Conditions: Lymphoid Malignancies Lymphoma Hodgkin Lymphoma Non-hodgkin Lymphoma
Keywords: Lymphoid Malignancies Lymphoma Hodgkin Lymphoma Non-hodgkin Lymphoma Follicular Lymphoma Diffuse Large B-Cell Lymphoma Anaplastic Large Cell Lymphoma Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Mantle Cell Lymphoma Marginal Zone Lymphoma Burkitt Lymphoma Waldenstrom Macroglobulinemia Peripheral T-cell Lymphoma Cutaneous T-cell Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 58
Healthy volunteers: no

Brief summary:
This is an open label, phase I/IIa, 3 x 3 dose escalation study with an initial phase I followed by a disease focused phase II.

The primary objective of the phase I is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combinations of oral 5-azacitidine and romidepsin in patients with lymphoma. The safety and toxicity of this combination will be evaluated throughout the entire study.

If the combination of oral 5-azacitidine and romidepsin is found to be feasible and an MTD is established, the phase II part of the study will be initiated.

Phase II will consist of a 2 stage design of the combination of oral 5-azacitidine and romidepsin for patients with relapsed or refractory T-cell lymphomas.

Detailed description:
Subjects will receive oral 5-azacitidine and romidepsin, administered as follows: oral 5-azacitidine from Days 1-14 (Dose cohorts -1 to 5) or Days 1-21 (Dose cohort 6); and romidepsin administered intravenously on Days 8 (Dose cohorts 1-4) of a 28 day cycle, and Day 22 (Dose cohorts 5 and 6) of a 35 day cycle. Cohorts of 3 patients will be enrolled sequentially as outlined in the dose escalation scheme. Once the MTD is reached the Phase II part of the protocol will be initiated in patients with T-Cell Lymphoma.

Arms:
arm 1: Oral 5-Azacitidine 100 mg (Days 1-14) Romidepsin (10 mg/m2, Day 8), cycle length (28 days) arm 2: Oral 5-Azacitidine 100 mg (Days 1-14) Romidepsin (10 mg/m2, Days 8 and 15), cycle length (28 days) arm 3: Oral 5-Azacitidine 200 mg (Days 1-14) Romidepsin (10 mg/m2, Days 8 and 15), cycle length (28 days) arm 4: Oral 5-Azacitidine 300 mg (Days 1-14) Romidepsin (10 mg/m2, Days 8 and 15), cycle length (28 days) arm 5: Oral 5-Azacitidine 300 mg (Days 1-14) Romidepsin (14 mg/m2, Days 8 and 15), cycle length (28 days) arm 6: Oral 5-Azacitidine 300 mg (Days 1-14) Romidepsin (14 mg/m2, Days 8, 15 and 22), cycle length (35 days) arm 7: Oral 5-Azacitidine 300 mg (Days 1-21) Romidepsin (14 mg/m2, Days 8, 15 and 22), cycle length (35 days)

Interventions: intervention 1: RomiDEPsin 10 MG/M2 intervention 2: Oral 5-Azacitidine 100 MG intervention 3: Romidepsin 14 MG/M2 intervention 4: Oral 5-Azacitidine 200 MG intervention 5: Oral 5-Azacitidine 300 MG
Intervention descriptions: intervention 1: Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor".

Dose escalation (10 mg/m2) intervention 2: A pyrimidine nucleoside analogue of cytidine with antineoplastic activity.

Dose escalation (100 mg) intervention 3: Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor".

Dose escalation (14 mg/m2) intervention 4: A pyrimidine nucleoside analogue of cytidine with antineoplastic activity.

Dose escalation (200 mg) intervention 5: A pyrimidine nucleoside analogue of cytidine with antineoplastic activity.

Dose escalation (300 mg)

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
TITLE:    
PHASE I/IIA STUDY OF THE ORAL 5-AZACITIDINE IN COMBINATION WITH THE 
HISTONE DEACETYLASE INHIBITOR ROMIDEPSIN FOR THE TREATMENT OF 
PATIENTS WITH T-CELL LYMPHOMA AND GERMINAL-CENTER-DERIVED B-
CELL LYMPHOMA  
 
 
Coordinating Center: 
Columbia University Medical Center (CUMC) 
Participating Centers:  
H. Lee Moffitt Cancer Center & Research Institute 
 
Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance 
 
 
Principal Investigator: 
Owen A. O’Connor, MD, PhD 
 
Professor of Medicine and Experimental Therapeutics 
 
Director, Center for Lymphoid Malignancies 
 
owenoconnor@columbia.edu 
 
 
 
 
 
Co-Investigators: 
Jennifer Amengual, MD 
 
Assistant Professor of Medicine & Experimental Therapeutics 
 
JEA2149@columbia.edu 
 
 
Changchun Deng, MD, Ph.D. 
 
Assistant Professor of Clinical Medicine & Experimental Therapeutics 
 
CD2448@columbia.edu 
 
 
Ahmed Sawas, MD 
 
Instructor in Clinical Medicine 
 
AS4386@columbia.edu 
 
 
Lubomir Sokol, MD, Ph.D. 
 
Site Principal Investigator 
 
H. Lee Moffitt Cancer Center & Research Institute 
 
Lubomir.Sokol@moffitt.org 
 
 
Andrei R Shustov, MD 
 
Site Principal Investigator 
 
Fred Hutchinson Cancer Research Center 
 
Seattle Cancer Care Alliance 
 
ashustov@seattlecca.org 
  
 
CUMC Protocol #:  
AAAM3752 
 
Protocol Type / Version # / Version Date: Amendment 1.4/ Version 1 / 20June2018 
 
ClinicalTrials.gov Identifier: 
NCT01998035 


 
 
 
 
 
i 
PROTOCOL SYNOPSIS 
Title: 
Phase I/IIa study of oral 5-azacitidine in combination with the histone deacetylase 
inhibitor romidepsin for the treatment of patients with T-cell lymphomas  
 
Study Design: 
 
This is an open label, phase I/IIa, 3 x 3 dose-escalation study with an initial phase I 
followed by a disease focused phase II.  
 
The primary objective of the phase I is to determine the maximum tolerated dose (MTD) 
and dose limiting toxicity (DLT) of the combinations of oral 5-azacitidine and 
romidepsin in patients with lymphoma.  The safety and toxicity of this combination will 
be evaluated throughout the entire study.  
 
If the combination of oral 5-azacitidine and romidepsin is found to be feasible and an 
MTD is established, the phase II part of the study will be initiated.   
 
Phase II will consist of a 2 stage design of the combination of oral 5-Azacitidine and 
romidepsin for patients with relapsed or refractory T-cell lymphomas. 
 
Objectives: 
 
A. 
Phase I: 
Primary Objectives 
• Determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of 
the combination of oral 5-azacitidine and romidepsin. 
• Evaluate the safety and toxicity of the combination of oral 5-azacitidine and 
romidepsin. 
 
Secondary Objectives 
• Describe the maximum number of cycles received  
• Describe the number of dose delays and dose reductions at the MTD 
• Describe the anti-tumor activity of the combination  
• Evaluate the overall response rate (ORR), progression free survival (PFS), and 
duration of response (DOR) of the study population.  
 
Exploratory Objectives 
• Evaluate pharmacodynamic markers of drug effect in paired tissue biopsies (pre- and 
post- treatment) including gene expression and genome wide methylation patterns.  
• Establish the pharmacokinetic profile for oral 5-azacitidine and romidepsin when 
given as a combination in Cycle 1 at various time intervals as listed in Figure 1.   
 


 
 
 
 
 
ii
B. Phase II:  
 
 
Primary Objectives 
 
 
 
• Estimate the ORR (complete + partial response) of the combination of oral 5-
azacitidine and romidepsin in patients with relapsed/refractory T-cell Lymphoma. 
 
 
 
Secondary Objectives 
• Estimate the DOR and PFS of the combination in patients with T-cell lymphoma.   
• Estimate the overall survival of patients with T-cell lymphoma on study. 
• Identify potential pre-treatment biomarkers of response based on GEP and/or 
methylation array) to clinical outcome.  
 
Exploratory Objectives 
• Evaluate pharmacodynamic markers of drug effect in paired tissue biopsies (pre- and 
post- treatment) including gene expression and genome wide methylation patterns. 
 
C. Exploratory Cohort: Germinal Center B-cell Lymphoma: 
     Primary Objectives 
• Determine the overall response rates (complete responses + partial responses) of oral 
azacytidine and romidepsin in patients with GC-derived B-cell lymphomas. 
• Determine Progression Free Survival (PFS) and Time to Treatment Failure (TTF) 
• Determine the Duration of Response (DOR)  
Secondary Objectives: 
• Determine the safety and tolerability of oral azacytadine and romidepsin in patients with 
relapsed or refractory GC-derived B-cell lymphoid malignancies. 
• Evaluate the pharmacokinetic (PK) profile of oral azacytadine and romidepsin. 
• Evaluate and compare pharmacodynamic (PD) endpoints with PK endpoints. PD endpoints 
will include the evaluation of paired gene expression profiles of primary patient samples 
on study. 
 
 
Target Population 
 
Phase I: Patients with relapsed or refractory non-Hodgkin lymphoma, Hodgkin 
lymphoma  
Phase II: Patients with untreated or relapsed or refractory T-Cell Lymphoma 
Exploratory Cohort: Patients with relapsed or refractory Germinal Center-Derived B-
Cell Lymphoma 
 
Inclusion Criteria  
• Phase I: Patients must have histologically confirmed relapsed or refractory non-


 
 
 
 
 
iii 
Hodgkin lymphoma or Hodgkin lymphoma (defined by WHO criteria), with no 
accepted curative options. 
Phase II: Patients must have histologically confirmed T-cell lymphoma (as defined 
by WHO criteria), including central nervous system (CNS) involvement or 
lymphomatous meningitis.  
Exploratory Cohort: Patients with histologically confirmed relapsed or refractory 
Germinal Center (GC)-derived B-Cell Lymphoma (diffuse large B-cell (DLBCL) and 
follicular lymphoma (FL)) defined by the WHO and Hans criteria with no accepted 
curative options. (Appendix 5) 
• There is no upper limit for the number of prior therapies 
• Evaluable Disease in the Phase I, and measurable disease as defined in Section 11.1 
in the Phase II. 
• Age >18 years. 
• ECOG performance status <2  
• Patients must have adequate organ and marrow function as defined in Section 3.1.6 
• Adequate Contraception 
• Ability to understand and the willingness to sign a written informed consent 
document. 
 
Exclusion Criteria 
 
• Prior Therapy 
o 
Exposure to chemotherapy or radiotherapy within 2 weeks prior to 
entering the study or those who have not recovered from adverse events 
due to agents administered more than 2 weeks earlier.  
o 
Systemic steroids that have not been stabilized (≥ 5 days) to the equivalent 
of ≤10 mg/day prednisone prior to the start of the study drugs. 
o 
No other investigational agents are allowed. 
• History of allergic reactions to oral 5-azacitidine or romidepsin.  
• Uncontrolled inter-current illness 
• Pregnant women  
• Nursing women  
• Current malignancy or history of a prior malignancy, as outlined in Section 3.3.7 
• Patient known to be Human Immunodeficiency Virus (HIV)-positive  
• Active Hepatitis A, Hepatitis B, or Hepatitis C infection 
 
Treatment Plan (Phase I) 
Patients will be treated with oral 5-azacitidine and romidepsin administered as follows 
(detailed in Tabel 2): escalating oral 5-azacitidine from Days 1-14 (Dose cohorts -1 to 5)or 
Days 1-21 (Dose Cohort 6); and romidepsin administered intravenously on Days 8, 15 
(Dose cohorts 1-4) of a 28 day cycle and Day 22 (Dose Cohorts 5 and 6) of a 35 day cycle.  
Cohorts of 3 patients will be enrolled sequentially as outlined in the dose escalation scheme 


 
 
 
 
 
iv 
(Table 2). Once the MTD is reached the Phase II part of the protocol will be initiated in 
patients with T-Cell Lymphoma (Figure 2).  
 
Treatment Plan (Phase II and Exploratory Cohort) 
 
Patients will be treated with oral 5-azacytidine and romidepsin at the MTD (i.e the 
Recommended Phase 2 Dose, or RP2D).  The treatment will be administered as follows: oral 5-
azacytidine 300 mg (flat dose) Days 1-14 and romidepsin 14 mg/m2 on Days 8, 15, and 22 on an 
every 35 day cycle.  .   
 
Duration of Treatment 
Patients will be treated until one of the following events: 
• 
Disease progression 
• 
Unacceptable adverse event(s), DLTs 
• 
Withdrawal of consent 
• 
General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in the judgment of the investigator 
• 
An event that in the judgment of the treating physician warrant’s discontinuation of 
therapy.  
 
Sample Size 
Phase I 
An estimated 36 patients (max of 45) will be accrued to the initial Phase I study; a minimum 
of 3 patients will be treated at each of the 6 dose levels (Dose Escalation and de-escalation; 
Tables 3 & 4). If a DLT is reached early we will treat fewer patients.  We will expand the 
cohort which meets criteria for a DLT to a total of 6. 
 
Phase II 
The phase II part of the study will accrue a total of 24 patients.  
 
Exploratory Cohort 
The exploratory cohort part of the study will accrue a total of 10 patients. 
 
Safety 
Patients will be monitored carefully for the development of adverse events as well as 
clinical and/or radiographic evidence of disease response.  Adverse events will be 
evaluated according to criteria outlined in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0. 
 
Efficacy Outcome 
Overall response rates will be evaluated using clinical parameters, CT scan (PET/CT scan is 
optional) and bone marrow biopsy, as outlined by the 2007 International Harmonization Project 
criteria.[1]  
 
Pharmacokinetic Analyses ( T-Cell Population ONLY) 


 
 
 
 
 
v
• Pharmacokinetic studies will be performed on up to 10 patients in the Phase 2. A pre-
treatment blood sample will be obtained prior to starting 5-azacytidine and romidepsin.  On 
day 8 of cycle 1, blood samples will be obtained from patient’s at fixed time intervals after 
administration of Romidepsin (t1/2 = 3.5 hours) to determine the plasma level of both 
romidepsin and oral 5-azacitidine. The patient will be directed to take 5-azacytidine at the 
time the romidepsin infusion begins. This will be compared to the known pharmacokinetic 
data for the individual agents in order to identify any possible effect of the combination. The 
proposed time points are shown in Figure 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Drug Administration and Pharmacokinetic Sampling Schedule (Day 1) 
Within 2 
hours of 
infusion 
start 
PK 
sample 
Predose 
PK Sample 
End of 
Infusion 
(EOI) of 
Azacitadine 
 
* All PKs should be drawn within 15 minutes of specified time. 
 
1 
Minute 
Start of 
Azacitadine 
 
 
30  
Minutes 
PK 
sample 
30 min 
post 
EOI 
1 
Hour
PK 
sample 
1 hr 
post 
EOI 
0 
3 
Hour
PK 
sample 
3hrs 
post 
EOI 
 
2.5 
Hour
PK 
sample 
2.5 hrs 
post 
EOI
 
 2 
Hour
PK 
sample 
2 hrs 
post 
EOI 
  
1.5 
Hour
PK 
sample 
1.5 hrs 
post 
EOI 
 
 
Time 
Activity 
Figure 1a: Drug Administration and Pharmacokinetic Sampling Schedule (Day 8) 
Within 2 
hours of 
infusion 
start 
PK 
sample 
Predose 
PK Sample 
End of 
Infusion 
(EOI) of 
Azacitadine 
 
4 
Hours 
Start o 
Romidepsin 
Infusion 
 
 
4.50  
Hours 
PK 
sample 
30 min 
post 
EOI 
5 
Hour
PK 
sample 
1 hr 
post 
EOI 
 
48 
Hour
24 
Hour
7 
Hour
PK 
sample 
3 hrs 
post 
EOI 
  
6 
Hour
PK 
sample 
2 hrs 
post 
EOI 
 
 
Time 
PK 
sample 
48hrs 
post 
EOI 
PK 
sample 
24 hrs 
post 
EOI 
24 
Hour
48 
Hour
PK 
sample 
24hrs 
post 
EOI 
PK 
sample 
48hrs 
post 
EOI 


 
 
 
 
 
vi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCHEMA 
Table 1: Regimen Description 
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Oral 
5-
azacitidine  
Standard 
Premedications 
300 
mg 
(flat dose)  
PO Days 1-14 
 
Days 1-14  
35 days 
Romidepsin 
Antiemetic  
14 mg/m2 
IV over 4 hours  
 
Days 8, 15 
and 22  
** Doses as appropriate for assigned dose level. 
 
Table 2:  Dose Escalation Scheme for the Combination of Oral 5-azacitidine and  
 
 Romidepsin 
Dose Escalation Schedule 
 
Dose 
Level 
Dose 
 
Oral 5-azacitidine 
(Flat dose [mg]) 
 
Romidepsin 
(mg/m2 rounded to 
14mg/m2) 
Cycle Length 
Level -1 
100 (Days 1-14) 
10 (Day 8) 
28 
Level 1 
100 (Days 1-14) 
10 (Days 8 & 15) 
28 
Figure 1b: Drug Administration and Pharmacodynamic Sampling Schedule  
Cycle 1 Day 1 
PD Sample 
Pre-dose 
Cycle 1 Day 8 
PD Sample 
Pre-dose 
Cycle 1 Day 15 
Cycle 1 Day 22 
Cycle 2 Day 1  
Time 
Activity 
PD Sample 
Pre-dose 
PD Sample 
Pre-dose 
PD Sample 
Pre-dose 


 
 
 
 
 
vii
Level 2 
200 (Days 1-14) 
10 (Days 8 &15) 
28 
Level 3 
 300 (Days 1-14) 
10 (Days 8 & 15) 
28 
Level 4 
300 (Days 1-14) 
14 (Days 8 & 15) 
28 
Level 5 
300 (days 1-14) 
14 (Days 8, 15 and 
22) 
35 
Level 6 
 
300 Days (1-21) 
14 (Days 8, 15, 22) 
35 
 
 
 
Figure 2: Drug Administration Schema 
 
Dose Levels -1 through 4 
Day                       1    
 8                             15  
          21                  28  
Oral 5-azacitidine                                               
Romidepsin 
                                                                                    
 
Dose Level 5 
Day                       1    
 8                             15  
          21               28          35 
Oral 5-azacitidine                                              
Romidepsin 
                                                                                                                     
 
Dose Level 6 
Day                       1    
 8                             15  
          21                28          35 
Oral 5-azacitidine                                                                    
Romidepsin 
                                                                                                                     
 
Table 3:  Dose Escalation & De-Escalation Decision Rules: 
Number of Patients 
with DLT at a Given 
Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 additional patients experience DLT, proceed to the 
next dose level. 
• If 1 or more of this group experience DLT, then dose escalation is 
stopped, and this dose is declared the maximally administered 
dose (MAD), and the dose level below is the MTD.   


 
 
 
 
 
viii 
>2 
Dose escalation will be stopped.  This dose level will be declared the 
maximally administered dose (highest dose administered).   
<1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. At least 6 patients must 
be entered at the recommended phase 2 dose. 
 
 


 
 
 
 
 
ix 
Figure 3: Study Plan Flow Chart 
 
Schema:  Phase 1  
 
 
 
 
 
 
 
 
 
 
 
                                                         
 
 
 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
 
History, Physical, Performance Status, 
Laboratory data, Biopsies and PET/CT 
scan, photo-documentation 
CYCLE 1 
Intervention 
Oral 5-azacitidine will be given PO QD Days 1-14 (+/- D1-21) and romidepsin given intravenously once a 
week for 2 consecutive weeks, on days 8 and 15 (+/- D22) on a 28 or 35 day cycle. 
 
Evaluations 
Safety evaluations on Days 1, 8 and 15 (22 if dose levels 5 or 6) 
Laboratory Evaluations Days 1,8 and15 (22 if dose levels 5 or 6) 
Future Cycles 
Intervention 
Oral 5-azacitidine and romidepsin will be administered as given in Cycle 1. 
 
Tests 
Safety evaluations on Day 1 
Laboratory Evaluations Days 1, 8, 15 (22 if dose levels 5 or 6) 
CT scans at the end of cycles 2 and 6 . Then CT q3-6 months, until disease progression or initiation of new 
therapy at the discretion of the Investigator. (PET/CT is optional) 
Discontinuation 
• 
Disease progression 
• 
Unacceptable adverse event(s), DLTs 
• 
Withdrawal of consent 
• 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator 
• 
An event that in the judgment of the treating physician warrants discontinuation of therapy. 
 


 
 
 
 
 
x
A. Schema Phase  II and Exploratory Cohort  
 
 
• 
Oral 5-azacitidine and romidepsin administered at the MTD of the combination to patients with T-Cell 
Lymphoma: oral 5-azacytidine at 300 mg (flat dose) Days 1-14 and romidepsin 14 mg/m2 on Days 8, 15 and 22 
on a 35 day cycle. 
• 
For Exploratory Cohort Only: Lymph node biopsy for determination of gene expression profile 
Discontinuation 
• 
Disease progression 
• 
Unacceptable adverse event(s), DLTs 
• 
Withdrawal of consent 
• 
General or specific changes in the patient's condition render the patient unacceptable for further treatment in 
the judgment of the investigator 
• 
An event that in the judgment of the treating physician warrant’s discontinuation of therapy. 
CYCLE 1 
Intervention 
Drugs are administered as outlined above 
Evaluations 
Safety evaluations on Days 1, 8, 15 and  22.  
Laboratory Evaluations Days 1,8, 5 and 22 
For Exploratory Cohort Only: 
Optional lymph node biopsy on day 8 -21  
Future Cycles 
Intervention 
Both drugs given at the MTD 
 
Tests 
Safety evaluations on Day 1 
Laboratory Evaluations Days 1, and each day of romidepsin 
CT scans at the end of cycles 2 and 6. Then CT scans q3-6 months, until disease progression or initiation of new therapy. 
(PET/CT is optional) 
 


 
 
 
 
 
xi 
Table of Contents 
PROTOCOL SYNOPSIS ............................................................................................................................................. i 
1. 
OBJECTIVES................................................................................................................................................ 1 
1.1. 
Phase I Primary Objectives ............................................................................................................... 1 
1.2. 
Phase I Secondary Objectives ........................................................................................................... 1 
 
1.3. 
Phase I Exploratory Objectives …………………………………………………………………….1 
1.4. 
Phase II Primary Objectives .............................................................................................................. 1 
1.5. 
Phase II Secondary Objectives .......................................................................................................... 1 
 
1.6. 
Phase II Secondary Objectives ……………………………………………………………………..1 
2. 
BACKGROUND ............................................................................................................................................ 2 
2.1 
 Background on Lymphoid Malignancies ......................................................................................... 2 
2.2 
 Oral 5-azacitidine ............................................................................................................................. 3 
2.2.1 
Overview ............................................................................................................................ 3 
2.2.2  
Mechanism of Action ......................................................................................................... 4 
2.2.3 
Clinical Pharmacokinetics .................................................................................................. 4 
2.2.4 
Safety .................................................................................................................................. 4 
2.2.5 
Efficacy in Non-Hodgkin Lymphoma ................................................................................ 5 
2.3 
Romidepsin: ...................................................................................................................................... 6 
2.3.1  
Histone deacetylases and HDAC Inhibitors........................................................................ 6 
2.3.2  
Mechanism of Action of Romidepsin ................................................................................. 6 
2.3.3 
Nonclinical Pharmacology of Romidepsin ......................................................................... 7 
2.3.4                      
Nonclinical Toxicology of Romidepsin ................................................. 7 
2.3.5  
Clinical Pharmacokinetics of Romidepsin .......................................................................... 8 
2.3.6  
Safety of Romidepsin ......................................................................................................... 8 
2.3.7 
Efficacy of Romidepsin ...................................................................................................... 9 
2.4 
Rationale for the Study ..................................................................................................................... 9 
2.4.1 
Hypothesis and Preliminary Data ....................................................................................... 9 
3. 
PATIENT SELECTION ............................................................................................................................. 14 
3.1 
Inclusion Criteria for Lymphoma .................................................................................................... 14 
3.2 
 Exclusion Criteria .......................................................................................................................... 15 
4. REGISTRATION PROCEDURES ...................................................................................................................... 16 
4.1       General Guidelines ............................................................................................................................ 16 
4.2 
Screening......................................................................................................................................... 16 
4.3 
Informed Consent ............................................................................................................................ 17 
4.3.1  
Study Informed Consent ................................................................................................... 17 
4.3.2 
Consent and Use of Tissue Specimens for Research ........................................................ 18 
4.4 
Registration Process ........................................................................................................................ 18 
5. 
TREATMENT PLAN ................................................................................................................................. 19 
5.1 
Agent Administration ...................................................................................................................... 19 


 
 
 
 
 
xii
5.1.1 
Dose Escalation Scheme ................................................................................................... 19 
5.1.2 
Regimen Description ........................................................................................................ 20 
5.1.3 
Required Blood Parameters and Other Investigations Prior  to Each Treatment .............. 20 
5.1.4 
Guidelines for Study Drug Administration ....................................................................... 21 
5.1.5 
Maximum Tolerated Dose ................................................................................................ 21 
5.1.6  
Dose De-escalation Decision Rules: ................................................................................. 21 
5.1.7 
Prophylactic Medicines and Supportive Care ................................................................... 22 
5.1.8      Cardiac Monitoring ........................................................................................................... 23 
5.1.8.1  Cardiac Alert Findings ...................................................................................................... 23 
5.1.8.2 Electrocardiograms ........................................................................................................... 24 
5.2 
 Dose-Limiting Toxicity .................................................................................................................. 24 
5.3 
 General Concomitant Medication and Supportive Care Guidelines .............................................. 25 
5.4 
 Duration of Therapy ....................................................................................................................... 26 
5.5 
Duration of Follow Up .................................................................................................................... 27 
5.6 
Criteria for Removal from Study .................................................................................................... 27 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ........................................................................................ 27 
6.1 
 Dose Delays ................................................................................................................................... 27 
6.2 
 Resuming Administration of Study Drug ....................................................................................... 27 
6.3 
Dose Modifications ......................................................................................................................... 28 
6.3.1   
Romidepsin Dose Modifications....................................................................................... 28 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .................................................. 30 
7.1 
Safety Evaluation Procedures ......................................................................................................... 30 
7.2 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ........................................... 31 
7.2.1 
CAEPRs for Oral 5-azacitidine ......................................................................................... 31 
7.2.2 
CAEPRs for Romidepsin .................................................................................................. 34 
7.2.2.4  Efficacy in Humans ............................................................................................................ 36 
7.3  
Adverse Event Characteristics ........................................................................................................ 38 
7.4 
Expedited Adverse Event Reporting ............................................................................................... 38 
7.4.1    Expedited Reporting Guidelines ....................................................................................... 39 
7.4.2 
Protocol-Specific Expedited Adverse Event Reporting  Exclusions................................. 40 
7.5 
 Pregnancy on Study ....................................................................................................................... 40 
7.6 
Routine Adverse Event Reporting .................................................................................................. 41 
8. 
PHARMACEUTICAL INFORMATION ................................................................................................. 41 
8.1 
Oral 5-azacitidine ............................................................................................................................ 41 
8.2 
Romidepsin ..................................................................................................................................... 42 
8.3 
Agent Accountability ...................................................................................................................... 45 
9. 
Pharmacokinetic & Pharmacodynamic Studies ....................................................................................... 45 
9.1 
Pharmacokinetic Studies ................................................................................................................. 45 
9.2 
Pharmacodynamic Studies .............................................................................................................. 45 
9.2.1 
Biopsies (Optional) ........................................................................................................... 45 
9.2.2 
Handling of Specimens ..................................................................................................... 46 
10. 
STUDY CALENDAR .................................................................................................................................. 46 


 
 
 
 
 
xiii 
11. 
MEASUREMENT OF EFFECT ................................................................................................................ 46 
11.1 
Evaluation of response: ................................................................................................................... 46 
11.1.1 
Definitions ........................................................................................................................ 46 
11.1.2 
Disease Parameters ........................................................................................................... 46 
11.1.3 
Methods for Evaluation of Measurable Disease in NHL .................................................. 47 
11.2 
Response Criteria ............................................................................................................................ 47 
11.2.1 
Evaluation of Measurable Disease in NHL ....................................................................... 47 
11.2.3 
Response Definitions ........................................................................................................ 48 
11.2.4 
Evaluation of Best Response ............................................................................................ 48 
11.2.5     Overall Response Rate ...................................................................................................... 48 
12. 
 DATA REPORTING / REGULATORY REQUIREMENTS ................................................................ 49 
12.1 
 Data Reporting ............................................................................................................................... 49 
12.1.1 
Monitoring ........................................................................................................................ 49 
12.1.2 Responsibility for Data Submission ..................................................................................... 49 
12.2  
Data Safety Monitoring Board ........................................................................................................ 49 
12.3 
Investigator Reporting Responsibilities .......................................................................................... 49 
12.4  
Study auditing ................................................................................................................................. 49 
12.5 
Protocol amendments ...................................................................................................................... 49 
12.6 
Protocol deviations .......................................................................................................................... 49 
13. 
 STATISTICAL CONSIDERATIONS ...................................................................................................... 50 
13.1 
Study Design/ Primary Endpoints ................................................................................................... 50 
13.2 
Sample Size/Accrual Rate ............................................................................................................... 50 
13.3 
Analysis of Secondary Endpoints ................................................................................................... 51 
REFERENCES .......................................................................................................................................................... 52 
Appendix 1: Medications That May Cause QTc Prolongation .............................................................................. 53 
Appendix 2: Medications That May Inhibit CYP3A4 ............................................................................................ 58 
Appendix 3 Canadian Cardiovascular Society Angina Classification .................................................................. 60 
Appendix 4  New York Heart Association Classification of Cardiac Disease ...................................................... 61 
 
 
 
  
 
 
 


 
 
1 
 
1. OBJECTIVES 
 
1.1. 
Phase I Primary Objectives 
 
 
 
• Determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the 
combination of oral 5-azacitidine and romidepsin. 
• Evaluate the safety and toxicity of the combinations of oral 5-azacitidine and romidepsin. 
 
1.2. 
Phase I Secondary Objectives 
 
• Describe the maximum number of cycles received  
• Describe the number of dose delays and dose reductions at the MTD 
• Describe the anti-tumor activity of the combination 
• Evaluate the overall response rate (ORR), progression free survival (PFS), and duration of 
response (DOR) of the study population.  
 
1.3 
Phase I Exploratory Objectives 
 
• Evaluate pharmacodynamic markers of drug effect in paired tissue biopsies (pre- and post- 
treatment), including gene expression profiling and genome wide methylation status.  
• Evaluate the pharmacokinetic profile for oral 5-azacitidine and romidepsin when given as a 
combination in cycle 1 at various time intervals as listed in figure 1. 
  
1.4 
Phase II Primary Objectives 
 
 
 
• Estimate the ORR (complete + partial response) of the combination of oral 5-azacitidine and 
romidepsin in patients with relapsed/refractory T-Cell Lymphoma. 
 
1.5 
Phase II Secondary Objectives 
 
• Estimate the DOR and PFS of the combination in patients with T-Cell Lymphoma.   
• Estimate the overall survival of patients with T-Cell Lymphoma on study. 
• Identify potential pre-treatment biomarkers of response based on GEP and/or methylation 
array) to clinical outcome.  
 
1.6 
Phase II Exploratory Objectives 
 
• Evaluate pharmacodynamic markers of drug effect in paired tissue biopsies (pre- and post- 
treatment) including gene expression and genome wide methylation patterns.  
• Evaluate pharmacokinetic profile for oral 5-azacytidine and romidepsin when given as a 
combination 
 
 
 
 
 
 
 


 
 
2 
 
1.7 Exploratory Cohort Primary Objectives 
• Determine the overall response rates (complete responses + partial responses) of oral 
azacitidine and romidepsin in patients with GC-derived B-cell lymphomas. 
• Determine Progression Free Survival (PFS) and Time to Treatment Failure (TTF) 
• Determine the Duration of Response (DOR)  
• Determine the safety and tolerability of oral azacytadine and romidepsin in patients with relapsed 
or refractory GC-derived B-cell lymphoid malignancies. 
1.8 Exploratory Cohort Secondary Objectives 
 
• Evaluate the pharmacokinetic (PK) profile of oral azacitidine and romidepsin. 
• Evaluate and compare pharmacodynamic (PD) endpoints with PK endpoints. PD endpoints will 
include the evaluation of paired gene expression profiles of primary patient samples on study. 
 
 
2. BACKGROUND 
2.1 
 
Background on Lymphoid Malignancies 
The non- Hodgkin lymphomas (NHL) represent a heterogeneous group of malignancies. Under the rubric 
of lymphoma exist some of the fastest growing cancers known to science, (Burkett’s lymphoma, 
lymphoblastic lymphoma/leukemia), as well as some of the most indolent (small lymphocytic lymphoma, 
follicular lymphoma, and marginal zone lymphoma). This remarkable diversity of biology imposes 
significant challenges. The first is on the pathologists who seek to understand the cell of origin and 
differentiate what are sometimes subtle differences between the related sub-types of disease. The second 
is on oncologists who seek to identify the best treatments for these subtypes, with the ever-increasing 
likelihood that our new understanding of the molecular pathogenesis of these diseases will result in an 
increase in new drugs for specific target populations.   
 
In the United States, NHL represents 4-5% of all new cancer cases, and is the fifth leading cause of cancer 
death.  In 2004, there were an estimated 54, 379 cases in the United States, and approximately 19,450 
deaths.[2]  Hodgkin lymphoma is a rare malignancy, with approximately 7,500 cases diagnosed yearly 
in the United States. An evaluation of the distribution of non-Hodgkin lymphoma subtypes was 
performed on the 114,548 cases of lymphoid neoplasms diagnosed between 1992-2001 in the 
Surveillance Epidemiology and End Results(SEER) registries, of which 87,666 were B-cell lymphoid 
neoplasms, 6,228 were considered T/Natural Killer (NK) cell neoplasms, and about 10,042 were 
attributed to Hodgkin lymphoma.[3] As a group, the diffuse, large-cell lymphomas (DLBCL) account for 
approximately one-third of all NHLs.  
 
The peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive non-Hodgkin 
lymphomas (NHLs).  They account for 10-15% of all newly diagnosed cases of NHL. The current annual 
prevalence of PTCL in the U.S. is estimated to be approximately 9,500 patients. PTCL- Not Otherwise 
Specified (NOS), a nodal subtype, is the most common T-Cell Lymphoma in the US and Europe. PTCL 
is often associated with a worse prognosis compared to its B-cell counterparts.  Anthracycline based 
therapies typically provide a 5 year survival of less than 30%. Pralatrexate-azacitidine was the first drug 
approved for patients with relapsed/refractory PTCL[5]. The mature T-Cell Lymphomas also include the 
cutaneous T-Cell Lymphomas (CTCL), the 2 most common forms of which are mycosis fungoides (MF) 
and Sézary syndrome (SS). Between 2,000 and 3,000 new cases of CTCL occur in the United States each 
year. MF is categorized as limited stage (IA, IB, and IIA) or plaque/patche disease limited to skin, and 
advanced stage (IIB to IVB), characterized by cutaneous tumors and involvement of the blood, lymph 


 
 
3 
 
nodes, bone marrow, or visceral organs. SS is characterized by generalized erythroderma and abnormal 
lymphoid cells in the blood. Limited-stage disease may be effectively treated with skin-directed therapies 
including topical nitrogen mustard or psoralen plus ultraviolet A therapy. However, in patients with 
advanced disease, control is often short lived, and the disease is relentlessly progressive. Although 
response rates to cytotoxic chemotherapy range from 60 to 80% in patients with advanced disease, the 
median duration of response is usually measured in months. While agents with novel mechanisms of 
action have been pursued, including retinoids, interferon, monoclonal antibodies, and denileukin diftitox; 
none have been found to be curative. Romidepsin has single-agent clinical activity with significant and 
durable responses in patients with CTCL & PTCL[4]. 
 
GC derived lymphomas include GC-DLBCL and follicular lymphoma (FL), the two most common 
subtypes of lymphoma.  Together they make up more than 50% of all lymphomas with an incidence of 
nearly 35,000 per year.  Although the prognosis for these lymphoma subtypes is relatively good  
compared to other lymphoma subtypes, there are presently limited targeted treatment  for these diseases.  
Salvage treatment options often include combination chemotherapy followed by autologous stem cell 
transplant, though many patients are not eligible for this therapy.  The germinal center (GC) is a 
compartment of the lymph node that is responsible for generating high affinity antibodies via somatic 
hyper-mutation (SHM) and class switch recombination.  Epigenetic modifiers such as EZH2, MLL, p300 
and CBP, and the transcriptional repressor Bcl6 are essential to B-cell development, and are considered 
necessary for mutagenesis and silencing of tumor suppressor genes which facilitate SHM. This physiologic 
state is partly achieved by decreased acetylation and increased methylation of histones enforcing a 
transcriptionally repressed chromatin state.  Mutations affecting these epigenetic and transcriptional 
modifiers have been identified as driving events in Germinal Center (GC) derived lymphomas.Given the high 
frequency of epigenetic derangements in germinal center (GC)-derived lymphomas, the use of histone 
deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors in combination are likely 
to have a synergistic effect, and this therapeutic response may be predicted by specific epigenetic 
disturbances that could be characterized by unique gene expression profiles. 
 
2.2 
 
Oral 5-azacitidine  
 
2.2.1          Overview 
 
Azacitidine is a pyrimidine nucleoside analog of cytidine that was first introduced for the treatment of 
AML in adults in 1976. (12) The antitumor effects of the drug are thought to be secondary to 
cytotoxicity as well as by hypomethylation of DNA. (13, 14, 15) Treatment of cells with azacitidine 
leads to inhibition of DNA, RNA, and protein synthesis. Once incorporated into the tRNA, azacitidine 
causes inhibition of tRNA methyltransferases, which interferes with tRNA methylation and defective 
acceptor function of transfer RNA. (16) In addition, azacitidine interferes with de novo thymidylate 
synthesis, adding to its cytotoxicity. Chan et al. were able to demonstrate that azacitidine causes a 
significant decrease in tumor methylation. (15) Biopsy specimens of 10 patients with EBV-associated 
tumors (nasopharyngeal carcinoma, Hodgkin lymphoma, and AIDS-associated diffuse small 
noncleaved lymphoma) were obtained before and after treatment with azacitidine at 75 mg/m2/day 
intravenously for 7 days. Using methylation-specific PCR, genomic sequencing, and 
immunohistochemistry, post-treatment specimens were found to have reversal of dense CpG 
methylation. (15) 
Loss of DNA methylation is an important event in carcinogenesis. The role of CpG methylation in 
tumorigenesis includes the silencing of tumor suppressor genes, loss of expression of DNA repair 
enzymes, and loss of imprinting. There have been reports of decreased DNA methylation in colonic 
epithelium of patients with familial polyposis coli. Other examples illustrating the role of methylation 


 
 
4 
 
in cancer include the development of hepatocellular carcinoma in rats that are fed a methyl deficient 
diet, hypomethylation of H-ras and MYC genes in multiple tumors, and the finding of increased 
methylation of CpG islands of DNA in tumor models. (16)                                                                                                 
2.2.2            Mechanism of Action 
 
Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert 
its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity 
on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine 
required for maximum inhibition of DNA methylation in vitro does not cause major 
suppression of DNA synthesis. Hypomethylation may restore normal function to 
genes that are critical for differentiation and proliferation. The cytotoxic effects of 
azacitidine cause the death of rapidly dividing cells, including cancer cells that are 
no longer responsive to normal growth control mechanisms. Non-proliferating cells 
are relatively insensitive to azacitidine. 
 
2.2.3            Clinical Pharmacokinetics 
 
The pharmacokinetics of azacitidine were studied in 6 MDS patients following a 
single 75 mg/m2 subcutaneous (SC) dose and a single 75 mg/m2 intravenous (IV) 
dose. Azacitidine is rapidly absorbed after SC administration; the peak plasma 
azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour. The bioavailability 
of SC azacitidine relative to IV azacitidine is approximately 89%, based on area 
under the curve. Mean volume of distribution following IV dosing is 76 ± 26 L. 
Mean apparent SC clearance is 167 ± 49 L/hour and mean half-life after SC administration 
is 41 ± 8 minutes. 
 
Published studies indicate that urinary excretion is the primary route of elimination 
of azacitidine and its metabolites. Following IV administration of radioactive 
azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the 
radioactive dose. Fecal excretion accounted for <1% of administered radioactivity 
over 3 days. Mean excretion of radioactivity in urine following SC administration of 
14C-azacitidine was 50%. The mean elimination half-lives of total radioactivity 
(azacitidine and its metabolites) were similar after IV and SC administrations, about 
4 hours. 
 
 
 
2.2.4             Safety 
The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced 
tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% 
the recommended human daily dose on a mg/m2 basis) administered IP 3 times per week for 52 weeks. 
An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was 
seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m2, approximately 8% the recommended 
human daily dose on a mg/m2 basis) once a week for 50 weeks. A tumorigenicity study in rats dosed 
twice weekly at 15 or 60 mg/m2 (approximately 20% to 80% the recommended human daily dose on a 
mg/m2 basis) revealed an increased incidence of testicular tumors compared with controls. 
  
Azacitidine is both mutagenic, and clastogenic in bacterial and/or mammalian cell systems and 
induces chromosomal aberrations in vitro. 
 
Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death 


 
 
5 
 
(increased resorption) after a single IP injection of 6 mg/m2 (approximately 8% of the recommended 
human daily dose on a mg/m2 basis) azacitidine on gestation Day 10.  Developmental abnormalities in 
the brain have been detected in mice given azacitidine on or before gestation Day 15 at doses of ~3-12 
mg/m2 (approximately 4-16% the recommended 
human daily dose on a mg/m2 basis). In rats, azacitidine was clearly embryotoxic when given IP 
on gestation Days 4 to 8 (postimplantation) at a dose of 6 mg/m2 (approximately 8% the 
recommended human daily dose on a mg/m2 basis), although treatment in the preimplantation 
period (on gestation Days 1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal 
abnormalities in rats after a single IP dose of 3 to 12 mg/m2 (approximately 8% the recommended 
human daily dose on a mg/m2 basis) given on gestation Day 9, 10, 11 or 12. The fetal anomalies 
included: CNS anomalies (exencephaly/encephalocele), limb anomalies 
(micromelia, club foot, syndactyly, oligodactyly) and others (microphthalmia, micrognathia, 
gastroschisis, edema, and rib abnormalities). In this study azacitidine caused fetal death when 
administered 3 to 12 mg/m2 on gestation Days 9 and 10: average number of live animals per 
litter was reduced to 9% of control at the highest dose on gestation Day 9. 
 
Administration of azacitidine to male mice at 9.9 mg/m2 (approximately 9% of the recommended 
human daily dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice 
resulted in decreased in fertility and loss of offspring during subsequent embryonic and postnatal 
development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15-30 mg/m2 
(approximately 20-40%, the recommended human daily dose on a mg/m2 basis) resulted in decreased 
weight of the testes and epididymides, and decreased sperm counts accompanied by decreased 
pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 
16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated females when examined 
on Day 2 of gestation. 
 
Through 18 May 2012, approximately 5,300 patients have been exposed to azacitidine during 
completed or ongoing Celgene-sponsored studies (n = 1,120 [992 with azacitidine injectable and 
185 with azacitidine oral; 57 patients received both formulations]) or non-Celgene-sponsored 
studies (n = 4,190) worldwide. 
 
The most commonly reported adverse reactions with azacitidine treatment were hematological 
reactions (eg, anemia, thrombocytopenia, neutropenia, leukopenia), GI events (eg, nausea, vomiting), 
and injection site reactions. Adverse reactions associated with IV azacitidine were similar in frequency 
and severity compared with SC azacitidine.  
 
2.2.5             Efficacy in Non-Hodgkin Lymphoma 
To date, there has been little experience with 5-azacitidine in patients with lymphoma.  To date, 5-
azacitidine has been approved by the US Food & Drug Administration for the treatment of: 
• Myelodysplastic syndrome (MDS) 
• Chronic myelomonocytic leukemia (CMMol) 
This study represents the first to explore a hypomethylation inhibitor in patients with lymphoid 
malignancies.  Dr. Cerchietti and colleagues conducted a phase I trial in patients with newly diagnosed 
diffuse large B-cell lymphoma. Eleven of the 12 patients enrolled were more than 60 years old when 
diagnosed, making them at at high risk for tumor recurrence after initial treatment. The patients were 
pretreated with azacitidine, in escalating doses, 8 days prior to initiation of 6 cycles of standard 
chemotherapy. 


 
 
6 
 
Of the 12 patients, 11 had a complete response and 10 remained in complete remission for up to 28 
months. Side effects from pretreatment with azacitidine were minimal. Two patients who were treated 
with the maximum dose of azacitidine had dose-limiting toxicities. 
The researchers conducted the clinical trial based on the results of their extensive preclinical 
experiments to determine the mechanisms by which lymphomas evade chemotherapy drugs. They 
found that compared with normal cells, all diffuse large B-cell lymphomas possess a high degree of 
aberrant DNA methylation, a process which “silences” certain genes, causing resistance to treatment. 
Using diffuse large B-cell lymphoma cells and mice bearing human lymphoma xenografts, the 
researchers showed that DNA methyltransferase inhibitors are most effective if administered prior to 
chemotherapy, but not concurrently. They also found the gene SMAD1 to be silenced in the 
unresponsive tumors. 
When the researchers looked for SMAD1 status in the biopsy specimens collected from patients 
enrolled in the phase I trial, they found that after treatment with azacitidine, there was a decrease in 
SMAD1 methylation and increase in SMAD1 protein, providing proof of principle 
 
 
2.3 
Romidepsin: 
 
2.3.1           Histone deacetylases and HDAC Inhibitors 
Histone deacetylases (HDAC) are enzymes that catalyze the removal of acetyl groups from the lysine 
residues of various proteins, including histones and transcription factors.  HDAC inhibitors can induce 
tumor cell growth arrest, differentiation, or apoptosis in vitro and inhibit tumor growth in animals[14-
15].  The transcription of genes is regulated at least in part by acetylation of nucleosomal histones.  The 
core nucleosomal histones are the most widely studied of the proteins that become acetylated following 
inhibition of HDAC activity[16].  In some cancer cells, there is an overexpression of HDACs, or an 
aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core 
nucleosomal histones.  Hypoacetylation of histones is associated with a condensed chromatin structure 
and repression of gene transcription.  Inhibition of HDAC activity allows for the accumulation of acetyl 
groups on the histone lysine residues resulting in an open chromatin structure and transcriptional 
activation. 
2.3.2           Mechanism of Action of Romidepsin 
Romidepsin (depsipeptide, FR901228, FK228, NSC 630176) is a relatively unique HDACi as it is a 
prodrug. Upon entering cells romidepsin is reduced to an active compound, capable of preferentially 
interacting with the zinc in the active site of the HDAC1, HDAC2 and HDAC3 (Class I)[17].  
Romidepsin was granted full regulatory approval by the U.S. FDA for the treatment of relapsed 
CTCL.  This approval is based on pooled data obtained from an NCI directed phase II trial of 
Romidepsin in CTCL and a registration directed trial by Celgene.  This pooled analysis reported a 
response rate of 41% with a duration of response of approximately 14 months[18]. Ongoing studies 
continue to support the impressive activity of Romidepsin in PTCL with ORR of 31% and duration 
of responses in the range of 9 months.  
 
Other HDAC inhibitors presently in clinical trials include belinostat and panobinostat, both of which 
have demonstrated promising activity in T cell lymphomas. These and other data have clearly 


 
 
7 
 
established that HDACI as a class appear to have significant activity in T-cell lymphomas for reasons 
that are not clearly understood. HDAC inhibitors work through a myriad of different mechanisms 
including:  (1) alteration in the expression of genes that regulate cell cycle including upregulation of 
p21/p27, and down regulation of Cyclin  D; (2) acetylation of non-histone proteins including STAT-
3, RelA/p65p53, HIF-1alpha, Hsp 90 in a way that may impair their function and  influence cell 
growth and survival; (3) direct activation of apoptotic pathways by affecting the balance between 
the antiapoptotic proteins like BCL-2 and the proapoptotic proteins like BAX and BAK.[19]  
However, it has been difficult to assign any one or more of the above listed mechanisms as the 
mechanisms of action of HDAC inhibitors against any given tumor type, let alone in the T cell 
lymphomas.  It is not even clear if histone acetylation is essential for the biological activity and 
apoptosis that is being seen in T cell lymphomas.   
 
Interestingly, H3 acetylation can be demonstrated in tissue samples and mononuclear cells of 
patients who have been treated with HDACI, irrespective of their response to the therapy [19].  
Nonetheless, attempts at understanding these mechanisms have involved gene expression profiling 
on paired tissue samples both pre- and post-treatment that has shown that only 5-10 % of the genome 
can be affected by HDACI.  As many genes are regulated as are down-regulated following treatment 
with most HDACI.  These changes have been shown to occur within a few hours of exposure (4 
hours in one study)[20]. The genes that were consistently affected included genes that affected cell 
cycle (CCNDI, IGFI) apoptosis (septin10, TEF, SORBBS2), angiogenesis ( GUCY1A1, ANGPT1) 
and immune modulation (LAIR1)[21]. QT-PCR was used to confirm that that the findings on gene 
array analysis were indeed biologically accurate, with a strong correlation between gene array and 
the PCR data.  Tumor tissue specimens treated with various HDACI have shown an increase in 
histone acetylation, decreased vascularity and translocation of nuclear proteins like STAT-s which 
is associated with inactivation. [22] 
 
2.3.3           Nonclinical Pharmacology of Romidepsin 
 
Romidepsin is highly protein bound in plasma (92% to 94%) over the concentration range of 50 ng/mL 
to 1000 ng/mL with α1-acid-glycoprotein (AAG) being the principal binding protein. 
Romidepsin undergoes extensive metabolism in vitro primarily by CYP3A4 with minor contribution 
from CYP3A5, CYP1A1, CYP2B6, and CYP2C19. At therapeutic concentrations, romidepsin did not 
competitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in vitro. 
 
2.3.4           Nonclinical Toxicology of Romidepsin 
Romidepsin has been investigated in clinical trials. Major hematologic toxicity includes: anemia, 
leukopenia, lymphopenia and thrombocytopenia. Thus, blood counts are monitored during treatment and 
dose modifications may be necessary. 
In addition, it was found that romidepsin may cause QTc prolongation/ECG changes. While this has been 
exhaustively studied it is believed drug:drug interaction with select antiemetics may be responsible for 
the QTc prolongation. Nonetheless, obtaining baseline and periodic ECG (12-lead) and correcting 
electrolyte (potassium, magnesium, and calcium) abnormalities prior to and during treatment is highly 
recommended. T-wave and ST-segment changes have also been reported. 
Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in 
vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was 
not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated 


 
 
8 
 
dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, 
respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface 
area. Based on non-clinical findings, male and female fertility may be compromised by treatment with 
Romidepsin.  
 
Please refer to the romidepsin Complete Investigators Brochure for detailed information. 
2.3.5             Clinical Pharmacokinetics of Romidepsin 
 
Romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 to 24.9 mg/m2 when 
administered intravenously over 4 hours in patients with advanced cancers. In patients with T cell 
lymphomas who received 14 mg/m2 of romidepsin intravenously over a 4-hour period on days 1, 8 and 
15 of a 28-day cycle, geometric mean values of the maximum plasma concentration (Cmax) and the area 
under the plasma concentration versus time curve (AUC0-inf) were 377 ng/mL and 1549 ng*hr/mL, 
respectively.  
 
Following 4-hour intravenous administration of romidepsin at 14 mg/m2 on days 1, 8 and 15 of a 28-day 
cycle in patients with T cell lymphomas, the terminal half-life (t1/2) was approximately 3 hours. No 
accumulation of plasma concentration of romidepsin was observed after repeated dosing. 
2.3.6               Safety of Romidepsin  
  
The safety of romidepsin was evaluated in 185 patients with CTCL in 2 single arm clinical studies in 
which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies 
was 5.6 months (range: <1 to 83.4 months). 
 
The most common drug-related adverse events in patients treated with romidepsin could be classified 
into 4 symptom complexes: gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease, 
vomiting, and constipation), constitutional symptoms (fatigue, chills), hematologic abnormalities 
(thrombocytopenia, anemia) and taste disorders (dysgeusia, dry mouth). Most of the adverse 
experiences were manageable. In fact, most of the very common adverse events were reversible and 
could be managed using conventional supportive care for chemotherapy. On the whole, treatment with 
romidepsin was well tolerated. 
 
Serious adverse reactions reported in > 2% of patients in Study 1 included infection, sepsis, and pyrexia. 
In Study 2, serious adverse reactions in > 2% of patients were infection, supraventricular arrhythmia, 
neutropenia, fatigue, edema, central line infection, ventricular arrhythmia, nausea, pyrexia, leukopenia, 
and thrombocytopenia. Most deaths were due to disease progression. In Study 1, there were two deaths 
due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection 
(4), myocardial ischemia, and acute respiratory distress syndrome. 
 
Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. 
Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, QT 
prolongation, and dyspnea. 
 
Complete and updated adverse events are available in the Investigational Drug Brochure and the IND Safety 
Letters. 
 


 
 
9 
 
2.3.7             Efficacy of Romidepsin  
Positive results were reported  in 71 patients with CTCL treated on the multicenter NCI study of 
romidepsin administered as a 4-hour infusion on days 1, 8, and 15 of a 28-day cycle with a starting dose 
of 14 mg/m2[19]. The ORR was 34%, with a CR observed in four patients, a PR in 20, and SD in 26. The 
median time to progression for patients with a major response (CR or PR) was 15.1 months.   
Very encouraging responses have also been reported in patients with peripheral T-cell lymphoma 
(PTCL). ORR of 31%, as a single agent in 48 patients, including four CR and 11 PR [25]. The overall 
median duration of response for all patients was 9 months. 
In 2011, the US FDA approved romidepsin for patients with relapsed/refractory PTCL. 
2.4 
Rationale for the Study 
 
2.4.1               Hypothesis and Preliminary Data 
 
Targeting HDAC’s in patients with TCL has proven to be a valuable therapeutic approach [7].  Vorinostat 
became the first HDACi approved for the treatment of cancer, for patients with relapsed and refractory 
CTCL in 2006, followed in 2009 by the approval of romidepsin and expanded in 2011 to include patients 
with relapsed and refractory PTCL.  The promising experience with HDACi in T-cell lymphoma, driven 
by empirical observations, established that 
targeting the ‘epigenome’ was a viable treatment 
strategy for select sub-types of lymphoma, albeit, 
only 
effective in about one-third of all TCL patients 
[8, 
9]. Experiences from myeloid leukemia and 
myelodysplastic syndrome have suggested that 
combinations of epigenetically targeted drugs, 
including HDACi plus hypomethylating agents 
(HoMe), may have more therapeutic value than 
either of these agents alone.  In addition, HDACi 
were 
shown to decrease DNMT-1, leading to reduced 
genomic methylation and gene activation [15].  
These data suggest that the overlapping 
influences HDACi and HoME on the epigenome 
could be exploited in rational combinations.   
 
To date we have evaluated these two drug classes 
in 
combination in a variety of preclinical models of 
T-
cell lymphoma, [16], and have explored the 
influence of the individual drugs and their 
combination on gene expression in different sub-
types of T-cell lymphoma.  These data revealed 
substantial 
synergism 
between 
the 
hypomethylating agents (decitabine and 5-
azacitidine) and various HDACi including romidepsin, belinostat, vorinostat and panobinostat with 
synergy coefficients ranging between 0.1 and 0.9 (see Figure below) [17].  While the synergy seen here 
was observed following a modest (~12 hr) lead in of the HoMe agent, it suggests a class effect between 
the different HDACi and the HoMe agent, where the IC10-20 of each drug against the specific cell line was 
used in the combination. These data also underscore the fact that there are many variables that determine 


 
 
10 
 
this degree of synergy, including the particular drug-drug combination, drug concentration, schedule and 
duration of exposure.   
 
We recently showed that the combination of romidepsin and the HoMe agent decitabine reversed the 
malignant phenotype of all T-cell lymphoma cell lines tested, with each individual drug having only a 
partial effect on the expression signature (Figure 3) [17].  The GEP data also demonstrated that while 
common sub-sets of genes could be affected, the greatest number of ‘unique’ genes perturbed were seen 
in those cells treated with the combination, where nearly 1000 unique genes were altered, strongly 
supporting the hypothesis that the synergism seen at the cellular level and in the in vivo model, was also 
seen at the molecular level. The Venn diagram below illustrates the principle: the effects of the two drugs 
alone are largely different (only 39 genes modified in common by all the treatment groups), while most 
of the effects induced by the single agent treatment are maintained in the combination group (174 genes 
out of 191 for romidepsin and 211 genes out of 221 for decitabine). Interestingly, an additional 944 
unique genes (i.e. genes not affected by the single agents) are modulated only by the combination 
treatment, strongly supporting the hypothesis of ‘molecular synergism’.  
 
 
Collectively, these data suggest that dual targeting of the epigenome in T-cell lymphoma may represent 
an incremental improvement in our ability to treat the disease compared to single agent (or class) 
approaches predicated on HDAC inhibitors alone.   
 
1. Of patients with Germinal Center (GC)-DLBCL treated 
with standard therapy, 30% will relapse (12) and less 
than half of these patients will be eligible for intensive 
salvage therapy (13).  There is a need to improve 
therapeutic options as there are limited-to-no targeted 
approaches for salvaging patients with refractory GC-
DLBCL. As we have reviewed in Clinical Cancer 
Research (14)(Fig 4), new discoveries into the molecular 
pathogenesis of this disease have created enthusiasm 
around the development of precision targeted strategies 
(Fig 5).  Although it is known that mutations in BCL6, 
EZH2, histone acetyltransferases (HATs) and other 
epigenetic modifiers all contribute to silencing of tumor 
suppressors, it is not known what effects simultaneous epigenetic dysregulation have on the biology of 
GC-lymphomas, or their responsiveness to targeted treatment.  Given the clustering of epigenetic mutations 
in GC-derived lymphomas, the possibility of directly targeting HATs combined with targeting of 
complimentary epigenetic machinery may serve as a promising future treatment paradigm for this specific 
Figure 1. Cytotoxicity curves in H9 and HH following 
exposure to decitabine and HDAC inhibitor . The tables 
list synergy coefficients for the specified combination. 
[R=romidepsin;B=belinostat;S=SAHA; 
L=LBH589/panobinostat.] In subsequent experiments 
with a SCID Beige Xenograft Mouse Model of HH-
CTCL, mice were treated i.p. for 3 cycles with decitabine, 
belinostat and the combination. Statistically significant 
tumor growth inhibition was observed in the combination 
cohort compared to all the others. 
Figure 4: Schematic of derangements in Germinal Center 
Lymphoma 
↓MLL 
↓HAT 


 
 
11 
 
disease entity (Fig 5)(14). Past studies have focused on 
individually targeting these factors, but not studying 
them together as a whole. Our laboratory has made 
several pivotal observations regarding the targeting of 
epigenetic operations in DLBCL. Using a translational 
approach, we have taken direct observations from the 
laboratory and applied them to clinical trials.  Some 
examples include:We have established that targeting the 
Bcl6 : p53 axis with HDAC and Sirtuin inhibitors 
inactivates Bcl6 and activates p53 leading to clinically 
meaningful responses in patients with lymphoma 
(Amengual Blood 2013)(8) (Fig 6, 7). 
2. We have demonstrated that combinations of DNMT 
and HDAC inhibitors are synergistic in DLBCL and led 
to modulation of SMAD1 and DNMT3A which are 
known to influence chemotherapy resistance (Kalac 
Blood 2011)(10) (Fig 8). 
 
Modulating Acetylation of the Bcl6 : p53 Axis. Small molecule inhibitors of HDACs help maintain 
transcriptionally active chromatin, theoretically allowing for expression of tumor suppressor genes (22). 
Three HDAC inhibitors, vorinostat (23, 24), belinostat (25), and romidepsin (26, 27), have been all 
approved by the FDA for the treatment of T-cell lymphoma. Despite approval in T-cell lymphoma, single 
agent HDAC inhibitors have demonstrated limited activity in relapsed DLBCL (28).  I have demonstrated that 
the combination of niacinamide (N), a sirtuin inhibitor, and HDAC inhibitors (romidepsin (R), vorinostat (V), 
belinostat (B), or panobinostat (P)) leads to synergistic cytotoxicity in GC-DLBCL but not ABC-DLBCL (Fig 
6)[Amengual, et. al (8)].  Figure 3 represents the synergy co-effiecients of combinations of 4 different HDAC 
inhibitors with niacinamide in 8 DLBCL cell lines.  Red boxes indicate synergistic interactions.  As represented 
here, the GC-DLCBL cells are more sensitive to the combination.  Our group developed a genetically 
engineered mouse (lambda-myc crossed with mCherry fluorescent CD19) which develops spontaneous B-cell 
lymphoma. This mouse model expresses similar levels of Bcl6 and p53 as the GC-DLCBL cell lines (29).  
Following exposure to romidepsin and niacinamide, mouse lymphoid tissue demonstrated acetylation of both 
Bcl6 and p53 measured by immunoprecipitation as well as modulation of downstream targets BLIMP1 and 
p21 measured by immunoblot (Fig 7).  The combination was well tolerated in mice and led to increased tumor 
growth delay compared to either drug alone as measured by in vivo imaging (Fig 7).  These findings 
demonstrated for the first time the potential clinical application of previous published data cited above.  
Translating these results, we conducted a phase I clinical study of vorinostat and niacinamide in 
relapsed/refractory lymphoma which demonstrated an ORR of 24% (NCT00691210).  This proof-of-principle 
study demonstrates a potential role of combined HDAC inhibition therapy in B-cell lymphomas (8). In 
addition, it suggests that the cumulative epigenetic derangements of GC-DLBCL may be amenable to targeted 
therapy through modulation of the acetylation state. 
3.  
Combined targeting with HDAC and DNMT inhibitors. Converse to the effects of acetylation, DNA 
hypermethylation can lead to transcriptional silencing of tumor suppressor genes and resistance to 
chemotherapy.  Unlike HATs, mutations in DNMTs have not been identified in DLBCL, however they have 
been found to be overexpressed (DNMT1 by 48%) and this has been linked to clinical stage(30).  Pre-clinical 
studies have shown that histone deacetylation and DNA methylation are linked, and cooperate to inactivate a 
host of tumor suppressor genes (31).  We have demonstrated synergy between HDAC and DNMT inhibitors in 
T- and B-cell lymphomas(9, 10).  The combination of decitabine with panobinostat demonstrated potent 
Figure 5: Schematic of epigenetic modulation in GC-
lymphomas 


 
 
12 
 
synergy in vitro, which was validated in a xenograft model of GC-DLBCL where the combination led to marked 
Figure 6: Combination of niacinamide with HDAC 
inhibitors is synergistic in GC-DLBCL 
Figure 8: Panobinostat is synergistic with decitabine in 
preclinical models of GC- DLBCL
Figure 7: Combination of niacinamide with romidepsin 
leads to acetylation of Bcl6 and p53 in mice and 
decreased tumor burden 
Ac-Bcl6 
Bcl6 
Total Ig 
BLIMP1 
Ac-p53 
p53 
p21
Actin 
Control        N          R          N+R        N-->R 
Decitabine 


 
 
13 
 
tumor growth delay compared to either agent alone (Fig 8).   This combination also led to unique effects on 
gene expression, where treatment with panobinostat led to an increase in SMAD1 and DNMT3A which may 
explain the synergistic benefit of DNMT and HDAC inhibition(10).  This concept has been recently 
translated to the clinic in a study of azacitadine in combination with romidepsin for the treatment of 
patients with relapsed/refractory lymphomas (NCT 01998035)(32) and as a method to re-sensitize 
DLBCL to chemotherapy (NCT 0243536) (33).  These findings underscore that modulating both 
acetylation and methylation has a path to the clinic for GC-DLCBL. 
 
 
2.4.2 Phase I Experience and Determination of MTD 
 
Twenty-six patients were enrolled in the Phase I study and were evaluable for toxicity. Median age was 51 yrs (23-
79) and 58% were male. The median number of prior therapies was 6.5 (range 1-18). Histologies included HL 
(N=12), DLBCL (N=5), follicular lymphoma (N=3), ATLL (N=2), CTCL (N=2), cutaneous ALCL (N=1), T-ALL (N=1). 
The entry dose in cohort 1 was azacytidine at 100 mg day 1 to 14 with romidepsin 10 mg/m2 day 8, 15 every 21 
days with no DLT detected. There were 2 DLTs in cohort 2 (azacytidine 200mg day 1 to 14 with romidepsin 10 
mg/m2 day 8, 15 every 21 days) consisting of 1 Grade 3 thrombocytopenia and 1 Grade 3 pleural effusion. In 
cohort 3, 3 additional patients were evaluated using the every 28 days schedule at the same dose level and no 
thrombocytopenia and/or other DLTs were observed. Dose escalation was continued until 2 DLT were observed 
in cohort 7 (azacytidine 300mg day 1 to 21 with romidepsin 14mg/m2 day 8, 15, 22 every every 35 days which 
resulted in 1 Grade 4 thrombocytopenia and 1 Grade 4 neutropenia. This dose level was declared maximum 
administered dose (MAD). Patients dosed at the maximum tolerated dose (MTD) of azacytidine 300 mg day 1 to 
14 and romidepsin 14 mg/m2 day 8, 15, 22 every 35 days  did not experience any toxicities.    
 
The toxicities reported in >10% of patients included: grade 3/4 toxicities represented by febrile neutropenia (19.2%) 
and thrombocytopenia (19.2%); grade 2 toxicities represented by back pain (7.7%), fatigue (11.5%), nausea 
(34.6%), vomiting (19.2%), pain (7.7%) and peripheral sensory neuropathy (7.7%) and grade 1 toxicities including 
fatigue (38.5%), nausea (23%), diarrhea (19.2%), malaise (19.2%), vomiting (19.2%), anorexia (15.4%), pain 
(15.4%), constipation (11.5%), cough (11.5%), fever (11.5%), general disorders and administration site complains 
(11.5%), dyspnea (7.7%), hypokalemia (7.7%), insomnia (7.7%), oral mucositis (7.7%) and pruritus (7.7%). 
 
Twenty-six patients were enrolled, of which 23 were evaluable for response. The overall response rate was 30%. 
Interestingly, as hypothesized, the ORR among the B- and T-cell patients were dramatically different, albeit the 
number of T-cell patients was quite small.  For instance, there were 18 patients with B-cell lymphoma, of which 
only 3 responded, giving an ORR of 17% among the B-cell lymphoma, which did not include any complete 
remission.  Among the 5 T-cell patients, 4 responded, for an ORR of 80%, and 2 of the 4 responses were complete 
remissions.  These responses included: (1)  a patients with refractory T-ALL who achieve a firs CR on study 
allowing a MUD-allogeneic stem cell transplant; (2) a patients with drug resistant CD8+ cutaneous cytotoxic T-cell 
lymponoma who attained a CR despite relapsing off pralatrexate; (3) a patient with HTLV-1 ATLL who attained a 
CR, and (4) a patient with CTCL who attained a major PR.  One patients with drug resistant tumor MF failed to 
respond.  We believe these observations, although early, are consistent with the laboratory data and our 
hypothesis, that this regimen is likely to have a highly lineage specific activity in patients with PTCL and CTCL. 


 
 
14 
 
Moreover, we believe the totality of the data support continued study of this promising combination. 
 
To date there have been 7 patients enrolled with either follicular or DLBCL.  Five of these patients were evaluable 
for response and 1 patient had a partial response (20%) and a second had stable disease. There is an emerging 
strong rational to evaluate patients with germinal center derived B-cell lymphoma with combination epigenetic 
therapy as will be discussed below.     
 
 
3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria for Lymphoma  
 
 
3.1.1 Phase I: Patients must have histologically confirmed relapsed or refractory non-Hodgkin 
lymphoma or Hodgkin lymphoma (WHO criteria), with no accepted curative options.  
Phase II: Patients with untreated, relapsed or refractory T-cell lymphoma, including patients with 
central nervous system (CNS) involvement or lymphomatous meningitis are allowed on study. 
Exploratory Cohort: Patients with histologically confirmed relapsed or refractory Germinal 
Center (GC)-derived B-Cell Lymphoma (diffuse large B-cell (DLBCL) and follicular 
lymphoma (FL)) defined by the WHO and Hans criteria with no accepted curative options. 
(Appendix 5) 
 
 
 
3.1.2. There is no upper limit for the number of prior therapies. Patients may have relapsed after prior 
autologous or allogeneic stem cell transplant. 
 
 
3.1.3  Evaluable Disease in the Phase I, and measurable disease as defined in Section 11.1 for the Phase 
II. 
 
 
3.1.4 Age >18 years. 
 
3.1.5 ECOG performance status <2  
 
 
3.1.6 Patients must have adequate organ and marrow function as defined below: 
 
− 
absolute neutrophil count  
>1,000/dL 
− 
platelets 
  
 
 
 
 
>75,000 total (>50,000 if bone marrow involvement) 
− 
bilirubin 
  
 
 
 
 
<1.5X institutional limits 
− 
AST(SGOT)/ALT(SGPT) 
<2.0X institutional upper limit of normal 
− 
 Serum creatinine  
 
 
within normal institutional limits 
 
OR 
− 
Creatinine clearance  
 
>50 mL/min/for patients with creatinine levels above institutional 
normal. 
 
3.1.7 Negative urine or serum pregnancy test for females of childbearing potential  
3.1.8 All females of childbearing potential must use an effective barrier method of contraception (either 
an IUDC or double barrier method using condoms or a diaphragm plus spermicide) during the 


 
 
15 
 
treatment period and for at least 1 month thereafter.   Male subjects should use a barrier method 
of contraception during the treatment period and for at least 3 months thereafter.  Female subjects 
should avoid the use of estrogen-containing contraceptives, since Romidepsin may reduce the 
effectiveness of estrogen-containing contraceptives.      
3.1.9 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
 
Exclusion Criteria 
 
 
 
 
3.2.1  
Prior Therapy 
 
 
❖ Exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the study or 
those who have not recovered from adverse events due to agents administered more than 
2 weeks earlier. 
 
❖ Systemic steroids that have not been stabilized ( ≥ 5 days) to the equivalent of ≤10 mg/day 
prednisone prior to the start of the study drugs. 
 
❖ No other concurrent investigational agents are allowed.  
 
 
3.2.3 History of allergic reactions to Oral 5-azacitidine or Romidepsin. 
 
3.2.4 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
 
3.2.5 Pregnant women  
 
3.2.6 Nursing women  
 
3.2.7 Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in 
situ of the cervix). Patients whose lymphoma has transformed from a less aggressive histology 
remain eligible. 
 
 
3.2.8 Patients known to be Human Immunodeficiency Virus (HIV)-positive  
 
 
3.2.9 Patients with active hepatitis A, hepatitis B, or hepatitis C infection. 
  
3.2.10 Concomitant use of CYP3A4 inhibitors (see Appendix 2) 
3.2.11 Any known cardiac abnormalities such as: 
• Congenital long QT syndrome 
• QTc interval ≥ 500 milliseconds; 
• Patients taking drugs leading to significant QT prolongation (See Appendix 1:  Medications That 
May Cause QTc Prolongation) 
• Myocardial infarction within 6 months of C1D1.  [Subjects with a history of myocardial infarction 
between 6 and 12 months prior to C1D1 who are asymptomatic and have had a negative cardiac 


 
 
16 
 
risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since 
the event, may participate]; 
• Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd 
degree AV block, or bradycardia (ventricular rate less than 50 beats/min);   
• Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV (see Appendix 3)  
In any patient in whom there is doubt, the patient should have a stress imaging study and, if 
abnormal, angiography to define whether or not CAD is present; 
• An ECG recorded at screening showing evidence of cardiac ischemia (ST depression of ≥2 mm, 
measured from isoelectric line to the ST segment).  If in any doubt, the patient should have a 
stress imaging study and, if abnormal, angiography to define whether or not CAD is present; 
• Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV 
definitions (see Appendix 4) and/or ejection fraction <40% by MUGA scan or <50% by 
echocardiogram and/or MRI;  
• A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade 
de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter 
defibrillator (AICD); 
• Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes; 
• Uncontrolled hypertension, i.e., blood pressure (BP) of ≥160/95; patients who have a history of 
hypertension controlled by medication must be on a stable dose (for at least one month) and meet 
all other inclusion criteria; or 
• Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-
blockers) 
3.3  
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
   
 
4. REGISTRATION PROCEDURES 
 
4.1       General Guidelines 
Eligible patients will be enrolled on study by the study team.   
 
Following enrollment, patients should begin protocol treatment within 14 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator. If a patient does not 
receive protocol therapy within 14 days of enrollment, the patient’s enrollment on the study may 
be canceled, at the discretion of the PI.   
 
4.2 
Screening 
 
All potential study patients will be screened and eligibility determined prior to enrollment.  
Unless otherwise specified, the following procedures and evaluations will be performed as 
noted in the study calendar (Section 10) prior to the start of study drugs (cycle 1, dose 1): 
 
1) Obtain written informed consent and privacy authorization prior to initiating any protocol-
required procedure that is not considered standard of care (See Section 4.3) 


 
 
17 
 
 
2) Review eligibility criteria 
 
3) Review medical chart for past medical/surgical history 
 
4) Record medications and prior treatment regiments 
 
5) Record response to prior treatment regimen(s) 
6) Document histopathology from: 
(i) Original diagnosis  
(ii) Tumor biopsy in the relapsed setting (if applicable) 
 
7) Documentation of known measurable disease parameters by the following procedures: 
• CT of neck, chest, abdomen, and pelvis (PET/CT optional) 
• Skin exam 
• Other imaging techniques documenting disease site other than neck, chest,           
abdomen, and pelvis, if applicable 
 
8) Obtain a 12-lead electrocardiogram (ECG) and calculate the QTc interval.  
 
9) Perform a comprehensive physical examination 
 
10)  Assess and record ECOG Performance Status 
 
11)  Local laboratory: Collect blood for hematology (CBC with differential counts), chemistry 
(Na, K, Cl, HCO3, BUN, creatinine, glucose, calcium, magnesium, including serum β-human 
chorionic gonadotropin [β-hCG] pregnancy test for women who are not postmenopausal or 
surgically sterile [within 7 days prior to cycle 1, dose 1 and again within 24 hours prior to first 
dose of the study drugs. ]), liver function tests (total protein, Albumin, AST, ALT, total 
bilirubin, direct bilirubin, alkaline phosphate). 
 
12) Calculate creatinine clearance using the glomerular filtration rate (GFR) according to the 
Cockroft and Gault Equation, only if screening serum creatinine is > 1.5 mg/dL: GFR* = (140 
– age [years]) x actual body weight (kg)72 x serum creatinine        
*For female patients, multiply by 0.85 
 
13) For Exploratory Cohort Only: A lymph node, core-needle biopsy, or bone marrow biopsy will be 
performed during the screening period for evaluation of gene expression profiling . 
 
4.3 
 
Informed Consent 
 
4.3.1 Study Informed Consent 
 
Study personnel must obtain documented consent from each potential patient prior to entering in a clinical 
study.  Consent must be documented on the IRB approved consent form by obtaining the dated signature 
both of the patient and of the investigator conducting the consent discussion.  If the patient is unable sign 
the consent form, then oral consent, attested to by the dated signature of an impartial witness (someone 
not involved with the conduct of the study), is the required alternative. 
 


 
 
18 
 
If the patient is illiterate, an impartial witness should be present during the entire informed consent 
reading and discussion.  Afterward, the patient should sign and date the informed consent, if capable.  
The impartial witness should also sign and date the informed consent along with the individual who read 
and discussed the informed consent (i.e., study staff personnel). 
 
 
The information from the consent form should be translated and communicated to the subject in language 
understandable to the subject.  Consent forms will be available in English and Spanish.  When the study 
participant is non-English and non-Spanish speaking, the consent form must be read accurately in its 
entirety by a qualified professional translator.   The translator will provide a written statement indicating 
that the consent form has been accurately translated from the accompanying English version, and that the 
study participant consents to participation.  The professional translator will sign the consent form as an 
impartial witness. 
 
A copy of the signed and dated consent form should be given to the patient before participation in the 
study. 
 
Patients may undergo study screening tests prior to giving written informed consent provided that these 
tests are considered part of standard care. 
 
The initial informed consent form and any subsequent revised written informed consent 
form, and written information will receive the IRB approval.  The patient or his/her legally acceptable 
representative will be informed in a timely manner if new information becomes available that may be 
relevant to the patient’s willingness to continue participation in the trial.  The communication of this 
information will be documented. 
 
 
4.3.2Consent and Use of Tissue Specimens for Research 
 
Patients who choose to participate in the optional biopsies will undergo a tissue biopsy pretreatment and 
a second biopsy between Day 8 and 21 of cycle 1.  The investigator or designee is responsible for 
explaining and verifying the subject’s consent before obtaining any biopsy. It will be explained to the 
patient that allowing the lymph node sample is encouraged, but optional, and participation in the 
associated clinical study is not dependent upon giving this sample.   
 
4.4 
Registration Process 
 
To register a patient, the following documents should be completed by a member of the research staff 
and delivered to the study coordinator: 
 
• Eligibility Screening Worksheet  
• Copy of required laboratory and imaging tests 
• Signed patient consent forms 
• HIPAA authorization form 
 
The Study Coordinator will verify eligibility.  To complete the registration process, the Coordinator will: 
• Assign a patient study number 
• Register the patient on the study 
• Confirm registration with the principal investigator 


 
 
19 
 
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration  
5.1.1Dose Escalation Scheme 
Cohorts of 3 patients will be administered oral 5-azacitidine and romidepsin starting at a dose of 100 mg 
for oral 5-azacitidine and 10 mg/m2 for romidepsin.  Dose escalations will then commence for each agent 
individually with a maximum oral 5-azacitidine dose of 300 mg and a romidepsin dose of 14 mg/m2 
representing the highest dose cohort.  The dose levels to be considered are outlined in the escalation 
schema in Table 2. The rules for dose escalation or de-escalation are outline in table 3. 
 
Table 1: Regimen Description 
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Oral 
5-
azacitidine  
Anitemetic 
 
300  mg 
(flat dose) 
PO   
Days 1-14  
35 days 
Romidepsin 
Antiemetic  
14 mg/m2 
IV over 4 hours  
(Administered first 
during cycle 1) 
Days 8, 15, 
22 (+/- D 
22) 
** Doses as appropriate for assigned dose level. 
 
Table 2:  Dose Escalation Scheme for the Combination of Oral 5-azacitidine and Romidepsin 
Dose Escalation Schedule 
 
Dose Level 
Dose 
 
Oral 5-azacitidine 
(Flat dose [mg]) 
 
Romidepsin 
(mg/m2 rounded to 
14mg/m2) 
Cycle Length 
Level -1 
100 (Days 1-14) 
10 (Day8) 
28 
Level 1 
100 (Days 1-14) 
10 (D8 & 15) 
28 
Level 2 
200 (Days 1-14) 
10 (Day 8 &15) 
28 
Level 3 
 300 (Days 1-14) 
10 (Day 8 & 15) 
28 
Level 4 
300 (Days 1-14) 
14 (day 8 & 15) 
28 
Level 5  
300 (days 1-14) 
14 (Days 8, 15 and 22) 
35 
Level 6 
 
300 Days (1-21) 
14 (Days 8, 15, 22) 
35 
 
 
 
Figure 2: Drug Administration Schema 
 
Dose Levels -1 through 4 
Day                       1    
  8                             15  
          22                    28 


 
 
20 
 
Oral 5-azacitidine                                                
Romidepsin 
                                                                                    
 
Dose Level 5 
Day                       1    
 8                             15  
          22             28           35 
Oral 5-azacitidine                                              
Romidepsin 
                                                                                                                
 
Dose Level 6 
Day                       1    
 8                             15  
          21  22          28           35 
Oral 5-azacitidine                                                                    
Romidepsin 
                                                                                                                     
 
The objective for the dose escalation scheme for Part I is to evaluate the safety and tolerability of various 
doses of combined oral 5-azacitidine and HDAC inhibition by romidepsin.   
 
Phase II will evaluate the efficacy (ORR) of the MTD of oral 5-azacitidine and romidepsin from Part I 
in patients with T-Cell Lymphoma. (See figure 2 for study plan flow chart) 
 
5.1.2Regimen Description (Phase 2) 
 
Treatment will be administered on an outpatient basis. Patients will be treated with oral 5-azacytidine 
and romidepsin at the MTD (i.e the Recommended Phase 2 Dose, or RP2D).  The treatment will be 
administered as follows: oral 5-azacytidine 300 mg (flat dose) Days 1-14 and romidepsin 14 mg/m2 on 
Days 8, 15, and 22 on an every 35 day cycle.   All patients receiving romidepsin will receive potassium 
and magnesium supplementation as recommended in the package insert of the product.  In all cycles 
romidepsin will be administered first over 4 hours.  Reported adverse events and potential risks for oral 
5-azacitidine and romidepsin are described in Section 7.  Appropriate dose modifications are described 
in Section 6.  No investigational or commercial agents or therapies other than those described may be 
administered with the intent to treat the patient's malignancy. 
 
5.1.3 
Required Blood Parameters and Other Investigations Prior 
 
to Each Treatment (Except Cycle 1 Day 1) 
Before the start of each treatment, patients should be reassessed and the following criteria must be 
fulfilled: 
 
• ANC >  1000/dL 
• Platelet count ≥ 50, 000/dL   
• Serum creatinine concentration ≤ 2.0 × ULN or ≤ baseline, or creatinine clearance >50 ml/min 
• AST (SGOT) and ALT (SGPT) ≤2.0 × ULN or ≤3.0 × ULN in presence of demonstrable liver 
metastases 
• Bilirubin concentration ≤2.0 × ULN  
• Serum potassium is ≥ institutional LLN and magnesium is ≥  laboratory LLN (supplements 
must be given to patients whose potassium is < laboratory LLN and/or whose magnesium is 
< laboratory LLN and serum electrolytes must be rechecked prior to romidepsin 
administration).  
• Recovery of any drug-related non-hematological toxicity to Grade 1 or less, unless otherwise 
indicated 


 
 
21 
 
• ECG schedule as specified in Section 5.1.8.2. 
 
5.1.4 
Guidelines for Study Drug Administration 
• Oral 5-azacitidine will be taken between the hours of 8 and 10 am daily (patient will be 
required to maintain a drug log recording side effects and time of dosage) on Days 1-14  
• Romidepsin will be administered over 4 hours through either a peripheral or central venous 
catheter on Days 8, 15, 22 of a 35 day cycle. It will be administered within 6 hours of the oral 
dose.  On the day of PK sampling in Cycle 1, the azacitidine will be taken with romidepsin. 
A dose of the anti-emetic will be administered in accordance with the package insert of 
romidepsin.  
• Administration of the study drugs will be allowed within 48 hours of the scheduled dates. 
• Missed doses will not be made up.  
 
5.1.5 
Maximum Tolerated Dose 
The dose-escalation rules and determination of the maximum tolerated dose (MTD) are outlined in Tables 
2 and 3.  Patients will be enrolled to receive oral 5-azacitidine and romidepsin in sequentially escalating 
doses until a maximum tolerated dose of the combination has been defined.  The maximum tolerated dose 
of oral 5-azacitidine  in combination with romidepsin will be defined as the dose level immediately below 
the dose level at which greater than or equal to 2 patients out of 6 patients in a cohort experience a dose-
limiting toxicity (DLT).   
 
Table 3:  Dose Escalation & De-Escalation Decision Rules: 
Number of Patients with 
DLT at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
If 0 of these 3 additional patients experience DLT, proceed to the next dose level. 
If 1 or more of this group experience DLT, then dose escalation is stopped, and this 
dose is declared the maximally administered dose (MAD), and the dose level below is 
the MTD.   
>2 
Dose escalation will be stopped.  This dose level will be declared the maximally 
administered dose (highest dose administered).   
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is generally the recommended phase 2 dose. At least 6 patients must be entered at 
the recommended phase 2 dose. 
 
5.1.6 Dose De-escalation Decision Rules: 
If a DLT is reached in the first cycle for a given patient, then the previous dose level will be utilized for 
that particular patient in subsequent cycles.  Should that patient experience a second DLT at that lower 
dose, they will be removed from the study.  Dose-escalation will resume until the maximally administered 
dose is achieved or MTD is reached. 
 
For example, according to the schema in Table 2, if DLT is reached at dose level 1 (romidepsin 10 mg/m2 
and oral 5-azacitidine 100 mg/m2), the frequency of romidepsin will be reduced to a Day 8 only dose.  
Dose escalation can resume starting at that point according to dose escalation rules (Table 3).  The same 


 
 
22 
 
applies if DLT is reached at all other levels prior to dose level four. 
 
Toxicities in cycles 2 and following may be accomodated by treating patients at one dose level below the 
present cohort. Toxicity in cycles 2 and beyond will not affect dose escalation for future patients.  
 
In the Phase 2, de-escalation should follow the Phase 1 escalation guidelines.  For instance, any recurrent 
Grade 3 toxicity, up to 3 de-escalations will be allowed, with the doses of the drugs being reduced to that 
described in Cohort 5 (azacytidine 300 mg Day 1-14, and romidepsin 14 mg/m2 Day 8 and 15 every 28 
days)→ Cohort 4 (azacytidine 300 mg Day 1-14, and romidepsin 10 mg/m2 Day 8 and 15 every 28 
days)and then Cohort 3 (azacytidine 200 mg Day 1-14, and romidepsin 10 mg/m2 Day 8 and 15 every 
28 days).  Any patient experienceing a Grade 4 toxicity should just be immediately dose reduced 
according to the guideline above.  In addition, patients can be dose reduced per the treating physicians 
discretion.    
 
Specifically, for hematologic toxicities, patients may receive GCSF for neutropenia.  For cases where 
patients miss a dose secondary to a recurrent Grade 3 ANC or platelet count, or Grade 4 hematologic 
toxicity, dose reductions should occur as noted above at the physicians discretion (i.e. reduce to Cohort 
5, then 4 then 3).   
 
5.1.7Prophylactic Medicines and Supportive Care 
Romidepsin is moderately emetogenic.  Standard institutional guidelines for anti-emetics will be used. 
Supportive treatment may include additional anti-emetics, anti-diarrheal, anti-pyretics, anti-histamines, 
analgesics, antibiotics, and blood products.  Patients who experience indigestion or gastroesophageal 
reflux symptoms on Romidepsin may be treated with Proton Pump Inhibitors (PPIs) as well as H2 
blockers as clinically indicated. 
 
 Patients who have pre-existing chronic anemia prior to receiving oral 5-azacitidine and romidepsin  may 
continue to receive erythropoietin or darbepoietin.  Post cycle 1, colony stimulating growth factors (e.g., 
filgrastim, peg-filgrastim, and sargramostim) may be used in patients who experience hematological 
toxicity per American Society of Clinical Oncology (ASCO) guidelines. After initiating treatment, 
anemia may be managed with growth factors according to the ASCO guidelines: 2006 Update of 
Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice 
Guideline http://www.jco.org/cgi/content/full/24/19/3187.  Neulasta should only be used if the interval 
to the next dose is ≥14 days. 
 
Patients will be permitted to receive appropriate supportive care measures as deemed necessary by the 
treating physician including but not limited to the items outlined below:   
 
• Diarrhea: Diarrhea should be treated promptly with appropriate supportive care, including 
loperamide.  Loperamide should not be taken prophylactically. Patients should be instructed 
to begin taking loperamide at the first sign of: 1) poorly formed or loose stool, 2) occurrence 
of more bowel movements than usual in one day or 3) unusually high volume of stool.  
Loperamide should be taken in the following manner: 4 mg at first onset of diarrhea, then 2 
mg after each unformed stool.  The daily dose of loperamide should not exceed 16 mg/day.  
Loperamide should be deferred if blood or mucus is present in the stool or if diarrhea is 
accompanied by fever. In this setting, appropriate diagnostic microbiologic specimens should 
be obtained to exclude an infectious etiology. Patients should also be advised to drink liberal 
quantities of clear fluids.  
  


 
 
23 
 
• Nausea/vomiting: Romidepsin is moderately emetigenic. Ondansteron 8 mg IV will be given 
prior to Romidepsin injections.  Nausea and vomiting should be treated aggressively, with 
agents such as prochlorperazine, metoclopramide, 5-HT-3 inhibitors, or benzodiazepines.  
Patients should be strongly encouraged to maintain liberal oral fluid intake during therapy, 
especially during the initial 14 days of each treatment cycle. 
 
• Fatigue:  May be cumulative with increasing cycles of therapy.  Can be treated as indicated 
by the treating physician. 
 
• Anemia: Treatment with oral 5-azacitidine  and romidepsin can cause dose-related anemia. 
Transfusions or erythropoetin may be utilized as clinically indicated for the treatment of 
anemia, but should be clearly noted as concurrent medications.  
 
• Thrombocytopenia: Treatment with Oral 5-azacitidine  and Romidepsin can cause dose-
related thrombocytopenia. Transfusion of platelets may be used if clinically indicated. Dose 
modification for thrombocytopenia is allowed in a manner consistent with the guidelines for 
dose modification (Section [6.3]). Prophylactic folic acid and vitamin B12 supplements may 
be necessary to reduce hematologic toxicity. 
 
• Neutropenia: Prophylactic use of colony-stimulating factors including G-CSF, pegylated G-
CSF or GM-CSF should not be utilized during the first cycle of therapy. These factors may 
be utilized if clinically indicated in subsequent cycles. 
 
• Hypokalemia or hypomagnesemia should be corrected prior to administration of 
Romidepsin, and consideration should be given to monitoring potassium and magnesium in 
symptomatic patients (e.g. patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac 
symptoms.) 
 
• Oral Mucositis: Oral 5-azacitidine may cause mucositis (includes stomatitis or mucosal 
inflammation of gastrointestinal and genitourinary tracts); which may require dosage 
modification. Prophylactic folic acid and vitamin B12 supplements are necessary to reduce 
treatment-related mucositis. 
 
• Hepatotoxicity:  Liver function test abnormalities have been observed with Oral 5-azacitidine 
use. Persistent abnormalities may indicate hepatotoxicity and may require dosage 
modification. 
 
5.1.8      Cardiac Monitoring 
Minor EKG changes are not uncommon following romidepsin administration.  Cardiac assessments 
must be performed for all study patients.  The Investigator must perform the primary assessment 
and is responsible for the cardiac safety of the patients (local cardiologist may be consulted, if 
preferred).  
  
5.1.8.1  
Cardiac Alert Findings 
 
In the event of an alert finding, the individual decision about a delay of administration, dose reduction, 
or withdrawal from the study will be made by the Investigator (in association with local cardiologist, if 
preferred).   All alerts must be confirmed via a manual read of the patients ECG; the machine reading 
alone is not adequate.  The following findings are considered to be cause for alert and if they occur, 


 
 
24 
 
should be reported as AEs or SAEs, as appropriate: 
• QTc ≥500 msec  
• Ventricular arrhythmia: VT (≥3 beats in a row) or VF; 
• Sinus tachycardia (pulse >140/min after recumbency);  
• Heart rate > 120 bpm with > 20 bpm increase from previous evaluation; 
• New occurrence of atrial dysrhythmias (SVT, atrial fibrillation, or atrial flutter); or 
• Abnormal ST and/or T-wave changes including ST depression of 2 mm (as measured from 
isoelectric line to the ST segment at a point 60 msec at the end of the QRS complex); T-wave 
inversion of 4 mm (measured from isoelectric line to peak of T-wave) as long as the main QRS 
vector is positive; 
• Ventricular tachycardia, including Torsade de Pointes. 
See Table 4 for recommended dose reductions. 
 
5.1.8.2 Electrocardiograms 
 
Single ECGs (12 lead) should be performed during screening (days -14 to -1) and weekly during cycle 
1. Subsequently, ECG will be performed on Day 8 of each cycle to cycle 6, then at the discretion of the 
Investigator (within 1 hour prior to the romidepsin administration, after administration of 
antiemetic/premedication).  
 
If the QTc is ≥500 msec, ECGs should be repeated 2 more times for a mean of three QTc 
values.  Minor ECG changes are expected following romidepsin administration (refer to current 
Investigator’s Brochure).  All abnormalities must be confirmed by the investigator’s manual read of the 
patient ECG (or local cardiologist, if preferred).  Abnormal alert findings, based on manual read, 
should be reported as AEs or SAEs, as appropriate.  ECGs must also be performed at the final study 
visit, whenever clinically indicated and at all visits for follow-up of AEs. 
 
5.1.8.3 All Dosing Days 
• ECGs within 1 hour prior to the administration of romidepsin (after administration of anti-emetic/pre-
medication) 
In case of the cardiac findings (alerts) above, an individual decision about a delay of administration, dose 
reduction, or withdrawal from the study will be made by the Investigator who may wish to consult with 
a local cardiologist. 
 
5.2 
 
Dose-Limiting Toxicity 
 
A dose limiting toxicity (DLT) is defined as any toxicity not specifically included in section 5.2 that 
occurs within cycle 1 and is considered at least “possibly related to study drug administration.”  DLT is 
also defined as any toxicity possibly related to drug, occurring up to 7 days after completion of cycle 1 
that results in a delay of initiating cycle 2.   For patients who discontinue study drug administration after 
Cycle 1, DLT will be defined as any toxicity not specifically included in section 5.2 that occurs within 
30 days of the last dose of drug on study, in cycle 1 that is considered at least possibly related to study 


 
 
25 
 
drug. 
 
DLTs include: 
 
• Hematologic dose-limiting toxicity will be defined as either Grade 4 neutropenia that does not 
resolve to ≤ Grade 2 within ≤ 7 days, any Grade 4 thrombocytopenia, or any Grade 5 
hematologic toxicity. At least three patients in each cohort must be evaluable for hematologic 
toxicity.  
• Non-hematologic dose-limiting toxicity will be defined as any Grade 3, 4 or 5 non-hematologic 
toxicity, with the specific exception of:   
• Grade 3 nausea or Grade 3 vomiting that in the opinion of the investigator occurs in the setting 
of inadequate compliance with supportive care measures specified in Section 5.1.7 and lasts for 
less than 48 hours. 
• Grade 3 diarrhea that in the opinion of the Investigator occurs in the setting of inadequate 
compliance with supportive care measures specified in Section 5.1.7 and lasts for less than 48 
hours.   
• Grade 3 dehydration that, in the opinion of the investigator, occurs in the setting of inadequate 
compliance with supportive care measures specified in Section 5.1.7 and lasts for less than 48 
hours. 
• Grade 3 acidosis or alkalosis that responds to medical intervention by returning to ≤ Grade 2 
within 48 hours. 
• Isolated (i.e. no other abnormalities) Grade 3 elevation of liver function tests (LFTs) without 
associated clinical symptoms, lasting for ≤ 5 days in duration. 
• Isolated (i.e. no other abnormalities) Grade 3 elevation of amylase without associated clinical 
symptoms, lasting ≤5 days 
• Grade 3 hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, or hypophosphatemia 
that responds to medical intervention. 
• Grade 3 hypercholesterolemia. 
• Grade 3 hypertriglyceridemia 
• Grade 2 Alopecia 
• Grade 3 Constipation 
• Grade 3 Fatigue  
 
Management and dose modifications associated with the above adverse events are outlined in Section 6. 
 
5.3 
 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of oral 5-azacitidine and romidepsin with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies.  The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with the potential to 
affect selected CYP450 isoenzymes. 
 
Carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients 
concurrently administered ISTODAX® and Coumadin derivatives 
 
Patients must be instructed not to take any additional medications (including over-the-counter products) 
during the trial without prior consultation with the PI. All medications taken within 30 days of screening 


 
 
26 
 
and medications and supportive therapies that are administered during the study must be recorded in the 
patient’s CRF and in the source documents. Supportive therapy, that is ongoing at baseline, will be 
permitted during the treatment phase of the study. If other therapy for the disease is required, continuation 
of the study treatment should be discussed with the lead investigator and sponsor. Concomitant 
medications for other medical conditions are permitted as clinically indicated subject to specific protocol 
requirements outlined below. 
Permitted medications and treatments  
• The prophylactic use of antiemetics is strongly encouraged, but antiemetics that significantly 
prolong QTc (e.g., palonosetron) or that significantly inhibit CYP3A4 (e.g., aprepitant) must be 
avoided (see Appendix 1, and 2, respectively).  Granisetron and ondansetron are the antiemetics 
most commonly utilized in other romidepsin clinical trials. 
• Patient’s electrolytes (serum potassium and magnesium) must be measured, and must receive 
supplement infusions to correct any levels outside of those stipulated per protocol.  Patients must 
then undergo a repeat biochemistry test to demonstrate values are within the accepted range before 
the patient is re-dosed with romidepsin. 
 
Prohibited concurrent therapy 
• Concomitant use of other anti-cancer therapies, including radiation, thalidomide, or other 
investigational agents is not permitted while subjects are receiving protocol therapy during the 
treatment phase of the study. 
• Any medications listed in Appendix 1 which may cause QTc prolongation or inducing torsades 
de pointes should not be used.  
• Concomitant use of CYP3A4 inhibitors with romidepsin should be avoided (excluding 
granisetron and ondansetron) to prevent potential increase in romidepsin exposure during 
concomitant treatment with these drugs.  Should a patient already enrolled on this study require 
treatment with these drugs (as listed in Appendix 2) romidepsin must be interrupted prior to 
starting these drugs and should not resume until a washout period of at least 5 half-lives has 
elapsed. 
• Strong CYP3A4 inhibitors may increase concentrations of ISTODAX® and should be avoided. 
• Potent CYP3A4 inducers may decrease concentrations of ISTODAX® and should be avoided 
• Any medications that have the potential to alter serum electrolytes (e.g., diuretics) should be 
monitored very closely for electrolyte abnormalities as these can contribute to the risk of QT 
prolongation and ventricular arrhythmias.  
 
PROPHYLACTIC MEASURES 
 
Subjects should receive allopurinol or rasburicase and other treatment considered appropriate for tumor 
lysis prophylaxis in cycle 1 as deemed necessary by the treating physician.  
Subjects should receive prophylactic anti-emetics prior to romidepsin administration. 
 
G-CSF may be given at each cycle. (Neulasta should only be given if there is a 14 day interval to the next 
dose). 
 
As noted previously, Serum potassium (K+) and Serum Magnesium (Mg+) will be verified before each 
dose of Romidepsin. Values ≤ laboratory LLN will be corrected prior to Romidepsin administration.  
 
5.4 
 
Duration of Therapy 
 


 
 
27 
 
Treatment may continue until one of the following criteria applies: 
• Disease progression 
• Unacceptable adverse event(s), DLTs 
• Withdrawal of consent 
• General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator 
• An event that in the judgment of the treating physician warrant’s discontinuation of therapy 
• There is no pre-specified number of cycles allowed 
 
5.5 
Duration of Follow Up 
 
Patients will have an end of study visit 4 weeks +/- 5 days after their last dose of drug to evaluate safety.  
Patients will be further followed every three months after the 4-week safety evaluation for one year, or 
until they begin a new treatment for their disease, for evaluation of delayed toxicity. Patients removed 
from study for unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. 
 
For patients who have stable disease or better after 6 cycles of therapy, tumor assessment will be 
performed by medical history, physical, CBC with differential and chemistries every 3 months until 
progression of disease occurs.  CT (PET/CT optional) will not be routinely used to monitor complete 
responses after 6 months, but rather, will be used when indicated, due to concern for disease progression. 
 
5.6 
Criteria for Removal from Study 
 
Patients will be removed from treatment when any of the criteria listed in Section 5.4 applies. The reason 
for study removal and the date the patient was removed must be documented in the Case Report Form. 
 
Subjects/patients may withdraw at any time or be dropped from the study at the discretion of the 
investigator should any untoward effects occur. In addition, a subject/patient may be withdrawn by the 
investigator if he/she violates the study plan or for administrative and/or other safety reasons. The 
investigator or study coordinator will notify the appropriate parties within 2 business days when a subject 
has been discontinued/ withdrawn due to an adverse event (Section 7).  When a subject 
discontinues/withdraws prior to study completion, all applicable activities scheduled for the final study 
visit should be performed at the time of discontinuation. Any adverse events present at the time of 
discontinuation/withdrawal will be followed until resolution. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
 
Dose Delays 
 
• Study drugs can be administered within 48 hours of their scheduled time.  
• Study drugs will be held for DLTs until adverse event returns to ≤ Grade 2  
• If interruption lasts for more than 14 days, study treatment will be discontinued. 
 
6.2 
 
Resuming Administration of Study Drug  
 
For toxicities that can be treated or prevented, such as nausea, vomiting, diarrhea and neutropenia, 
mucositis, treatment may be resumed at the previous dose once supportive measures have been 
instituted and toxicity recovers to Grade 2 or less.   


 
 
28 
 
 
6.3 
Dose Modifications 
 
If oral 5-azacitidine and romidepsin administration leads to a DLT beyond cycle 1 at a given dose level, 
dose modifications will occur in accordance with the drugs’ FDA approved package insert for 
romidepsin, or as outlined in the dose (de)escalation tables.  These post Cycle 1 DLTs will not count 
towards the overall determination of MAD & MTD for this study.    
 
6.3.1   
Romidepsin Dose Modifications 
 
Romidepsin dose modification in case of cardiac toxicity 
 
The guidelines for cardiac monitoring and timing of ECG assessments are presented in Table 7.  
Prolongation of QTc ≥500 msec is considered to be an alert associated with romidepsin administration 
 
TABLE 7:  Dose Modification in Case of Cardiac Toxicity 
 
Parameter/Symptoms 
Change 
Action 
Dosing/ 
Continuation 
Sinus tachycardia 
Pulse >140/min after 
recumbency 
Hold further dosing and treat 
appropriately.  If desired, the 
medical monitor or a local 
cardiologist may be consulted.  
If resolved, restart romidepsin at 
the next reduced level below. 
If not resolved, take off study. 
Atrial dysrhythmia (SVT, atrial 
fibrillation, or atrial flutter) 
New occurrence 
Prolongation of QTc compared 
to baseline 
To ≥500 msec 
 
Heart rate  
> 120 bpm with > 20 bpm 
increase from previous 
evaluation; 
Ventricular tachycardia 
≥3 beats in a row 
Ventricular fibrillation; Torsade 
de Pointes 
New occurrence 
Hold further dosing and treat 
appropriately.  The medical 
monitor should be notified 
immediately and local 
cardiologist should be 
consulted. 
Hold further dosing until 
medical monitor and cardiologist 
evaluation is complete 
A subsequent episode of any of the above, despite dose 
reduction 
Take off study 
T-wave morphology 
Inversion of ≥4 mma 
Hold further dosing and treat 
appropriately.  If desired, the 
medical monitor or a local 
cardiologist may be consulted. 
If resolved, restart romidepsin at 
the next reduced level below. In 
some patients, ST segment and 
T-wave morphology changes 
may recur despite a dose 
reduction.  In such cases, further 
treatment should be held until 
the ECG changes resolve.  If the 
patient experiences no 
concomitant clinical events, 
treatment may be resumed at the 
next reduced level below. 
If not resolved, take off study 
ST-segment 
Depression of ≥2 mmb 
NOTE: Cardiac findings that require dose modification should be reported as AEs or SAEs as appropriate. 
a Measured from isoelectric line to peak of T-wave. 
bMeasured from isoelectric line to ST segment. 
 
Romidepsin dose modification for Other Non-Hematologic and Hematologic Toxicities 


 
 
29 
 
All previously established or new toxicities observed any time, with the exception of those mentioned 
above, are to be managed as summarized in Table 8: 
TABLE 8: 
Dose Modifications for Romidepsin  
Dose Modifications for Romidepsin  
CTCAE Grade or Abnormal Value 
Romidepsin 
Thrombocytopenia 
Grade 1 (75 x 109/L -  LLN) 
Grade 2 (50 -  75 x 109/L) 
Maintain dose level 
Maintain dose level 
Grade 3 or 4 thrombocytopenia: 
 
 
 
 
 
OR 
 
Thrombocytopenia that requires 
platelet transfusion or recurrent 
Grade 3 or 4 thrombocytopenia 
Hold subsequent doses of therapy until 
thrombocytopenia returns to ≤Grade 2 or baseline and 
continue at full dose 
 
 
 
Hold subsequent doses of therapy until 
thrombocytopenia returns to ≤Grade 2 or baseline and 
permanently reduce dose of romidepsin to the next 
reduced level below..  If the same toxicity recurs 
despite dose reduction, patients should be taken off 
study.  
 
Neutropenia (ANC) 
Grade 1 (1.5 x 109/L -  LLN) 
Grade 2 (1.0 -  1.5 x 109/L) 
Maintain dose level 
Maintain dose level 
Grade 3 and 4 neutropenia:  
 
 
 
 
Hold subsequent doses of therapy until specific 
cytopenia returns to ≤Grade 1 or baseline and continue 
at full dose 
 
 
Febrile Neutropenia 
Febrile (≥38.5ºC) Grade 4 
neutropenia or recurrent Grade 3 or 4 
neutropenia:  
Hold subsequent doses of therapy until neutropenia 
returns to ≤Grade 1 or baseline and permanently 
reduce dose of romidepsin to the next reduced level 
below..  If the same toxicity recurs despite dose 
reduction, patients should be taken off study 
All Other Non-Hematologic Drug Toxicities (not mentioned in previous tables) 
Grade 1 or 2: 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
Maintain dose level 
 
Hold treatment with romidepsin until toxicity returns 
to ≤Grade 1 or baseline, then restart therapy at full 
dose.  If Grade 3 toxicity recurs, reduce dose of 
romidepsin to the next reduced level below..  This is a 
permanent dose reduction. 
 
Grade 4 toxicity:  Hold treatment with romidepsin until 
toxicity returns to ≤Grade 1 or baseline, and then 
restart therapy at the next reduced level below..  This is 
a permanent dose reduction  
 
 
Dose interruption or study discontinuation is not required for lymphopenia of any grade.   
In general, if study drug has been held and the toxicity does not resolve, as defined above, then drug must 


 
 
30 
 
be discontinued. 
Note:  Dose reductions should not be performed for alopecia or for nausea or vomiting that was not 
treated with aggressive anti-emetic support.  
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
7.1 
Safety Evaluation Procedures 
 
Adverse Event Reporting 
An adverse event is defined as any unfavorable and unintended change in the structure, function, or 
chemistry of the body temporally associated with the use of the study drugs, whether or not considered 
related to the use of the product. Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the 
study drugs product, is also an adverse event. 
 
Adverse events may occur in the course of receiving study drugs or within the follow-up period specified 
by the protocol, as well as from overdose (whether accidental or intentional), from abuse, and from 
withdrawal. 
 
Adverse events will be graded and recorded throughout the study according to NCI-CTCAE, version 4.0.  
Toxicities will be characterized in terms including duration, intensity, and time to onset.  Safety endpoints 
will include all types of adverse events, in addition to laboratory safety assessments, ECOG performance 
scale status, ECGs, and vital signs. 
 
The investigator must assess all abnormal laboratory results for their clinical significance.  If any 
abnormal laboratory result is considered clinically significant, the investigator must provide details about 
the action taken with respect to the test drug and about the patient’s outcome. 
 
The following safety evaluations will be performed during patient screening and at defined points during 
the course of the study: 
 
• 
Vital signs 
• 
Laboratory studies complete blood count (CBC), serum chemistry, urinalysis,  
 
 
coagulation studies (PT/PTT), pregnancy test, LDH 
• 
Electrocardiograms (ECG) 
• 
Physical examinations 
• 
Performance Status Evaluation using the ECOG scale 
• 
Adverse event monitoring using the NCI CTCAEv4.0 
 
The STUDY FLOW CHART (Section 10) provides specific details on collection time points.  
 
Serious Adverse Event (SAE) Definition  
A serious adverse event is one that at any dose (including overdose): 
• 
 Results in death 
• 
Is life-threatening1 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 


 
 
31 
 
• 
Results in persistent or significant disability or incapacity2 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event3 
• 
Pregnancy 
 
 1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious adverse event; it does 
not refer to a serious adverse event that hypothetically might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability to carry 
out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in situations 
where none of the outcomes listed above occurred.  Important medical events that 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 should also usually be considered serious.  Examples of such 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.  A new diagnosis of cancer during 
the course of a treatment should be considered as medically important.  
 
Note: Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations; for example, important medical events 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 outcomes listed in the definition above. Any adverse event is considered a serious 
adverse event if it is associated with clinical signs or symptoms judged by the investigator to have a 
significant clinical impact. 
Hospitalizations that do not meet these criteria are: 
 
• 
reasons described in the protocol, e.g., drug administration, protocol-required testing 
• 
social reason in the absence of an AE 
• 
Surgery or procedure planned prior to entry into the trial 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list 
of AEs (Section 7.2) and the characteristics of an observed AE (Section 7.3) will determine whether the 
event requires expedited (via AdEERS) in addition to routine reporting.    
 
Ongoing monitoring of the clinical safety data in this trial will be performed consistent with procedures 
outlined in the DSMC charter. This review will pay particular attention to Grade 3 or 4 adverse events, 
serious adverse events (SAEs), adverse events that lead to discontinuation and adverse events that lead 
to dose reduction. Should the incidence of any particular adverse event, or combination of events, rise to 
a level of clinical concern the DSMC will be notified for possible review of the emergent adverse events. 
 
 
 
 
7.2 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
7.2.1CAEPRs for Oral 5-azacitidine  
 


 
 
32 
 
7.2.1.1 Clinical Trials Experience 
In Study AZA-001 and Studies 8921/9221 with SC administration of azacitidine, adverse 
reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, 
and injection site erythema/reaction tended to increase in incidence with higher doses of 
azacitidine. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of 
SC treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, 
nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, 
dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions 
that increased in frequency over the course of treatment. Overall, adverse reactions were 
qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be 
specifically associated with the IV route of administration included infusion site reactions (eg, 
erythema or pain) and catheter site reactions (eg, infection, erythema, or hemorrhage). 
 
In general, the most common AEs reported during the azacitidine clinical trials reflect the underlying 
nature of the disease and the cytotoxic properties of azacitidine. No clinically significant differences 
were seen when the safety data were analyzed for age, gender, or MDS subtypes. 
 
Of the most frequently occurring adverse reactions (≥20%) in azacitidine-treated patients during the 
AZA-001 study, the majority was transient, non-serious, and resolved during the study. 
 
These most common adverse reactions can be managed through delays or dose decrease of azacitidine 
and concomitant treatment. Further details are provided below. 
 
Hematological Events 
The most commonly reported adverse reactions associated with azacitidine treatment were 
hematologic events, including anemia, thrombocytopenia, neutropenia, and leukopenia. Bone 
marrow failure or pancytopenia were also reported less frequently. Complete blood counts 
should be performed at baseline, prior to administration of each dosing cycle, and whenever 
deemed clinically necessary to monitor potential toxicity or response. After administration of the 
recommended dosage for the first cycle, dosage for subsequent cycles should be adjusted. There is a 
greater risk of these events occurring during the first 2 cycles, after which they occur with less 
frequency in patients with restoration of hematological function. Most hematological adverse reactions 
were managed by routine monitoring of CBCs and delaying azacitidine administration in the next 
cycle, prophylactic antibiotics and/or growth factor support (eg, granulocyte colony stimulating factor 
[G-CSF]) for neutropenia and transfusions for anemia or thromobocytopenia as required. 
 
Infections 
Myelosupression may lead to neutropenia and an increased risk of infection. Serious adverse 
reactions such as neutropenic sepsis (0.8%) and pneumonia (2.5%) were reported in patients 
receiving azacitidine. Infections may be managed with the use of anti-infectives plus growth 
factor support (eg, G-CSF) for neutropenia. 
 
Hemorrhagic Events 
Bleeding may occur with patients receiving azacitidine. Serious adverse reactions such as GI 
hemorrhage (0.8%) and intracranial hemorrhage (0.5%) have been reported. Other hemorrhagic 
AEs have also been reported, including conjunctival hemorrhage, eye hemorrhage, and 
hemorrhoidal hemorrhage. Patients should be monitored for signs and symptoms of bleeding, 
particularly those with pre-existing or treatment-related thrombocytopenia. 
 


 
 
33 
 
Hypersensitivity 
Serious hypersensitivity reactions (0.25%) have been reported in patients receiving azacitidine. 
In case of an anaphylactic like reaction, treatment with azacitidine should be immediately 
discontinued and appropriate symptomatic treatment initiated. 
 
Injection Site Reactions 
The majority of skin and SC adverse reactions were associated with the injection site. During 
Study AZA-001, injection site erythema and injection site reaction (nonspecific) were managed 
with corticosteroids and/or antihistamines, and non-steroidal anti-inflammatory drugs (NSAIDs); 
however, the majority of such events did not require concomitant treatment and none of these 
adverse reactions led to temporary or permanent discontinuation of azacitidine, or reduction of 
azacitidine dose. The majority of these adverse reactions occurred during the first 2 cycles and 
tended to decrease with subsequent cycles. 
 
Gastrointestinal Events 
Nausea and vomiting are common AEs that accompany therapy with azacitidine, especially 
following high doses administered rapidly by IV bolus. During the CALGB clinical trials, nonsteroidal 
antiemetics were used to counteract these AEs and allowed the continuation of 
azacitidine therapy. The majority of patients received prochlorperazine or a 5-HT3 receptor 
antagonist (eg, granisetron, ondansetron). During Study AZA-001, antiemetic therapy for 
nausea/vomiting most commonly included metoclopramide, ondansetron, or domperidone. 
Constipation has also been commonly reported during treatment with azacitidine and may be a 
consequence of the recommended antiemetic pre-treatment. During Study AZA-001, if treated, 
constipation was most commonly managed with stool softeners and/or laxatives (eg, lactulose 
and coloxyl with senna). 
 
Diarrhea is also a commonly reported adverse event associated with azacitidine therapy. 
Diarrhea may be more frequent and/or more severe in patients receiving orally administered 
azaciditine. It is recommended that patients experiencing diarrhea associated with azacitidine be 
managed according to the publication in the Journal of Clinical Oncology (Benson, 2004). A dose 
reduction of oral azacitidine may be appropriate based on the severity of diarrhea observed and the 
response to treatment intervention. 
 
Renal Adverse Reactions 
Severe renal tubular dysfunction has been reported in patients receiving azacitidine. This event 
may be manifested as renal tubular acidosis (serum bicarbonate < 20 mEq/L in association with 
alkaline urine), hypophosphatemia, hypokalemia, or hyponatremia, with or without increases in 
serum creatinine and BUN. Serum bicarbonate, BUN, and creatinine should be monitored 
periodically and dosage adjustments may need to be made. 
 
Hepatic Adverse Reactions 
Patients with extensive tumor burden due to metastatic disease have been rarely reported to 
experience progressive hepatic coma and death during azacitidine treatment. 
 
7.2.1.2  Serious Adverse Reactions 
Through 18 May 2012, approximately 5,300 patients have been exposed to azacitidine during 
completed or ongoing studies including 1,120 in Celgene-sponsored studies and 4,190 in non- 
Celgene-sponsored studies. 
 


 
 
34 
 
The most frequently reported adverse reactions with azacitidine treatment were hematological 
reactions including anemia, thrombocytopenia, neutropenia and leukopenia, gastrointestinal 
events including nausea, vomiting, abdominal pain, constipation, diarrhea, and injection site 
reactions (with SC administration). Adverse reactions associated with intravenously administered 
azacitidine were similar in frequency and severity compared with subcutaneously-administered 
azacitidine. The overall safety profile of azacitidine from the ongoing clinical studies is 
consistent with that described in this IB; however, diarrhea may be more frequent and/or more 
severe in patients receiving orally-administered azacitidine. 
 
The most common serious adverse reactions noted from the pivotal study and also reported in the 
supporting studies included febrile neutropenia and anemia. Other reported serious adverse 
reactions included neutropenic sepsis, pneumonia, thrombocytopenia, and hemorrhagic events 
(eg, cerebral hemorrhage). 
 
Post-marketing Safety Data 
Adverse drug reactions reported from post-marketing experience have been similar in type and 
severity to those reported in azacitidine clinical trials.  
 
 
7.2.2 
CAEPRs for Romidepsin 
Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia[4].   
7.2.2.1 Clinical Trials Experience 
In a study with 71 patients, the median number of administered cycles was four (1-to 72 cycles). Among 
the administered doses 76% were full doses, 7% were escalated doses, and 17% were reduced doses. 
Eight doses were held; three doses in three patients were held as a result of thrombocytopenia (< 50 x 
109/L), two were held for persistent grade 3 nausea, and three were held as a result of persistent grade 3 
fatigue[4]. 
Common nonhematologic adverse effects (any grade) included fatigue (41%), nausea (52%), vomiting 
(20%), and anorexia (21%). Hematologic abnormalities included leukopenia (31%), granulocytopenia 
(37%), lymphopenia (21%), thrombocytopenia (39%), and anemia (37%). Transient elevations of liver 
function tests, AST or ALT, were observed in 13 patients; two additional patients had isolated grade 1 
hyperbilirubinemia. Hyperuricemia was noted in 11 patients (eight patients with grade 1 and three 
patients with grade 3), and hypophosphatemia was noted in six different patients. ECG changes were 
noted consisting of asymptomatic T-wave flattening (71%) or ST segment depression (9%). Toxicities in 
later cycles mirrored those observed in the first cycle. Infections occurred in 38 patients (54%) over 58 
cycles (11%), including bacterial infections of the skin and upper respiratory, pulmonary, GI, and urinary 
tracts; bacteremia; and sepsis, and were not related to neutropenia[4].  
The most common AEs reported among subjects who received romidepsin monotherapy include GI 
disturbances 
(nausea, 
vomiting, 
constipation, 
diarrhea), 
hematologic 
toxicities 
(anemia, 
thrombocytopenia, neutropenia), and asthenic conditions (fatigue, asthenia, lethargy).  Other types of 
events commonly seen with romidepsin include anorexia, clinical chemistry abnormalities 
(hypocalcemia, hypoalbuminemia, hyperglycemia, and hypomagnesemia), pyrexia, and taste 
disturbances.   


 
 
35 
 
Overall, the incidence of AEs was higher among those with hematologic malignancies, including T-cell 
lymphomas (343 of 353 subjects; 97%) than among those with solid tumors (337 of 428 subjects; 79%).  
Review of AEs by system complex showed that  particular types of AEs generally occurred at a higher 
incidence among subjects with hematologic malignancies than those with solid tumors, including 
gastrointestinal disorders (77% versus 61%, respectively), general disorders and administration site 
conditions (74% versus 57%, respectively), blood and lymphatic system disorders (43% versus 24%, 
respectively), infections and infestations (39% versus 13%, respectively), and skin and subcutaneous 
tissue disorders (29% versus 13%, respectively).  Although the incidence of AEs was higher among 
subjects with hematologic malignancies than in subjects with solid tumors, the particular types of AEs 
reported were generally similar by indication.   
Overall, the incidence of Grade 3 or greater AEs among subjects who received romidepsin monotherapy 
was higher among these with hematologic malignancies (227 of 353 subjects; 64%) than among those 
with solid tumors (235 of 428 subjects; 55%).  As was the case for AEs overall, the particular types of 
Grade 3 or higher AEs reported were generally similar by indication.   
 
7.2.2.2 Summary of SAEs 
The incidence of SAEs, regardless of relationship to romidepsin, among subjects receiving romidepsin 
monotherapy was similar among those with hematologic malignancies and solid tumors (37% versus 
34%, respectively). Furthermore, the SAE profile was generally similar between subjects with 
hematologic malignancies and solid tumors.  Among the 353 subjects receiving romidepsin monotherapy 
with hematologic malignancies, the most commonly reported SAEs included pyrexia (21 subjects; 6%), 
neutropenia (including the MedDRA preferred terms (PT) neutrophil count decreased and neutrophil 
count) (16 subjects; 5%), thrombocytopenia (including the MedDRA PT (s) platelet count decreased and 
platelet count) (16 subjects; 5%), hypotension NOS (12 subjects; 3%), and dehydration and febrile 
neutropenia (11 subjects each; 3%).  Among the 428 subjects receiving romidepsin monotherapy with 
solid tumors, the most commonly reported SAEs were vomiting NOS (26 subjects; 6%), nausea 
(24 subjects; -6%), dyspnea (17 subjects; 4%), anemia (including the MedDRA PT(s) hemoglobin 
decreased and hemoglobin) (15 subjects; 4%), and dehydration and fatigue (12 subjects each; 3%). 
Three deaths occurred among patients with CTCL while on study, and three deaths occurred within 30 
days of removal from study. Those who died on study one had hypertrophic cardiac disease with 
significant valvular pathology but no evidence of acute infarction or myocyte injury. Two patients died 
from sepsis 10 and 12 days after administration of romidepsin, one patient with Escherichia coli and 
another with methicillin-resistant Staphylococcus aureus. Each of the three patients who died within 30 
days of study removal had been removed as a result of progression of disease and died after receiving 
cytotoxic chemotherapy[4]. 
Additional data on the most commonly reported SAEs is available in the investigator brochure. 
7.2.2.3  Cardiovascular Effects  
There have been reports of cardiovascular effects of HDAC inhibitors including an effect on QTc 
prolongation18,19,20 Data on File with Celgene Corporation 2006. Several treatment-emergent 
morphological changes in ECGs (including T wave and ST-segment changes) have been reported in 
clinical studies with romidepsin.  Many of these ECG morphologic abnormalities were determined by 
automated machine readings and were also observed at baseline.  These ECG changes were transient and 
were not associated with functional cardiovascular changes or with symptoms.  No cardiac events of 
torsade de pointes have been reported.  A comprehensive evaluation of the cardiac effects of romidepsin, 
including rigorous statistical analyses that followed the guidelines specified in International Conference 


 
 
36 
 
on Harmonisation (ICH) E14, was performed under the direction of an expert cardiologist.  Analyses 
performed were primarily based on data from 3 clinical studies of romidepsin:  Study GPI-04-0001 in 
subjects with CTCL; NCI Study 1312 in subjects with CTCL, PTCL, or other T-cell lymphomas; and 
Study GPI-06-0005 in subjects with advanced solid tumors or hematologic malignancies.   
A series of analyses were performed on the pool of studies as well as on individual study data to assess 
the impact of romidepsin on QTc prolongation, and, for Studies GPI-04-0001 and GPI-06-0005, to 
determine the potential confounding impact on this parameter of antiemetics given prior to romidepsin.  
In an analysis of the romidepsin concentration-QTc relationship based on data from 110 subjects in 3 
clinical studies, a mean 2.7 msec increase (90% confidence interval [CI] upper bound 5.3 msec) in QTcF 
interval was measured following infusion of romidepsin when compared to baseline post-antiemetic 
administration.  The reported increase in QTcF interval was a mean 5 msec (90% CI upper bound 7.7 
msec) in a subanalysis from Studies GPI-04-0001 and GPI-06-0005 (n=74), comparing QTc interval pre-
antiemetic administration to post-infusion.  Data from NCI Study 1312 shows that this QTcF change 
persists to 24 hours, with a return to baseline by 48 hours, while in the smaller GPI-06-0005 study, QTcF 
peaked 2 hours post-infusion and there was no QTcF effect seen at 24 hours.  Based on these analyses, it 
was concluded that a significant portion of the change in QTcF was associated with anti-emetic 
administration. 
In all studies, mean HR was shown to increase by approximately 10 bpm after study drug administration, 
with a return to baseline by 24 hours.  This rise in HR and the resulting deficiencies in standard QT heart 
rate correction formulae likely contribute to an artifactual calculation in the change in the QTc interval 
when compared to baseline.  Pharmacodynamic models, where the predominant effect seen was related 
to HR, with no evidence of a concentration – QTc relationship, support this hypothesis. 
Shift tables showed that, in this disease population, evidence of morphologic ECG abnormalities existed 
at baseline.  In addition, the frequency of treatment emergent abnormalities was similar to the frequency 
of abnormal to normal transitions, particularly between dosing days.  ECG changes were not associated 
with functional impairment. 
Per current ICH E14 guidelines, the findings from these studies show that the QTc changes are below the 
regulatory threshold of concern, particularly considering that these studies were conducted in a target 
population of generally older subjects with advanced malignancies, often with significant comorbidities 
and concomitant medication usage. Notably, there were no absolute QTc values greater than 480 msec, 
no increases of ≥ 60 msec and no cardiac events of torsade de pointes.  One subject had a ventricular 
arrhythmic event, but also had evidence of intracardiac lymphoma.  Therefore, based upon these data, 
romidepsin does not have a significant effect on the QT interval.  There is a mild effect on HR that is no 
longer apparent 20 hours after study drug administration.  Due to this effect on HR, there may be an 
artifactual change in the QTc interval due to the inherent inadequacy of correction formulae as the HR 
moves away from 60 bpm.  In addition, there does appear to be a transient change in the T-wave / ST-
segment in some subjects that may affect the precise determination of the T-wave in a clinical setting.  
After the data cutoff date for this protocol introduction, a single report of QTc prolongation to a maximum 
value of 534 msec, from a minimum baseline value of 437 msec, has been reported from a subject in a 
clinical study of romidepsin and bortezomib for multiple myeloma.  The event was reported as possibly 
related to romidepsin and unlikely related to bortezomib.  The subject had also received ondansetron, 
which has been reported to prolong QTc. 
7.2.2.4  Efficacy in Humans 
To date more than 870 subjects have received romidepsin in clinical trials.  Antitumor activity has been 
observed in both solid and hematologic tumor types.  


 
 
37 
 
CTCL 
The activity of romidepsin was evaluated in a total of 135 evaluable subjects (EP) with CTCL in Study 
GPI-04-0001 and NCI Study 1312.  Across all 135 evaluable subjects with CTCL, the overall response 
rate (ORR) was 41% (55/135) and the complete response (CR) rate was 7% (10/135).  Subjects with 
advanced disease had a similar ORR as subjects with earlier stage disease: 42% for ≥Stage IIB and 38% 
for Stage I or IIA disease.  Romidepsin was active in all sites of disease, including skin, lymph nodes, 
viscera, and blood.  The median duration of response was 454 days (14.9 months).  Although the median 
time to response was 57 days (1.9 months), in some cases an objective response to romidepsin was 
achieved after ≥6 months.  Across all 135 subjects included in the pooled EP Analysis Set, median time 
to disease progression was 252 days (8.3 months).  In Study GPI-04-0001, treatment alleviated pruritus 
in most subjects (48 of 52, 92%) who entered the study with this symptom. 
PTCL and other T-cell Lymphomas 
The activity of romidepsin was evaluated in a Phase 2, NCI-sponsored study in 48 subjects with PTCL 
or other T-cell lymphomas.  Of these 48 subjects, 28 had PTCL and 20 had other T-cell lymphomas, 
including angioimmunoblastic, primary cutaneous large T-cell, gamma-delta T-cell, and anaplastic large 
T-cell lymphomas17. 
Among all 48 subjects, the ORR (CR+PR) was 31% (15/48).  The CR and PR rates were 8% (4/48) and 
23% (11/48), respectively.  Fifteen percent (15%; 7/48) of subjects experienced stable disease.  When 
response was evaluated among the 34 subjects who received 2 cycles of therapy, the ORR was 44% 
(15/34) and the CR and PR rates were 12% (4/34) and 32% (7/34), respectively.  Twenty-one percent 
(7/34) of subjects who received 2 cycles of therapy experienced stable disease. 
Solid Tumors 
The activity of romidepsin in combination with gemcitabine has been evaluated in a Phase 1, study in 33 
subjects with pancreatic cancer and other solid tumors (breast, lung, ovarian, and other).  Overall, 45% 
(15/33) experienced stable disease. Of these 15 subjects, 12 experienced stable disease for >4 cycles, 
including 5 subjects with pancreatic cancer, 4 with breast cancer, and 1 each with NHL and ovarian and 
ampullary cancer. 
Complete and updated adverse events are available in the Investigational Drug Brochure and the IND 
Safety Letters. 
 
7.2.2.5 Discontinuations 
 
Sixteen patients developed progression of disease; seven patients withdrew from study, mainly to seek 
alternative therapy; two patients withdrew as a result of adverse events of infection and fatigue, and three 
patient died on study (discussed earlier). Progression of disease without evidence of response was noted 
in fifteen patients [4].  
7.2.2.6 Dose Modifications 
 
Protocol-mandated dose reductions were required for 42 doses in 20 patients for the following reasons: 
33 dose reductions were a result of thrombocytopenia (> 50 but < 75 x 109/L), four were a result of 
granulocytopenia (> 0.5 but < 1 x 109 cells/L), three were a result of persistent nausea, and two were a 
result of fatigue. The remainder of the doses less than 14 mg/m2 (n = 208) were administered as permanent 
dose reductions in patients who previously had a dose held or had one or more protocol-mandated dose 
reductions [4].  


 
 
38 
 
 
 
7.3  
Adverse Event Characteristics  
 
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.   A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
web site (http://ctep.cancer.gov). 
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.2 above) for expedited 
reporting purposes only.   
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.4 
Expedited Adverse Event Reporting 
 
The Principal Investigator agrees to provide appropriate parties with copies of all serious adverse 
experiences*, within two working days.  Additionally, the Principal Investigator agrees to report any 
pregnancy occurring in association with use of a oral 5-azacitidine and romidepsin to the appropriate 
parties.  
 
Expedited reporting by investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in writing using 
a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of being aware of the 
event.  The written report must be completed and supplied to Celgene by facsimile within 24 hours/1 
business day.  The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s), if available.  Information not available 
at the time of the initial report (e.g., an end date for the adverse event or laboratory values received after 
the report) must be documented on a follow-up report.  A final report to document resolution of the SAE 
is required.  The Celgene tracking number (RM-NHL-PI-0010) and the institutional protocol number 
should be included on SAE reports (or on the fax cover letter) sent to Celgene.  A copy of the fax 
transmission confirmation of the SAE report to Celgene should be attached to the SAE and retained with 
the patient records. 
 
 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax:   
(908) 673-9115 
E-mail: 
drugsafety@celgene.com 


 
 
39 
 
 
Report of Adverse Events to the Institutional Review Board 
Reportable information should always be reported by the PI directly to the IRB within 5 working days 
from when the PI learns of the event or new information.   
  
Investigator Reporting to the FDA 
The investigator is responsible for reporting any SAEs to the FDA.  Serious adverse events (SAEs) that 
are unlisted/unexpected, and at least possibly associated to the drug, and that have not previously 
been reported in the Investigators brochure, or reference safety information document should be reported 
promptly to the Food and Drug Administration (FDA) by telephone (1-800-332-1088), fax (1-800-FDA-
0178), or via MedWatch Online.  Fatal or life threatening SAEs that meet the criteria for reporting to the 
FDA must be reported to the FDA within 7 calendar days after awareness of the event.  All other SAEs 
that meet the criteria for reporting to the FDA must be reported to the FDA within 15 calendar days after 
awareness of the event.  A clear description of the suspected reaction should be provided along with an 
assessment as to whether the event is drug or disease related.    
 
Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following information: 
 
• 
Any AE associated with the use of drug in this study or in other studies that is both serious and 
unexpected. 
• 
Any finding from tests in laboratory animals that suggests a significant risk for human subjects 
including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected AE(s) or 
significant risks to subjects. 
 
The Investigator must keep copies of all AE information, including correspondence with Celgene and the 
IRB/EC, on file (see Section 11.4 for records retention information). 
 
7.4.1    
Expedited Reporting Guidelines  
 
Note:  All deaths on study require expedited reporting regardless of causality.  Attribution to 
treatment or other cause must be provided. 
 
• 
Expedited AE reporting timelines defined: 
➢ “1 business day; 5 calendar days” – The investigator must initially report the AE within 1 
business day of learning of the event followed by a complete report within 5 calendar days 
of the initial 24-hour report. 
➢ “10 calendar days” - A complete report on the AE must be submitted within 10 calendar 
days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions.   
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported if the event occurs following treatment. 


 
 
40 
 
 
7.4.2 
Protocol-Specific Expedited Adverse Event Reporting 
 
Exclusions 
 
For this protocol, certain AEs/grades are exceptions to the Expedited Reporting Guidelines and do not 
require expedited reporting.  The following AEs must be reported through the routine reporting 
mechanism (Section 7.4): 
 
Table 8: CTCAE AE Reporting Exclusions 
 
 
CTCAE 
Cat
ego
ry 
 
Adverse Event 
 
Grade 
Hospitalization/ 
Prolong
ation of 
Hospital
ization 
 
Attribution 
Blood/Bone 
Ma
rro
w 
Neutropenia <7 
days 
without 
fever 
4 
No 
Yes 
Blood/ Bone 
Ma
rro
w 
Thrombocyotope
nia <7 
days 
without 
bleeding 
4 
No 
Yes 
 
7.5 
 
Pregnancy on Study 
 
Both Oral 5-azacitidine and Romidepsin can cause fetal harm when administered to a pregnant woman.  
There are no adequate and well-controlled studies of either agent in pregnant women. 
 
Women of child bearing potential will be advised to avoid becoming pregnant while receiving 
treatment with either Oral 5-azacitidine, Romidepsin or the combination .  Women enrolled in this 
study should either be post-menopausal, free from menses for > 2 years, surgically sterilized, or willing 
to use 2 adequate barrier methods of contraception to prevent pregnancy or agree to abstain from 
heterosexual activity throughout the study, starting with visit 1.  Women of child-bearing potential must 
have a negative serum pregnancy test (-hCG) within 72 hours prior to receiving the first dose of 
romidepsin.  Men enrolled in the study must also agree to an adequate method of contraception for the 
duration of the study. 
If a patient or their partner inadvertently becomes pregnant while on study, the patient will immediately 
be removed from the study and the drugs will be discontinued. Investigators will follow the patient 
monthly and document the patient’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to Appropriate parties within 24 hours if the outcome is a 
serious adverse event (i.e. death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). If a male patient’s partner becomes pregnant on study, the 
pregnancy will be reported to appropriate parties. Reporting of pregnancy will follow the guidelines 
outlined in Section 7.4. 
 
Pregnancies 
Pregnancy of a female subject or the female partner of a male subject occurring while the subject is on 
romidepsin or within 4 weeks after the subject’s last dose of romidepsin are considered expedited 


 
 
41 
 
reportable events.  If the subject is on romidepsin, it is to be discontinued immediately.  The pregnancy 
must be reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the 
pregnancy by phone and facsimile using the SAE Form. 
 
The Investigator will follow the pregnant female until completion of the pregnancy, and must notify 
Celgene Drug Safety of the outcome as specified below.  The Investigator will provide this information 
as a follow-up to the initial SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the procedures for 
Expedited Reporting of SAEs to Celgene (i.e., report the event to Celgene Drug Safety by facsimile 
within 24 hours of the Investigator’s knowledge of the event). 
 
In the case of a live “normal” birth, Celgene Drug Safety should be advised as soon as the information 
is available. 
 
7.6 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.   
 
For 30 days subsequent to study completion or withdrawal, new onset adverse events will be captured.  
Follow up of these events will follow the same procedure as described above for AEs observed during 
the study period. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial agents 
administered in this study can be found in Section 7.2. 
 
8.1 
Oral 5-azacitidine 
 
Product description:  
Vidaz® (5-AZA for injectable suspension) contains AZA, which is a pyrimidine nucleoside analog of 
cytidine.  It has the following chemical structure: 
 
Chemical Structure of Azacitidine 
 
 
 
 
 
Azacitidine is 4-amino-1-â-D-ribofuranosyl-s-triazin-2(1H)-one. The empirical formula is 
C8H12N4O5. The molecular weight is 244.  


 
 
42 
 
 
Azacitidine is a white to off-white solid. Azacitidine was found to be insoluble in acetone, ethanol, and 
methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene 
glycol; sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methyl-2-
pyrrolidone, normal saline and 5% Tween 80 in water; and soluble in dimethylsulfoxide (DMSO). 
 
The finished product is supplied in a sterile form for reconstitution as a suspension for subcutaneous 
injection or reconstitution as a solution with further dilution for intravenous infusion. Vials of 
VIDAZA® contain 100 mg of azacitidine and 100 mg mannitol as a sterile lyophilized powder. 
 
Solution preparation: 
Reconstitute the number of azacitidine vials to achieve the desired dose. Reconstitute each vial with 10 
mL sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved.  The resulting 
solution will contain azacitidine 10 mg/ml.  The solution should be clear. Parenteral drug product should 
be inspected visually for particulate matter and discoloration prior to administration, whenever solution 
and container permit. 
Withdraw the required amount of azacitidine solution to deliver the desired dose and inject into a 50-100 
mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer’s Injection.  Unused 
portions should be properly discarded.  
 
Intravenous Solution Incompatibility 
Azacitidine is incompatible with 5% dextrose solutions, Hespan or solutions that contain bicarbonate. 
These solutions have the potential to increase the rate of degradation of azacitdine and should be avoided. 
 
Storage requirements:   
Store unreconstituted vials at 25º C (77º F); excursions permitted to 15º-30º C (59º-86º F) (See USP 
Controlled Room Temperature).  There is no need to protect azacitidine from exposure to light. 
 
 
 
Stability:   
Azacitidine reconstituted for intravenous administration may be stored at 25º C (77 º F), but 
administration must be completed within 1 hour of reconstitution.  Unused portions should be properly 
discarded.  
 
Administration 
Azacitadine solution should be administered intravenously. Administer the total dose over a period of 10-
40 minutes.  The administration must be completed with 1 hour of reconstitution of the azacitidine vial. 
Unused portions should be properly discarded.  
 
8.2 
Romidepsin  
 
Romidepsin is a unique bicyclic depsipeptide originally isolated from Chromobacterium violaceum 
strain 968.7  Romidepsin is an antineoplastic agent that has been identified as a novel HDAC inhibitor.  
Romidepsin has been shown to induce hyperacetylation of histones and other nonhistone protein 
species resulting in a variety of phenotypic changes, induction of the upregulation of gene transcription, 
G1 and G2/M arrest of the cell cycle, morphological reversion of transformed cells, cell growth 
inhibition, apoptotic cell death, and inhibition of angiogenesis. 
 


 
 
43 
 
Figure 2: Chemical Structure 
 
The molecular formula of romidepsin is C24H36N4O6S2, its molecular weight is 540.71, and its chemical 
name is: (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methyletheyl)-2-oxa-12,13-dithia-5,8,20,23-
tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone. 
 
Mechanism of Action 
Romidepsin is a unique bicyclic depsipeptide originally isolated from Chromobacterium violaceum strain 
968.[7] Results of early nonclinical studies showed that romidepsin inhibited the growth of the Ha-ras-
transformed NIH3T3 clonal cell line, Ras-1, and induced reversion of the transformed morphology to 
normal within 1 day at a concentration of 2.5 ng/mL.[8] While mRNA expression of the c myc oncogene 
in Ras-l cells was decreased in the presence of romidepsin, Ha-ras mRNA expression was unaffected by 
24-hour exposure to 2.5 ng/mL of romidepsin. Romidepsin blocked cell cycle transition from G0/G1 to 
S phase and induced nuclear quiescence. The course of c-myc suppression paralleled that of G0/G1 arrest 
and correlated with the morphologic reversion of the transformed cells. These results led to the proposal 
that the growth inhibition and G0/G1 arrest resulted from romidepsin blocking the ras-mediated signal 
transduction pathway.[9] Other investigations of the effect of romidepsin on G1 to S transition of the cell 
cycle showed that romidepsin inhibits signal transduction through MAP kinase and causes p53- 
independent G1 arrest.[10] Romidepsin has also been identified as a histone deacetylase (HDAC) 
inhibitor similar to trichostatin A based on its ability to cause arrest of the cell cycle at both G1 and G2/M 
phases,  to induce internucleosomal breakdown of chromatin, and to inhibit intracellular HDAC activity 
resulting in an accumulation of marked amounts of acetylated histone species within M 8 cells.[11] 
 
In both in vitro and in vivo systems, romidepsin has been shown to elicit a range of biological activities, 
including HDAC inhibition, induction or repression of gene expression, cell cycle arrest, differentiation, 
cell growth inhibition, apoptotic cell death, morphological reversion of transformed cells, and inhibition 
of angiogenesis.15  The manner in which romidepsin and other HDAC inhibitors exert their biological 
effects has not been fully elucidated.  The current view is that these agents inhibit, to a greater or lesser 
extent, the activity of Class I (HDACs 1, 2, 3, 8), Class II (HDACs 4, 5, 6, 7, 9, 10), and Class IV 
(HDAC 11) HDACs, causing chromatin remodeling and altered gene expression, which results in 
biological effects that are deleterious to tumor cell growth and survival.  There is a growing body of 
evidence that HDAC inhibitors can also target substrates other than histones and that the posttranslational 
modification of cellular proteins by acetylation may play an important role in the biological activities of 
HDAC inhibitors.16  
Product description:   
ISTODAX® (Romidepsin) is a histone deacetylase (HDAC) inhibitor indicated for the treatment of 
cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. 
 
NH
O
HN
HN
HN
H3C
O
CH3
O
CH3
CH3
O
CH3
O
S
S
O
H
H
H
H


 
 
44 
 
Solution preparation: 
Romidepsin is supplied as a kit including a sterile, lyophilized powder in a single-use vial containing 10 
mg of romidepsin and 20 mg of the bulking agent, povidone, USP. In addition, each kit includes one 
sterile Diluent vial containing 2 mL (deliverable volume) of 80% propylene glycol, USP, and 20% 
dehydrated alcohol, USP. 
 
NDC 46026-983-01: ISTODAX® KIT containing 1 vial of romidepsin, 10 mg and 1 vial of diluent for 
romidepsin, 2 mL per carton 
 
Storage requirements:  
 
The dual pack is to be stored at 20 to 25ºC (68 to 77°F), excursions permitted between 15 to 30°C (59 to 
86°F) [USP controlled room temperature].Romidepsin (for infusion) is stable for at least 36 months at 
25°C/60% relative humidity (RH) as well as for 6 months at 40°C/75% RH and is stable against heat (for 
3 months at 50°C) and humidity (for 3 months at 25°C/83% RH).  The drug should be reconstituted by 
appropriately trained personnel using aseptic technique.  A volume of 2 mL of reconstitution diluent is 
added to the lyophilized powder and swirled until contents of the vial are free from visible particles.  The 
reconstituted product stock solution at 5 mg/mL is chemically stable for at least 8 hours at room 
temperature.  However, whenever possible, drug should be prepared within 4 hours of dose 
administration. A volume of the 5 mg/mL stock solution containing the appropriate dose for the patient 
will be diluted in 0.9% Sodium Chloride Injection, USP (0.9% saline) for intravenous infusion, as 
directed by the protocol.  This dilution should result in a final drug concentration within the demonstrated 
stability range of 0.02 to 0.16 mg/mL for reconstituted romidepsin, that is compatible with polyvinyl 
chloride (PVC), ethylene vinyl acetate (EVA), and polyethylene (PE) intravenous infusion bags; glass 
bottles may also be used.  The romidepsin infusion solution is chemically stable for at least 24 hours at 
room temperature.  However, whenever possible, drug should be prepared within 4 hours of dose 
administration. 
Administration 
Romidepsin should be handled in a manner consistent with recommended safe 
procedures for handling cytotoxic drugs.  
 
The lyophilized, sterile finished product contains romidepsin, 10 mg/vial and 20 mg/single use vial 
Povidone, USP, and hydrochloric acid to adjust pH.  Romidepsin (for infusion) is supplied in a dual-pack 
configuration with a single use Diluent for Romidepsin vial that contains 2 mL of 80% Propylene Glycol, 
USP, and 20% Dehydrated Alcohol (ethanol), USP; sterile for use in reconstitution of Romidepsin (for 
Infusion).  
Romidepsin must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium 
Chloride Injection, USP before intravenous infusion.  
• Each 10 mg single-use vial of romidepsin must be reconstituted with 2 mL of the supplied Diluent. 
With a suitable syringe, aseptically withdraw 2 mL from the supplied Diluent vial, and slowly inject 
it into the romidepsin for injection vial. Swirl the contents of the vial until there are no visible 
particles in the resulting solution. The reconstituted solution will contain the romidepsin 5 mg/mL. 
The reconstituted the romidepsin  solution is chemically stable for at least 8 hours at room 
temperature.  
• Extract the appropriate amount of the romidepsin from the vials to deliver the desired dose, using 
proper aseptic technique. Before intravenous infusion, further dilute the romidepsin in 500 mL 0.9% 
Sodium Chloride Injection, USP. 


 
 
45 
 
• Infuse over 4 hours. 
 
The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), 
polyethylene (PE) infusion bags as well as glass bottles, and is chemically stable for at least 24 hours 
when stored at room temperature. However, it should be administered as soon after dilution as 
possible. 
 
  Please refer to the FDA approved package insert for further information[27].  
Supplier(s) 
Celgene Corporation will supply ISTODAX® (romidepsin) to study participants at no charge. 
 
Allos Therapeutics will supply Oral 5-azacitidine to study participants at no charge 
 
3.3.3 Non-Clinical Studies 
Potent antitumor effects of romidepsin have been demonstrated both in vitro and in vivo.[7,12] In vitro, 
romidepsin exerted antiproliferative activity against 12 human solid tumor cell lines (IC50 ranged from 
0.5 to 5.9 nM), but was less potent against cultured normal cells. It was found that the longer the duration 
of romidepsin exposure, the lower the concentration of drug necessary to induce the antiproliferative 
activity. Similar IC50 values were found in a study of 13 lymphoid cell lines.[15] In a severe combined 
immunodeficiency disease (SCID) mouse lymphoma model, male mice inoculated intraperitoneally (IP) 
with U-937 cells and treated with romidepsin (0.1 to 1 mg/kg, IP) once or twice a week survived longer 
[median survival times of 30.5 days (0.56 mg/kg) and 33 days (0.32 mg/kg)], than saline-treated mice 
(20 days).[14] Two of 12 mice treated with 0.56 mg/kg romidepsin survived past the observation period 
of 60 days. 
Romidepsin Monotherapy 
As of 31 December 2008, a total of 781 subjects received at least one dose of romidepsin as monotherapy, 
including 353 subjects with hematologic malignancies and 428 subjects with solid tumors.  The 
population of 428 subjects with solid tumors includes 26 pediatric subjects treated with romidepsin in 
NCI Study ADVL0212. 
 
8.3 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, 
will maintain a careful record of the inventory and disposition of all agents received from 
appropriate parties. 
 
9. Pharmacokinetic & Pharmacodynamic Studies 
 
9.1 
Pharmacokinetic Studies 
The pharmacokinetic studies are noted on Figure 1.  
 
 
9.2 
Pharmacodynamic Studies 
The pharmacodynamic studies are noted on Figure 1.  
 
9.2.1Biopsies (Optional) 
 


 
 
46 
 
The patient will have the option of checking off boxes within the main consent form for this study to 
indicate consent or denial for the following optional studies.   
 
A lymph node fine needle aspiration (FNA), core-needle biopsy or bone marrow biopsy will be performed 
prior to therapy and on between day 8 and 21 of cycle 1 after oral 5-azacitidine and romidepsin 
administration.  Fine needle aspirations will be performed as follows: 
 
Fine Needle Aspirations (FNA): A series of FNAs will be performed on palpable tumors in consenting 
patients as a function of drug exposure. 
 
In general, at least 6 aspirations will be made using a sterile 10 cc syringe over the larger volume of the 
palpable tumor. Once the needle is placed into the tumor, the plunger will be withdrawn and pushed 
several times to obtain a sufficient sample from that location. Once withdrawn from the tumor, the syringe 
will be flushed clean in 1-2 mL of RPMI. This procedure will be repeated up to 6 times in one tumor, 
flushing the syringe needle in the same 1-2 mL of RPMI. Previous experiences in mice have established 
that performing fewer than 6 aspirations on any given tumor is associated with irreproducible results. 
Once the samples are acquired, the cells will be centrifuged, and resuspended in 1 mL of RPMI.  
 
Correlations with the results of these studies will then be compared to the pharmacokinetic profile in 
order to establish the relationship with concentration, and the previous data obtained on the in vitro 
studies. 
 
Tumor Tissue Biopsies: The biopsies will be performed by a surgeon if necessary, or by interventional 
radiology.  A cytopathologist will evaluate the biopsy for tumor cells microscopically at the time of the 
biopsy.  If multiple lymph nodes are available, the safest lymph node will be selected. The choice of FNA 
versus biopsy will be made based on safety, accessibility, and likelihood of being pathologic.  A biopsy 
confirming recurrent or refractory disease is mandatory for participation in study.  The second FNA or 
biopsy is encouraged, but is not mandatory. Correlative studies will be performed on de-identified tissue 
samples. Tissue will be labeled only with the protocol-specific unique identifier. 
 
Bone Marrow Biopsy: a bone marrow aspirate and biopsy will be performed by the study team. 
 
9.2.2 
Handling of Specimens 
 
A frozen section will be performed to determine if there is lymphoma.  Thereafter, biopsies may be snap-
frozen or sent for tissue processing, and flagged for use in the protocol.  Paraffin blocks will be made to 
confirm histological diagnosis, and appropriate immunohistochemical staining will be performed.  
 
Remaining tissue will be used for the pharmacodynamic analysis.  
 
 
 
 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted as indicated in the table below, prior to start of protocol therapy.  
Scans must be done <4 weeks prior to the start of therapy.  In the event that the patient’s condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next 


 
 
47 
 
cycle of therapy. 
Cycle 
 
1      
2- onward 
 
 
 
 
Screening 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
 
Day 
1 
Day 
8 
Day 
15 
Day  
22 
 
End of 
treatment 
End of Study 
(4 weeks after 
last dose) 
Follow-upj 
Eligibility & Safety 
Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
Xe 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
Xe 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
Xe 
 
 
 
 
 
 
 
 
 
 
 
Concurrent 
Medications 
Xf  
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
Xf  
Xg 
X 
X 
X 
X 
 
 
 
X 
X 
X 
Vital Signs, weight 
Xf 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
Performance Status  
Xf 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
CBC w/ differential 
Xf 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistriesa, i 
Xf 
Xg 
 
 
 
X 
 
 
 
X 
X 
X 
EKG 
Xe 
 
X 
 
 
 
X 
 
 
X 
X 
 
Toxicity Assessment 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Serum -hCG 
Xf 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
Xe 
Xg 
 
 
 
 
 
 
 
 
 
 
Creatinine clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
Drug Dispensation 
 
 
 
 
 
 
 
 
 
 
 
 
Oral 5-azacitidine 
 
X 
 
 
 
X 
 
 
 
 
 
 
Romidepsin 
 
 
X 
X 
     X 
 
X 
X 
X 
 
 
 
Efficacy 
Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
CT (PET/CT 
optional) 
Xe 
 
 
 
 
 
Xb 
 
 
 
 
 
Brain MRI 
Xe, l 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow 
Biopsyk 
X 
 
 
 
 
 
 
 
 
Xc 
 
 
Lymph Node 
Assessment 
Xe 
 
 
 
 
 
 
 
 
 
 
 
PK/Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
Lymph Node Biopsy, 
FNA, or Bone 
Marrow Biopsy 
(Optional) 
Xe 
 
Xl 
 
 
 
 
 
 
 
 
 
PK 
 
Xd 
Xd 
 
 
X 
 
 
 
 
 
 
Correlative Blood 
Sample 
 
Xh 
Xh 
Xh 
Xh 
Xh 
 
 
 
 
 
 
a) Chemistries include: Chem *, Mg+, K+, Creatinine, Hepatic Function Panel (LFTs, bilirubin), and LDH.  On romidepsin days of cycles 2 and onward, full 
chemistries may be drawn, but only K+ and Mg+ are required. 
b) CT to occur after cycle 2 and 6, Then CT q3-6 months, until disease progression or initiation of new therapy at the discretion of the Investigator. (PET/CT is 
optional)  
c) Bone Marrow biopsy will be required after cycle 2 for patients with bone marrow involvement at baseline who have a complete response by imaging and physical 
exam 
d) PK  for Oral 5-azacitidine /Romidepsin:  See figure 1 for details. 
e) To be done within 4 weeks of treatment start date 
f) To be done within 1 week of treatment start date 
g) Not necessary if conducted within 72 hours of screening assessment 
h) PD  for Oral 5-azacitidine /Romidepsin:  See figure 1 for details. 
i) Sodium, potassium, chloride, calcium, and glucose are part of the electrolyte assessment at every time point.  Magnesium and phosphorous will be added to the 
electrolyte panel at Screening, and repeated before administration of romidepsin. 
j) Follow-up visits will be every 3 months for 1 year, or until the patient begins a new treatment for their disease for any patient that did not progressed on study.   
k) Based on clinical assessment 
l) For CNS disease only. Follow up MRI to be done at the discretion of the treating investigator. 
ALL SCHEDULED EVENTS +/- 3 DAYS 


 
 
46 
 
 
11. MEASUREMENT OF EFFECT 
 
The primary objective of this study is to evaluate the safety and tolerability of the study drugs.  The 
measurement of toxicity is outlined in Section 7. 
 
Although clinical response is not the primary endpoint of this trial, patients with measurable disease will 
be assessed by standard criteria.  Patients will be re-evaluated at the end of even numbered cycles. 
Response will be evaluated with physical exam, computerized tomography (CT) and tissue biopsies as 
defined by the guidelines of the International Harmonization Project Group 2007 Revised Response 
Criteria. [1] Positron emission tomography / computerized tomography (PET/CT) will be utilized if 
available (optional). MM patients will be evaluated using criteria described in section 11.2.2 
 
11.1 
Evaluation of response: 
 
For the phase I part of the study measurable disease will be utilized as the reference for response. For the 
phase II part of the study evaluable disease criteria will be utilized for response assessment.  
 
11.1.1 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity starting from Day 1 of Cycle 1. 
 
Evaluable for objective response.  Patients who have received at least one day of therapy, and have had 
their disease re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered. 
 
11.1.2 
Disease Parameters  
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in two 
dimension (longest diameter to be recorded) as >20 mm with conventional techniques (PET/CT, MRI, x-
ray) or as >10 mm with spiral CT scan.  All tumor measurements will be recorded in millimeters (or 
decimal fractions of centimeters).  Tumor volume will be recorded as the sum of the product of the 
diameters (SPD) of the largest predominant target lesions.  
 
FDG avidity is based on comparison with background tissues.  There is no specific SUV value that is 
considered a cut-off. 
 
Non-measurable disease (evaluable disease).  All other lesions (or sites of disease), including small 
lesions (<10 mm using spiral CT scan), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all 
non-measurable. 
 
Target lesions.  All measurable lesions up to a maximum of 6 lesions total, representative of all involved 
organs, should be identified as target lesions and recorded and measured at baseline.  Target lesions 
should be selected on the basis of their SUV avidity (High SUV lesions will be prioritized, even if not 
the largest lesions) and size (lesions with the largest SPD diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).  An SPD for all target lesions will 


 
 
47 
 
be calculated and reported as the baseline sum SPD.  The baseline sum SPD will be used as reference by 
which to characterize the objective tumor response based on CT criteria. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over and 
above the 6 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
 
11.1.3 
Methods for Evaluation of Measurable Disease in NHL 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 
1 week before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation 
by clinical examination when both methods have been used to assess the antitumor effect of a treatment. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by  
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
CT, PET/CT and MRI  These techniques should be performed with cuts of 10 mm or less in slice thickness 
contiguously.  Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm.  This 
applies to tumors of the chest, abdomen, and pelvis.  Head and neck tumors and those of extremities 
usually require specific protocols. 
 
Ultrasound (US) Will not be used for disease assessment 
 
11.2 
Response Criteria 
 
11.2.1 
Evaluation of Measurable Disease in NHL  
 
Table 10 outlines the response criteria used to evaluate disease response to therapy. 
 
 
 
 
Table 10 : Response Criteria for NHL 
Response 
Definition 
Nodal Masses 
Spleen/Liver 
Bone Marrow CR 
CR 
Disappearance of all 
evidence 
of disease 
a) FDG-avid or PET positive 
prior to therapy; mass 
of any size permitted if PET 
negative 
(b) Variably FDG-avid or PET 
negative; regression to 
normal size on CT 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared on 
repeat 
biopsy; if 
indeterminate 
by morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable 
disease and no new 
sites 
50% decrease in SPD of up to 6 
largest dominant 
masses; no increase in size of 
other nodes 
50% decrease in 
SPD of nodules 
(for 
single nodule in 
Irrelevant if positive 
prior 
to therapy; cell type 
should be specified 


 
 
48 
 
(a) FDG-avid or PET positive 
prior to therapy; one or 
more PET positive at previously 
involved site 
(b) Variably FDG-avid or PET 
negative; regression on CT 
greatest 
transverse 
diameter); no 
increase in size 
of 
liver or spleen 
SD 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET positive 
prior to therapy; PET 
positive at prior sites of disease 
and no new sites 
on CT or PET 
(b) Variably FDG-avid or PET 
negative; no change in 
size of previous lesions on CT 
 
 
Relapsed or 
PD 
Any new lesion or 
increase 
by   50% of 
previously 
involved sites from 
nadir 
Appearance of a new lesion(s)   
1.5 cm in any axis, 
  50% increase in SPD of more 
than one node, 
or   50% increase in longest 
diameter of a 
previously identified node   1 
cm in short axis 
Lesions PET positive if FDG-
avid lymphoma or PET 
positive prior to therapy 
50% increase 
from 
nadir in the SPD 
of 
any previous 
lesions 
New or recurrent 
involvement 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, 
computed tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, 
progressive disease. 
 
11.2.3 
Response Definitions 
 
Complete Response (CR): Disappearance of all non-target lesions by PET/CT 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a later 
time by the review panel (or Principal Investigator). 
 
11.2.4 
Evaluation of Best Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  The patient's best response assignment will depend on the achievement of 
both measurement and confirmation criteria. 
 
11.2.5     
Overall Response Rate 
 
Overall Response Rate (OR) = CR + PR based on evaluation of best response in each patient. 


 
 
49 
 
 
12.  
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse 
Events: List and Reporting Requirements). 
 
12.1 
 Data Reporting 
 
12.1.1 
Monitoring 
 
The Institutional Review Board (IRB) at Columbia University Medical Center will monitor this study. 
 
12.1.2 Responsibility for Data Submission 
 
The Study Coordinator is responsible for compiling data for all participants and for providing the data to 
the Principal Investigator for review.   
 
12.2  Data Safety Monitoring Board  
 
The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center’s 
Data Safety Monitoring Board (DSMB) will oversee conduct of the study, patient safety and all  
interim analyses as specified in the data analysis plan.  Detailed guidelines regarding the  
structure, function and decision-making mechanisms for the Data Safety Monitoring Board are  
provided in the DSMB charter. 
 
12.3 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
 
An IND is not needed for this study as both agents are commercially available. 
 
12.4  Study auditing 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and in the 
US Code of Federal Regulations. 
Investigators must enter study data onto CRFs or other data collection system.  The Investigator will 
permit study-related audits by Celgene or its representatives, IRB/EC review, and regulatory inspection(s) 
(e.g., FDA, EMEA, TPP), providing direct access to the facilities where the study took place, to source 
documents, to CRFs, and to all other study documents. 
 
12.5 
Protocol amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and reviewed by Celgene.  
Amendments should only be submitted to IRB/EC after consideration of Celgene review.  Written 
verification of IRB/EC approval will be obtained before any amendment is implemented.   
 
12.6 
Protocol deviations 
When an emergency occurs that requires a deviation from the protocol for a subject, a deviation will be 
made only for that subject.  A decision will be made as soon as possible to determine whether or not the 
subject (for whom the deviation from protocol was effected) is to continue in the study.  The subject’s 
medical records will completely describe the deviation from the protocol and state the reasons for such 
deviation.  In addition, the Investigator will notify the IRB/EC in writing of such deviation from protocol. 


 
 
50 
 
 
Non-emergency minor deviations from the protocol will be permitted with approval of the Principal 
Investigator.  
 
13.  
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/ Primary Endpoints 
Phase I 
This is an open label, single institution Phase I, 3-3 dose-escalation study.  The primary objective is to 
determine the MTD of oral 5-azacitidine in combination with romidepsin.  The safety and toxicity of this 
combination will be evaluated. 
 
All patients who receive any amount of drug will be available for toxicity. Adverse events will be 
graded using the NCI CTCAE v4.0. 
 
The dose escalation scheme will follow the guideline in Section 5.1.1. 
 
Toxicities will be described by intensity at each dose level 
 
Phase II 
Phase 2 will consist of the combination of oral 5-azacitidine + romidepsin in patients with PTCL.  (See 
figure 2 for study plan flow chart) 
 
Exploratory Cohort 
The Exploratory Cohort will be descriptive in nature. 
 
13.2 
Sample Size/Accrual Rate 
 
Phase I 
An estimated 36 patients (max of 45) will be accrued during dose escalation as outlined in Figure 2. Once 
the MTD is reached 9 further patients will be enrolled at the MTD dose.  
 
The MTD is defined as the level at which <1 out of 3 or ≤2 out of 6 patients have DLTs at highest dose 
level below the maximally administered dose. 
 
Phase II 
Once the initial phase is complete, the phase II will open to allow for a total accrual of 24 patients.  
 
We estimate accrual of an average of 4 patients per month, with a goal of completing accrual within 12 
months. 
 
Based on an optimal 2 - stage design, we can test the null hypothesis that the overall response rate is 
≤25% versus the alternative that the overall response rate is ≥50%. If the combination is actually not 
effective, there is a 0.049 probability of concluding that the combination is effective (target alpha = 0.05); 
if the combination is actually effective, there is a 0.2 probability of concluding that is ineffective (power 
= 80%).  With 9 patients treated in the first stage, if 2 or fewer patients have a response within a stratum, 
the trial will be terminated.  If the trial continues to the second stage, an additional 15 patients will be 
studied. If 9 or fewer patients respond by the end of the second stage, the combination will not be 
considered for further study. The total number of patients studied will be 24. The probability of early 


 
 
51 
 
stopping for this trial is 0.60. The expected sample size when the true response rate is 0.25 is 15. 
 
Exploratory Cohort 
A total of 10 patients with GC-derived lymphoma will be accrued.   
 
We estimate an average accrual of 1-2 patients per month, with a goal of completing accrual within 12 
months. 
 
13.3 
Analysis of Secondary Endpoints  
 
Phase I 
The maximum number of cycles will be described by dose level. 
 
The number of delays >7 days will be described at the MTD. 
 
ORR as defined by the guidelines of the International Harmonization Project Group 2007 Revised 
Response Criteria, and will be tabulated by dose level. (See Section 11.2.1.)  Response rates will be based  
on all patients who receive at least one day of medication. 
 
Phase II and Exploratory Cohort 
Primary Objective: To estimate ORR defined as best response by 4 cycles.  
 
Disease and patient characteristics at baseline will be summarized using descriptive statistics. For 
qualitative variables, frequency distributions and proportions will be provided; for quantitative variables, 
summary statistics (e.g., mean, median, quartiles, standard deviations, etc) and graphical displays (e.g., 
box plots).  Overall response rates will be estimated upon completion of the study along with exact 95% 
confidence intervals.  
 
 
 
 
 


 
 
52 
 
REFERENCES 
1. 
Cheson, B.D.,et al., Revised response criteria for malignant lymphoma.J Clin Oncol, 2007. 25(5):p.579-86. 
2. 
Jemal, A., et al., Cancer statistics, 2004. CA Cancer J Clin, 2004. 54(1): p. 8-29. 
3. 
Morton, L.M., et al., Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood, 2006. 
107(1): p. 265-76. 
4. 
Piekarz, R.L., et al., Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as 
monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol, 2009. 27(32): p. 5410-7. 
5. 
Malik, S., et al., FolotynTM (Oral 5-azacitidine Injection) for the Treatment of Patients with Relapsed or 
Refractory Peripheral T-Cell Lymphoma: Food and Drug Administration Drug Approval Summary. Clin Cancer 
Res, 2010. 
6. 
Jagannath,S.,M.A.Dimopoulos,and S.Lonial,Combined proteasome and histone deacetylase inhibition: A 
promising synergy for patients with relapsed/refractory multiple myeloma.Leuk Res,2010.34(9): p. 1111-8. 
7. 
O'Connor, O.A., et al., Phase II-I-II study of two different doses and schedules of oral 5-azacitidine, a high-affinity 
substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity 
in T-cell malignancies. J Clin Oncol, 2009. 27(26): p. 4357-64. 
8. 
DeGraw, J.I., et al., Synthesis and antitumor activity of 10-propargyl-10-deazaaminopterin. J Med Chem, 1993. 
36(15): p. 2228-31. 
9. 
Wang, E.S., et al., Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human 
lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression. Leuk Lymphoma, 2003. 
44(6): p. 1027-35. 
10. 
Kastrup, I.B., et al., Genetic and epigenetic alterations of the reduced folate carrier in untreated diffuse large B-
cell lymphoma. Eur J Haematol, 2008. 80(1): p. 61-6. 
11. 
Zain, J. and O. O'Connor, Oral 5-azacitidine: basic understanding and clinical development. Expert Opin 
Pharmacother, 2010. 11(10): p. 1705-14. 
12. 
Thompson, C.A., FDA approves oral 5-azacitidine for treatment of rare lymphoma. Am J Health Syst Pharm, 
2009. 66(21): p. 1890. 
13. 
Marchi, E., et al., Oral 5-azacitidine Is Synergistic with the Proteasome Inhibitor Bortezomib in In vitro and In vivo 
Models of T-Cell Lymphoid Malignancies. Clin Cancer Res, 2010. 16(14): p. 3648-58. 
14. 
Johnstone, R.W., Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov, 
2002. 1(4): p. 287-99. 
15. 
Marks, P., et al., Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer, 2001. 1(3): p. 194-202. 
16. 
Grunstein, M., Histone acetylation in chromatin structure and transcription. Nature, 1997. 389(6649): p. 349-52. 
17. 
Furumai, R., et al., FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer 
Res, 2002. 62(17): p. 4916-21. 
18. 
Piekarz, R.L. and S.E. Bates, Epigenetic modifiers: basic understanding and clinical development. Clin Cancer 
Res, 2009. 15(12): p. 3918-26. 
19. 
Bates, S.E., et al., Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T-cell 
lymphoma. Br J Haematol, 2010. 148(2): p. 256-67. 
20. 
Byrd, J.C., et al., Depsipeptide (FR901228): a novel therapeutic agent with selective, in vitro activity against 
human B-cell chronic lymphocytic leukemia cells. Blood, 1999. 94(4): p. 1401-8. 
21. 
Imesch, P., D. Fink, and A. Fedier, Romidepsin reduces histone deacetylase activity, induces acetylation of 
histones, inhibits proliferation, and activates apoptosis in immortalized epithelial endometriotic cells. Fertil Steril, 
2010. 
22. 
Woo, S., et al., Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and 
relapsed peripheral T-cell lymphoma. Clin Cancer Res, 2009. 15(4): p. 1496-503. 
23. 
Byrd, J.C., et al., A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia 
and acute myeloid leukemia. Blood, 2005. 105(3): p. 959-67. 
24. 
Klimek, V.M., et al., Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) 
in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clin Cancer Res, 2008. 
14(3): p. 826-32. 
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Piekarz R, W.J., Frye R, Results of a phase 2 NCI multicenter study of romidepsin in patients with relapsed 
peripheral T-cell lymphoma (PTCL) [abstract]. . ASH Annual Meeting Abstracts 2008, 2008. 112(1567). 
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Hartlapp, I., et al., Depsipeptide induces cell death in Hodgkin lymphoma-derived cell lines. Leuk Res, 2009. 33(7): 
p. 929-36. 
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StatBite: FDA oncology drug product approvals in 2009. J Natl Cancer Inst, 2010. 102(4): p. 219.  
 
 


 
 
53 
 
Appendix 1: Medications That May Cause QTc Prolongation 
 
The following table presents a list of drugs that may prolong the QTc.  These drugs are prohibited 
during the study.  Romidepsin may be administered after a 5 half-life washout period elapses following 
the use of these drugs.  Washout period is based on roughly 5 half-lives and rounded to a convenient 
interval. 


 
 
54 
 
Medications That May Cause QTc Prolongation 


 
 
55 
 
Compound 
(Brand Name) 
Compound Half-Life 
Possible 
Washout 
Period 
(Hours) 
Possible 
Washout 
Period 
(Days) 
Antiarrhythmics 
 
 
 
Amiodarone (Cordarone, Pacerone) 
58 days (15-142) 
36 days (active metabolite) 
 
180 
Disopyramide (Norpace, Norpace CR) 
6.7 hr (4-10) 
36 
 
Dofetilide (Tikosyn) 
10 hr 
48 
 
Flecainide (Tambocor) 
20 hr (12-27) 
 
5 
Ibutilide (Corvert) 
6 hr (2-12) (variable among patients) 
36 
 
Procainamide (Pronestyl, Procanbid, Procan) 
3-4 hr for PA and NAPA (active metabolite) 
24 
 
Quinidine (Quinaglute, Cardioquin, Quinidex) 
6-8 hr in adult; 3-4 hr in children 
36 
 
Sotalol (Betapace, Sorine) 
12 hr 
72 
 
Antibiotics 
 
 
 
Clarithromycin (Biaxin, Biaxin XL) 
Nonlinear PK 3-4 hr (250 mg Q12) 
5-7 hr (500 mg Q12) 
36 
 
Erythromycin (Benzamycin, Eyrc, E-glades, 
Erygel, E-solve 2, Akne-Mycin, Eryderm, Sansac, 
Erythro-Statin, Erymax, Staticin, T-Stat, 
C-solve-2, Erycetter, PCE, Ery-Tab, E-Mycin, E-
Base, E.E.S., Eryped, E.E.S 200, E.E.S 400, 
Pediamycin, Eryzole, Erythrocin) 
Each salt form has different half-life 
 
 
Gatifloxacin (Tequin, Tequin Teqpaq) 
7-14 hr 
48 
 
Grepafloxacin (Raxar) 
16 hr 
 
3 
Antibiotics (cont’d) 
 
 
 
Levofloxacin (Levaquin, Quixin, Elequin) 
6-8 hr 
48 
 
Moxifloxacin (Avelox, Vigamox) 
12 ± 1.3 hr 
72 
 
Sparfloxacin (Zagam) 
20 hr (16-30) 
 
4 
Telithromycin (Ketex) 
2-3 hr 
24 
 
Anticonvulsants 
 
 
 
Felbamate (Felbatol) 
20-23 hr 
 
5 
Fosphenytoin (Cerebyx) 
12-29 hr 
 
6 
Antidepressants 
 
 
 
Venlaflaxine (Effexor) 
5 ± 2 hr for parent comp. 
11± 2 hr for OVD (active metabolite) 
60 
 
Antidiarrheals 
 
 
 
Octreotide (Sandostatin) 
1.7 hr 
12 
 
Antiemetics 
 
 
 
Dolasetron (Anzemet) 
8.1 hr 
 
 
Droperidol (Inapsin) 
2.2 hr 
10 
 
Domperidone (Motilium) 
7-8 hr 
48 
 
Palonosetron (Aloxi) 
40 hr 
 
10 
Antihypertensives 
 
 
 
Moexipril/Hydrochlorothiazide (Uniretic) 
2-9 hr(include active metabolite) for moexipril; 
5.6-14.8 hr for HCTZ 
48 
 
Antimalarials 
 
 
 
Halofantrine (Halfan) 
6-10 days (variable among individuals) 
 
45 
Quinidine (Quinaglute, Cardioquin, Quinidex) 
6-8 hr in adult; 3-4 hr in children 
36 
 
Antimanics 
 
 
 
Lithium (Eskalith, Lithobid, Lithonate) 
24 hr (10-50) 
 
7 
Antineoplastics 
 
 
 


 
 
56 
 
Compound 
(Brand Name) 
Compound Half-Life 
Possible 
Washout 
Period 
(Hours) 
Possible 
Washout 
Period 
(Days) 
Arsenic trioxide (Trisenox) 
Not characterized 
 
 
Tamoxifen (Nolvadex) 
5-7 days (biphasic) 
 
30 
Antiprotozoals 
 
 
 
Pentamidine (NebuPent, Pentam) 
6.4 ± 1.3 hr 
36 
 
Antipsychotic agents 
 
 
 
Chlorpromazine (Thorazine) 
30 ± 7 hr 
 
7 
Haloperidol (Haldol) 
18 ± 5 hr 
 
5 
Mesoridazine (Serentil) 
24-48 hr (animal study) 
 
10 
Pimozide (Orap) 
55 hr 
 
14 
(Continued from previous page)  
 
 
 
Antipsychotic agents (cont’d) 
 
 
 
Quetiapine (Seroquel) 
6 hr 
36 
 
Risperidone (Risperdal, Risperdal Consta) 
3-20 hr (extensive to poor metabolizer) 
9-hydroxyrisperidone (active metabolite) T ½ = 
21-30 hr (extensive to poor metabolizer) 
 
4 
Thioridazine (Mellaril) 
20-40 hr (Phenothiazines) 
 
7 
Ziprasidone (Geodon, Zeldox) 
7 hr 
36 
 
Antispastics 
 
 
 
Tizanidine (Zanaflex) 
2.5 hr 
12 
 
Antivirals 
 
 
 
Amantadine (Symadine, Symmetrel) 
17 ± hr  (10-25) 
 
4 
Foscarnet (Foscavir) 
87.5 ±  41.8 hr 
(distribution and release from bone) 
 
20 
Analgesics 
 
 
 
Levomethadyl (Orlaam) 
Multiple compartment PK with active 
metabolite 
2.6 day for LAAM, 
2 day for nor-LAAM, 
4 day for dinor-LAAM 
 
20 
Asthma medications 
 
 
 
Salmeterol (Advair Diskus, Serevent, Serevent 
Diskus) 
5.5 hr (only one datum)  
36 
 
Calcium channel blockers 
 
 
 
Bepridil (Vascor) 
42 hr (26-64) 
 
10 
Isradipine (DynaCirc) 
8 hr (multiple metabolites) 
48 
 
Nicardipine (Cardene) 
~2 hr post IV infusion 
12 
 
Cholinergic enhancers 
 
 
 
Cisapride (Propulsid) 
6-12 hr, up to 20 hr 
60 
 
Diuretics 
 
 
 
Indapamide (Lozol) 
14 hr (biphasic elimination) 
 
3 
Immunosuppressants 
 
 
 
Tacrolimus (Prograf, Protopic) 
~34 hr in healthy patients ; ~19 hr in kidney 
transplant 
 
7 
Migraine medications 
 
 
 
Naratriptan (Amerge) 
6 hr 
36 
 
Sumatriptan (Imitrex) 
2.5 hr 
12 
 
Zolmitriptan (Zomig) 
2.8-3.7 hr (higher in female) 
18 
 
Narcotic pain relievers 
 
 
 


 
 
57 
 
Compound 
(Brand Name) 
Compound Half-Life 
Possible 
Washout 
Period 
(Hours) 
Possible 
Washout 
Period 
(Days) 
Methadone (Dolophine, Methadose) 
15-30 hr 
 
7 
 
 
Sedatives 
 
 
 
Chloral hydrate 
Readily converted to Trichloroethanol 
(active metabolite T½= 7-10 hour) 
48 
 
References: 
Physician’s Desk Reference 2002 
Facts and Comparisons (update to June, 2000) 
The Pharmacological Basis of Therapeutics 9th Edition, 1996 
 


 
 
58 
 
Appendix 2: Medications That May Inhibit CYP3A4  
 
The following table presents a list of drugs that may inhibit CYP3A4.  As romidepsin is predominately metabolized by 
CYP3A4, inhibition of this enzyme could result in elevated plasma levels or increased exposure to romidepsin.  Romidepsin 
may be administered after a 5 half-life washout period elapses following the use of these drugs. Washout period is based on 
roughly 5 half-lives and rounded to a convenient interval. 
 
Medications That May Inhibit CYP3A4 
Compound 
(Brand Names) 
Compound Half-
Life 
Possible 
Washout 
Period - Hours 
Possible 
Washout 
Period - Days 
Azole Antifungals 
 
 
 
Clotrimazole (Mycelex, Lotrimin, Lotrisone) 
Not available 
 
 
Ketoconazole (Nizoral, Ketozole) 
6 hr (2-8 hr) 
30 hr 
 
Itraconazole (Sporanox) 
21 hr 
 
5 days 
Fluconazole (Diflucan) 
3 hr 
15 hr 
 
Miconazole (Monistat) 
57 hr 
 
11 days 
HIV Protease Inhibitors 
 
 
 
Ritonavir (Norvir, Kaletra) 
4 hr 
20 hr 
 
Indinavir (Crixivan) 
2 hr 
10 hr 
 
Saquinavir (Invirase, Fortovase) 
5 hr 
25 hr 
 
Nelfinavir (Viracept) 
4 hr 
20 hr 
 
Delavirdine (Rescriptor) 
6 hr 
30 hr 
 
Macrolide Antibiotics 
 
 
 
Troleandomycin (Tao) 
Not available 
 
 
Erythromycin (Benzamycin, Eyrc, E-glades, Erygel, E-solve 2, Akne-
Mycin, Eryderm, Sansac, Erythro-Statin, Erymax, Staticin, T-Stat, C-
solve-2, Erycetter, PCE, Ery-Tab, E-Mycin, E-Base, E.E.S., Eryped, 
E.E.S 200, E.E.S 400, Pediamycin, Eryzole, Erythrocin) 
2 hr 
10 hr 
 
Clarithromycin (Prevpac, Biaxin) 
5 hr 
25 hr 
 
Other Antibiotics 
 
 
 
Chloramphenicol (Chloromycetin, Chloroptic) 
4 hr 
20 hr 
 
Ciprofloxacin (Ciprodex, Cipro, Ciloxan) 
4 hr 
20 hr 
 
Norfloxacin (Noroxin, Chibroxin) 
4 hr 
20 hr 
 
Serotonin Reuptake Inhibitors (SSRI’s) 
 
 
 
Fluoxetine (Prozac, Sarafem, Symbyax) 
Fluoxetine 5 days 
Norfluoxetine 
(active 
metabolite) 12 
days (4-16 days) 
 
60 days 
Nefazodone (Serzone) 
3 hr 
15 hr 
 
Fluvoxamine (Luvox) 
16 hr 
 
3 days 
Antiemetics 
 
 
 
Aprepitant (Emend) 
11 hr  
(9-13 hr) 
 
2 days 
Oral Contraceptives 
 
 
 
Ethinyl-estradiol (Kariva, Velivet, Mircette, Desogen, Cyclessa, Ortho-
Cept, Yasmin, Demulen, Zovia, NuvaRing, Seasonale, Lessina, Portia, 
Levlite, Nordette, Aviane, Enpresse, Trivora, Levora, Alesse, Triphasil, 
Ortho Evra,  Ovcon, Nortrel, Gencept, Balziva, Brevicon, Norinyl, 
Norethin, Aranelle, Ortho-Novum, Modicon, Tri-Norinyl, Femhrt, Junel, 
Loestrin, Estrostep, Microgestin, Tri-Previfem, Previfem,  Tri-Sprintec,  
Sprintec, Ortho Tri-Cyclen, Cryselle, Low-ogestrel, Ogestrel, Lo/Ovral, 
15 hr 
 
3 days 


 
 
59 
 
Compound 
(Brand Names) 
Compound Half-
Life 
Possible 
Washout 
Period - Hours 
Possible 
Washout 
Period - Days 
Ovral) 
Oral Contraceptives (cont’d) 
 
 
 
Mifepristone (Mifeprex, RU-486) 
18 hr 
 
4 days 
Gestodene 
20-22 hr 
 
5 days 
Histamine H2-Receptor Antagonists 
 
 
 
Cimetidine (Tagamet) 
2 hr 
10 hr 
 
Antiarrhythmic Drugs 
 
 
 
Quinidine (Quinaglute, Cardioquin, Quinidex) 
7 hr 
35 hr 
 
Amiodarone (Cordarone, Pacerone) 
53 days 
(15-142 days) 
 
265 days 
Antihypertensives 
 
 
 
Diltiazem (Taztia, Cartia, Cardizem, Dilt-CD, Dilacor, Teczem, Tiamate. 
Trizac) 
3 hr 
[7 hr for extended 
release (Trizac)] 
15 hr 
35 hrs 
 
Verapamil (Tarka, Verelan, Isoptin, Covera-HS, Calan) 
8 hr 
40 hr 
 
Calcium Channel Blocker 
 
 
 
Mibefradil (Posicor) 
21 hr 
(17-25 hr) 
 
5 days 
Others 
 
 
 
Grapefruit juice 
Not available 
 
 
Star fruit 
Not available 
 
 
 


 
 
60 
 
Appendix 3 Canadian Cardiovascular Society Angina Classification 
 
Class I 
Ordinary physical activity, (e.g., walking and climbing stairs) does not cause angina; angina occurs with 
strenuous, rapid, or prolonged exertion at work or recreation.  
Class II 
Slight limitation of ordinary activity; angina occurs on walking or climbing stairs rapidly; walking uphill; 
walking or stair climbing after meals, in cold, in wind, or under emotional stress; or only during the few 
hours after awakening; when walking > 2 blocks on level ground; or when climbing more than 1 flight of 
stairs at a normal pace and in normal conditions.   
Class III 
Marked limitation of ordinary physical activity; angina occurs on walking 1  to 2 blocks on level ground or 
climbing 1 flight of stairs at a normal pace in normal conditions.  
Class IV 
Inability to perform any physical activity without discomfort; anginal symptoms may be present at rest.  
Campeau L. Grading of angina pectoris. Circulation 1975;54:522-3. 
 
 


 
 
61 
 
Appendix 4  New York Heart Association Classification of Cardiac Disease 
 
NYHA Classification of Cardiac Disease 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of 
the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 1994:253-256. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
62 
 
Appendix 5: Hans Criteria 
 
 
 
 
Christine P. Hans et al. Blood 2004;103:275-282