+ T-cell enriched PBMC’s and HTLV-1 specific 
generated peptides will be performed before belinostat, at Day 8, and at the end of cycle 1 (Day 
21). CTL studies will be performed at Dr. Barber’s laboratory (37-41).
1.9.3
Molecular effects of belinostat in ATLL
We hypothesize that belinostat will exert its anti-neoplastic effects in ATLL cells through a variety 
of molecular mechanisms including the activation of silenced key cellular genes (i.e. cell cycle 
regulators and tumor suppressors), and suppression of HBZ, which is the only HTLV-1 protein 
that is consistently expressed in all ATLL tumors; this protein is thought to play a major role in 
HTLV-1 latency and propagation of immortalized clones. To investigate the molecular effects of 
belinostat we will isolate CD4+ T-cell from enriched PBMCs before and shortly after belinostat 
treatment initiation (48-72 hours). We will determine histone acetylation, HBZ and Tax mRNA 
and protein levels, and expression of various cellular genes affected by viral proteins or epigenetic 
effects of belinostat. These studies will be performed at UM Genomics Core facilities, and at 
Ramos and Barber laboratories.
1.9.4
Immunohistochemistry Studies on ATLL tumors
Immunohistochemistry studies for ATLL associated markers will be performed in collaboration 
with the hematopathology lab (Dr. Jennifer Chapman). ATLL important markers include, but are 
not limited to: CD25, CD30, and MUM-1. While the sample number of this clinical trial may not 
be powered to detect events significantly associated with disease subtype, phenotype, malignant 
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course, and treatment resistance, these studies will provide us with preliminary data to conduct 
further exploratory studies in future.
2.0 OBJECTIVES
2.1
Primary Objectives

To determine the complete molecular response (CMR) rate after adding belinostat as 
consolidation therapy for ATLL during AZT-based maintenance treatment.

To determine the safety of adding belinostat to AZT-based regimen as consolidation 
therapy for ATLL.
Note: Adverse event data regarding the use of AZT (+/- IFNα or PEG-IFNα) and 
belinostat as consolidation treatment will be collected in this study (as per NCI CTCAE 
version 4.03). Strict dose modification guidelines have been established for this protocol 
(Section 10.0).
2.2
Secondary Objectives

To evaluate the clinical response rates, and at minimum 1-year failure-free survival 
(FFS) and overall survival (OS)

To investigate whether belinostat disrupts HTLV-1 latency in vivo

To determine whether belinostat provokes an immune or cytotoxic T-cell response 
load in vivo

To determine the impact of belinostat/AZT (+/- IFNα) on HTLV-1 proviral load as a 
measure of HTLV-1 infected reservoirs, and clonal abundance in vivo.
2.3
Exploratory Objectives

To study the molecular mechanisms of belinostat on ATLL cells in vivo, including 
but not limited to determining its effects on histone acetylation, expression of HTLV-
1 genes including Tax and HTLV-1 basic zipper factor (HBZ), and expression of 
various cellular genes affected by viral proteins or epigenetic effects of belinostat.

To bank available baseline ATLL specimens in order to perform genomic studies 
including next generation RNA and exome sequencing to identify putative 
biomarkers that can predict treatment response and disease outcome.
3.0 ENDPOINTS
3.1
Primary endpoints
Complete Molecular Response (CMR): The proportion of subjects achieving CMR will 
be reported.  Complete Molecular Response (CMR) is defined as the disappearance of 
malignant clone(s), as proven by negative T-cell receptor gene rearrangement studies of 
peripheral blood DNA, and bone marrow if previously involved (see Section 14.0).
In addition 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. 
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Molecular response will be evaluated based upon T-cell clonality studies to be conducted 
at the end of cycles 3 and 8 while subjects are on or off belinostat, and at the end of 
months 9 and 12 while subjects are receiving no treatment, interferon-alfa, or standard 
AZT-based maintenance treatment (after belinostat completion).
Safety: Treatment-related adverse events (AEs) including serious adverse events (SAEs). 
AEs will be assessed by and assigned severity and treatment attribution using the 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCICTCAE), Version 4.03.
3.1.1
Evaluable for Molecular Response:

Eligible subjects who receive at least three (3) doses of belinostat (with AZT), 
have evaluable disease at baseline and at least one post-baseline molecular 
disease assessment.
3.1.2
Evaluable for Safety:

Eligible subjects who receive at least one dose of belinostat and AZT study 
treatment.
3.2
Secondary endpoints
Clinical Response: Clinical response per Section 14.0 will be evaluated during treatment 
by scheduled assessments.  The overall best clinical response rate is defined as the 
proportion of subjects with clinical complete response (CR) or partial response (PR). 
3.2.1
Evaluable for Clinical Response:

Eligible subjects, who receive at least one dose of belinostat and AZT study 
treatment, have evaluable disease at baseline and at least one post-baseline 
clinical disease assessment. 
1-year Failure-Free Survival (FFS): Subjects will be evaluated during treatment or by 
follow-up assessments post-treatment. 1-year 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. In patients who transfer out to 
to another institution of clinic, FFS data will be collected from existing medical records 
obtained from outside and communication with any treating physician.
1-year Overall Survival (OS): Follow-up for OS post initiation of treatment will occur 
every 3 months during year 1 under the proposed study. Survival data from existing 
medical records or telephone contact every 6 months for up to 5 years from treatment 
initiation or until death or withdrawal of consent from the study for the purpose of 
reporting trial result updates in the future. 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.
3.2.2
Evaluable for FFS and OS:

Eligible subjects who receive at least one dose of belinostat and AZT study 
treatment.
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3.3
Exploratory endpoints
Serial blood sampling at specified time points to describe the molecular and epigenetic 
actions of belinostat in combination with AZT.
3.3.1
Evaluable for Molecular, Biomarker& Genomic Studies:
Eligible subjects who receive at least one dose of belinostat and AZT study 
treatment and provide at least one sample of blood for molecular studies, and for 
banking left over material for future biomarker and genomic studies in the future. 
4.0 SUBJECT RECRUITMENT & SCREENING
Sites must have this protocol approved by their Institutional IRB before they may screen and 
enroll participants in the study.
Potential subjects will be recruited from investigators’ clinical practices.  The identification 
of subjects must protect the subjects’ privacy.  Privacy refers to persons and their interest in 
controlling the access of others to themselves.
Both men and women of all races and ethnic groups are eligible for this trial. Once a potential 
participant has been identified and the current version of Informed Consent Form has been 
signed by the potential participant or legally authorized representative (LAR), site Principal 
Investigator or Sub-Investigator must contact Dr. Juan Carlos Ramos to discuss the case. 
Relevant source documents including subject medical history and physical exam, previous 
and concomitant therapies/medications, admission or discharge notes, diagnostic reports, 
pathologic confirmation of diagnosis, and relevant subject-specific written communication, as 
applicable will be submitted to University of Miami Study Project Manager for Coordinating 
Center PI review. Confirmation of enrollment must be obtained prior to subject enrollment.
5.0 PATIENT SELECTION
5.1
Inclusion Criteria
5.1.1
Histologically or cytologically documented adult T-cell leukemia/lymphoma 
(ATLL) with the following characteristics (for definition of ATLL subtypes see 
Appendix H):

Any stage of disease,

Aggressive types (for definition of ATLL subtypes see Appendix H),

Documented presence of ATLL cells in peripheral blood by either morphology, 
histology, flow cytometry or gene rearrangement studies 
5.1.2
One of the following:
Initiated AZT/IFNα therapy prior or at the time of enrollment.
 OR 
          Received chemotherapy or other antineoplastic drug therapy ≥ 2 weeks prior to 
enrollment 
with 
the 
exception 
of 
dose-reduced 
vincristine/and 
or 
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cyclophosphamide, or high dose steroids, administered for cytoreductive purpose. 
(Note: Continuation of zidovudine and interferon therapy is allowed.)
5.1.3
Presence of ATLL based on morphology, histology, flow cytometry, or T-cell 
clonality in peripheral blood during screening period prior enrollment
5.1.4
Documented HTLV-1 infection: Documentation may be serologic assay (ELISA) 
confirmed by Western blot or polymerase chain reaction (PCR). 
5.1.5
Measurable 
or 
evaluable 
disease, 
including 
presence 
of 
ATLL 
by 
immunophenotyping from either histology or flow cytometry studies, or molecular 
disease as evidence by T-cell clonality detected by gene rearrangement studies.
5.1.6
18 years of age or older.
5.1.7
Karnofsky performance status (KPS) ≥ 50% or ECOG performance status ≤ 3 (See 
Appendix C)
5.1.8
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:  
o
transaminase ≤ 2.5 the institutional upper limit of normal (ULN), 
o
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 is suspected]
5.1.9
Patients who are human immunodeficiency virus positive (HIV+) are also eligible.
5.1.10 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.
5.1.11 Patients receiving erythropoietin or G-CSF from baseline are eligible.
5.2
Exclusion Criteria
5.2.1
Patients with progressive disease (after previous chemotherapy or AZT/IFNα) at 
the time of enrollment.
5.2.2
Patients with chronic leukemia with favorable features, or smoldering type ATLL 
(for definition of ATLL subtypes see Appendix H).
5.2.3
Patients receiving any other investigational agents within 14 days prior to initiation 
of study therapy. (Exception: Patients actively receiving IFN-alfa-2b, PEG-IFN-alfa-
2b, or similar forms of IFN-alfa are permitted).
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5.2.4
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.
5.2.5
Pregnant or breast-feeding women.
5.2.6
Known hypersensitivity to histone deacetylases (HDACs), zidovudine, belinostat 
or any component of the formulation(s).
5.2.7
 Acute hepatitis or decompensated liver disease unless due to lymphoma. Chronic 
hepatitis will be required to be on prophylactic treatment during the study if provided 
liver function test meet criteria listed above without evidence of cirrhosis to be eligible.
5.2.8
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.
5.2.9
Known NYHA Class 3 or 4 heart disease as per Appendix D.
5.2.10 Known ejection fraction < 45% or institutional limit of normal range
5.2.11 Psychological, familial, sociological or geographical conditions likely in the 
judgment of the Investigator(s) to interfere or limit compliance with study 
requirements/treatment.
6.0 Enrollment Procedures
Participating sites must first receive written permission from the Coordinating Center to 
enroll a participant. 
The following documents must be provided to the Coordinating Center and the Protocol 
Chair for registration approval (i.e., enrollment of a consented subject):
1. De-Identified, signed consent document(s) and HIPAA
2. Completed Registration Cover Sheet
3. Signed/dated eligibility checklist
4. All De-Identified eligibility source documents (e.g., lab reports, scans, test, etc.)
5. Desired timeline for the registration / proposed start date for treatment
Please refer to study specific manual of Procedures for further details. 
6.1
Cancellation Guidelines
If a patient does not receive protocol therapy, the patient may withdraw.  Contact the 
CRS Representative, or e-mail the information including the reasons for withdrawal 
within 10-business days.
6.2
Emergency Registration
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If an emergency registration takes place after business hours, the items listed above must 
be submitted by the next business day.
7.0 STUDY DESIGN
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), interferon-alfa-2a, 
pegylated 
interferon-alfa-2b 
(PEG-IFN-alfa-2b), 
peginterferon-alfa-2a 
or 
generic 
preparations of IFN-alfa that become commercially available to replace existing agents or the 
one approved by patient’s insurance. For subjects receiving interferon therapy at baseline, the 
corresponding interferon 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) as tolerated for at least 6 more months.
Subjects will be restaged at the end of belinostat Cycle 3 (-7 days) or end of Month 3, 
belinostat Cycle 8 or end of month 6 (-14 days), end of Month 9 (≤14 days) and end of Month 
12 (≤14 days).  Subjects who have progression of disease at any of these time points will be 
taken off study treatment.  See Sections 12.0 and 14.0 for details.
At the end of Cycle 3, 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) or end of Month 6, subjects who achieve 
or maintain a complete molecular response (CMR) with no evidence of minimal residual 
disease (MRD) may continue to receive AZT (±IFN-alfa) at the discretion of the investigator. 
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 may 
continue to receive AZT (± IFN-alfa) at the discretion of the investigator for 3 more months, 
up 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.
At least 10 subjects are expected to be enrolled at Sylvester Comprehensive Cancer Center 
(SCCC), University of Miami affiliated hospitals, including Jackson Memorial Hospital, and 
any future collaborating sites. Expected time to complete total accrual is approximately 5 
years. Expected time to study completion is 6 years (12 months after the last enrollment) from 
the time of first enrollment.
Correlative evaluations will also be performed at specified visits.  Please refer to Section 13.0 
CORRELATIVE STUDIES and Appendices F & G for specific details.
8.0 TREATMENT PLAN
During belinostat administration, a cycle of treatment will consist of 3 weeks or 21 days (±3 
days).  Thereafter, AZT (+/- IFN-alfa) may be continued monthly up to the end of Month 12. 
Trial treatment should be administered after all procedures/assessments have been completed 
as detailed in Section 12.0. See also Section 8.6.1 for Concurrent Medications and 
Prophylactic Measures. 
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8.1
Zidovudine (AZT)
Zidovudine shall be administered in the outpatient setting as 300 mg tablets orally (PO), 
three times daily (TID) or continue the dose patient was receiving prior to enrollment 
along with belinostat for 21 days on cycles 1 to 8, followed by maintenance therapy (+/- 
IFN-alfa) up to the end of Month 12. For patients who are AZT-experienced, as well as 
for patients who are AZT-naïve, zidovudine must be administered at least 24-hours prior 
to the first dose (i.e. 24-hours before C1D1) of belinostat. AZT may be administered for 
a minimum of 12 months from the beginning of the study. Because AZT is a standard 
maintenance drug for ATLL, starting the drug before enrolment should not be considered 
a deviation from the protocol whatsoever.
For additional information on zidovudine including mechanism of action, drug 
metabolism, pharmacokinetics & toxicology, known side effects, composition, and 
storage recommendations, (see Section 9.2).
8.2
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.  (UGT1A1 activity is reduced in individuals with genetic 
polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 
polymorphism. Approximately 20% of the black population, 10% of the white 
population, and 2% of the Asian population are homozygous for the UGT1A1*28 allele. 
Because belinostat is primarily (80-90%) metabolized by UGT1A1, the clearance of 
belinostat could be decreased in patients with reduced UGT1A1 activity (e.g., patients 
with UGT1A1*28 allele). Testing for the UGT1A1*28 allele is not required for eligibility 
on this study.
Every effort to target infusion timing to be as close to days 1 to 5, and infusion times 30 
minutes as possible, should be made. However, given the variability of outpatient 
scheduling conflicts (including weekend and holidays), infusion pumps, a window of +3 
days for scheduled drug administration, and -5 minutes and +10 minutes infusion times 
is permitted (i.e. 30 minute infusion time -5 min/+10min).
For additional information on belinostat including mechanism of action, drug 
metabolism, pharmacokinetics & toxicology, known side effects, composition, and 
storage recommendations, (see Section 9.1).
8.3
Interferon alfa-2b (IFN-α-2b) or pegylated interferon alfa-2b (PEG-IFN-α-2b) 
or other forms of IFN-alfa that become commercially available to replace existing 
preparations or those preferred by patient’s insurance. 
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 based on (PegIntron 
recommended dosing, rounded up to the closest dose to existing vial/syringe dose 
preparations) once weekly, subcutaneously (SQ) for up to 12 months. Subjects should be 
advised to only use the brand and type of interferon that their doctor prescribes. They 
should not use another brand of interferon or switch between interferon alfa-2b and peg 
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interferon alfa-2b in vials and/or injection pens without talking to their doctor(s) first. In 
case interferon alfa-2b or pegylated interferon alfa-2b are unavailable or not covered by 
the subject’s medical insurance, other commercially available forms of IFN-alfa may be 
administered at doses recommended by package insert only after approval by the protocol 
Chair, and administration doses for such form of interferon may be modified (dose-
reduced) at the protocol Chair’s discretion based on previous treatment tolerance.
For additional information on IFN-alfa-2b, PEG-IFN-alfa-2b/-2a including mechanism 
of action, drug metabolism, pharmacokinetics & toxicology, known side effects, 
composition, and storage recommendations, (see Section 9.3 and 9.4, respectively).
8.4
Lymphodepletion therapy: A one-time administration of standard low dose 
cyclophosphamide (up to 375 mg/m2) will be permitted during cycle 1 after administration 
of Day 5 (+ 7 days) belinostat to treat any increase in absolute lymphocyte count, which 
may occur transiently during cycle 1 after belinostat from re-activation of HTLV-1 in 
ATLL or T-lymphocytes based on early trial observations.
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8.5
Treatment Schema
Table 2:  Treatment Schema
Regimen Description
Agent
Premedication; 
Precautions (see 
also Section 8.6.1 
Concurrent 
Medications/ 
Prophylactic 
Measures)
Dose
Route
Schedule
Cycle 
Length 
for 
belinostat
BelinostatA
(see Appendix E)
1,000 mg/m2 
or 750 
mg/m2B
IV
30 min 
Days 1-5 x 8 
cycles
Zidovudine 
(AZT)A
(see Appendix I)
300mg tablet
PO
3 times a day 
(or continue 
previous dose 
prior to 
enrollment) x 
12 months
(OPTIONAL)
IFN-alfa-2b 
or
(for subjects 
already receiving 
IFN)
5 million IU
SQ
Daily x 12 
months
(OPTIONAL)
IFN-alfa-2a 
or
(for subjects 
already receiving 
IFN)
5 million IU
SQ
Daily x 12 
months
(OPTIONAL)
PEG-IFN-
alfa-2a
(for subjects 
already receiving 
PEG-IFN)
Package insert 
dose
SQ 
Once weekly x 
12 months
(OPTIONAL)
PEG-IFN-
alfa-2b
(for subjects 
already receiving 
PEG-IFN)
1.5 μg/kg 
SQ 
Once weekly x 
12 months
21 days 
(3 weeks)
(OPTIONAL) 
Lymphodeple
ting therapy
(for any increase 
in absolute 
lymphocyte 
count)
Cyclo-
phosphamide
375 mg/m2
IV
60 
mins
Once
Cycle 1 only
(after Day 5 
belinostat)
1 day
AZidovudine must be administered (for patients who are AZT-experienced, as well as for 
patients who are AZT-naïve) at least 24-hours prior to the first dose (i.e. 24-hours before 
C1D1) of belinostat
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BAs per FDA-approved Package Insert: In patients known to be homozygous for the 
UGT1A1*28 allele, the starting belinostat dose must be 750mg/m2.
8.6
Treatment Dispensation, Compliance and Accountability
8.6.1
Belinostat (Beleodaq®)
Eligible subjects shall be treated with the investigational supply of belinostat, as provided by 
Acrotech Biopharma, LLC.  Clinical supplies may not be used for any purpose other than that 
stated in the protocol.
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified.
Receipt and dispensing of investigational product must be recorded by authorized person(s) at the 
trial site.  The Investigator is responsible for maintaining accurate records of the clinical supplies 
received from Acrotech Biopharma, LLC, the amount dispensed to subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy.  It is the Investigator’s responsibility 
to arrange for the disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept.
8.6.2
Zidovudine (AZT, Retrovir®)
(During cycles 1-8 of belinostat administration). Eligible subjects will be prescribed the 
appropriate number of zidovudine capsules required for 21 days of dosing, plus an additional 3-
day supply to account for visit scheduling. The subject will be requested to maintain a medication 
diary of each dose of zidovudine (AZT).  The date, time and dose should be recorded at each 
dosing time point to confirm that each dose of zidovudine was taken for each day. See Appendix 
I for the dosing diary.
If a dose of zidovudine AZT is missed due to subject error/oversight, then s/he should take the 
zidovudine AZT dose within 6 hours of the missed dose.  If more than 6 hours have elapsed, that 
missed dose should be omitted.  The subject should resume treatment at the next scheduled dosing 
time point and the reason for missed dose reported on the dosing diary. NOTE: Although patients 
will be requested to maintain a medication diary, missed doses of AZT due to error/oversight 
will not be deemed significant since AZT is an acceptable NCCN standard guideline for first-
line and maintenance treatment of ATLL.
If a dose of zidovudine AZT is held due to an AE, SAE or at the Investigator’s discretion, then 
s/he should resume treatment at the Investigator’s discretion taking into account all of the dose 
modification/discontinuation guidelines provided in Section 10.0 Treatment/Dose Modifications.
8.6.3
Interferon Alfa-2b (INTRON® A) OR Peg interferon Alfa-2b (PEGINTRON®) 
OR other commercially available forms of Interferon Alfa-2b (INTRON® A) OR Peg 
interferon Alfa-2b (PEGINTRON® in the case these brands become unavailable.
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For subjects receiving interferon therapy at baseline, continue during belinostat/AZT consolidation 
and for up to 6 more months thereafter. The commercial supply of INTRON® A or 
PEGINTRON® will be used (Subjects should not switch between interferon alfa-2b, peg-
interferon alfa-2b, or other commercially available forms of interferon alfa that replace these 
agents in vials and/or injection pens without talking to their clinical trial’s doctor(s) first).
8.7
Supportive Care Guidelines
8.7.1
Concurrent Medications/ Prophylactic Measures
Central Nervous System (CNS) Prophylaxis:  Subjects who have not previously received 
meningeal prophylaxis with intrathecal chemotherapy may receive prophylaxis at the discretion of 
the investigator or treating physician. It is recommended that lumbar puncture and prophylactic 
intrathecal chemotherapy is postponed until absolute lymphocyte blood count is less than 3.5 X 
103/l
Antiretroviral therapy (ART): Subjects who are HIV positive may receive antiretroviral therapy at 
the discretion of the investigator. Zidovudine (AZT) as part of ART regimen is prohibited. 
Antiretroviral regimens may be modified before or during the course of protocol treatment as 
necessitated by the occurrence of drug-induced toxicities or based upon measurement of viral load.
Prevention of tumor lysis syndrome:  Subjects with evidence of high tumor burden (bulky disease, 
bone marrow involvement, LDH > twice the upper limit of normal) should receive allopurinol 300 
mg daily starting 24 hours prior to the initiation of chemotherapy followed for at least the first 
seven treatment days.  Appropriate IV hydration should be maintained and serum electrolytes, 
BUN, phosphorous, creatinine, calcium and uric acid should be monitored closely.  Allopurinol 
dosing may be adjusted at the discretion of the treating physician.
Antibiotics may be administered as clinically indicated, at the discretion of the treating 
Investigator.
Topical, anti-infectives and/or antifungal agents are permitted.
Growth factors may be used as clinically indicated, at the discretion of the treating Investigator.
Pneumocystis Carinii Prophylaxis: All subjects should receive prophylaxis with co-trimoxozole, 
dapsone, atovaquone, or inhaled pentamidine as per recommended, standard of care guidelines.
8.8
Duration of Treatment
While on-study subjects will receive a maximum of 8 cycles (about 6 months) of 
belinostat consolidation therapy with AZT (±IFN-alfa). Thereafter, depending upon 
restaging assessments and clinical/molecular evaluations, subjects may receive an 
additional 6 months of AZT-based maintenance therapy (±IFN-alfa).
8.9
Duration of Follow-Up
All subjects will be followed at approximately ≤30 days (+/- 7 days) after the last dose 
of belinostat for toxicity.
Subjects who achieve/maintain CR and have completed one year of therapy (i.e. 8 cycles 
of belinostat/AZT by about 6 months, with AZT-based maintenance therapy for an 
additional 6 months), will be followed every 3 months (±14 days) for clinical assessment 
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(Complete PE, CBC, CMP, and LDH), with response assessment (CT, BMX and skeletal 
X-ray survey if indicated) every 6 months for 1 year.
Thereafter, these subjects will continue to be followed every 6 months (± one month) 
during Years 3 to 5 at a minimum for survival via a telephone call.
Subjects who are off treatment after early discontinuation not due to disease progression 
may remain on the study and will be followed for clinical assessments mentioned above 
and for overall and failure free-survival for at least 12 months or until they receive new 
treatment, at which time they will be censored.
Subjects who discontinue treatment for disease progression will come off treatment 
and will be followed for survival every 6 months (±one month) for up to 5 years. 
Subjects who withdraw consent will come off study
9.0 TREATMENT/ DOSE MODIFICATIONS
9.1
Dose Modification Guidelines
9.1.1
Hematologic Toxicity (grade 4 neutropenia or thrombocytopenia unless present at 
baseline due to lymphomatous bone marrow involvement)
For new Grade 4 thrombocytopenia, hold all drugs until the toxicity grade returns to ≤Grade 2. 
Once the toxicity grade returns to ≤ Grade 2, belinostat should be administered at 75% the original 
dose (i.e. 750 mg/m2) on the next cycle. Subjects may receive AZT and IFNα (if applicable) at the 
original dose(s). In the case of known bone marrow involvement by lymphoma, subjects may 
continue to receive AZT and/or IFNα (standard maintenance treatment for ATLL to prevent 
disease progression) at reduced doses at the discretion of the investigator regardless of AE grade 
level if not recovered. AZT and/or IFNα may be also held at any time at the discretion of the 
investigator.
For new Grade 4 neutropenia (based on absolute neutrophil count or ANC), hold all drugs until 
the toxicity grade returns to ≤ Grade 3. Once the toxicity grade returns to ≤ Grade 3, belinostat 
should be administered at 75% the original dose (i.e. 750 mg/m2). Subjects may receive AZT and 
IFNα or PEG-IFN-alfa2b (if applicable) at the original dose(s). In the case of known bone marrow 
involvement by lymphoma, subjects may continue to receive AZT and/or IFNα (standard 
maintenance treatment for ATLL to prevent disease progression) at reduced doses at the discretion 
of the investigator regardless of AE grade level if not recovered. AZT and/or IFNα may be also 
held at any time at the discretion of the investigator.
If Grade 4 thrombocytopenia or Grade 4 neutropenia recur after the above dose adjustments, then 
all drugs will be held until the toxicity grade returns to ≤ Grade 2 platelets and/or ≤ Grade 3 ANC, 
or to baseline in patients with lymphomatous bone marrow involvement at initial presentation 
before treatment. Once the toxicity grade returns to these limits, belinostat should administered at 
75% the previous dose on the next cycle (second dose reduction). AZT should be reduced to 300 
mg twice daily or lower at the discretion of the investigator. If applicable, IFNα-2b should be 
reduced to 5MU three times week and PEG-IFN-alfa-2b should be restarted at 50% of the previous 
dose. Other commercially available substitutes of interferon alfa that replace these agents should 
be re-started at 50% of the previous dose. In the case of known bone marrow involvement by 
lymphoma, subjects may continue to receive AZT and/or IFNα (standard maintenance treatment 
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for ATLL to prevent disease progression) at reduced doses at the discretion of the investigator 
regardless of AE grade level if not recovered. AZT and/or IFNα may be also held at any time at 
the discretion of the investigator.
If Grade 4 thrombocytopenia or Grade 4 neutropenia recur, then all drugs will be held until the 
toxicity grade returns to ≤ Grade 2 platelets and/or ≤ Grade 3 ANC, or to baseline in patients with 
lymphomatous bone marrow involvement at initial presentation before treatment. Discontinue 
belinostat in subjects who have recurrent ANC less than 0.5 x 109/L and/or recurrent platelet count 
nadirs less than 25 x 109/L after two dosage reductions. Once the toxicity grade returns to ≤ Grade 
3, subjects may re-start AZT, and IFNα or PEG-IFN-alfa2b if applicable, at the previous doses.
In subject with lymphomatous bone marrow involvement who present with grade 4 
neutropenia or thrombocytopenia grade 4 prior to next treatment, study drugs will be held 
at the discretion of the investigator and if continued reasons should be documented in the 
medical record.
If any of these drug-induced toxicities persist for more than 28 days at any time or recur 
after belinostat was discontinued, then all drugs will be permanently stopped, and the subject 
will be removed from the study. Exception: In the case of known bone marrow involvement 
by lymphoma, subjects may continue to receive AZT and/or IFNα (standard maintenance 
treatment for ATLL to prevent disease progression) at reduced doses at the discretion of the 
investigator regardless of AE grade level and continue on the study. AZT and/or IFNα may 
be also held at any time at the discretion of the investigator during this time.
G-CSF or GM-CSF may be used for neutropenia > Grade 3, at the discretion of the investigator.
Platelet and blood transfusions, and recombinant erythropoietin (rEPO), may be given at any time 
at the discretion of the investigator.
9.1.2
Non-Hematological Toxicity: Hepatotoxicity
For Grade 2 or greater elevations in AST (SGOT) and/or ALT (SGPT), or elevation of total 
bilirubin ≥ 1.5 institutional upper limit of normal, all study medications will be held. Once the 
toxicity grade returns to ≤ Grade 1 and total bilirubin returns to < 1.5 institutional upper limit of 
normal within 14 days, belinostat should be administered at 75% the original dose (i.e. 750 mg/m2). 
AZT should be reduced to 300 mg twice daily. When applicable, IFNα2b should be reduced to 
5MU three times weekly and PEG-IFN-alfa2b or equivalent drug form  restarted at 50% of the last 
dose.
If Grade 2 or greater elevations in AST (SGOT) and/or ALT (SGPT), or elevation of total bilirubin 
≥ 1.5 institutional upper limit of normal persist for 14 days, then belinostat will be discontinued 
and the subject will be removed from the study.
If Grade 2 or greater elevations in AST (SGOT) and/or ALT (SGPT) and/or elevation of total 
bilirubin ≥ 1.5 institutional upper limit of normal recur then all drugs will be held. Once the toxicity 
grade returns to ≤ Grade 1 and total bilirubin returns to < 1.5 institutional upper limit of normal 
within 14 days, belinostat should be administered at 75% the previous dose. AZT should be re-
started at 300 mg twice daily. Whenever applicable, IFN-alfa2b orPEG-IFN-alfa2b or equivalent 
drug form should be held and discontinued.
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If Grade 2 or greater elevations in AST (SGOT) and/or ALT (SGPT) and/or elevation of total 
bilirubin ≥ 1.5 institutional upper limit of normal recur then all drugs will be discontinued and the 
subject will be removed from the study.
9.1.3
Non-Hematological Toxicity: Gastrointestinal Toxicity
Belinostat should be withheld if ≥ Grade 3 drug-related nausea, vomiting, diarrhea, or dehydration. 
After resolution to Grade 1 or less, belinostat may be re-started 75% the previous dose.  
If ≥ Grade 3 toxicity recurs at the reduced dose the drug will then be discontinued permanently. 
Subjects may continue to receive AZT and IFNα2b/PEG-IFN-alfa2b (or equivalent drug form) at 
the discretion of the Investigator.
9.1.4
Pregnancy
Belinostat will be stopped for subjects who become pregnant. If this drug is used during pregnancy, 
or if the subject becomes pregnant while taking this drug, the subject should be apprised of 
potential hazard to the fetus. See also Appendix A.
AZT and IFN-alfa2b/ PEG-IFN-alfa2b or equivalent drug form may be continued at the discretion 
of the Investigator(s).
Males and females must agree to use adequate birth control during participation in this trial and 
for 3 months after completing therapy.
9.1.5
Grade ≥3 Fatigue, Anorexia and/or Mood Alteration
When applicable, IFN-α should be held first in subjects receiving this drug until the toxicity grade 
returns to ≤ Grade 2 or baseline. IFN-α should be reduced to 5MU three times weekly and PEG-
IFN-alfa2b or equivalent drug form restarted at 50% of the last dose. In subject(s) not receiving 
IFN-α2b/PEG-IFN-alfa2b or equivalent drug form, belinostat should be withheld until toxicity is 
Grade 1 or less. Belinostat may then be re-started at 75% the previous dose. If ≥ Grade 3 toxicity 
recurs belinostat should be withheld until toxicity is Grade 1 or less. Belinostat may be restarted 
75% the previous dose.  If ≥ Grade 3 toxicity recurs at the reduced dose (second dose reduction) 
the drug will then be discontinued permanently, and the subject will be removed from the study. 
If any of these toxicities persists for more than 14 days, then all study medications will be 
permanently discontinued.
10.0 TREATMENT DISCONTINUATION
Treatment may be discontinued for any of the following reasons:

The subject demonstrates progression of disease (Exception: Subjects may remain on the 
study if in the opinion of the Investigator, he/she is deriving clinical benefit from study 
treatment)

The subject withdraws consent from the study

The subject has not received study treatment for >35 days due to an adverse event/toxicity 
(See Section 10.0). Exception: Subjects may remain on the study if in the opinion of the 
Investigator, he/she is deriving clinical benefit from being in the protocol). Patients who 
have been previously removed from the study after treatment discontinuation and 
who have not received other therapies or progressed may re-enter the study after 
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re-consent for the purpose of capturing progression-free data and continue disease 
assessments and monitor any unresolved toxicities as per protocol, as long as they 
do not progress or receive any new treatment. Those receiving AZT and/or IFN as 
standard maintenance will be also allowed to re-enter the study.

The subject experiences an adverse event that in the opinion of the Investigator makes 
continued study treatment an unacceptable risk

The subject becomes pregnant (also see Appendix A: Expedited Adverse Event Reporting 
Requirements)

The subject requires continuous treatment with a prohibited concomitant drug(s) for 
which no safe alternatives can be substituted

The subject is significantly noncompliant with the requirements of the protocol
Should discontinuation of study therapy occur, all efforts should be made to execute/ report 
End-of-Treatment and Follow-up Evaluations as completely as possible and to determine/ 
document the reason for discontinuation (unless the patient withdraws consent for follow-
up).
If a subject wishes to withdraw consent from the study, the PI must be notified. The 
information regarding withdrawal (i.e. subject identifiers and date of withdrawal) should be 
documented in the subject’s record and updated within any other research database(s).
11.0 SCHEDULE OF CLINICAL & LABORATORY EVALUATIONS
Prior to performing any study-specific procedures or evaluations, written informed consent 
and authorization for the use of protected health information (HIPAA) must be obtained in 
accordance with all applicable policies, regulations and laws.  Investigator(s) should also 
perform routine clinical and laboratory evaluations as necessary for standard of care treatment.  
Correlative evaluations must also be performed at specified visits.  Please refer to Section 
13.0 CORRELATIVE STUDIES and Appendices F & G for specific details.
11.1
Pre-Treatment Evaluations (Screening)
The following must be collected/performed ≤ 21days prior to Cycle 1, day 1 of treatment 
with the exception of some laboratory tests as specified. Clinical and laboratory 
evaluations performed as part of routine standard of care do not need to be repeated if 
performed within the appropriate window.

Complete medical history that includes:
o
Date of initial and/or relapsed diagnosis of lymphoma. A copy of the 
pathology and/or flow cytometry report must be available in the medical 
record.
o
Presence or absence of “B” symptoms (i.e. unexplained fevers, night 
sweats, involuntary weight loss > 10% of normal body weight)
o
History of other symptoms related to ATLL.
o
History of drug allergies.
o
Current medication list.
o
Previous therapy received for this lymphoma.

Complete physical examination (PE): includes neurologic examination, careful 
measurement of all palpable peripheral lymph nodes and measurement of other 
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sites of disease present on physical examination including skin. Palpable lymph 
nodes or masses should be measured in at least two dimensions.

ECOG or Karnofsky performance score (ECOG PS or KPS). See also Appendix 
C

Vital signs (V/S: including heart rate (HR), blood pressure (BP), respiratory rate 
(RR), and oral temperature (oral temp)

Weight

Height

Baseline laboratory tests (to be repeated within 48 hours prior to initiation of 
zidovudine (unless patient was already on this drug), unless otherwise indicated:
o
Blood chemistries: serum electrolytes, creatinine, total bilirubin, calcium, 
phosphorous, AST, ALT, alkaline phosphatase, total protein, albumin
o
Hematology: CBC, with differential, and platelet (PLT) count
o
LDH level
o
Uric acid level
o
Hepatitis profile including hepatitis B surface antibody, hepatitis B 
surface antigen and hepatitis C antibody (within 6 months prior to 
enrollment).
o
Serum pregnancy test if premenopausal within 14 days prior to treatment 
initiation and at any time during protocol therapy if pregnancy is 
suspected.
o
Leukemia-lymphoma standard panel (flow cytometry) with standard T-
cell receptor gene rearrangement (i.e. by multiplex PCR) within 14 days 
prior to enrollment but not within 14 days of any previous therapy 
(excluding zidovudine and interferon) to determine presence of clonal 
disease.

Correlative studies (see Section 13.0)

12-Lead ECG

Staging Evaluation: The following studies will be done for baseline evaluation of 
the extent of disease within 30 days prior to on-study treatment initiation in 
subjects already on AZT-IFN and 14 days after any previous therapy (excluding 
zidovudine and interferon):
o
CT scans of the chest, abdomen, and pelvis (C/A/P) with contrast unless 
contraindicated, in which case nuclear imaging methods for lymphoma 
staging can be used or non-contrast CTs. Optional: Skeletal X-ray survey 
(chest, skull, shoulder girdle, spine, and pelvic girdle and bone survey) to 
check for bone lytic lesions if the patient had hypercalcemia upon initial 
diagnosis and no visible bone lesions on CT scans.
o
Bone marrow biopsy unless there is confirmed evidence of leukemia in 
peripheral blood, in which case it is not needed at baseline but can be done 
at the discretion of the investigator; If performance of BM biopsy will 
delay treatment initiation (e.g., falling on a weekend or holiday), it may 
be delayed ±3 days or must be performed to confirm CR at the end of 
month 2 (i.e. at the end of cycles 3), month 6 (i.e. at the end of cycles 8) 
and at the end of months 9 and 12.
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o
Lumbar puncture with routine studies and cytology will be done at the 
discretion of the treating Investigator(s) if lymphomatous CNS 
involvement is suspected. It is discouraged in patients with blood 
circulating ATLL cells (i.e. active leukemia) unless otherwise warranted 
by symptoms.
11.2
Evaluations on Treatment
Collection of Concomitant Medications and Adverse Events (AEs) should occur 
throughout the study, as described.  Patients will be asked to maintain a medication diary 
for AZT (see Section 8.5.2 and Appendix I).  
11.2.1 Cycle 1 Day 1 (assessments done one day before can be used, including baseline 
evaluations)

Complete physical examination: includes neurologic examination, careful 
measurement of all palpable peripheral lymph nodes and measurement of other 
sites of disease present on physical examination including skin. Palpable lymph 
nodes or masses should be measured in at least two dimensions.

ECOG or Karnofsky performance score (Appendix C)

Vital signs (HR, BP, RR, and oral temp)

Weight

CBC with differential and platelet count

Blood chemistries: serum electrolytes, creatinine, total bilirubin, calcium, 
phosphorous, AST, ALT, alkaline phosphatase, total protein, albumin

LDH level
11.2.2 Cycle 1, days 3 to 4 (72 to 96 hours after belinostat initiation)

CBC, with differential and platelet count

Blood chemistries (serum electrolytes, creatinine, total bilirubin, calcium, 
phosphorous, AST, ALT, alkaline phosphatase, total protein, albumin), and 
LDH level.

Correlative studies (see Section 13.0)
11.2.3 Cycle 1, day 8 (±1 day)

CBC, with differential and platelet count

Blood chemistries (serum electrolytes, creatinine, total bilirubin, calcium, 
phosphorous, AST, ALT, alkaline phosphatase, total protein, albumin), and 
LDH level.

Correlative studies (see Section 13.0)
11.2.4 Cycle 1, day 15 (±3 days)

CBC, with differential and platelet count (to check nadirs)
11.2.5 Correlative studies (see Section 13.0) Subsequent Cycles 2 through 8, day 1 (≤ 3 
days prior to day 1) (end of cycles assessments can be used and do not need to be 
repeated)
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
Complete physical examination: includes neurologic examination, careful 
measurement of all palpable peripheral lymph nodes and measurement of other 
sites of disease present on physical examination including skin. Palpable 
lymph nodes or masses should be measured in at least two dimensions.

vital signs (HR, BP, RR, and oral temp)

weight

ECOG or Karnofsky performance score (Appendix C)

CBC, with differential and platelet count

Blood chemistries (serum electrolytes, creatinine, total and direct bilirubin, 
calcium, phosphorous, AST, ALT, alkaline phosphatase, total protein, 
albumin), and LDH level.

Correlative studies only prior Cycle 2 (see Section 13.0)
11.2.6 Subsequent Cycles 2 through 8, day 8 (± 3 days)

CBC, with differential and platelet count (as standard safety to check nadirs)
11.2.7 Subsequent Cycles 2 through 8, day 15 (±3 days)

CBC, with differential and platelet count (as standard safety to check nadirs)
11.2.8 End of Cycle 3 (≤7 days prior to cycle 4)

Complete Physical examination: Palpable lymph nodes on physical 
examination should be measured in at least two dimensions

CBC, with differential and platelet count

Blood chemistries (serum electrolytes, creatinine, total bilirubin, calcium, 
phosphorous, AST, ALT, alkaline phosphatase, total protein, albumin), and 
LDH level.

Leukemia-lymphoma standard panel (flow cytometry with standard T-cell 
receptor gene rearrangement (i.e. by multiplex PCR). In case of persistent 
ATLL evidence by flow cytometry, T-cell receptor gene rearrangement (i.e. 
by multiplex PCR) is not required.

CT scans of the chest, abdomen, and pelvis (C/A/P) with contrast unless 
contraindicated, in which case nuclear imaging methods for lymphoma staging 
can be used or non-contrast CTs. If non-contrast CT-PET is obtained, for 
instance in patients where IV contrast is contraindicated due to allergy or renal 
dysfunction, it is recommended that only the CT portion be used for response 
assessment during treatment. Optional: Skeletal X-ray Survey if positive for 
bone lesions at baseline.

Correlative studies (see Section 13.0)

Bone marrow biopsy (if presumed or involved at baseline to confirm CR)
11.2.9 End of Cycle 8 (≤14 days prior to Day 21)

Complete Physical examination: palpable lymph nodes on physical 
examination should be measured in at least two dimensions.

Standard laboratory tests:
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o
CBC, with differential and platelet count
o
Blood chemistries (serum electrolytes, creatinine, total bilirubin, 
calcium, phosphorous, AST, ALT, alkaline phosphatase, total protein, 
albumin), and LDH level.

Leukemia-lymphoma panel (flow cytometry) with standard T-cell receptor 
gene rearrangement (i.e. by multiplex PCR). In case of persistent ATLL 
evidence by flow cytometry, T-cell receptor gene rearrangement (i.e. by 
multiplex PCR) is not required.

Correlative studies (see Section 13.0)

Standard restaging:

CT scans of the neck (if involved at baseline only), chest, abdomen, and pelvis. 
Optional: Skeletal X-ray Survey if positive for bone lesions at baseline.

Bone marrow biopsy (if presumed or involved at baseline to confirm CR)
Note: Subjects who have clinical or molecular evidence of ATLL without evidence of disease 
progression may remain on study receiving AZT (or AZT/ IFNα) or may be removed from 
treatment protocol to receive alternative therapies at the discretion of the treating Investigator. 
Subjects who maintain or achieve a complete remission will continue on the study.
11.2.10
End of Month 9 (≤14 days)

Physical examination: palpable lymph nodes on physical examination should 
be measured in at least two dimensions.

Standard laboratory tests:
o
CBC, with differential and platelet count
o
Blood chemistries (serum electrolytes, creatinine, total bilirubin, 
calcium, phosphorous, AST, ALT, alkaline phosphatase, total protein, 
albumin), and LDH level.

Leukemia-lymphoma panel (flow cytometry) with standard T-cell receptor 
gene rearrangement (i.e. by multiplex PCR). In case of persistent ATLL 
evidence by flow cytometry, T-cell receptor gene rearrangement (i.e. by 
multiplex PCR) is not required.

Correlative studies (see Section 13.0)

Standard restaging:

CT scans of the neck (if involved at baseline only), chest, abdomen, and pelvis. 
Optional: Skeletal X-ray Survey if positive for bone lesions at baseline.

Bone marrow biopsy (if presumed or involved at baseline to confirm CR)
Note: Subjects who maintain a response with clinical or molecular evidence of 
ATLL may remain on study receiving AZT (or AZT/ IFNα) or may be removed 
from the protocol to receive alternative therapies at the discretion of the treating 
Investigator. Subjects who maintain or achieve a complete remission will continue 
on the study.
11.2.11
End of Month 12 (≤14 days)

Physical examination: palpable lymph nodes on physical examination should 
be measured in at least two dimensions.
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
Standard laboratory tests:
o
CBC, with differential and platelet count
o
Blood chemistries (serum electrolytes, creatinine, total bilirubin, 
calcium, phosphorous, AST, ALT, alkaline phosphatase, total protein, 
albumin), and LDH level.

Leukemia-lymphoma panel (flow cytometry) with standard T-cell receptor 
gene rearrangement (i.e. by multiplex PCR). In case of persistent ATLL 
evidence by flow cytometry, T-cell receptor gene rearrangement (i.e. by 
multiplex PCR) is not required. 

Correlative studies (see Section 13.0)

Standard restaging (±4 weeks) or more frequently if clinically indicated: CT 
scans of the neck (if involved at baseline only), chest, abdomen, and pelvis. 
Optional: Skeletal X-ray Survey if positive for bone lesions at baseline.

Bone marrow biopsy (if involved at baseline and only to confirm CR)
Note: If at the end of month 12, no minimal residual disease is detected, patients may continue 
AZT (or AZT/IFNα2b) at the discretion of the treating Investigator.
11.3
Off-Treatment Evaluations (Early Discontinuation not due to disease 
progression, End of Treatment or EOT visit)
At ≤ 30-days after the last dose of study treatment or before the initiation of new anti-
cancer therapy (early discontinuation not due to disease progression), whichever occurs 
first, the following assessments should be performed: 

Complete physical examination (PE): includes neurologic examination, careful 
measurement of all palpable peripheral lymph nodes and measurement of other 
sites of disease present on physical examination including skin. Palpable lymph 
nodes or masses should be measured in at least two dimensions.

ECOG or Karnofsky performance score (ECOG PS or KPS) See also Appendix 
C

Vital signs (V/S: including heart rate (HR), blood pressure (BP), respiratory rate 
(RR), and oral temperature (oral temp))

Weight

CBC, with differential and platelet count

Blood chemistries (serum electrolytes, creatinine, total bilirubin, calcium, 
phosphorous, AST, ALT, alkaline phosphatase, total protein, albumin), and LDH 
level.

Leukemia-lymphoma panel (flow cytometry) in the absence of clinical disease 
and only to confirm complete remission
with standard T-cell receptor gene rearrangement (i.e. by multiplex PCR) in the absence of clinical 
disease only to confirm complete remission. In case of persistent ATLL evidence by flow 
cytometry, T-cell receptor gene rearrangement (i.e. by multiplex PCR) is not required. 

Correlative studies (see also Section 13.0): Patients who discontinue 
belinostat/AZT treatment prior to completion of study therapy for any reason (e.g. 
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disease progression) will have 5 yellow tops drawn for HTLV-1 proviral load. 
(Appendix G).

Standard restaging (±4 weeks) or more frequently if clinically indicated: CT scans 
of the neck (if involved at baseline only), chest, abdomen, and pelvis

Bone marrow biopsy (if presumed or involved at baseline to confirm CR if patient 
agrees)
11.4
Follow-up Evaluations
Subjects who achieve/maintain CR and have completed one year of protocol treatment 
(i.e. 8 cycles of belinostat/AZT followed by AZT-based maintenance therapy) and 
subjects who are removed from belinostat treatment early and remain on the study will 
be followed every 3 months (±30 days) up to the end of month 24 according to study 
calendar for clinical assessments:
Complete physical examination (PE): includes neurologic examination, careful 
measurement of all palpable peripheral lymph nodes and measurement of other sites of 
disease present on physical examination including skin. Palpable lymph nodes or masses 
should be measured in at least two dimensions.
•
ECOG or Karnofsky performance score (ECOG PS or KPS) See also Appendix C,
•
Vital signs (V/S: including heart rate (HR), blood pressure (BP), respiratory rate 
(RR), and oral temperature (oral temp)
•
Weight
•
CBC, with differential and platelet count
Response assessment will then be performed every 6 months for 1 year.:
•
Skeletal X-ray Survey if positive for bone lesions at baseline
•
CT scans of the neck, chest, abdomen, and pelvis
•
Bone marrow biopsy (if involved at baseline and only to confirm CR)
Thereafter, these subjects will continue to be followed every 6 months (± one month) 
during year 3 to 5, for overall survival via a telephone call, at a minimum and failure-free 
survival from available medical records.
Subjects who are removed from the study for disease progression or due to adverse 
event will be followed for survival every 6 months (±one month) for 5 years.
Subjects who withdraw consent will come off study. 
11.5
Calendar of Clinical and Laboratory Evaluations
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A The baseline laboratory tests: CBC with differentials and PLT, CMP (electrolytes, creatinine, total 
bilirubin, calcium, phosphorus, AST, ALT, alk phos, total protein, albumin), LDH, and uric acid are to 
be repeated within 48-hours prior to the initiation of zidovudine (AZT) (Day 1) unless subject was already 
on this drug prior to enrollment).  
B Baseline hepatitis profile including hepatitis B surface antibody, hepatitis B surface antigen, and hepatitis 
C antibody are to be done within 6 months prior to study enrollment.
C Skeletal X-ray survey (skull, chest, pelvic and shoulder girdle, spine and bone survey) is optional at 
baseline and thereafter and ONLY if hypercalcemia is present at baseline/ pretreatment and if no bone 
lesions were identified by CT scan.
Screenin
g
End of 
Cycle 3
End of 
Cycle 8, 
9M and 
12M
End of 
Treatment
Follow up
Day -1
Day 1
Days    
3-4
Day 8 
±2 days
Day 15 
±2 days
Day 1   
(≤3 
days) 
Day 8 
(±2 
days)
Day 15 
±2 days
Day 21 
(≤7 
days)
EDT       
(≤35 days)
±30 days
Informed Consent
X
Eligibility
X
Complete Medical History
X
Complete PE
X
X
X
F
X
X
X
X
I
ECOG PS or KPS
X
X
X
F
X
V/S (HR, BP, RR, and oral 
temp)
X
X
X
F
X
Height
X
Weight
X
X
X
F
X
CBC w/ diff, PLT
X
A
X
X
X
X
X
F
X
X
X
X
X
X
I
CMP
X
X
X
X
X
F
X
X
X
X
I
LDH
X
X
X
X
X
F
X
X
X
Uric acid
X
Hepatitis profile
X
Serum Pregnancy test
E
X
Leukemia/Lymphoma 
standard panel (by Flow 
Cytometry)
X
X
X
X
Standard T-cell receptor 
gene rearrangement (by 
multiplex PCR)
X
X
X
12 Lead ECG
X
Skeletal Survey
X
X
C
X
C
X
C  I
CT (neck, C/A/P) with 
contrast unless 
contrindicated)
X
X
X
X
I
Bone Marrow Biopsy
G
X
X
X
X
X
I
Lumbar Puncture with 
routine studies and 
cytology
H
X
Zidovudine (AZT); sec 8.5.2
X
D
Belinostat
Optional: IFN-α-2b or PEG-
IFN-α2b
X
Correlative studies (see Sec 
13.0 and Appenices F & G 
for details)
X
X
X
X
X
X
X
X
Concomitant Medications
Adverse Events
XJ
Survival (Can be done via 
telephone call)
X
I
X
X
X
X
X (Starting at Cycle 1 Day 1 to Cycle 8 Day 21)
Cycle 1
 Cycles 2, 3, 4, 5, 6, 7, and 
8
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D Zidovudine (AZT) to be administered at least 24-hours prior to the first dose of belinostat (for patients 
who are AZT-experienced, as well as for patients who are AZT-naïve) (i.e. 24-hours before C1D1 of 
belinostat).
ERepeat pregnancy test, serum Theophylline and thyroid stimulating hormone (TSH) after 
baseline/screening only, if clinically indicated.
FDo not need to repeat for Cycle 2, day 1 if these assessments completed within the day before (i.e. Cycle 
1, day 21).
GIf performance of bone marrow biopsy will delay treatment initiation (e.g., falling on a weekend or 
holiday), it may be delayed ±3 days but must be performed to confirm CR at the end of months 2, 6, 9, 
and 12 (i.e. at the end of cycles 3, 8, and end of months 9 and 12 during AZT maintenance treatment).
HLumbar puncture with routine studies and cytology will be done at the discretion of the treating 
Investigator(s) if lymphomatous CNS involvement is suspected.  It is discouraged in patients with blood 
circulating ATLL cells (i.e. active leukemia) unless otherwise warranted by symptoms.
I Follow up schedule for patients who achieve/maintain CR and completed 1 year of therapy: every 3 months 
(±one month) for clinical assessment (Complete PE, CBC, CMP, and LDH), with response assessment 
(CT, BMX and Skeletal scans if indicated only) every 6 months for 1 year (during Year 2). Then every 6 
months (±one month) during Years 3 to 5, for overall survival (OS) via a telephone call, at minimum. 
Subjects who discontinue treatment for disease progression will come off treatment and will be followed 
for survival every 6 months (±one month) for 5 years. Adverse events will be collected starting on Day 1 
of treatment and continuing until 30 days post treatment
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12.0
 SCHEDULE OF CORRELATIVE EVALUATIONS
Venous blood will be collected at the following time points (up to 10-ml per tube) for 
immunologic assays as well as molecular evaluations and analysis of ATLL and HTLV-1 
clones.  Please also refer to Appendices F and G for more information. 
12.1
Pre-Treatment Specimen Collection (Screening)
The following must be collected/ performed within 7 days prior to administering Cycle 
1, day 1 of treatment:

Immune response and cytotoxic T-cell (CTL) assays: a total of 3 green cap tubes will 
be collected (See Appendix F).

Molecular, TCR PVL, and clonal abundance studies: A total of 5 yellow cap tubes 
will be collected for processing to perform the following: (See Appendix G)
o
Measurements of baseline histone acetylation, Tax, and HBZ levels
o
 HTLV-1 proviral (PVL) load (single molecule droplet-based digital PCR)
12.2
On Treatment Specimen Collection
12.2.1 Cycle 1, days 3 to 4 (72 to 96 hours after belinostat initiation)

5 yellow cap tubes for correlative studies: to investigate molecular 
mechanisms of belinostat on ATLL cells (MOL), including HTLV-1 
reactivation (PVL), histone acetylation, and expression of HTLV-1 genes Tax 
and HBZ (see also Appendix G)
12.2.2 Cycle 1, day 8 (± 3 days)
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
3 green cap tubes for immune response and cytotoxic T-cell assays (see also 
Appendix F)
12.2.3 Cycle 1, day 15 (±3 days)

5 yellow cap tubes for HTLV-1 proviral load and clonal abundance studies 
(see also Appendix G)
12.2.4 Cycle 1, day 21 (± 3 days)

3 green cap tubes (for immune response and cytotoxic T-cell assays as also 
detailed in Appendix F)
12.2.5 End of Cycle 3 (≤7 days prior to day 21)

5 yellow cap tubes for HTLV-1 proviral load and clonal abundance studies (as 
in Appendix G)
12.2.6 End of Cycle 8 (≤14 days prior to day 21)

5 yellow cap tubes for HTLV-1 proviral load and clonal abundance studies (as 
in Appendix G)
12.2.7 End of Month 9 (≤14 days prior)

5 yellow cap tubes for HTLV-1 proviral load and clonal abundance studies (as 
in Appendix G)
12.2.8 End of Month 12 (≤14 days prior)

5 yellow cap tubes for HTLV-1 proviral load and clonal abundance studies (as 
in Appendix G)
12.3
Off-Treatment Specimen Collection (End of Treatment or EOT visit)
The following must be performed at the EOT visit and should occur 30-days (± 7 days) 
after the last dose of study treatment.

5 yellow cap tubes for HTLV-1 proviral load and clonal abundance studies (as 
in Appendix G)
12.4
Calendar of Specimen Collection for Correlative Studies
Table 3: Table of Correlative Studies
Time points
MOL (5 yellow 
top)*
PVL (5 yellow top)*
CTL (3 green top)
After enrollment (≤7 days prior to 
treatment initiation)
X (5 yellow tops (Acid Citrate Dextrose 
(ACD) solutions A/B additives –Trisodium 
citrate 22.0/13.2, citric acid 8.0/4.8 and 
dextrose 24.5/14.7 (in g/L) total for both 
assays together)
X 
(Sodium 
heparin,Lithium 
heparin)
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Cycle 1, day 3-4(±1 day)
X
Cycle 1, day 8 (±1)
X
Cycle 1, day 15 (±2)
X
Cycle 1, day 21 (≤3)
X
Cycle 3, day 21 (≤7)
X
Cycle 8, day 21 (≤14)
X
End of Month 9,  (≤14 days)
X
End of Month 12,  (≤14 days)
X
End 
of 
Treatment(early 
discontinuation not due to disease 
progression)
X
13.0 MEASUREMENT OF EFFECT
All subjects will be evaluated during (including pre- and post-dose) cycle 1, 8 (i.e. end of 
month 6), and at the end of months 9 and 12 by physical examination, white blood cell counts 
(WBC), and measurements of any initially elevated serum markers due to tumor, including 
calcium, lactose dehydrogenase (LDH), alkaline phosphatase, and liver enzymes.
Complete re-staging by imaging scans and evaluations for molecular response by gene 
rearrangement studies (i.e. minimal residual disease) will also be done at these time points.
Thereafter, follow-up for lymphoma subjects will be conducted at least every 6 months in year 
2. After this period, patients will be followed as routine/standard-of-care approximately every 
6 months or sooner if clinically indicated for up to 5 years from treatment initiation for the 
purpose of future trial results updates.
Comparison to baseline/pre-study evaluations will be made for imaging scans, bone marrow 
biopsy (if marrow was initially involved), and peripheral blood smear (if applicable). 
13.1
Response Assessment
Response is assessed on the basis of clinical, radiologic, molecular and pathologic (i.e. 
bone marrow) criteria. Studies will be performed after belinostat end of cycle 3, cycles  
8 (end of month 6), at the end of months 9 and 12 under this study, and then every 6 
months up to year 2.

CT scans remain the standard for evaluation of nodal disease. 
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o
If non-contrast CT-PET is obtained, for instance in patients where IV contrast is 
contraindicated due to allergy or renal dysfunction, it is recommended that only 
the CT portion be used for response assessment during treatment. 
o
After the completion of treatment, the PET portion can be useful for confirming 
CR or relapse/progression, however positive PET findings could be seen in 
reactive lymph nodes, especially in patients with HTLV-1. 
o
Thoracic, abdominal, and pelvic scans will be performed for restaging even if 
those areas were not initially involved because of the unpredictable pattern of 
recurrence in ATLL. 

A bone marrow aspirate and biopsy should only be performed to confirm a CR if they 
were initially positive or if it is clinically indicated by new abnormalities in the 
peripheral blood counts or blood smear

Evaluation for minimal residual disease will be done by standard flow cytometry and 
T-cell receptor gene rearrangement studies.
13.2
Complete Response (CR)
The designation of Complete Response (CR) requires the following:

Complete disappearance of all detectable clinical evidence of disease and disease-
related symptoms if present before therapy.

Absolute lymphocyte count must be < 3.5 X 103/l with no more than 5% of 
circulating typical lymphocytes cells on peripheral blood by morphology

Normalization of those biochemical abnormalities (e.g. calcium) definitely 
assignable to the tumor.

All lymph nodes and nodal masses must have regressed on CT to normal size (1.5 
cm in their greatest transverse diameter for nodes > 1.5 cm before therapy). 
Previously involved nodes that were 1.1 to 1.5 cm in their long axis and more than 
1.0 cm in their short axis before treatment must have decreased to 1.0 cm in their 
short axis after treatment.  (Lymph nodes should be considered abnormal if the long 
axis is more than 1.5 cm regardless of the short axis. If a lymph node has a long axis 
of 1.1 to 1.5 cm, it should only be considered abnormal if its short axis is more than 
1.0. Lymph nodes ≤ 1.0 x ≤ 1.0 cm will not be considered as abnormal for relapse or 
progressive disease).

The spleen and/or liver, if considered to be enlarged before therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical examination 
and should be considered normal size by imaging studies, and nodules related to 
lymphoma should disappear. However, determination of splenic involvement is not 
always reliable because a spleen considered normal in size may still contain 
lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood 
volume, the use of hematopoietic growth factors, or other causes other than 
lymphoma.

If the bone marrow was involved by lymphoma before treatment, the infiltrate must 
be cleared on repeat bone marrow biopsy. The biopsy sample on which this 
determination is made must be adequate. If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample that is 
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negative by immunohistochemistry but that demonstrates a small population of clonal 
lymphocytes by flow cytometry will be considered a CR until data become available 
demonstrating clear difference in subject outcome.

No new sites of disease.

May have minimal residual disease at the molecular level.

Stable complete response: Response must be durable for at least 1 month.

Standard CT-PET if available and if covered by insurance may be used to confirm 
CR.
13.3
Partial Response (PR)
The designation of Partial Response (PR) requires the following:

At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of 
the largest dominant nodes or nodal masses. These nodes or masses should be 
selected according to all of the following: they should be clearly measurable in at 
least two perpendicular dimensions, if possible they should be from disparate regions 
of the body, and they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved.

No increase should be observed in the size of other nodes, liver, or spleen.

Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single 
nodules, in the greatest transverse diameter.

With the exception of splenic and hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present.

Bone marrow assessment is irrelevant for determination of a PR if positive before 
treatment. However, if positive, the cell type should be specified in the report, (e.g., 
large-cell lymphoma or small neoplastic B cells). 
o
Subjects who achieve a CR by the above criteria (Section 14.2), but who have 
persistent morphologic bone marrow involvement will be considered partial 
responders.
o
In cases when the bone marrow was involved before therapy and a clinical CR 
was achieved, but no bone marrow assessment was performed after treatment, 
subjects should also be considered partial responders.

No new sites of disease should be observed

At least 50% decrease in absolute lymphocyte count from baseline if it continues to 
be > 3,500 cells/µl.

(Stable Partial Response :) Response must be durable for at least 1 month.

Standard CT-PET if available and if covered by insurance may be used to help 
determine response and to evaluate any suspicious new disease.
13.4
Stable Disease (SD)
Stable Disease is defined as less than a PR (see above) but is not progressive disease (see 
below).
13.5
Progressive Disease (PD, non-responders)
The designation of Progressive Disease (PD, non-responders) require the following:
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
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. 
o
If CT/PET is done FDG uptake in a previously unaffected site should only be 
considered relapsed or progressive disease after confirmation with other 
modalities. 
o
In subjects with no prior history of pulmonary lymphoma, new lung nodules 
identified by CT are mostly benign. Thus, a therapeutic decision should not be 
made solely on the basis of the PET without histologic confirmation.

At least a ≥ 50% increase from nadir in the SPD of any previously involved nodes or 
in a single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). 

To be considered progressive disease, a lymph node with a diameter of the short axis 
of less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 x1.5 cm or more than 
1.5 cm in the long axis.

At least a 50% increase in the longest diameter of any single previously identified 
node more than 1 cm in its short axis.

At least 50% increase in absolute lymphocyte count from the greater of the following: 
baseline absolute lymphocyte count or 3.5 X 103/l (cut off normal absolute 
lymphocyte count in patients with HTLV-1). To meet PD criteria the 50% increase 
in absolute lymphocyte should be confirmed by repeat CBC on or after 3 days. Note: 
A transient increase in absolute lymphocyte count during cycle 1, which may 
occur after belinostat (possibly due to re-activation of HTLV-1), and transient 
(sporadic) skin lesions that disappear during treatment will not be considered 
disease progression.

Standard CT-PET if available and if covered by insurance may be used to help 
determine response and to evaluate any suspicious new disease.
13.6
Recurrent Disease
Recurrent disease is defined as the appearance of tumor following documentation of a
 
complete remission.
13.7
Time to Response
Time to response is defined as time from the first dose of chemotherapy until 
documentation of first response.
13.8
Time to progression
Time to progression is defined as time from initiation of chemotherapy to documentation 
of first progression.
14.0 ADVERSE EVENTS
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for   Adverse Events (CTCAE) version 4.03 or subsequent new versions will be utilized for 
adverse event reporting.
14.1
Purpose
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies, as well as those who 
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will enroll in future studies using similar agents.  Adverse events are reported in a routine 
manner at scheduled times during a trial.  Additionally, certain adverse events must be 
reported in an expedited manner for timelier monitoring of patient safety and care.
14.2
Adverse Event
Adverse Event (AE): Can be any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, 
medical treatment, or procedure without judgment about causality.  An adverse event can 
arise from any use and from any route of administration, formulation, or dose including 
an overdose. This includes any newly occurring event or a previous condition that has 
increased in severity or frequency since initiation of a drug, medical treatment, or 
procedure.
Abnormal Findings
In any clinical assessment, a value outside the normal or reference range (such as a 
clinical laboratory, vital sign, or ECG) will not be reported or assessed as an AE unless 
that value is considered to be of clinical significance by the investigator.  A value of 
clinical significance is one that leads to discontinuation or delay in protocol treatment, 
dose modification, therapeutic intervention*, or is considered to be a clinically significant 
new finding or change from baseline by the investigator.
*Transfusion support administered to offset clinical symptoms of anemia or 
thrombocytopenia will not be considered therapeutic intervention.
Signs and Symptoms
Signs/symptoms resulting from an underlying clinical diagnosis should be documented 
as one comprehensive AE.  If no underlying clinical diagnosis can be identified, each 
sign/symptom should be reported as a separate independent event.  (A new or worsening 
event resulting from an underlying clinical diagnosis or a reaction to concurrent 
medications should be documented as a separate independent AE unless it is within the 
normal range of fluctuation for that patient.)
Grade Changes/Fluctuations
AEs will be reported at the maximum grade/severity experienced for the duration of the 
event.  Should one particular event warrant further investigation, additional details may 
be collected at the discretion of the Principal Investigator.
Progression of Disease
Progression of disease, if documented in accordance to standard of care, should not be 
reported as an AE.
Tests and Procedures
Tests and procedures should not be reported as AEs.  The underlying clinical diagnosis 
(or sign/symptom in the event an underlying clinical diagnosis is not known) requiring 
testing or a procedure, should be reported as an adverse event if it meets criteria for 
reporting.
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14.3
Serious Adverse Events (see also Appendix A)
Serious AE (SAE) means any untoward medical occurrence that occurs at any dose:
1. Results in death.
2. Is life-threatening.
The term "life-threatening" in the definition of "serious" refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe).
3. Requires inpatient hospitalization or prolongation of present hospitalization.
Elective hospitalization to simplify protocol treatment/evaluations or to treat a 
baseline condition that did not worsen from baseline will not be considered an SAE.
4. Results in persistent or significant disability/incapacity.
Disability is defined as a substantial disruption of a person’s ability to conduct normal 
life functions.
5. Is a congenital anomaly/birth defect.
6. Is a medically important event.
A medically important event may not be immediately life threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above, or involves suspected 
transmission via a medicinal product of an infectious agent.   Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an 
infectious agent.
Clarification should be made between the terms serious and severe because they ARE 
NOT synonymous.  The term severe is often used to describe the intensity (severity) 
of a specific event (as in mild, moderate, or severe myocardial infarction); the event 
itself, however, may be of relatively minor medical significance (such as a severe 
headache).  This is NOT the same as serious, which is based on patient/event outcome 
or an action criterion described above and is usually associated with events that pose 
a threat to a patient’s life or functioning.  A severe AE does not necessarily need to 
be considered serious.  For example, persistent nausea of several hours duration may 
be considered severe nausea but not an SAE.  On the other hand, a stroke resulting in 
only a minor degree of disability may be considered mild but would be defined as an 
SAE based on the above noted criteria.  Seriousness (not severity) serves as a guide 
for defining regulatory reporting obligations.
14.4
Adverse Event Collection Period
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In this protocol, adverse events include only treatment-emergent adverse events.  A 
treatment-emergent adverse event (TEAE) is defined as any event that begins or worsens 
after the start of protocol treatment.  All baseline-emergent adverse events, any event that 
begins or worsens after completion of the informed consent but prior to the start of 
protocol treatment, should be reported as a Baseline/Comorbid Condition.
All adverse events that occur within ≤ 30 days of the last dose of study therapy will be 
reported and followed until resolution.  Resolution is defined as a return to baseline status 
or the stabilization of an event with the expectation that it will remain chronic.  
(Exception: If a patient begins an alternative therapy that confounds accurate assessment 
of AEs within ≤ 30 days of the last dose of study therapy, all adverse event collection 
will stop and any ongoing events will be left open.)
14.5
Adverse Event Reporting Requirements
The information to be reported in AEs will be assessed by and assigned severity using 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE), Version 4.03.  The NCI CTCAE provides descriptive terminology and a 
grading scale for each adverse event listed.  A copy of the NCI CTCAE v4.03can be 
downloaded 
from 
the 
CTEP 
home 
page 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html).
Information to be reported in the description of each adverse event may be included, but 
is not limited to:
1. Clinical Diagnosis of the event as determined by NCI CTCAE, Version 
4.03descriptive terminology.  If no clinical diagnosis can be identified, each 
sign/symptom should be reported as a separate independent event.
2. Date of onset of the AE (start date).
3. Date of resolution of the AE (end date).
4. Severity of the event determined by NCI CTCAE, Version 4.03 grading scale.
5. Relationship of the AE to study therapy.  Categorized as follows:
Definite
The adverse event is clearly related to the investigational agent(s)
Probable
The adverse event is likely related to the investigational agent(s)
Possible
The adverse event may be related to the investigational agent(s)
Unlikely
The adverse event is doubtfully related to the investigational agent(s)
Unrelated
The adverse event is clearly not related to the investigational agent(s)
6. Whether or not the AE is Serious or Not Serious as defined in Section 15.3 Serious 
Adverse Events.
7. Whether the AE is Suspected and/or Unexpected.
Suspected
Any AE for which there is a reasonable possibility that the drug caused 
the AE. For the purposes of expedited safety reporting, ‘reasonable 
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possibility’ means there is evidence to suggest a causal relationship 
between the drug and the AE.
Unexpected
Any AE for which the nature or severity of the event is not consistent 
with the applicable product information, e.g., the Investigator’s 
Brochure or Package Insert.
8. Action taken as a result of the AE.
9. Outcome.
14.6
Expedited Adverse Event Reporting Requirements
All AEs, regardless if serious or not, will be described in the source documents, reported 
on the applicable AE page of the CRFs, and entered into Velos.  However, certain adverse 
events must also be reported in an expedited manner for timelier monitoring of patient 
safety and care.  Appendix A provides information about these expedited reporting 
requirements.
15.0 STATISTICAL CONSIDERATIONS
15.1
Overview
The primary objectives of this prospective clinical study in ATLL patients with leukemia 
types (chronic or acute) receiving belinostat-based treatment are the following:
1)
To determine the complete molecular response (CMR) rate after adding belinostat 
as consolidation therapy for ATLL during AZT-based maintenance treatment.
2)
To determine the safety of adding belinostat to AZT-based maintenance regimen 
(+/- IFNα or PEG-IFNα) as consolidation therapy for ATLL.
Secondary objectives are to determine best clinical response, failure-free survival, and 
overall survival. Correlative and scientific endpoints in this study include investigating 
whether belinostat disrupts HTLV-1 latency in vivo, determining whether belinostat 
provokes a cytotoxic T-cell response in vivo, measuring the overall impact of 
belinostat/AZT on HTLV-1 proviral load in vivo, and determining its effects on histone 
acetylation, HTLV-1 basic zipper factor (HBZ) and Tax expression. 
15.2
Definitions

A patient is considered to be on study at the time an informed consent is signed.

Evaluable patients will be study-eligible patients who initiate the study treatment, 
receiving at least one (1) dose of belinostat, regardless of treatment being completed. 
However, those patients who will be considered Evaluable for the primary 
endpoint “molecular response” will be study-eligible patients who receive at least 
three (3) doses of belinostat (with AZT), have evaluable disease at baseline and at 
least one post-baseline molecular disease assessment. All evaluable patients will be 
assessed for treatment response, toxicity, disease progression, and survival.

Patients are considered to be on treatment as long as they continue to receive study 
treatment.  Patients who are off treatment will remain on study and will be followed 
for toxicity, response, progression, and survival.
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Exclusions (not evaluable patients) from study:

Patients who are enrolled on study but not treated (do not receive any dose of study 
treatment) will be excluded from all analyses. Reasons for such withdrawals, such as 
eligibility not confirmed or consent withdrawn, will be characterized.

Any patient who is treated but later found to be ineligible for study (a “protocol 
violation”) will be withdrawn from study but followed for survival and toxicity. Such 
patient experience will be characterized separately from that of evaluable patients.

Failure–free survival (FFS) will be measured from the date of treatment initiation 
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 will 
be censored at the last documented date of failure-free status.

Overall survival (OS) will be measured from the date of initiation of study treatment 
until date of death from any cause. In the absence of death, the follow-up will be 
censored at date last known to be alive (censored observation).
15.3
Sample Size
This study plans to enroll up to a total minimum of 10 (in the case primary end point is 
reached) or maximum of 20 evaluable patients with the leukemic form of ATLL within 
a period of 5 years and follow them for a minimum of 1 year to obtain information on 
response to belinostat-based treatment, disease progression and overall survival. 
Expected time to study completion is approximately 6 years from date open to 
enrollment. The main objective of this study is to investigate whether adding belinostat 
to AZT-based consolidation therapy eradicates residual ATLL. The study can be closed 
at protocol Chair’s discretion after reaching the primary end point. A study with 20 
patients treated with belinostat will have 80% power to detect a complete molecular 
response (CMR) rate of 20.2% based on a one-sided binomial test at the 10% significance 
level (7.6% actual significance level), and assuming an expected complete molecular 
response rate without treatment of 5% (1/20).  (Hintze, J. (2014). PASS 13. NCSS, LLC. 
Kaysville, Utah, USA. www.ncss.com.) Based on a sample size n=10, we can calculate 
the 90% lower-limit confidence interval from the observed complete molecular response 
rate (P). With n=10, two or more complete molecular responses are needed to conclude 
at the target 10% one sided significance level that the true rate is greater than 5%. Note 
that the lower limit is 5.5% if observed rate is 20%, 11.6% if observed rate is 30% (3 
responses in 10), and 18.8% if observed rate is 40% (4 responses in 10 patients). A 
sample size of 10 produces a one-sided 90% lower-limit confidence interval with a 
distance from the observed sample proportion 0.4 to the lower limit that is equal to 0.212.
───────────────
Confidence Intervals for One Proportion
Numeric Results for One-Sided Lower-Limit Confidence Intervals for One Proportion 
Confidence Interval Formula: Exact (Clopper-Pearson)
 
 
Target
Actual
 
 
 
Distance
 
Sample
Distance
Distance
Observed
 
 
from P to
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Confidence
Size
from P to
from P to
Proportion
Lower
Upper
Limit if
Level
(N)
Lower Limit
Lower Limit
(P)
Limit
Limit
P = 0.5
0.9
10
 
0.145
0.2
0.055
1
0.233
0.9
10
 
0.184
0.3
0.116
1
0.233
0.9
10
 
0.212
0.4
0.188
1
0.233
0.9
10
 
0.233
0.5
0.267
1
0.233
0.9
20
 
0.11
0.2
0.09
1
0.162
0.9
20
 
0.134
0.3
0.166
1
0.162
0.9
20
 
0.151
0.4
0.249
1
0.162
0.9
20
 
0.162
0.5
0.338
1
0.162
 
Tests for One Proportion
 
Numeric Results for Testing One Proportion using the Exact Test 
───────────────────────────
Alternative Hypothesis: One-Sided   (H0: P ≤ P0 vs. H1: P > P0)
                                  Proportion     Proportion                                                                                 
                                    Given H0       Given H1      Difference        Target         Actual       Reject H0
Power*                 n                 P0                  P1             P1-P0         Alpha       Alpha*†              If R ≥
0.80000               10          0.0500            0.2710            0.2210          0.100           0.086                    2
0.80000               20          0.0500            0.2020            0.1520          0.100           0.075                    3
 
15.4
Statistical Analyses
Analysis of primary and secondary endpoints will be based on all evaluable patients, as 
per Section 16.2.
Adverse events and toxicities will be tabulated by severity and attribution to treatment 
according to the NCI CTCAE 4.03 criteria.
Baseline descriptive statistics will be provided for study patients. These will include 
demographic variables (age, sex and race), and disease characteristics (tumor stage, 
tumor size, lymph nodes).  
The complete molecular response (CMR) rate, as well as overall clinical response rate 
(CR+PR) and rates of the individual categories of best clinical response (CR, PR, SD, 
and PD) will be estimated by the percentage of patients achieving each specific response 
type. The precision of these estimates will be characterized by the corresponding 95% 
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confidence intervals using the exact binomial method. The duration of response will be 
summarized (median and range) for each response type.
Addressing the primary objective, we will also report the proportion of patients with 
minimal (molecular) residual disease present among responders at the end of months 2, 
6, 9, and 12.
Addressing secondary objectives, the Kaplan-Meier method will be used in the analysis 
of failure-free survival (FFS) and overall survival (OS). We will report median FFS and 
OS times and corresponding rates at 6 and 12 months. 
Addressing other secondary objectives, we 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.
16.0 DATA REPORTING
Data must be submitted according to the protocol requirements for all patients registered.  
Patients for whom documentation is inadequate to determine eligibility will generally be 
deemed ineligible.
16.1
Data and Safety Monitoring
The Sylvester Comprehensive Cancer Center (SCCC) Data and Safety Monitoring 
Committee (DSMC) will monitor this clinical trial according to the Cancer Center’s DSM 
Plan.  In its oversight capacity, the DSMC bears responsibility for suspending or 
terminating this study.  DSMC oversight of the conduct of this trial includes ongoing 
review of accrual and adverse event (AE) data, and periodic review of the combination 
therapy of belinostat with AZT (and Interferon-alfa2b when applicable). The guidelines 
appearing in the Section 17.2is offered for DSMC consideration in assessing AEs.  In 
addition, the DSMC will review reports from all audits, site visits, or study reviews 
pertaining to this clinical trial and take appropriate action.  The SCCC DSM Plan to 
which this study is subject can also be found at www.sylvester.org.
16.2
Early Stopping Rules (for Interim Monitoring of Toxicity)
In the following sections, we provide stopping guidelines for the DSMC in its review of 
accumulating data on toxicity over the course of this trial. The proposed guidelines were 
developed using Bayesian methods, which can be applied at any stage of enrollment 
without advance specification of the number of interim analyses to be performed, or the 
number of patients evaluable for toxicity at the time such assessments are made. Under 
the Bayesian method, we assign a prior probability (level of belief at the start of the trial) 
to a range of possible values for the true toxicity rate.  As data on treated patients become 
available, each of these probability distributions is revised and the resulting posterior 
probability becomes the basis for recommending either early termination or continuation 
of the study. Underlying assumptions for the prior distributions are also presented.
16.2.1 Guidelines for interim monitoring of toxicity
If a treatment-related (possible, probable or definite) death occurs, enrollment will be suspended 
and continuation of the study will be reassessed by the DSMC. 
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Due to the nature of the disease and the patients' preexisting conditions, we expect grade 3 or 4 
hematologic toxicities to occur in at least 50% of the already bone marrow-compromised 
leukemic patients. The hematologic toxicities we expect to occur are leukopenia (low white 
blood cell count), neutropenia (low percentage and absolute neutrophil count), lymphopenia (low 
percentage and absolute lymphocyte count), anemia (low hemoglobin and hematocrit), and 
thrombocytopenia (low platelets). 
Unexpected grade 3 and 4 treatment–related (possible, probable, or definite) toxicities may occur 
in 10% or less of the patients on study.  
We suggest as a guideline for possible early termination, evidence that the proportion of patients 
experiencing unexpected treatment-related grade 3 or 4 toxicity exceeds 15% (see Section 9.0 for 
expected toxicity).  Specifically, we suggest as a guideline for early termination a posterior 
probability of 95% or higher that the rate of unexpected treatment-related grade 3 or higher 
toxicity exceeds 15%. The table below present’s specific instances where this guideline is met, 
suggesting early termination due to evidence of an excessive level of unexpected toxicity. 
Table 4: Early Termination Guidelines for Unexpected Toxicity
Number of patients experiencing 
unexpected, treatment-related grade 3 
or 4 toxicity (%)
Number of patients 
assessed for toxicity
5
3 to 6
6
7 to 10
7
11 to 14
8
15 to 19
To illustrate the stopping guidelines, suppose that 5 evaluable patients have been 
assessed for toxicity and 3 of them have experienced unexpected treatment-related 
grade 3 or 4 toxicity (row 2 of the above table.) Under this circumstance, the 
observed rate of unacceptable unexpected toxicity is 60%, resulting in a posterior 
probability of 96.7% that the true underlying rate exceeds 15%, thereby 
suggesting early termination of study. 
Posterior probabilities for the table above are calculated under a weak prior beta 
distribution with parameters β1=0.2 and β2=1.8, which corresponds to an 
expected unacceptable-toxicity rate of 10% based on very limited information, 
roughly equal to having studied 2 patients. This prior distribution implies also a 
prior chance of only 21.6% that true rate of unacceptable unexpected toxicity is 
15% or greater. 
16.3
Interim Review of Safety Data (Role of the Research Team)
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The protocol management team, consisting of two of the investigators for this study AND 
the statistician, will continuously monitor study accruals, toxicities, and response to 
treatment.
The protocol management team may convene at their discretion to review the 
accumulated safety data.  Accrual will continue as long as the protocol management team 
has no clinical concerns regarding the incidence of unexpected, treatment-related Grade 
3 or 4 adverse events. Within 10 working days, after 5 patients enrolled in the trial are 
treated for at least one month the protocol management team will review the safety data.
Consideration must be given to amending or closing this study if the incidence of Grade 
3 or higher adverse events is exceedingly high compared to the incidence reported for 
previous or ongoing trials.
16.4
Study Termination
The DSMC/IRB retains the right to terminate the study for any cause, suspend patient 
enrollment and related study materials from the study site at any time. Specific instances, 
which may precipitate such termination at a site, are as follows:

Deviation from protocol requirements

Inaccurate and/or incomplete data recording on a recurrent basis

Unauthorized use of investigational products or administration to any subject not 
enrolled as part of the protocol

Delinquent fulfillment of obligation on the part of the Investigator with regard to 
adverse reaction reporting, unacceptable patient enrollment or other 
responsibilities as outlined in this protocol.
17.0 STUDY MONITORING
This study will be monitored according to http://research.med.miami.edu/clinical-
research/crors/monitoring and http://uresearch.miami.edu/regulatory-compliance-
services/rcqa. 
18.0 INVESTIGATOR RESPONSIBILITIES
18.1
Investigator Responsibility/Performance
The investigator will ensure that this study is conducted in accordance with all 
regulations governing the protection of human subjects. The investigator will ensure that 
all work and services described in or associated with this protocol will be conducted in 
accordance with the investigational plan, applicable regulations, and the highest 
standards of medical and clinical research practice.
18.2
Confidentiality
The investigator must ensure that each subject’s anonymity will be maintained and each 
subject’s identity will be protected from unauthorized parties.  A number will be assigned 
to each subject upon study entry and the number and the subject’s initials will be used to 
identify the subject for the duration of the study.  The investigator will maintain all 
documents related to this study in strict confidence.
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18.3
Informed Consent and Permission to Use Protected Health Information
It is the responsibility of the investigator to obtain written informed consent from each 
subject participating in this study after adequate explanation, in lay language, of the 
methods, objectives, anticipated benefits, and potential hazards of the study.  The 
investigator must also explain that the subject is completely free to refuse to enter the 
study or to discontinue participation at any time (for any reason) and receive alternative 
conventional therapy as indicated.  Prior to study participation, each subject will sign an 
IRB approved informed consent form and receive a copy of same (and information 
leaflet, if appropriate).  For subjects not qualified or able to give legal consent, consent 
must be obtained from their legally authorized representative (LAR). The investigator or 
designee must explain to the subject before enrollment into the study that for evaluation 
of study results, the subject’s protected health information obtained during the study may 
be shared with the study sponsor, regulatory agencies, and the IRB.  It is the 
investigator’s (or designee’s) responsibility to obtain permission to use protected health 
information per HIPAA from each subject, or if appropriate, the subjects’ parent or legal 
guardian.
18.4
Source Documentation and Investigator Files
The investigator must maintain adequate and accurate records to fully document the 
conduct of the study and to ensure that study data can be subsequently verified.  These 
documents should be classified into two separate categories:  (1) investigator study file 
and (2) subject clinical source documents that corroborate data collected on the CRF’s.  
Subject clinical source documents may include hospital/clinic patient records; physician's 
and nurse's notes; appointment book; original laboratory, ECG, EEG, radiology, 
pathology, and special assessment reports; pharmacy dispensing records; subject diaries; 
signed informed consent forms; and consultant letters.  When the CRF or any form is 
used as the source document, this must be clearly stated in the investigator study file. 
Minimally, the following be documented in source documents:
Medical history/physical condition and diagnosis of the subject before involvement in 
the study sufficient to verify protocol entry criteria
Study number, assigned subject number, and verification that written informed consent 
was obtained (each recorded in dated and signed notes on the day of entry into the 
study)
Progress notes for each subject visit
Documentation of treatment
Laboratory test results
Adverse events (action taken and resolution)
Condition and response of subject upon completion of or early termination from the 
study
18.5
Recording and Processing of Data
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If using hard copies of CRF’s, study center personnel will complete individual CRF’s in 
black ink.  All corrections to entered data will be made by drawing a single line through 
the information to be corrected without obscuring it.  All corrections will be initialed, 
dated and explained, if necessary.  The use of “white-out” or obscuring correction tape 
will be prohibited.  A CRF is required for every patient who received any amount of 
study treatment.  The investigator will ensure that the CRF’s are accurate, complete, 
legible and timely. Separate source records are required to support all CRF entries except 
those for which use of the CRF as source document is clearly allowed per note in the 
investigator study file.
Data must be submitted according to the protocol requirements for ALL patients 
registered.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible.
Data must be submitted according to the protocol requirements for ALL patients 
registered.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible.
A list of forms to be submitted, as well as expectation dates may be found in Appendix 
B.
18.6
Non-Protocol Research
No investigative procedures other than those described in this protocol will be undertaken 
on the enrolled subjects without the agreement of the IRB.
18.7
Ethics
The investigator agrees to conduct the study in compliance with the protocol, current 
good clinical practices, and all applicable (local, FDA) regulatory guidelines and 
standard of ethics.
UM Ethics Programs’ Research Ethics Consultation Service (RECS) is a free resource 
for 
UM 
Researchers. 
 
See 
the 
website 
for 
further 
information: 
http://www.miami.edu/index.php/ethics/projects/recs/
18.8
Essential documents for the conduct of a clinical trial
Essential documents are those documents with individually and collectively permit 
evaluation of the conduct of a trial and the quality of the data produced. The following 
documents should be on file: 1) 1572 (for studies involving IND drugs or devices); 2) 
CV’s and license of all Investigators; 3) IRB documentation/correspondance and 4) 
Documentation of IRB certification
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9. Waldmann TA. Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune 
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13. Phillips AA, Shapira I, Willim RD, et al. A critical analysis of prognostic factors in North 
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Cancer. 2010 Jul 15;116(14):3438-46. doi: 10.1002/cncr.25147.
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14. Ceesay MM1, Matutes E, Taylor GP, Fields P, Cavenagh J, Simpson S, Ho A, Devereux S, 
Mufti GJ, Pagliuca A. Phase II study on combination therapy with CHOP-Zenapax for 
HTLV-1 associated adult T-cell leukaemia/lymphoma (ATLL). Leuk Res. 2012 
Jul;36(7):857-61.
15. Ratner L, Harrington W, Feng X, et al; AIDS Malignancy Consortium. Human T cell 
leukemia virus reactivation with progression of adult T-cell leukemia-lymphoma.PLoS 
One. 2009;4(2):e4420.
16. Tsukasaki K, Utsunomiya A, Fukuda H, et al; Japan Clinical Oncology Group Study 
JCOG9801. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell 
leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol. 
2007 Dec 1;25(34):5458-64.
17. Gill PS, Harrington W Jr, Kaplan MH, et al. Treatment of adult T-cell leukemia-lymphoma 
with a combination of interferon alfa and zidovudine.  N Engl J Med. 1995;332:1744-1748.
18. Hermine O., Bouscary D., Gessain A., et al. Treatment of adult T-cell leukemia-lymphoma 
with zidovudine and interferon alfa.  N Engl J Med. 1995;332:1749-1751.
19. Matutes E, Taylor GP, Cavenagh J, et al.  Interferon alpha and zidovudine therapy in adult 
T-cell leukaemia lymphoma: response and outcome in 15 patients.  Br J Haematol.  
2001;113:779-784.
20. Hermine O, Allard I, Levy V, et al.  A prospective phase II clinical trial with the use of 
zidovudine and interferon-alpha in the acute and lymphoma forms of adult T-cell 
leukemia/lymphoma.  Hematol J.2002;3:276-282.
21. Ramos JC, et al. IRF-4 and c-Rel expression in antiviral therapy resistant adult T-cell 
leukemia/lymphoma.  Blood 2007. 109:3060-3068.
22. Bazarbachi A. et al. Meta-analysis on the use of zidovudine and interferon-alfa in adult T-
cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin 
Oncol. 2010 Sep 20; 28 (27):4177-83. Epub 2010 Jun 28
23. Tsukasaki K, Hermine O, Bazarbachi A, et al. Definition, prognostic factors, treatment, 
and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international 
consensus meeting. J Clin Oncol. 2009 Jan 20;27(3):453-9.
24. Ego T, et al. The interaction of HTLV-1 Tax with HDAC1 negatively regulates the viral 
gene expression. Oncogene 2002 Oct 17;21(47):7241-6.
25. Matsuoka M, Green PL. The HBZ gene, a key player in HTLV-1 pathogenesis. 
Retrovirology. 2009 Aug 3;6:71.
26. Lenzmeier BA, et al. Human T-cell leukemia virus type 1 Tax requires direct access to 
DNA for recruitment of CREB binding protein to the viral promoter.Mol Cell Biol. 1998 
Feb;18(2):721-31.
27. Lezin A, et al.Histone deacetylase mediated transcriptional activation reduces proviral 
loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients. Blood. 2007 
Nov 15;110 (10):3722-8.
28. Afonso PV, et al. Highly active antiretroviral treatment against STLV-1 infection 
combining reverse transcriptase and HDAC inhibitors.Blood. 2010 Nov 11;116(19):3802-
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29. BELEODAQ™ (belinostat) for injection [prescribing information] Henderson, NV: 
Spectrum Pharmaceuticals, Inc; 2014.
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30. O’Connor OA, Masszi T, Savage KJ, et al. Belinostat, a novel pan-histone deacetylase 
inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): 
results from the BELIEF trial. J Clin Oncol. 2013;31(Suppl) abstract 8507.
31. Mori N, et al. Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells. 
Blood. 1999 Apr 1;93(7):2360-8.
32. Sun SC, Yamaoka S. Activation of NF-kappaB by HTLV-I and implications for cell 
transformation. Oncogene. 2005 Sep 5;24(39):5952-64.
33. Jeang KT. HTLV-1 and adult T-cell leukemia: insights into viral transformation of cells 30 
years after virus discovery. J Formos Med Assoc. 2010 Oct;109(10):688-93
34. Lairmore MD, et al. Animal models for human T-lymphotropic virus type 1 (HTLV-1) 
infection and transformation. Oncogene. 2005 Sep 5;24(39):6005-15.
35. Bazarbachi A, Suarez F, Fields P, Hermine O. How I treat adult T-cell 
leukemia/lymphoma. Blood. 2011 Aug 18;118(7):1736-45. doi: 10.1182/blood-2011-03-
345702. Epub 2011 Jun 14.
36. van Dongen JJ, et al.  Design and standardization of PCR primers and protocols for 
detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect 
lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. 
Leukemia.  2003. 17:2257-317.
37. Komanduri KV, St John LS, de Lima M, McMannis J, Rosinski S, McNiece I, Bryan SG, 
Kaur I, Martin S, Wieder ED, Worth L, Cooper LJ, Petropoulos D, Molldrem JJ, Champlin 
RE, Shpall EJ. Delayed immune reconstitution after cord blood transplantation is 
characterized by impaired thymopoiesis and late memory T-cell skewing. Blood. 
2007;110(13):4543-51.
38. Martins SL, St John LS, Champlin RE, Wieder ED, McMannis J, Molldrem JJ, Komanduri 
KV. Functional assessment and specific depletion of alloreactive human T cells using flow 
cytometry. Blood. 2004;104(12):3429-36.
39. Komanduri KV, Donahoe SM, Moretto WJ, Schmidt DK, Gillespie G, Ogg GS, Roederer 
M, Nixon DF, McCune JM. Direct measurement of CD4+ and CD8+ T-cell responses to 
CMV in HIV-1 infected subjects. Virology. 2001;279(2):459-30.
40. Ozdemir E, St John LS, Gillespie G, Rowland-Jones S, Champlin RE, Molldrem JJ, 
Komanduri KV. Cytomegalovirus reactivation following allogeneic stem cell 
transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T 
cells. Blood. 2002;100(10):3690-7.
41. Kim TK, St John LS, Wieder ED, Khalili J, Ma Q, Komanduri KV. Human late memory 
CD8+ T cells have a distinct cytokine signature characterized by CC chemokine production 
without IL-2 production. J Immunol. 2009;183(10):6167-74.
42. Oncogenic HTLV Tax Suppression of Primary Innate Immune Signaling Pathway. Hyun 
J, Ramos JC, Toomey N. J Virol. 2015 May 1;89(9):4880-93.
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APPENDIX A: EXPEDITED ADVERSE EVENT (AE) REPORTING REQUIREMENTS
For all AEs that meet criteria for expedited reporting, the Principal Investigator (PI) is obligated 
to pursue and provide follow-up reporting information until the event has resolved or until an 
acceptable medical endpoint has been reached (i.e. for the duration specified in the protocol), or 
the patient is lost to follow-up.
The PI and all applicable research study team members should become familiar with the safety 
profile of the investigational agent(s) and/or intervention at the start of the study and for the 
duration of the research, e.g. by reviewing the Investigator’s Brochure (IB) and any Safety Reports 
released by the Sponsor, as applicable.
A. FDA Expedited Reporting
a.
Sponsor-Investigators i.e. IND Holders, have additional reporting requirements to the 
FDA and other committees, and should consult the applicable regulations and agency 
guidelines for these requirements.
b. Since this protocol involves the use of FDA IND agent(s), completion of the FDA 
MedWatch 3500A Reporting Form is required for Sponsor-Investigators.  The Form 
can be obtained electronically at: 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0483
34.pdf
i. All serious, unexpected (unanticipated) and suspected adverse events must be directly 
reported to the FDA within 15 calendar days of being made known to the Principal 
Investigator (PI).
ii. All fatal or life-threatening AEs must be directly reported to the FDA within 7 calendar 
days of being made known to the PI.
c.
For more information regarding reporting to the FDA, please refer to the FDA 
website for REPORTING GUIDELINES: 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm
B. IRB Expedited Reporting
a.
All Investigators should also be aware of local Institutional requirements for AE 
reporting.  For more information regarding the IRB policy, please refer to the UM 
HSRO’s Investigator Manual: http://hsro.med.miami.edu/documents/HRP-103_-
_INVESTIGATOR_MANUAL_4.11.2014.docx and the UM HSRO SOP on New 
Information (HRP-024) 
https://eprost.med.miami.edu/eProst/Doc/0/HLJ5OTJVQEH419E0I6QPT3B199/HRP
-024%20-%20SOP%20-%20New%20Information.docx
b. All AEs that are serious, unanticipated and probably related will be reported to the IRB 
within ten (10) working days of being made known to the PI.
c.
Events that are more frequent than anticipated or more severe than expected must be 
reported to the IRB within ten (10) working days of being made known to the PI.
d. All unanticipated deaths must be reported to the IRB within 24 hours of being made 
known to the PI.
APPENDIX B: PERFORMANCE STATUS SCALES
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As published in Am J Clin Oncol: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, 
McFadden ET, Carbone PP. Toxicity and Response Criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol 1982;5:649-655. The Eastern Cooperative Oncology Group, Robert 
Comis, MD, Group Chair.
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APPENDIX C: NYHA CLASSIFICATION OF HEART DISEASE
New York Heart Association (NYHA) classification of heart disease
NYHA Class
Symptoms
I
No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath 
when walking, climbing stairs etc.
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20–100 m). Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients.
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APPENDIX D: INFORMATION ON POSSIBLE DRUG INTERACTIONS
Information on Possible Interactions with Other Agents for Patients and Their Caregivers and Non-
Study Healthcare Team*
[Note to Investigators:  This suggested appendix consists of an “information sheet” to be handed 
to the patient at the time of enrollment.  Use or modify the text as appropriate for the study agent, 
so that the patient is aware of the risks and can communicate with their regular prescriber(s) and 
pharmacist.  A convenient wallet-sized information card is also included for the patient to clip out 
and retain at all times. This document must be IRB-reviewed and approved prior to patient 
distribution.]
The patient ____________________________ is enrolled on a clinical trial using the experimental 
agent belinostat(Beleodaq®).  This form is addressed to the patient, but includes important 
information for others who care for this patient.
Belinostat (Beleodaq®) interacts with some drugs.  Because of this, it is very important to tell 
your study doctors about all of your medicine before you start this study.  It is also very important 
to tell them if you stop taking any regular medicine, or if you start taking a new medicine while 
you take part in this study.  When you talk about your medicine with your study doctor, include 
medicine you buy without a prescription at the drug store (over-the-counter remedy), or herbal 
supplements such as St. John’s wort.
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:

Belinostat (Beleodaq®) must be used very carefully with other medicines such as 
carvedilol, levothyroxine, paracetamol, and raloxifene.  Combined use can lead to harmful 
side effects and/or reduce the effectiveness of those medications.

You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.

Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered harmful.

Your prescribers should consult a medical reference to see if any medicine they want to 
prescribe is on a list of drugs to avoid.

Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the generic 
name and determine, with the pharmacist’s help, whether there could be an adverse 
interaction.
Other medicines can be a problem with your study drug(s).

You should check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement.

Your regular prescriber should check a medical reference or call your study 
doctor before prescribing any new medicine for you.  Your study doctor’s 
name is
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_____________________________________ and he or she can be contacted at
_____________________________________.
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APPENDIX E: IMMUNOLOGIC ASSAYS
Venous blood will be collected in 3 green tubes (Sodium heparin or Lithium heparin) (10 ml 
capacity) from patients diagnosed with leukemia-type (chronic or acute) ATLL at baseline prior 
to the initiation of belinostat, and after belinostat at the end of week 1 cycle 1 (Day 8), and end of 
cycle 1 (Day 21). These tubes will be collected in addition to any blood required for standard 
diagnostic laboratory tests processed by the hospital (i.e. cell counts, serologies, chemistries, and 
flow cytometry studies). Collected blood specimens will be processed on the same day by the local 
lab. Peripheral blood mononuclear cell (PMBC) cells will be freshly isolated from peripheral blood 
by centrifugation using standard Lymphoprep (ficol) procedure. At any future collaborating sites, 
the extracted cells will be cryopreserved in liquid nitrogen for transport to Dr. Ramos’ s laboratory 
(University of Miami-Sylvester Comprehensive Cancer Center) at below shipping address. All 
assays described below have been validated in cryopreserved samples in prior clinical studies.
Immunologic Assays: In order to capture data defining the quantity, maturation/differentiation 
status and overall function of the recovering immune system, both phenotypic and functional flow 
cytometry panels will be employed to assess total numbers of mononuclear cell subsets, as well as 
global immune function, in addition to T cell responses directed at HTLV-1. Immunophenotyping: 
A modified version of the panels utilized to study immune reconstitution of cord blood transplant 
recipients will be employed (37). In multiple panels, the immunophenotyping will include staining 
for CD4, CD8, CD45RA, CD27 (to define naïve/memory CD4+ and CD8+T subsets); CD25, 
CD127 and intracellular Foxp3 staining (to define Treg, which may be altered by HDI therapy), 
CD14 (monocytes), CD16 and CD56 (NK cells), and CD19 (B cells). Studies of HTLV-1-specific 
and global T cell function antigen-specific T cell responses (including specific for HTLV-1, will 
be assessed using CFC, to assess polyfunctional T cell responses critical for protective immunity 
(e.g., secreting combinations of cytokines shown to be relevant for control of persistent 
retroviruses) (39-41). To assess the hypothesis that HTLV-1 specific CD8+ T cells will be 
augmented by this clinical strategy, antigen-specific responses by stimulating PBMCs will be 
assessed using the following antigens:  1) HTLV-1 lysates, 2) Purified HTLV-1 Tax protein; 3) 
super antigen staphylococcus enterotoxin B (SEB); 4) for CMV-seropositive donors (estimated to 
be >80% of HTLV-1+ patients), CMV pp65 and IE1 peptide mixtures. Using published methods 
(40-42), PBMCs will be stimulated for 6 hr and stained for CD4, CD8, CD27, CD45RA, and 
intracellular cytokines IL-2, IFN-α, TNF-α, and MIP1-b as previously described. FACS data will 
be acquired on a 4-laser, 15-color LSRII (Becton Dickinson) and will be analyzed using FlowJo 
software.
Shipping address:
Attn: Dr. Ramos Laboratory
University of Miami, Miller School of Medicine
Department of Hematology/Oncology (M877)
1501 NW 10thAvenue
Papanicolau (PAP) Building, Room 531
Miami, FL  33136
Tel: (305) 243-4605
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APPENDIX F: MOLECULAR EVALUATION/ ANALYSIS OF ATLL AND HTLV-
1+CLONES
Venous blood will be collected in 5 yellow top tubes (Acid Citrate Dextrose (ACD) solutions A/B 
additives –Trisodium citrate 22.0/13.2, citric acid 8.0/4.8 and dextrose 24.5/14.7 (in g/L)) (10 ml 
capacity) from patients diagnosed with leukemia-type (chronic or acute) ATLL prior to the 
initiation of AZT and belinostat. These tubes will be collected in addition to any blood required 
for standard diagnostic laboratory tests processed by the hospital (i.e. cell counts, serologies, 
chemistries, flow cytometry, and gene rearrangement studies) at baseline, 48-72 hours after 
belinostat treatment (i.e. Day 3 or 4), (cycle 1) Day 15, and end of cycles 3 (i.e. Day 21 of cycle 3 
or prior cycle 4), 8 (i.e. Day 21 of cycle 8), at the end of month 9 &12, and at the end of treatment 
visit.  Collected blood specimens will be processed on the same day by the local lab. Peripheral 
blood mononuclear cell (PMBC) cells will be freshly isolated from peripheral blood by 
centrifugation using standard Lymphoprep (ficol) procedure. At collaborating sites, the extracted 
cells will be cryopreserved in liquid nitrogen for transport to Dr. Ramos’ laboratory (University of 
Miami-Sylvester Comprehensive Cancer Center) at the shipping address below. After thawing, a 
portion of cells will be subjected to magnetic CD4-enrichement by negative selection using 
commercially available kits. These cells will serve as source for protein, genomic and proviral 
DNA, and RNA, after standard extraction procedures.
Clonality and clonal abundance studies: Subjects will be assessed for minimal residual disease 
at baseline, and at specified times during treatment (after cycles 3 and 8), at the end of months 9, 
12. Multiplex PCR designed to detect T-cell receptor gene rearrangements will be performed by 
immunopathology lab using extracted DNA from PBMC’s (36). Samples will be analyzed at 
baseline, at the above time points during and post belinostat therapy, and when relapses occur off 
treatment. Where available, DNA from lymphomatous tissue or body fluids will also be analyzed.
Measurement of HTLV-1 proviral loads and reactivation: HTLV-1 proviral loads will be 
measured using extracted DNA from PBMC’s cells before belinostat, during treatment (Day 15, 
after cycles 3 and 8), at the end of months 9 and 12 by single molecule droplet based digital PCR 
at UM Oncogenomics core facility.
Measurement of HTLV-1 reactivation: CD4+ enriched PBMC’s cells will be assayed at 
baseline, and 48-72 hours after belinostat treatment for HTLV-1 Tax expression using HTLV-1 at 
UM Oncogenomics core facility by single molecule droplet-based digital RT-PCR using extracted 
RNA at UM Oncogenomics core facility.
Molecular effects of belinostat: To study the molecular mechanisms of belinostat on ATLL cells 
in vivo CD4+ enriched PBMC’s cells collected at baseline, and 48-72 hours after belinostat 
treatment. Extracted protein will be analyzed for acetylation of histone proteins, expression of 
HTLV-1 proteins HBZ and Tax, and cellular genes affected by viral proteins or by epigenetic 
effects of belinostat by Western Blot.  Extracted RNA will be analyzed for Tax and HBZ by single 
molecule droplet based digital PCR UM Oncogenomics core facility.
Shipping address:
Attn: Dr. Ramos Laboratory
University of Miami Miller School of Medicine
Department of Hematology/Oncology (M877)
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1550 NW 10th Avenue 
Papanicolau (PAP) Building, Room 531
Miami, FL  33136
Tel: (305) 243-4605
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APPENDIX G: DEFINITION OF CLINICAL SUBTYPES OF ATLL
1. Smoldering
a.
5% or more abnormal lymphocytes of T-cell nature in peripheral blood
b. presence of skin lesions
c.
absence of hypercalcemia
d. absence of visceral and lymph node involvement
e.
pulmonary lesions may be present
f.
normal LDH level
g. if <5% circulating leukemic cells are present, there must be at least either 
histologically-proven skin and/or pulmonary lesions present
2. Chronic
a.
absolute lymphocytosis (≥4 X 109/L) greater
b. elevated lactate dehydrogenase (LDH) < twice baseline or normal value
c.
lymphadenopathy and involvement of the spleen, liver, skin and lungs may be present
d. 5% or more abnormal T lymphocytes in the peripheral blood may be present.
e.
no hypercalcemia
f.
no CNS, bone or gastrointestinal tract  involvement
g. no ascites or pleural effusion
3. Lymphomatous: Patients with lymphoma type should have histologically-proven 
lymphadenopathy and no leukemic manifestation that is defined as no lymphocytosis (<4 X 
109/L) and 1% or less abnormal T-lymphocytes.
4. Acute: Remaining ATL patients who usually have leukemic manifestation and tumor lesions, 
but are not classified as any of the three other types –
a.
elevated lymphocyte count
b. morphologically atypical circulating mature T-helper lymphocytes that express the 
CD4 antigen
c.
lymphadenopathy, hepatosplenomegaly, skin, and any other tumor lesions or organ 
involvement may be present
d. elevated LDH
e.
hypercalcemia with or without lytic bone lesions (seen in approximately 50% of 
patients)
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APPENDIX H: PATIENT DOSING DIARY
Note to Investigators: This appendix consists of a “directions sheet and diary” to be given to the 
patient for each cycle of belinostat/AZT (±IFN-alfa), for the planned treatment duration of Cycles 
1 to 8 (i.e. about 6 months).  After belinostat completion, standard AZT-based maintenance therapy 
(±IFN-alfa) during months 7 to 12 are dependent on subject’s disease status and/or at the 
Investigator’s discretion. These sheets MUST be approved by the Institutional Review Board 
(IRB) before they may be given to patients.
Diary Directions 
Begin taking zidovudine (AZT) as your doctor has told you to during the study.  Do not change 
your dose unless your doctor tells you to do so: 
1. Each dose of AZT should be taken by mouth.  For this study, your doctor is asking you to take 
300mg of AZT three times a day, in divided doses, or continuation of same dose taken prior to 
enrollment at the discretion of the treating investigator physician, or a specified dose made after 
any adjustments made during the study.
2. You should not eat 2 hours before and 1 hour after each dose. Do not chew, crush or break 
tablets.  Swallow each tablet whole. 
3. If a dose is missed, you may take the missed dose if it has been less than 6 hours from your 
scheduled dose. Do not make up missed doses if it has been more than 6 hours from your scheduled 
dose. 
7. Taking certain drugs may interfere with the absorption of zidovudine (AZT).  Please discuss 
with your doctor(s) before taking medications like stavudine, ribavirin, doxorubicin, or 
ganciclovir.
8. Please be sure to contact your Doctor, if you may have any questions.       
9. Please bring the empty bottle or any leftover tablets and this dosing diary to your next clinic 
visit. You will be asked to complete this diary every 21-days for about 6 months.
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Patient Dosing Diary
Zidovudine (AZT) Dose Level: 300 mg, up to three times a day, days 1-21
Patient Initials (L, F, M):          Patient ID: ______________________  
Cycle: ______
(Please also see Diary Directions listed on the page before.) This is a diary on which you are to record the 
date, time and number of tablets you take each day on the days that you are supposed to take zidovudine 
(AZT). You should take your scheduled dose of each tablet. If you forget to take a dose, please write “0”, but 
remember to take your prescribed dose at the next regularly scheduled time.  
Day
Date(s)
# 
of 
tablets
Time Taken 
(Circle AM or PM)
# 
of 
tablets
Time 
Taken 
(Circle AM or PM)
# 
of 
tablets
Time 
Taken 
(Circle AM or PM)
1
AM
PM
AM
PM
AM
PM
2
AM
PM
AM
PM
AM
PM
3
AM
PM
AM
PM
AM
PM
4
AM
PM
AM
PM
AM
PM
5
AM
PM
AM
PM
AM
PM
6
AM
PM
AM
PM
AM
PM
7
AM
PM
AM
PM
AM
PM
8
AM
PM
AM
PM
AM
PM
9
AM
PM
AM
PM
AM
PM
10
AM
PM
AM
PM
AM
PM
11
AM
PM
AM
PM
AM
PM
12
AM
PM
AM
PM
AM
PM
13
AM
PM
AM
PM
AM
PM
14
AM
PM
AM
PM
AM
PM
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15
AM
PM
AM
PM
AM
PM
16
AM
PM
AM
PM
AM
PM
17
AM
PM
AM
PM
AM
PM
18
AM
PM
AM
PM
AM
PM
19
AM
PM
AM
PM
AM
PM
20
AM
PM
AM
PM
AM
PM
21
AM
PM
AM
PM
AM
PM
Patient Signature: _______________________________
Date: _________________
APPENDIX I: BIOBANKING CONSIDERATIONS
Blood banking:
Patient specimens will be used to develop a specimen bank that will serve as an invaluable resource 
for current and future research by the investigators named on this study.  Blood samples will be 
obtained from all consenting study patients.  
Upon collection of the samples from the patients, a code system will be used to de-identify all 
samples, assigning a unique code to each specimen.  The samples will be tied to patient-identifying 
information only at the time of sample collection.  The patient's name will be written on the 
specimen collection tubes.  Once the samples are de-identified, which will happen as soon as the 
sample tubes arrive in Dr. Ramos’ lab, the patient's name will be blacked out on the original sample 
tubes and the original tubes will be discarded in biohazardous waste, which is subsequently sent 
for incineration.  
The database will be the only location where patient's names will be tied to their code.  The 
database will be kept on a password protected computer in Dr. Ramos’ research lab and only Dr. 
Ramos and his research staff named on this protocol will have access to the database.  The only 
information that will be stored with the actual samples in the bank is the code identifier used to 
identify each sample.  No samples will be accepted into the bank unless the subject's signed consent 
form has first been submitted.
Blood obtained for research purposes (in 10 ml tubes) will be drawn at the same time as other 
blood samples are being collected.  The research samples will be incorporated with other blood 
draws being done as standard of care for their treatment.  
Data and Specimen Banking
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Samples in the bank will be stored indefinitely, or until the patient withdraws consent for inclusion 
in the protocol.  At that time all samples and data will be destroyed.  All patient samples will be 
stored in Dr. Ramos’ laboratory: Medical Oncology Laboratory, Sylvester Comprehensive Cancer 
Center, 1550 NW 10th Ave, Pap 531, Miami, FL 33136 (Pap Building). Phone number: (305) 243-
4605 (lab).  Access to patient identifiers, including “hidden” variables, is customizable for each 
user and will be limited to the investigators listed on this protocol.  
Researchers wishing to gain access to either the clinical data (de-identified) or samples must first 
submit the appropriate IRB protocol for use and analysis of the information.  Upon approval, the 
investigator will then be granted appropriate access to the data and/or samples as indicated by 
his/her respective protocol.  
The only investigator who will have access to samples and data being kept in the bank is Dr. Ramos 
and his research staff named specifically for maintenance of the bank. The database will be the 
only location where patient's names and medical record numbers will be tied to their code 
identifiers. The only information that will be stored with the actual samples in the bank is the code 
identifier used to identify each sample.  
Data Management
As discussed above, the data will be maintained entirely in an online platform behind the university 
firewall and requiring UM CaneID password identification.  This protocol covers establishing the 
database and the sample bank and is not comprehensive for use of the samples.  
Additional IRB approval will be necessary to use and publish any additional research performed 
using this data and the specimens.  
Risks to Subjects
This study poses minimal risks to the subjects.  They may undergo additional discomfort due to 
the additional blood draws however the times of draws are designed to correspond with the 
additional blood draws required for clinical care.  Additionally, there is a small risk of the 
compromise of their protected health information (PHI) however Researchers are taking maximal 
precautions to prevent this due to the rapid coding of the blood samples and entirely web-based 
platform of the clinical database.  
There are no additional costs to the patient associated with collecting the additional samples for 
this study during routine tests/procedures.
Potential Benefits to Subjects
There is no direct benefit to the patients by participating in this study.  There may ultimately be 
significant benefit to other patients based on improved understanding of the pathogenesis and 
mechanisms behind the diseases.  
Setting
Obtaining phlebotomy samples may be performed at UMHC, UMH or SCCC depending on the 
setting of the patient’s procedures.  Storage of the specimens and the database was summarized 
above.  
Resources Available
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Dr. Ramos is a PI with experience in the design and use of retrospective and prospective clinical 
databases for research material(s).  Drs. Ramos’ and Komanduri’s laboratory also have extensive 
experience in the establishment of models from blood specimens.  
Recruitment Methods
Prospective participants will be patients of the Investigators named in this protocol that they see 
in their clinic, and will be approached by the Investigators named in this protocol personally during 
a standard or study clinic visit.  Subjects will receive no compensation for participation in the study 
and participation will not affect clinical care.
Local Number of Subjects
Up to 20 prospective subjects.
Confidentiality
The only investigators who will have access to samples and data being kept in the bank are Dr. 
Ramos and his research staff. The bank database will be the only location where patient's names 
will be tied to their code identifiers. The only information that will be stored with the actual 
samples in the bank is the code identifier used to identify each sample. 
Data and specimens will be maintained in the bank indefinitely. If at some point in time, a subject 
decides they wish to remove their specimens and data from the bank, any remaining samples 
belonging to that patient will be destroyed and their data removed from the database.
Provisions to Protect the Privacy Interests of Subjects
All samples will be de-identified to protect each subjects’ identity as detailed above.  All PHI 
included in the database will be hidden and access will be limited to those requiring it for 
establishment and maintenance of the database.  All discussions of participation in the study will 
be performed in private clinic rooms.  Signed HIPAA Authorization will be obtained from all 
subjects.
Consent Process
Written informed consent for the prospective use of data and samples for purposes of this protocol 
will be obtained. Patients will be provided with an informed consent process during their clinic 
visits and/or routine care visits.  For subjects not qualified or able to give legal consent, consent 
must be obtained from their legally authorized representative (LAR).
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APPENDIX J: AGENTS (DRUG FORMULATION AND PROCUREMENT)
Belinostat
[Refer 
to 
the 
FDA-approved 
package 
insert 
for 
more 
information: 
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=84b2e16e-f0d1-4757-8da8-
79dfa83aab79.]
Other name(s)
PXD101, Beleodaq®
Mechanism of Action
Beleodaq is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups 
from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the 
accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis 
of some transformed cells. Belinostat shows preferential cytotoxicity towards tumor cells 
compared to normal cells. Belinostat inhibited the enzymatic activity of histone deacetylases at 
nanomolar concentrations (<250 nM).
Drug Metabolism, Pharmacokinetics and Toxicology
Belinostat is primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected 
to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, 
CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes 
responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, 
(3-ASBA) are not known.
The pharmacokinetic characteristics of belinostat were analyzed from pooled data from phase 1/2 
clinical studies that used doses of belinostat ranging from 150 to 1200 mg/m. The total mean 
plasma clearance and elimination half-life were 1240 mL/min and 1.1 hours, respectively. The 
total clearance approximates average hepatic blood flow (1500 mL/min), suggesting high hepatic 
extraction (clearance being flow dependent).
UGT1A1 Inhibitors: Belinostat is primarily metabolized by UGT1A1. Avoid concomitant 
administration of Beleodaq with strong inhibitors of UGT1A1.
Warfarin: Co-administration of Beleodaq and warfarin resulted in no clinically relevant increase 
in plasma exposure of either R-warfarin or S-warfarin that would require a dose adjustment.
Carcinogenicity studies have not been performed with belinostat.
Belinostat was genotoxic in a bacterial reverse mutation test (Ames assay), an in vitro mouse 
lymphoma cell mutagenesis assay, and an in vivo rat micronucleus assay. 
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Beleodaq may impair male fertility. Fertility studies using belinostat were not conducted. 
However, belinostat effects on male reproductive organs observed during the 24-week repeat-dose 
dog toxicology study included reduced organ weights of the testes/epididymides that correlated 
with a delay in testicular maturation.
Management of Agent-Specific Adverse Events
Hematologic Toxicity
Beleodaq can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or 
anemia; monitor blood counts weekly during treatment, and modify dosage as necessary.
Infections
Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with 
Beleodaq. Do not administer Beleodaq to subjects with an active infection. Subjects with a history 
of extensive or intensive chemotherapy may be at higher risk of life threatening infections.
Hepatotoxicity
Beleodaq can cause fatal hepatotoxicity and liver function test abnormalities. Monitor liver 
function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until 
recovery, or permanently discontinue Beleodaq based on the severity of the hepatic toxicity.
Tumor Lysis Syndrome
Tumor lysis syndrome has occurred in Beleodaq-treated patients in the clinical trial of patients 
with relapsed or refractory PTCL. Monitor patients with advanced stage disease and/or high tumor 
burden and take appropriate precautions.
Gastrointestinal Toxicity
Nausea, vomiting and diarrhea occur with Beleodaq and may require the use of antiemetic and 
antidiarrheal medications.
Embryo-fetal Toxicity 
Beleodaq can cause fetal harm when administered to a pregnant woman. Beleodaq may cause 
teratogenicity and/or embryo-fetal lethality because it is genotoxic and targets actively dividing 
cells. Women of childbearing potential should be advised to avoid pregnancy while receiving 
Beleodaq. If this drug is used during pregnancy, or if the patient becomes pregnant while taking 
this drug, the patient should be apprised of potential hazard to the fetus.
Composition
Beleodaq is a histone deacetylase inhibitor with a sulfonamide-hydroxamide structure. The 
chemical name of belinostat is (2E)-N-hydroxy-3-[3-(phenylsulfamoyl) phenyl]prop-2-enamide. 
The structural formula is as follows:
The molecular formula is C15H14N2O4S and the molecular weight is 318.35 g/mol.
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Storage Recommendations and Dosage Forms
For injection: 500 mg, lyophilized powder in single-use vial for reconstitution.
Beleodaq (belinostat) for injection is supplied in single vial cartons; each 30 mL clear vial contains 
sterile, lyophilized powder equivalent to 500 mg belinostat.
NDC 68152-108-09: Individual carton of Beleodaq 30 mL single-use vial containing 500 mg 
belinostat. 
Store Beleodaq (belinostat) for injection at room temperature 20°C to 25°C (68°C to 77°F). 
Excursions are permitted between 15°C and 30°C (59°F and 86°F). Retain in original package 
until use. [see USP Controlled Room Temperature]. 
Beleodaq is a cytotoxic drug. Follow special handling and disposal procedures.
Dispensation and Accountability
See also Section 8.5.1; Belinostat will be supplied by Spectrum Pharmaceuticals, Inc. 
Beleodaq® (belinostat) for injection is supplied in single vial cartons; each 30 mL clear vial 
contains sterile, lyophilized powder equivalent to 500 mg belinostat.
Manufacturer contact information:
CENEXI-Laboratoires Thissen S.A., 
Rue de la papyrée, 2-4-6 , 
1420 BRAINE L’ALLEUD, 
BELGIUM
Drug Label Information:
Patient ID: ________                                                    Study # XXXXXXXX
Belinostat (PXD101) For Injection 500mg/vial
Batch No:  XXXXX                            Store at 20 - 25°C
See protocol for administration directions
Caution :  New Drug -- Limited by United States law to investigational use
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Sponsor : XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
Any City, Any State XXXXX
Tel :  XXX-XXX-XXXX
Zidovudine
[Refer 
to 
the 
FDA-approved 
package 
insert 
for 
more 
information: 
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6df09f15-b102-431c-adde-
d7aeef6f5d84.]
Other name(s)
azidothymidine (AZT), Retrovir®
Mechanism of Action
Zidovudine is an antiviral agent.  It is a synthetic nucleoside analogue. Intracellularly, zidovudine 
is phosphorylated to its active 5’-triphosphate metabolite, zidovudine triphosphate (ZDV-TP).  The 
principle mode of action of ZDV-TP is inhibition of reverse transcriptase (RT) via DNA chain 
termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the 
cellular DNA polymerases alpha and gamma and has been reported to be incorporated into the 
DNA of cells in culture. 
Drug Metabolism, Pharmacokinetics and Toxicology
Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine is 
GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of 
zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose following oral 
administration and 18% and 60%, respectively, following IV dosing. A second metabolite, 3′-
amino-3′-deoxythymidine (AMT), has been identified in the plasma following single-dose IV 
administration of zidovudine. The AMT AUC was one-fifth of the zidovudine AUC. 
Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from 2 
mg per kg every 8 hours to 10 mg per kg every 4 hours.
Following IV dosing, dose-independent kinetics was observed over the range of 1 to 5 mg per kg. 
The mean steady-state peak and trough concentrations of zidovudine at 2.5 mg per kg every 4 
hours were 1.1 and 0.1 mcg per mL, respectively.
In adults, following oral administration, zidovudine is rapidly absorbed and extensively 
distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was 
equivalent when zidovudine was administered as RETROVIR tablets or syrup compared with 
RETROVIR capsules. The pharmacokinetic properties of zidovudine in fasting adult subjects are 
summarized in the table below [where a): Median [range] for 50 paired samples drawn 1 to 8 hours 
after the last dose in subjects on chronic therapy with RETROVIR and b): Approximate range.]
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Carcinogenesis
Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats (60 
females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per 
day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 
30, and 40 mg per kg per day after day 90 because of treatment-related anemia, whereas in rats 
only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg 
per day on Day 279.
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 non-metastasizing squamous cell 
carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the 
highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose 
animal. No vaginal tumors were found at the lowest dose.
In rats, 2 late-appearing (after 20 months), non-metastasizing vaginal squamous cell carcinomas 
occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose 
in rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by 
AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the 
recommended therapeutic dose of 100 mg every 4 hours.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
Two trans placental carcinogenicity studies were conducted in mice. One study administered 
zidovudine at doses of 20 mg per kg per day or 40 mg per kg per day from gestation Day 10 
through parturition and lactation with dosing continuing in offspring for 24 months postnatally. 
The doses of zidovudine administered in this study produced zidovudine exposures approximately 
3 times the estimated human exposure at recommended doses. After 24 months, an increase in 
incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other 
organ in either gender. These findings are consistent with results of the standard oral 
carcinogenicity study in mice, as described earlier. A second study administered zidovudine at 
maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1,000 mg per kg 
non-pregnant body weight or approximately 450 mg per kg of term body weight) to pregnant mice 
from Days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, 
liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of 
zidovudine.
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Mutagenesis
Zidovudine was mutagenic in a 5178Y/TK mouse lymphoma assay, positive in an in vitro cell 
transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and 
positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic 
study in rats given a single dose. 
Impairment of Fertility
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based 
on body surface area, had no effect on fertility judged by conception rates. 
Animal Toxicology and/or Pharmacology
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg per kg per day revealed 
no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal 
toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 
mg per kg per day and rabbits given 500 mg per kg per day. The doses used in the teratology 
studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 
66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations 
(after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 
hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a 
dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose 
of 3,000 mg per kg per day (very near the oral median lethal dose in rats of 3,683 mg per kg) 
caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose 
resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. 
(Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg 
per day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per 
day or less.
Management of Agent-Specific Adverse Events
RETROVIR is contraindicated in patients who have had a potentially life-threatening 
hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components 
of the formulations. 
Hematologic Toxicity/Bone Marrow Suppression
RETROVIR should be used with caution in patients who have bone marrow compromise 
evidenced by granulocyte count less than 1,000 cells per mm or hemoglobin less than 9.5 g per 
dL. Hematologic toxicities appear to be related to pretreatment bone marrow reserve and to dose 
and duration of therapy.
In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the most 
significant adverse events observed. In patients who experience hematologic toxicity, a reduction 
in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 
weeks. There have been reports of pancytopenia associated with the use of RETROVIR, which 
was reversible in most instances after discontinuance of the drug. However, significant anemia, in 
many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood transfusions, 
has occurred during treatment with RETROVIR alone or in combination with other anti-
retrovirals.
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Frequent blood counts are strongly recommended to detect severe anemia or neutropenia in 
patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease who 
are treated with RETROVIR. For HIV-1-infected individuals and patients with asymptomatic or 
early HIV-1 disease, periodic blood counts are recommended. If anemia or neutropenia develops, 
dosage interruption may be needed.
Latex
The vial stoppers for RETROVIR injection contain natural rubber latex which may cause allergic 
reactions in latex-sensitive individuals.
Myopathy
Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, 
have been associated with prolonged use of RETROVIR.
Lactic Acidosis /Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported 
with the use of nucleoside analogues alone or in combination, including zidovudine and other anti-
retrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to 
antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised 
when administering RETROVIR to any patient with known risk factors for liver disease; however, 
cases have also been reported in patients with no known risk factors. Treatment with RETROVIR 
should be suspended in any patient who develops clinical or laboratory findings suggestive of 
lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even 
in the absence of marked transaminase elevations).
Use with Interferon- and Ribavirin-based Regimens in HIV-1/HCV Co-infected Patients
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside 
analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamics 
interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was co-
administered with zidovudine in HIV-1/HCV co-infected subjects, exacerbation of anemia due to 
ribavirin has been reported when zidovudine is part of the HIV regimen. 
Co-administration of ribavirin and zidovudine is not advised. Consideration should be given to 
replacing zidovudine in established combination HIV-1/HCV therapy, especially in patients with 
a known history of zidovudine-induced anemia.
Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving 
combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients 
receiving interferon alfa with or without ribavirin and zidovudine should be closely monitored for 
treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. 
Discontinuation of zidovudine should be considered as medically appropriate. Dose reduction or 
discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical 
toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see 
the complete prescribing information for interferon and ribavirin).
Use with Other Zidovudine-containing Products
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RETROVIR should not be administered with combination products that contain zidovudine as one 
of their components (e.g., COMBIVIR [lamivudine and zidovudine] tablets or TRIZIVIR 
[abacavir sulfate, lamivudine, and zidovudine] tablets).
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination 
antiretroviral therapy, including RETROVIR. During the initial phase of combination 
antiretroviral treatment, patients whose immune systems respond may develop an inflammatory 
response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, 
cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may 
necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have 
also been reported to occur in the setting of immune reconstitution; however, the time to onset is 
more variable, and can occur many months after initiation of treatment.
Fat Redistribution
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement 
(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid 
appearance,” have been observed in patients receiving antiretroviral therapy. The mechanism and 
long-term consequences of these events are currently unknown. A causal relationship has not been 
established.
Composition
RETROVIR is the brand name for zidovudine (formerly called azido thymidine [AZT]), a 
pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3′-
azido-3′-deoxythymidine; it has the following structural formula:
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a 
solubility of 20.1 mg per mL in water at 25°C. The molecular formula is C10H13N5O4 .
RETROVIR capsules are for oral administration. Each capsule contains 100 mg of zidovudine and 
the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose, and sodium 
starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink, consists 
of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and 
titanium dioxide.
Storage Recommendations and Dosage Forms
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Oral Dosing: The recommended oral dose of RETROVIR is 300 mg twice daily in combination 
with other antiretroviral agents.
RETROVIR 100-mg capsules are supplied as white, opaque cap and body capsules containing 100 
mg zidovudine per capsule. Each capsule is printed with “Wellcome” and unicorn logo on cap and 
“Y9C” and “100” on body.
Bottles of 100 (NDC 49702-211-20).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
Dispensation and Accountability
Zidovudine is commercially available. See also Section 8.5.2.
Instruct subjects that if they miss a dose, they should just take their next dose at the usual time. 
Subjects should not double their next dose.
Interferon alfa-2b
[Refer 
to 
the 
FDA-approved 
package 
insert 
for 
more 
information: 
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=30789790-8317-49f9-b97b-
8c5ba17b53d2.] 
Other name(s)
INTRON® A, IFN-alfa-2b
Mechanism of Action
General
The interferons are a family of naturally occurring small proteins and glycoproteins with molecular 
weights of approximately 15,000 to 27,600 daltons produced and secreted by cells in response to 
viral infections and to synthetic or biological inducers.
Preclinical Pharmacology
Interferons exert their cellular activities by binding to specific membrane receptors on the cell 
surface.
Once bound to the cell membrane, interferons initiate a complex sequence of intracellular events. 
In vitro studies demonstrated that these include the induction of certain enzymes, suppression of 
cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity of 
macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and 
inhibition of virus replication in virus-infected cells.
In a study using human hepatoblastoma cell line HB 611, the in vitro antiviral activity of alpha 
interferon was demonstrated by its inhibition of hepatitis B virus (HBV) replication.
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The correlation between these in vitro data and the clinical results is unknown. Any of these 
activities might contribute to interferon's therapeutic effects.
Drug Metabolism, Pharmacokinetics and Toxicology
Serum Neutralizing Antibodies
In INTRON A-treated patients tested for antibody activity in clinical trials, serum anti-interferon 
neutralizing antibodies were detected in 0% (0/90) of patients with hairy cell leukemia, 0.8% 
(2/260) of patients treated intralesionally for condylomata acuminata, and 4% (1/24) of patients 
with AIDS-Related Kaposi's Sarcoma. Serum neutralizing antibodies have been detected in less 
than 3% of patients treated with higher INTRON A doses in malignancies other than hairy cell 
leukemia or AIDS-Related Kaposi's Sarcoma. The clinical significance of the appearance of serum 
anti-interferon neutralizing activity in these indications is not known. 
Serum anti-interferon neutralizing antibodies were detected in 7% (12/168) of patients either 
during treatment or after completing 12 to 48 weeks of treatment with 3 million IU TIW of 
INTRON A therapy for chronic hepatitis C and in 13% (6/48) of patients who received INTRON 
A therapy for chronic hepatitis B at 5 million IU QD for 4 months, and in 3% (1/33) of patients 
treated at 10 million IU TIW.
Serum anti-interferon neutralizing antibodies were detected in 9% (5/53) of pediatric patients who 
received INTRON A therapy for chronic hepatitis B at 6 million IU/m TIW. Among all chronic 
hepatitis B or C patients, pediatrics and adults with detectable serum neutralizing antibodies, the 
titers detected were low (22/24 with titers less than or equal to 1:40 and 2/24 with titers less than 
or equal to 1:160). The appearance of serum anti-interferon neutralizing activity did not appear to 
affect safety or efficacy. 
Pharmacokinetics
The pharmacokinetics of INTRON A were studied in 12 healthy male volunteers following single 
doses of 5 million IU/m administered intramuscularly, subcutaneously, and as a 30-minute 
intravenous infusion in a crossover design.
The mean serum INTRON A concentrations following intramuscular and subcutaneous injections 
were comparable. The maximum serum concentrations obtained via these routes were 
approximately 18 to 116 IU/mL and occurred 3 to 12 hours after administration. The elimination 
half-life of INTRON A following both intramuscular and subcutaneous injections was 
approximately 2 to 3 hours. Serum concentrations were undetectable by 16 hours after the 
injections.
After intravenous administration, serum INTRON A concentrations peaked (135-273 IU/mL) by 
the end of the 30-minute infusion, then declined at a slightly more rapid rate than after 
intramuscular or subcutaneous drug administration, becoming undetectable 4 hours after the 
infusion. The elimination half-life was approximately 2 hours.
Urine INTRON A concentrations following a single dose (5 million IU/ml) were not detectable 
after any of the parenteral routes of administration. This result was expected since preliminary 
studies with isolated and perfused rabbit kidneys have shown that the kidney may be the main site 
of interferon catabolism.
There are no pharmacokinetic data available for the intralesional route of administration.
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Contraindications
INTRON A is contraindicated in patients with:
Hypersensitivity to interferon alpha or any component of the product
Autoimmune hepatitis
Decompensated liver disease
INTRON A and REBETOL combination therapy is additionally contraindicated in:
Patients with hypersensitivity to ribavirin or any other component of the product
Women who are pregnant
Men whose female partners are pregnant
Patients with hemoglobinopathies (e.g., thalassemia major, sickle cell anemia)
Patients with creatinine clearance less than 50 mL/min.
(See REBETOL prescribing information for additional information.)
Management of Agent-Specific Adverse Events
General
Moderate to severe adverse experiences may require modification of the patient's dosage regimen, 
or in some cases termination of INTRON A therapy. Because of the fever and other "flu-like" 
symptoms associated with INTRON A administration, it should be used cautiously in patients with 
debilitating medical conditions, such as those with a history of pulmonary disease (e.g., chronic 
obstructive pulmonary disease) or diabetes mellitus prone to ketoacidosis. Caution should also be 
observed in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism) or 
severe myelosuppression.
Cardiovascular Disorders
INTRON A therapy should be used cautiously in patients with a history of cardiovascular disease.
Those patients with a history of myocardial infarction and/or previous or current arrhythmic 
disorder who require INTRON A therapy should be closely monitored (see PRECAUTIONS, 
Laboratory Tests). Cardiovascular adverse experiences, which include hypotension, arrhythmia, 
or tachycardia of
150 beats per minute or greater, and rarely, cardiomyopathy and myocardial infarction have been 
observed in some INTRON A-treated patients. Some patients with these adverse events had no 
history of cardiovascular disease. Transient cardiomyopathy was reported in approximately 2% of 
the AIDS-Related Kaposi's Sarcoma patients treated with INTRON A. Hypotension may occur 
during INTRON A administration, or up to 2 days post-therapy, and may require supportive 
therapy including fluid replacement to maintain intravascular volume. 
Supraventricular arrhythmias occurred rarely and appeared to be correlated with preexisting 
conditions and prior therapy with cardio toxic agents. These adverse experiences were controlled 
by modifying the dose or discontinuing treatment, but may require specific additional therapy.
Cerebrovascular Disorders
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Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with 
interferon alpha-based therapies, including INTRON A. Events occurred in patients with few or 
no reported risk factors for stroke, including patients less than 45 years of age. Because these are 
spontaneous reports, estimates of frequency cannot be made and a causal relationship between 
interferon alpha-based therapies and these events is difficult to establish.
Neuropsychiatric Disorders
DEPRESSION AND SUICIDAL BEHAVIOR INCLUDING SUICIDAL IDEATION, 
SUICIDAL ATTEMPTS, AND COMPLETED SUICIDES, HOMICIDAL IDEATION, AND 
AGGRESSIVE BEHAVIOR SOMETIMES DIRECTED TOWARDS OTHERS, HAVE BEEN 
REPORTED IN ASSOCIATION WITH TREATMENT WITH ALPHA INTERFERONS, 
INCLUDING INTRON A THERAPY. If patients develop psychiatric problems, including clinical 
depression, it is recommended that the patients be carefully monitored during treatment and in the 
6-month follow-up period.
INTRON A should be used with caution in patients with a history of psychiatric disorders. 
INTRON A therapy should be discontinued for any patient developing severe psychiatric disorder 
during treatment. 
Obtundation and coma have also been observed in some patients, usually elderly, treated at higher 
doses. While these effects are usually rapidly reversible upon discontinuation of therapy, full 
resolution of symptoms has taken up to 3 weeks in a few severe episodes. If psychiatric symptoms 
persist or worsen, or suicidal ideation or aggressive behavior towards others is identified, it is 
recommended that treatment with INTRON A be discontinued and the patient followed, with 
psychiatric intervention as appropriate. Narcotics, hypnotics, or sedatives may be used 
concurrently with caution and patients should be closely monitored until the adverse effects have 
resolved. Suicidal ideation or attempts occurred more frequently among pediatric patients, 
primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-
therapy follow-up. Cases of encephalopathy have also been observed in some patients, usually 
elderly, treated with higher doses of INTRON A. 
Treatment with interferons may be associated with exacerbated symptoms of psychiatric disorders 
in patients with co-occurring psychiatric and substance use disorders. If treatment with interferons 
is initiated in patients with prior history or existence of psychiatric condition or with a history of 
substance use disorders, treatment considerations should include the need for drug screening and 
periodic health evaluation, including psychiatric symptom monitoring. Early intervention for 
reemergence or development of neuropsychiatric symptoms and substance use is recommended.
Bone Marrow Toxicity
INTRON A therapy suppresses bone marrow function and may result in severe cytopenias 
including aplastic anemia. It is advised that complete blood counts (CBC) be obtained pretreatment 
and monitored routinely during therapy (see PRECAUTIONS, Laboratory Tests). INTRON A 
therapy should be discontinued in patients who develop severe decreases in neutrophil (less than 
0.5 × 10 /L) or platelet counts (less than 25 × 10 /L) (see DOSAGE AND ADMINISTRATION, 
Guidelines for Dose Modification).
Ophthalmologic Disorders
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Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, 
retinal hemorrhages and cotton wool spots; optic neuritis, papilledema, and serous retinal 
detachment may be induced or aggravated by treatment with interferon alfa-2b or other alpha 
interferons. All patients should receive an eye examination at baseline. Patients with preexisting 
ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic 
ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular 
symptoms should receive a prompt and complete eye examination. Interferon alfa-2b treatment 
should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Endocrine Disorders
Infrequently, patients receiving INTRON A therapy developed thyroid abnormalities, either 
hypothyroid or hyperthyroid. The mechanism by which INTRON A may alter thyroid status is 
unknown. Patients with preexisting thyroid abnormalities whose thyroid function cannot be 
maintained in the normal range by medication should not be treated with INTRON A. Prior to 
initiation of INTRON A therapy, serum TSH should be evaluated. Patients developing symptoms 
consistent with possible thyroid dysfunction during the course of INTRON A therapy should have 
their thyroid function evaluated and appropriate treatment instituted. Therapy should be 
discontinued for patients developing thyroid abnormalities during treatment whose thyroid 
function cannot be normalized by medication.
Discontinuation of INTRON A therapy has not always reversed thyroid dysfunction occurring 
during treatment. Diabetes mellitus has been observed in patients treated with alpha interferons. 
Patients with these conditions who cannot be effectively treated by medication should not begin 
INTRON A therapy.
Patients who develop these conditions during treatment and cannot be controlled with medication 
should not continue INTRON A therapy.
Gastrointestinal Disorders
Hepatotoxicity, including fatality, has been observed in interferon alpha-treated patients, including 
those treated with INTRON A. Any patient developing liver function abnormalities during 
treatment should be monitored closely and if appropriate, treatment should be discontinued.
Pulmonary Disorders
Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, 
pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure and/or patient 
deaths, may be induced or aggravated by INTRON A or other alpha interferons. Recurrence of 
respiratory failure has been observed with interferon re-challenge. The etiologic explanation for 
these pulmonary findings has yet to be established. Any patient developing fever, cough, dyspnea, 
or other respiratory symptoms should have a chest X-ray taken. If the chest X-ray shows 
pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient should be 
closely monitored, and, if appropriate, interferon alpha treatment should be discontinued. While 
this has been reported more often in patients with chronic hepatitis C treated with interferon alpha, 
it has also been reported in patients with oncologic diseases treated with interferon alpha.
Autoimmune Disorders
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Rare cases of autoimmune diseases including thrombocytopenia, vasculitis, Raynaud's 
phenomenon, rheumatoid arthritis, lupus erythematosus, and rhabdomyolysis have been observed 
in patients treated with alpha interferons, including patients treated with INTRON A. In very rare 
cases the event resulted in fatality. The mechanism by which these events developed and their 
relationship to interferon alpha therapy is not clear. Any patient developing an autoimmune 
disorder during treatment should be closely monitored and, if appropriate, treatment should be 
discontinued.
Human Albumin
The powder formulations of this product contain albumin, a derivative of human blood. Based on 
effective donor screening and product manufacturing processes, it carries an extremely remote risk 
for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease 
(CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have 
ever been identified for albumin.
AIDS-Related Kaposi's Sarcoma
INTRON A therapy should not be used for patients with rapidly progressive visceral disease (see 
CLINICAL PHARMACOLOGY). Also of note, there may be synergistic adverse effects between 
INTRON A and zidovudine. Patients receiving concomitant zidovudine have had a higher 
incidence of neutropenia than that expected with zidovudine alone. Careful monitoring of the 
WBC count is indicated in all patients who are myelosuppressed and in all patients receiving other 
myelosuppressive medications. The effects of INTRON A when combined with other drugs used 
in the treatment of AIDS-related disease are unknown.
Chronic Hepatitis C and Chronic Hepatitis B
Patients with decompensated liver disease, autoimmune hepatitis or a history of autoimmune 
disease, and patients who are immunosuppressed transplant recipients should not be treated with 
INTRON A. There are reports of worsening liver disease, including jaundice, hepatic 
encephalopathy, hepatic failure, and death following INTRON A therapy in such patients. Therapy 
should be discontinued for any patient developing signs and symptoms of liver failure.
Chronic hepatitis B patients with evidence of decreasing hepatic synthetic functions, such as 
decreasing albumin levels or prolongation of prothrombin time, who nevertheless meet the entry 
criteria to start therapy, may be at increased risk of clinical decompensation if a flare of 
aminotransferases occurs during INTRON A treatment. In such patients, if increases in ALT occur 
during INTRON A therapy for chronic hepatitis B, they should be followed carefully, including 
close monitoring of clinical symptomatology and liver function tests including ALT, prothrombin 
time, alkaline phosphatase, albumin, and bilirubin. In considering these patients for INTRON A 
therapy, the potential risks must be evaluated against the potential benefits of treatment.
Peripheral Neuropathy
Peripheral neuropathy has been reported when alpha interferons were given in combination with 
telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was 
observed with the combination use of telbivudine and pegylated interferon alfa-2a as compared to 
telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the 
treatment of chronic hepatitis B has not been demonstrated.
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Use with Ribavirin (see also REBETOL prescribing information)
REBETOL may cause birth defects and/or death of the unborn child. REBETOL therapy should 
not be started until a report of a negative pregnancy test has been obtained immediately prior to 
planed initiation of therapy. Patients should use at least two forms of contraception and have 
monthly pregnancy tests (see CONTRAINDICATIONS and PRECAUTIONS, Information for 
Patients).
Combination treatment with INTRON A and REBETOL was associated with hemolytic anemia.
Hemoglobin less than 10 g/dL was observed in approximately 10% of adult and pediatric patients 
in clinical trials. Anemia occurred within 1 to 2 weeks of initiation of ribavirin therapy. 
Combination treatment with INTRON A and REBETOL should not be used in patients with 
creatinine clearance less than 50 mL/min. See REBETOL prescribing information for additional 
information.
PRECAUTIONS
General
Acute serious hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, 
anaphylaxis) have been observed rarely in INTRON A-treated patients; if such an acute reaction 
develops, the drug should be discontinued immediately and appropriate medical therapy instituted. 
Transient rashes have occurred in some patients following injection, but have not necessitated 
treatment interruption.
While fever may be related to the flu-like syndrome reported commonly in patients treated with 
interferon, other causes of persistent fever should be ruled out.
There have been reports of interferon, including INTRON A, exacerbating preexisting psoriasis 
and sarcoidosis as well as development of new sarcoidosis. Therefore, INTRON A therapy should 
be used in these patients only if the potential benefit justifies the potential risk.
Variations in dosage, routes of administration, and adverse reactions exist among different brands 
of interferon. Therefore, do not use different brands of interferon in any single treatment regimen.
Triglycerides
Elevated triglyceride levels have been observed in patients treated with interferons, including 
INTRON A therapy. Elevated triglyceride levels should be managed as clinically appropriate. 
Hypertriglyceridemia may result in pancreatitis. Discontinuation of INTRON A therapy should be 
considered for patients with persistently elevated triglycerides (e.g., triglycerides greater than 1000 
mg/dL) associated with symptoms of potential pancreatitis, such as abdominal pain, nausea, or 
vomiting. 
Drug Interactions
Interactions between INTRON A and other drugs have not been fully evaluated. Caution should 
be exercised when administering INTRON A therapy in combination with other potentially 
myelosuppressive agents such as zidovudine. Concomitant use of alpha interferon and 
theophylline decreases theophylline clearance, resulting in a 100% increase in serum theophylline 
levels.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with INTRON A have not been performed to determine carcinogenicity.
Interferon may impair fertility. In studies of interferon administration in nonhuman primates, 
menstrual cycle abnormalities have been observed. Decreases in serum estradiol and progesterone 
concentrations have been reported in women treated with human leukocyte interferon. Therefore, 
fertile women should not receive INTRON A therapy unless they are using effective contraception 
during the therapy period. INTRON A therapy should be used with caution in fertile men.
Mutagenicity studies have demonstrated that INTRON A is not mutagenic.
Studies in mice (0.1, 1.0 million IU/day), rats (4, 20, 100 million IU/kg/day), and cynomolgus 
monkeys (1.1 million IU/kg/day; 0.25, 0.75, 2.5 million IU/kg/day) injected with INTRON A for 
up to 9 days, 3 months, and 1 month, respectively, have revealed no evidence of toxicity. However, 
in cynomolgus monkeys (4, 20, 100 million IU/kg/day) injected daily for 3 months with INTRON 
A, toxicity was observed at the mid and high doses and mortality was observed at the high dose.
However, due to the known species-specificity of interferon, the effects in animals are unlikely to 
be predictive of those in man. 
INTRON A in combination with REBETOL should be used with caution in fertile men. See the 
REBETOL prescribing information for additional information.
Composition
INTRON A (Interferon alfa-2b) for intramuscular, subcutaneous, intralesional, or intravenous 
Injection is a purified sterile recombinant interferon product.
INTRON A recombinant for Injection has been classified as an alpha interferon and is a water-
soluble protein with a molecular weight of 19,271 daltons produced by recombinant DNA 
techniques. It is obtained from the bacterial fermentation of a strain of Escherichia coli bearing a 
genetically engineered plasmid containing an interferon alfa-2b gene from human leukocytes. The 
fermentation is carried out in a defined nutrient medium containing the antibiotic tetracycline 
hydrochloride at a concentration of 5 to 10 mg/L; the presence of this antibiotic is not detectable 
in the final product. The specific activity of interferon alfa-2b, recombinant is approximately 2.6 
× 10 IU/mg protein as measured by the HPLC assay.
Storage Recommendations and Dosage Forms
Storage
INTRON A Powder for Injection/Reconstitution
INTRON A Powder for Injection should be stored in the refrigerator at 2° to 8°C (36°-46°F). After 
reconstitution, the solution should be used immediately, but may be stored up to 24 hours at 2° 
to8°C (36°-46°F). Throw away any medicine left in the vial after you withdraw 1 dose.
INTRON A Solution for Injection in Vials
INTRON A Solution for Injection in vials should be stored in the refrigerator at 2° to 8°C (36°-
46°F).
INTRON A Solution for Injection should not be frozen and should be kept away from heat. Throw 
away any unused INTRON A Solution for Injection remaining in the vial after one month.
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General
IMPORTANT: INTRON A is supplied as 1) Powder for Injection/Reconstitution; 2) Solution for 
Injection in Vials. 
Not all dosage forms and strengths are appropriate for some indications. It is important that you 
carefully read the instructions below for the indication you are treating to ensure you are using an 
appropriate dosage form and strength.
To enhance the tolerability of INTRON A, injections should be administered in the evening when 
possible.
To reduce the incidence of certain adverse reactions, acetaminophen may be administered at the 
time of injection.
The solution should be allowed to come to room temperature before using.
Prior to administration, the INTRON A Powder for Injection is to be reconstituted with the 
provided Diluent for INTRON A (Sterile Water for Injection USP) (see DOSAGE AND 
ADMINISTRATION).
INTRON A Powder for Injection is a white to cream-colored powder.
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These packages do not require reconstitution prior to administration (see DOSAGE AND 
ADMINISTRATION). INTRON A Solution for Injection is a clear, colorless solution.
Dispensation and Accountability
INTRON A is commercially available.
Reconstitution of INTRON A Powder for Injection
Reconstitute INTRON A Powder for Injection with 1 mL of Sterile Water for Injection, USP. The 
Sterile Water for Injection supplied contains 5 mL and is intended for single use. Discard the 
unused portion. The reconstituted solution is clear and colorless to light yellow. The INTRON A 
powder reconstituted with Sterile Water for Injection USP is a single-use vial and does not contain 
a preservative. DO NOT RE-ENTER VIAL AFTER WITHDRAWING THE DOSE. DISCARD 
UNUSED PORTION (see DOSAGE AND ADMINISTRATION). Once the dose from the single 
dose vial has been withdrawn, the sterility of any remaining product can no longer be guaranteed.
Pooling of unused portions of some medications has been linked to bacterial contamination and 
morbidity.
• Intramuscular, Subcutaneous, or Intralesional Administration
Inject 1 mL Diluent (Sterile Water for Injection USP) for INTRON A into the INTRON A vial. 
Swirl gently to hasten complete dissolution of the powder. The appropriate INTRON A dose 
should then be withdrawn and injected intramuscularly, subcutaneously, or intralesionally (see 
MEDICATION GUIDE and Instructions for Us e for detailed instructions).
Please refer to the MEDICATION GUIDE and Instructions for Us e for detailed, step-by-step 
instructions on how to inject the INTRON A dose. After preparation and administration of the 
INTRON A injection, it is essential to follow the procedure for proper disposal of syringes and 
needles (see MEDICATION GUIDE and Ins tructions for Us e for detailed instructions).
Parenteral drug products should be inspected visually for particulate matter and discoloration prior 
to administration.
• Intravenous Infusion
The infusion solution should be prepared immediately prior to use. Based on the desired dose, the 
appropriate vial strength(s) of INTRON A should be reconstituted with the diluent provided. Inject 
1 mL Diluent (Sterile Water for Injection USP) for INTRON A into the INTRON A vial. Swirl 
gently to hasten complete dissolution of the powder. The appropriate INTRON A dose should then 
be withdrawn and injected into a 100-mL bag of 0.9% Sodium Chloride Injection USP. The final 
concentration of INTRON A should not be less than 10 million IU/100 mL. 
INTRON A Solution for Injection in Vials
INTRON A Solution for Injection is supplied in two multi-dose vials. The solutions for injection 
do not require reconstitution prior to administration; the solution is clear and colorless.
The appropriate dose should be withdrawn from the vial and injected intramuscularly, 
subcutaneously, or intralesionally.
INTRON A Solution for Injection is not recommended for intravenous administration.
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Please refer to the MEDICATION GUIDE and Instructions for Us e for detailed, step-by-step 
instructions on how to inject the INTRON A dose. After preparation and administration of 
INTRON A, it is essential to follow the procedure for proper disposal of syringes and needles.
INTRON A Powder for Injection
INTRON A Powder for Injection, 10 million IU per vial and Diluent for INTRON A (Sterile Water 
for Injection USP) 5 mL per vial; boxes containing 1 INTRON A vial and 1 vial of INTRON A 
Diluent (NDC 0085-4350-01).
INTRON A Powder for Injection, 18 million IU per vial and Diluent for INTRON A (Sterile Water 
for Injection USP) 5 mL per vial; boxes containing 1 vial of INTRON A and 1 vial of INTRON A 
Diluent (NDC 0085-4351-01).
INTRON A Powder for Injection, 50 million IU per vial and Diluent for INTRON A (Sterile Water 
for Injection USP) 5 mL per vial; boxes containing 1 INTRON A vial and 1 vial of INTRON A 
Diluent (NDC 0085-4352-01).
INTRON A Solution for Injection in Vials
INTRON A Solution for Injection, 18 million IU multi-dose vials (22.8 million IU per 3.8 mL per 
vial); boxes containing 1 vial of INTRON A Solution for Injection (NDC 0085-1168-01).
INTRON A Solution for Injection, 25 million IU multi-dose vials (32 million IU per 3.2 mL per 
vial); boxes containing 1 vial of INTRON A Solution for Injection (NDC 0085-1133-01).
Peg interferon alfa-2b
[Refer 
to 
the 
FDA-approved 
package 
insert 
for 
more 
information: 
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b70816bb-913a-467f-acb8-
67ef62cf8dac.]
Other name(s)
PEGINTRON®, PEG-IFN-alfa-2b
Mechanism of Action
Pegylated recombinant human interferon alfa-2b is an inducer of the innate antiviral immune 
response. 
The biological activity of Peg Intron is derived from its interferon alfa-2b moiety. Peg interferon 
alfa-2b binds to and activates the human type 1 interferon receptor. Upon binding, the receptor 
subunits dimerize, and activate multiple intracellular signal transduction pathways. Signal 
transduction is initially mediated by the JAK/STAT activation, which may occur in a wide variety 
of cells. Interferon receptor activation also activates NFκB in many cell types. Given the diversity 
of cell types that respond to interferon alfa-2b, and the multiplicity of potential intracellular 
responses to interferon receptor activation, peg interferon alfa-2b is expected to have pleiotropic 
biological effects in the body.
The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully 
understood. Ribavirin has direct antiviral activity in tissue culture against many RNA viruses. 
Ribavirin increases the mutation frequency in the genomes of several viruses and ribavirin 
triphosphate inhibits HCV polymerase in a biochemical reaction.
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Antiviral Activity
The anti-HCV activity of interferon was demonstrated in cell culture using self-replicating HCV-
RNA (HCV replicon cells) or HCV infection and resulted in an effective concentration (EC) value 
of 1 to 10 IU/mL.
The antiviral activity of ribavirin in the HCV-replicon is not well understood and has not been 
defined because of the cellular toxicity of ribavirin.
Resistance
HCV genotypes show wide variability in their response to pegylated recombinant human 
interferon/ribavirin therapy. Genetic changes associated with the variable response have not been 
identified.
Cross-resistance
There is no reported cross-resistance between pegylated/non-pegylated interferons and ribavirin.
Drug Metabolism, Pharmacokinetics and Toxicology
Following a single subcutaneous dose of Peg Intron, the mean absorption half-life (t ½ ka) was 4.6 
hours. Maximal serum concentrations (Cmax) occur between 15 and 44 hours post dose, and are 
sustained for up to 48 to 72 hours. The Cmax and AUC measurements of Peg Intron increase in a 
dose related manner. After multiple dosing, there is an increase in bioavailability of Peg Intron. 
Week 48 mean trough concentrations (320 pg/mL; range 0, 2960) are approximately 3-fold higher 
than Week 4 mean trough concentrations (94 pg/mL; range 0, 416). The mean Peg Intron 
elimination half-life is approximately 40 hours (range 22-60 hours) in patients with HCV infection. 
The apparent clearance of Peg Intron is estimated to be approximately 22 mL/hr·kg. Renal 
elimination accounts for 30% of the clearance.
Pegylation of interferon alfa-2b produces a product (Peg Intron) whose clearance is lower than that 
of non-pegylated interferon alfa-2b. When compared to INTRON A, Peg Intron (1 mcg/kg) has 
approximately a 7-fold lower mean apparent clearance and a 5-fold greater mean half-life, 
permitting a reduced dosing frequency. At effective therapeutic doses, Peg Intron has 
approximately 10-fold greater Cmax and 50-fold greater AUC than interferon alfa-2b.
Renal Dysfunction
Following multiple dosing of Peg Intron (1 mcg/kg subcutaneously given every week for 4 weeks) 
the clearance of Peg Intron is reduced by a mean of 17% in subjects with moderate renal 
impairment (creatinine clearance 30-49 mL/min) and by a mean of 44% in subjects with severe 
renal impairment (creatinine clearance 10-29 mL/min) compared to subjects with normal renal 
function. Clearance was similar in subjects with severe renal impairment not on dialysis and 
subjects who are receiving hemodialysis. The dose of Peg Intron for monotherapy should be 
reduced in patients with moderate or severe renal impairment [see Dosage and Administration 
(2.3) and REBETOL labeling]. REBETOL should not be used in patients with creatinine clearance 
less than 50 mL/min [see REBETOL labeling, WARNINGS].
Gender
During the 48-week treatment period with Peg Intron, no differences in the pharmacokinetic 
profiles were observed between male and female subjects with chronic hepatitis C infection.
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Geriatric Patients
The pharmacokinetics of geriatric subjects (65 years of age and older) treated with a single 
subcutaneous dose of 1 mcg/kg of Peg Intron were similar in Cmax , AUC, clearance, or 
elimination half-life as compared to younger subjects (28-44 years of age).
Pediatric Patients
Population pharmacokinetics for Peg Intron and REBETOL (capsules and oral solution) were 
evaluated in pediatric subjects with chronic hepatitis C between 3 and 17 years of age. In pediatric 
patients receiving Peg Intron 60 mcg/m /week subcutaneously, exposure may be approximately 
50% higher than observed in adults receiving 1.5 mcg/kg/week subcutaneously. The 
pharmacokinetics of REBETOL (dose-normalized) in this trial were similar to those reported in a 
prior trial of REBETOL in combination with INTRON A in pediatric subjects and in adults.
Effect of Food on Absorption of Ribavirin
Both AUC and Cmax increased by 70% when REBETOL capsules were administered with a high-
fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose 
pharmacokinetic trial. 
Drug Interactions
Drugs Metabolized by Cytochrome P-450 
The pharmacokinetics of representative drugs metabolized by CYP1A2 (caffeine), CYP2C8/9 
(tolbutamide), CYP2D6 (dextromethorphan), CYP3A4 (midazolam), and N-acetyltransferase 
(dapsone) were studied in 22 subjects with chronic hepatitis C who received Peg Intron (1.5 
mcg/kg) once weekly for 4 weeks. Peg Intron treatment resulted in a 28% (mean) increase in a 
measure of CYP2C8/9 activity.
Peg Intron treatment also resulted in a 66% (mean) increase in a measure of CYP2D6 activity; 
however, the effect was variable as 13 subjects had an increase, 5 subjects had a decrease, and 4 
subjects had no significant change.
No significant effect was observed on the pharmacokinetics of representative drugs metabolized 
by CYP1A2, CYP3A4, or N-acetyltransferase. The effects of Peg Intron on CYP2C19 activity 
were not assessed.
Methadone
The pharmacokinetics of concomitant administration of methadone and Peg Intron were evaluated 
in 18 Peg Intron-naïve chronic hepatitis C subjects receiving 1.5 mcg/kg Peg Intron 
subcutaneously weekly.
All subjects were on stable methadone maintenance therapy receiving greater than or equal to 40 
mg/day prior to initiating Peg Intron. Mean methadone AUC was approximately 16% higher after 
4 weeks of Peg Intron treatment as compared to baseline. In 2 subjects, methadone AUC was 
approximately double after 4 weeks of Peg Intron treatment as compared to baseline. 
Use with Ribavirin, Zidovudine, Lamivudine, and Stavudine
Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine, lamivudine, and 
stavudine.
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However, in a trial with another pegylated interferon in combination with ribavirin, no 
pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite 
concentrations) or pharmacodynamics (e.g., loss of HIV/HCV virologic suppression) interaction 
was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were 
co-administered as part of a multi-drug regimen to HIV/HCV co-infected subjects. 
Didanosine
Exposure to didanosine or its active metabolite (dideoxyadenosine 5'- triphosphate) is increased 
when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities.
Management of Agent-Specific Adverse Events
Adults
Study 1 compared Peg Intron monotherapy with INTRON® A monotherapy. Study 2 compared 
combination therapy of Peg Intron/REBETOL with combination therapy with INTRON 
A/REBETOL. In these clinical trials, nearly all subjects experienced one or more adverse 
reactions. Study 3 compared a Peg Intron/weight-based REBETOL combination to a Peg 
Intron/flat dose REBETOL regimen. Study 4 compared two Peg Intron (1.5 mcg/kg/week and 1 
mcg/kg/week) doses in combination with REBETOL and a third treatment group receiving 
Pegasys (180 mcg/week)/Copegus (1000-1200 mg/day).
Adverse reactions that occurred in Studies 1 and 2 at greater than 5% incidence are provided in 
Table A (below) by treatment group. Due to potential differences in ascertainment procedures, 
adverse reaction rate comparisons across trials should not be made. Table B (below) summarizes 
the treatment-related adverse reactions in Study 4 that occurred at a greater than or equal to 10% 
incidence.
Table A: Adverse Reactions Occurring in >5% of Subjects
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Table B: Treatment-related Adverse Reactions (≥10% incidence) by Descending Frequency
The adverse reaction profile in Study 3, which compared Peg Intron/weight-based REBETOL 
combination to a Peg Intron/flat-dose REBETOL regimen, revealed an increased rate of anemia 
with weight-based dosing (29% vs. 19% for weight-based vs. flat-dose regimens, respectively). 
However, the majority of cases of anemia were mild and responded to dose reductions.
The incidence of serious adverse reactions was comparable in all trials. In the Peg Intron 
monotherapy trial (Study 1) the incidence of serious adverse reactions was similar (about 12%) in 
all treatment groups. In Study 2, the incidence of serious adverse reactions was 17% in the Peg 
Intron/REBETOL groups compared to 14% in the INTRON A/REBETOL group. In Study 3, there 
was a similar incidence of serious adverse reactions reported for the weight-based REBETOL 
group (12%) and for the flat dose REBETOL regimen.
In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of 
therapy.
Some subjects experienced ongoing or new serious adverse reactions during the 6-month follow-
up period.
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There have been 31 subject deaths that occurred during treatment or during follow-up in these 
clinical trials. In Study 1, there was 1 suicide in a subject receiving Peg Intron monotherapy and 2 
deaths among subjects receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death). 
In Study 2, there was 1 suicide in a subject receiving Peg Intron/REBETOL combination therapy, 
and 1 subject death in the INTRON A/REBETOL group (motor vehicle accident). In Study 3, there 
were 14 deaths, 2 of which were probable suicides, and 1 was an unexplained death in a person 
with a relevant medical history of depression. In Study 4, there were 12 deaths, 6 of which occurred 
in subjects receiving Peg Intron/REBETOL combination therapy; 5 in the Peg Intron 1.5 
mcg/REBETOL arm (N=1019) and 1 in the Peg Intron 1 mcg/REBETOL arm (n=1016); and 6 of 
which occurred in subjects receiving Pegasys/Copegus (N=1035). There were 3 suicides that 
occurred during the off-treatment follow-up period in subjects who received Peg Intron (1.5 
mcg/kg)/REBETOL combination therapy.
In Studies 1 and 2, 10% to 14% of subjects receiving Peg Intron, alone or in combination with 
REBETOL, discontinued therapy compared with 6% treated with INTRON A alone and 13% 
treated with INTRON A in combination with REBETOL. Similarly in Study 3, 15% of subjects 
receiving Peg Intron in combination with weight-based REBETOL and 14% of subjects receiving 
Peg Intron and flat-dose REBETOL discontinued therapy due to an adverse reaction. The most 
common reasons for discontinuation of therapy were related to known interferon effects of 
psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse reactions. In Study 4, 
13% of subjects in the Peg Intron
1.5 mcg/REBETOL arm, 10% in the Peg Intron 1 mcg/REBETOL arm, and 13% in the Pegasys 
180 mcg/Copegus arm discontinued therapy due to adverse events. In Study 2, dose reductions 
due to adverse reactions occurred in 42% of subjects receiving Peg Intron (1.5 mcg/kg)/REBETOL 
and in 34% of those receiving INTRON A/REBETOL. The majority of subjects (57%) weighing 
60 kg or less receiving Peg Intron (1.5 mcg/kg)/REBETOL required dose reduction. Reduction of 
interferon was dose-related (Peg Intron 1.5 mcg/kg more than Peg Intron 0.5 mcg/kg or INTRON 
A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL was similar across all three 
groups, 33% to 35%. The most common reasons for dose modifications were neutropenia (18%) 
or anemia (9%). Other common reasons included depression, fatigue, nausea, and 
thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more 
frequently with weight-based dosing (WBD) compared to flat dosing (29% and 23%, respectively). 
In Study 4, 16% of subjects had a dose reduction of Peg Intron to 1 mcg/kg in combination with 
REBETOL, with an additional 4% requiring the second dose reduction of Peg Intron to 0.5 mcg/kg 
due to adverse events, compared to 15% of subjects in the Pegasys/Copegus arm, who required a 
dose reduction to 135 mcg/week with Pegasys, with an additional 7% requiring a second dose 
reduction to 90 mcg/week with Pegasys.
In the Peg Intron/REBETOL combination trials the most common adverse reactions were 
psychiatric, which occurred among 77% of subjects in Study 2 and 68% to 69% of subjects in 
Study 3. These psychiatric adverse reactions included most commonly depression, irritability, and 
insomnia, each reported by approximately 30% to 40% of subjects in all treatment groups. Suicidal 
behavior (ideation, attempts, and suicides) occurred in 2% of all subjects during treatment or 
during follow-up after treatment cessation [see Warnings and Precautions (5.2)]. In Study 4, 
psychiatric adverse reactions occurred in 58% of subjects in the Peg Intron 1.5 mcg/REBETOL 
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arm, 55% of subjects in the Peg Intron 1 mcg/REBETOL arm, and 57% of subjects in the Pegasys 
180 mcg/Copegus arm.
Peg Intron induced fatigue or headache in approximately two-thirds of subjects, with fever or 
rigors in approximately half of the subjects. The severity of some of these systemic symptoms 
(e.g., fever and headache) tended to decrease as treatment continued. In Studies 1 and 2, application 
site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately 
twice the incidence with Peg Intron therapies (in up to 75% of subjects) compared with INTRON 
A. However, injection-site pain was infrequent (2-3%) in all groups. In Study 3, there was a 23% 
to 24% incidence overall for injection site reactions or inflammation.
In Study 2, many subjects continued to experience adverse reactions several months after 
discontinuation of therapy. By the end of the 6-month follow-up period, the incidence of ongoing 
adverse reactions by body class in the Peg Intron 1.5/REBETOL group was 33% (psychiatric), 
20% (musculoskeletal), and 10% (for endocrine and for GI). In approximately 10% to 15% of 
subjects, weight loss, fatigue, and headache had not resolved.
Individual serious adverse reactions in Study 2 occurred at a frequency less than or equal to 1% 
and included suicide attempt, suicidal ideation, severe depression; psychosis, aggressive reaction, 
relapse of drug addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy, myocardial 
infarction, angina, pericardial effusion, retinal ischemia, retinal artery or vein thrombosis, 
blindness, decreased visual acuity, optic neuritis, transient ischemic attack, supraventricular 
arrhythmias, loss of consciousness; neutropenia, infection (sepsis, pneumonia, abscess, cellulitis); 
emphysema, bronchiolitis obliterans, pleural effusion, gastroenteritis, pancreatitis, gout, 
hyperglycemia, hyperthyroidism and hypothyroidism, autoimmune thrombocytopenia with or 
without purpura, rheumatoid arthritis, interstitial nephritis, lupus-like syndrome, sarcoidosis, 
aggravated psoriasis; urticaria, injection-site necrosis, vasculitis, and photo toxicity.
Subjects receiving Peg Intron/REBETOL as re-treatment after failing a previous interferon 
combination regimen reported adverse reactions similar to those previously associated with this 
regimen during clinical trials of treatment-naïve subjects.
Laboratory Values
Adults
Changes in selected laboratory values during treatment with Peg Intron alone or in combination 
with REBETOL treatment are described below. Decreases in hemoglobin, neutrophils, and 
platelets may require dos e reduction or permanent dis continuation from therapy [see Dosage and 
Administration (2.3) and Warnings and Precautions (5.1, 5.7)].
Hemoglobin
Hemoglobin levels decreased to less than 11 g/dL in about 30% of subjects in Study 2. In Study 3, 
47% of subjects receiving WBD REBETOL and 33% on flat-dose REBETOL had decreases in 
hemoglobin levels less than 11 g/dL. Reductions in hemoglobin to less than 9 g/dL occurred more 
frequently in subjects receiving WBD compared to flat dosing (4% and 2%, respectively). In Study 
2, dose modification was required in 9% and 13% of subjects in the Peg Intron/REBETOL and 
INTRON A/REBETOL groups. In Study 4, subjects receiving Peg Intron (1.5 mcg/kg)/REBETOL 
had decreases in hemoglobin levels to between 8.5 to less than 10 g/dL (28%) and to less than 8.5 
g/dL (3%),   whereas in subjects receiving Pegasys 180 mcg/Copegus these decreases occurred in 
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26% and 4% of subjects, respectively. Hemoglobin levels became stable by treatment Weeks 4 to 
6 on average. The typical pattern observed was a decrease in hemoglobin levels by treatment Week 
4 followed by stabilization and a plateau, which was maintained to the end of treatment. In the 
PegIntronmonotherapy trial, hemoglobin decreases were generally mild and dose modifications 
were rarely necessary [see Dosage and Administration (2.3)].
Neutrophils 
Decreases in neutrophil counts were observed in a majority of subjects treated with Peg Intron 
alone (70%) or as combination therapy with REBETOL in Study 2 (85%) and 
INTRONA/REBETOL (60%). Severe potentially life-threatening neutropenia (less than 0.5 × 10 
/L) occurred in
1% of subjects treated with Peg Intron monotherapy, 2% of subjects treated with 
INTRONA/REBETOL, and in approximately 4% of subjects treated with Peg Intron/REBETOL 
in Study 2. Two percent of subjects receiving Peg Intron monotherapy and 18% of subjects 
receiving Peg Intron/REBETOL in Study 2 required modification of interferon dosage. Few 
subjects (less than1%) required permanent discontinuation of treatment. Neutrophil counts 
generally returned to pretreatment levels 4 weeks after cessation of therapy [see Dosage and 
Administration (2.3)].
Platelets 
Platelet counts decreased to less than 100,000/mm in approximately 20% of subjects treated with 
Peg Intron alone or with REBETOL and in 6% of subjects treated with INTRON A/REBETOL. 
Severe decreases in platelet counts (less than 50,000/mm) occur in less than 4% of subjects. 
Patients may require discontinuation or dose modification as a result of platelet decreases [see 
Dosage and Administration (2.3)]. In Study 2, 1% or 3% of subjects required dose modification of 
INTRON A or Peg Intron, respectively. Platelet counts generally returned to pretreatment levels 4 
weeks after the cessation of therapy.
Triglycerides 
Elevated triglyceride levels have been observed in patients treated with interferon alphas, including 
Peg Intron [see Warnings and Precautions (5.17)].
Thyroid Function 
Development of TSH abnormalities, with or without clinical manifestations, is associated with 
interferon therapies. In Study 2, clinically apparent thyroid disorders occurred among subjects 
treated with either INTRON A or Peg Intron (with or without REBETOL) at a similar incidence 
(5% for hypothyroidism and 3% for hyperthyroidism). Subjects developed new-onset TSH 
abnormalities while on treatment and during the follow-up period. At the end of the follow-up 
period,7% of subjects still had abnormal TSH values [see Warnings and Precautions (5.4)].
Bilirubin and Uric Acid. In Study 2, 10% to 14% of subjects developed hyperbilirubinemia and 
33% to38% developed hyperuricemia in association with hemolysis. Six subjects developed mild 
to moderate gout.
Immunogenicity
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As with all therapeutic proteins, there is potential for immunogenicity. Approximately 2% of 
subjects receiving Peg Intron (32/1759) or INTRON A (11/728) with or without REBETOL 
developed low-titer(less than or equal to 160) neutralizing antibodies to Peg Intron or INTRON A. 
The clinical and pathological significance of the appearance of serum-neutralizing antibodies is 
unknown. The incidence of antibody formation is highly dependent on the sensitivity and 
specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing 
antibody) positivity in an assay may be influenced by several factors, including assay 
methodology, sample handling, timing of sample collection, concomitant medications, and 
underlying disease. For these reasons, comparison of the incidence of antibodies to Peg Intron with 
the incidence of antibodies to other products may be misleading.
Carcinogenesis and Mutagenesis
Peg Intron has not been tested for its carcinogenic potential. Neither Peg Intron nor its components, 
interferon or methoxypolyethylene glycol, caused damage to DNA when tested in the standard 
battery of mutagenesis assays, in the presence and absence of metabolic activation.
Use with Ribavirin: See ribavirin labeling for additional warnings relevant to Peg Intron therapy 
in combination with ribavirin.
Impairment of Fertility
Peg Intron may impair human fertility. Irregular menstrual cycles were observed in female 
cynomolgus monkeys given subcutaneous injections of 4239 mcg/m Peg Intron alone every other 
day for 1 month (approximately 345 times the recommended weekly human dose based upon body 
surface area). These effects included transiently decreased serum levels of estradiol and 
progesterone, suggestive of anovulation. Normal menstrual cycles and serum hormone levels 
resumed in these animals 2 to 3 months following cessation of Peg Intron treatment. Every other 
day dosing with 262 mcg/m (approximately 21 times the weekly human dose) had no effects on 
cycle duration or reproductive hormone status. The effects of Peg Intron on male fertility have not 
been studied.
Composition
Peg Intron, peg interferon alfa-2b, is a covalent conjugate of recombinant alfa-2b interferon with 
monomethoxy polyethylene glycol (PEG). The average molecular weight of the PEG portion of 
the molecule is 12,000 daltons. The average molecular weight of the Peg Intron molecule is 
approximately 31,000 daltons. The specific activity of peg interferon alfa-2b is approximately 0.7 
× 108 IU/mg protein.
Interferon alfa-2b is a water-soluble protein with a molecular weight of 19,271 daltons produced 
by recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of 
Escherichia coli bearing a genetically engineered plasmid containing an interferon gene from 
human leukocytes.
Storage Recommendations and Dosage Forms
Peg Intron is supplied in both vials and the REDIPEN single-use pre-filled pen for subcutaneous 
use.
Vials
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Each vial contains either 74 mcg, 118.4 mcg, 177.6 mcg, or 222 mcg of Peg Intron as a white to 
off-white tablet-like solid that is whole/in pieces or as a loose powder, and 1.11 mg dibasic sodium 
phosphate anhydrous, 1.11 mg monobasic sodium phosphate dehydrate, 59.2 mg sucrose, and 
0.074 mg polysorbate 80. Following reconstitution with 0.7 mL of the supplied Sterile Water for 
Injection USP, each vial contains Peg Intron at strengths of either 50 mcg per 0.5 mL, 80 mcg per 
0.5 mL, 120 mcg per 0.5 mL, or 150 mcg per 0.5 mL.
REDIPEN single-use pre-filled pen
REDIPEN pre-filled pen is a dual-chamber glass cartridge containing lyophilized Peg Intron as a 
white to off-white tablet or powder that is whole or in pieces in the sterile active chamber and a 
second chamber containing Sterile Water for Injection USP. Each Peg Intron REDIPEN pre-filled 
pen contains either 67.5 mcg, 108 mcg, 162 mcg, or 202.5 mcg of Peg Intron, and 1.013 mg dibasic 
sodium phosphate anhydrous, 1.013 mg monobasic sodium phosphate dehydrate, 54 mg sucrose, 
and 0.0675 mg polysorbate 80. Each cartridge is reconstituted to allow for the administration of 
up to 0.5 mL of solution. Following reconstitution, each REDIPEN pre-filled pen contains Peg 
Intron at strengths of either 50 mcg per 0.5 mL, 80 mcg per 0.5 mL, 120 mcg per 0.5 mL, or 150 
mcg per 0.5 mL for a single use. Because a small volume of reconstituted solution is lost during 
preparation of Peg Intron, each REDIPEN pre-filled pen contains an excess amount of Peg Intron 
powder and diluent to ensure delivery of the labeled dose.
Storage
Peg Intron REDIPEN single-use pre-filled pen
Peg Intron REDIPEN pre-filled pen should be stored at 2-8°C (36-46°F).
After reconstitution, the solution should be used immediately, but may be stored up to 24 hours at 
2-8°C (36-46°F). The reconstituted solution contains no preservative, and is clear and colorless. 
DO NOT FREEZE. Keep away from heat.
Peg Intron Vials
Peg Intron should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP 
Controlled Room Temperature]. After reconstitution with supplied diluent, the solution should be 
used immediately but may be stored up to 24 hours at 2-8°C (36-46°F). The reconstituted solution 
contains no preservative, and is clear and colorless.  DO NOT FREEZE. Keep away from heat.
Dispensation and Accountability
Peg intron is commercially available.
Patients should be advised to read the FDA-approved patient labeling (Medication Guide and 
Instructions for Use). A patient should self-inject Peg Intron only if it has been determined that it 
is appropriate, the patient agrees to medical follow-up as necessary, and training in proper injection 
technique 
has 
been 
given 
to 
him/her.(For 
patent 
information: 
www.merck.com/product/patent/home.html.)
Instructions for Use
Patients receiving Peg Intron should be directed in its appropriate preparation, handling, 
measurement, and injection, and referred to the Instructions for Use for Peg Intron Powder for 
Solution and Peg Intron REDIPEN Single-use Pre-filled pen.
-       Study #: 20150567        Effective Date: 12/23/2025

CONFIDENTIAL
Version #: 9.0
eProst# 20150567
Version Date: 9December 2025
Page 113 of 113
Patients should be instructed that the Sterile Water for Injection vial supplied with Peg Intron 
Powder for Solution contains an excess amount of diluent (5 mL) and only 0.7 mL should be 
withdrawn to reconstitute Peg Intron Powder for Solution. The vial of Sterile Water for Injection 
is intended for single use only. Discard the unused portion of the sterile water. Do not save or 
reuse.
Patients should be directed to store Peg Intron before mixing as follows:
Peg Intron REDIPEN single-use pre-filled pens: store in the refrigerator between 36-46°F (2-8°C)
Peg Intron Powder for Solution: store at room temperature between 59-86°F (15-30°C)
Patients should be instructed on the importance of site selection for self-administering the 
injection, as well as the importance on rotating the injection sites.
Disposal Instructions
Patients should be thoroughly instructed in the importance of proper disposal. After preparation 
and administration of Peg Intron for Injection, patients should be advised to use a puncture-
resistant container for the disposal of used syringes, needles, and the REDIPEN pre-filled pen. The 
full container should be disposed of in accordance with state and local laws. Patients should also 
be cautioned against reusing or sharing needles, syringes, or the REDIPEN pre-filled pen.
CYCLOPHOSPHAMIDE:
Cyclophosphamide is an alkylating agent and is cell cycle nonspecific. It causes cross-linking of 
DNA and is the most active single agent in the treatment of non-Hodgkin’s lymphoma. Side effects 
of cyclophosphamide include nausea, vomiting, myelosuppression and alopecia. Sterility and 
testicular atrophy are common in men and amenorrhea is seen in women. Hemorrhagic cystitis is 
caused by metabolites of cyclophosphamide excreted through the urine. Bladder irritation can be 
reduced by adequate hydration. Please refer to the approved package insert for complete 
prescribing and toxicity information.
-       Study #: 20150567        Effective Date: 12/23/2025