A Phase 1 Study of Romidepsin, CC-486 (5-azacitidine), Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-cell Malignancies
Phase: PHASE1
Conditions: Cutaneous T-Cell Lymphoma, Mature T-cell Malignancies, Peripheral T-Cell Lymphoma, Relapsed/ Refractory T-cell Malignancies
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: RAdR for R/R TCM
Version Date:   12/04/2025
1
Abbreviated Title: RAdR for R/R TCM 
NIH Protocol #: 20C0127 
Version Date: 12/04/2025
NCT Number: NCT04447027
Title: A Phase 1 Study of Romidepsin, CC-486 (5-azacitidine), dexamethasone, and 
lenalidomide (RAdR) for relapsed/refractory T-cell malignancies
NCI Principal Investigator:
Max Gordon, M.D.
Lymphoid Malignancies Branch (LYMB)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
Building 10, Room 3B38
National Institutes of Health (NIH)
Bethesda, MD  20892
Phone:  240-858-7151
Email: max.gordon@nih.gov 
Drug Name:
Romidepsin
(ISTODAX®; 
Investigational 
Supply)
CC-486 
(5-azacitidine; 
Investigational 
Supply)
Lenalidomide
(Revlimid®; 
Investigational 
Supply)
Dexamethasone
IND Number:
147481
Sponsor:
CCR
Manufacturer:
Bristol Myers 
Squibb
Bristol Myers 
Squibb
Bristol Myers 
Squibb
Generic
Supplier
Bristol Myers 
Squibb
Bristol Myers 
Squibb
Bristol Myers 
Squibb
CC Pharmacy

Abbreviated Title: RAdR for R/R TCM
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PRÉCIS
Background:
•
Mature T-cell malignancies (TCM) are rare and heterogeneous group of leukemias and 
lymphomas accounting for 5 to 10% of all lymphomas in the US
•
Patients with systemic TCM are most commonly treated with a CHOP (cyclophosphamide, 
doxorubicin, vincristine and prednisone)-like regimens, that produce long-term 
progression-free survival in about 30% of these cases
•
Patients with relapsed/refractory (R/R) TCM have very poor prognosis with median overall 
survival of less than 1 year. Treatment options for R/R TCM are very few and of limited 
efficacy, thus novel treatment strategies are urgently needed. 
•
Mutations in epigenetic regulators are common in aggressive TCMs and standard treatment 
with histone deacetylase inhibitors (HDACi) such as romidepsin show modest clinical 
activity with single agent the overall response (ORR) around 25%
•
Combination of romidepsin and 5-azacitidine (hypomethylating agents) was synergistic in 
preclinical models, and has demonstrated high clinical activity with an ORR of 79%
•
Many TCMs rely on The Ikaros-dependent NF-kB/IRF4 signaling pathway to maintain 
proliferation, which is why lenalidomide, which induces degradation of Ikaros and 
downregulates IRF4, has single agent activity in R/R TCM with ORR of 26% to 42%, 
depending on the subtype.
•
Lenalidomide synergizes with romidepsin and enhances tumor cell death in TCM cell lines, 
predicting that the addition of lenalidomide to the established romidepsin/ CC-486 (5-
azacitidine) combination will further improve efficacy.
Objectives:
•
To determine the safety and toxicity profile and the maximum tolerated dose (MTD) of the 
four-drug combination of CC-486 (5-azacitidine), romidepsin, lenalidomide and 
dexamethasone in patients with TCM
Eligibility:
•
Refractory/relapsed TCM (excluding in Cutaneous T-Cell Lymphoma) defined as follows:
o
Patients with systemic disease
o
Have received at least one line of prior therapy 
o
Must have received brentuximab vedotin if the disease is anaplastic large cell 
lymphoma or CD30-positive cutaneous T-cell lymphoma
•
Age ≥ 18 years of age
•
ECOG performance status of ≤ 2 (or ≤ 3 if decrease is due to the disease)
•
Histologically or cytologically confirmed relapsed and/or refractory mature TCM
•
Adequate organ and marrow function
Design:
•
Open-label, single-center, uncontrolled Phase 1 study

Abbreviated Title: RAdR for R/R TCM
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•
 “3 + 3” design will be used to determine the MTD of dose-escalated lenalidomide with 
fixed dose of romidepsin and CC-486 (5-azacitidine)
•
An expansion cohort of 9 patients will be evaluated at the MTD
•
Maximum 6 cycles (28-day cycle) of combination therapy 
•
To explore all dose levels, including further evaluation in a dose expansion cohort, the 
accrual ceiling will be set at 30 patients

Abbreviated Title: RAdR for R/R TCM
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
o
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR 
Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.

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TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
STATEMENT OF COMPLIANCE ................................................................................................4
TABLE OF CONTENTS ................................................................................................................5
1
INTRODUCTION ...................................................................................................................9
1.1
Study Objectives ...............................................................................................................9
1.2
Background .......................................................................................................................9
1.3
Epigenetic regulatory genes in TCM ..............................................................................12
1.4
Role of IRF4 in TCM......................................................................................................13
1.5
Investigational agents......................................................................................................14
1.6
Clinical activities of investigational agents in T-cell Malignancies ...............................21
1.7
Synergistic effect of romidepsin and 5-azacitidine.........................................................23
1.8
Synergistic effect of romidepsin and lenalidomide.........................................................24
1.9
5-azacitidine in combination with lenalidomide.............................................................24
1.10
Rationale of combination of lenalidomide, romidepsin and CC-486 (oral 5-azacitidine)
24
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................26
2.1
Eligibility Criteria ...........................................................................................................26
2.2
Recruitment Strategies ....................................................................................................28
2.3
Screening Evaluation ......................................................................................................29
2.4
Participant Registration and Status update Procedures...................................................30
2.5
Treatment Assignment Procedures .................................................................................30
2.6
Baseline Evaluation.........................................................................................................31
3
STUDY IMPLEMENTATION .............................................................................................33
3.1
Study Design...................................................................................................................33
3.2
Dose Limiting Toxicity...................................................................................................35
3.3
Dose Escalation...............................................................................................................36
3.4
Drug Administration .......................................................................................................37
3.5
Dose Modification...........................................................................................................40
3.6
Protocol Stopping rule ....................................................................................................47
3.7
On Study Evaluations......................................................................................................47
3.8
Post-Treatment Evaluations ............................................................................................48

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3.9
Study Calendar................................................................................................................50
3.10
Cost And Compensation .................................................................................................54
3.11
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................54
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................55
4.1
Acceptable Medications..................................................................................................55
4.2
Concomitant Medications To Be Used With Caution ....................................................55
4.3
Prohibited Medications ...................................................................................................56
5
CorrelatIve Studies for research ............................................................................................57
5.1
Biospecimen Collection ..................................................................................................57
5.2
Blood Samples ................................................................................................................58
5.3
Tissue Samples................................................................................................................59
5.4
Other Samples.................................................................................................................60
5.5
Biomarker and Research Methods ..................................................................................60
5.6
Sample Storage, Tracking, and Disposition....................................................................62
5.7
Samples for Genetic/Genomic Analysis .........................................................................62
6
DATA COLLECTION AND EVALUATION .....................................................................62
6.1
Data Collection ...............................................................................................................62
6.2
Data Sharing Plans..........................................................................................................63
6.3
Response Criteria ............................................................................................................64
6.4
Toxicity Criteria..............................................................................................................67
7
NIH REPORTING REQUIREMENTS/ DATA SAFETY MONITORING PLAN .............67
7.1
Definitions.......................................................................................................................67
7.2
OHSRP Office Of Compliance And Training / IRB Reporting......................................67
7.3
NCI Clinical Director Reporting.....................................................................................67
7.4
NIH Required Data And Safety Monitoring Plan...........................................................68
8
SPONSOR PROTOCOL/ SAFETY REPORTING...............................................................68
8.1
Definitions.......................................................................................................................68
8.2
Assessment Of Safety Events .........................................................................................70
8.3
Reporting Of Serious Adverse Events ............................................................................70
8.4
Waiver Of Expedited Reporting To CCR.......................................................................70
8.5
Safety Reporting Criteria To The Pharmaceutical Collaborators ...................................71
8.6
Reporting Pregnancy.......................................................................................................71
8.7
Regulatory Reporting For Studies Conducted Under CCR-Sponsored IND..................71

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8.8
Sponsor Protocol Deviation Reporting ...........................................................................71
9
CLINICAL MONITORING..................................................................................................72
10
STATISTICAL CONSIDERATIONS ..................................................................................73
10.1
Statistical Hypothesis......................................................................................................73
10.2
Sample Size Determination.............................................................................................73
10.3
Population for Analysis...................................................................................................74
10.4
Statistical Analyses .........................................................................................................74
11
COLLABORATIVE AGREEMENTS..................................................................................75
11.1
Clinical Trials Agreement (CTA)- Celgene....................................................................75
12
HUMAN SUBJECTS PROTECTIONS................................................................................75
12.1
Rationale For Subject Selection......................................................................................75
12.2
Participation of Children.................................................................................................75
12.3
Participation of Subjects Unable to Give Consent..........................................................76
12.4
Evaluation of Benefits and Risks/Discomforts ...............................................................76
12.5
Risks/Benefits Analysis ..................................................................................................76
12.6
Consent Process and Documentation..............................................................................78
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................79
13.1
Study Discontinuation And Closure ...............................................................................79
13.2
Quality Assurance And Quality Control.........................................................................79
13.3
Conflict Of Interest Policy ..............................................................................................80
13.4
Confidentially and Privacy..............................................................................................80
14
PHARMACEUTICAL INFORMATION .............................................................................81
14.1
Romidepsin (DEPSIPEPTIDE, FK228, ISTODAX®)...................................................81
14.2
CC-486 (5-azacitidine)....................................................................................................82
14.3
Lenalidomide (Revlimid)................................................................................................83
14.4
Dexamethasone ...............................................................................................................85
15
REFERENCES ......................................................................................................................86
16
APPENDIX............................................................................................................................93
16.1
Appendix A:  Performance Status Criteria .....................................................................93
16.2
Appendix B:  Global Response Score and Definitions of Response in Skin, Lymph 
Nodes, Viscera, and Blood ........................................................................................................94
16.3
Appendix C:  CYP3A4 Inducers and Inhibitors .............................................................96

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16.4
Appendix D: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods for Lenalidomide..................................................................................97
16.5
Appendix E:  Medications That May Cause QTc Prolongation ...................................100
16.6
Appendix F:  Study Drug Diary....................................................................................105

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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
•
Determine the safety and toxicity profile and the maximum tolerated dose (MTD) of 
lenalidomide given as part of a four-drug combination treatment with romidepsin, CC-486 
(5-azacitidine) and dexamethasone to patients with mature T-cell malignancies (TCM).
1.1.2
Secondary Objectives
•
Evaluate the potential antitumor activity of the romidepsin, CC-486 (5-azacitidine) and 
lenalidomide combination by assessing the overall response rate (ORR), complete 
response (CR) rate, duration of response (DOR), progression-free survival (PFS), event-
free survival (EFS), and overall survival (OS).
1.1.3
Exploratory Objectives
•
Evaluate changes in peripheral blood immune cell subsets and cytokine profiles, and 
correlation of these changes with clinical outcome.
•
Evaluate changes in circulating tumor DNA to identify potential prognostic or predictive 
markers in patients with T-cell malignancies. 
•
Collect and store peripheral blood and other tissue samples for future correlative studies.
1.2
BACKGROUND
1.2.1
Peripheral T-cell lymphoma
Peripheral T-cell lymphoma (PTCL) is a rare heterogeneous group of neoplasms in mature T-cell 
malignancies (TCM) which account for 5-10% of all lymphomas. Currently, the World Health 
Organization (WHO) classification combines mature T- and NK-cell neoplasms under the 
umbrella term PTCL and the category is composed of 24 different entities, based on the different 
morphologic, phenotypic, molecular, and clinical features, including disease site [1]. Compared 
with B-cell lymphomas, many types of PTCL develop not in lymph nodes, but in specific 
extranodal sites such as extranodal NK/T cell lymphoma, nasal type (ENKL) in the nasal cavity, 
enteropathy-associated T-cell lymphoma (EATL) in the small intestine and hepatosplenic T-cell 
lymphoma (HSTL) in the liver and spleen. The most common histologic subtype is peripheral T-
cell lymphoma, not otherwise specified (PTCL-NOS), followed by angioimmunoblastic T-cell 
lymphoma (AITL) or anaplastic large cell lymphoma (ALCL), either ALK positive (ALK+) or 
ALK negative (ALK-) and these three types account for about 60% of all cases of PTCLs [2], 
however, it is still rare that the age-adjusted incidence in the U.S. for PTCL-NOS, AITL and ALCL 
is 0.30, 0.05 and 0.25 per 100,000 person-years, respectively [3-5].
The presentation of patients with PTCL largely depends on the subtype. PTCL-NOS, AITL, and 
ALCL often present with generalized lymphadenopathy, and there is also frequent involvement of 
the skin, gastrointestinal tract, liver, spleen, and bone marrow. In contrast, a number of rare specific 
subtypes, such as ENKL, HSTL, and EATL, present with primarily with extranodal disease, and 
other subtypes, such as adult T-cell leukemia (ATL) and T prolymphocytic leukemia (T-PLL), 
may have a leukemic presentation. Advanced stage disease (stages III and IV) is common for most 
of these diseases, constituting 69% of PTCL-NOS 69%, 89% of AITL, 65% of ALK+ALCL, 58% 
of ALK-ALCL, 69% of EATL, and 90% of HSTL.

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1.2.2
Cutaneous T-cell lymphoma 
Cutaneous T-Cell Lymphomas (CTCLs) are a clinically heterogeneous subgroup of PTCL/TCM, 
accounting for most lymphomas arising in skin. Mycosis fungoides (MF) and Sézary syndrome 
(SS) are defined by their cutaneous lesions that result from the accumulation of a T-helper 
memory/effector subset with a CD4+, CD8-, CD45RO+CLA+ phenotype in skin and blood [1]. 
Most commonly, MF starts as an indolent and chronic dermatitis in the sun shielded areas. The 
incidence of CTCL was initially increased and now it is plateaued with currently 1.0 per 100,000 
person/year, based on Surveillance, Epidemiology, and End Results (SEER) registry data, with the 
highest incidence rates being reported among males and African-Americans [6].
1.2.3
Treatment of relapsed/refractory PTCL and CTCL
Excluding a small proportion of indolent subtypes, PTCL is often treatment-resistant and is 
associated with poor prognosis [7]. Patients with systemic TCM are most commonly treated with 
CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like therapy, which is 
associated with long-term progression-free survival of about 30% [8-10]. Previous reports showed 
that the median PFS and OS after the first recurrence or disease progression were generally less 
than one year particularly without stem cell transplant [11-13]. British Columbia Cancer Agency 
reported that there was only a small difference in the OS between patients who received 
chemotherapy and those who did not (6.5 vs 3.7 months, respectively), indicating the need for new 
treatment strategies [13]. 
Early stage MF is characterized by eczematous or psoriasiform dermatitis covering < 80% body 
surface area without evidence of blood or visceral involvement. As the majority of CTCL patients 
present with patch/plaque stage MF and have an excellent prognosis, the initial goal of therapy is 
to improve symptoms and quality of life while avoiding treatment-related toxicity. Early MF is 
usually indolent and treated with combination skin-directed therapy. However, once they stopped 
responding to topical treatment or transformed to SS when needing systemic treatment, the 
prognosis remains poor with median PFS of less than a year [14].
Over the last decade, the U.S. Food and Drug Administration (FDA) approved several drugs with 
novel mechanisms of action for the treatment of patients with recurrent PTCL including cutaneous 
T-cell lymphoma (CTCL); these included vorinostat in 2006, pralatrexate in 2009, brentuximab 
vedotin (BV) for ALCL in 2011, romidepsin in 2011, belinostat in 2014 and mogamulizumab in 
2018. 
While these drugs are additions to the therapeutic options, they are approved by the response rate 
not by survival benefit, although response rates were generally less than 30% with the exception 
of BV for patients with ALCL, and an actual impact on long-term outcome is not proven. MD 
Anderson Cancer Center retrospectively analyzed 321 patients with PTCL-NOS and AITL and 
found that the median PFS after pralatrexate and romidepsin as single agents were 3.0 and 2.5 
months, respectively which was not significantly different from chemotherapy approach [11]. Also, 
meta-analysis of available treatments for relapsed/refractory PTCL showed that even though 
approved, belinostat and pralatrexate have lower safety than several other regimens (Figure 1) 
[15]. 
These studies indicate that even with the recent new drug approvals, single agent efficacy is limited 
for all these drugs, that there has been no significant improvement in survival even with multiple 
successive salvage treatments, and that new  therapies  with higher efficacy and improved  safety 

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profile are needed.
Figure 1:  Safety and efficacy of treatments for relapsed/refractory PTCL
1.2.3.1
Brentuximab Vedotin
Brentuximab vedotin (BV) is an antibody-drug conjugate that consists of the CD30-specific 
monoclonal antibody conjugated with monomethyl auristatin E (MMAE) by linker peptide. 
Binding of the antibody-drug conjugate to CD30 on the cell surface causes internalization of the 
conjugate by endocytosis, and the drug subsequently travels to the lysosome, where proteases 
cleave the linker releasing the MMAE to cytosol [16]. 
In a pivotal phase II study of patients with relapsed or refractory systemic ALCL, the ORR and 
CR rate were 86% and 57%, respectively [17]. The median PFS duration was 13.3 months, which 
was significantly longer than the PFS of the most recent prior therapy (hazard ratio: 0.48, p=0.001). 
Long-term follow-up data from this study showed that the median duration of response for patients 
who achieved CR extended to 26.3 months, and 4-year OS was 64% [18, 19]. On the basis of 
results from this trial, the FDA approved BV for the treatment of patients with ALCL in whom at 
least one prior multidrug chemotherapy regimen had failed. 
BV also showed activity in CTCL. Phase 3 study comparing BV to methotrexate or bexarotene in 
patients with CTCL showed significantly higher response rate (56.3% versus 12.5%) with BV [20] 
and approved by FDA. 
Due to these findings BV is considered a standard therapeutic option for patients with 
relapsed/refractory ALCL and CTCL. Therefore, patients with ALCL and CD30 positive CTCL 
must have had prior BV or be intolerant to it to be enrolled in the study. Although BV is a very 

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effective treatment, 2-year OS after BV failure is only 27.1% [21] and new investigational 
treatment is warranted.
1.3
EPIGENETIC REGULATORY GENES IN TCM
Many aggressive TCM, particularly AITL, have mutations of epigenetic modifiers that directly or 
indirectly involved in the regulation of DNA methylation/hydroxymethylation such as TET2, 
DNMT3A, IDH2, CREBBP and EP300 [22-26]. Mutations in IDH2 and TET2 reduce 5hmC levels 
due to global hypermethylation of promoters and CpG islands, likely contributing to TCM 
lymphomagenesis [27]. TET2 mutations are seen in up to 70% of PTCL patients, specifically 42-
83% of patients with AITL, 28-48.5% in PTCL NOS, and 10% in ATLL [28]. DNMT3A functions 
as a DNA methyltransferase catalyzing cytosine methylation of CpG islands in promoters leading 
to transcriptional silencing. Mutations in DNMT3A have been identified in about 11-33% of 
patients with PTCL and the mutations frequently co-exist with TET2 mutation [23], which may 
ultimately lead to transcriptional repression [29]. DNMT3A and TET1 mutations are also seen in 
CTCL and SS [30, 31]. Various TCM have different frequency of mutations in epigenetic 
regulators (Figure 2). 
Figure 2: T-cell development and common mutations in TCM
Mutation is epigenetic regulatory gene is common in ATLL. Shah et al. showed that 17 of 30 
patients (57%) with ATLL had mutations in some of genes in epigenetic and histone modifying 
genes (TET2, EZH2, MED12, PBRM1, DNMT3A, KMT2A, HIST1H1E, SPEN, IDH1, 

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SMARCB1, and ASXL1), the most common being EP300 (6/30, 20%).[32] The patients with 
mutation in epigenetic regulation showed shorter survival outcome showing the clinical impact of 
these mutations and potential benefit from treatment focusing on epigenetic regulation such as the 
histone deacetylase (HDAC) inhibitor romidepsin. In fact, in the phase I study of romidepsin and 
pralatrexate, three of five patients with multiple relapsed ATLL responded to the treatment.
Empiric findings of clinical efficacy of histone deacetylase inhibitors (HDAC inhibitors) in PTCL 
first drove research and later findings strongly supported to further explore epigenetic modifiers 
such as HDAC inhibitors and hypomethylating agents (HMA) in TCM (Figure 3) [28].
Figure 3: Epigenetic regulators and target agents
1.4
ROLE OF IRF4 IN TCM
One-third of PTCLs have over-expression of interferon regulatory factor-4 (IRF4) which regulates 
transcription factors involved in lymphocyte growth and differentiation [33]. The mechanism of 
IRF4 overexpression is not entirely clear; however, copy number abnormalities were seen in some 
cases. There is a positive feedback loop involving CD30, NF-kB, and IRF4 that drives PTCL cell 
proliferation [33]. Silencing of IRF4 by siRNA in PTCL cell line inhibited proliferation, 
downregulated MYC gene expression, and attenuated Myc protein expression (Figure 4). It 
therefore seems that IRF4 overexpression drives tumor growth in TCM, and would be a candidate 
therapeutic target. 
Lenalidomide is an immunomodulatory drug approved for the treatment of multiple myeloma 
(MM) and MDS. In the study using MM cell line, lenalidomide induces degradation of Ikaros and 
downregulates IRF4 [34]. The treatment with lenalidomide was associated with a decrease in MYC 
levels, decreased cell proliferation and cell death. In eight MM cell lines, high IRF4 levels 
correlated with increased lenalidomide sensitivity. This finding was confirmed with patients. IRF4 
expression was evaluated using real time PCR in bone marrow sample from 154 patients with MM 

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and patients who had high IRF4 expression showed significantly longer OS by lenalidomide 
treatment.
Figure 4:  Signaling pathway for survival and proliferation of TCM
1.5
INVESTIGATIONAL AGENTS
Romidepsin, 5-azacitidine, and lenalidomide have all shown clinical activity in many different T-
cell malignancies.
1.5.1
Romidepsin
Romidepsin is a unique bicyclic depsipeptide originally isolated from Chromobacterium 
violaceum strain 968. Romidepsin is one of the HDAC inhibitors which are considered as 
epigenetic modulating agents that induce accumulation of acetylated nucleosomal histones and 
induce differentiation and/or apoptosis. 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. 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 

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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. Other investigations of the effect of romidepsin on the G1 
to S transition of the cell cycle showed that romidepsin inhibits signal transduction through MAP 
kinase and causes p53- independent G1 arrest. 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.
1.5.1.1
Indication and usage
ISTODAX® is a histone deacetylase (HDAC) inhibitor indicated for:
•
Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least 
one prior systemic therapy.
•
Treatment for patients with peripheral T-cell lymphoma (PTCL) who have received at 
least one prior therapy
1.5.1.2
Non-clinical studies
Potent antitumor effects of romidepsin have been demonstrated both in vitro and in vivo. 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. 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). Two of 12 mice treated with 0.56 mg/kg 
romidepsin survived past the observation period of 60 days.
1.5.1.3
Summary of adverse events
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, hypomagnesemia), pyrexia, and taste 
disturbances.  
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).  

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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.  Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor 
stage CTCL and 2% of patients with Stage III/IV PTCL in clinical trials. Patients with advanced 
stage disease and/or high tumor burden should be closely monitored, appropriate precautions 
should be taken, and treatment should be instituted as appropriate.
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.  
1.5.1.4
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%).
1.5.1.5
Cardiovascular effects
There have been reports of cardiovascular effects of HDAC inhibitors including an effect on QTc 
prolongation. 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 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 

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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.
1.5.2
CC-486 (5-azacitidine)
CC-486 (5-azacitidine), an analog of the pyrimidine nucleoside cytidine, has effects on cell 
differentiation, gene expression, and deoxyribonucleic acid (DNA) synthesis and metabolism, and 
causes cytotoxicity. Since the early 1970s, 5-azacitidine has been investigated in the United States 
(US) for the treatment of acute leukemia. Clinical trials have focused primarily on patients with 
disease refractory to conventional chemotherapy. These investigations indicated 5-azacitidine has 
activity in the treatment of acute myeloid leukemia (AML). Clinical trials from the 1980’s through 
recent years have been conducted to evaluate the effects of 5-azacitidine in a variety of other 
malignant and hematologic disorders, including solid tumors, hemoglobinopathies (thalassemia 

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and sickle cell anemia), and myelodysplastic syndromes (MDS) as well as the use of 5-azacitidine 
in the treatment of AML in elderly patients.
1.5.2.1
Indication and usage
Vidaza®, CC-486, (5-azacitidine for injection) is approved by the US Food and Drug 
Administration (FDA) for all 5 subtypes of the French-American-British (FAB) classification 
system of MDS: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if 
accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia 
with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and 
chronic myelomonocytic leukemia (CMMoL). Vidaza is also approved by the European 
Commission (EU) for the treatment of adult patients who are not eligible for hematopoietic stem 
cell transplantation (HSCT) with the following: intermediate-2 (INT-2) and high-risk MDS 
according to the International Prognostic Scoring System (IPSS), CMMoL with 10% to 29% 
marrow blasts without myeloproliferative disorder, and AML with 20% to 30% blasts and 
multilineage dysplasia, according to World Health Organization (WHO) classification. Vidaza can 
be administered by the intravenous (IV) or subcutaneous (SC) routes as designated by country 
approval. As of 18 May 2017, Vidaza (5-azacitidine injectable) has received marketing 
authorization in 84 countries worldwide, including the US and EU.     
An oral formulation of CC-486 (5-azacitidine) has been developed and is currently being evaluated 
in clinical trials, either as a single agent or in combination with other drugs, for the treatment of 
hematological and solid malignancies. As of September 2020, oral CC-486 is approved by the US 
FDA under the name Onureg® as a maintenance treatment for adult patients with AML who 
achieved a first CR or CR with incomplete blood count recovery (CRi) after intensive induction 
chemotherapy and who are unable to complete intensive curative therapy, such as HSCT.
1.5.2.2
Summary of adverse events
As of 18 May 2017, approximately 20,408 subjects have been treated with 5-azacitidine in clinical 
studies, with 2,312 in the Celgene development program worldwide (1,242 with 5-azacitidine 
injectable, 876 with CC-486 (5-azacitidine oral), and 198 with 5-azacitidine injectable and oral), 
8,656 through National Cancer Institute (NCI)-sponsored clinical studies in the US, and an 
estimated 18,096 in non-Celgene sponsored studies globally. In addition, it is estimated that 
cumulative exposure to 5-azacitidine during marketing experience is 317,690 patients. Therefore, 
overall estimated cumulative exposure to 5-azacitidine during clinical trials and commercial 
experience is 338,098.  
In general, the most common AEs reported during the 5-azacitidine clinical trials reflect the 
underlying nature of the disease and the cytotoxic properties of 5-azacitidine. The most commonly 
reported adverse reactions with 5-azacitidine treatment were hematological reactions including 
anemia, thrombocytopenia, neutropenia, febrile neutropenia, and leukopenia, gastrointestinal 
events including nausea, vomiting, abdominal pain, constipation, and diarrhea, fungal pneumonia 
and injection site reactions (with SC administration). Adverse reactions associated with IV 
administered 5-azacitidine were similar in frequency and severity compared with SC-administered 
5-azacitidine; adverse reaction that appeared to be specifically associated with the IV route of 
administration included infusion site reactions (e.g., erythema or pain) and catheter site reactions 
(e.g., infection, erythema, or hemorrhage) as well as decreased weight, decreased appetite, 
differentiation syndrome and renal failure. Additional toxicities may also occur, including serious 
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For the most frequently reported Treatment Emergent Adverse Events (TEAEs) (≥ 10% of 
subjects), the highest incidence of first occurrence was observed within Cycles 1-2. In general, no 
clinically relevant differences were seen when the safety data were analyzed for age, sex, or MDS 
subtypes. The most common adverse reactions can be managed through delays or dose decrease 
of 5-azacitidine and/or supportive measures. The overall safety profile of 5-azacitidine from the 
ongoing clinical studies is consistent with that described in the IB; however, diarrhea may be more 
frequent and/or more severe in patients receiving orally-administered CC-486 (5-azacitidine).
1.5.3
Lenalidomide
1.5.3.1
Mechanism of action
Lenalidomide is a proprietary IMiD® compound of Celgene Corporation.  IMiD® compounds 
have both immunomodulatory and anti-angiogenic properties which could confer antitumor and 
anti-angiogenic effects.  
Lenalidomide demonstrates pleiotropic activities in distinct cell types that result in direct antitumor 
effects on cancer cells, inhibition of stromal growth factor support, and enhancement of host 
anticancer immunity.  The clinical activity of lenalidomide has been most notable in B-cell 
malignancies including MM, MCL, DLBCL, FL, and B-cell CLL.  
The activity of lenalidomide may be further subdivided into the following categories: direct 
antiproliferative activity against hematopoietic tumor cells; immunomodulatory activity including 
upregulation of T cell and NK cell responses; and inhibition of monocyte responses, 
antiangiogenic activity, and pro erythropoietic activity.
Lenalidomide’s pleiotropic activities in a range of cell types including MM cells and immune 
effector cells suggest modulation of multiple molecular pathways. Studies conducted to identify 
the molecular target(s) of lenalidomide have shown that it physically associates with the protein 
cereblon (encoded by the CRBN gene), a protein required for the teratogenic effects of thalidomide 
in zebrafish and chicken embryos.  Cereblon is a substrate receptor for an ubiquitin E3-ligase 
complex containing deoxyribonucleic acid (DNA) damage-binding protein 1 (DDB1), cullin 4 
(CUL4), and regulator of cullins 1 (Roc1) proteins (CRL4cereblon).  Upon binding to Cereblon, 
lenalidomide induces the ubiquitination of substrate proteins, including Ikaros (encoded by the 
gene IKZF1) and Aiolos (encoded by the gene IKZF3), thus targeting them for proteasomal-
dependent degradation.  It was also demonstrated that the expression of Cereblon in MM cells is 
linked to the anti-proliferative effects of lenalidomide and to the acquired resistance in vitro.  The 
downstream anti-proliferative and pro-apoptotic effects of Ikaros and Aiolos are linked to the 
subsequent downregulation of the MM growth-promoting factors c-Myc and IRF4. 
Ikaros and Aiolos are zinc finger transcription factors initially discovered as regulators of the T 
cell receptor and are required for proper hematopoiesis, particularly lymphocyte development and 
plasma cell maturation. Cereblon expression also mediates the T-cell response to lenalidomide 
through the targeted degradation of Ikaros and Aiolos.  In activated T cells in which cereblon was 
transiently decreased, interleukin-2 (IL-2) and TNF-α induction by lenalidomide was markedly 
reduced.  Since IL-2 and TNF-α are important for tumor surveillance by activated T cells, these 
results indicate that some of the immunomodulatory effects of lenalidomide are mediated via initial 
binding to cereblon.  Specifically, upon engagement with the CRL4cereblon, lenalidomide induced 
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concentration-dependent manner. Because Ikaros and Aiolos are known repressors of the IL-2 
promoter, their degradation in response to lenalidomide and other IMiDs® compounds, explains 
the enhanced T cell IL-2 production.
In summary, lenalidomide exhibits potent anti-tumor activity in B cell malignancies, which 
appears to be mediated through the protein target, cereblon.  While specific cereblon interaction 
networks are still to be defined, these results are key for further understanding of the mechanism 
of lenalidomide effects.
1.5.3.2
Indication and usage
Revlimid® (lenalidomide) is indicated for the treatment of patients with transfusion-dependent 
anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion 
5q cytogenetic abnormality with or without additional cytogenetic abnormalities.  Revlimid® is 
also approved in combination with dexamethasone for the treatment of patients with multiple 
myeloma and Revlimid® has recently been approved in the treatment of patients with mantle cell 
lymphoma whose disease has relapsed or progressed after two prior therapies, one of which 
included bortezomib.
1.5.3.3
Summary of adverse events
Most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study medication 
include: Leukopenia, Neutropenia, Febrile neutropenia, Granulocytopenia, Lymphopenia; 
Anemia; Thrombocytopenia; Vision Blurred; Diarrhea; Upper abdominal pain, Abdominal pain, 
Toothache, Constipation; Dyspepsia; Nausea; Vomiting; Asthenia; Fatigue; Edema, Peripheral 
edema; Pyrexia; Chills; Pneumonia, Bronchitis, Upper respiratory tract infection, Urinary tract 
infection, Erysipelas, Gastroenteritis, Herpes simplex, Herpes zoster, Influenza, Lower respiratory 
tract infection, Sinusitis, Sepsis, Bacteremia; Nasopharyngitis, Pharyngitis; Rhinitis; Weight loss; 
Decreased 
appetite; 
Hyperglycemia; 
Hypokalemia, 
Hypocalcemia, 
Hypophosphatemia,  
Hypomagnesemia, Hyponatremia; Pain in extremity, Pain in limb, Arthralgia, Back pain, Bone 
pain, Muscle spasms, Musculoskeletal pain, Muscle cramp, Chest pain and Myalgia; Dizziness; 
Dysgeusia, Headache; Cataract; Hypoaesthesia; Neuropathy, Peripheral neuropathy, Peripheral 
sensory neuropathy; Tremor; Cough; Dyspnea; Epistaxis; Pulmonary embolism, Deep vein 
thrombosis; Dry skin; Pruritus; Rash, Hypersensitivity (in uncommon category); Depression; 
Insomnia and recently Vertigo.
1.5.3.4
Additional Toxicity Information
•
Venous Thromboembolism: Venous thromboembolism including deep vein thrombosis 
(DVT) and pulmonary embolism (PE) has been reported in patients during treatment for 
NHL generally, occurring at incidences from ~7% up to 20%.[35] [36] [37] In lenalidomide 
clinical trials, DVT and PE were reported in 7 (2.6%) and 6 (2.2%) of 266 subjects with 
relapsed or refractory NHL receiving lenalidomide in clinical studies NHL-002 and NHL-
003[38, 39].  Anti-thrombotic prophylaxis was not suggested in NHL-002 but was required 
for subjects considered to be at high risk of developing DVT in NHL-003. In a study 
evaluating lenalidomide plus rituximab versus lenalidomide alone in relapsed follicular 
lymphoma subjects, thrombosis was reported in 2 (4%) of the combination arm versus 7 
(16%) in the single agent arm.[40] In an additional study evaluating lenalidomide plus 
rituximab in MCL patients 2 (5%) Grade 3 and 1 (5%) Grade 4 thromboembolic events 
were reported. [41]

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•
Second New Cancers: According to researchers, patients with cancer have a higher risk of 
developing a second new cancer when compared to people without cancer. In clinical 
studies of newly diagnosed multiple myeloma, a higher number of second cancers were 
reported in patients treated with induction therapy and/or bone marrow transplant then 
lenalidomide for a long period of time compared to patients treated with induction therapy 
and/or bone marrow transplant then placebo.
1.6
CLINICAL ACTIVITIES OF INVESTIGATIONAL AGENTS IN T-CELL MALIGNANCIES
1.6.1
Romidepsin
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, had an ORR of 34%, including CR rate of 6%, including skin, lymph nodes, viscera, and 
blood. The median duration of response was 454 days (14.9 months) [42].  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. 
Patients in the pivotal study for CTCL had an ORR of 34%, including CR rate of 6%, and a median 
duration of response (DOR) of 15 months [42].
PTCL and other T-cell Lymphomas. Romidepsin inhibited cell proliferation and induced 
apoptosis through inhibiting PI3K/AKT/mTOR pathway in PTCL [43]. A phase II study (N=130) 
in relapsed/refractory PTCL showed ORR of 25% with CR rate of 15% [44]. Romidepsin was 
given at 14 mg/ m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The median 
PFS was 4 months overall. It should be noted; however, that responses were frequently durable 
with the median duration of response was 28 months. The most common grade 3-4 adverse events 
were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). 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 lymphomas.
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.
1.6.2
5-azacitidine
Although 5-azacitidine has not been formally evaluated in prospective trial as single agent for 
TCM, anecdotal cases of successful treatment with 5-azacitidine are reported in patients who have 
both AITL and MDS [45, 46]. Recurrent mutations of in genes involved in DNA methylation 
regulation similar to MDS have been described in PTCL, especially in AITL, suggests that PTCL 
can be sensitive to HMA. In a case series of 19 patients who received 5-azacitidine for the 

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treatment of PTCL (and MDS) showed ORR of 53%, and it was significantly higher in patients 
with AITL patients than in patients with other PTCL entities (Figure 5: 75% versus 15%, p=0.02) 
[47]. In the trial of 5-azacitidine for MDS, the common side effects from the treatment were 
hematological (rates are above 50% in all three lineage due to nature of original MDS).
Figure 5:  Response duration of 5-azacitidine in PTCL
1.6.3
Lenalidomide
Lenalidomide showed activity to PTCL [48-50]. Lenalidomide, at the dose of 25 mg, was given 
on days 1 to 21 of each 28-days cycle. A phase II study with 39 patients evaluating lenalidomide 
monotherapy to untreated who are not candidate for combination chemotherapy and 
relapsed/refractory PTCL showed ORR of 26% with CR rate of 8%, and the median DOR was 13 
months (Figure 6) [48]. In subgroup analysis, untreated PTCL patients demonstrated an ORR of 
50% with a median DOR of 21 months suggesting better efficacy of lenalidomide in earlier course 
of treatment. Another small phase II study focusing on patients with PTCL-NOS showed an ORR 
of 30% [50].  In a multicentre phase II trial with 54 patients conducted in France, the ORR was 
22% with CR rate of 11% [49]. Non-significant slightly higher response was seen in patients with 
AITL with the ORR of 31% compared to 20% in PTCL-NOS. The median PFS and the median 
duration of response in all patients were 2.5 and 3.6 months, respectively. Lenalidomide also 
showed activity in patients with refractory MF/SS with ORR of 28% [51]. A phase 2 trial of 
lenalidomide in patients with relapsed/refractory ATLL showed ORR of 42%, including 4 
confirmed and 1 unconfirmed CR [52]. Based on this study, lenalidomide was approved in Japan 
for use in patients with R/R ATLL. The common side effects from lenalidomide are fatigue, rash 
and hematological toxicities with grade 3-4 thrombocytopenia and neutropenia observed in 10-
20% and 10-15% of patients, respectively. 

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Figure 6:  Response of lenalidomide in PTCL
1.7
SYNERGISTIC EFFECT OF ROMIDEPSIN AND 5-AZACITIDINE
Romidepsin and 5-azacitidine showed synergistic anti-proliferative effect in vitro for PTCL and 
CTCL by activating caspase cascade and inducing apoptosis (Figure 7) [53, 54]. As a single agent, 
romidepsin and decitabine (same class of medication to 5-azacitidine) modulated 76 and 54 genes, 
respectively, in various PTCL and CTCL cell lines by treatment; however, the combination 
modulated 390 more genes that are mainly involved in regulation of apoptosis [54]. 
Figure 7:  Synergistic effect of romidepsin and HMA
Also, in our preclinical studies of drug combinations for ATLL, 5-azacitidine acted synergistically 
with most of the drugs tested (unpublished data). 
This combination, romidepsin and 5-azacitidine has proven its marked activity in clinical setting 
in a phase I/II trial [55, 56]. ORR in patients with T-cell lymphoma was 79% (11 of 14 patients), 
including 6 patients with CR (43%). Interestingly, all 6 patients with AITL have responded. 
Although with short follow up, response seems to be durable and some patients showing DOR 
over a year. The most frequent grade 3-4 hematologic adverse effects were neutropenia (39%), 

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lymphopenia (39%), and thrombocytopenia (28%). The most common non-hematologic grade 3-
4 adverse events were febrile neutropenia (8%). The recommended phase 2 dose of the 
combination was CC-486 (5-azacitidine) 300 mg orally days 1-14 and romidepsin 14 mg/m2 days 
8, 15, and 22 on a 35-day cycle. 
1.8
SYNERGISTIC EFFECT OF ROMIDEPSIN AND LENALIDOMIDE
The combination of lenalidomide and romidepsin showed synergistic effect and enhanced cell 
death in PTCL cell lines by inducing apoptosis (Figure 8) [57]. This apoptosis is mediated by 
caspase activation and the combination inactivated the AKT, MAPK, and STAT3 pathways.
Figure 8: Synergistic effect of romidepsin and lenalidomide
An early phase I/II study has been conducted to evaluate the combination of romidepsin and 
lenalidomide [58]. In 21 patients reported (11 PTCL, 10 CTCL), ORR was 53%, with a median 
event-free survival of 3.8 months. The MTD was romidepsin 14 mg/m2 IV on days 1, 8, and 15 
and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. Given the longer median DOR of 
lenalidomide used as single agent in untreated PTCL patients, a phase II study is currently 
investigating the role of the combination of lenalidomide and romidepsin in untreated PTCL 
patients (NCT02232516). 
1.9
5-AZACITIDINE IN COMBINATION WITH LENALIDOMIDE
There have been no trials of combination 5-azacitidine and lenalidomide in TCM. In phase I study 
of MDS, MTD was 5-azacitidine 75 mg/m2 on days 1 to 5 and lenalidomide 10 mg on days 1 to 
21 in 28-day cycle [59]. Due to the nature of leukemic disease, hematological toxicity of this 
combination were difficult to assess, however, grade 3-4 non-hematological toxicities were not 
common and was manageable [60]. Within 36 patients enrolled, 8 patients had a dose reduction of 
lenalidomide: 6 were reduced from 10 to 5 mg and completed the study at 5 mg, whereas 2 were 
reduced to 5 mg and later were increased back to 10 mg.
1.10 RATIONALE OF COMBINATION OF LENALIDOMIDE, ROMIDEPSIN AND CC-486 (ORAL 5-
AZACITIDINE)
Due to clinical activity of all three agents and synergies seen in 2 drug combinations among three 
drugs, we hypothesize that three drug combination in addition to dexamethasone can potentially 
block multiple critical pathway TCM requires for proliferation and survival (Figure 4).
With the safety profiles and MTDs of all lenalidomide/romidepsin, 5-azacitidine/romidepsin and 
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dexamethasone may decrease tumor flares associated with lenalidomide and therefore improve its 
tolerability, the combination of all four agents is ready to be tested in a phase I trial. 
Based on PK/PD data and phase I study of CC-486 (oral 5-azacitadine) in MDS as well as safety 
data from prior study of romidepsin in combination with 5-azacitidine [55, 56], CC-486 (oral 5-
azacitidine) dose will be 300mg orally. CC-486 (oral 5-azacitidine) was initially tested in phase I 
study in patients with MDS, chronic myelomonocytic leukemia or acute myeloid leukemia and the 
MRD was 480mg daily (day 1-7, 28-day cycle) [61]. Later in phase II study, lower dose with 
longer duration of CC-486 was tested due to short half-life of CC-486 (5-azacitidine) and showed 
that 300mg orally (day 1-14, 28-day cycle) was safe and efficacy was comparable to subcutaneous 
5-azacitidine 75 mg/m2 administered for 7 days (28-days cycle) [62].
1.10.1 Doses of lenalidomide, romidepsin, and CC-486 (oral 5-azacitidine)
Phase I/II trial of romidepsin and CC-486 (5-azacitidine) determined romidepsin of 14 mg/m2 days 
8, 15, and 22, and CC-486 (5-azacitidine) of 300 mg orally days 1-14 on a 35-day cycle 
recommended dose; however, to make cycle shorter and to add lenalidomide, we will reduce the 
dose of both drugs to CC-486 (5-azacitidine) of 300 mg orally days 1-10 and romidepsin of 12 
mg/m2 days 1 and 10. If this dosing schedule of CC-486 (5-azacitidine) and romidepsin allows for 
lenalidomide to be given at the maximum dose planned (25 mg orally days 1-10), the protocol will 
be amended to allow for a higher dose of romidepsin (14 mg/m2 days 1 and 10).
1.10.2 Number and duration of cycles
As noted above, allogeneic stem cell transplantation is the only curative treatment for R/R TCMs. 
The proposed regimen was therefore primarily developed as 1) an induction regimen for patient 
who are not in at least a partial remission, and are therefore not eligible for a transplant, and 2) a 
bridge to an allogeneic hematopoietic stem cell transplant (alloSCT) for patients who have residual 
disease after one or more systemic treatment and therefore have refractory lymphoma, although 
they may be considered a transplant candidate. Patients with lymphoid malignancies who respond 
to most treatment, including the drugs used in this regimen, do so within the first 4 cycles of 
treatment. Total number of cycles is therefore limited to 6 in this trial. 
With our clinical experience in aggressive TCM at NIH particularly with ATLL showing 
progression within 4 weeks, treatment cycle is set as every 3 weeks (every 21 days). A shorter 
treatment cycle will also allow for more frequent response evaluations and more timely referrals 
for an alloSCT. If the proposed treatment schedule is consistently associated with prolonged 
neutropenia requiring treatment delays in the majority of patients, the protocol will be amended to 
administer treatment every 4 weeks (every 28 days). 
1.10.3 Changes in Study Design
The original dosing schema included a window for lenalidomide alone for seven days before 
adding in the combination of romidepsin, CC-486 (5-azacitidine), dexamethasone, and 
lenalidomide and a cycle length of 21 days. After completing the dose escalation phase, we 
decided to remove the lead-in window due to the risk for toxicities related to cytokine release 
observed in CTCL participants treated with single agent lenalidomide. Additionally, as almost all 
participants have had their cycles delayed to 28 days, we are extending the cycle to 28 days and 
removing the lenalidomide window for the remaining participants. Extending the cycles to 28 
days would be safer and more tolerable for the participants without affecting the efficacy of the 
treatment regimen. The remaining patients will be enrolled onto our newly added, Arm 3.

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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Patients must have relapsed after or progressed during at least one line of prior 
systemic therapy (which may include allogeneic stem cell transplantation) for mature 
T or NK/T neoplasm, i.e. have relapsed and/or refractory mature T and NK neoplasm 
per 2016 WHO classification excluding chronic lymphoproliferative disorder of NK 
cells, aggressive NK-cell leukemia, and Cutaneous T-Cell Lymphoma.  
2.1.1.2
T or NK/T neoplasm from initial diagnosis or recurrence must be histologically or 
cytologically proven and diagnosis be confirmed by the Laboratory of Pathology, NCI, 
2.1.1.3
Patients with ALCL or CD30 positive MF/SS must have relapsed after or become 
intolerant to prior anti-CD30 targeting therapy treatment with brentuximab vedotin 
2.1.1.4
For patients without circulating leukemia/lymphoma cells detectable by flow 
cytometry, a formalin fixed tissue block or 15 slides of tumor sample (archival or fresh) 
must be available at enrollment for performance of correlative studies. NOTE: 
Patients without circulating malignant cells must be willing to have a tumor biopsy if 
prior tissue or adequate archival tissue is not available (i.e., post-enrollment and prior 
to treatment).
2.1.1.5
Disease must be measurable with at least one measurable lesion by RECIL 2017 or 
mSWAT criteria (see Section 6.3), or have an abnormal clonal T-cell population 
detectable by peripheral blood flow cytometry
2.1.1.6
Age >18 years
2.1.1.7
ECOG performance status ≤2, or ≤ 3 if the decreased performance status is deemed to 
be due to disease and not residual toxicity from prior therapy or other causes (see 
Appendix A). 
2.1.1.8
Adequate organ and marrow function as defined below: 
Absolute neutrophil count
≥ 1,000/mcL
Platelets
≥ 75,000/mcL
Total bilirubin
≤ 1.5 X institutional upper limit of normal (ULN) 
AST(SGOT)/ALT(SGPT)
≤ 2.5 X institutional ULN
Serum Creatinine 
OR
Creatinine Clearance
≤ 1.5 mg/dL 
OR
≥ 60 mL/min/1.73 m2 as calculated by direct 
measurement of 24-hour urine for creatinine 
clearance
2.1.1.9
Negative serum or urine pregnancy test at screening for individuals of childbearing 
potential (IOCBP)
NOTE: IOCBP is defined as any individual of childbearing potential who has 

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experienced menarche and who has not undergone successful surgical sterilization or 
who is not postmenopausal.  IOCBP must have a negative pregnancy test (HCG blood 
or urine) during screening.
2.1.1.10 All study participants must be registered into the mandatory Revlimid REMS® 
program and be willing and able to comply with the requirements of the REMS® 
program (see Appendix D).
2.1.1.11 Individuals of child-bearing potential and individuals who can father children must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and for at least 
6 months after completion of treatment for individuals, and for at least 3 months after 
completion of treatment for individuals who can father children. Individuals of 
reproductive potential must adhere to the scheduled pregnancy testing as required in 
the Revlimid REMS® program (see Appendix D).
2.1.1.12 Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.2
Exclusion Criteria
2.1.2.1
Patients who are receiving any other investigational agents.
2.1.2.2
Anti-cancer treatment within 2 weeks prior to enrollment. (4 weeks for monoclonal 
antibodies and 6 weeks for nitrosoureas or mitomycin C). 
2.1.2.3
Patients who have received two of the following drugs at any point: lenalidomide, 
romidepsin, and 5-azacitidine. Patients who have received only one of the three drugs 
remain eligible.
2.1.2.4
Patients with  a diagnosis of CTCL are excluded from participation in the expansion 
cohort. 
2.1.2.5
Other malignancy that requires ongoing systemic hormonal therapy, chemotherapy, or 
immunotherapy. 
2.1.2.6
History of allergic reactions or known or suspected hypersensitivity attributed to 
compounds of similar chemical or biologic composition to lenalidomide, romidepsin 
and 5-azacitidine
2.1.2.7
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection requiring systemic therapy, or psychiatric illness/social situations that 
would limit compliance with study requirements.
•
Human immunodeficiency virus (HIV)-infected patients on effective anti-
retroviral therapy with undetectable viral load within 6 months are eligible for 
this trial.
•
For patients with evidence of chronic hepatitis B virus (HBV) infection, the 
HBV viral load must be undetectable on suppressive therapy, if indicated.
•
Patients with a history of hepatitis C virus (HCV) infection must have been 
treated and cured. For patients with HCV infection who are currently on 
treatment, they are eligible if they have an undetectable HCV viral load.

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2.1.2.8
History of inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis), celiac 
disease (i.e., sprue), prior gastrectomy or upper bowel removal, or any other 
gastrointestinal disorder or defect that would interfere with the absorption, distribution, 
metabolism or excretion of the study drug and/or predispose the subject to an increased 
risk of gastrointestinal toxicity.
2.1.2.9
Clinically significant (i.e., active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months 
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart 
Association Classification Class II), congenital long QT syndrome,  or other serious 
cardiac arrhythmia including 2nd degree atrio-ventricular (AV) block type II, 3rd degree 
AV block, or bradycardia (ventricular rate less than 50 beats/min). 
2.1.2.10 Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or 
other causes.
2.1.2.11 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.
2.1.2.12 Triplicate average baseline QTcF interval ≥ 480 ms 
2.1.2.13 Patients taking drugs leading to significant QT prolongation (see Appendix E) Note: 
A 5 half-life washout period must have elapsed following the use of these drugs prior 
to administration of romidepsin.  
2.1.2.14 Concomitant use of rifampin and other strong CYP3A4 inhibitors and inducers (see 
Appendix C) within 2 weeks prior to starting protocol therapy.
2.1.2.15 Other severe acute or chronic medical conditions including psychiatric conditions such 
as recent (within the past year) or active suicidal ideation or behavior; or laboratory 
abnormalities that may increase the risk associated with study participation or study 
treatment administration or may interfere with the interpretation of study results and, 
in the judgment of the investigator, would make the patient inappropriate for entry into 
this study.
2.1.2.16 Pregnant or lactating individuals. Pregnant individuals are excluded from this study 
because lenalidomide is a Class X agent with the potential for teratogenic or 
abortifacient effects. Because there is an unknown but potential risk for adverse events 
in nursing infants secondary to treatment of the participant of childbearing potential 
with lenalidomide, breastfeeding should be discontinued if the participant of 
childbearing potential is treated with lenalidomide.  These potential risks may also 
apply to other agents used in this study.
2.2
RECRUITMENT STRATEGIES
Study participants will be recruited from the population of patients screened in the lymphoid 
malignancies clinic of the National Institutes of Health. These will include both referrals from 
outside physicians as well as patient self-referrals. This protocol may be abstracted into a plain 
language announcement posted on NIH websites: https://ccr.cancer.gov/ Lymphoid-Malignancies-
Branch and https://ClinicalTrials.gov, on NIH social media platforms, and on the official Lymphoid 
Malignancy Branch social media accounts. 

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2.3
SCREENING EVALUATION
2.3.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:
•
Email, written, in person or telephone communications with prospective subjects 
•
Review of existing medical records to include H&P, laboratory studies, etc.  
•
Review of existing MRI, x-ray, or CT images
•
Review of existing photographs or videos
•
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
2.3.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for study 
01C0129.  Assessments performed at outside facilities or on another NIH protocol within the 
timeframes below may also be used to determine eligibility once a patient has signed the consent.
Assessments and procedures to confirm study eligibility should be completed within 28 days prior 
to registration (unless otherwise noted). See also the Study Calendar provided in Section 3.9. 
2.3.2.1
Clinical Evaluations
•
Disease history, including: diagnosis, treatment (e.g., systemic treatments, radiation 
and surgeries), disease status, and significant prior/ongoing side effects and symptoms
•
Complete medical and social history, including: all active conditions considered to be 
clinically significant by the treating investigator, as well as smoking history
•
Physical examination, including: height (screening only), weight, vital signs (i.e., 
temperature, pulse, respiratory rate, and blood pressure); review of medications and 
symptoms/side effects; and, assessment of performance status 
2.3.2.2
Laboratory Evaluations
NOTE:  Results from outside NIH are accepted.
•
CBC with differential, platelets and reticulocyte count
•
Chemistry panels (as noted) or specific analyte required for eligibility, including: 
Creatinine (i.e., Acute Care Panel); serum calcium, phosphate, magnesium and albumin 
(i.e., Mineral Panel); ALT, AST, total bilirubin (i.e., Hepatic Panel, direct bilirubin if 
indicated); LDH
•
Serum Lipase and Amylase
•
Coagulation panel, including: PT/INR and a PTT
•
Thyroid function tests, including: thyroid stimulating hormone (TSH) with reflex free 
thyroxine (T4)
•
Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody, Hepatitis C antibody 
(HCVAb) (qualitative), HIV 1/2 antibody (qualitative) and HTLV-1/2 serologies 
(within 3 months). NOTE:  For individuals with a positive hepatitis B core antibody, 
HBV DNA PCR will be performed to screen for subclinical infection; for patients with 

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positive hepatitis C antibody, HCV PCR will be performed; for patients with positive 
HIV antibodies, HIV1/2 viral load will be checked.
•
Urinalysis (with microscopic examination if abnormal)
•
Serum or urine pregnancy test (B-HCG) for individuals of childbearing potential
•
Clonal T-cell receptor rearrangement by PCR (peripheral blood and/or tissue), within 
3 months prior to enrollment.
2.3.2.3
Imaging Studies 
NOTE:  Results from outside NIH are accepted. Other body areas may be imaged if 
clinically indicated. 
•
CT neck, chest, abdomen and pelvis (CT should be performed with IV contrast, unless 
patient is allergic or has renal insufficiency; other imaging may be substituted at the 
discretion of the investigator (such as MRI))
•
PET/CT torso (extremities to be included if there is confirmed or suspected disease 
involvement)
•
MRI of brain (only in patients with suspected involvement of CNS)
2.3.2.4
Cardiac Evaluation (within 3 months)
•
Electrocardiogram (EKG)
•
Transthoracic echocardiogram
2.3.2.5
Pulmonary Evaluation (if indicated)
•
Diffusing capacity/alveolar volume (DLCO/VA) forced expiratory volume in 1 
second (FEV1) for patients with significant pulmonary or smoking history.
2.3.2.6
Other Procedures
•
Pathologic review/confirmation of diagnosis by Laboratory of Pathology, NCI (no time 
limit). If archival sample is not available or not adequate, a fresh tumor biopsy and/or 
peripheral blood sample will be obtained.
2.4
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at: https://nih.sharepoint.com/sites/NCI-CCR-OCD-
Communications/SitePages/OEC-Administrative---Clinical-Research-(ADCR).aspx?Mode=Edit.
2.5
TREATMENT ASSIGNMENT PROCEDURES
NOTE: For NCI CCR registration and enrollment system purposes only
2.5.1
Cohorts
Number
Name
Description
1
Mature T-cell 
malignancies:  Dose 
Escalation (Closed: 
prior to amendment 
12/07/2022)
Relapsed/refractory mature T-cell malignancies: (up to 24 
evaluable patients; 5 dose levels)

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Number
Name
Description
2
Mature T-cell 
malignancies:  Dose 
Expansion
Relapsed/refractory mature T-cell malignancies (not 
including CTCL): (up to 6 additional evaluable patients; 9 
total evaluable at the MTD)
2.5.2
Arms
Number
Name
Description
1
Experimental 
Treatment:  Dose 
Escalation (Closed: 
prior amendment 
12/07/2022)
Lenalidomide by oral intake at escalating doses of 5, 10, 15, 
or 20 mg/day on days -7 to 10 of each 21-day cycle (max 6 
cycles) with CC-486 (5-azacitidine) at 300mg/day by oral 
intake on days 1-10, romidepsin at 12mg/m2 by IV infusion 
on Day 1 and 10 and dexamethasone at 40mg by oral intake 
on days 1 and 10 of each cycle, to determine MTD
2
Experimental 
Treatment:  Dose 
Expansion(Closed: 
with amendment 
12/07/2022)
Lenalidomide by oral intake at 20mg on days 1 to 10 of 
each 28-day cycle (max 6 cycles) with CC-486 (5-
azacitidine) at 300mg/day by oral intake on days 1-10, 
romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and 
dexamethasone at 40mg by oral intake on days 1 and 10 of 
each cycle
3
Experimental 
Treatment:  Dose 
Expansion
Lenalidomide by oral intake at 20mg (MTD) on days 1 to 
10 of each 28-day cycle (max 6 cycles) with CC-486 (5-
azacitidine) at 300mg/day by oral intake on days 1-10, 
romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and 
dexamethasone at 40mg by oral intake on days 1 and 10 of 
each cycle
2.5.3
Arm Assignment
Subjects in Cohort 1 will be directly assigned to Arm 1. Subjects in Cohort 2 will be directly 
assigned to Arm 2.
Once Amendment version 12/07/2022 is approved, new participants enrolled to Cohort 2 will be 
assigned to Arm 3 (without the lenalidomide window).
2.6
BASELINE EVALUATION
The following should be performed within 28 days prior to the first dose of lenalidomide unless 
otherwise noted; tests performed as part of screening do not need to be repeated if they were 
performed within the specified window prior to initiating treatment.  
2.6.1
Clinical Evaluations
•
Medical history (interim)
•
Physical examination including weight, vital signs (i.e., temperature, pulse, respiratory 
rate, and blood pressure); review of concomitant medications and symptoms/side 

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effects; and assessment of performance status (ECOG performance score, see 
Appendix A).
2.6.2
Laboratory Evaluations 
NOTE:  Results from outside NIH are accepted
•
Required within 24 hours prior to prescribing lenalidomide:
o
Serum or urine pregnancy test (B-HCG) for individuals of childbearing 
potential 
•
Required within 14 days:
o
Serum or urine pregnancy test (B-HCG) for individuals of childbearing 
potential (required within 10-14 days of prescribing lenalidomide). 
Prescriptions must be filled within 7 days as required by Revlimid REMSTM.
o
CBC with differential, platelets and reticulocyte count
o
Chemistry panels including: Acute Care (sodium, potassium, chloride, CO2, 
glucose, BUN, creatinine), Mineral Panel (serum calcium, phosphate, 
magnesium and albumin) and Hepatic Panel (alkaline phosphatase, ALT, AST, 
total and direct bilirubin)
o
Others: LDH, Uric acid, Total protein
o
Coagulation panel, including: PT/INR and aPTT
o
Iron panel (includes: ferritin, transferrin, iron), folate, vitamin B12
o
C-reactive protein (CRP)
o
Serum Lipase and Amylase
o
Urinalysis (with microscopic examination if abnormal)
o
HLA typing (A, B, C, DR, DQ)
•
Required within 28 days:
o
Lymphocyte Phenotype: T, B and NK cell subsets
o
Peripheral blood flow cytometry
2.6.3
Imaging Studies
Every participant should have an evaluation of known sites of disease as part of baseline 
evaluation. NOTE:  Only results from NIH are accepted 
•
One or more of the following studies: CT, MRI, FDG-PET and/or clinical photography
•
Patients with neurological symptoms or signs should undergo MRI scan* of the brain 
and lumbar puncture
*NOTE: The MRIs to be done in this study may involve the use of the contrast agent 
gadolinium, if clinically indicated. The risks associated with MRIs and contrast are 
discussed in the consent form.
2.6.3.1
Other Procedures
•
Bone marrow biopsy and aspiration to assess lymphoma involvement (within 3 
months)

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•
Selected patients with cutaneous disease (as determined by physician PI or AI) will 
have clinical photography and dermatology assessment performed to assess their skin 
disease
2.6.4
Research Correlates
NOTE: See Section 5 for additional information. The following sample types will be 
collected for correlative research studies:  
•
Required:  
o
Blood samples for lymphocyte subset testing and circulating tumor DNA
o
Blood, buccal swab, or saliva for germline DNA
o
Tumor Tissue (archival or fresh)
•
Optional:  
o
Blood samples for tissue immune cell subset comparison (as outlined in Section 
5.1)
o
Bone marrow biopsy
o
Tumor biopsy is required if archival tissue is not available or adequate; 
otherwise, this is optional.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
To determine the maximum tolerated dose (MTD), and the safety and toxicity profile of the 
combination of lenalidomide, CC-486 (5-azacitidine) and romidepsin in patients with 
refractory/relapsed TCM, a phase 1 open-label, non-randomized, single-center study will be 
conducted at the NCI. A standard “3 + 3” design will be used to determine the MTD of dose-
escalated lenalidomide in combination with fixed doses of CC-486 (5-azacitidine), romidepsin (R) 
and dexamethasone (D) with an expansion cohort at the MTD. 
In patients with relapsed or refractory TCM, lenalidomide will be administered by oral intake in a 
dose-escalation with a starting dose of 5mg daily, a second dose level of 10mg daily, a third dose 
level at 15mg daily, and a fourth dose level at 20mg daily on days -7 to day 10 of first cycle (see 
Table 1 for additional dose levels and schedules, cycles are 21 days each). After the second cycle, 
lenalidomide will be given from day 1 to day 10 in each cycle for up to six cycles. CC-486 (5-
azacitidine) with a dose of 300mg oral intake daily will be given on day 1 to day 10, romidepsin 
will be administered at a dose of 12 mg/ m2 on days 1 and 10 (±2 days) and dexamethasone will 
be given on day 1 and 10 (±2 days) of the cycle. 
After approval of Amendment 12/07/2022: Participants will receive six cycles (each 28 days in 
length) of: lenalidomide at the MTD from day 1 to day 10, CC-486 (5-azacitidine) at a dose of 
300mg oral intake daily given on day 1 to day 10, romidepsin administered at a dose of 12 mg/ 
m2 on days 1 and 10 (±2 days) and dexamethasone on day 1 and 10 (±2 days) of the cycle.
Treatment will continue for a maximum of 6 cycles or until toxicity (i.e., dose limiting toxicity) as 
found in Section 3.9 or toxicity requiring discontinuation as defined in Section 3.5) or progressive 
disease.

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The treatment will be repeated for up to 6 cycles. The patients are allowed to proceed to stem cell 
transplantation (SCT) if eligible during and after the protocol treatment. Patients who undergo 
SCT before all 6 cycles of protocol treatment are administered will be taken off therapy. All 
patients who undergo SCT will continue to be followed for survival, but not for toxicity (see 
Section 3.8)
 
Table 1: Dose level and schedule for lenalidomide, CC-486 (5-azacitidine), romidepsin and 
dexamethasone
DL
Lenalidomide
Day 1 -10
(7 days lead in 
for 1st cycle)
CC-486 (5-
azacitidine)
Day 1 to 10
Romidepsin
Day 1 and day 10
Dexamethasone
Day 1 and day 10
-2
0 mg
200 mg PO
10 mg/m2 IV
40 mg PO
-1 
2.5 mg 
200 mg PO
12 mg/m2 IV
40 mg PO 
1*
5 mg
300 mg PO
12 mg/m2 IV
40 mg PO
2
10 mg
300 mg PO
12 mg/ m2 IV
40 mg PO
3
15 mg
300 mg PO
12 mg/ m2 IV
40 mg PO
4
20 mg
300 mg PO
12 mg/ m2 IV
40 mg PO
* starting dose level
As of 
Amendment 
12/07/2022:
Lenalidomide
Day 1 to 10
CC-486 (5-
azacitidine)
Day 1 to 10
Romidepsin
Day 1 and day 10
Dexamethasone
Day 1 and day 10

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DL
Lenalidomide
Day 1 -10
(7 days lead in 
for 1st cycle)
CC-486 (5-
azacitidine)
Day 1 to 10
Romidepsin
Day 1 and day 10
Dexamethasone
Day 1 and day 10
DL
4 (MTD)
20 mg
300 mg PO
12 mg/ m2 IV
40 mg PO
3.2
DOSE LIMITING TOXICITY
A dose-limiting toxicity (DLT) is defined as: any treatment-emergent and related severe (grade ≥ 
3) toxicity, i.e., toxicity deemed related to lenalidomide, romidepsin and/or CC-486 (5-azacitidine) 
by the PI or designee and occurring during the MTD observation time, defined as day -7 until end 
of cycle 1 (normally day 22). Each patient must receive all doses of the investigational medications 
during cycle 1 to be considered as successfully completing the DLT evaluation period.
The following toxicities and conditions will be recorded, however they will not be considered to 
be DLTs:
3.2.1
Hematologic exceptions 
•
Grade 3 or 4 lymphocytopenia without clinical signs of infection grade 2 or above.
o
Lenalidomide, romidepsin and CC-486 (5-azacitidine) will be continued in the 
event of asymptomatic grade 3 or 4 lymphocytopenia, unless there are clinical 
signs of significant infection (persistent fevers, labile blood pressure, localized 
complaints or findings on physical examination, hypoxia or organ dysfunction).
•
Grade 3 neutropenia without clinical signs of infection grade 2 or above.
o
Lenalidomide, romidepsin and CC-486 (5-azacitidine) will be continued in the 
event of grade 3 neutropenia unless there are clinical signs of significant 
infection, as listed above.
•
Grade 3 thrombocytopenia without signs of bleeding that resolved within 7 days of 
holding the study drug(s) (See Section 3.5.1 for study drug holding parameters).
•
Grade 3 anemia that improves to Grade ≤2 after transfusion of up to two units of pRBCs 
and does not recur within 7 days. 
•
Grade 3 febrile neutropenia (grade 3 febrile neutropenia at any time during therapy will 
be considered an SAE but not DLT)
3.2.2
Non-Hematologic exceptions
•
Transient (< 72 hours) grade 3 hypoalbuminemia, hypokalemia, hypomagnesemia, 
hyponatremia or hypophosphatemia which responds to medical intervention. 
Lenalidomide, romidepsin and CC-486 (5-azacitidine) will be continued while the 
metabolic abnormalities are corrected by intravenous or oral supplementation 
•
Patients who require short term hospitalization (3 days or less) only for fluid and 
electrolyte disturbances secondary to anorexia, nausea/vomiting/diarrhea which are 
common AEs for 5-azacitidine, lenalidomide and romidepsin individually and more so 
for the combination. This exception does not apply to secondary organ dysfunction 
resulting from this biochemical derangements or patients that require vasopressor BP 
support.

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•
Grade 3 rash that resolves to grade ≤2 within 7 days of holding the study drug(s) (See 
Section 3.5.1 for study drug holding parameters).
Management and dose modifications associated with the above adverse events are outlined in 
Section 3.5. Occurrence of any DLT-defining toxicity after the first 28 days of treatment will 
lead to dose modification as specified below; however, it will not be deemed a DLT for purposes 
of dose escalation.
3.3
DOSE ESCALATION
Dose escalation will proceed according to the following schedule (Table 2). Dose escalation will 
follow the following guidelines (Table 3).  Each patient will continue treatment at the dose level 
they were enrolled – there will be no intra-patient dose escalation. In case of severe toxicity, the 
lenalidomide dose should be reduced by one dose level, dose adaption of the other drugs as per 
investigators discretion.
The MTD is the dose level at which no more than 1 of up to 6 patients experience DLT during the 
DLT evaluation window(s), or the dose below that at which at least 2 (of ≤6) patients have DLT. 
The protocol will be amended to note the MTD once determined.
NOTE:  If enrollment to the current or next higher dose level cannot proceed because a patient at 
the current dose level is still within the DLT window, screened patients who are in need of urgent 
treatment may be enrolled at the next lower dose level as long as the ≤6 patient limit per dose level 
is maintained. In the event that these additionally enrolled patients experience DLT(s) after formal 
evaluation of dose level determinations has taken place, the Principal Investigator will review and 
assess if any changes to the ongoing protocol/dose escalation or safety parameters need to be 
considered. 
NOTE: After the dose escalation portion was completed, the MTD of lenalidomide was 
determined to be 20mg.
Table 2: Lenalidomide Dose Escalation Schedule
Dose Level
Lenalidomide
Level -2
0 mg
Level -1
2.5 mg
Level 1
5mg – Starting dose
Level 2
10mg
Level 3
15mg
Level 4
20mg
Table 3:  Dose Escalation Guidelines
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.

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Number of Patients with DLT at a 
Given Dose Level
Escalation Decision Rule
>2
Dose escalation will be stopped.  This dose level will be declared 
the maximally administered dose (highest dose administered).  
Three (3) additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously at that dose.
1 out of 3
Enter at least 3 more patients at this dose level.
• If 0 of these 3 patients experience DLT, proceed to the next 
dose level.
• If 1 or more of this group suffer DLT, then dose escalation is 
stopped, and this dose is declared the maximally administered 
dose.  Three (3) additional patients will be entered at the next 
lowest dose level if only 3 patients were treated previously at 
that dose.
≤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.
3.4
DRUG ADMINISTRATION
3.4.1
Summary of Original Study Design
Prior to approval of Amendment dated 12/07/2022, the original study design included a 7 day 
lead-in window of lenalidomide monotherapy to assess early clinical activity of this agent prior 
to combination therapy. 
The standard treatment cycle was 21 days (3 weeks), except for the first cycle where we had 7 
days lead in phase for lenalidomide (lead in was allowed to be shorter for patients requiring 
urgent treatment with the four-drug combination due to rapid disease progression, at PI 
discretion). The maximum allowable delay for completion of cycle 1 treatment was 1 week (7 
days) in order to best assess the tolerability of this treatment. The maximum allowable delay for 
completion of treatment in all subsequent cycles was 3 weeks (21 days). The minimum window 
between initiation of new cycles was 19 days. For the dose escalation Cohort 1, treatment was 
administered on an inpatient basis during the first 2 days (after lead-in period) of the first cycle, 
and as outpatient during subsequent weeks and cycles unless decided otherwise by the principal 
investigator based on clinical judgment.
After 20 patients were enrolled and the dose escalation Cohort 1 Arm 1 was fully accrued, the 
study design was modified to remove the 7 day lenalidomide window (Amendment 12/07/2022).
3.4.2
Summary of Current Study Design (as of Amendment 12/07/2022)
For the Dose Expansion Cohort 2 Arm 3, treatment will be administered as outpatient for all 
cycles unless decided otherwise by the principal investigator based on clinical judgment. The 
standard treatment cycle will be 28 days (4 weeks). Reported adverse events and potential risks 
are described in Section 14. Appropriate dose modifications are described in Section 3.5. No 
investigational or commercial agents or therapies other than those described below may be 
administered during the study therapy period with the intent to treat the patient's malignancy. See 
Table 4 below for description of drug regimen.
 A cycle may be delayed for the following reasons:

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•
Scheduling or other administrative reasons (no more than 14 days)
•
Administration of COVID-19 vaccination (if the delay would not result in more than 6 
weeks treatment-free period) 
•
Toxicity/dose management as defined below
Table 4: Drug Regimen
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Lenalidomide
Aspirin for 
thrombosis 
prophylaxis
As per dose 
level***
Oral
Days 1 to10
Romidepsin
Premedicate with 
ondansetron or 
granisetron *
12mg/ m2 in 
500 mL NS
IV over 
4 hours
Days 1 and 10 
(± 2 days)
CC-486 (5-
azacitidine)
Premedicate with 
ondansetron or 
granisetron **
300mg
Oral
Days 1 to 10
Dexamethasone
No premedication
40mg
Oral
Days 1 and 10
(± 2 days)
* Mandatory for the first cycle; subsequently based on clinical judgement
** Not mandatory, administer based on clinical judgement
*** Doses as appropriate for assigned dose level
For a full detailed product description and administration guidelines, see Section 14. Infusions may 
be done peripherally or via central venous access device (if present; not required to be placed by 
the study). 
NOTE: Cycles beyond Cycle 1 may not commence until the laboratory criteria in Section 
2.1.1.8 are met and non-laboratory treatment-emergent AEs have resolved to grade ≤2 (grade ≤1 
if at related to treatment).
3.4.3
Agent-specific Information and Instructions
3.4.3.1
Lenalidomide
Patients will receive lenalidomide for 10 days through Cycles 1-6 of treatment (see schema Section 
3.1).
Lenalidomide is administered orally once daily and should be taken around the same time each 
day with at least 8 ounces of water.  The capsules must be swallowed whole and may be taken 
with or without food. 
3.4.3.2
Romidepsin
Romidepsin will be administered on day 1 and 10 of each cycle through a peripheral or central 
intravenous catheter over 4 hour period.  If patients are also taking antiemetics to relieve the side 
effects associated with romidepsin these should be administered at least 60 minutes before the 
romidepsin.  Patients concurrently receiving romidepsin and warfarin should have PT and INR 

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levels checked more frequently.  The use of rifampin and CYP3A inducers should be avoided for 
the duration of the study (see Section 4 and Appendix C).
3.4.3.3
CC-486 (5-azacitidine)
CC-486 (5-azacitidine) will be administered on days 1 through 10 of each cycle in the clinic.  CC-
486 (5-azacitidine) will be taken orally, with or without food.  The tablets/ capsules must be 
swallowed whole and may be taken with or without food.   
3.4.3.4
Dexamethasone
Dexamethasone will be administered orally on Days 1 and 10.  
3.4.3.5
Study Drug Diaries
Patients will be required to complete and return a drug diary as a memory aid to help document 
the date and time of all self-administered study drugs (Appendix F). This drug diary as well as 
study drug containers and any unused study drug should be returned to the research team at the 
end of each cycle of therapy.
3.4.4
Supportive Medications
3.4.4.1
Prophylactic and supportive care for lenalidomide
Patients who are not already on prophylactic or therapeutic doses of anticoagulants will be given 
aspirin 81mg by oral intake for prophylaxis of venous thromboembolism.
3.4.4.2
Prophylactic and supportive care for romidepsin and CC-486 (5-azacitidine)
Patients will be given ondansetron 16 mg orally or 8 mg IV (or equivalent dose of granisetron 
orally or transdermal in case of allergy or intolerance to ondansetron) to prevent chemotherapy-
associated nausea. Anti-emetics may be omitted during the second and subsequent cycles at 
investigators’ discretion.
3.4.4.3
Other modalities or procedures
•
Patients deemed by the PI or treating investigator to be at high risk for CNS relapse who 
have not received CNS prophylaxis as part of their prior treatment may receive prophylaxis 
in the form of cytarabine 40 mg, methotrexate 15 mg, and hydrocortisone 50 mg 
administered intrathecally (IT) no earlier than Day 2 of Cycle 1 and every 3-6 weeks 
thereafter for up to six doses. Cytarabine or methotrexate may be omitted in case of prior 
intolerance or toxicity attributed to either drug. Platelet counts of ≥70,000 /uL need to be 
confirmed prior to each administration.
•
If CNS disease is detected at screening or during prophylactic IT drug administration, IT 
treatment listed above will be administered twice weekly until abnormal lymphoid cells 
are no longer detectable by cytology or flow cytometry, then weekly for four additional 
doses.
•
Patients with bulky disease (one or more lymph nodes ≥10cm), high leukemic cell count 
(≥50,000 cells/mm3) or who are for other reasons deemed by the PI or designate to be at 
an increased risk for tumor lysis syndrome will have the laboratory evaluations as listed in 
Study Calendar (Section 3.9).   
•
Patients will be observed in the day hospital or the inpatient unit for at least 30 minutes 
after administration of romidepsin for potential infusion-related reactions.

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3.4.5
Missed doses
All missed doses of the protocol medications administered orally (CC-486 (5-azacitidine), 
lenalidomide, and dexamethasone) will be recorded in the primary source documentation at the 
time of the next patient visit. If a dose is not taken at the scheduled time and it has been less than 
12 hours since the regularly scheduled time, it can be taken as soon as possible on the same day.  
If it has been more than 12 hours, the missed dose may be skipped, but the next dose should be 
taken at the normal time on the following day. The patient should not take extra doses to make up 
the missed dose.
If the patient has an episode of emesis and vomits a dose of one or more drugs, these will be 
recorded as missed and will not be re-administered. If there is only suspicion that the doses were 
vomited because emesis occurred, but there is no clear evidence for it, these doses will not be 
recorded as missed.
3.5
DOSE MODIFICATION 
Previous clinical trial experience treating patients with relapsed refractory TCMs indicates 
significant efficacy for the 2 drug combinations of romidepsin and oral 5-azacitidine [63] or 
romidepsin and Lenalidomide  [58], but the AE listings shown below in Table 5 also illustrate 
the potential for overlapping toxicity that may make it difficult to attribute specific AEs to only 
one of the investigational agents as well as highlight the potential for more significant AEs with 
the addition of the 3rd active agent.  While patient safety is always of foremost concern, there 
will be interest in maintaining dose intensity and continuing treatment to accurately assess the 
clinical activity of this regimen. The single agent safety experience will provide important 
insight into each drugs contribution to the hematologic and GI toxicities, but individual AEs may 
require interrupting treatment, dose reduction or discontinuation of more than 1 drug. 
Table 5: Adverse Event listings for Romidepsin/5-azacitidine Treatment 
emergent AEs occurring in 10% or more of the patients (n = 25)
AE
Total
Grade 1-2
Grade 3-4
Decreased platelet count
18 (72)
6 (24)
12 (48)
Decreased neutrophil count
17 (68)
7 (28)
10 (40)
Nausea
17 (68)
15 (60)
2 (8)
Hyperglycemia
15 (60)
14 (56)
1 (4)
Anemia
14 (56)
10 (40)
4 (16)
Fatigue
14 (56)
13 (52)
1 (4)
Decreased lymphocyte count
13 (52)
5 (20)
8 (32)
Diarrhea
12 (48)
12 (48)
—
Constipation
12 (48)
12 (48)
—
Vomiting
12 (48)
10 (40)
2 (8)

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AE
Total
Grade 1-2
Grade 3-4
Hypoalbuminemia
11 (44)
11 (44)
—
Anorexia
10 (40)
10 (40)
—
Increased creatinine
10 (40)
10 (40)
—
Fever
8 (32)
7 (28)
1 (4)
Abdominal pain
7 (28)
6 (24)
1 (4)
Upper respiratory infection
7 (28)
6 (24)
1 (4)
Hypocalcemia
7 (28)
7 (28)
—
Headache
6 (24)
6 (24)
—
Weight loss
6 (24)
6 (24)
—
Hypophosphatemia
6 (24)
4 (16)
2 (8)
Hyponatremia
5 (20)
5 (20)
—
Dysgeusia
5 (20)
5 (20)
—
Increased aspartate aminotransferase
5 (20)
5 (20)
1 (4)
Hypokalemia
5 (20)
5 (20)
—
Rash maculopapular
4 (16)
4 (16)
—
Increased blood bilirubin
4 (16)
2 (8)
2 (8)
Urinary tract infection
4 (16)
3 (12)
1 (4)
Cough
4 (16)
4 (16)
—
Chronic kidney disease
4 (16)
4 (16)
—
Malaise
3 (12)
3 (12)
—
Nasal congestion
3 (12)
3 (12)
—
Hypoglycemia
3 (12)
3 (12)
—
Hypercalcemia
3 (12)
3 (12)
—
Increased alanine aminotransferase
3 (12)
2 (8)
1 (4)
Hypernatremia
3 (12)
3 (12)
—
Myalgia
3 (12)
3 (12)
—
Peripheral sensory neuropathy
3 (12)
3 (12)
—
Edema in the limbs
3 (12)
3 (12)
—

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AE
Total
Grade 1-2
Grade 3-4
Dizziness
3 (12)
3 (12)
—
Arthralgia
3 (12)
3 (12)
—
Febrile neutropenia
3 (12)
—
3 (12)
Dyspepsia
3 (12)
3 (12)
—
Back pain
3 (12)
3 (12)
—
Table 5.1 Toxicities occurring in ≥10% of participants and all grade three and grade four 
toxicities for Regimen A (romidepsin and lenalidomide) 
Regimen A
Any grade occurring 
in ≥10% n (%)
Grade 3
Grade 4
Hematological toxicities
43
88%
24
49%
18
37%
Anemia
16
33%
13
27%
–
–
Febrile neutropenia
–
–
3
6%
–
–
Neutropenia
28
57%
15
31%
9
18%
Thrombocytopenia
30
61%
18
37%
8
16%
Lymphocyte count decreased
28
57%
16
33%
9
18%
White blood cell decreased
22
45%
18
37%
4
8%
Liver function toxicities
9
18%
2
4%
–
–
Alanine aminotransferase 
increased
–
–
–
–
–
–
Aspartate aminotransferase 
increased
–
–
–
–
–
–
Alkaline phosphatase increased
–
–
1
2%
–
–
Blood bilirubin increased
5
10%
1
2%
–
–
Hypoalbuminemia
–
–
–
–
–
–
Electrolyte toxicities
27
55%
24
49%
–
–
Hyperglycemia
8
16%
7
14%
–
–
Hypermagnesemia
10
20%
10
20%
–
–

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Regimen A
Any grade occurring 
in ≥10% n (%)
Grade 3
Grade 4
Hypocalcemia
5
10%
5
10%
–
–
Hypoglycemia
–
–
–
–
–
–
Hypokalemia
6
12%
6
12%
Hypomagnesemia
–
–
–
–
–
–
Hyponatremia
–
–
1
2%
–
–
Hypophosphatemia
8
16%
8
16%
–
–
Creatinine increased
–
–
–
–
–
–
Other toxicities
48
98%
20
41%
–
–
Abdominal pain
6
12%
–
–
–
–
Anorexia
18
35%
1
2%
–
–
Arthralgia
–
–
1
2%
–
–
Chills
–
–
–
–
–
–
Constipation
19
39%
–
–
–
–
Dehydration
3
6%
–
–
Diarrhea
19
39%
–
–
–
–
Dysgeusia
30
61%
–
–
–
–
Dyspnea
5
10%
1
2%
–
–
Electrocardiogram QT corrected 
interval prolonged
–
–
1
2%
–
–
Fatigue
31
63%
11
22%
–
–
Fever
5
10%
–
–
–
–
Generalized muscle weakness
–
–
1
2%
Headache
–
–
–
–
–
–
Hypotension
–
–
–
–
–
–
Lung infection
3
6%

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Regimen A
Any grade occurring 
in ≥10% n (%)
Grade 3
Grade 4
Malaise
–
–
–
–
–
–
Myalgias
7
14%
–
–
–
–
Nausea
30
63%
–
–
–
–
Phlebitis
–
–
–
–
–
–
Rash Maculo-Papular
–
–
1
2%
–
–
Syncope
–
–
1
2%
–
–
Tumor lysis syndrome
–
–
1
2%
–
–
Upper respiratory infection
–
–
1
2%
–
–
Vomiting
15
27%
–
–
–
–
Weight loss
12
22%
–
–
–
–
3.5.1
Treatment modifications for adverse reactions
All treatment modifications should be discussed with the senior clinical investigators on the study. 
Treatment modifications will follow the guidelines outlined in Table 6. Any given dose 
modification after Cycle 1 can be repeated twice in a patient as long as the patient is benefiting 
from therapy and does not meet off-treatment criteria. 
If a toxicity which requires modification of therapy per Table 6 occurs during the window period 
(day -7 to day -1) and does not meet the definition of a DLT, cycle 1 day 1 may start after resolution 
to grade ≤1 (grade ≤2 for anemia).
All grading scales in the following tables are according to the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.
Table 6: Dose Modification of Lenalidomide, romidepsin and CC-486 (5-azacitidine) for 
treatment related AEs
Event
Initial management
Follow-up Management
Cycle 1 DLT Evaluation Period
Grade 1 AEs
Any AE
Continue treatment
Continue monitoring and laboratories at 
least once weekly
Grade 2 AEs
ANC: <1.5 - 1.0 x 109/L
Continue treatment
Monitor cell counts at least twice 
weekly
Pegfilgrastim*

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Event
Initial management
Follow-up Management
Platelet: < 75,000 - 
50,000/mcL
Consider holding treatment for up to 7 
days
Monitor cell counts at least twice 
weekly
Restart treatment when platelet count 
>75,000/mcL
Hgb: < 10.0 - 8.0g/dL
Continue treatment
Monitor cell counts at least twice 
weekly
Consider transfusion before cycle 2
Any other AE
Continue treatment
Continue monitoring and laboratories 
once weekly
Grade 3 AEs
ANC: <1.0 -0.5  x 109/L
Hold treatment for up to 7 days
Restart treatment at full doses 
Monitor cell counts at least twice 
weekly
G-CSF# and Pegfilgrastim*; 
Platelet: <50,000 - 
25,000/mcL
Hold treatment for up to 7 days
Restart treatment at when platelets > 75, 
000/mcL
Monitor cell counts at least twice 
weekly
If platelets are not > 75,000/mcL the 
patient is off treatment DLT
Hgb < 8.0g/dL
Hold treatment for up to 7 days
Restart treatment after transfusion 
Monitor cell counts at least twice 
weekly
Transfusion until Hgb > 9 g/L
Any other AE
Hold treatment for up to 7 days
Restart treatment when AE has resolved 
to ≤ grade 1
Continue monitoring and laboratories at 
least twice weekly
If the AE has not improved to ≤ 
grade 1, the patient is off treatment 
DLT
Grade 4 AEs at any time during cycle 1
Any AE
Discontinue treatment
Off treatment DLT
Cycles 2 through 6
Event
Initial management
Follow-up Management
Grade 1 AEs
Any AE
Continue treatment
Continue monitoring and laboratories at 
least once weekly
Grade 2 AEs
ANC: <1.5 – 1.0 x 109/L
Continue treatment
Monitor cell counts at least twice 
weekly 
Platelets <75,000 to 
50,000/mcL
Continue treatment
Monitor cell counts at least twice 
weekly
Hgb: < 10.0 – 8.0g/dL
Continue treatment
Consider transfusion before the start of 
next cycle
Any other AE
Continue treatment
Continue monitoring and laboratories at 
least twice weekly

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Event
Initial management
Follow-up Management
Grade 3 AEs
1st event: continue treatment
Monitor cell counts at least twice 
weekly and use
G-CSF support for the remainder of 
current cycle and all future cycles
2nd event: hold lenalidomide and 5-
azacytidine for remainder of cycle; 
next cycle may resume once ANC is 
>1.0 
Monitor cell counts at least twice 
weekly and use G-CSF support
 Dose reduce both 5-azacytidine and 
lenalidomide for the next cycle
3rd event: hold lenalidomide and 5-
azacytidine for remainder of cycle; 
next cycle may resume once ANC is 
>1.0
Monitor cell counts at least twice 
weekly and use G-CSF support
2nd dose reduction of 5-azacytidine 
and lenalidomide and 
consider dose reduction of romidepsin 
with the next cycle
ANC: < 1.0 - 0.5  x 109/L
Or
4th event: hold lenalidomide and 5-
azacytidine for remainder of cycle
Off study treatment
Platelet: <50,000 - 
25,000/mcL
1st event: hold lenalidomide and 5-
azacytidine for remainder of cycle; 
next cycle may resume once platelets 
are >75,000/mcL
2nd event: hold lenalidomide and 5-
azacytidine for remainder of cycle; 
next cycle may resume once platelets 
are >75,000/mcL
3rd event: hold lenalidomide and 5-
azacytidine for remainder of cycle
Dose reduce both 5-azacytidine and 
lenalidomide for the next cycle
2nd dose reduction of both 5-
azacytidine and lenalidomide for the 
next cycle; consider dose reduction of 
romidepsin
Off study treatment
Hgb < 8.0g/dL
Continue treatment and consider blood 
transfusion
Monitor cell counts at least twice 
weekly
1st event: hold study treatment for the 
remainder of the cycle
Continue monitoring and laboratories at 
least twice weekly 
1st Dose reduction of 5-azacytidine 
and lenalidomide for the next cycle
Any other grade 3 AE 
at least possibly related 
to study treatment
2nd event: hold treatment for the 
remainder of the cycle
3rd event: hold study treatment for the 
remainder of the cycle
2nd dose reduction of 5-azacytidine 
and lenalidomide and consider 1st 
dose reduction of romidepsin
                        Off study treatment
Grade 4 AEs
ANC < 0.5 x 109/L
or 
Platelets <25,000/mcL
1st event: hold study treatment  for the 
remainder of the cycle; next cycle may 
resume once ANC is >1.0 and platelets 
are >75,000/mcL
Monitor cell counts at least twice 
weekly 
Dose reduce  5-azacytidine and 
lenalidomide next cycle
Consider dose reduction of 
romidepsin

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Event
Initial management
Follow-up Management
2nd event: hold study treatment for the 
remainder of the cycle
Monitor cell counts at least twice 
weekly
2nd dose reduction of 5-azacytidine, 
lenalidomide with next cycle,
1st dose reduction of romidepsin
Hgb Life threatening
Discontinue treatment
Off treatment unacceptable toxicity
1st event: hold treatment 7 to 14 days
Continue monitoring and laboratories at 
least twice weekly
1 to 2 dose level reduction of 5-
azacytidine or lenalidomide or 
romidepsin for most likely causative 
agent or all 3 drugs
Consider discontinuation of 
treatment
Any other AE
2nd event: discontinue treatment
Off treatment unacceptable toxicity
3.5.2
Lenalidomide dose modifications for decreased creatinine clearance
For each cycle to commence, creatinine clearance must be > 60 mL/min/1.73 m2 calculated by 
eGFR in the clinical lab per Section 2.1.1.8.  For a decrease of creatinine clearance, which occurs 
during the cycle, the dose of lenalidomide will be modified per Table 7. Decreases of creatinine 
clearance deemed treatment-related, may result in discontinuation of protocol therapy as per Table 
6. 
Table 7: Lenalidomide renal dose adjustments
Creatinine clearance
calculated by eGFR in the clinical lab
Lenalidomide dose
Lenalidomide schedule
Days 1 to 10
(Day -7 to 10 for first cycle)
31-60 mL/min/1.73 m2 
Reduce by 50%
Daily
≤30 mL/min/1.73 m2
Reduce by 50%
Every other day
3.6
PROTOCOL STOPPING RULE
In the event of patient death (grade 5) determined to be related to the investigational treatment, 
further enrollment will be halted, consideration will be given to discontinuing treatment for all 
active patients and suspension of the protocol until the exact cause of the death is fully 
understood and whether the protocol should be terminated. 
3.7
ON STUDY EVALUATIONS
Prior to romidepsin administration (Day 1 and 10), pre-dose assessments must be performed (up 
to 3 days prior). After Cycle 1, pre-dose assessments may be performed up to 3 days prior to a 
cycle except where otherwise noted. The results from all procedures/tests must be reviewed prior 
to initiation of each cycle of treatment for consideration of dose modifications and delay of therapy. 

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Treatment with lenalidomide, romidepsin and CC-486 (5-azacitidine) will continue for six cycles 
or until disease progression, unacceptable treatment-related toxicity or other reasons outlined in 
Section 3.11.1.
Refer to the Study Calendar (Section 3.9) for a complete list of procedures to be performed at each 
scheduled study visit. See also Section 5 for all samples to be collected for correlative research. 
During treatment, it is expected that all laboratory and clinical assessments be conducted at the 
NIH (including post-treatment imaging evaluations); results from outside NIH will only be 
accepted at the discretion of the investigator.
NOTE:  Recently a patient treated in this study had symptoms of an unusual very uncommon 
serious toxicity called rhabdomyolysis related to one of the study drugs which is damage to skeletal 
muscles that produces significant elevations in the serum of muscle enzymes like creatinine kinase 
or aldolase. If a patient experiences suspicious symptoms, or has physical exam findings 
suggestive of this toxicity, the patient will be evaluated clinically (e.g., blood and urine tests will 
be performed) at the direction of the Principal Investigator/treating investigator to determine if the 
patient is having this toxicity. 
3.8
POST-TREATMENT EVALUATIONS
Patients who discontinue investigational therapy before completing protocol treatment due to 
disease progression will be followed clinically until completion of the Safety Follow-up Visit or 
until death, whichever occurs first. These patients will continue to be followed for overall survival 
as outlined Section 3.8.2. Patients removed from study treatment for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the adverse event.
3.8.1
Safety Follow-Up Visit
The safety follow-up visit should occur 30 days (+7 days) after the last dose of trial treatment, or 
before the initiation of a new anti-cancer treatment, whichever comes first. Required testing is as 
noted in the Study Calendars (Section 3.9). All AEs that occur prior to the Safety Follow-Up Visit 
should be recorded.  See section 6.1.1for documentation of AEs after study treatment has ended.
3.8.2
Follow-Up Visits - Prior to Disease Progression 
Patients who complete trial treatment without evidence of disease progression will move into the 
Follow-up Phase and may be assessed every 60 days (± 7 days) for 6 months; then every 90 days 
(± 14 days) for 2 years; then every six months (± 28 days) for 2 years, then annually (±6 weeks) 
after finishing treatment by radiologic imaging or other clinical assessments to monitor disease 
status. Every effort should be made to collect information regarding disease status until the start 
of new anti-neoplastic therapy, disease progression, death, or end of the study If the patient cannot 
return to the Clinical Center for any of these visits, a request will be made to have a local physician 
or laboratory collect a CBC with differential and send the results. If this is not possible, patients 
may be assessed by telephone or email for symptoms. 
3.8.3
Follow-Up Visits - Survival/Post-Disease Progression
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted (e.g., phone, email, etc.; 
in-person visit not required) at least every 3 to 6 months to collect information on new anti-cancer 
treatments received and to assess for survival status until death, withdrawal of consent, or the end 
of the study, whichever occurs first (see Study Calendar, Section 3.9).   Any adverse events which 

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are present at the time of discontinuation should be followed in accordance with the safety 
requirements.  

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3.9
STUDY CALENDAR
Study Cycles
Post-Treatment
Follow-Up
Procedure
Screening
Baseline
C1
C2-6
Disease 
Evaluations
End of Treatment 
and
Disease Progression
Safety1
Follow-Up
(Prior to PD)
Survival
(Post-PD)
Scheduling Window (Days):
-35 
to -82
1
(±3)
10
(±3)
15
(±3)
1
(±3)
10
(±3)
Every 2 
cycles3
Treatment 
discontinuation/PD 4
Day 30
(+7)
Every 60 or 
90 days5
Every 3 
months6
Confirmation of Diagnosis 7
X
Clonal T-cell receptor 
rearrangement by PCR
X
Medical, social and disease 
history8
X
X
Physical Exam and ECOG PS 9
X
X
X
X
X
X
X
Symptoms/Adverse Events 
Assessment, Concomitant 
Medication Review
X
X
X
X
X
X
X
CBC with Differential
X
X
X
X
X
X 
X
X
X
Reticulocyte Count
X
X
X
X
X
X
Chemistry Panels 10
X
X
X
X
X
X 
X
X
X
LDH, Serum Lipase and 
Amylase
X
X     X
X
X
X
X
X
X
PT/INR and aPTT22
X
X
X
X
X
X
TSH and free T4
X
Urinalysis
X
X
X
Pregnancy Test11 
X
X
X 
(weekly during cycle 1)
X
X
EKG, TTE
X
Pulmonary function tests 12
X

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Study Cycles
Post-Treatment
Follow-Up
Procedure
Screening
Baseline
C1
C2-6
Disease 
Evaluations
End of Treatment 
and
Disease Progression
Safety1
Follow-Up
(Prior to PD)
Survival
(Post-PD)
Scheduling Window (Days):
-35 
to -82
1
(±3)
10
(±3)
15
(±3)
1
(±3)
10
(±3)
Every 2 
cycles3
Treatment 
discontinuation/PD 4
Day 30
(+7)
Every 60 or 
90 days5
Every 3 
months6
HBsAg, HBcAb, HCVAb, HIV 
Antibody, HTLV-1/213
X
Imaging studies 14
X
X
X
X
X
MRI, Lumbar Puncture 15
X
X
X
X
Bone Marrow Aspiration/Biopsy 
16
X
X
X
Flow Cytometry17
X
X
X
X
X
Clinical photography and 
dermatology assessment/ global 
score 18
X
X
X
X
Radiologic Evaluation/ tumor 
measurement19
X
X
X
X
Uric Acid, Total Protein
X
X
X
X
X
HLA typing (A, B, C, DR, DQ) 
X
T, B, NK cell subsets
X
X
X
X
X
X
Iron panels, Folate, and B12, C-
reactive Protein
X
X
X20
Research Blood, Buccal and/or 
Saliva Samples21
X
Tissue Samples
X
Refer to Table Section 5.1.1
Survival Status
X
NOTE:  Any other tests should be performed as clinically indicated.  See Section 3.4 for drug administration information.  See Section 5 for 
information on research blood samples/correlative studies to be collected.

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1 30 days (+7) following last dose of any study drug (via clinic or phone). If initiating new anti-cancer therapy within 30 days after last dose of any study drug, 
30-day safety follow-up visit must occur before first dose of new therapy.
2 Screening and Baseline evaluations should be performed within 28 days prior to enrollment and dosing, respectively, unless otherwise noted and with the 
following exceptions:  Confirmation of diagnosis (no time limit); HIV antibody, HTLV-1/2 serologies, Hepatitis B surface antigen and Hepatitis C antibody, 
EKG, TTE, bone marrow aspiration/biopsy and Clonal T-cell receptor rearrangement by PCR (all within 3 months), baseline pregnancy testing (within 10 – 14 
days and within 24 hours prior to prescribing lenalidomide) NOTE: Any screening tests performed within the specified time frame for baseline do not need to be 
repeated. 
3 To be performed on Day 21 (±2 days) of Cycles 2, 4, and 6. Confirmatory scans should also be obtained 4 weeks following initial documentation of objective 
response.
4 To be done at end of treatment (30 days after last dose of study treatment; may be combined with 30 day safety follow-up, if timing coincides). If subject to 
initiate new anti-cancer therapy assessments should occur before the first dose of the new therapy.
5 Follow-up to occur about every 60 days (±7 days) for first 6 months, every 90 days (±14 days) for 2 years, then every 6 months (± 28 days) for another   2 years 
and then annually (± 6 weeks) until disease progression or initiation of new anti-cancer therapy.
6 After disease progression or initiation of new anti-cancer therapy, contact for survival about every 3 to 6 months (±4 weeks).
7 Pathologic review/confirmation of diagnosis by Laboratory of Pathology, NCI (no time limit). If archival sample is not available or not adequate, a fresh tumor 
biopsy and/or peripheral blood sample will be obtained.
8 Complete medical history at screening/baseline.  Interim on study and in follow-up. Disease and social history required only at screening.
9 Physical exams to include vitals, weight, and height (screening only).
10 Chemistry panels include:  Acute care, Hepatic, and Mineral. For screening, Chemistry panels (as noted) or specific analyte required for eligibility, including: 
Creatinine (i.e., Acute Care Panel); serum calcium, phosphate, magnesium and albumin (i.e., Mineral Panel); ALT, AST, total bilirubin (i.e., Hepatic Panel, 
direct bili if indicated). If a patient has physical exam evidence or complains of symptoms suggestive of rhabdomyolysis, clinical work-up will be performed 
(e.g., creatinine kinase, aldolase, possibly serum myoglobin and additional urine studies) to determine if the patient is experiencing rhabdomyolysis and the tests 
will be repeated to monitor for resolution of this event; dose modification or interruption or discontinuation of treatment will occur, as needed.
11 Individuals of childbearing potential with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of lenalidomide 
treatment, including dose interruptions and then every 28 days throughout the remaining duration of lenalidomide treatment, including dose interruptions, at 
lenalidomide discontinuation, and at Day 28 following lenalidomide discontinuation.  If menstrual cycles are irregular, the pregnancy testing must occur weekly 
for the first 28 days of lenalidomide treatment, including dose interruptions, and then every 14 days throughout the remaining duration of lenalidomide 
treatment, including dose interruptions, at lenalidomide discontinuation, and at Day 14 and Day 28 following lenalidomide discontinuation.
12 Diffusing capacity/alveolar volume (DLCO/VA) forced expiratory volume in 1 second (FEV1) for patients with significant pulmonary or smoking history.
13 HBV DNA PCR, HCV PCR, and/or HIV 1/2 viral load will be tested for patients with positive serologies.
14At screening CT scans of neck, chest, abdomen, and pelvis should be performed (with IV and PO contrast, unless patient is allergic or has renal insufficiency; 
other imaging may be substituted at the discretion of the investigator). Other body areas may be imaged if clinically indicated. MRI of the brain is only required

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in patients with suspected involvement of CNS. Also, at screening, a FDG-PET/CT torso (extremities to be included if there is confirmed or suspected disease 
involvement). At baseline one or more of the following studies: CT, MRI, FDG-PET/ CT and or clinical photography; MRI of the brain is only required in 
patients with suspected involvement of CNS.  A FDG-PET/ CT will be done after Cycle 2 and at the End of Treatment. 
15 Patients with neurological symptoms or signs should undergo MRI scan of the brain and lumbar puncture.
16 Baseline bone marrow aspiration/ biopsy with flow cytometry must be done within 3 months prior to starting treatment. During post-treatment follow-up, 
repeat bone marrow aspiration/ biopsy needed only to confirm a CR.
17 Clinical peripheral blood flow cytometry (Laboratory of Pathology, NCI) may be done for disease evaluation of patients who had circulating leukemic cells 
detected at baseline, and for patients with CTCL regardless of their baseline results.
18 To be performed in selected patients with cutaneous disease (as determined by PI or AI).
19 Dermatology assessment & Global/mSWAT scoring  be used instead of/ in addition to radiologic evaluation for patients with predominantly cutaneous disease.
20 Patients with elevated CRP and soluble IL2Rɑ will have them repeated every 6 weeks as part of disease evaluation.
21 Samples for correlative research are to be collected as indicated in Section 5. If archival tissue is not available or adequate, baseline punch biopsy of the skin or 
core needle biopsy of a lymph node/visceral lesion is required, otherwise this is optional.
22 PT/ INR and aPTT are required at screening, baseline and before procedures (as clinically indicated). Other timepoints are optional as tubes are available.

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3.10 COST AND COMPENSATION
3.10.1 Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they are 
not covered by insurance their company. 
3.10.2 Compensation
No direct compensation will be provided on the study.
3.10.3 Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation. Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the subject as 
appropriate.  The amount and form of these payments are determined by the NCI Travel and 
Lodging Reimbursement Policy.  
3.11 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all patients complete a safety visit 
approximately 30 days following the last dose of study therapy. Additional safety visits and follow-
up will continue as per Section 3.8.
3.11.1 Criteria for removal from protocol therapy
Patients who meet the following criteria should be discontinued from protocol therapy:
•
Completion of protocol therapy (i.e., up to 6 cycles) 
•
Confirmed disease progression
•
Intercurrent illness that prevents further administration of treatment
•
Unacceptable toxicities as listed in Section 3.9 or those toxicities listed in Section 3.5 
that requires treatment to be stopped.
•
Subject’s request to withdraw from protocol therapy
•
Investigator’s decision to withdraw the patient
•
Subject’s non-compliance with trial treatment or procedure requirements that requires 
removal in the opinion of the PI
•
Pregnancy
•
The drug manufacturer can no longer provide the study agent
•
Study is cancelled for any reason
3.11.2 Off-Study Criteria
•
Subject requests to be withdrawn from study
•
Subject is lost to follow-up
•
Death 
•
Study is cancelled for any reason

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3.11.3 Lost to Follow-up
A participant will be considered lost to follow-up if they fail to return for two (2) scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
•
The site will attempt to contact the participant and reschedule the missed visit within 3 
business days and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, an IRB approved certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record or study file. 
•
Should the participant continue to be unreachable, they will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.
For premedication and supportive care measures, see Section 3.4.3.1, 3.4.3.2 and 3.4.3.3.
4.1
ACCEPTABLE MEDICATIONS
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care. All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications. If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date may also be included on the 
CRF.
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  
4.2
CONCOMITANT MEDICATIONS TO BE USED WITH CAUTION
Concomitant medications that fall into the categories below could potentially lead to adverse 
reactions and should be considered cautionary (except where noted). If a potential study patient is 
taking any of the medications in the categories described below, the investigator must assess and 
document the use of medications known or suspected to fall in the following medication 
categories:
•
Growth factors: initiation of G-CSF support (e.g. filgrastim or pegfilgrastim) will be 
administered at the discretion of the investigator for instances of G2 or higher neutropenia 
or as prophylaxis to prevent neutropenia. If short-acting G-CSF is initiated (e.g., 
filgrastim), dosing should continue daily until the patient completes their day 14 study 
therapy AND the neutrophil count > 5000 cells/L.  Alternatively, patients may receive 

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long-acting G-CSF (e.g., pegfilgrastim) at the discretion of the investigator. Once G-CSF 
(filgrastim or pegfilgrastim) has been initiated during a previous cycle, the patient should 
receive prophylactic G-CSF support during all subsequent cycles of therapy.  Short-acting 
G-CSF (e.g., filgrastim) should be given daily starting on day 3 (+/-1 day) and should 
continue until the patient completes their day 14 study therapy AND the neutrophil count 
> 5000 cells/L. Alternatively, patients may receive prophylaxis with long-acting G-CSF 
(e.g., pegfilgrastim) administered on day 3 (+/-1 day) of each cycle at the discretion of the 
investigator.
•
Romidepsin concomitantly with warfarin:  Monitor PT and INR more frequently in patients 
concurrently receiving romidepsin and warfarin. It is not known if there is an interaction 
with co-administration of lenalidomide and warfarin.  Close monitoring of PT and INR is 
recommended.
•
Digoxin:  For subjects taking digoxin, periodic monitoring of digoxin plasma levels is 
recommended due to increased Cmax and AUC with concomitant lenalidomide therapy 
(please see prescribing information).
•
Erythropoietin stimulating agents or estrogen containing therapies:  Subjects taking 
concomitant therapies such as erythropoietin stimulating agents or estrogen containing 
therapies, may have an increased risk of venous thromboembolism (please see prescribing 
information).
•
CYP3A4 inhibitors:  After the DLT evaluation window, subjects who need to start 
treatment with strong CYP3A4 inhibitors (Appendix C), should be monitored closely for 
toxicities.  These are prohibited during the DLT window.
4.3
PROHIBITED MEDICATIONS
Patients are prohibited from receiving the following therapies during treatment on this trial:
•
Other therapy for the disease under study not specified in this protocol, unless specifically 
noted as permitted
•
Investigational agents other than lenalidomide, romidepsin and CC-486 (5-azacitidine)
•
Rifampin and other strong CYP3A4 inducers (Appendix C)
•
Agents that may cause QTc prolongation (Appendix E) 
•
Radiation therapy 
NOTE: Radiation therapy to a symptomatic solitary lesion may be allowed at the 
investigator’s discretion.  
•
Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, typhoid vaccine and 
FluMist. 
A list of common CYP3A inhibitors or inducers is provided in Appendix C; a comprehensive list 
of inhibitors, inducers, and substrates may be found at:
http://medicine.iupui.edu/clinpharm/ddis/table.aspx.
This website is continually revised and should be checked frequently for updates.

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Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study treatment. Patients may 
receive other medications that the investigator deems to be medically necessary.
5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
5.1.1
Summary
This study will test the feasibility of concomitant NFϰ-B inhibition with lenalidomide and 
epigenetic modification with CC-486 (5-azacitidine) and romidepsin in patients with T-cell 
malignancies. Although increased efficacy with the combination has been demonstrated in vitro, 
effects of the combined treatment on the tumor microenvironment, circulating immune cell 
subsets, cytokine production, and exosome composition are not known. The correlative studies 
performed in this trial will focus on how lenalidomide alone and in combination affects tumor 
cells, immune cell subsets, and cytokines in tumor tissue and peripheral blood, and whether these 
may represent a predictive or prognostic biomarker in patients with TCMs. 
Composition of the tumor microenvironment will be analyzed via immunohistochemistry, flow 
cytometry, and single-cell RNAseq before treatment, after 7 days of single-agent lenalidomide, 
and after 15 days of combined treatment with lenalidomide, romidepsin, and CC-486 (5-
azacitidine). Differences in circulating immune cell subsets associated with administration will be 
followed throughout treatment to both study the effects of combined therapy on the immune 
system, and to identify potential biomarkers that would be predictive of response. Circulating 
tumor DNA and exosome composition will be followed and analyzed with the same goal in mind. 
Germline DNA will be sequenced to distinguish circulating tumor DNA from other cell-free DNA.
Time Points†
Sample
Collection Details*
Baseline 4
(C1 D-7)
C1 
D1
C1 
D10
C1 
D15
C2-6
D1
C2-6 
D10
Follow-
up#
Supervising 
Laboratory/ 
Investigator
^
Blood Samples
Lymphocyte subset 
testing
• 2 x 10mL K2EDTA 
(lavender-top) tubes
X
X
X
(X)
(X)
(X)1
DLM
PBMC banking
• 3 x 10mL Na-heparin 
(green-top) tube
X
X
X
(X)
X
(X)
X
 Leidos CSL
Circulating tumor 
DNA, plasma 
banking**
• 1 x 10mL K2EDTA tube
• 1 x 10mL Streck/BCT 
tube
X
X
X
X2
Leidos CSL
Tissue Samples
Tissue immune cell 
subsets
• Two core biopsy samples 
in RPMI 1640 with 10% 
human serum and 
antibiotics
• One core biopsy sample 
in formalin
NOTE:  Samples may be 
tumor tissue or bone 
marrow aspirate/biopsy 
X***
(X)
(X)
(X)
At disease 
progression
(RPMI 1640)
and
DLM/ 
NCI LP 
(formalin)

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Time Points†
Sample
Collection Details*
Baseline 4
(C1 D-7)
C1 
D1
C1 
D10
C1 
D15
C2-6
D1
C2-6 
D10
Follow-
up#
Supervising 
Laboratory/ 
Investigator
^
Other Samples
Germline DNA
• Blood, Buccal Swab, or 
Saliva (preferred) – see 
5.4
X
Leidos CSL
(X) = Optional; samples will be collected if adequate time/staff available for processing, and if research blood drawn is less than 
the allowed limit noted in Section 5.1.3. If an optional sample is not collected at baseline, it would also not be collected in follow-
up unless specifically requested by the PI. 
^ The location of specimen processing or analysis may be adjusted with the permission of the PI or laboratory investigator.
*Tubes/media may be adjusted at the time of collection based upon materials available or to ensure the best samples are collected 
for planned analyses.
** May be omitted if research blood drawn would be over the allowed limit noted in Section 5.1.3.
***Tumor biopsy (bone marrow, skin, or ultrasound-guided LN biopsies) is required if archival tissue is not available or 
adequate; otherwise, this is optional  
† All time points during treatment are ±3 days. All follow-up time points are ±7 days. 
#Subjects who discontinue treatment for a reason other than disease progression and who do not start new treatment should 
continue to have study bloods collected at the scheduled time points.
1 At the end of treatment only.
2 At each follow-up visit prior to disease progression, as specified in Section 3.8.2.
4 With the exception of tissue immune cell subset (if applicable) and Germline DNA which are to be collected during Baseline, 
samples correlating to the lead-in window will no longer be collected as the lead-in window has been retired.
5.1.2
Sample Collection and Processing
5.1.3
Summary
The planned sample collection will be done as specified below and analyses described below may 
be done on leftover and/or shared sample portions from the respective laboratories, as needed. In 
addition to the prospectively collected samples below, leftover portions of samples sent for routine 
laboratory testing (e.g., plasma from CBC/hematologies) may also be retrieved for research tests 
prior to being discarded. The planned prospective analyses are identified below; laboratories may 
share resources or collaborate on analyses, if appropriate.
Portions of all samples may be banked for future research analyses; prospective consent will be 
obtained during the informed consent process.  
Tissue samples will also be sent to the Hematopathology Section of the National Cancer Institute 
Laboratory of Pathology, by courier service.
5.2
BLOOD SAMPLES
All blood samples will be drawn by NIH Clinical Center phlebotomy, inpatient unit, outpatient 
clinic, or day hospital staff.
5.2.1
Lymphocyte subset testing by flow cytometry (FACS)
•
Collect blood in EDTA tubes; gently invert tubes 8-10 times immediately after collection 

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•
Labels listing the patient's name, date of birth, date and time of the blood draw will be 
affixed to all the tubes by the staff person who obtained the samples.
•
Lymphoid Malignancies Branch Clinical Research personnel will arrange for these 
samples to be delivered to: Immunology Lab, NIH Clinical Center Bldg. 10/ Room 2C410. 
If the Immunology Section Laboratory is unable to perform these analyses (Lymphocyte 
Subset Testing-CTCL for patients with cutaneous T-cell lymphoma and Lymphocyte 
Subset Testing-antiTAC for all other patients) on the specified days, this assessment maybe 
omitted or replaced with standard TBNK panel
5.2.2
Cell-free DNA (cfDNA), circulating tumor DNA (ctDNA) and plasma banking
•
Collect 10 mL of blood in one cell-free DNA (e.g., Streck BCT/collection tubes) and 10 
mL of blood in one K2EDTA tube; gently invert the tubes 8-10 times immediately after 
collection. 
•
Labels listing the patient's name, date of birth, date and time of the blood draw will be 
affixed to all the tubes by the staff person who obtained the samples. Plasma will be isolated 
and frozen at -80ºC until analysis (e.g., centrifuged at 1800 x g for 10 minutes at room 
temperature; plasma transferred/frozen in aliquots of 1.5-2 mL each).
•
Lymphoid Malignancies Branch Clinical Research personnel will arrange for these 
samples to be delivered to Clinical Support Laboratory, Leidos Biomedical Research, 
Inc.in Frederick, MD for sample processing per established techniques maintained within 
standard operating procedures in the laboratory.
5.2.3
Peripheral blood mononuclear cell (PBMC) banking
•
Collect blood in 10 mL Na-heparin (green-top) tubes; gently invert tubes 8-10 times 
immediately after collection.
•
Labels listing the patient's name, date of birth, date and time of the blood draw will be 
affixed to all the tubes by the staff person who obtained the samples. Peripheral blood 
mononuclear cells (PBMCs) will be isolated by Ficoll-High-Paque Density Gradient 
Centrifugation and frozen at -20°C or lower until analysis.
•
Lymphoid Malignancies Branch Clinical Research personnel will arrange for these 
samples to be delivered to Clinical Support Laboratory, Leidos Biomedical Research, 
Inc.in Frederick, MD for sample processing per established techniques maintained within 
standard operating procedures in the laboratory.
5.3
TISSUE SAMPLES
5.3.1
Immunohistochemistry (IHC)
•
Archival block(s) or slides (i.e., at least 15 unstained slides, 5-microns) are required at 
baseline for participants if there are no circulating lymphoma cells or if the amount of 
circulating leukemia/lymphoma cells is insufficient to perform the correlative studies. 
Patients with prior skin, lymph node, or visceral biopsies performed at NIH or outside 
institutions must make specimen blocks available to the NCI Pathology Department for 
analysis. If no prior biopsies are available at the time of screening, patients with Cutaneous 
T-cell lymphoma and other lymphoma with skin involvement will undergo a punch biopsy 
of a skin lesion, performed by an NIH Clinical Center dermatologist. Patients with lymph 
node and/or visceral involvement will undergo an 18g core biopsy performed by the 

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Department of Radiology and Imaging Sciences’ Interventional Radiologists (IR). An 
optional biopsy will be performed in the same manner at timepoints listed in 5.1.1.
•
Prior specimen blocks will be sent to NCI Pathology Department via FedEx. For patients 
with no prior samples who undergo biopsy as part of screening (if needed for diagnosis) or 
baseline, core tumor tissue (or bone marrow aspirate/biopsy) samples will be collected and 
placed in appropriate media (e.g., RPMI 1640 with 10% human serum and antibiotics, and 
formalin) and processed per established techniques.  As indicated (Sections 5.1 and 5.2), 
samples will be sent to the Department of Laboratory Medicine (DLM)/ NCI Laboratory 
of Pathology (LP) for concurrent routine histologic analysis and reporting and IHC testing 
and tumor-associated immune cells in addition to research testing (i.e., storage for 
subsequent single-cell analyses).
5.4
OTHER SAMPLES
5.4.1
Germline DNA
•
Germline DNA will be collected by blood, buccal swab, and/or saliva samples 
(preferred).  These will ideally be collected at baseline; however, may be collected at 
any point on study based on supplies.  Standardized, commercial collection kits or tubes 
will be used (e.g., 1, 5-10 mL K2EDTA tube for blood; Isohelix SK-1 for buccal swabs; 
Salviette/Oragene® for saliva).  In the case of buccal swabs, two (2) samples may be 
collected in order to ensure adequate DNA collection.    
•
Lymphoid Malignancies Branch Clinical Research personnel will arrange for these 
samples to be delivered to Clinical Support Laboratory, Leidos Biomedical Research, 
Inc. in Frederick, MD for sample processing per established techniques maintained 
within standard operating procedures in the laboratory.
5.5
BIOMARKER AND RESEARCH METHODS
The technology platforms that are able to interrogate genomic structure and function are constantly 
in flux; therefore, the exact nature of the methodologies that will be employed will be assessed at 
the time that the samples are collected and ready for analysis. The protocol will be amended at that 
time, if needed, to describe the intended techniques prior to initiating the analyses.
Note: Platforms and procedures for analysis may be adjusted based upon current technology 
and/or collaborations in place at the time of actual analyses.
The following are technologies that are currently in use for each planned analysis:  
5.5.1
Molecular Profiling
Immunohistochemical (IHC) analyses, including FISH and/or PCR testing, will take part in tumor 
tissue samples, including but not necessarily limited to CD2, CD3, CD4, CD5, CD7, CD8, CD14, 
CD16, CD20, CD25, CD38, CD45RA, CD45RO, CD56, CD62L, CD69, CD79a/CD79b, CD122, 
Foxp3, perforin, gamma/delta, CXCR3, CCR4, and NKG2D.
5.5.2
Immune Subset Analysis
Peripheral blood mononuclear cells (PBMC) will be assessed using multiparameter flow cytometry 
for immune subsets including but not necessarily limited to CD8+ T-cells, CD4+Foxp3- T-cells, 
Tregs, Tex, Th1, Th2 and Th17+ CD4+ T-cells, NK cells and subsets, monocyte subsets, MDSC 

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subsets. Assessment may include functional markers, i.e. PD-1, Tim-3, CTLA-4, PD-L1, HLA-
DR, Ki67 and/or CD40.
5.5.3
cfDNA/ctDNA
Since the methods of molecular monitoring in the peripheral blood is an emerging field with 
numerous technologies under development, the storage of peripheral blood mononuclear cells 
(PBMC), serum, and plasma will all be performed allowing for future comparison of the different 
compartments for analytes that include cell-free circulating tumor DNA (ctDNA), and RNA 
sequencing of circulating tumor cells. Studies to be performed on these samples include: 
cfDNA/ctDNA for liquid genotyping as a non-invasive dynamic monitoring of disease as well as 
monitoring for individual molecular aberrations that herald progression or disease transformation; 
specifically, amplification and sequencing of the VDJ segment of the immunoglobulin receptor is 
planned. Germline DNA obtained from saliva, blood, or buccal mucosa will be used to 
discriminate somatic from germline mutations during cfDNA and ctDNA analyses. 
5.5.4
DNA/RNA Sequencing 
Genomic DNA and total RNA will be extracted from tumor samples using a Qiagen All-prep kit. 
For individual target genes that are recurrently mutated in T-cell malignancies, classical Sanger 
sequencing will be performed on PCR amplicons, using primers surrounding the known sites of 
mutation. To broadly assess mutations, next generation sequencing (e.g., on an Illumina HiSeq 
2000 platform) will be employed, using a paired end sequencing strategy of libraries constructed 
from tumor DNA. DNA will either be sequenced in its entirety from a whole genome library or 
will be first enriched for exonic sequences using the Agilent Sure Select system, aiming for 30X 
or 100X average coverage per base, respectively. The sequence fragments will be mapped back to 
the genome using the BWA algorithm. Of sequences overlapping a particular base pair in the 
genome, the percent mutant calls greater that 20% with a minimum of 25X coverage will be 
considered as an arbitrary threshold for single nucleotide variants (SNVs). SNVs that are not 
present in the matched normal sample will be considered candidate somatic mutations. 
A related technology, RNA-Seq, utilizes RNA from the tumor specimen to create a cDNA library 
for high-throughput sequencing. RNA-seq will be performed using Illumina kits followed by high-
throughput sequencing on an Illumina HighSeq 2000 machine. The cutoffs for coverage and 
percent mutant calls mentioned above will also be used to identify putative SNVs. RNA 
sequencing will also be used to read out digital gene expression across the genome as described.
Recent advances in genomic technologies enable GEP at the single cell level, a distinct advantage 
over conventional GEP which cannot always distinguish tumor vs non-tumor gene expression.  
Single-cell approaches allow identification of the evolution of rare populations of resistant tumor 
cells, as well as identification of TME cells critical for the survival of the tumor. The Center for 
Cancer Research (CCR) has recently opened a single cell analysis core facility with expert staff 
headed by Dr. Michael Kelly within the CCR Genomics Core.  This facility has the ability to take 
purified viably frozen cells banked from patient biopsies and prepare them, using well-validated 
10X Genomics technology, for single-cell RNA sequencing.  This core is directly integrated with 
the NCI Sequencing core facility to provide high-quality, deep-sequencing of the single cell RNA-
SEQ samples, as well as ‘first-pass’ data processing and analysis.  Data will then be transferred to 
lymphoma researchers and bio-informaticians for further analysis of gene expression patterns and 
cellular population dynamics.

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5.5.5
Future Use
Any blood, tissue, or other products or portions leftover from other analyses will be stored for 
future research.  
5.6
SAMPLE STORAGE, TRACKING, AND DISPOSITION
5.6.1
General
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples 
will not be sent outside NIH without appropriate approvals and/or agreements, if required.
5.7
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.7.1
Description of the scope of genetic/genomic analysis
The research correlates for this study are expected to include DNA/RNA sequencing of tumors, 
including circulating tumor (ct) DNA. In addition, whole exome sequencing may include 
evaluation for known lymphoma mutations. For any genetic studies performed, the results will be 
deposited in a database such as dbGaP per NIH requirements.  Although there is controlled access 
to such a database, such a submission carries theoretical risks of revealing the identity of the 
subject.  This is discussed in the consent.
5.7.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
Confidentiality for genetic samples will be maintained as described (Section 5.6).  In addition, a 
Certificate of Confidentiality has been obtained for this study.
5.7.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for this study are defined as disorders appearing in the American College of 
Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis. 
5.7.4
Genetic Counseling
Subjects will be contacted at this time with a request to provide a sample to be sent to a CLIA 
certified laboratory.  If the research findings are verified in the CLIA certified lab, the subject will 
be offered the opportunity to come to NIH to have genetic education and counseling to explain 
this result; at the time of any such event(s), these activities will be funded by the NCI/CCR in 
consideration of the specific circumstances.  If the subject does not want to come to NIH, a referral 
to a local genetic healthcare provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
6.1.1
Summary
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. 

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The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts. Primary and final analyzed data will have 
identifiers so that research data can be attributed to an individual human subject participant.
All adverse events (AEs), including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until return to baseline or stabilization of 
event.
Document AEs from the first study intervention, Study Day 1 through 30 days after the last 
intervention. Beyond 30 days after the last intervention, only adverse events which are serious and 
related to the study intervention need to be recorded.  
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in Section 7.2.1.
6.1.2
Data Collection/Recording Exceptions
6.1.2.1
Abnormal Laboratory Values
An abnormal laboratory value will be recorded as an AE only if the laboratory abnormality is 
characterized by any of the following:
•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization
•
Is judged by the Investigator to be of significant clinical impact
•
If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the test drug and about the 
patient’s outcome.
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:
_X_ Coded, linked data in an NIH-funded or approved public repository.  
_X_ Coded, linked data in another public repository
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
_X_ Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:
_X_ An NIH-funded or approved public repository.  Insert name or names: ClinicalTrials.gov, 

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dbGaP.
_X_ BTRIS (automatic for activities in the Clinical Center)
_X_ Approved outside collaborators under appropriate individual agreements.  
_X_ Publication and/or public presentations.
When will the data be shared?
_X_ Before publication.
_X_ At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
6.3.1
Response Assessments 
Tumor response will be assessed by the investigator using the RECIL 2017 criteria [66] for all 
patients with T-cell lymphoma other than CTCL. Global Response Score [67], and modified 
severity weighted assessment tool (mSWAT) [68] will be used for patients with CTCL. For 
leukemic disease, leukemic cells (ATL, Sezary or T-PLL) as percentage of PBMCs will also be 
assessed and reported separately and response will be assessed using consensus guideline [69]. 
Patient will be re-evaluated for response as outlined in the Study Calendar, Section 3.9.
6.3.1.1
Response Criteria for PTCL
RECIL 2017 criteria [66] use the Deauville five-point scale for assessment of response via FDG-
PET. The five-point scale (5-PS) has been validated for use at interim staging and at the end of 
treatment and was adopted as the preferred reporting method at the First International Workshop 
on PET in Lymphoma in Deauville, France (i.e., Deauville criteria), and in several international 
trials.
The 5-PS PS scores the most intense uptake in a site of initial disease:
1. if present, as follows: no uptake or no residual uptake (when used at interim)
2. slight uptake, but below blood pool (mediastinum)
3. uptake above mediastinal, but below or equal to uptake in the liver
4. uptake slightly to moderately higher than liver
5. markedly increased uptake or any new lesion (on response evaluation) 
The sum of longest diameter (SLD) is used for assessment of tumor burden. In patients with 
disseminated disease, a maximum of three target lesions should be selected and used to estimate 
tumor response. Target lesions should be selected from those with the largest size that can be 
reproducibly measured and preferably representing multiple sites and/organs. In most cases, lymph 
nodes can be considered target lesions if the lymph node longest diameter measures ≥15 mm. A 
lymph node measuring between 10 and 14 mm is considered abnormal but should not be selected 
as a target lesion. Lymph nodes measuring <10 mm in diameter are considered normal. In certain 
anatomical sites (inguinal, axillary, and portocaval), normal lymph nodes may exist in a narrow, 
elongated form, and such nodes should not be selected as target lesions if alternatives are available. 
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size, and the ease of reproducibility of repeated measurements, with a minimum measurement of 
the longest diameter of ≥ 15 mm. All other lesions should be identified as nontarget lesions and 
should be recorded at baseline, without the need to measure them. Nontarget lesions should be 
followed and reported as present, absent, or clear progression.
Table 86: Response categories based on assessment of target lesions
% Change in sum of diameters of target lesions from nadir
CR
PR
MR
SD
PD
% change from 
baseline
•
Complete 
disappearance of 
all target lesions 
and all nodes with 
long axis <10mm
•
>30% decrease in 
the sum of longest 
diameters of target 
lesions (PR) with 
normalization of 
FDG-PET
>30% 
decrease in 
the sum of 
longest 
diameters of 
target 
lesions but 
not a CR
>10% 
decrease in 
the sum of 
longest 
diameters 
of target 
lesions but 
not a PR 
(<30%)
<10% 
decrease 
or < 20% 
increase in 
the sum of 
longest 
diameters 
of target 
lesions
•
>20% increase in the 
sum of longest 
diameters of target 
lesions
•
For small lymph nodes 
measuring <15 mm 
post therapy, a 
minimum absolute 
increase of 5 mm and 
the long diameter 
should exceed 15 mm
•
Appearance of a new 
lesion
FDG-PET
Normalization of 
FDG-PET (Deauville 
score 1-3)
Positive 
(Deauville 
score 4-5)
Any
Any
Any
Bone marrow 
involvement
Not involved
Any
Any
Any
Any
New lesions
No
No
No
No
Yes or No
CR, complete response; CT, computerized tomography; FDG-PET, [18F]2-fluoro-2-deoxy-D-glucose; MR, minor 
response; PD, progression of disease; PR, partial response; SD, stable disease.
6.3.1.2
Response Criteria for CTCL
Global Response (GR) score (Appendix B) will be used for assessing response in patients with 
CTCL [67]. GR score incorporates separate responses in each component of the TNBM staging 
(i.e., skin, nodes, viscera and blood; (Appendix B). No patient with a global OR should have less 
than a PR in the skin.
The mSWAT [68] is an instrument utilized to track the skin tumor burden in MF/SS. It measures 
the percentage total body-surface area (TBSA, %) involvement separately for patches, plaques, 
and tumors within 12 body regions using the patient's palm and fingers representing 1% of TBSA. 
Patients with erythroderma are assessed for percentage of TBSA involved with patches and/or 
plaques. The percentage of TBSA for each lesion type is multiplied by a number (patch = 1, plaque 
= 2; tumor = 4) and summed to derive the mSWAT score. The mSWAT for each patient will be 
determined by the same individual at all study visits.
A complete response (CR) requires 100% clearing of skin disease and a partial response (PR) 
requires ≥ 50% reduction in the mSWAT score compared with baseline. CR/PR requires 
confirmation by repeat assessment after ≥ 4 weeks. Stable disease is defined as less than 50% 
reduction to less than 25% increase in the mSWAT score compared with baseline. PD is defined 
as ≥ 25% increase in the mSWAT score from baseline or ≥ 50% increase in the sum of the products 
of the greatest diameters of pathologically positive lymph nodes compared with baseline.

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Time to response is the time from the first treatment dose until the patient first meets the criteria 
for a 50% decrease in the GR score. The duration of response (DOR) is the time from first CR/PR 
until the GR score is increased from nadir to more than 50% of the difference between the baseline 
and nadir scores. Time to progression (TTP) is the time from start of treatment until PD. If patients 
go off treatment for any purpose, this date is used for determination of TTP and/or DOR.
Table 9: Calculating mSWAT Score
Assessment of Involvement in Patient’s Skin
Body Region
% BSA in Body Region
Patch1
Plaque2
Tumor3
Head
7
Neck
2
Anterior trunk
13
Arms
8
Forearms
6
Hands
5
Posterior trunk
13
Buttocks
5
Thighs
19
Legs
14
Feet
7
Groin
1
Subtotal of lesion BSA
Weighing factor
x1
x2
x4
Subtotal lesion BSA x 
weighing factor
NOTE:  mSWAT score equals summation of each column line.
Abbreviations: BSA, body surface area; mSWAT, modified Severity Weighted Assessment Tool.
1 Any size lesion without induration or significant elevation above the surrounding uninvolved skin; poikiloderma 
may be present
2 Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present.
3 Any solid or nodular lesion > 1cm in diameter with evidence of deep infiltration in the skin and/or vertical 
growth.
6.3.2
Best Overall 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.
6.3.3
Duration of Response
The duration of response (DOR) is measured from the time measurement criteria are met for CR 
or PR (whichever is recorded first) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started), death, or, in the absence of PD, date of last assessment.

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6.3.4
Event-Free Survival
Event-free survival (EFS) is defined as the duration of time from the date of study enrollment until 
time of disease relapse, disease progression, alternative anti-lymphoma therapy, or death, 
whichever occurs first.
6.3.5
Progression-Free Survival
Progression-free survival (PFS) is defined as the duration of time from the date of study enrollment 
until time of disease relapse, disease progression, or death, whichever occurs first.
6.3.6
Overall Survival
Overall survival (OS) is defined as the time from the date of study enrollment until time of death 
from any cause.
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
7
NIH REPORTING REQUIREMENTS/ DATA SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/hrpp-policy-guidelines/.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/hrpp-policy-guidelines/. 
Note: Only IND Safety Reports that meet the definition of an unanticipated problem or present 
new information that might affect the willingness of participants to enroll or remain on the study 
will need to be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/hrpp-policy-guidelines/.
7.3
NCI CLINICAL DIRECTOR REPORTING
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  

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To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team
The clinical research team will meet at least once weekly when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation will 
be made during the meeting based on the toxicity data from prior patients and documented in the 
meeting minutes.
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in Section 
7.2.1 will be submitted within the appropriate timelines.
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.
7.4.2
Safety Monitoring Committee (SMC)
NOTE:  CCR SMC was added in an amendment; protocol version 11/12/2021.
This protocol will be periodically reviewed by an intramural Safety Monitoring Committee. 
comprising physicians, biostatisticians and a lay member selected based on experience, area of 
expertise, reputation for objectivity, absence of conflicts of interest and knowledge of or 
experience with clinical trial research. Initial review will occur as soon as possible after the annual 
NIH Intramural IRB continuing review date. Subsequently, each protocol will be reviewed as close 
to annually as the quarterly meeting schedule permits or more frequently as may be required by 
the SMC based on the risks presented in the study. For initial and subsequent reviews, protocols 
will not be reviewed if there is no accrual within the review period. 
The SMC will operate under the rules of an approved charter that will be written and reviewed at 
the organization meeting of the SMC.  Each review will focus on unexpected protocol-specific 
safety issues that are identified during the conduct of the clinical trial.
Written outcome letters will be generated in response to the monitoring activities and submitted to 
the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
8
SPONSOR PROTOCOL/ SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2)).

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8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death,
•
A life-threatening adverse event (see section 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions
•
A congenital anomaly/birth defect
•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32).
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  
•
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.

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8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution (return to baseline or stabilization) of the event, seriousness and outcome. The 
assessment of severity and relationship to the study product will be done only by those with the 
training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal 
investigator or sub-investigator.  AEs occurring during the collection and reporting period will be 
documented appropriately regardless of relationship.  AEs will be followed through resolution 
(return to baseline or stabilization).
SAEs will be:
•
Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
principal investigator or sub-investigator.
•
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.
•
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4.
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety.  Any exceptions to the expedited reporting requirements are found 
in section 8.4.
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted via an electronic SAE reporting system (e.g. HiLIT). In the event 
of system downtime or issues , SAE reports will be submitted using the CCR SAE Report form 
to the sponsor at: OSROSafety@mail.nih.gov. CCR SAE report form and instructions can be 
found at: 
https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-Communications/SitePages/Forms-and-
Instructions.aspx?csf=1&web=1&e=uWBX 
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR
As progression free survival, which includes death due to disease progression is part of the study 
objectives, and captured as an endpoint in this study, death due to disease progression will not be 
reported in expedited manner to the sponsor. However, if there is evidence suggesting a causal 
relationship between the study drug and the event, report the event in an expedited manner 
according to section 8.3.

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8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement.
8.6
REPORTING PREGNANCY
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-
Communications/SitePages/Forms-and-Instructions.aspx?csf=1&web=1&e=uWBXtI 
8.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the pregnancy becomes known.
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.6.2
Paternal exposure
Individuals who can father children should refrain from fathering a child or donating sperm during 
the study and for 28 days after the last dose of lenalidomide and for 3 months after the last dose of 
CC-486 (5-azacitidine).
Pregnancy of the patient’s partner is not considered to be an AE. The outcome of all pregnancies 
occurring from the date of the first dose until 6 months after the last dose should, if possible, be 
followed up and documented. Pregnant partners may be offered the opportunity to participate in 
an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry study) to 
provide data about the outcome of the pregnancy for safety reporting purposes.
8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the study product and 
the adverse event.  CCR will notify FDA and all participating investigators (i.e., all investigators 
to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND 
safety report of potential serious risks from clinical trials or any other source, as soon as possible, 
in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.8
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual of 
Operational Procedures (MOP) and other Sponsor approved study related, GCP, or protocol-
specific procedural requirements on the part of the participant, the Investigator, or the study site 
staff inclusive of site personnel performing procedures or providing services in support of the 
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It is the responsibility of the study Staff to document any protocol deviation identified by the Staff 
or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. 
The entries into the PDTS online application should be timely, complete, and maintained per CCR 
PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source records 
and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation 
reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance 
with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations.
9
CLINICAL MONITORING
Clinical site monitoring is conducted to ensure: 
•
That the rights of the participants are protected; 
•
that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures, and,  
•
the quality and integrity of study data and data collection methods are maintained.
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good 
Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory 
requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates. 
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study start to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will take place at the study 
site(s).  Monitoring visit reports will describe visit activities, observations, findings of protocol 
non-adherence and associated action items or follow-up required for resolution of findings.  
Monitoring reports will be distributed to the study PI, NCI CCR QA, coordinating center (if 
applicable) and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance.

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10 STATISTICAL CONSIDERATIONS
10.1 STATISTICAL HYPOTHESIS
•
Primary Endpoint(s): 
o
Maximum tolerated dose (MTD) of lenalidomide administered orally in 
combination with romidepsin and CC-486 (5-azacitidine) for up to 6 cycles
o
Frequency (number and percentage) of treatment-emergent AEs
•
Secondary Endpoint(s):
o
Overall response rate (including complete response rate and partial response rate), 
after treatment
o
Duration of response, after treatment 
o
Progression-free survival after treatment 
o
Event-free survival after treatment
o
Overall survival
10.2 SAMPLE SIZE DETERMINATION
The MTD will be based on the assessment of DLT during the first cycle of treatment and will be 
defined as the dose level at which less than one-third of patients (0 of 3 or 0-1 of 6 patients) treated 
experience a DLT, with the next higher dose level demonstrating one-third or a greater number of 
patients (≥ 2 of 3 or ≥ 2 of 6 patients) having a DLT.  If a subject did not experience a DLT and 
did not finish one cycle of treatment (21 days) they will not be evaluable for determination of the 
MTD and would be replaced in the dose level.  An additional 3 to 6 patients will be enrolled at the 
MTD, so that a total of 9 patients will be treated at this dose. 
Using this dose-escalation scheme the probability of escalating to the next dose level will be based 
on the true rate of DLT at the current doses given by the following table (each group will be 
considered independently of the other); Thus, if the true underlying proportion of DLTs is 50% at 
the current dose there is a 17% probability of escalating to the next dose. 
True toxicity at a given dose
10%
20%
30%
40%
50%
60%
Probability of escalating
0.91
0.71
0.49
0.31
0.17
0.08
If all four dose levels are evaluated with 6 patients per dose level and 9 total patients at the MTD, 
a maximum of 27 evaluable patients will be enrolled. Similarly, if all dose levels are evaluated 
with 3 patients per dose level and 9 total patients at the MTD, the minimum number of evaluable 
patients required will be 18. To account of unevaluable patients, accrual ceiling will be set at 36. 
It is expected that the accrual can be completed in 29 months. 
A maximum of 30 patients will be enrolled over 29 months, at a rate of 1-2 patients per month.
After execution of amendment 12/07/2022, we will no longer enroll into the original Arm 2 
expansion cohort and will test a new modified dose-expansion arm removing the lenalidomide 
lead-in window and expanding the cycle length to 28 days to enroll the remaining participants.

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10.3 POPULATION FOR ANALYSIS
10.3.1 Evaluable for toxicity: 
All patients will be evaluable for toxicity from the time of their first treatment with lenalidomide, 
romidepsin and CC-486 (5-azacitidine).
10.3.2 Evaluable for objective response: 
Only those patients who have measurable disease present at baseline, have received at least one 
cycle 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 above, Section 
6.3. (NOTE:  Patients who exhibit objective disease progression prior to the end of Cycle 1 will 
also be considered evaluable.)
10.3.3 Evaluable Non-Target Disease Response:  
Patients who have lesions present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease. The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions. 
10.3.4 Evaluable for DLT:
All participants who either completed cycle 1 treatment or experienced a DLT during cycle 1 
will be evaluable for DLT. If a participant did not experience DLT and did not finish cycle 1 
treatment, they will not be evaluable for toxicity and will be replaced in the dose level.
10.4 STATISTICAL ANALYSES
10.4.1 General Approach
The response rate will be determined and reported along with a 95% Agresti-Coull confidence 
interval [70]. Other time-to-event outcomes will be reported using Kaplan-Meier curves. 
10.4.2 Analysis of the Primary Endpoints
Safety summaries will include summaries in the form of tables and listings. Reports will include 
the frequency (number and percentage) of treatment emergent AEs grouped by severity of the AE 
(per CTCAE, v5.0) and by relationship to study drug (e.g., lenalidomide, romidepsin, CC-486 (5-
azacitidine) in any combinations).
Laboratory shift tables containing counts and percentages will be prepared by treatment 
assignment, laboratory parameter, and time. Summary tables will be prepared for each laboratory 
parameter. Figures of changes in laboratory parameters over time will be generated.
Results of vital sign assessments, ECGs, and physical exams will be tabulated and summarized.
10.4.3 Analysis of the Secondary Endpoints
Overall response rate (ORR), complete response (CR) rate will be estimated. Every report of 
response rates and time to progression should contain all patients included in the study. For the 
response calculation, the report should contain at least a section with all eligible patients. Another 
section of the report may detail the response rate for evaluable patients only.  However, a response 
rate analysis based on a subset of patients must explain which patients were excluded and for which 
reasons.  95% confidence limits will be given.

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The duration of response (DOR), overall survival (OS), event-free survival (EFS), and progression 
free survival (PFS) will be estimated using Kaplan-Meier curves with appropriate confidence 
intervals reported. For EFS, PFS, and OS, censoring time is defined as time from baseline to date 
of last follow-up. DOR for responders also calculated using the Kaplan-Meier approach is defined 
in section 6.3.3.  Censoring time for duration of response is defined as time from the initial 
response to date of last follow-up.
10.4.4 Safety Analyses
The type, grade and frequency of toxicities will be reported.
10.4.5 Baseline Descriptive Statistics
Descriptive statistics (including means, standard deviations, and medians for continuous variables 
and proportions and CIs for discrete variables) will be used to summarize data as appropriate.
10.4.6 Planned Interim Analyses
No interim analyses are planned because of the single stage design of the trial.
10.4.7 Tabulation of Individual Participant Data
None.
10.4.8 Exploratory Analyses
The exploratory objectives such as seeking to identify potential biomarkers or T-cell clones in 
peripheral blood which are associated with response, will be assessed using descriptive statistics 
as well as non-parametric methods such as exact Wilcoxon rank sum tests. The analyses will be 
done without formal adjustment for multiple comparisons, but in the context of the number of tests 
performed.
11 COLLABORATIVE AGREEMENTS 
11.1 CLINICAL TRIALS AGREEMENT (CTA)- CELGENE
A CTA (#01166) between the National Cancer Institute and Celgene, the manufacturer of 
lenalidomide, romidepsin and CC-486 (5-azacitidine) was executed on 11/24/2020.
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
All subjects from both sexes and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria outlined in the protocol and provide informed consent to protocol participation. 
Pregnant or nursing individuals are excluded because of the potential teratogenic effects of 
therapy. 
We expect individuals who can father children and individuals of childbearing potential to be 
equally represented among the enrolled patients. 
12.2 PARTICIPATION OF CHILDREN
Subjects under the age of 18 are excluded because recurrent T-cell lymphomas are rare in young 
patients, and the inclusion of an occasional younger patient will not provide generalizable 
information that would justify their inclusion on this study. Additionally, because no dosing or 
adverse event data are currently available on the use of lenalidomide, romidepsin and CC-486 (5-

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azacitidine) in patients <18 years of age, children are excluded from this study, but may be eligible 
for future pediatric trials.
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults who are unable to consent are excluded from enrolling in this study.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired.  For this reason and because there is a prospect of direct benefit from 
research participation during treatment (Section 12.5), and because overall survival is one of the 
secondary outcomes, all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for 
research and care, and assign a substitute decision maker on the “NIH Advance Directive for 
Health Care and Medical Research Participation” form so that another person can make decisions 
about their medical care in the event that they become incapacitated or cognitively impaired during 
the course of the study.  
Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation to assess ongoing capacity of the subjects and to identify an LAR, as needed.
Please see Section 12.6.1 for consent procedure.
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
The potential benefit of adding lenalidomide to romidepsin and CC-486 (5-azacitidine) 
combination in treatment of mature T-cell malignancies is unknown, but romidepsin and CC-486 
(5-azacitidine) combination have shown activity as outlined in Section 1.7. There is a risk of 
additive toxicity of the two drugs, in particular for hematologic toxicities (including neutropenia, 
thrombocytopenia), fatigue, rash, Liver Function Test (LFT) and abnormalities.
12.5 RISKS/BENEFITS ANALYSIS
12.5.1 Known Potential Risks
The potential risks of adding romidepsin, CC-486 (5-azacitidine), dexamethasone, and 
lenalidomide include, in particular, GI disturbances (nausea, vomiting, constipation, diarrhea, 
abdominal pain), hematologic toxicities (anemia, thrombocytopenia, neutropenia, leukopenia, 
febrile neutropenia), and asthenic conditions (fatigue, asthenia, lethargy), edema, anorexia, clinical 
chemistry abnormalities (hypocalcemia, hypoalbuminemia, hyperglycemia, hypomagnesemia), 
pyrexia and insomnia.
As noted in Table 4: Drug Regimen, premedication will be given prior to each cycle to reduce the 
risk of these AEs occurring.  Subjects will be monitored closely, and manufacturer 
recommendations for delaying and discontinuing study medications and initiating supportive 
therapy will be followed.
12.5.1.1 Risks related to Imaging
CT, PET, and/ or MRI scans may be used to monitor a patient’s disease on this study.  CT and 
PET scans expose a patient to radiation; the amount depends on the number of body areas scanned. 
In addition, CT, PET and MRI scans involve use of contrast (oral and/or IV).  An IV line may need 
to be inserted for administration of the contrast agent and can cause pain at the site where the IV 
is placed.  There is also a small risk of bruising or infection. If a contrast agent is given with the 
scan there is a small risk of having a reaction to the contrast.  In the small group of patients who 
have a reaction, the most common symptoms are nausea, pain in the vein where the contrast was 

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given, headache, a metallic or bitter taste in the mouth, and a warm or flushing feeling that lasts 
from 1-3 minutes.  Rarely, these symptoms may require treatment.  In very rare cases, people have 
had more severe allergic reactions that result in skin rashes, shortness of breath, wheezing, or 
lowering of the blood pressure.
12.5.1.2 Risks from Radiation Exposure
The procedures for performing the chest CT and 18F-FDG PET/CT scans will follow clinical 
policies, no special procedures apply to these additional assessments for research purposes.  In 
summary, subjects may receive additional radiation exposure from up to eight (8) additional CT 
scans of the neck, chest, abdomen, and pelvis, and three (3) additional 18F-FDG PET/CT scans. 
The total additional radiation dose for research purposes will be approximately 14 rem. Such 
radiation exposure is associated with an increased risk of cancer.
12.5.1.3 Risks from Blood Draws
The possible side effects of drawing blood include pain, bleeding, bruising, dizziness, light-
headedness, fainting and, on rare occasions, local blood clot formation or infection with redness 
and irritation of the vein. Up to about 8.6 tablespoons of blood may be collected at any day, up to 
about 25.9 tablespoons may be collected within 8 weeks.
12.5.1.4 Risks from Bone Marrow Biopsy and Aspirate
A numbing agent that can cause a stinging or burning sensation may be injected at the site of your 
bone marrow biopsy. The biopsy needle will go through the skin into the bone and may produce a 
brief, sharp pain. As the bone marrow liquid is taken from the bone, there may be a brief, sharp 
pain. Since the inside of the bone cannot be numbed, this procedure may cause some discomfort, 
however not all people experience discomfort. The possible side effects associated with a bone 
marrow biopsy include pain, bleeding, bruising, and infection, as well as a reaction to the numbing 
agent.  
12.5.1.5 Risks from Tumor Biopsy
The likely side effects include discomfort or pain, redness, swelling, and/or bruising at the site of 
the needle insertion. Bleeding from the site of the needle insertion is a less likely risk. Rarely, 
significant infection or bleeding from this procedure, allergic reaction to the anesthetic, or 
formation of a scar at the site of needle entry occurs. The procedure may be performed under 
conscious sedation.
12.5.1.4 Risks from Conscious Sedation
The common side effects of conscious sedation include drowsiness, delayed reflexes, hypotension, 
headache, and nausea.  These are generally mild and last no more than a few hours.
12.5.1.5 Catheter insertion
Insertion of catheters can cause site pain, inflammation of the vein, bruising, infection, blood clots, 
leak of the infused liquid, and if this is a central line, puncture of the lung that can result in lung 
collapse.
12.5.1.6 Risks from Saliva Capture and/or Buccal Swab collection
There are no risks associated with the saliva capture and buccal swab collection. The buccal swab 
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12.5.2 Known Potential Benefits
The benefit of taking romidepsin, CC-486 (5-azacitidine), dexamethasone, and lenalidomide are 
unknown.  All four drugs have shown clinical activity in T-cell malignancies as noted in section 
1.10.  
12.5.3 Assessment of Potential Risks and Benefits
Since relapsed/ refractory PTCL and CTCL are associated with a poor prognosis and a median 
overall survival of less than 2 years, new treatment strategies are needed. Single agent therapy has 
proven unable to provide durable responses, and combination therapy is necessary, as is the case 
with B-cell malignancies. We hypothesize that the four-drug combination can potentially block 
multiple critical pathways TCMs require for proliferation and survival. The safety profiles and 
MTDs of lenalidomide/romidepsin, CC-486 (5-azacitidine)/romidepsin and CC-486 (5-
azacitidine)/lenalidomide combinations are established. Dexamethasone is added to the 
combination to further improve tolerability, as lenalidomide-associated skin flares were a major 
toxicity in the lenalidomide combination trials. Pulse instead of continuous therapy is also used to 
minimize toxicity and improve tolerability. Finally, the 3+3 design ensures that patients will not 
be unduly exposed to higher than tolerated doses of the study drugs.
12.6 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting.  A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
local policy, including HRPP Policy 303) per discretion of the designated study investigator and 
with the agreement of the participant/consent designee(s). Whether in person or remote, the 
privacy of the subject will be maintained. Consenting investigators (and participant/consent 
designee, when in person) will be located in a private area (e.g., clinic consult room). When 
consent is conducted remotely, the participant/consent designee will be informed of the private 
nature of the discussion and will be encouraged to relocate to a more private setting if needed. 
Note: When required, witness signature will be obtained similarly as described below for the 
investigator and participant.
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or on the electronic document.    
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:
•
Adobe platform (which is not 21 CFR Part 11 compliant); or, 
•
iMedConsent platform (which is 21 CFR Part 11 compliant)

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During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location, but is not required.  
Both the investigator and the subject will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found at: https://nih.sharepoint.com/sites/NCI-CCR-OCD-
Communications/SitePages/OEC-Administrative---Clinical-Research-(ADCR).aspx?Mode=Edit.
12.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.6. 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to investigators, funding 
agencies, the Investigational New Drug (IND) sponsor and regulatory authorities, as applicable.  
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the 
reason(s) for the termination or suspension. Study participants will be contacted, as applicable, 
and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 

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(recorded), and reported in compliance with the protocol, International Council for Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the NIH has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest.
13.4 CONFIDENTIALLY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by the clinical site and by NCI CCR research staff will be secured and password protected. At the 
end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
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criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.
14 PHARMACEUTICAL INFORMATION
This study will be conducted under a CCR-held IND: IND #147481.
14.1 ROMIDEPSIN (DEPSIPEPTIDE, FK228, ISTODAX®)
14.1.1 Source Acquisition and Accountability
Romidepsin (ISTODAX®) is a commercially available agent. An investigational supply will be 
provided by Bristol Myers Squibb to the NCI for dispensing to study participants as per an arranged 
research agreement.  
14.1.2 Toxicity 
See Section 1.5.1.3 , 1.5.1.4 and 1.5.1.5 for a summary of AEs and SAEs.
14.1.3 Formulation and preparation 
The lyophilized, sterile finished product contains romidepsin, 10 mg/vial, and Povidone, 
compendial grade (Ph. Eur./USP), 20 mg/vial. ISTODAX (romidepsin) for injection is supplied in 
a dual-pack configuration with a single-use diluent for romidepsin vial that contains 2 mL of 80% 
propylene glycol, compendial grade (Ph. Eur./USP), and 20% dehydrated alcohol (ethanol), 
compendial grade (Ph. Eur./USP); sterile for use in reconstitution of the lyophilized powder. After 
reconstitution with 2 mL of the supplied diluent, the reconstituted solution will contain romidepsin 
5 mg/mL.
A volume of the resultant 5 mg/mL stock solution containing the appropriate dose for the patient 
is diluted in 0.9% sodium chloride injection, compendial grade (Ph. Eur./USP), to a final drug 
concentration, as recommended in the labeling or as directed in the protocol.
The romidepsin infusion solution is compatible with polyvinyl chloride (PVC), ethyl vinyl acetate 
(EVA), and polyethylene (PE) IV infusion bags, as well as glass bottles. Individual study protocols 
may stipulate different doses and dosing schedules.
Romidepsin should be handled in a manner consistent with recommended safe procedures for 
handling cytotoxic drugs.
Romidepsin must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium 
Chloride Injection (Ph.Eur./USP) before IV 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 romidepsin 5 mg/mL. 
The reconstituted solution is chemically stable for at least 8 hours at room temperature
14.1.4 Stability and Storage 
Unopened vials must be stored as directed.

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The reconstituted drug product should be stored as directed on the label or in the protocol.
The reconstituted stock solution at 5 mg/mL is chemically stable for at least 8 hours at room 
temperature, and 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. The drug should be administered as soon after dilution as possible.
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration, whenever solution and container permit.
14.1.5 Administration procedures
Extract the appropriate amount of romidepsin from the vials to deliver the desired dose, using 
proper aseptic technique. Before IV infusion, further dilute romidepsin in 500 mL 0.9% Sodium 
Chloride Injection (Ph.Eur./USP). Infuse over 4 hours. Romidepsin is a cytotoxic drug. Use 
appropriate handling procedures.  See section 3.4.3.2 for administration details.
14.1.6 Incompatibilities
The romidepsin infusion solution is compatible with polyvinyl chloride (PVC), ethyl vinyl acetate 
(EVA), and polyethylene (PE) IV infusion bags, as well as glass bottles. Refer to section 3.4.3.2 
and section 4.3.  Please see the prescribing information for romidepsin.  
14.2 CC-486 (5-AZACITIDINE)
14.2.1 Source Acquisition and Accountability
CC-486 (5-azacitidine) is an investigational agent that will be provided by Bristol Myers Squibb.  
Bristol Myers Squibb will provide the investigational supply to the NCI for dispensing to the study 
participants as per an arranged research agreement.  
14.2.2 Toxicity 
See Section 1.5.2.2 for a summary of AEs.
14.2.3 Formulation and preparation 
Different formulations of oral CC-486 (5-azacitidine) have been developed and are being used in 
clinical studies.  CC-486 (5-azacitidine) has been developed for clinical investigation in strengths 
of 20, 60, 100, 150, 200, and 300 mg tablets. The CC-486 (oral 5-azacitidine formulations) may 
use any of the following excipients:  mannitol USP, silicified microcrystalline cellulose NF, 
crospovidone NF, magnesium stearate NF, croscarmellose sodium, vitamin E TPGS NF, 
methacrylic acid copolymer (enteric coating) NF, Opadry coating, triethyl citrate NF, talc USP, 
hydroxypropyl cellulose NF, and hard gelatin capsule.  CC-486 (5-azacitidine) capsules contain 
100 mg of the active ingredient only. Only tablets will be provided for this study.
14.2.4 Stability and Storage 
Store as directed on the label. CC-486 (5-azacitidine) is a cytotoxic drug and, as with other 
potentially toxic compounds, caution should be exercised when handling and preparing CC-486 
(5-azacitidine). If reconstituted 5-azacitidine comes into contact with the skin, immediately and 
thoroughly wash with soap and water. If it comes into contact with mucous membranes, flush 
thoroughly with water.  Procedures for proper handling and disposal of CC-486 (5-azacitidine) 
(vials or reconstituted CC-486 (5-azacitidine), tablets, or capsules) should be applied according to 

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standards established at each facility for cytotoxic drugs. If a vial, capsule, or tablet is broken or 
damaged, dispose of the drug product and do not use.
14.2.5 Administration procedures
CC-486 (5-azacitidine) is taken by mouth with or without food. See section 3.4.3.3 for additional 
details.
14.2.6 Incompatibilities
No formal clinical drug interaction studies with CC-486 (5-azacitidine) have been conducted.
Based on in-vitro data, CC-486 (5-azacitidine) metabolism does not appear to be mediated by 
cytochrome P450 isoenzymes (CYPs); therefore, CYP inhibitors and inducers are unlikely to have 
any impact on the metabolism of CC-486 (5-azacitidine). Clinically relevant inhibitory or 
inductive effects of azacitidine on the metabolism of CYP450 substrates are unlikely.
14.3 LENALIDOMIDE (REVLIMID)
14.3.1 Source Acquisition and Accountability
Lenalidomide (Revlimid®) is a commercially available agent. Bristol Myers Squibb will provide 
the investigational supply to the NCI for dispensing to the study participants as per an arranged 
research agreement.  
14.3.2 Toxicity 
See 1.5.3.3 for a summary of AEs and see the prescribing information for lenalidomide/ 
REVLIMID®.
There are boxed warnings for lenalidomide, embryo-fetal toxicity (please see Appendix D), 
hematologic toxicity and venous thromboembolism. Lenalidomide can cause significant 
neutropenia and thrombocytopenia; for venous thromboembolism please see background section 
(Section 1.5.3.3).
In addition, there are warnings regarding allergic reactions, tumor lysis syndrome, tumor flare 
reaction and second primary malignancies.
Allergic reactions: Hypersensitivity, anaphylaxis, angioedema, Stevens-Johnson syndrome and 
toxic epidermal necrolysis have been reported.
Tumor lysis syndrome: Fatal instances of tumor lysis syndrome have been reported during 
treatment with lenalidomide. The subjects at risk of tumor lysis syndrome are those with high 
tumor burden prior to treatment. These subjects should be monitored closely and appropriate 
precautions taken.
Tumor flare reactions: Serious tumor flare reactions have occurred during investigational use of 
lenalidomide for chronic lymphocytic leukemia and lymphoma.
Adverse Events: Most frequently reported adverse events reported during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of presumed relationship to 
study medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal 
pain, nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, 
UTI, Upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial 
infarction, chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone 
pain, generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural 

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effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, death not specified and fractures. Other
rare or uncommon adverse events are gastrointestinal hemorrhage (Uncommon), small intestinal 
obstruction (Rare), chest pain (Rare), hepatocellular injury (Rare), decreased appetite 
(Uncommon), peripheral neuropathy (Uncommon), hypoxia (Rare), and pleuritic pain (Rare).
Second new cancers: Please see background (Section 1.5.3.4).
14.3.3 Formulation and preparation 
Lenalidomide will be supplied as capsules for oral administration.  Each capsule contains the 
following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose 
sodium, and magnesium stearate. Lenalidomide will be shipped to the pharmacy at the study site 
in individual bottles or blister packs. Bottles or blister packs will contain a sufficient number of 
capsules to last for 1 cycle of dosing. Lenalidomide must be dispensed in the original packaging 
with the label clearly visible. Only enough lenalidomide for 1 cycle of therapy may be provided to 
the subject each cycle.
14.3.4 Stability and Storage 
Store as directed on package label. Please see local prescribing information for Revlimid® for 
detailed instructions on storage conditions and stability.  Store at 20°C - 25°C (68°F - 77°F); 
excursions permitted to 15°C - 30°C (59°F - 86°F).  Care should be exercised in the handling of 
REVLIMID. REVLIMID capsules should not be opened or broken. If powder from REVLIMID 
contacts the skin, wash the skin immediately and thoroughly with soap and water. If REVLIMID 
contacts the mucous membranes, flush thoroughly with water.
Procedures for the proper handling and disposal of anticancer drugs should be considered.
14.3.5 Administration procedures
Lenalidomide is taken by mouth with or without food. See section 3.4.3.1 for administration 
details.
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide will be 
provided in accordance with Celgene/BMS Corporation’s Revlimid REMS® program.  Per 
standard Revlimid REMS® program requirements, all physicians who prescribe lenalidomide for 
research subjects enrolled into this trial, and all research subjects enrolled into this trial, must be 
registered in, and must comply with, all requirements of the Revlimid REMS® program (see 
Appendix D).  
Further information about the Revlimid REMS® program is available at: 
https://www.celgeneriskmanagement.com
14.3.6 Incompatibilities
In vitro studies demonstrate that lenalidomide is not a substrate of CYP enzymes. In addition, 
lenalidomide shows little inhibitory or induction potential towards the CYP enzymes in vitro. 
Hence, coadministration of CYP substrates, inhibitors, or inducers with lenalidomide is not likely 
to result in clinically relevant drug-drug interactions in humans.

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In vitro, lenalidomide is not a substrate of BCRP, MRP1, MRP2, MRP3, OAT1, OAT3, 
OATP1B1, OCT1, OCT2, MATE1, OCTN1, or OCTN2. Thus, it is unlikely that substrates or 
inhibitors of these transporters would affect lenalidomide disposition in humans.
Lenalidomide is not an inhibitor of BSEP, BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, 
or OCT2. Thus, lenalidomide is not anticipated to cause any significant drug-drug interactions due 
to inhibition of these transporters.
Lenalidomide is not an inhibitor of UGT1A1 and is not anticipated to cause any significant drug-
drug interactions due to UGT1A1 inhibition.
Please refer to Sections 3.4.3.1, 4 for full drug interactions and toxicities.
14.4 DEXAMETHASONE
14.4.1 Source Acquisition and Accountability
Dexamethasone is commercially available and will be purchased by the CCR and supplied to the 
patients enrolled on the study by the NIH Clinical Center Pharmacy Department.
14.4.2 Toxicity
The most commonly reported toxicities have included: insomnia, mood changes, increased 
appetite, gastrointestinal problems, muscle weakness, increased blood sugar levels, impaired 
wound healing and fluid retention.  Please refer to package insert for a complete listing of all 
toxicities.
14.4.3 Formulation and Preparation
Dexamethasone is commercially available in oral pill and liquid formulations; it is intended that 
we will exclusively use the pill formulation in this study. All formulation excipients are 
compendial and are commonly used in oral formulations.
14.4.4 Stability and Storage
Dexamethasone will be packaged in opaque high-density polyethylene plastic bottles with labels 
bearing the appropriate label text as required by governing regulatory agencies. All supplied drug 
will be dispensed in child-resistant packaging.
Please refer to the package insert for additional guidance on drug preparation, handling and storage
14.4.5 Administration Procedures
Dexamethasone will be administered orally per the drug administration schedule in Section 
3.4.3.4.

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15 REFERENCES 
Include relevant, current key references for proposed study.
1.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini 
M, Salles GA, Zelenetz AD et al: The 2016 revision of the World Health Organization 
classification of lymphoid neoplasms. Blood 2016, 127(20):2375-2390.
2.
Vose J, Armitage J, Weisenburger D: International peripheral T-cell and natural 
killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 
2008, 26(25):4124-4130.
3.
Adams SV, Newcomb PA, Shustov AR: Racial Patterns of Peripheral T-Cell 
Lymphoma Incidence and Survival in the United States. J Clin Oncol 2016, 
34(9):963-971.
4.
Chihara D, Ito H, Matsuda T, Shibata A, Katsumi A, Nakamura S, Tomotaka S, Morton 
LM, Weisenburger DD, Matsuo K: Differences in incidence and trends of 
haematological malignancies in Japan and the United States. British journal of 
haematology 2013.
5.
Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS: Lymphoma 
incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006, 
107(1):265-276.
6.
Korgavkar K, Xiong M, Weinstock M: Changing incidence trends of cutaneous T-cell 
lymphoma. JAMA Dermatol 2013, 149(11):1295-1299.
7.
Project IT-CL: International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma 
Study: Pathology Findings and Clinical Outcomes. Journal of Clinical Oncology 
2008, 26(25):4124-4130.
8.
Simon A, Peoch M, Casassus P, Deconinck E, Colombat P, Desablens B, Tournilhac O, 
Eghbali H, Foussard C, Jaubert J et al: Upfront VIP-reinforced-ABVD (VIP-rABVD) 
is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results 
of the randomized phase III trial GOELAMS-LTP95. British journal of haematology 
2010, 151(2):159-166.
9.
Reimer P, Rudiger T, Geissinger E, Weissinger F, Nerl C, Schmitz N, Engert A, Einsele 
H, Muller-Hermelink HK, Wilhelm M: Autologous stem-cell transplantation as first-
line therapy in peripheral T-cell lymphomas: results of a prospective multicenter 
study. J Clin Oncol 2009, 27(1):106-113.
10.
Vose J, Armitage J, Weisenburger D, International TCLP: International peripheral T-
cell and natural killer/T-cell lymphoma study: pathology findings and clinical 
outcomes. J Clin Oncol 2008, 26(25):4124-4130.
11.
Chihara D, Fanale MA, Miranda RN, Noorani M, Westin JR, Nastoupil LJ, Hagemeister 
FB, Fayad LE, Romaguera JE, Samaniego F et al: The survival outcome of patients 
with relapsed/refractory peripheral T-cell lymphoma-not otherwise specified and 
angioimmunoblastic T-cell lymphoma. British journal of haematology 2017, 
176(5):750-758.

Abbreviated Title: RAdR for R/R TCM
Version Date:   12/04/2025
87
12.
Ellin F, Landstrom J, Jerkeman M, Relander T: Real-world data on prognostic factors 
and treatment in peripheral T-cell lymphomas: a study from the Swedish 
Lymphoma Registry. Blood 2014, 124(10):1570-1577.
13.
Mak V, Hamm J, Chhanabhai M, Shenkier T, Klasa R, Sehn LH, Villa D, Gascoyne RD, 
Connors JM, Savage KJ: Survival of patients with peripheral T-cell lymphoma after 
first relapse or progression: spectrum of disease and rare long-term survivors. J 
Clin Oncol 2013, 31(16):1970-1976.
14.
Jawed SI, Myskowski PL, Horwitz S, Moskowitz A, Querfeld C: Primary cutaneous T-
cell lymphoma (mycosis fungoides and Sezary syndrome): part II. Prognosis, 
management, and future directions. J Am Acad Dermatol 2014, 70(2):223 e221-217; 
quiz 240-222.
15.
Yang YT, Tai CJ, Chen C, Wu HC, Mikhaylichenko N, Chiu HT, Chen YY, Hsu YE: 
Highly Diverse Efficacy of Salvage Treatment Regimens for Relapsed or Refractory 
Peripheral T-Cell Lymphoma: A Systematic Review. PloS one 2016, 
11(10):e0161811.
16.
Sutherland MS, Sanderson RJ, Gordon KA, Andreyka J, Cerveny CG, Yu C, Lewis TS, 
Meyer DL, Zabinski RF, Doronina SO et al: Lysosomal trafficking and cysteine 
protease metabolism confer target-specific cytotoxicity by peptide-linked anti-
CD30-auristatin conjugates. The Journal of biological chemistry 2006, 281(15):10540-
10547.
17.
Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, Ramchandren 
R, Fanale M, Connors JM et al: Brentuximab vedotin (SGN-35) in patients with 
relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II 
study. J Clin Oncol 2012, 30(18):2190-2196.
18.
Pro B, Advani RH, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, 
Ramchandren R, Fanale MA, Connors JM et al: Four-Year Survival Data from an 
Ongoing Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed 
or Refractory Systemic Anaplastic Large Cell Lymphoma. Blood 2014, 
124(21):Abstract 3095.
19.
Pro B, Advani RH, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, 
Ramchandren R, Fanale MA, Connors JM et al: Three-Year Survival Results From An 
Ongoing Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or 
Refractory Systemic Anaplastic Large Cell Lymphoma. Blood 2013, 122(Abstract 
1809).
20.
Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, Zinzani PL, 
Wolter P, Sanches JA, Ortiz-Romero PL et al: Brentuximab vedotin or physician's 
choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, 
open-label, randomised, phase 3, multicentre trial. Lancet 2017, 390(10094):555-566.
21.
Chihara D, Wong S, Feldman T, Fanale MA, Sanchez L, Connors JM, Savage KJ, Oki Y: 
Outcome of patients with relapsed or refractory anaplastic large cell lymphoma who 
have failed brentuximab vedotin. Hematol Oncol 2019, 37(1):35-38.

Abbreviated Title: RAdR for R/R TCM
Version Date:   12/04/2025
88
22.
Wang C, McKeithan TW, Gong Q, Zhang W, Bouska A, Rosenwald A, Gascoyne RD, 
Wu X, Wang J, Muhammad Z et al: IDH2R172 mutations define a unique subgroup 
of patients with angioimmunoblastic T-cell lymphoma. Blood 2015, 126(15):1741-
1752.
23.
Sakata-Yanagimoto M, Enami T, Yoshida K, Shiraishi Y, Ishii R, Miyake Y, Muto H, 
Tsuyama N, Sato-Otsubo A, Okuno Y et al: Somatic RHOA mutation in 
angioimmunoblastic T cell lymphoma. Nature genetics 2014, 46(2):171-175.
24.
Palomero T, Couronne L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia 
A, Carpenter Z, Abate F, Allegretta M, Haydu JE et al: Recurrent mutations in 
epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. 
Nature genetics 2014, 46(2):166-170.
25.
Odejide O, Weigert O, Lane AA, Toscano D, Lunning MA, Kopp N, Kim S, van 
Bodegom D, Bolla S, Schatz JH et al: A targeted mutational landscape of 
angioimmunoblastic T-cell lymphoma. Blood 2014, 123(9):1293-1296.
26.
Lemonnier F, Couronne L, Parrens M, Jais JP, Travert M, Lamant L, Tournillac O, 
Rousset T, Fabiani B, Cairns RA et al: Recurrent TET2 mutations in peripheral T-cell 
lymphomas correlate with TFH-like features and adverse clinical parameters. Blood 
2012, 120(7):1466-1469.
27.
Lemonnier F, Poullot E, Dupuy A, Couronne L, Martin N, Scourzic L, Fataccioli V, 
Bruneau J, Cairns RA, Mak TW et al: Loss of 5-hydroxymethylcytosine is a frequent 
event in peripheral T-cell lymphomas. Haematologica 2018, 103(3):e115-e118.
28.
Ma H, O'Connor OA, Marchi E: New directions in treating peripheral T-cell 
lymphomas (PTCL): leveraging epigenetic modifiers alone and in combination. 
Expert Rev Hematol 2019, 12(3):137-146.
29.
Couronne L, Bastard C, Bernard OA: TET2 and DNMT3A mutations in human T-cell 
lymphoma. N Engl J Med 2012, 366(1):95-96.
30.
Park J, Yang J, Wenzel AT, Ramachandran A, Lee WJ, Daniels JC, Kim J, Martinez-
Escala E, Amankulor N, Pro B et al: Genomic analysis of 220 CTCLs identifies a novel 
recurrent gain-of-function alteration in RLTPR (p.Q575E). Blood 2017, 
130(12):1430-1440.
31.
Kiel MJ, Sahasrabuddhe AA, Rolland DCM, Velusamy T, Chung F, Schaller M, Bailey 
NG, Betz BL, Miranda RN, Porcu P et al: Genomic analyses reveal recurrent 
mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome. 
Nat Commun 2015, 6:8470.
32.
Shah UA, Chung EY, Giricz O, Pradhan K, Kataoka K, Gordon-Mitchell S, Bhagat TD, 
Mai Y, Wei Y, Ishida E et al: North American ATLL has a distinct mutational and 
transcriptional profile and responds to epigenetic therapies. Blood 2018, 
132(14):1507--1518.
33.
Boddicker RL, Kip NS, Xing X, Zeng Y, Yang ZZ, Lee JH, Almada LL, Elsawa SF, 
Knudson RA, Law ME et al: The oncogenic transcription factor IRF4 is regulated by 
a novel CD30/NF-kappaB positive feedback loop in peripheral T-cell lymphoma. 
Blood 2015, 125(20):3118-3127.

Abbreviated Title: RAdR for R/R TCM
Version Date:   12/04/2025
89
34.
Lopez-Girona A, Heintel D, Zhang LH, Mendy D, Gaidarova S, Brady H, Bartlett JB, 
Schafer PH, Schreder M, Bolomsky A et al: Lenalidomide downregulates the cell 
survival factor, interferon regulatory factor-4, providing a potential mechanistic 
link for predicting response. British journal of haematology 2011, 154(3):325-336.
35.
Lyman GH, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, 
Flowers CR, Francis CW, Gates LE et al: Venous thromboembolism prophylaxis and 
treatment in patients with cancer: American Society of Clinical Oncology clinical 
practice guideline update. J Clin Oncol 2013, 31(17):2189-2204.
36.
Zhou X, Teegala S, Huen A, Ji Y, Fayad L, Hagemeister FB, Gladish G, Vadhan-Raj S: 
Incidence and risk factors of venous thromboembolic events in lymphoma. Am J 
Med 2010, 123(10):935-941.
37.
Park LC, Woo SY, Kim S, Jeon H, Ko YH, Kim SJ, Kim WS: Incidence, risk factors 
and clinical features of venous thromboembolism in newly diagnosed lymphoma 
patients: results from a prospective cohort study with Asian population. Thromb Res 
2012, 130(3):e6-12.
38.
Wiernik PH, Lossos IS, Tuscano JM, Justice G, Vose JM, Cole CE, Lam W, McBride K, 
Wride K, Pietronigro D et al: Lenalidomide monotherapy in relapsed or refractory 
aggressive non-Hodgkin's lymphoma. J Clin Oncol 2008, 26(30):4952-4957.
39.
Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, Bouabdallah R, 
Haioun C, Tilly H, Guo P et al: An international phase II trial of single-agent 
lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. 
Ann Oncol 2011, 22(7):1622-1627.
40.
Leonard JP, Jung SH, Johnson J, Pitcher BN, Bartlett NL, Blum KA, Czuczman M, 
Giguere JK, Cheson BD: Randomized Trial of Lenalidomide Alone Versus 
Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: 
CALGB 50401 (Alliance). J Clin Oncol 2015, 33(31):3635-3640.
41.
Wang M, Fowler N, Wagner-Bartak N, Feng L, Romaguera J, Neelapu SS, Hagemeister 
F, Fanale M, Oki Y, Pro B et al: Oral lenalidomide with rituximab in relapsed or 
refractory diffuse large cell, follicular and transformed lymphoma: a phase II 
clinical trial. Leukemia 2013, 27(9):1902-1909.
42.
Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, Scarisbrick J, 
Reddy S, Robak T, Becker JC et al: Final results from a multicenter, international, 
pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 
2010, 28(29):4485-4491.
43.
Valdez BC, Brammer JE, Li Y, Murray D, Liu Y, Hosing C, Nieto Y, Champlin RE, 
Andersson BS: Romidepsin targets multiple survival signaling pathways in 
malignant T cells. Blood Cancer J 2015, 5:e357.
44.
Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Borchmann 
P, Morschhauser F, Wilhelm M et al: Results from a pivotal, open-label, phase II 
study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after 
prior systemic therapy. J Clin Oncol 2012, 30(6):631-636.

Abbreviated Title: RAdR for R/R TCM
Version Date:   12/04/2025
90
45.
Saillard C, Guermouche H, Derrieux C, Bruneau J, Frenzel L, Couronne L, Asnafi V, 
Macintyre E, Trinquand A, Lhermitte L et al: Response to 5-azacytidine in a patient 
with TET2-mutated angioimmunoblastic T-cell lymphoma and chronic 
myelomonocytic leukaemia preceded by an EBV-positive large B-cell lymphoma. 
Hematol Oncol 2017, 35(4):864-868.
46.
Cheminant M, Bruneau J, Kosmider O, Lefrere F, Delarue R, Gaulard P, Radford I, 
Derrieux C, Hermine O, Lemonnier F: Efficacy of 5-azacytidine in a TET2 mutated 
angioimmunoblastic T cell lymphoma. British journal of haematology 2015, 
168(6):913-916.
47.
Delarue R, Dupuis J, Sujobert P, Barbieux S, Marçais A, Tournilhac O, Lachenal F, 
Cheminant M, Sarkozy C, Fataccioli V et al: Treatment with Hypomethylating Agent 
5-Azacytidine Induces Sustained Response in Angioimmunoblastic T Cell 
Lymphomas. Blood 2016, 128(22):4164-4164.
48.
Toumishey E, Prasad A, Dueck G, Chua N, Finch D, Johnston J, van der Jagt R, Stewart 
D, White D, Belch A et al: Final report of a phase 2 clinical trial of lenalidomide 
monotherapy for patients with T-cell lymphoma. Cancer 2015, 121(5):716-723.
49.
Morschhauser F, Fitoussi O, Haioun C, Thieblemont C, Quach H, Delarue R, Glaisner S, 
Gabarre J, Bosly A, Lister J et al: A phase 2, multicentre, single-arm, open-label study 
to evaluate the safety and efficacy of single-agent lenalidomide (Revlimid) in 
subjects with relapsed or refractory peripheral T-cell non-Hodgkin lymphoma: the 
EXPECT trial. Eur J Cancer 2013, 49(13):2869-2876.
50.
Zinzani PL, Pellegrini C, Broccoli A, Stefoni V, Gandolfi L, Quirini F, Argnani L, Berti 
E, Derenzini E, Pileri S et al: Lenalidomide monotherapy for relapsed/refractory 
peripheral T-cell lymphoma not otherwise specified. Leuk Lymphoma 2011, 
52(8):1585-1588.
51.
Querfeld C, Rosen ST, Guitart J, Duvic M, Kim YH, Dusza SW, Kuzel TM: Results of 
an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory 
mycosis fungoides and Sezary syndrome. Blood 2014, 123(8):1159-1166.
52.
Ishida T, Fujiwara H, Nosaka K, Taira N, Abe Y, Imaizumi Y, Moriuchi Y, Jo T, 
Ishizawa K, Tobinai K et al: Multicenter Phase II Study of Lenalidomide in Relapsed 
or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002. J Clin Oncol 2016, 
34(34):4086-4093.
53.
Rozati S, Cheng PF, Widmer DS, Fujii K, Levesque MP, Dummer R: Romidepsin and 
Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in 
CTCL. Clin Cancer Res 2016, 22(8):2020-2031.
54.
Marchi E, Zullo KM, Amengual JE, Kalac M, Bongero D, McIntosh CM, Fogli LK, 
Rossi M, Zinzani PL, Pileri SA et al: The combination of hypomethylating agents and 
histone deacetylase inhibitors produce marked synergy in preclinical models of T-
cell lymphoma. British journal of haematology 2015, 171(2):215-226.
55.
Falchi L, Lue JK, Montanari F, Marchi E, Amengual JE, Sawas A, Deng C, Khan K, Kim 
H, Atkins LE et al: Combined Hypomethylating Agents (HMA) and Histone 
Deacetylase Inhibitors (HDACi) Exhibit Compelling Activity in Patients with 

Abbreviated Title: RAdR for R/R TCM
Version Date:   12/04/2025
91
Peripheral T-Cell Lymphoma (PTCL) with High Complete Response Rates in 
Angioimmunoblastic T-Cell Lymphoma (AITL). Blood 2018, 132(Suppl 1):1002-
1002.
56.
O'Connor OA, Falchi L, Lue JK, Marchi E, Kinahan C, Sawas A, Deng C, Montanari F, 
Amengual JE, Kim HA et al: ORAL 5-AZACYTIDINE AND ROMIDEPSIN 
EXHIBIT MARKED ACTIVITY IN PATIENTS WITH PTCL: A 
MULTICENTER PHASE I STUDY. Blood 2019:blood.2019001285.
57.
Cosenza M, Civallero M, Fiorcari S, Pozzi S, Marcheselli L, Bari A, Ferri P, Sacchi S: 
The histone deacetylase inhibitor romidepsin synergizes with lenalidomide and 
enhances tumor cell death in T-cell lymphoma cell lines. Cancer Biol Ther 2016, 
17(10):1094-1106.
58.
Mehta-Shah N, Lunning MA, Boruchov AM, Ruan J, Nair S, Lynch P, Byrne R, 
Moskowitz AJ, Matasar MJ, Gerecitano JF et al: A phase I/II trial of the combination 
of romidepsin and lenalidomide in patients with relapsed/refractory lymphoma and 
myeloma: Activity in T-cell lymphoma. Journal of Clinical Oncology 2015, 
33(15_suppl):8521-8521.
59.
Sekeres MA, List AF, Cuthbertson D, Paquette R, Ganetzky R, Latham D, Paulic K, 
Afable M, Saba HI, Loughran TP, Jr. et al: Phase I combination trial of lenalidomide 
and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol 
2010, 28(13):2253-2258.
60.
Sekeres MA, Tiu RV, Komrokji R, Lancet J, Advani AS, Afable M, Englehaupt R, 
Juersivich J, Cuthbertson D, Paleveda J et al: Phase 2 study of the lenalidomide and 
azacitidine combination in patients with higher-risk myelodysplastic syndromes. 
Blood 2012, 120(25):4945-4951.
61.
Garcia-Manero G, Gore SD, Cogle C, Ward R, Shi T, Macbeth KJ, Laille E, Giordano H, 
Sakoian S, Jabbour E et al: Phase I study of oral azacitidine in myelodysplastic 
syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin 
Oncol 2011, 29(18):2521-2527.
62.
Garcia-Manero G, Gore SD, Kambhampati S, Scott B, Tefferi A, Cogle CR, Edenfield 
WJ, Hetzer J, Kumar K, Laille E et al: Efficacy and safety of extended dosing 
schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic 
syndromes. Leukemia 2016, 30(4):889-896.
63.
Falchi L, Ma H, Klein S, Lue JK, Montanari F, Marchi E, Deng C, Kim HA, Rada A, 
Jacob AT et al: Combined oral 5-azacytidine and romidepsin are highly effective in 
patients with PTCL: a multicenter phase 2 study. Blood 2021, 137(16):2161-2170.
64.
El-Saghir J, Nassar F, Tawil N, El-Sabban M: ATL-derived exosomes modulate 
mesenchymal stem cells: potential role in leukemia progression. Retrovirology 2016, 
13(1):73.
65.
Welsh JA, Kepley J, Bartfield A, Savage J, Miljkovic MD, Gorgens A, Waldmann TA, 
Conlon KC, McKinnon K, Camphausen K et al: Development of a Multiplex-To-Single 
Exosome Analysis (MT-SEA) Pipeline to Characterize Exosomes Associated with 

Abbreviated Title: RAdR for R/R TCM
Version Date:   12/04/2025
92
Tumor Progression and Responses to Treatment. . In: International Society for 
Extracellular Vesicles Annual Meeting; Barcelona, Spain.  2018.
66.
Younes A, Hilden P, Coiffier B, Hagenbeek A, Salles G, Wilson W, Seymour JF, Kelly 
K, Gribben J, Pfreunschuh M et al: International Working Group consensus response 
evaluation criteria in lymphoma (RECIL 2017). Annals of Oncology 2017, 
28(7):1436-1447.
67.
Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, Wood GS, Willemze 
R, Demierre M-F, Pimpinelli N et al: Clinical End Points and Response Criteria in 
Mycosis Fungoides and Sézary Syndrome: A Consensus Statement of the 
International Society for Cutaneous Lymphomas, the United States Cutaneous 
Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the 
European Organisation for Research and Treatment of Cancer. Journal of Clinical 
Oncology 2011, 29(18):2598-2607.
68.
Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, Frankel SR, Chen C, 
Ricker JL, Arduino JM et al: Phase IIb multicenter trial of vorinostat in patients with 
persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin 
Oncol 2007, 25(21):3109-3115.
69.
Tsukasaki K, Hermine O, Bazarbachi A, Ratner L, Ramos JC, Harrington W, Jr., 
O'Mahony D, Janik JE, Bittencourt AL, Taylor GP et al: Definition, prognostic factors, 
treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal 
from an international consensus meeting. J Clin Oncol 2009, 27(3):453-459.
70.
Agresti A, Coull BA: Approximate Is Better than "Exact" for Interval Estimation of 
Binomial Proportions. The American Statistician 1998, 52(2):119-126.

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16 APPENDIX 
16.1 APPENDIX A:  PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization indicated. Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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16.2 APPENDIX B:  GLOBAL RESPONSE SCORE AND DEFINITIONS OF RESPONSE IN SKIN, 
LYMPH NODES, VISCERA, AND BLOOD
Global Response Score
Global Score
Definition
Skin
Nodes
Blood
Viscera
CR
Complete disappearance of all 
clinical evidence of disease
CR
All categories have CR/NI
PR
Regression of measurable 
disease
CR
All categories do not have a CR/NI and no 
category has a PD
PR
No category has a PD and if any category 
involved at baseline at least one has a CR 
or PR
SD
Failure to attain CR, PR, or PD 
representative of all disease
PR
No category has a PD and if any category 
involved at baseline, no CR or PR in any
SD
CR/NI, PR, SD in any category and no 
category has a PD
PD
Progressive disease
PD in any category
Relapse
Recurrence of disease in prior 
CR
Relapse in any category
Abbreviations: CR, complete response; NI, noninvolved; PR, partial response; PD, progressive disease; 
SD, stable disease.
Response in Skin
Response
Definition
Complete response
100% clearance of skin lesions
Partial response
50%-99% clearance of skin disease from baseline without new tumors (T3) in 
patients with T1, T2 or T4 only skin disease
Stable disease
<25% increase to <50% clearance in skin disease from baseline without new 
tumors (T3) in patients with T1, T2, or T4 only skin disease
Progressive disease
≥25% increase in skin disease from baseline or
New tumors (T3) in patients with T1, T2, or T4 only skin disease or
Loss of response: in those with complete or partial response, increase of skin 
score of greater than the sum of nadir plus 50% baseline score
Relapse
Any disease recurrence in those with complete response
Notes:
Percentages refer to mSWAT score.
A biopsy of normal appearing skin is unnecessary to assign a complete response. However, a skin 
biopsy should be performed of a representative area of the skin if there is any question of residual 
disease (persistent erythema or pigmentary change) where otherwise a complete response would exist. 
If histologic features are suspicious or suggestive of mycosis fungoides/Sézary syndrome, the response 
should be considered a partial response only.

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Response in Lymph Nodes
Response
Definition
CR
All lymph nodes are now ≤1.5 cm in greatest transverse (long axis) diameter by method 
used to assess lymph nodes at baseline or biopsy negative for lymphoma; in addition, 
lymph nodes that were N3 classification and ≤1.5 cm in their long axis and >1 cm in 
their short axis at baseline, must now be ≤1 cm in their short axis or biopsy negative for 
lymphoma
PR
Cumulative reduction ≥50% of the SPD of each abnormal lymph node at baseline and no 
new lymph node >1.5 cm in the diameter of the long axis or >1.0 cm in the diameter of 
the short axis if the long axis
is 1-1.5 cm diameter
SD
Fails to attain the criteria for CR, PR, and PD
PD
>50% increase in SPD from baseline of lymph nodes OR
Any new node >1.5cm in the long axis or >1cm in the short axis if 1-1.5 cm in the long 
axis that is proven to be N3 histologically OR
Loss of response: >50% increase from nadir in SPD of lymph nodes in those with PR 
(whichever occurs first)
Relapse
Any new lymph node >1.5 cm in the long axis in those with CR proven to be N3 
histologically
Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum linear 
dimension (major axis) ⨉ longest perpendicular dimension (minor axis); SD, stable disease; PD, 
progressive disease.
Response in Viscera
Response
Definition
CR
Liver or spleen or any organ considered involved at baseline should not be enlarged on 
physical exam and should be considered normal by imaging; no nodules should be 
present on imaging of liver or spleen; any post treatment mass must be determined by 
biopsy to be negative for lymphoma
PR
>50% regression in any splenic or liver nodules, or in measurable disease (SPD) in any 
organs abnormal at baseline; no increase in size of liver or spleen and no new sites of 
involvement
SD
Fails to attain the criteria for CR, PR, and PD
PD
>50% increase in size (SPD) of any organs involved at baseline OR
New organ involvement OR
Loss of response: >50% increase from nadir in the size (SPD) of any previous organ 
involvement in those with PR (whichever occurs first)
Relapse
New organ involvement in those with CR
Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum linear 
dimension (major axis) ⨉ longest perpendicular dimension (minor axis); SD, stable disease; PD, 
progressive disease.

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16.3 APPENDIX C:  CYP3A4 INDUCERS AND INHIBITORS
Inhibitors of CYP3A are defined as follows. A comprehensive list of inhibitors can be found at 
the following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. The general 
categorization into strong, moderate, and weak inhibitors according to the website is displayed 
below. Refer to Section 4.2 and 4.3 on instructions for concomitant use of CYP3A inhibitors and 
inducers with study medications.
Inhibitors of CYP3A
Inducers of CYP3A
Strong inhibitors: 
INDINAVIR 
NELFINAVIR 
RITONAVIR 
CLARITHROMYCIN
ITRACONAZOLE 
KETOCONAZOLE 
POSACONAZOLE
NEFAZODONE 
SAQUINAVIR 
TELITHROMYCIN
SUBOXONE 
Moderate inhibitors: 
aprepitant 
erythromycin 
diltiazem 
fluconazole 
grapefruit juice 
Seville orange juice 
verapamil 
 
Weak inhibitors: 
cimetidine 
All other inhibitors: 
amiodarone 
NOT azithromycin 
chloramphenicol 
boceprevir 
ciprofloxacin 
delaviridine 
diethyl-dithiocarbamate 
fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
norfloxacin 
norfluoxetine 
star fruit 
telaprevir 
troleandomycin 
voriconazole
gestodene
norfluoxetine
Carbamazepine 
Efavirenz 
Nevirapine 
Barbiturates 
Glucocorticoids 
Modafinil 
Oxcarbarzepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s Wort 
Troglitazone 
Source: http://medicine.iupui.edu/clinpharm/ddis/table.aspx   

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16.4 APPENDIX D: RISKS OF FETAL EXPOSURE, PREGNANCY TESTING GUIDELINES AND 
ACCEPTABLE BIRTH CONTROL METHODS FOR LENALIDOMIDE
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant individuals and nursing individuals has not been studied nor 
has the effect of lenalidomide on human eggs and sperm. Lenalidomide is structurally related to 
thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-
threatening birth defects. An embryofetal development study in animals indicates that 
lenalidomide produced malformations in the offspring of female monkeys who received the drug 
during pregnancy. The teratogenic effect of lenalidomide in humans cannot be ruled out. 
Therefore, a risk minimization plan to prevent pregnancy must be observed.
All study participants must be registered into the mandatory Revlimid REMSTM program, and be 
willing and able to comply with the requirements of Revlimid REMSTM. 
Criteria for individuals of childbearing potential (ICBP) 
This protocol defines an individual of childbearing potential as a sexually mature person who: 1) 
has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
The investigator must ensure that:
•
Individuals of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that they have an adequate level of understanding.  
•
Individuals NOT of childbearing potential acknowledge that they understand the hazards 
and necessary precautions associated with the use of lenalidomide.
•
Individuals who can father children taking lenalidomide acknowledge that they understand 
that traces of lenalidomide have been found in semen, that they understand the potential 
teratogenic risk if engaged in sexual activity with an individual of childbearing potential 
or an individual of childbearing potential, and that they understand the need for the use of 
a condom even if they undergo a vasectomy, if engaged in sexual activity with an 
individual of childbearing potential or pregnant female.  
Contraception  
Individuals of childbearing potential (ICBP) enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this study: 1) for at least 28 days before 
starting lenalidomide; 2) throughout the entire duration of lenalidomide treatment; 3) during dose 
interruptions; and 4) for at least 28 days after lenalidomide discontinuation. 
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. ICBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception: 
•
Highly effective methods:
o
Intrauterine device (IUD)

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o
Hormonal (birth control pills, injections, implants)
o
Tubal ligation 
o
Partner’s vasectomy 
•
Additional effective methods:
o
Male condom
o
Diaphragm
o
Cervical Cap 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of 
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be 
considered particularly in patients with neutropenia. 
Pregnancy Testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for individuals of childbearing potential, including individuals of childbearing potential 
who commit to complete abstinence, as outlined below. 
Before starting lenalidomide 
Individuals of Childbearing Potential: 
ICBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to 
prescribing lenalidomide. The first pregnancy test must be performed within 10–14 days prior to 
prescribing lenalidomide and the second pregnancy test must be performed within 24 hours prior 
to prescribing lenalidomide. The patient may not receive lenalidomide until the Investigator has 
verified that the results of these pregnancy tests are negative. 
Individuals Who Can Father Children: 
Must agree to practice complete abstinence or agree to use a condom during sexual contact with 
pregnant individuals or individuals of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 28 days following lenalidomide 
discontinuation, even if he has undergone a successful vasectomy. 
During study participation and for 28 days following lenalidomide discontinuation 
Individuals of Childbearing Potential: 
•
ICBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of lenalidomide treatment, including dose interruptions and then every 28 
days throughout the remaining duration of lenalidomide treatment, including dose 
interruptions, at lenalidomide discontinuation, and at Day 28 following lenalidomide 
discontinuation.  If menstrual cycles are irregular, the pregnancy testing must occur 
weekly for the first 28 days of lenalidomide treatment, including dose interruptions, and 
then every 14 days throughout the remaining duration of lenalidomide treatment, including 
dose interruptions, at lenalidomide discontinuation, and at Day 14 and Day 28 following 
lenalidomide discontinuation.  

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•
At each visit, the Investigator must confirm with the ICBP that they are continuing to use 
two reliable methods of birth control at each visit during the time that birth control is 
required.  
•
If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide must 
be immediately discontinued.  
•
Pregnancy testing and counseling must be performed if a patient misses their period or if 
their pregnancy test or their menstrual bleeding is abnormal. Lenalidomide treatment must 
be temporarily discontinued during this evaluation.  
•
Individuals of childbearing potential must agree to abstain from breastfeeding during study 
participation and for at least 28 days after lenalidomide discontinuation.  
Individuals Who Can Father Children:  
•
Must practice complete abstinence or use a condom during sexual contact with pregnant 
individuals or individuals of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 28 days following 
lenalidomide discontinuation, even if he has undergone a successful vasectomy.  
•
If pregnancy or a positive pregnancy test does occur in the partner of an individual who 
can father children during study participation, the investigator must be notified 
immediately.  
•
Individuals who can father children should not donate semen or sperm during therapy or 
for at least 28 days following discontinuation of lenalidomide.  
Additional Precautions:  
•
Patients should be instructed never to give lenalidomide to another person.  
•
Patients should not donate blood during therapy and for at least 28 days following 
discontinuation of lenalidomide.  
•
Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle of 
therapy.  
•
Any unused lenalidomide must be returned as instructed through the Revlimid REMSTM 
program.  

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16.5 APPENDIX E:  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.

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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

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Compound
(Brand Name)
Compound Half-Life
Possible 
Washout 
Period 
(Hours)
Possible 
Washout 
Period 
(Days)
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
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

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Compound
(Brand Name)
Compound Half-Life
Possible 
Washout 
Period 
(Hours)
Possible 
Washout 
Period 
(Days)
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
Methadone (Dolophine, Methadose)
15-30 hr
7
Sedatives
Chloral hydrate
Readily converted to Trichloroethanol
(active metabolite T½= 7-10 hour)
48

Abbreviated Title: RAdR for R/R TCM
Version Date:   12/04/2025
104
References:
Physician’s Desk Reference 2002
Facts and Comparisons (update to June, 2000)
The Pharmacological Basis of Therapeutics 9th Edition, 1996

Abbreviated Title: RAdR for R/R TCM
Version Date:   12/04/2025
105
16.6 APPENDIX F:  STUDY DRUG DIARY

Abbreviated Title: RAdR for R/R TCM
Version Date:   12/04/2025
106
Study Drug Diary
Patient Initials: 
Principal Investigator: Gordon
Patient Study ID #: 
Research Nurse:
Drug Doses:
Lenalidomide (days 1-10): _________
CC-486 (5-azacitidine):  ___________
Cycle #:  _______
Instructions:
•
Use this diary to record all doses of oral study medication taken.  
•
You should bring this study drug diary and each of your study medications (including 
leftover pills and empty bottles) with you to each clinic visit. 
•
On clinic days, oral medications must be brought with you and taken in clinic.
•
Contact us if you have any side effects or before starting any new medications or over-the-
counter drugs.
•
If you have questions at any time, please contact your doctor or nurse.
Study Drugs:
The study medications should be taken as follows, the dose of each will be assigned to you by your 
doctor:  
Lenalidomide capsules should be taken with a glass of water with or without food
Dexamethasone tablets will be given in clinic and taken by mouth (PO)
CC-486 (5-azacitdine) capsules should be taken with a glass of water with or without food
Romidepsin is given by IV, in the clinic
Additional Information:
•
Each of the study drugs should be taken at about the same time each day, with or without 
food as described above
•
If you do not remember to take all or any of the medications on any day, please tell us.  
Do not make-up the dose or take extra the following day to make-up for the missed dose.
•
If you vomit after taking a dose, you should not take another dose that day.  
•
Lenalidomide and CC-486 (5-azacitidine) are to be administered orally once daily.  The 
capsules are to be taken around the same each day with (8 ounces of water).  The capsules 
must be swallowed whole and may be taken with or without food.   If a dose is not taken at 
the scheduled time and it has been less than 12 hours since the regularly scheduled time, it 
can be taken as soon as possible on the same day.  If it has been more than 12 hours, skip the 
missed dose but take the next dose at the normal time on the following day  Do not take extra 
doses to make up the missed dose.  Do not take 2 doses at the same time.
•
Patients who are not already on prophylactic or therapeutic doses of anticoagulants will be 
given aspirin 81mg to be taken by mouth daily
•
Patients will be given ondansetron 8mg by oral or by IV to prevent chemotherapy-associated 
nausea on Days 1 and 10 (may be omitted during cycles 2-6 per doctor’s instructions)

Abbreviated Title: RAdR for R/R TCM
Version Date:   12/04/2025
107
Study Drug Diary:
Please record the dose/number of pills of each study drug taken in the table below:
Lenalidomide/ 
Revlimid®
CC-486 (5-Azacitidine)
Dexamethasone
Romidepsin
Comments
(Please note reason if dose is 
missed)
Cycle 
Day
Date
#/ Dose 
Taken
Time
#/ Dose 
Taken
Time
1
PO in 
clinic
IV in 
Clinic
2
3
4
5
6
7
8
9
10
 
PO in 
clinic
IV in 
Clinic
11-28
STAFF USE ONLY
Date returned/reviewed:  
Staff member:  
Notes/Comment