Phase II Study of Romidepsin Plus Lenalidomide for Patients With Previously Untreated PTCL
Phase: PHASE2
Conditions: Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Hepatosplenic T-cell Lymphoma, Peripheral T-cell Lymphoma, Stage I Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IA Mycosis Fungoides/Sezary Syndrome, Stage IB Mycosis Fungoides/Sezary Syndrome, Stage II Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IIA Mycosis Fungoides/Sezary Syndrome, Stage IIB Mycosis Fungoides/Sezary Syndrome, Stage III Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IIIA Mycosis Fungoides/Sezary Syndrome, Stage IIIB Mycosis Fungoides/Sezary Syndrome, Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IVA Mycosis Fungoides/Sezary Syndrome, Stage IVB Mycosis Fungoides/Sezary Syndrome
Sponsor: Northwestern University

Study Number:  NU 14H04
RV-CL-PTCL-PI-003974
Version: November 17, 2021 (Amendment 11)
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Phase II Study of Romidepsin Plus Lenalidomide for Patients with Previously 
Untreated PTCL
Principal Investigator:
Jonathan Moreira, MD
Northwestern University
676 N. St. Clair Street, Suite 850
Chicago, IL 60611
Phone: 312-695-6180
Fax: 312-695-6189
jonathan.moreira@northwestern.edu
Sub-Investigators & Participating Sites:
Northwestern University
Leo Gordon, MD
Jane Winter, MD
Shuo Ma, MD, PhD
Weill Cornell Medical College
Jia Ruan, M.D., Ph.D
The Joan & Sanford I. Weill Medical College of 
Cornell University
1300 York Avenue
New York, NY 10065
Phone:  212-746-2932
jruan@med.cornell.edu
City of Hope
Jasmine Zain, MD
Main Campus (Duarte
1500 East Duarte Road, MOB-3
Duarte, CA 91010
Phone: (626) 471-9300
Fax: (626) 301-8889
jazain@coh.org 
Biostatistician:
Borko Jovanovic, PhD
Northwestern University
borko@northwestern.edu
Study Drugs:
Romidepsin
Lenalidomide
IND Number & Holder:
#123,818 
Funding Source: 
Celgene
Version Date:
November 17, 2021 (Amendment 11)
Coordinating Center:
Clinical Trials Office (CTO)
Robert H. Lurie Comprehensive Cancer Center
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL  60611
https://www.cancer.northwestern.edu/research/clinical-trials-
office/index.html
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Table of Contents
Study Schema ..............................................................................................................................................4
Study Summary ............................................................................................................................................5
1.0
Introduction – Background and Rationale.........................................................................................6
2.0
Study Objectives and Endpoints.....................................................................................................11
3.0
Patient Eligibility..............................................................................................................................12
4.0
Treatment Plan ...............................................................................................................................15
5.0
Study Procedures ...........................................................................................................................22
6.0
Assessment of Endpoints ...............................................................................................................24
7.0
Adverse Events...............................................................................................................................27
8.0
Drug Information .............................................................................................................................32
9.0
Exploratory Studies.........................................................................................................................37
10.0
Statistical Considerations ...............................................................................................................38
11.0
Study Management.........................................................................................................................39
References .................................................................................................................................................43
Appendix A – Modified Cumulative Illness Rating Scale (CIRS) ................................................................46
Appendix B – ECOG Performance Status..................................................................................................47
Appendix C – Concomitant Medications – Prohibited or Cautionary Use...................................................48
Appendix D – Creatinine Clearance ...........................................................................................................49
Appendix E – Protocol History of Changes.................................................................................................50
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List of Abbreviations
AE
Adverse Event
AITL 
Angioimmunoblastic T-Cell Lymphoma
ALCL 
Anaplastic Large Cell Lymphoma
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AST 
Aspartate Aminotransferase
ATLL
Adult T-cell Lymphoma/Leukemia
BUN
Blood Urea Nitrogen
BSA
Body Surface Area
CBC
Complete Blood Count
CHOP
Cyclophosphamide, Doxorubicin, Vincristine and Prednisone
CIRS
Cumulative Illness Rating Scale
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CRR
Complete Response Rate
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCL
Cutaneous T-Cell Lymphoma
CTO
Clinical Trials Office
DLBCL
Diffuse Large B-Cell Lymphoma
DOR
Duration of Response
DSMB
Data and Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
EFS
Event-Free Survival
FL
Follicular Lymphoma
H&P
History & Physical Exam
HDAC
Histone Deacetylase
HIV
Human Immunodeficiency Virus
HL
Hodgkin Lymphoma
IV (or iv)
Intravenously
LDH
Lactate Dehydrogenase
MCL
Mantle Cell Lymphoma
MM
Multiple Myeloma
NCI
National Cancer Institute
NHL
Non-Hodgkin Lymphoma
ORR
Overall Response Rate
OS
Overall Survival
PTCL
Peripheral T-Cell Lymphoma
PD
Progressive Disease
PFS
Progression Free Survival
p.o.
per os/by mouth/orally
PR
Partial Response
PRR
Partial Response Rate
REMS
Risk Evaluation and Mitigation Strategy
RP2D 
Recommended phase II dose
SAE
Serious Adverse Event
SCT
Stem Cell Transplant
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
TMA
Tissue MicroArray
TTFCC
Time to First Cytotoxic Chemotherapy
WBC
White Blood Cells
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Study Schema
     
     CR, PR or SD                                                                               PD
Eligibility
Diagnosed with one of the following PTCL histologic subtypes:

Anaplastic large cell lymphoma

Angioimmunoblastic T-cell lymphoma

Enteropathy-type T-cell lymphoma

Hepatosplenic γδ T-cell lymphoma

Peripheral T-cell lymphoma, NOS

Subcutaneous panniculitis-like T-cell lymphoma

Transformed mycosis fungoides

Adult T-cell lymphoma/leukemia (ATLL)
Must have measurable disease and no prior systemic treatment
Continue therapy until:

Progression

Intolerable toxicity

Withdrawal of consent

Completion of 1 year of treatment
Response Assessment
Response assessed with imaging (either NM PET/CT or diagnostic CT 
with or without contrast) after cycles 3 and 6 and then every 6 months 
thereafter
Treatment
Cycle = 28 days:

Romidepsin (10 or 14 mg/m2 depending on the cycle) IV D1, 8, and 15 of each cycle

Lenalidomide 25 mg PO daily D1-21 of each cycle
Off treatment
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Study Summary
Title
Phase II Study of Romidepsin Plus Lenalidomide for Patients with 
Previously Untreated PTCL
Version
November 17, 2021 (Amendment 11)
Methodology
Phase II, open-label, single-arm, Simon two-stage, multicenter
Study Duration
Approximately 24 months
Study Centers
Lead site: Northwestern University Robert H. Lurie Comprehensive Cancer 
Center
Participating Sites: City of Hope, Cornell Medical College
Objectives
Primary
Evaluate the efficacy of romidepsin plus lenalidomide in patients with PTCL; 
this will be done by evaluating the objective response rate by Cheson 
criteria.
Secondary objectives:
1.
Evaluate safety (as defined by frequency and severity of toxicity 
events).
2.
Further evaluate efficacy as measured by PFS and OS measured at 1 
and 3 years after beginning treatment.
3.
Further evaluate efficacy as measured by duration of response and time 
to first cytotoxic chemotherapy.
Exploratory objectives: 
1.
Further evaluate the use of NM PET/CT vs CT imaging in PTCL.
2.
Validate a new prognostic model for newly diagnosed PTCL.
3.
Investigate the tumor immunohistochemical profile to identify potential 
biomarkers associated with prognosis and treatment response.
Study Population
Up to 35 adult patients with previously untreated PTCL (see specific 
histologic subtypes in Schema and Section 3.0) may be enrolled to obtain 
20 evaluable patients.
Treatment Plan
Patients will receive treatment in cycles defined as 28 days each:

Romidepsin 10 mg/m2 IV on days 1, 8, and 15 of each cycle (dose 
escalated to 14 mg/m2 if tolerated first 6 doses)

Lenalidomide 25 mg PO daily days 1- 21 of each cycle
Patients may receive treatment for up to 1 year (unless discontinued prior 
to that for progression of disease, intolerable toxicity, or withdrawal of 
consent)
Statistical 
Methodology
The study will analyze n=20 evaluable patients. This will allow us to 
estimate the underlying true response rate with a half width of an 
approximate 95% confidence interval equal to 1.96x0.5/sqrt(20) = 
1.96x0.11 = 0.22. 
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1.0
Introduction – Background and Rationale
1.1
Disease Background
Peripheral T-cell lymphoma (PTCL) is an uncommon subset of non-Hodgkin lymphoma 
(NHL) that carries a poor prognosis with frequent early relapses despite intensive 
therapy. PTCL represents approximately 10-15% of all NHL in Western populations. 
PTCLs originate from mature post-thymic T-cells.[1] The current World Health 
Organization (WHO) classification for lymphoid malignancies incorporates 
immunophenotyping, molecular, clinical, and pathologic features for diagnosis of the 
differing subtypes.[2] Understanding the biologic nature of this disease has been difficult 
given the rarity and the heterogeneity of the histologic subtypes.
In North America, the most common subtype of PTCL is PTCL, unspecified (PTCLu), 
which comprises a heterogeneous group of predominantly nodal T-cell lymphomas. 
PTCLu do not have consistent immunophenotypic, genetic, or clinical features. Less 
common PTCL subtypes include the predominantly nodal systemic anaplastic large cell 
lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL). Rare subtypes of 
PTCL include NK/T-cell lymphoma nasal type, enteropathy type T-cell lymphoma, 
hepatosplenic γδ T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and 
the adult T-cell lymphoma/leukemia (ATLL) which is associated with HTLV-1 infection. All 
these rare subtypes of PTCL are predominantly extranodal with the exception of ATLL.[3] 
Primary treatment for most subtypes of PTCL remains anthracycline-based regimens, 
predominantly the combination of cyclophosphamide, doxorubicin, vincristine and 
prednisone (CHOP). The primary response rate for all PTCL subtypes remains at less 
than 60% and most patients will relapse after initial treatment with cytotoxic agents.[4] 
The median survival of all PTCL patients (excluding the ALK-positive ALCL subtype) is 
approximately 3-4 years, with a 5-year survival of less than 30%. The 5-year survival rate 
for ALK-positive ALCL is 60-90%. Further intensification of therapy, with either the 
addition of etoposide (e.g., CHOEP), or with consolidative autologous stem cell transplant 
(autoSCT), has not been shown to improve outcomes. The value of anthracyclines as 
part of upfront therapy is also unclear. At present, there remain no therapies approved 
specifically for PTCL.
Such data, along with the recent regulatory approval of several novel, reasonably well-
tolerated agents (particularly in comparison to CHOP-like regimens) for 
relapsed/refractory NHL, has led to the hypothesis that these agents might form a novel 
and highly active upfront therapy for patients with PTCL.
1.2
Histone Deacetylases (HDAC) and HDAC Inhibitors
Histone deacetylases (HDAC) are enzymes that catalyze the removal of acetyl groups 
from the lysine residues of various proteins, including histones and transcription factors. 
The transcription of genes is partially regulated by acetylation of nucleosomal histones. 
The core nucleosomal histones are the most widely studied of the proteins that become 
acetylated following inhibition of HDAC activity.[5] In some cancer cells, there is an 
overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic 
transcription factors causing hypoacetylation of core nucleosomal histones. 
Hypoacetylation of histones is associated with a condensed chromatin structure and 
repression of gene transcription. 
Inhibition of HDAC activity allows for the accumulation of acetyl groups on the histone 
lysine residues resulting in an open chromatin structure and transcriptional activation. 
HDAC inhibitors can induce tumor cell growth arrest, differentiation, or apoptosis in vitro 
and inhibit tumor growth in animals.[6, 7] HDAC inhibitors as a class appear to have 
significant activity in T-cell lymphomas for reasons that are not clearly understood. HDAC 
inhibitors work through several different mechanisms including alteration in the 
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expression of genes that regulate cell cycle, acetylation of non-histone proteins that may 
impair their function to influence cell growth and survival, and by direct activation of 
apoptotic pathways.[8] Attempts at understanding the mechanisms of HDAC inhibitors 
have involved gene expression profiling on paired tissue samples both pre- and post-
treatment that have shown only 5-10 % of the genome can be affected. As many genes 
are unregulated as are down regulated following treatment with most HDAC inhibitors. 
The genes that were consistently affected included genes that alter cell cycle (CCNDI, 
IGFI), apoptosis (septin10, TEF, SORBBS2), angiogenesis (GUCY1A1, ANGPT1), and 
immune modulation (LAIR1).[9] QT-PCR was used to confirm that the findings on gene 
array analysis were indeed biologically accurate, with a strong correlation between gene 
array and the PCR data. Tumor tissue specimens treated with various HDAC inhibitors 
have shown an increase in histone acetylation, decreased vascularity, and translocation 
of nuclear proteins like STAT-s which is associated with inactivation.[10]
1.2.1
Romidepsin
Romidepsin (Istodax®, FK228) is a HDAC inhibitor commercially available from 
Celgene. It is a unique HDAC inhibitor as it is a prodrug. Upon entering cells 
romidepsin is reduced to an active compound, capable of preferentially 
interacting with the zinc in the active site of the HDAC1, HDAC2 and HDAC3 
(Class I).[11] Romidepsin currently has FDA approval for patients with cutaneous 
T-cell lymphomas (CTCL) that have received at least one prior therapy (as well 
as for relapsed/refractory PTCL – see 1.2.4 below). It is currently being assessed 
for the treatment of a variety of malignant and inflammatory diseases. 
1.2.2
Toxicity and Safety of Romidepsin
The clinical experience with romidepsin from multiple clinical trials has shown a 
well tolerated toxicity profile. Phase 1 trials have provided the safety profile and 
dosing schedule.[12, 13] Romidepsin doses ranging from 1.0 to 24.9 mg/m2 
administered intravenously over 4 hours have been investigated in treatment of 
advanced cancers.[14] A more standardized regimen has been defined as 14 
mg/m2 intravenously over a 4 hour period on days 1, 8 and 15 of a 28-day 
cycle.[15] The major hematologic toxicity includes anemia, leukopenia, 
lymphopenia, and thrombocytopenia. Other common adverse events include 
gastrointestinal symptoms, constitutional symptoms, and dysgeusia. In addition, 
it was found that romidepsin may cause QTc prolongation/ECG changes 
however this may be the result of a drug:drug interaction with select antiemetics. 
Based on non-clinical findings, male and female fertility may be compromised by 
treatment with Romidepsin. 
1.2.3
Efficacy of Romidepsin
The use of romidepsin is best established in CTCL. A phase II trial with 
romidepsin in relapsed CTCL showed single agent activity in patients that 
previously had been heavy pretreated with a median of 4 prior therapies.[16] A 
total of 71 patients were treated with an overall response rate (ORR) of 34% 
including 4 patients with a complete response. The median duration of response 
(DOR) was 13.7 months. This trial and a registration directed trial by Gloucester 
Pharmaceuticals, previous owners of romidepsin, led to full regulatory approval 
by the FDA for the treatment of relapsed CTCL. A phase II trial of romidepsin in 
patients with heavily treated relapsed/refractory PTCL demonstrated an ORR of 
25% with median DOR lasting a somewhat remarkable 17 months.[15] The 
treatment regimen was romidepsin administered as a 4-hour infusion on days 1, 
8, and 15 of a 28-day cycle with a dose of 14 mg/m2. Based on this trial, 
romidepsin gained FDA approval in 2011 for use in relapsed/refractory PTCL. 
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1.3
Immunomodulatory and Antineoplastic Agents
Thalidomide gained notoriety in the 1960s due to profound limb deformities observed in 
infants of pregnant women who used the medication for morning sickness. Laboratory 
based re-evaluation of the agent in the 1990s later showed important antiangiogenic, 
anti-inflammatory, and antineoplastic effects. By the early 2000s, thalidomide had 
emerged as a new treatment for multiple myeloma (MM). Subsequently, other more 
potent derivatives of thalidomide have been developed including pomalidomide and 
lenalidomide.[17] 
1.3.1
Lenalidomide
Lenalidomide (Revlimid®, CC-5013) and its predecessor, thalidomide, are 
proprietary IMiD™ compounds of Celgene Corporation. Lenalidomide is an orally 
available and more potent thalidomide derivative that has a more favorable side 
effect profile. The exact mechanism of action is unclear, however lenalidomide 
has been shown to have immunomodulatory and anti-angiogenic effects. In 
general, its effects include inhibition of regulatory T-cells, co-stimulation of other 
T-cell subsets, inhibition of cell cycle regulatory proteins, and downregulation of a 
variety of cytokines including IL-6 and TNFα.[18] Preclinical studies have shown 
that lenalidomide inhibits neovascularization via VEGF inhibition of the P13K-Akt 
pathway signaling. It also has an inhibitory effect on protein interactions critical 
for endothelial cell cord formation including HIF-1α expression, the main mediator 
of hypoxia-mediated effects and a key driver of angiogenesis and metastasis.[19, 
20] The dual mechanism of action with both direct tumorical activity and 
immunomodulation has shown promising responses in hematologic 
malignancies. 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; it is also 
approved in combination with dexamethasone for the treatment of patients with 
multiple myeloma that have received at least one prior therapy.
1.3.2
Toxicity and Safety of Lenalidomide
The clinical experience with lenalidomide from multiple clinical trials has shown a 
well tolerated toxicity profile. Phase 1 trials have provided the initial safety profile 
and dosing schedules.[21-23] Doses up to 50 mg daily have been evaluated in 
both hematologic and solid tumor populations. Lenalidomide has less 
myelosuppression when a 7-day break is introduced, and the most common 
schedule selected for further development is 25 mg daily on Days 1-21, followed 
by a 7-day drug “holiday”. A majority of side effects are mild and include rash, 
pruritus, diarrhea, and fatigue. Grade 3 and 4 toxicities observed in these trials 
include neutropenia and thrombocytopenia in approximately 10% of patients. 
Importantly, severe constipation, neuropathy and somnolence that characterize 
thalidomide were not seen.
Based on the history of limb defects associated with thalidomide, prescribers 
must enroll patients through a restricted program under a Risk Evaluation and 
Mitigation Strategy (REMS), called the REVLIMID REMSTM program. The 
program provides a structured process for monitoring prescriptions of this 
teratogenic agent. 
1.3.3
Efficacy of Lenalidomide
The use of lenalidomide is best established in multiple myeloma (MM) however 
there are several clinical trials investigating the use of lenalidomide monotherapy 
in patients with relapsed lymphomas. Lenalidomide monotherapy was reported in 
aggressive lymphomas composed on diffuse large B-cell lymphoma (DLBCL), 
grade 3 follicular lymphoma (FL), mantle cell lymphoma (MCL), and transformed 
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FL.[24] The ORR was 35% with a median duration of response to 6.2 months 
and median progression free survival (PFS) of 4 months. The trial included a 
population of heavily pre-treated patients with a median of 4 prior regimens and 
30% had previously relapsed following an autologous stem cell transplant 
(autoSCT). The same regimen was studied in indolent non-Hodgkin lymphomas 
(NHL) with a similar heavily pretreated population including 50% with refractory 
disease. Here the ORR was 23% in all patients and 27% in relapsed FL.[25] 
Interestingly, the median PFS was only 4.4 months however the median DOR for 
responding patients is greater than 16.5 months. Lenalidomide monotherapy 
appears particularly active in mantle cell lymphoma, with an ORR of 53% and a 
median DOR of 13.7 months.[26] In 2013, lenalidomide was approved for 
relapsed/refractory MCL in patients with prior exposure to bortezimib containing 
regimens based on the phase II “EMERGE” trial.[27] A completed international 
phase II trial (NHL-003) published follow up results for the MCL subset of 
patients. They report ORR was 35% with 12% complete responses with a 
median DOR of 16.3 months. Median PFS was 8.8 months and OS has yet to be 
reached.[28] These single agent studies as well as preclinical studies of potential 
synergy have prompted an intense development agenda for lenalidomide in NHL, 
with many trials currently underway.
1.4
Study Rationale
The toxicity associated with anthracycline-containing regimens (eg, CHOP) prevent its 
safe deployment in a substantial portion of patients with newly diagnosed PTCL. In 
addition, intensification does not clearly yield improved clinical outcomes. The emerging 
regimen for relapsed/refractory NHLs with combination romidepsin and lenalidomide 
supports promising responses. In patients with PTCL, particularly those with AITL, the 
use of either romidepsin or lenalidomide may provide therapeutic options. The safety of 
combination therapy with these two agents has already been evaluated in other 
malignancies. 
Romidepsin was approved in 2011 for the treatment of patients with relapsed/refractory 
PTCL based upon results of a phase II trial that demonstrated an overall response rate 
(ORR) of 25%, with median DOR lasting a somewhat remarkable 17 months.[15] The 
drug was well-tolerated with fatigue, infections, and cytopenias observed as the main 
toxicities. Lenalidomide was approved in 2013 for the treatment of relapsed/refractory 
mantle cell lymphoma (MCL) based upon phase II data demonstrating an ORR of 25% in 
heavily pre-treated patients.[27] Two separate phase II trials of lenalidomide in 
relapsed/refractory PTCL, involving a total of 44 patients, each demonstrated ORR of 
30%.[29, 30] The main adverse events in both trials consisted of cytopenias and fatigue. 
A third, ongoing trial is evaluating the role of lenalidomide in Japanese patients with 
PTCL with particular focus on those with adult T-cell leukemia/lymphoma (ATLL).[31] 
Romidepsin and lenalidomide each appear to have particularly notable activity in patients 
with angioimmunoblastic T-cell lymphoma (AITL), which is the second most frequent type 
of PTCL in North America. Specifically, median DOR has not been reached and is at 
least 48 months among patients with relapsed/refractory AITL treated with romidepsin as 
part of the phase II registration trial.[32] Durable responses of over two years have 
likewise been reported for patients with relapsed/refractory AITL receiving 
lenalidomide.[33] 
Currently, a Phase I/II trial evaluating the combination of romidepsin and lenalidomide in 
patients with relapsed hematologic malignancies is open to enrollment (NCT01755975). 
The trial included a 3+3 design with five dosing cohorts to determine the maximal 
tolerated dose with a total of 20 patients treated on the study. Results presented at 
ASCO annual meeting in 2014 revealed that the combination was well-tolerated[34]. A 
dose limiting toxicity was demonstrated in one patient of seven receiving romidepsin 14 
mg/m2 with lenalidomide 25 mg. The most common grade 3-4 toxicities included 
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electrolyte abnormalities, myelosuppression, and transaminitis. The trial enrolled patients 
with a range of lymphoma subtypes including eight patients with T-cell NHL. An ORR of 
66% was seen in six evaluable patients including two patients with PTCL-NOS and one 
patient with AITL. The trial is proceeding to the phase II portion with romidepsin 10 
mg/m2 and lenalidomide 25 mg as a recommended dose schedule. A second phase I/IIa 
trial evaluating combination romidepsin and lenalidomide is currently open for patients 
with relapsed/refractory Hodgkin lymphoma (HL), mature T-cell lymphoma (including 
CTCL and PTCL), and MM (NCT01742793). Results from this clinical trial are not 
available.
We propose proceeding with a phase II trial evaluating the safety and efficacy of the 
combination of romidepsin and lenalidomide in patients with previously untreated PTCL. 
The treatment population will include patients ≥ 60 years of age who often have 
comorbidities that prevent the use of cytotoxic chemotherapy. In addition, the trial will 
enroll patients age ≥ 18 years to < 60 years with a cumulative illness rating scale (CIRS) 
score ≥ 6 or deemed ineligible for cytotoxic chemotherapy by the treating investigator. A 
CIRS score ≥ 6 is a previously established cutoff to define increased treatment risk. The 
proposed dosing and schedule for romidepsin and lenalidomide are both FDA approved. 
The protocol will allow an increased dose of romidepsin from 10 mg/m2 to 14 mg/m2 
pending tolerance assessment. The initial romidepsin dose of 10 mg/m2 is chosen to 
avoid potential cytopenias with combination therapy. Up to 35 patients may be treated on 
the protocol in order to achieve a total of 20 evaluable. The trial will include a two-side 
design with an early assessment of futility following treatment of the first 12 patients with 
an early stopping point if 6 or fewer patients have a complete or partial response. 
Response will be determined by interval imaging; the 3 month response assessment time 
point will be used for the purposes of the interim efficacy analysis. Patients may be 
treated for up to 1 year or until progression of disease, intolerable toxicity, or withdrawal 
by patient.  
1.5
Exploratory Studies 
Prior translational research has looked to incorporate marker expression into a clinical 
prognostic tool.[35]  While no clear marker has been identified for PTCL, several may 
help predict a poor outcome including EBER, CD15, and Ki-67. A protein, nm23-H1, that 
is over expressed in lymphoma cells is an emerging marker that may predict a poorer 
prognosis.[36] Two cytotoxic molecules, TIA-1 and granzyme B, have been correlated 
with a more aggressive clinical course.[37] Another study showed high expression of IL-6 
and TNF-α expression in PTCL which is particularly interesting given the down regulation 
of these proteins with administration of one of  our study drugs, lenalidomide.[38] 
Correlative studies will be analyzed on collected blood and tissue samples. In addition to 
the study objectives, we plan to assess tumor samples for the immunohistochemical 
biomarkers that may correlate with prognosis and more importantly with treatment 
response. A tissue microarray (TMA) of paraffin-embedded lymphoid tissue biopsies of all 
patients will be created in order to determine how marker expression correlates with 
clinical outcome.
A new prognostic model was recently defined for PTCL. An analysis of the SEER registry 
was conducted to evaluate the impact of variables including age, race, histology, and 
stage.[38] In this model, overall survival can be predicted however further validation is 
required. Enrolled patients will provide a prospective look at this proposed predictive 
model. 
The current standard modality for staging and response assessment in PTCL remains CT 
imaging. The role of NM PET/CT in management of PTCL is poorly understood though 
often utilized in clinical practice. Prior analysis has shown that NM PET/CT can identify 
additional sites of disease however there is no influence on treatment decisions[39]. 
Conversely, the role of NM PET/CT in the management of other lymphomas is well 
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established. The use of NM PET/CT in Hodgkin lymphoma is now standard of care. Use 
of NM PET/CT in non-Hodgkin lymphomas including DLBCL and FL has proven useful in 
staging and guiding treatment decisions[40]. We will investigate the role of NM PET/CT in 
the treatment of PTCL. 
2.0
Study Objectives and Endpoints
2.1
Primary Objective & Endpoint
The primary objective of this phase II trial will be to evaluate the efficacy of the 
combination of romidepsin plus lenalidomide in patients with previously untreated PTCL. 
The endpoint for this objective will be objective response rate (ORR), defined per Cheson 
criteria. Response will be assessed by imaging after cycles 3 and 6, and then every 6 
months thereafter. Response at 3 months (after cycle 3) will be used for purposes of the 
interim efficacy analysis.
2.2
Secondary Objectives & Endpoints
2.2.1
Evaluate the safety of the combination of romidepsin and lenalidomide.
The endpoint will be the frequency and severity of toxicity events using the NCI 
CTCAE v 4.03.
2.2.2
Further evaluate efficacy of the combination of romidepsin and lenalidomide. 
The endpoints will be progression-free survival (PFS) and overall survival (OS) at 
1 and 3 years after start of treatment as well as the duration of response from 
start of therapy, defined per Cheson criteria. 
2.2.3
Evaluate the delay to cytotoxic chemotherapy
The endpoint will be time (in months) to first cytotoxic chemotherapy (TTFCC) 
from start of treatment.
2.3
Exploratory Objectives & Endpoints
2.3.1
Evaluate the use of NM PET/CT vs CT imaging in PTCL.
The endpoint will be a review of the utilized imaging modalities during treatment 
as a tool of response assessment. When both imaging modalities are chosen for 
a patient, response assessment will be compared. 
2.3.2
Validate a new prognostic model for newly diagnosed PTCL.[41]
The endpoint will be clinical biomarkers including age, race, histology, and stage 
as an assessment of prognosis. 
2.3.3
Investigate the tumor immunohistochemical profile to identify potential 
biomarkers associated with prognosis and treatment response. 
The endpoint we be comparison of immunohistochemical profiles with treatment 
outcomes on archived tissue samples.
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3.0
Patient Eligibility
The target population for this phase II study is patients with histologically confirmed (previously 
untreated) peripheral T-cell lymphoma (PTCL). Northwestern University will serve as the lead site 
and coordinating center for this study. Participating sites will include Weill Cornell Medical 
College, and City of Hope.
A total of 20 evaluable subjects will be needed for this trial; up to 35 may be accrued to obtain 20 
who are evaluable. Approximately 3 potentially eligible patients are seen per month, and it is 
anticipated that at least 1 per month will be accrued (once all sites are up and running). Potential 
patients may be referred to the Principal Investigator (PI) at Northwestern University, , or to the 
local PI at each participating site.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and exclusion criteria to be registered to 
the study. Study treatment may not begin until a subject is registered. After registration, treatment 
should begin with 14 days. Please refer to Section 11.4 for complete instructions regarding 
registration procedures.
3.1
Inclusion Criteria
3.1.1
Histologically confirmed diagnosis of PTCL (using the most recent edition of the 
WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues as 
guidance) including: 
•
Anaplastic large cell lymphoma, ALK-negative 
•
Angioimmunoblastic T-cell lymphoma 
•
Enteropathy-type T-cell lymphoma 
•
Hepatosplenic γδ T-cell lymphoma 
•
Peripheral T-cell lymphoma, unspecified (NOS) 
•
Transformed mycosis fungoides
•
Subcutaneous panniculitis-like T-cell lymphoma
•
Adult T-cell lymphoma/leukemia (ATLL) in need of systemic therapy. 
NOTE: Patients with adequate archived (well-preserved, formalin-fixed) biopsy 
tissue remaining will be required to submit a portion for exploratory studies. This 
is not optional if tissue is available; however, lack of adequate tissue for 
exploratory studies will not preclude patients from participating. 
3.1.2
Patients must have bi-dimensionally measurable disease (≥1 cm) by CT imaging. 
NOTE: Patients with marrow-only disease are eligible; response for these 
patients will be assessed by repeat bone marrow biopsy.
3.1.3
Patients must fit into one of the following categories:
•
Age ≥ 18 years to < 60 years with a cumulative illness rating scale (CIRS) 
score ≥ 6 OR deemed ineligible for cytotoxic chemotherapy by the treating 
investigator (see Appendix A for CIRS scoring[42])
•
≥ 60 years
3.1.4
Patients must have adequate organ and marrow function (documented within 14 
days prior to registration) as outlined below:
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System
Laboratory Values
Hematologic
ANC
≥ 750/mcl
Hemoglobin
≥ 8 g/dl
Platelets
≥ 50,000/mcl
Hepatic
Total Bilirubin
≤ 2x upper limit normal (ULN)
AST (SGOT) and ALT (SPGT)
≤ 3x ULN
Renal
Creatinine Clearance
≥ 30 mL/min
See Appendix D to reference the Cockgroft-Gault equation for 
calculating creatinine clearance. 
3.1.5
Patients must have an ECOG performance status ≤ 2 (see Appendix B).
3.1.6
All patients must agree to use effective contraception while on study, and all 
patients must agree to undergo counseling sessions every 28 days about 
pregnancy precautions and risks of fetal exposure.
Females of childbearing potential (FCBP) must either commit to continued 
abstinence from heterosexual intercourse or begin TWO acceptable methods of 
birth control: one highly effective method and one additional effective method AT 
THE SAME TIME, at least 28 days before starting lenalidomide, during 
lenalidomide therapy, during dose interruptions, and for at least 28 days following 
discontinuation of lenalidomide therapy (refer to the patient resources materials 
or http://www.revlimidrems.com for more information).
Males receiving lenalidomide must agree to use a latex condom during any 
sexual contact with FCBPs even if they have undergone a successful vasectomy.
NOTE: A FCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy

Has not been naturally postmenopausal for at least 12 consecutive months 
(i.e., has had menses at any time in the preceding 12 consecutive months).
FCBP should be referred to a qualified provider of contraceptive methods, if 
needed.
3.1.7
FCPB must have a negative urine or serum pregnancy test within 7 days prior to 
registration, and be willing to adhere to the scheduled pregnancy testing as 
required in the Revlimid REMS® program. 
NOTE: Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
3.1.8
Patients must be free of any prior malignancies for ≥1 year at the investigator’s 
discretion. 
NOTE:  The exception to this would be currently treated squamous cell and basal 
cell carcinoma of the skin, carcinoma in situ of the cervix, breast, or bladder, or 
surgically removed melanoma in situ of the skin (stage 0) with histologically 
confirmed free margins of excision.  
3.1.9
All study participants must be registered into the mandatory Revlimid REMS® 
program, and be willing and able to comply with the requirements of REMS®.
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3.1.10
Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration.
 
3.2
Exclusion Criteria
3.2.1
Patients with a diagnosis of any of the following are not eligible:
•
Anaplastic large cell lymphoma, ALK-positive 
•
Anaplastic large-cell lymphoma, primary cutaneous type
•
Precursor T-lymphoblastic lymphoma/leukemia
•
Mycosis fungoides/Sezary syndrome (except transformed MF)
•
NK-cell leukemia
•
T-cell granular lymphocytic leukemia
•
T-cell prolymphocytic leukemia.
3.2.2
Patients must not have received prior systemic therapy for PTCL (except for 
corticosteroids, which are permitted to treat lymphoma for 10 or fewer days at 
any dose; no washout period required in this case as long as they discontinue 
prior to starting study therapy). 
NOTE: Corticosteroids are permitted on study for treatment of any condition 
other than PTCL. 
NOTE: Topical treatment may have been given for prior existence of cutaneous 
lymphoma that has since become systemic PTCL. However, these topical 
therapies should be stopped at time of registration.
3.2.3
Patients who received chemotherapy (including monoclonal antibodies) or 
radiotherapy, administered for any condition, ≤28 days prior to registration are 
not eligible.
3.2.4
Patients who have received any other HDAC inhibitors or IMID 
agents for any reason are not eligible.
3.2.5
Patients receiving ongoing treatment with any other investigational agents are 
not eligible.
3.2.6
Patients receiving concurrent immunosuppressive medications post-transplant 
(at the time of registration) are not eligible.  
3.2.7
Patients with known CNS (central nervous system) involvement of lymphoma are 
not eligible.
3.2.8
Patients who have an uncontrolled intercurrent illness including, but not limited 
to any of the following are not eligible:
•
ongoing or active infection
•
symptomatic congestive heart failure
•
unstable angina pectoris
•
cardiac arrhythmia
•
psychiatric illness/social situations that would limit compliance with study 
requirements.
3.2.9
Patients with a known HIV infection are not eligible.
3.2.10
Patients who are pregnant or actively nursing an infant are not eligible.
3.2.11
Patients with a QT interval > 480 msec (using the Bazett's formula) ≤28 
days prior to registration are not eligible. 
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4.0
Treatment Plan
Patients will be treated in cycles of 28 days (±3 days). Patients will receive romidepsin (at a dose 
of either 10 or 14 mg/m2 – see 4.1.1 for details) IV on days 1, 8, and 15 as well as lenalidomide 
25 mg PO daily on days 1- 21 of each cycle. Treatment may continue for one year or until 
disease progression or unacceptable toxicity. Patients who do not achieve a response of PR or 
better should continue to be treated only if they have SD (i.e., not PD), and if they do not have 
other options available that would present a more favorable risk/benefit ratio. Clinical suspicion of 
progressive disease (PD) or loss of response should be investigated radiographically (or by 
repeat bone marrow biopsy for marrow-only disease), and if confirmed, will result in removal from 
active therapy; such patients will remain in study follow up. In this case, it is strongly 
recommended that investigators consider early initiation CHOP or similar
chemoimmunotherapy (off trial).
Treatment will be based on weight at baseline. Dosing should only be modified if the patient's 
weight has changed by more than 10% from baseline or the BSA has changed more than 5%.
It is intended that all treatments will be administered on an outpatient basis.  However, treatment 
can be initiated during hospitalization (i.e., for newly-diagnosed patients), and can continue during 
unforeseen hospitalizations, but only at the discretion of the local primary investigator (PI).
4.1
Treatment Dosage & Administration
4.1.1
Romidepsin
Romidepsin will be administered IV on days 1, 8, and 15 of each 28-day cycle. 
Initially, romidepsin will be given at a dose of 10 mg/m2; patients who tolerate 2 
or more cycles (or 6 total doses) at 10mg/m2 may be escalated to 14 mg/m2 for 
later cycles if the following criteria are met: a) patient has not achieved a CR, and 
b) patient has not experienced a drug-related grade 3-4 AE. If the treating-
investigator wishes to escalate a patient that has experienced > grade 3 
treatment-related AEs, the QAM must be notified and DSMC approval granted 
prior to escalation. Patients who are escalated to 14 mg/m2 may be de-escalated 
back to 10 mg/m2 at the discretion of the treating investigator, but must remain at 
that dose for the duration of study treatment (i.e. may not be re-escalated to 14 
mg/m2). All changes in dosing should be clearly documented in the patients’ 
medical records.
On days where romidepsin is given, it does not matter whether administration 
occurs before or after oral lenalidomide. Infusion should occur over a span of 
approximately 4 hours.
Approximately 30 minutes prior to each infusion of romidepsin, it is 
recommended that patient be given premedication with Zofran 16 mg IVPB and 
dexamethasone 10 mg IVPB (or equivalent per treating investigator’s discretion).
4.1.2
Lenalidomide
Lenalidomide will be given orally (PO) at a dose of 25 mg daily on days 1-21 of 
each 28 day cycle. NOTE: The dose and schedule should be adjusted in patients 
with moderate or severe renal impairment who are enrolled on the study 
(creatinine clearance < 60 mL/min). Please refer to Table 1b below for details. 
Lenalidomide should be taken at approximately the same time each day 
(preferably in the morning) with water. Lenalidomide capsules may be taken with 
or without food. Patients will be instructed to not crush, chew or open capsules. 
Only enough pills for 1 cycle may be dispensed at one time (prior to the start of 
each cycle). On days where patients will have romidepsin infusion, it does not 
matter whether lenalidomide is taken before or after the IV infusion. 
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If a dose of lenalidomide is missed, it should be taken as soon as possible on the 
same day.  If it is missed for the entire day, it should not be made up (i.e. patients 
should not take 2 doses the following day). Patients will be given a mediation 
diary on which to record all doses taken, missed, or skipped. This diary will be 
reviewed with study staff during visits prior to the start of each new cycle (before 
medication for upcoming cycle is dispensed). 
4.1.3
Treatment regimen & supportive therapies
Table 1 below summarizes the treatment regimen and recommended supportive 
therapies for patients on this trial.
Table 1a: Treatment Regimen
Agent
Recommended 
Premedications1
Dose
Route
Schedule3
Duration
10 
mg/m2
IV 
Days 1, 8, 
15
1 year or 
until POD
Romidepsin2
30 min prior:
5-HT3 receptor 
antagonist4
Dexamethasone 10 
mg IVPB
14
mg/m2
IV
Days 1, 8, 
15
1 year or 
until POD
Lenalidomide
None
25 mg5
po
Daily
Days 1-215 
1 year or 
until POD
1Premedication protocol is for romidepsin infusions and includes recommended agents 
and doses; similar alternate medications may be given at the discretion of the 
treating investigator. 
2The parameters specified in the shaded boxes represent optional dose increase if 
patient tolerates 2 or more cycles (6 total doses) at 10 mg/m2
3Each cycle will be 28 days; romidepsin infusions should occur within ±3 days of day 1, 
and within +3 days of days 8 and 15. 
4The recommended agent/dose is Zofran 16 mg IVPB or equivalent.
5The dose and schedule of lenalidomide should be adjusted for patients with moderate or 
severe renal impairment, as detailed in Table 1b below.
Table 1b: Lenalidomide Dose Adjustments for Patients with Renal Impairment
Category
Renal Function
Dose and Schedule
Moderate
Creatinine clearance 30-60 ml/min1
10 mg daily (Days 1-21)
Severe
Creatinine clearance < 30 ml/min 
(not requiring dialysis)1
15 mg every other day (Days 1, 3, 5, 7, 9, 
11, 13, 15, 17, 19, and 21)
1  Creatinine clearance (CrCl) will be measured and calculated prior to initiating each cycle as 
described in the Study Procedures Table in Section 5.0.  (Refer to Appendix D for instructions 
on calculating CrCl). The dose of lenalidomide will be adjusted per Table 1b. Any questions 
regarding dose calculations/adjustments should be directed to the Lead PI. 
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4.2
Toxicities, Dosing Delays, and Dose Modifications
All patients receiving at least one treatment on this protocol will be evaluable for toxicity 
endpoints. Each patient will be assessed for the development of toxicity according to the 
Time and Events Table (See Section 5). Toxicity will be assessed according to the NCI-
CTCAE v 4.03. Dose adjustments should be made according to the system showing the 
greatest degree of toxicity. Toxicity should be attributed to one study drug whenever 
possible. Modifications/delays may apply to only the drug which caused toxicity, or both if 
appropriate. If lenalidomide and/or romidepsin are dose-reduced, they may not be re-
escalated (unless clinically indicated and after discussion with the PI). If study drug is 
delayed more than 21 days (1 treatment cycle), treatment may be discontinued after 
discussion with the PI. 
Refer to Table 2 below for dose modification instructions. Additionally, with PI approval, 
dose modifications (interruptions and reductions) may be permitted for any grade AE 
deemed intolerable by the patient, or per treating investigator discretion (with PI 
approval), if thought to be in the best interest of the patient.
Please also refer to sections of this protocol that contain more detailed information on the 
potential adverse events and risks associated with each agent (Sections 1.2.2 and 1.3.2).  
Doses reduced per protocol due to occurrence of adverse events are not counted as 
missed doses.
4.2.1
Pregnancy
Female patients who become pregnant, are suspected to be pregnant, or have a 
positive pregnancy test while on lenalidomide must discontinue study treatment 
immediately. If the female partner of a male patient becomes pregnant, the male 
patient taking lenalidomide should notify the investigator, and the pregnant 
partner should be advised to call their healthcare provider immediately. See 
section 7.2.6 for pregnancy reporting requirements. 
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Table 2: Non-Hematologic Drug-Related Toxicity Dose Delays/Reductions
CTCAE v 4.03 Grade
Romidepsin1,3
Lenalidomide1,3
0-2
No change from original starting 
dose
No change from original starting 
dose
Exception: Any grade of blistering 
rash requires lenalidomide 
discontinuation. 
3-4
Hold until resolved to ≤ Grade 1, 
then dose reduce 1 level2
Hold until resolved to ≤ Grade 1, 
then resume at same dose, with 
the following exceptions:
Grade 3 non-blistering rash or 
neuropathy: Hold lenalidomide 
and follow weekly. If the toxicity 
resolves to ≤ Grade 1 (Grade 2 for 
rash) prior to Day 21 of the current 
cycle, reduce dose by 5 mg and 
restart through Day 21 of the 
current cycle. Otherwise, omit for 
remainder of cycle and reduce the 
dose by 5 mg at the start of the 
next cycle. Omitted doses are not 
made up.
Grade 4 non-blistering rash or 
neuropathy, any grade blistering 
rash: Discontinue lenalidomide.
Grade 3 or 4 tumor lysis 
syndrome: Hold until resolved to ≤ 
Grade 1, then reduce dose by 5 
mg and resume.
Grade 3 or 4 tumor flare: Hold 
dose and start corticosteroids, 
NSAIDs, and/or narcotics. Once 
toxicity resolves to ≤ Grade 1, 
reduce dose by 5 mg and resume.
2nd or 3rd episode of 3
Hold until resolved to ≤Grade 1, 
then dose reduce 1 level2
Hold until resolved to ≤ Grade 1, 
then reduce dose by 5 mg
Any recurrence of 4
Remove from trial therapy
Remove from trial therapy
1 Toxicity should be attributed to one study drug whenever possible. Modifications/delays may apply to only the 
drug which caused toxicity, or both if appropriate. 
2Romidepsin dose reductions: 1 level dose reduction of 14 mg/m2 to 10 mg/m2 or dose reduction of 10 mg/m2 to 8 
mg/m2. 
3 Additionally, with PI approval, dose modifications (interruptions and reductions) may be permitted for any grade 
AE deemed intolerable by the patient, or per treating investigator discretion (with PI approval), if thought 
to be in the best interest of the patient.
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Table 3: Hematologic Drug-Related Toxicity Dose Delays/Reductions
CTCAE v 4.03
Grade
Romidepsin1,3
Lenalidomide1,3
0-2
No change from original starting 
dose
No change from original starting 
dose
3-4 (neutropenia, 
thrombocytopenia, and/or 
anemia)
Hold until ANC ≥ 1.5x109/L and/or 
platelet count ≥75x109/L or 
baseline, restart at prior dose
Hold until resolved to ≤ Grade 1, 
then resume at same dose
4 (febrile (≥38.5°C) 
neutropenia, anemia, and/or 
thrombocytopenia requiring 
transfusion)
Hold until cytopenia returns to ≤ 
Grade 1 or baseline, dose reduce 
by 1 level2
Hold until resolved to ≤ Grade 1, 
then resume at same dose
2nd episode of grade 3-4
Hold until ANC ≥ 1.5x109/L and/or 
platelet count ≥75x109/L or 
baseline, dose reduce by 1 level2
Hold until resolved to ≤ Grade 1, 
then reduce dose by 5 mg
3rd episode of grade 3-4
Remove from trial
Remove from trial
1 Toxicity should be attributed to one study drug whenever possible. Modifications/delays may apply to only the 
drug which caused toxicity, or both if appropriate. 
2Romidepsin dose reductions: 1 level dose reduction of 14 mg/m2 to 10 mg/m2 or dose reduction of 10 mg/m2 to 8 
mg/m2. 
3 Additionally, with PI approval, dose modifications (interruptions and reductions) are permitted for any grade AE 
deemed intolerable by the patient, or per treating investigator discretion (with PI approval), if thought to 
be in the best interest of the patient.
4.3
Concomitant Medications/Treatments
NOTE: No other treatment modalities or procedures are required as part of the study 
treatment.  Any patient receiving radiation therapy and/or surgery related to progression 
of malignancy will be removed from protocol therapy. In addition, any patient that 
subsequently undergoes stem cell transplant will be removed from protocol therapy.
4.3.1
Recommended concomitant medications include:

5-HT3 receptor antagonist (such as Zofran 16 mg IVPB or equivalent dose) 
prior to romidepsin infusions

Dexamethasone 10 mg IVPB (or similar) prior to romidepsin infusions
4.3.2
Permitted concomitant medications:

Symptomatic treatment as needed for nausea, vomiting, and/or diarrhea, 
including 5-HT3 antagonists, corticosteroids, benzodiazepines, and anti-
motility agents

Topical and systemic treatment for rash, including corticosteroids.

Hormonal birth control medications.

Concurrent antiviral therapy for HBV surface antigen positivity. 

Corticosteroids are permitted for any indication other than to treat lymphoma 

Transfusions and growth factor are permitted at physician discretion and per 
institutional guidelines. 
4.3.3
Prohibited concomitant medications and treatments:

Concurrent chemotherapy, radiotherapy, or other investigational agents. 
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NOTE: Radiotherapy is permitted to treat a single non-target lesion for 
symptom control.

Corticosteroids intended to treat lymphoma (NOTE: There is no washout for 
prior corticosteroid treatment of lymphoma, however patients may not have 
received such corticosteroids for >10 days)

CYP3A4 inducers (see appendix C)
Note: As this list is constantly evolving, if a medication is incorrectly 
documented as prohibited in this protocol, documentation from the site 
pharmacist to the contrary will be acceptable for the purposes of registration.

High risk QTc prolonging agents in the case of patients who have developed 
QTc prolongation on study (see appendix C)
4.4
Duration of Therapy & Early Withdrawal
Treatment may continue for up to one (1) year or until any of the following occur, resulting 
in early withdrawal from study treatment (or in some cases withdrawal from the study as 
a whole):

disease progression

inter-current illness that prevents further administration of treatment

unacceptable toxicity

patient decides to withdraw from study treatment (or study as a whole)

general or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the treating investigator
Note: Patients who have not achieved PR or CR after 4 cycles should continue to be 
treated on the current protocol only if they have SD (i.e., not PD), AND if they do not have 
other options available that would present a more favorable risk/benefit ratio.  
Patients will be removed (withdrawn) from study therapy for any of the criteria listed 
above. The PI and the Quality Assurance Monitor (QAM) at NU is to be notified of such 
events; the reason(s) for removal and the date the patient was removed are to be 
documented in the appropriate electronic case report form (eCRF). The patient should be 
followed as described below in Section 4.5.
Patients who withdraw consent from the study as a whole will be noted to have withdrawn 
from both treatment and any further follow-up.
4.5
Duration of Follow Up
Once patients are off treatment for any reason, they will have a final off-treatment visit 
approximately 30 days post-last dose of study therapy. Thereafter, they will be followed 
with at least one clinic visit every 3 months for up to 1 year from start of treatment, then 
every 6 months up to 3 years from start of treatment (or until death, whichever occurs 
first). Patients removed from treatment for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event.
4.6
Patient Replacement
Any patient who is registered to the study and then withdrawn without receiving any study 
treatment may be replaced. Any patient who completes fewer than 2 total cycles of 
therapy and is withdrawn for any reason except POD or toxicity will still be considered 
evaluable for toxicity endpoints but will not be evaluable for efficacy endpoints; for the 
purpose of efficacy endpoints, another patient may be added to the accrual goal with the 
approval of the Data and Safety Monitoring Committee (DSMC) at NU.
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4.7
Suspension of Accrual
This study will be monitored in accordance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The 
DSMC will review all toxicity data, and in the event of an excessive toxicity, the DSMC 
may require suspension of accrual. 
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5.0
Study Procedures
Table 4: Time and Events
Study Period
Baseline
On Treatment10
(1 cycle = 28 days)
Off Treatment 
Visit
Follow-Up14
Procedures & 
Assessments
Screening9
Day 1 of Each 
cycle11
(±3 days)
Day 8 and 15 
of Each 
cycle11
(-1 to +3 days)
Response 
Assessments
28-Days Post 
Last Dose13
Survival 
Status
Informed 
consent
X
Medical history
X
Physical exam1
X
X
X
X
ECOG status
X
X
X
X
Imaging2, 12
X2
X12
X
Hematology 
Labs18, 9
X
X
X
Chemistry 
Labs3, 9
X
X
X
Pregnancy test4
 X4
X19
EKG5
X
Bone marrow 
biopsy17
X
X
X
Tissue for 
research6
X
REMS® 
program7
X
X
Adverse events8
X
X
X
Concomitant 
medications
X
X
Creatinine 
Clearance 
Check20
X
Lenalidomide 
treatment
X15
Romidepsin 
treatment
X16
1 Physical exam should include vitals (blood pressure, heart rate, temperature, respirations), height 
(baseline only), and weight.
2 Tumor assessment with diagnostic quality CT (chest, abdomen, pelvis; neck if clinically indicated) with 
or without contrast imaging within 28 days prior to registration; in addition, NM PET/CT is not 
required but encouraged prior to starting therapy (with or without contrast).
3 Lactate dehydrogenase (LDH), magnesium (Mg) and comprehensive metabolic panel (CMP) including 
albumin, alkaline phosphatase, ALT(SGPT), AST(SGOT), BUN, creatinine, electrolytes (sodium, 
potassium, calcium, chloride, bicarbonate), glucose, and total bilirubin.
4 Either urine or serum pregnancy test required within 7 days prior to registration for WOCBP; additional 
pregnancy testing required throughout the treatment period as outlined in the REMS® program.
5 EKG required within 28 days of registration (for eligibility) and then as clinically indicated thereafter.
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6 If available, archived tissue from a previous biopsy is required for exploratory studies (patients who do 
not have available/adequate tissue may still enroll). See Section 9 for details.
7 All study participants must be registered into the mandatory REMS® program, and be willing and able to 
comply with the requirements.
8 SAE’s will be collected from the time of consent until 30 days after treatment discontinuation. 
9 All screening procedures are required within 28 days prior to registration unless otherwise indicated. 
Chemistry and Hematology labs are required within 14 days of registration. 
10 Cycle 1 to begin within 14 days after registration; Treatment will continue up to 1 year unless any of the 
criteria in Section 4.4 are met.
11 One cycle = 28 days ±3 days for start of cycle. Day 8 and 15 each have a window of -1 to +3 days
12 Response will be assessed with diagnostic quality CT (chest, abdomen, pelvis; neck if clinically 
indicated) with or without contrast imaging after cycles 3 and 6 (±7 days), and then every 6 
months (±7 days). Response may be assessed more often if clinically indicated. Although not 
required, we encourage the use of NM PET/CT performed at baseline and repeated along the 
same schedule throughout (with or without contrast). 
13 All patients should have a visit approximately 28 days (+/- 7 days) post-last dose of study treatment. 
14 Once off treatment, patients will be followed clinically every 3 months (±7 days) for up to 1 year from 
start of study treatment, then every 6 months (±14 days) up to a total of 3 years (or until death, 
whichever comes first) for survival endpoints. 
15 Lenalidomide will be given at a dose of 25 mg PO daily on days 1-21 of each cycle (followed by a 7 day 
break prior to the start of the next cycle). Patients will be given a medication diary to complete, 
which will be reviewed with a member of the study team at visits.
16 Romidepsin will be administered intravenously on days 1, 8, and 15 of each cycle. The dose for the first 
2 cycles (6 doses total) will be 10 mg/m2; in some cases, patients may be escalated to a dose of 
14 mg/m2 for remaining cycles (see Section 4.1.1 for specific criteria). A window is allowed for 
romidepsin infusion visits (within ±3 days of day 1, and within -1 to +3 days of days 8 and 15).
17 Bone marrow biopsy will be done within 90 days of registration if clinically indicated, per treating 
physician’s discretion. In patients with known bone marrow involvement at baseline, a bone 
marrow biopsy will be performed after the patient achieves a CR. 
18 Complete blood count with differential will be performed weekly for the first 2 cycles, every other week 
for cycles 3-6, and at the start of each cycle thereafter.
19 Day 15 of each cycle only.
20 Creatinine clearance will be measured and calculated prior to initiating each cycle (Refer to Appendix D 
for instructions on calculating creatinine clearance). The dose of lenalidomide will be adjusted per 
Table 1b. Any questions regarding dose calculations/adjustments should be directed to the Lead 
PI. Refer to Section 4.1.3 for additional information. 
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6.0
Assessment of Endpoints
6.1
Toxicity Endpoints
The frequency and severity of adverse events will be assessed once per cycle according 
the NCI-CTCAE version 4.03. All patients who receive at least one dose of either study 
drug will be evaluable for toxicity endpoints.
6.2
Efficacy Endpoints
Response and progression will be evaluated using the 2007 Revised Response Criteria 
for Malignant Lymphoma (RRCML) as defined by Cheson, et al.[43] See Table 5 for a 
summary of the follow definitions:
6.2.1
Complete Remission (CR)
CR requires the following:
Complete disappearance of all detectable clinical evidence of disease and 
disease-related symptoms if present before therapy.
1.
Typically FDG-avid lymphoma: in patients with no pretreatment PET scan or 
when the PET scan was positive before therapy, a post-treatment residual 
mass of any size is permitted as long as it is PET negative.
Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, all 
lymph nodes and nodal masses must have regressed on CT to normal size 
(≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm before 
therapy). Previously involved nodes that were 1.1 to 1.5 cm in their long axis 
and more than 1.0 cm in their short axis before treatment must have 
decreased to ≤ 1.0cm in their short axis after treatment.
2.
The spleen and/or liver, if considered enlarged before therapy on the basis of 
a physical examination or CT scan, should not be palpable on physical 
examination and should be considered normal size by imaging studies, and 
nodules related to lymphoma should disappear. However, determination of 
splenic involvement is not always reliable because a spleen considered 
normal in size may still contain lymphoma, whereas an enlarged spleen may 
reflect variations in anatomy, blood volume, the use of hematopoietic growth 
factors, or causes other than lymphoma.
3.
If the bone marrow was involved by lymphoma before treatment, the infiltrate 
must have cleared on repeat bone marrow biopsy. The biopsy sample on 
which this determination is made must be adequate (with a goal of > 20 mm 
unilateral core). If the sample is indeterminate by morphology, it should be 
negative by immunohistochemistry. A sample that is negative by 
immunohistochemistry but that demonstrates a small population of clonal 
lymphocytes by flow cytometry will be considered a CR until data become 
available demonstrating a clear difference in patient outcome.
6.2.2
Partial Response (PR)
PR requires the following:
1.
At least a 50% decrease in sum of the product of the diameters (SPD) of up 
to six of the largest dominant nodes or nodal masses. These nodes or 
masses should be selected according to all of the following: they should be 
clearly measurable in at least 2 perpendicular dimensions; if possible they 
should be from disparate regions of the body; and they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are 
involved.
2.
No increase should be observed in the size of other nodes, liver, or spleen.
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3.
Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for 
single nodules, in the greatest transverse diameter. 
4.
With the exception of splenic and hepatic nodules, involvement of other 
organs is usually assessable and no measurable disease should be present.
5.
Bone marrow assessment is irrelevant for determination of a PR if the 
sample was positive before treatment. However, if positive, the cell type 
should be specified (e.g., large-cell lymphoma or small neoplastic B-cells). 
Patients who achieve a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement will be considered partial responders. 
When the bone marrow was involved before therapy and a clinical CR was 
achieved, but with no bone marrow assessment after treatment, patients 
should be considered partial responders.
6.
No new sites of disease should be observed.
7.
Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or 
if the PET scan was positive before therapy, the post-treatment PET should 
be positive in at least one previously involved site.
Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, CT 
criteria should be used.
6.2.3
Stable Disease (SD)
SD requires the following:
1.
A patient is considered to have SD when he or she fails to attain the criteria 
needed for a CR or PR, but does not fulfill those for progressive disease (see 
Relapsed Disease [after CR]/Progressive Disease [after PR, SD]).
2.
Typically FGD-avid lymphomas: the PET should be positive at prior sites of 
disease with no new areas of involvement on the post-treatment CT or PET.
Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan or if the pretreatment PET was negative, there must 
be no change in the size of the previous lesions on the post-treatment CT 
scan.
6.2.4
Relapsed Disease (after CR) or Progressive Disease (after PR or SD)
1.
Lymph nodes should be considered abnormal if the long axis is more than 
1.5 cm regardless of the short axis. If a lymph node has a long axis of 1.1 to 
1.5 cm, it should only be considered abnormal if its short axis is more than 
1.0. Lymph nodes ≤ 1.0 x ≤ 1.0 cm will not be considered as abnormal for 
relapse or progressive disease.
2.
Appearance of any new lesion more than 1.5 cm in any axis during or at the 
end of therapy, even if other lesions are decreasing in size. Increased FDG 
uptake in a previously unaffected site should only be considered relapsed or 
progressive disease after confirmation with other modalities. In patients with 
no prior history of pulmonary lymphoma, new lung nodules identified by CT 
are mostly benign. Thus, a therapeutic decision should not be made solely 
on the basis of the PET without histologic confirmation.
3.
At least a 50% increase from nadir in the SPD of any previously involved 
nodes, or in a single involved node, or the size of other lesions (e.g., splenic 
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or hepatic nodules). To be considered progressive disease, a lymph node 
with a diameter of the short axis of less than 1.0 cm must increase by ≥ 50% 
and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis.
4.
At least a 50% increase in the longest diameter of any single previously 
identified node more than 1 cm in its short axis.
5.
Lesions should be PET positive if observed in a typical FDG avid lymphoma 
or the lesion was PET positive before therapy unless the lesion is too small 
to be.
Table 5: Response and Progression from RRCML adopted from Cheson, et al.
6.2.5
Progression Free Survival
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression. PFS will be reported at 1 and 3 years after the 
start of treatment.
6.2.6
Overall Survival 
Overall survival (OS) is defined as the duration of time from start of treatment to 
time of death, up to three years from the start of study treatment. OS will be 
reported at 1 and 3 years after the start of treatment.
6.2.7
Duration of Response
6.2.7.1 Duration of overall response: 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) 
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).
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that recurrent disease is 
objectively documented.
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6.2.7.2 Duration of stable disease: 
Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started. 
6.2.8
Time to first cytotoxic chemotherapy
Time to first cytotoxic chemotherapy (TTFCC) is defined as the time from start of 
study treatment to time of first dose of anti-neoplastic cytotoxic chemotherapy 
that is administered to treat lymphoma.  This does not include corticosteroids, 
antivirals, or chemotherapeutic agents used for either non-neoplastic diseases or 
other malignant processes (not lymphoma). 
6.3
Exploratory Endpoints
6.3.1.
Evaluate the use of NM PET/CT vs. CT imaging in PTCL.
The endpoint will be a review of the utilized imaging modalities during treatment 
as a tool of response assessment. All patients will have CT imaging for 
enrollment and response assessment time points as outlined in Table 4. When 
both imaging modalities are chosen for a patient (per treating investigator’s 
discretion), response assessment will be compared.
6.3.2
Validate a new prognostic model for newly diagnosed PTCL.[41]
The endpoint will be clinical biomarkers including age, race, histology, and stage 
as obtained at enrollment. A points based system will be used to correlate with 
recently developed prognostic model. 
6.3.3
Investigate the tumor immunohistochemical profile to identify potential 
biomarkers associated with prognosis and treatment response. 
The endpoint we be comparison of immunohistochemical profiles with treatment 
outcomes on archived tissue samples. A tumor microarray on paraffin-embedded 
tissue samples will be constructed for comparison. Tissue will be obtained from 
patients who have tissue available at baseline for these studies. If tissue is not 
available, it will not preclude patients from participating. However, for those with 
tissue available, it is a mandatory component of participation.
7.0
Adverse Events
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents.  Adverse events are reported in a 
routine manner at scheduled times during a trial.  All adverse events will be reported on 
the appropriate eCRF.  Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care. 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until: 

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline

any abnormal laboratory values have returned to baseline

there is a satisfactory explanation other than the study drug for the changes 
observed

death
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7.2
Definitions & Descriptions
7.2.1
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention. 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation).
7.2.2
Severity of Adverse Events
All AEs will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. The CTCAE v4.03 is available at 
http://ctep.cancer.gov/reporting/ctc.html.
If no CTCAE grading is available, the severity of an AE is graded as follows:
1.
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.
2.
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.
3.
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.
4.
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.
5.
Fatal (grade 5): the event caused death.
7.2.3
Serious Adverse Events
All SAEs, regardless of attribution, occurring during the study (from the time of 
consent) or within 30 days of the last administration of study drug must be 
reported to the PI upon discovery or occurrence.  Additional expedited or routine 
reporting may be required, depending on the nature of the SAE (as outlined 
below).  A “serious” adverse event is defined in regulatory terminology as any 
untoward medical occurrence that:
1.
Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.
2.
Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe.
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3.
Requires in-patient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours.
4.
Results in persistent or significant disability or incapacity.
5.
Is a congenital anomaly/birth defect.
6.
Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of “Serious 
Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
7.2.4
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSO)
A UPIRSO includes events that are unanticipated in terms of nature, severity, or 
frequency, place the research subject or others at a different or greater risk of 
harm, and are deemed to be related or possibly related to participation in the 
study.  
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:

is unexpected (in terms of nature, severity, or frequency) given the 
procedures described in the research protocol documents (e.g., the IRB-
approved research protocol and informed consent document) and the 
characteristics of the human subject population being studied

is related or possibly related to participation in the research ("possibly 
related" means there is a reasonable possibility that the incident, experience, 
or outcome may have been caused by the procedures involved in the 
research); and 

suggests that the research places human subjects or others at a greater risk 
of harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized, even if no harm has actually occurred.
7.2.5
Attributions
Determine whether the adverse event is related to the protocol therapy.  Adverse 
events should be attributed to one study drug whenever possible.
Attribution categories are as follows:
1.
Definite – The AE is clearly related to the study treatment.
2.
Probable – The AE is likely related to the study treatment.
3.
Possible – The AE may be related to the study treatment.
4.
Unrelated – The AE is clearly NOT related to the study treatment.
7.2.6
Pregnancy
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the 
subject is on IP, or within 30 days of the subject’s last dose, are considered 
immediately reportable events.  IP is to be discontinued immediately. The 
pregnancy, suspected pregnancy, or positive pregnancy test must be reported to 
Celgene Drug Safety immediately by facsimile, or other appropriate method, 
using the Pregnancy Initial Report Form, or approved equivalent form. The 
female subject may be referred to an obstetrician-gynecologist (not necessarily 
one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation.
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The Investigator will follow the female subject until completion of the pregnancy, 
and must notify Celgene Drug Safety immediately about the outcome of the 
pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up 
Report Form, or approved equivalent form. 
IF THE OUTCOME OF THE PREGNANCY WAS ABNORMAL (E.G., 
SPONTANEOUS OR THERAPEUTIC ABORTION), THE INVESTIGATOR 
SHOULD REPORT THE ABNORMAL OUTCOME AS AN AE.  IF THE 
ABNORMAL OUTCOME MEETS ANY OF THE SERIOUS CRITERIA, IT MUST 
BE REPORTED AS AN SAE TO CELGENE DRUG SAFETY IMMEDIATELY BY 
FACSIMILE, OR OTHERAPPROPRIATE METHOD, WITHIN 24 HOURS OF 
THE INVESTIGATOR’S KNOWLEDGE OF THE EVENT USING THE NU SAE 
REPORT FORM.
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the IP should also be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the  
NU SAE Report Form.
7.2.6.1
Male Subjects
If a female partner of a male subject taking investigational product 
becomes pregnant, the male subject taking lenalidomide should notify 
the Investigator, and the pregnant female partner should be advised to 
call their healthcare provider immediately.
7.2.7
Overdose
Overdose, as defined for this protocol, refers to romidepsion and lenalidomide 
dosing only.  
On a per dose basis, an overdose is defined as the following amount over the 
protocol-specified dose of lenalidomide or romidepsin assigned to a given 
patient, regardless of any associated adverse events or sequelae.
PO      any amount over the protocol-specified dose
IV        10% over the protocol-specified dose      
On a schedule or frequency basis, an overdose is defined as anything more 
frequent than the protocol required schedule or frequency.  
On an infusion rate basis, an overdose is defined as any rate faster than the 
protocol-specified rate.  Complete data about drug administration, including any 
overdose, regardless of whether the overdose was accidental or intentional, 
should be reported in the case report form.   
7.3
Expedited Reporting of SAEs
7.3.1
Reporting to the QAM/DSMC:
All SAEs must be reported to the assigned Quality Assurance Monitor (QAM) 
within 24 hours of becoming aware of the event 
(croqualityassurance@northwestern.edu). Completion of the NU CTO SAE Form 
is required. The completed form should assess whether or not the event qualifies 
as a UPIRSO. The report should also include:

Protocol description and number

Patient’s Identification Number

Description of event, severity, treatment, and outcome if known

Supportive laboratory results and diagnostics
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
Hospital Discharge Summary (if available)

Country of incidence
All SAEs will be reported to, and reviewed by, the DSMC per the DSMP.
7.3.2
Reporting to the NU IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow their local 
IRB guidelines for reporting to their local IRBs.
•
Any death of an NU subject that is unanticipated in nature and at least 
possibly related to study participation will be promptly reported to the NU IRB 
within 24 hours of notification. 
•
Any death of a non-NU subject that is unanticipated and at least possibly 
related and any other UPIRSOs will be reported to Northwestern University 
and to the NU IRB within 5 working days of notification.
•
Information pertaining to an NU subject that fits into any of the categories 
listed on the Reportable New Information page will be reported to the NU IRB 
within 5 business days of knowledge or notification.
7.3.3
Reporting to the FDA:
In the event that an IND is granted for this study, the following notifications will be 
handled by the NU QAM (if the protocol is determined to be IND exempt, this 
section will not apply):

The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life-
threatening.

The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DSMC).
All other SAEs will be reported on an annual basis as part of the annual FDA 
report.
7.3.4
Reporting to Celgene
Any SAE that occurs in a study subject must be reported to Celgene within 24 
hours of first awareness of the event. The NU CTO SAE form will be used for 
reporting. The initial report must be as complete as possible, including an 
assessment of the causal relationship between the event and the investigational 
product, if available. Information not available at the time of the initial report (e.g., 
an end date for the adverse event or laboratory values received after the report) 
must be documented on a follow-up report.  A final report to document resolution 
of the SAE is required. The Celgene tracking number (RV-XX-PI-###), when 
available, and the institutional protocol number should be included on SAE 
reports (or on the fax cover letter) sent to Celgene.  A copy of the fax 
transmission or email confirmation of the SAE report to Celgene should be 
attached to the SAE and retained with the patient records. The Principal 
Investigator will assist in investigating any SAE and will provide any follow-up 
information reasonably requested by Celgene. The assigned study coordinator 
will facilitate all reporting to Celgene Drug Safety and email QA a copy of the 
report upon completion. Celgene Drug Safety can be notified at:
Celgene Corporation     
Global Drug Safety and Risk Management   
556 Morris Avenue
Building S12
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Summit, New Jersey 07901
Fax: (908) 673-9115
E-mail: drugsafety@celgene.com
7.3.5
Routine Reporting
All other adverse events, such as those that are expected, or are unlikely or 
definitely not related to the study participation, are to be reported on a regular 
basis to the assigned QAM for the study in accordance with the Robert H. Lurie 
Comprehensive Cancer Center’s Data Safety Monitoring Plan (DSMP). These 
will be reviewed by the Data and Safety Monitoring Committee on an on-going 
basis. 
 
7.4
Stopping Rules 
The study will be stopped early if there are 6 or fewer responses (CR or PR at the 3 
month response assessment time point) in the first 12 patients, as this will be considered 
evidence of inadequate efficacy. Regardless of overall accrual status, individual patients 
(enrolled in the first stage) who demonstrate clinical benefit (SD or better) may continue 
to receive study treatment up to 1 year in accordance with the duration of therapy criteria 
(see Section 4.4). In addition, the Data Safety Monitoring Committee will monitor the 
study in accordance with the DSMP and may suspend or close the study to accrual at 
any point if required, as out lined in the DSMP.
8.0
Drug Information
8.1
Romidepsin
Refer to the romidepsin package insert for complete information.
8.1.1
Other Names
Istodax; Romidepsin for Injection; FK228; depsipeptide
8.1.2
Classification
Romidepsin is a histone deacetylase (HDAC) inhibitor indicated for the 
treatment of CTCL in patients who have received at least 1 prior systemic 
therapy. At room temperature, romidepsin is a white powder and is described 
chemically as (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1methylethyl)-2-
oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16ene-3,6,9,19,22-
pentone. The empirical formula is C24H36N4O6S2. 
The molecular weight is 540.71 and the structural formula is:
8.1.3
Mode of Action
Romidepsin is a unique bicyclic depsipeptide originally isolated from 
Chromobacterium violaceum strain 968. Romidepsin is an antineoplastic agent 
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that has been identified as a novel HDAC inhibitor. Romidepsin has been shown 
to induce hyperacetylation of histones and other nonhistone protein species 
resulting in a variety of phenotypic changes, induction of the upregulation of gene 
transcription, G1 and G2/M arrest of the cell cycle, morphological reversion of 
transformed cells, cell growth inhibition, apoptotic cell death, and inhibition of 
angiogenesis. In vitro, romidepsin causes the accumulation of acetylated 
histones, and induces cell cycle arrest and apoptosis of some cancer cell lines 
with IC50 values in the nanomolar range. The mechanism of the antineoplastic 
effect of romidepsin observed in nonclinical and clinical studies has not been fully 
characterized.
8.1.4
Supply, Storage, and Stability
Romidepsin is supplied as a kit including a sterile, lyophilized powder in a single-
use vial containing 10 mg of romidepsin and 20 mg of the bulking agent, 
povidone, USP. In addition, each kit includes one sterile Diluent vial containing 2 
mL (deliverable volume) of 80% propylene glycol, USP, and 20% dehydrated 
alcohol, USP. 
NDC 46026-983-01: ISTODAX
® KIT containing 1 vial of romidepsin, 10 mg and 1 
vial of diluent for romidepsin, 2 mL per carton. 
The carton must be stored at 20° to 25°C, excursions permitted between 15° to 
30°C. (See USP Controlled Room Temperature.) Keep out of reach of children. 
8.1.5
Preparation, Protocol Dose, and Administration
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, USP before intravenous infusion. 
Each 10 mg single-use vial of romidepsin must be reconstituted with 2 mL of the 
supplied Diluent. With a suitable syringe, aseptically withdraw 2 mL from the 
supplied Diluent vial, and slowly inject it into the romidepsin for injection vial. 
Swirl the contents of the vial until there are no visible particles in the resulting 
solution. The reconstituted solution will contain romidepsin 5 mg/mL. The 
reconstituted romidepsin solution is chemically stable for at least 8 hours at room 
temperature. However, whenever possible, drug should be prepared within 4 
hours of dose administration.
Extract the appropriate amount of romidepsin from the vials to deliver the desired 
dose, using proper aseptic technique. Before intravenous infusion, further dilute 
romidepsin in 500 mL 0.9% Sodium Chloride Injection, USP. 
Infuse over 4 hours. Patients will receive romidepsin (at a dose of either 10 or 14 
mg/m2 – see 4.1.1 for details) IV on days 1, 8, and 15 of each cycle.
The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl 
acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles. 
Romidepsin is stable for 24 hours at room temperature after reconstitution per 
package insert
Parenteral drug products should be inspected visually for particulate matter and 
discoloration before administration, whenever solution and container permit.
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8.1.6
Availability & Drug Ordering
Romidepsin will be provided to research subjects for the duration of their 
participation in this trial by the Celgene Corporation at no charge to them or their 
insurance providers. Romidepsin ordering instructions are available at the 
Northwestern Oncology Trial Information System (NOTIS) website -contact 
croqualityassurance@northwestern.edu for any issues/concerns.
8.1.7
Side Effects
The most common side effects of romidepsin include nausea, fatigue, infections, 
vomiting, anorexia, anemia, thrombocytopenia, ECG T-wave changes, 
neutropenia, and lymphopenia.
8.1.8
Nursing Implications
Implement appropriate cardiovascular precautions, such as the monitoring of 
electrolytes and ECGs at baseline and as clinically indicated thereafter.
8.2
Lenalidomide 
Refer to the lenalidomide package insert for complete information.
8.2.1
Other Names
Revlimid®, IMiD CC-5013
8.2.2
Classification
Immunomodulatory drug with antiangiogenic and antineoplastic properties. The 
chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-
dione. The empirical formula for lenalidomide is C13H13N3O3, and the gram 
molecular weight is 259.3. It has the following chemical structure:
8.2.3
Mode of Action
Lenalidomide is a thalidomide analogue indicated for the treatment of multiple 
myeloma (MM), myelodysplastic syndrome (MDS) associated with deletion 5q, 
and mantle cell lymphoma (MCL). Lenalidomide has been used successfully to 
treat both inflammatory disorders and malignancies. Lenalidomide has been 
shown to induce direct anti-tumor effects, alter the tumor microenvironment, and 
play a role in immunomodulatory activity. 
Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic 
tumor cells including multiple myeloma, mantle cell lymphoma, and del (5q) 
myelodysplastic syndromes in vitro. Lenalidomide causes a delay in tumor 
growth in some in vivo nonclinical hematopoietic tumor models including multiple 
myeloma. Immunomodulatory properties of lenalidomide include activation of T 
cells and natural killer (NK) cells, increased numbers of NKT cells, and inhibition 
of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In multiple 
myeloma cells, the combination of lenalidomide and dexamethasone synergizes 
the inhibition of cell proliferation and the induction of apoptosis.
8.2.4
Storage, Supply, and Stability
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Lenalidomide is an off-white to pale-yellow solid powder. Lenalidomide is 
supplies as white opaque capsules imprinted “REV” on one half and “25 mg” on 
the other half in black ink: 25 mg bottles of 21 (NDC 59572-425-21) or 25 mg 
bottles of 100 (NDC 59572-425-00). 
Lenalidomide should be stored away from moisture and direct sunlight and 
protected from excessive heat and cold. Capsules should be stored at 20°C - 
25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [See USP 
Controlled Room Temperature].
Care should be exercised in the handling of lenalidomide. Lenalidomide capsules 
should not be opened or crushed. If powder from lenalidomide contacts the skin, 
wash the skin immediately and thoroughly with soap and water. If lenalidomide 
contacts the mucous membranes, flush thoroughly with water. Procedures for the 
proper handling and disposal of anticancer drugs should be considered. 
At the study sites, all investigational study drugs will be stored in a locked, safe 
area to prevent unauthorized access. Before lenalidomide is dispensed, patients 
must 1) have a negative pregnancy test (if applicable) and 2) be counseled about 
the risks associated with teratogenic agents. 
8.2.5
Protocol Dose & Administration
Lenalidomide will be administered on an out-patient basis at a dose of 25 mg 
daily on days 1-21 of each 28-day cycle. Lenalidomide is taken by mouth with or 
without food. Patients should not crush, chew or open capsules. Only a supply 
sufficient for 1 cycle may be dispensed at one time. Investigators may not mail 
lenalidomide to patients. 
8.2.6
Potential Drug Interactions
In vitro, lenalidomide did not significantly inhibit marker enzyme activities for 
CYP1A2, CYP2C9, CYP2C19, CYP2E1, or CYP3A4. In rats, no induction of any 
CYP450 enzymes was observed. These data suggest that lenalidomide is not 
likely to cause metabolic drug interactions in man.
8.2.7
Availability 
Lenalidomide 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 the Celgene 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. Please see additional resource material on the Revlimid REMS® site 
at: http://www.revlimidrems.com. 
Lenalidomide supplies are dispensed in individual bottles of capsules. Each 
bottle will identify the contents as study medication.  In addition, the label will 
bear Celgene’s name, quantity contained and the standard caution statement as 
follows:  “Caution: New drug - Limited by Federal law to investigational use.” 
Lenalidomide should not be handled by FCBP unless wearing gloves. The study 
drug label must be clearly visible. Additional labels must not cover the Celgene 
label. Lenalidomide will be shipped directly to patients or to the clinic site for IND 
studies.  Bottles will contain a sufficient number of capsules for one cycle of 
dosing. Only enough lenalidomide for one cycle of therapy will be supplied to the 
patient each cycle.
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Lenalidomide must be ordered from Biologics, Inc., using the “REVLIMID 
(Lenalidomide) Study Drug Shipment Request Form (IND STUDY)” (see 
Northwestern Oncology Trial Information System [NOTIS] website). A patient 
must have signed consent and the REMS program requirements must be 
completed before the order will be filled. Note:  If Biologics receives the order by 
2PM Eastern time, the lenalidomide will be shipped overnight that day.  
Lendalidomide is shipped to the Investigational Pharmacy at each site.  The 
Investigational Pharmacy dispenses the lenalidomide to the patient.  Additional 
details will be provided prior to site activation, or by calling Biologics at 
800.693.4906, or by emailing croqualityassurance@northwestern.edu.
The Investigational Pharmacy at each site is responsible for taking an inventory 
of each shipment of study drug received, and comparing it with the 
accompanying study drug accountability form.  The investigational pharmacist 
will verify the accuracy of the information on the form, sign and date it, retain a 
copy in the study file, and return a copy to Celgene or its representative.
Celgene will provide instructions on the return or destruction of unused study 
drug. If any study drug is lost or damaged, its disposition should be documented 
in the source documents. Study drug supplies will be retained at the clinical site 
pending instructions for disposition by Celgene. Patients will be instructed to 
return empty bottles or unused capsules to the clinic site.  
8.2.8
Black Box Warning
8.2.9
Nursing/Patient Implications and Monitoring requirements
1.
Effective contraception must be used by patients for at least 4 weeks 
before beginning lenalidomide therapy, during lenalidomide therapy, 
during dose interruptions, and for 4 weeks following discontinuation of 
lenalidomide therapy. Reliable contraception is indicated even where 
there has been a history of infertility, unless due to hysterectomy or 
because the patient has been postmenopausal naturally for at least 24 
consecutive months. Two reliable forms of contraception must be used 
simultaneously, by females, unless continuous abstinence from 
heterosexual sexual contact is the chosen method. Females of 
childbearing potential should be referred to a qualified provider of 
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contraceptive methods, if needed. Males receiving lenalidomide must 
always use a latex condom during any sexual contact with females of 
childbearing potential even if they have undergone a vasectomy.
2. 
Caution patient not to drive or use hazardous machinery until the 
potential sedative effects of the drug are known in the patient.
3. 
Caution patient to report leg swelling or shortness of breath, because of 
the risk of thrombosis/embolism
4. 
Counsel patient to report abnormal sensations in hands or feet, such as 
decreased sensation or dysesthesia. Paresthesias are often noted early 
before neuropathy develops.
5.
Advise patient to immediately report rashes or fever.
Because of the embryo-fetal risk, lenalidomide is available only through a 
restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the 
REVLIMID REMSTM program (formerly known as the “RevAssist®” program). 
Required components of the REVLIMID REMSTM program include the following: 

Prescribers must be certified with the REVLIMID REMS™ program by 
enrolling and complying with the REMS requirements. 

Patients must sign a Patient-Prescriber agreement form and comply with the 
REMS requirements. In particular, female patients of reproductive potential 
who are not pregnant must comply with the pregnancy testing and 
contraception requirements.

Pharmacies must be certified with the REVLIMID REMS™ program, must 
only dispense to patients who are authorized to receive REVLIMID and 
comply with REMS requirements. 
Further information about the REVLIMID REMS™ program is available at 
http://www.revlimidrems.com or by telephone at 1-888-423-5436.
9.0
Exploratory Studies
9.1
Evaluate the use of NM PET/CT vs CT imaging in PTCL
The endpoint will be a review of the utilized imaging modalities during treatment as a tool 
of response assessment. All patients will have CT imaging for enrollment and response 
assessment time points as outlined in Table 4. When both imaging modalities are chosen 
for a patient (at treating investigator’s discretion), response assessment will be 
compared.
9.2
Validate a new prognostic model for newly diagnosed PTCL.
Variables for prognosis assessment are part of the eligibility checklist including age, race 
(African-American vs other), histology, and stage. Variables will be assigned points to 
determine a prognostic score. Survival by prognostic score are separated into three 
categories with score = 0-1, 2, or 3-5. Points assigned are outline below:
IRB #: STU00097620-CR0005 Approved by NU IRB for use on or after 3/21/2022 through 3/20/2023.

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9.3
Investigate the tumor immunohistochemical profile to identify potential biomarkers 
associated with prognosis and treatment response. 
9.3.1
Technique
A tissue microarray (TMA) of paraffin-embedded lymphoid tissue biopsies of all 
patients will be created and analyzed. This TMA will quantify expression of 
multiple markers in order to determine how such markers correlate with clinical 
outcome. Proposed analysis includes immunohistochemistry for CD4, CD8, CD5, 
CD7, CD8, CD15, CD20, CD30, EBER, Ki-67, p53, TIA-1, granzyme B, TCR F1, 
TNF-α, IL-6, and nm23-H1.
9.3.2
Tissue Collection
Paraffin-embedded tumor samples will be collected from prior diagnostic biopsies 
prior to enrollment. Construction of the TMA will require 1.0 to 1.5 mm punch 
cores for proper analysis. Samples will be sent to the Northwestern PathCore 
facility. Samples from outside institutions may be sent in batches. The analysis 
will be conducted by our collaborators in hematopathology. Collection of tissues 
samples is mandatory however if sample is inadequate a repeat biopsy will not 
be required nor will patients be excluded from clinical trial enrollment. 
10.0
Statistical Considerations
10.1
Primary Endpoint & Sample Size Calculations
The primary objective of this phase II trial will be to evaluate the efficacy of the 
combination of romidepsin plus lenalidomide in patients with previously untreated PTCL. 
The endpoint for this objective will be objective response rate (ORR), defined per Cheson 
criteria. Response will be assessed by imaging after cycles 3 and 6, and then every 6 
months thereafter.  Single agent romidepsin or lenalidomide have response rates of 
approximately 25% in patients with relapsed/refractory PTCL [3, 44, 45].  However, a 
recently presented study (unpublished) of the combination of romidepsin and 
lenalidomide demonstrated an objective response rate in relapsed/refractory PTCL of 
50%[46]. The front-line setting has not been tested. 
Due to recruitment issues, we will limit the study to n=20 evaluable patients. This will 
allow us to estimate the underlying true response rate with a half width of an approximate 
95% confidence interval equal to 1.96x0.5/sqrt(20) = 1.96x0.11 = 0.22. 
10.2
Secondary Endpoints
To evaluate the safety of the combination of romidepsin and lenalidomide, the endpoint 
will be the frequency and severity of toxicity events using the NCI CTCAE v 4.03. All 
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adverse events will be summarized as to type, severity, frequency, timing and attribution. 
Descriptive frequencies and proportions will be used for this analysis.
To further evaluate efficacy of the combination of romidepsin and lenalidomide, the 
endpoint will be progression-free survival (PFS) and overall survival (OS) at 1 and 3 
years after start of treatment as well as the duration of response from start of therapy, 
defined per Cheson criteria.  Kaplan-Meier curves will be determined for progression-free 
survival and overall survival and the one- and three-year point on this curve, along with 
90% confidence limits.  Duration of response will be summarized by descriptive statistics 
in responders (mean, median, range).
To evaluate the delay to cytotoxic chemotherapy, the endpoint will be time to first 
cytotoxic chemotherapy (TTFCC) from start of treatment.  This will be summarized by 
descriptive statistics (mean, median, range).
10.3
Exploratory Endpoints
To evaluate the use of NM PET/CT vs CT imaging in PTCL, the endpoint will be a review 
of the utilized imaging modalities during treatment as a tool of response assessment. 
When both imaging modalities are chosen for a patient, response assessment will be 
compared using Kappa statistics.
To validate a new prognostic model for newly diagnosed PTCL.[41], the endpoint will be 
clinical biomarkers including age, race, histology, and stage as an assessment of 
prognosis.  These factors will be related to response and survival using logistic 
regression and proportional hazards regression respectively.
To investigate the tumor immunohistochemical profile to identify potential, biomarkers 
associated with prognosis and treatment response, immunohistochemical profiles with 
related to treatment outcomes on archived tissue samples using the regression methods 
described above.
11.0
Study Management
11.1
Conflict of Interest
All investigators will follow the Northwestern University conflict of interest policy.
11.2
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
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11.3
Required Documentation (for multi-site studies)
Before the study can be initiated at any external participating sites, the following 
documentation must be provided to the Clinical Trials Office (CTO) at NU.

A copy of the official IRB approval letter for the protocol and informed consent

CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study

Form FDA 1572 appropriately filled out and signed with appropriate documentation

A copy of the IRB approved consent form

Executed clinical research contract
11.4
Registration Procedures
Patients may not begin protocol treatment prior to registration. All patient registrations will 
be registered centrally through the Clinical Trials Office (CTO) at Northwestern University 
before enrollment to study. In order for registrations to be processed efficiently, staff are 
asked to inform the QAM of date and time that by which the patient will need to be 
registered. Please contact the assigned Quality Assurance Monitor (QAM) or email the 
QA Department (croqualityassurance@northwestern.edu) for questions regarding patient 
registration.  
Prior to registration, eligibility criteria must be confirmed by the assigned QAM. The study 
coordinator will screen all subjects for potential registration via the web-based application 
NOTIS (Northwestern Oncology Trial Information System), which is available at: 
https://notis.nubic.northwestern.edu. Please note that a username and password is 
required to use this program, and will be provided during site activation prior to training 
on the NOTIS system.
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number:
•
Patient’s signed and dated informed consent form (upload to NOTIS and keep 
original hard copy in a secure location/study chart)
•
Eligibility checklist (signed and dated by the treating physician – upload to NOTIS)
•
Eligibility eCRF (complete in NOTIS)
•
Copy of the pathology report (upload to NOTIS)
Training on eCRF completion will be provided at the time of site activation. Please refer 
to the eCRF demonstration videos on the CTO website for additional instructions on 
registering a patient.
The QAM will review the registration, register the patient, assign a subject identification 
number, and send a confirmation of registration to study personnel. Registration will then 
be complete and the patient may begin study treatment.
11.5
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to the DSMP hyperlink for additional information). The level of risk attributed to this 
study requires High Intensity Monitoring, as outlined in the DSMP. The assigned Quality 
Assurance Monitor, with oversight from the Data and Safety Monitoring Committee, will 
monitor this study in accordance with the study phase and risk level. Please refer to 
NOTIS for additional data submission instructions.
11.6
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
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11.6.1
Emergency Modifications
Investigators may implement a deviation from, or a change of the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
For any such emergency modification implemented, an IRB modification form 
must be completed within five business days of making the change, and the 
QAM must be notified within 24 hours of such change.
11.6.2
Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form.
A protocol deviation is any change, divergence, or departure from the study 
design or procedures of a research protocol that is under the investigator's 
control and that has not been approved by the Institutional Review Board (IRB). 
Protocol deviations must be reported according to the policies and procedures of 
the IRB of record.
An unplanned protocol variance is considered a violation and may be considered 
an instance of Reportable New Information (RNI) if the variance:

Has harmed or increased the risk of harm to one or more research 
participants.

Has compromised the rights and welfare of the research subject

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the 
investigator(s).

Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies.
11.7
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be initiated and 
maintained by the assigned Medical Writer. Requests for revisions may come from 
multiple sources, including but not limited to the Principal Investigator, study team, drug 
company, or FDA.  It should also be noted that when an amendment to the protocol 
substantially alters the study design or the potential risk to the patient, a revised consent 
form might be required. 
All amendments will be subject to the review and approval of the appropriate local, 
institutional, and governmental regulatory bodies, as well as by Celgene. Amendments 
will be distributed by the lead institution (Northwestern) to all affiliate sites upon approval 
by the Northwestern University IRB.
11.8
Record Retention
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed 
patient consent forms).
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study.
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
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International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study.
11.9
Obligations of Investigators
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data.
11.10
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
DSMC Data Release Policies and Processes. The assigned QAM will prepare a 
preliminary data set for DSMC approval no later than 3 months after the study reaches its 
primary completion date, as defined by ClinicalTrials.gov. This is the date that the final 
patient was examined or received an intervention for the purposes of final collection of 
data for the primary outcome, whether the clinical trial concluded according to the pre-
specified protocol or was terminated. If the investigator would like data release to be 
approved by the DSMC prior to when study design specifies, and/or prior to three months 
after a study’s primary completion date, the PI must send a written request for data 
approval to the QAM which includes justification. Requests must be made a minimum of 
six to eight weeks in advance of the expected deadline. The request will be presented to 
the DSMC at their next available meeting. Any DSMC decisions regarding data release 
will be provided to the PI. If the request is approved, the QAM will present the data set to 
the DSMC for approval. A final, DSMC-approved dataset, as applicable, will then be 
released 6-8 weeks after the request was made. The investigators are expected to use 
only DSMC-approved data and statistical analyses any time they are disseminating trial 
data. The investigators must send a copy of the draft abstract/poster/manuscript to the 
study’s biostatistician and assigned QAM to confirm that the DSMC-approved data and 
statistical analyses are used appropriately. Once the biostatistician and QAM gives final 
approval, the publication may be submitted to external publisher.
11.11
Criteria for Suspension in Accrual
The following is a list of criteria that will trigger suspension of accrual. In the even that 
such a suspension would occur, the Data and Safety Monitoring Committee (DSMC) 
would have to approve re-opening of accrual pending appropriate protocol revision (if 
needed):

Interim/cumulative data for evidence of unacceptable rates and/or severity of study-
related adverse events;
Specifically, The Data and Safety Monitoring Committee at Northwestern University 
will analyze toxicity data every 2 weeks. After every 5 patients an interim analysis will 
be performed to determine whether there is excessive toxicity. These analyses will be 
done separately within each arm. Excessive toxicity will be defined as any grade ≥ 4 
neutropenia, grade ≥ 4 thrombocytopenia, or grade ≥ 3 organ toxicity (neurologic, 
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pulmonary, cardiac, gastrointestinal, genitourinary, renal, hepatic, cutaneous) with ≥3 
occurrences which is at least possibly related to the study regimen occurring in no 
more than 20%. Using a Bayesian approach with a non-informative (uniform) prior, it 
will be determined that there is excessive toxicity if the posterior probability of the 
toxicity rate being greater than 20% exceeds 80%. This will occur if there are 3 or 
more excessive toxicity events (as described above) out of 5 treated patients, 4 or 
more out of 10, 5 or more out of 15, 6 or more out of 20, 8 or more out of 25, or 9 or 
more out of 30. If, by 30 patients treated, the study has not been terminated for 
toxicity, it will continue to the goal accrual.
o
Incidence of >20% of any single excessive toxicity event (grade ≥ 4 
neutropenia or thrombocytopenia OR grade ≥ 3 organ toxicity - minimum 10 
patients treated)
o
Treatment-related mortality of three or more patients
o
Interim/cumulative data for evidence of efficacy according to pre-established 
statistical guidelines, if appropriate;
o
Clear lack of data quality, completeness, and timeliness; 
o
Clear deficits in performance issues of individual centers; 
o
Inadequacy of compliance with goals for recruitment and retention, including 
those related to the participation of women and minorities;
o
Failure to adhere to the protocol; 
o
Presence of factors that might affect the study outcome or compromise the 
confidentiality of the trial data (such as protocol violations, unmasking, etc.); 
o
Presence of factors external to the study, such as scientific or therapeutic 
developments that may impact participant safety or the ethics of conduct of 
the study.
References
1.
Savage, K.J., Peripheral T-cell lymphomas. Blood Rev, 2007. 21(4): p. 201-16.
2.
Jaffe, E.S., The 2008 WHO classification of lymphomas: implications for clinical practice and 
translational research. Hematology Am Soc Hematol Educ Program, 2009: p. 523-31.
3.
Toumishey, E., et al., Final report of a phase 2 clinical trial of lenalidomide monotherapy for 
patients with T-cell lymphoma. Cancer, 2015. 121(5): p. 716-23.
4.
Vose, J., J. Armitage, and D. Weisenburger, International peripheral T-cell and natural killer/T-cell 
lymphoma study: pathology findings and clinical outcomes. J Clin Oncol, 2008. 26(25): p. 4124-
30.
5.
Grunstein, M., Histone acetylation in chromatin structure and transcription. Nature, 1997. 
389(6649): p. 349-52.
6.
Johnstone, R.W., Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev 
Drug Discov, 2002. 1(4): p. 287-99.
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Marks, P., et al., Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer, 2001. 
1(3): p. 194-202.
8.
Bates, S.E., et al., Laboratory correlates for a phase II trial of romidepsin in cutaneous and 
peripheral T-cell lymphoma. Br J Haematol. 148(2): p. 256-67.
9.
Imesch, P., D. Fink, and A. Fedier, Romidepsin reduces histone deacetylase activity, induces 
acetylation of histones, inhibits proliferation, and activates apoptosis in immortalized epithelial 
endometriotic cells. Fertil Steril. 94(7): p. 2838-42.
10.
Woo, S., et al., Population pharmacokinetics of romidepsin in patients with cutaneous T-cell 
lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res, 2009. 15(4): p. 1496-503.
11.
Furumai, R., et al., FK228 (depsipeptide) as a natural prodrug that inhibits class I histone 
deacetylases. Cancer Res, 2002. 62(17): p. 4916-21.
12.
Byrd, J.C., et al., A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic 
lymphocytic leukemia and acute myeloid leukemia. Blood, 2005. 105(3): p. 959-67.
IRB #: STU00097620-CR0005 Approved by NU IRB for use on or after 3/21/2022 through 3/20/2023.

Study Number:  NU 14H04
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Page 44 of 61
13.
Marshall, J.L., et al., A phase I trial of depsipeptide (FR901228) in patients with advanced cancer. 
J Exp Ther Oncol, 2002. 2(6): p. 325-32.
14.
Sandor, V., et al., Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 
630176), in patients with refractory neoplasms. Clin Cancer Res, 2002. 8(3): p. 718-28.
15.
Coiffier, B., 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. 30(6): p. 631-6.
16.
Piekarz, R.L., et al., Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin 
as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol, 2009. 27(32): p. 
5410-7.
17.
Bartlett, J.B., K. Dredge, and A.G. Dalgleish, The evolution of thalidomide and its IMiD derivatives 
as anticancer agents. Nat Rev Cancer, 2004. 4(4): p. 314-22.
18.
Anderson, K.C., Lenalidomide and thalidomide: mechanisms of action--similarities and 
differences. Semin Hematol, 2005. 42(4 Suppl 4): p. S3-8.
19.
Lu, L., et al., The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple 
inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res, 
2009. 77(2): p. 78-86.
20.
Dredge, K., et al., Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and 
inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvasc Res, 2005. 69(1-2): 
p. 56-63.
21.
Bartlett, J.B., et al., Phase I study to determine the safety, tolerability and immunostimulatory 
activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and 
other advanced cancers. Br J Cancer, 2004. 90(5): p. 955-61.
22.
Dahut, W.L., et al., Phase I study of oral lenalidomide in patients with refractory metastatic 
cancer. J Clin Pharmacol, 2009. 49(6): p. 650-60.
23.
Sharma, R.A., et al., Toxicity profile of the immunomodulatory thalidomide analogue, 
lenalidomide: phase I clinical trial of three dosing schedules in patients with solid malignancies. 
Eur J Cancer, 2006. 42(14): p. 2318-25.
24.
Wiernik, P.H., et al., Lenalidomide monotherapy in relapsed or refractory aggressive non-
Hodgkin's lymphoma. J Clin Oncol, 2008. 26(30): p. 4952-7.
25.
Witzig, T.E., et al., Lenalidomide oral monotherapy produces durable responses in relapsed or 
refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol, 2009. 27(32): p. 5404-9.
26.
Habermann, T.M., et al., Lenalidomide oral monotherapy produces a high response rate in 
patients with relapsed or refractory mantle cell lymphoma. Br J Haematol, 2009. 145(3): p. 344-9.
27.
Goy, A., et al., Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or 
progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J Clin 
Oncol. 31(29): p. 3688-95.
28.
Zinzani, P.L., et al., Long-term follow-up of lenalidomide in relapsed/refractory mantle cell 
lymphoma: subset analysis of the NHL-003 study. Ann Oncol. 24(11): p. 2892-7.
29.
Dueck, G., et al., Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin 
lymphoma. Cancer. 116(19): p. 4541-8.
30.
Zinzani, P.L., et al., Lenalidomide monotherapy for relapsed/refractory peripheral T-cell 
lymphoma not otherwise specified. Leuk Lymphoma. 52(8): p. 1585-8.
31.
Uike, N., et al., Multicenter Phase I Dose-Escalation Study of Lenalidomide in Patients with 
Relapsed Adult T-Cell Leukemia-Lymphoma (ATL) or Peripheral T-Cell Lymphoma (PTCL). 54th 
ASH Annual Meeting, 2012. Abstract 2737.
32.
Coiffier, B., et al., Romidepsin Induces Durable Responses in Patients with Peripheral T-Cell 
Lymphoma: GPI-06-0002 Study Update. ASH 54th Annual Meeting, 2012. Abstract 3641.
33.
Fabbri, A., et al., Impressive activity of lenalidomide monotherapy in refractory 
angioimmunoblastic T-cell lymphoma: report of a case with long-term follow-up. Hematol Oncol.
34.
Lunning, M., et al. A Phase I/II Trial of the Combination of Romidepsin and Lenalidomide in 
Patients with Relapsed/Refractory Lymphoma and Myeloma: Phase I Results. in ASCO Annual 
Meeting. 2014. Chicago, IL.
35.
Went, P., et al., Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic 
prognostic score. J Clin Oncol, 2006. 24(16): p. 2472-9.
IRB #: STU00097620-CR0005 Approved by NU IRB for use on or after 3/21/2022 through 3/20/2023.

Study Number:  NU 14H04
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36.
Niitsu, N., H. Nakamine, and M. Okamoto, Expression of nm23-H1 is associated with poor 
prognosis in peripheral T-cell lymphoma, not otherwise specified. Clin Cancer Res. 17(9): p. 
2893-9.
37.
Asano, N., et al., Clinicopathologic and prognostic significance of cytotoxic molecule expression 
in nodal peripheral T-cell lymphoma, unspecified. Am J Surg Pathol, 2005. 29(10): p. 1284-93.
38.
Sheikha, A., et al., Peripheral T-cell lymphomas - cytokine profile and characteristic interleukin-4 
and tumor-necrosis-factor alpha-deficiency. Int J Oncol, 1994. 4(1): p. 91-5.
39.
Casulo, C., et al., 18F-fluorodeoxyglucose positron emission tomography in the staging and 
prognosis of T cell lymphoma. Leuk Lymphoma, 2013. 54(10): p. 2163-7.
40.
Gallamini, A. and A. Borra, Role of PET in Lymphoma. Curr Treat Options Oncol, 2014.
41.
Petrich, A., C. Nabhan, and I. Helenowski, Factors Affecting Survival in Peripheral T-cell 
Lymphoma (PTCL): A Population-Based Analysis of 8,802 Patients. Poster Abstract, 2014.
42.
Parmelee, P.A., et al., Validation of the Cumulative Illness Rating Scale in a geriatric residential 
population. J Am Geriatr Soc, 1995. 43(2): p. 130-7.
43.
Cheson, B.D., et al., Revised response criteria for malignant lymphoma. J Clin Oncol, 2007. 
25(5): p. 579-86.
44.
Coiffier, B., 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): p. 
631-6.
45.
Coiffier, B., et al., Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: 
pivotal study update demonstrates durable responses. J Hematol Oncol, 2014. 7: p. 11.
46.
Mehta-Shah, N., 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. 2015. 
33(15_suppl): p. 8521-8521.
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Appendix A – Modified Cumulative Illness Rating Scale (CIRS)
 
SCORE
1.
Cardiac
Heart only
2.
Hypertension
Rating based on severity; affect systems are 
rated separately
3.
Vascular
Blood, blood vessels and cells, marrow, 
spleen, lymphatics
4.
Respiratory
Lungs, bronchi, trachea below the larynx
5.
EENT
Eye, ear, nose, throat, larynx
6.
Upper GI
Esophagus, stomach, duodenum, biliary and 
pancreatic tree; do not include diabetes
7.
Lower GI
Intestines, hernias
8.
Hepatic
Liver only
9.
Renal
Kidneys only
10. Other GU
Ureters, bladder, urethra, prostate, genitals
11. Musculo-Skeletal-Integumentary
Muscle, bones, skin
12. Neurologic
Brain, spinal cord, nerves; do not include 
dementia
13. Endocrine-Metabolic
Diabetes, diffuse infections, infections, toxicity
14. Psychiatric/Behavioral
Dementia, depression, anxiety, agitation, 
psychosis
TOTAL
Each system is rated as follows:

0 = NONE: No impairment to that organ/system

1 = MILD: Impairment does not interfere with normal activity; treatment may or may not be 
required; prognosis is excellent. (Examples could be skin lesions, hernias, or hemorrhoids)

2 = MODERATE: Impairment interferes with normal activity; treatment is needed; prognosis is 
good. (Examples could be gallstones, diabetes, or fractures)

3 = SEVERE: Impairment is disabling; treatment is urgently needed; prognosis is guarded. 
(Examples could be resectable carcinoma, pulmonary emphysema, or congestive heart failure)

4 = EXTREMELY SEVERE: Impairment is life threatening; treatment is urgent or of no avail; 
prognosis is grave. (Examples could be myocardial infarction, cerebrovascular accident, 
gastrointestinal bleeding, or embolus) 
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Appendix B – ECOG Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
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Appendix C – Concomitant Medications – Prohibited or Cautionary Use 
Note: As these lists are constantly evolving, if a medication is incorrectly documented as prohibited in this 
protocol, documentation from the site pharmacist to the contrary will be acceptable for the purposes of 
registration.
CYP3A4 inducers (prohibited):
Carbamezepine
Ethosuximide
Griseofulvin
Phenytoin
Primidone
Progesterone
Rifabutin
Rifampin
Nafcillin
Nelfinavir
Nevirapine
Oxcarbazepine
Phenobarbital
Phenylbutazone
Rofecoxib 
St John’s wort
Sulfadimidine
Sulfinpyrazone
Troglitazone
High Risk QTc Prolonging Agents (cautionary use):
Note: The following medications are only prohibited in the case that a patient develops known QTc 
prolongation on study.
Amiodarone
Flecainide
Anagrelide
Halofantrine
Arsenic trioxide
Haloperidol
Azithromycin
Ibutilide
Chloroquine
Methadone
Chlorpromazine
Moxifloxacin
Citalopram
Ondansetron** 
Clarithromycin
Pentamidine
Disopyramide
Pimozide
Dofetilide
Quinidine
Dronedarone
Sevoflurane
Droperidol
Sotalol
Erythromycin
Thioridazine
Escitalopram
Vandetanib
**Will be given as pre-medication for romidepsin unless patient develops known QTc prolongation
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Appendix D – Creatinine Clearance
The following equations should be used to calculate creatinine clearance.
For males:
Creatinine Clearance
=
(140 - age [years] x weight [kg])
72 x (serum creatinine [mg/dL])
OR
(140–age [years] x weight [kg]) 
0.81 x (serum creatinine [µmol/L])
For females:
Creatinine Clearance = 0.85 (140-age [years] x weight [kg]) 
72 x (serum creatinine [mg/dL])
OR
0.85 (140-age [years] x weight [kg])
0.81 x (serum creatinine [µmol/L])
Source:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.
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Appendix E – Protocol History of Changes
Original Version Submitted to IRB & FDA – June 24, 2014
Amendment 1 – Changes Required During IRB & FDA Review – September 3, 2014
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
Cover-page
IND# listed as pending
IND# updated to 123,818
Administrative
Throughout
n/a
Corrects minor spelling 
and/or grammatical errors.
Administrative
Study Summary
Summary of statistical 
methodology appeared 
to suggest the study was 
designed to demonstrate 
superior response rates 
compared to historical 
controls. Percentages 
and accrual goals didn’t 
clearly align with other 
sections of the protocol.
Revised summary to more 
accurately reflect the design 
and numbers as described 
in the full statistical section.
Change requested by IRB 
during initial review.
1.4 (Study Rationale), 
7.4 (Stopping Rules)
Accrual goal not clear 
(35 vs. 32) and criteria 
for early stopping 
incorrectly listed as 5 of 
11 in the first stage.
Clarified that up to 35 
patients may be enrolled to 
achieve 32 evaluable; also 
corrected early stopping 
criteria to indicate that if 6 
or fewer of the first 12 
patients had a response, 
the study would be closed 
to further accrual.
Change requested by both 
FDA and IRB during initial 
review.
1.4 (Study Rationale), 
2.1 (Primary Objective 
& Endpoint), 10.1 
(Primary Endpoint & 
Sample Size 
Calculations)
Not clear what response 
assessment time point 
would be used for the 
purposes of evaluating 
early stopping.
Clarifies that response at 
the 3 month time point (after 
cycle 3) will be used to 
determine whether or not 
the trial meets early 
stopping criteria for efficacy.
Clarification requested by FDA 
during initial review.
3.2 (Exclusion Criteria)
Excluded patients with a 
QT interval > 500 msec.
Revised to exclude patients 
with a QT interval > 480 
msec.
Change requested by FDA 
during initial review.
4.0 (Treatment Plan), 
4.4 (Duration of 
Therapy)
n/a
Adds clarification that 
patients who do not achieve 
a response of PR should 
only remain on treatment up 
to 1 year if they have SD 
(not PD) AND if no other 
options are available that 
would offer a more 
favorable risk/benefit ratio.
Clarification requested by FDA 
during initial review.
4.1.1 (Romidepsin 
Administration), 5.0 – 
Table 4 (Time & 
Events)
Stated that patients who 
tolerated the regimen for 
2 cycles (6 doses) could 
be escalated to 14 
mg/m2 at the 
investigator’s discretion.
Revises this to allow 
escalation to the 14 mg/m2 
dose only if the patient has 
not achieved a CR and has 
not experienced any grade 
3-4 AEs.
Safety change required by 
FDA during initial review.
4.1.2 (Lenalidomide 
Administration), 4.1.3 
n/a
Adds different dosing for 
patients with moderate or 
Safety change required by 
FDA during initial review.
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(Table 1b)
severe renal impairment 
(creatinine clearance < 60 
ml/min) who are enrolled on 
the trial.
4.2 (Toxicities, Dosing 
Delays, and Dose 
Modifications)
Grade 3-4 non-
hematologic toxicities 
required to resolve to ≤ 
Grade 2 before further 
treatment.
Changed to require 
resolution to ≤ Grade 1; 
also notes that any 
recurrence of a grade 4 
non-hematologic toxicity 
must result in removal from 
trial therapy.
Safety change required by 
FDA during initial review.
4.4 (Duration of 
Therapy)
n/a
Adds “& Early Withdrawal” 
to the section title and 
clarifies that the occurrence 
of the listed events will 
result in early withdrawal 
from study treatment or (in 
some cases) the study as a 
whole.
Clarification requested by FDA 
during initial review.
4.7 (Suspension of 
Accrual)
n/a
New section added to clarify 
monitoring and the authority 
of the Data Monitoring 
Committee to suspend 
accrual in the event of 
excessive toxicity.
Clarification requested by FDA 
during initial review.
5.0 – Table 4: Time & 
Events
CBC required at 
baseline and once per 
cycle.
Changed to require CBC 
weekly for the first 2 cycles, 
then every other week for 
cycles 3-6, then at the start 
of each cycle thereafter.
Safety change required by 
FDA during initial review.
7.4 (Stopping Rules)
n/a
Clarifies that individual 
patients (enrolled in the first 
stage) who demonstrate 
clinical benefit (SD or 
better) may continue to 
receive study treatment up 
to 1 year in accordance with 
the duration of therapy 
criteria.
Clarification requested by IRB 
during initial review.
Amendment 2 – Additional Changes Required During FDA Review – October 3, 2014
Section(s) Affected
Prior Version
Amendment 2 Changes
Rationale
4.3.2 (Permitted 
Conmeds)
Stated that leukocyte 
growth factors may be 
given concurrently with 
protocol treatment.
Removes this statement.
Safety change required by 
FDA during initial review.
11.0 (Study 
Management)
n/a
Adds new section 11.11 to 
include a list of specific 
criteria that will trigger 
automatic suspension of 
study accrual.
Added per FDA requirement 
during initial review.
Amendment 3 – Additional Changes Required During FDA Review – December 17, 2014
Section(s) Affected
Prior Version
Amendment 3 Changes
Rationale
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11.11 (Criteria for 
Suspension of Accrual)
Definition of excessive 
toxicity included >20% of 
any single grade 4 
toxicity after at least 10 
subjects are treated, or 
more that 30% grade 4-5 
toxicity with at least 90% 
probability.
Revises this to rule to 
define the toxicity event as 
any grade ≥ 4 neutropenia, 
grade ≥ 4 
thrombocytopenia, or grade 
≥ 3 organ toxicity at least 
possibly related to the study 
regimen, and limits the 
toxicity events to no more 
than 20% with 80% 
posterior probability.
Revised per FDA requirement 
during review of clinical hold.
Amendment 4 – Changes due to Transition of PI – November 16, 2015
Section(s) Affected
Prior Version
Amendment 4 Changes
Rationale
Cover Page
Adam Petrich listed as 
PI and IND Holder
Removes Adam Petrich and 
adds Barbara Pro as PI and 
IND Holder
Administrative – change in 
faculty
Cover Page
Listed Yale Cancer 
Center as a participating 
site
Removes Yale and adds 
Ohio State University as a 
participating site
Administrative
Signature Page
Includes signature page
Removes signature page
Aligns with new NU protocol 
template
Schema, Study 
Procedures (Sec 5.0, 
Footnote 2, 11)
Response assessment 
included diagnostic CT 
with contrast
CT’s can be performed with 
or without contrast
Revised per discussion with PI
Patient Eligibility (Sec 
3.0)
Stated that study will be 
conducted in NMDTI
Removes language 
specifying NMDTI as 
location for study 
procedures
Allows flexibility to avoid 
deviations
3.1.1 - Lists “extranodal 
NK/T-cell lymphoma, 
nasal type” as included 
type of PTCL
3.1.1 – removes “extranodal 
NK/T-cell lymphoma, nasal 
type” as type of PTCL
Per PI discussion
3.1.1 - Included note 
specifying markers to be 
present for eligibility
3.1.1 – removes note for 
biomarkers
Per PI discussion – allows for 
less stringent eligibility
Inclusion Criteria (Sec 
3.1.1 & 3.1.6)
3.1.6 - Referred to 
attached for REMS 
program
3.1.6 – removes reference 
to REMS program
Referenced elsewhere
3.2.2 – Note listed twice
3.2.2 – Removes Second 
Note
Redundant
3.2.4 – “Patients who 
received prior exposure 
to…”
3.2.4 – “Patients who have 
received…”
Revised for clarity
Exclusion Criteria (Sec 
3.2.2, 3.2.4, 3.2.6
3.2.6 – “Patients who 
have known CNS…”
3.2.6 – “Patients with known 
CNS…”
Revised for clarity
“Each Cycle” column
“Day 1 of Each Cycle”
Revised for clarity
Study Procedures (Sec 
5.0)
n/a
Added column for Day 8 & 
15 of cycles
Revised for clarity
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Pregnancy test required 
“each cycle”
Footnote 18 – Pregnancy 
test only required D15 of 
each cycle
Revised for clarity
Footnote 5 – ECG 
required “at baseline”
Footnote 5 – ECG required 
“within 28 days of 
registration”
Revised for clarity
Footnote 8 – required 
physical exam and 
medical history to be 
within 14 days
Footnote 8 – requires only 
Chemistry and Hematology 
to be within 14 days
Per PI discussion – allows 
appropriate flexibility for 
procedure
Footnote 9 – allowed for 
labs to be used for C1D1 
if within 7 days
Footnote 9 – removes 
language, requiring new 
labs for C1D1
Per PI discussion – labs 
should be checked for safety
Footnote 16
Footnote 16 – Bone marrow 
biopsy “within 90 days of 
registration”
Per PI discussion – allows 
appropriate flexibility for 
procedure
Romidepsin Availability 
& Drug Ordering (Sec 
8.1.6)
“Please see separately 
attached Appendix F for 
details”
“Romidepsin order form is 
available at the NOTIS 
website – contact QA for 
any issues/concerns”
Administrative – allows for 
changes in order form without 
amending protocol
Lenalidomide 
Availability (Sec 8.2.7)
n/a
Adds instructions for 
ordering Revlimid through 
Biologics, Inc.
Administrative – study 
coordinator request
Amendment 5 – June 16, 2016
Section(s) Affected
Prior Version
Amendment 5 Changes
Rationale
Cover Page

Listed Ohio 
State University

Had incorrect 
address for 
Cornell Medical 
College

Removed Ohio 
State University

Added correct 
address for Cornell 
Medical College
Administrative – change in 
affiliate sites participating
Study Summary page

N/A

Updated 
Participating sites
Administrative – change in 
affiliate sites participating
Amendment 6 – March 10, 2017
Section(s) Affected
Prior Version
Amendment 6 Changes
Rationale
Cover Page; Study 
Summary; 3.0 (Patient 
Eligibility)
Included University of 
Washington as an 
affiliate site
Removes University of 
Washington from affiliates
Administrative 
Study Schema; 3.1.1 
(Inclusion Criteria); 
3.2.1 (Exclusion 
Criteria)
n/a
Adds adult T-cell lymphoma/ 
leukemia (ATLL) as eligible 
PTCL subtype (removes 
from excluded subtypes)
Expansion of eligibility to 
increase enrollment
Study Summary
Included short title and 
protocol number in 
summary
Removes short title and 
protocol number
To align with current NU 
protocol template
3.2.2 (Exclusion 
Criteria); 
4.3.2 (Permitted 
Corticosteroids were 
listed as being generally 
excluded in eligibility 
Adds clarification that 
corticosteroids are permitted 
on study to treat any 
Clarification – prior language 
was unclear whether 
corticosteroids of any type 
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Version: November 17, 2021 (Amendment 11)
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Concomitant 
Medications); 
4.3.3 (Prohibited 
Concomitant 
Medications)
criteria, and were not 
listed in concomitant 
medications
condition other than PTCL. 
Corticosteroids for PTCL are 
excluded during study 
treatment, but are permitted 
prior to treatment for 10 or 
fewer days 
were excluded, rather than 
steroids to treat PTCL
3.2.3, 3.2.10 (Exclusion 
Criteria)
Excluded chemotherapy 
and high QT “within 4 
weeks” prior to 
registration
Excludes chemotherapy and 
high QT“≤ 28 days” prior to 
registration
Clarification for simplicity
3.2.6 (Exclusion 
Criteria)
n/a
Expands CNS (central 
nervous system)
Clarification
4.0 (Treatment Plan); 
4.1.3 (Treatment 
regimen & supportive 
therapies); 5.0 (Study 
Procedures #10)
Allowed a cycle window 
of ±1 business day
Allows cycle window of ±3 
days
Allows greater flexibility for 
visits
4.1.1 (Romidepsin)
Patients may be 
escalated to 14mg/m2 
romidepsin if they don’t 
have grade 3-4 AE’s
Patients may be escalated 
to 14mg/m2 romidepsin if 
they don’t have drug-
related grade 3-4 AE’s
Clarification – only a drug-
related AE would preclude 
patients from escalating in 
dose
4.1.1 (Romidepsin); 
4.1.3 (Treatment 
regimen & supportive 
therapies); 4.3.1 
(Recommended 
Concomitant 
Medications Include); 
Recommended pre-
medications are Zofran 
16mg and 
dexamethasone 10mg 
(or similar agents)
Pre-medications are listed 
as Zofran 16mg and 
dexamethasone 10mg (or 
equivalent)
An equivalent dose is 
recommended (rather than 
saying “similar agent”, which 
may include a higher dose) to 
avoid higher doses that may 
prolong QTc (e.g. kytril > 2mg) 
4.1.3 (Treatment 
regimen & supportive 
therapies); 5.0 (Study 
Procedures #10,15)
“Romidepsin infusions 
should occur within 1 
business day of days 1, 
8, and 15”
“Romidepsin infusions 
should occur within ±3 days 
of day 1, and within +3 days 
of days 8 and 15.”
Allows greater flexibility on day 
1 (to align with cycle windows), 
but maintains appropriate 
window between infusions.
Table 1b: “Dose 
Adjustments…”
Table 1b: “Lenalidomide 
Dose Adjustments”
Clarification – previously 
unclear which drug was to be 
modified
4.1.3 (Treatment 
regimen & supportive 
therapies); 
Table 1b: severe renal 
impairment defined as 
CrCl ≤ 30
Table 1b: severe renal 
impairment defined as CrCl 
< 30
Discrepancy – CrCl = 30 
previously fell into both 
moderate and severe 
categories
4.2 (Toxicities, Dosing 
Delays, and Dose 
Modifications); 6.1 
(Toxicity Endpoints); 
7.2.2 (Severity of AE’s)
CTCAE v4.0
CTCAE v4.03
Administrative update
4.2 (Toxicities, Dosing 
Delays, and Dose 
Modifications); 7.2.5 
(Attributions)
Both study drugs were to 
be delayed or modified in 
the case of a drug-
related toxicity
Adds that toxicity should be 
attributed to one study drug 
whenever possible. 
Modifications/delays may 
apply to only the drug which 
caused toxicity, or both.
Clarification – clinically, if one 
study drug is not related to an 
AE, it should be continued as 
normal
4.2 (Toxicities, Dosing 
Delays, and Dose 
Modifications)
For any Grade 3-4 
toxicity, lenalidomide 
was to be resumed at 
the same dose upon 
Adds exceptions for Grade 
3-4 AE’s where the dose of 
lenalidomide should be 
reduced by 5mg (G3 rash or 
Aligns more closely with 
lenalidomide dosing in 
standard practice
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Version: November 17, 2021 (Amendment 11)
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resolution of the first 
occurrence
neuropathy, G3 or 4 tumor 
lysis syndrome or tumor 
flare) or discontinued (G4 
rash or neuropathy, or any 
grade blistering rash)
Romidepsin dose could 
be reduced from 
10mg/m2 to 7mg/m2
Changes dose reduction to 
8mg/m2 (from 10mg/m2)
To align with standard dosing
4.2.1 (Pregnancy)
n/a
Patients who become or are 
suspected to be pregnant 
while on study treatment 
must discontinue 
immediately. Refers to 7.2.6 
for reporting requirements
Required Celgene language 
for pregnancy reporting and 
monitoring.
Referenced appendix E 
for list of CYP3A4 
inducers
References appendix C and 
adds note that pharmacist 
list of prohibited CYP3A4 
inducers will take priority 
over list in the protocol. 
The list of CYP3A4 inducers is 
constantly evolving
4.3.3 (Prohibited 
Concomitant 
Medications); Appendix 
C
QTc prolonging agents 
were strictly prohibited
QTc prolonging agents are 
only prohibited in patients 
who develop QTc 
prolongation on study
QTc prolonging agents are not 
a risk unless a patient already 
has prolonged QTc; patients 
are required to have QTc ≤ 
480 msec before the study
n/a
Adds 1 cycle = 28 days
Clarification 
n/a
Adds cycle window (±3 
days)
Clarification 
#2: n/a
#2: CT’s must be of chest, 
abdomen, pelvis; neck if 
clinically indicated, and with 
or without contrast
Clarification 
#11: n/a
#11: Adds window of ±7 
days for CT’s, and clarifies 
they can be with or without 
contrast
Clarification
#13: n/a
#13: Adds windows for 
follow-up visits (±7 days for 
q3months and ±14 days for 
q6months)
Clarification 
5.0 (Study Procedures)
#16: Bone marrow 
biopsy was to be done at 
baseline and as 
response assessment for 
patients with marrow 
only disease and as 
clinically indicated in 
other patients
#16: Bone marrow biopsy 
will be done at baseline if 
clinically indicated. In 
patients with known bone 
marrow involvement at 
baseline, a biopsy will be 
performed after the patient 
achieves a CR
Clarification – language was 
previously unclear
7.2.6 (Pregnancy);
7.2.7 (Overdose)
n/a
Adds reporting 
requirements for patients 
who become pregnant or 
have an overdose of study 
treatment. Pregnancy and 
pregnancy outcomes must 
be reported on Celgene-
Additional safety language 
required by Celgene
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Version: November 17, 2021 (Amendment 11)
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specific forms, and 
overdose must be reported 
on case report forms.
7.3.4 (Reporting to 
Celgene)
n/a
Adds contact information 
(fax and email) for Celgene 
Drug Safety and additional 
reporting instructions
Clarification to align with 
Celgene protocol template
8.1.6 (Availability & 
Drug Ordering)
Referenced a drug 
shipment request form, a 
fax and email for 
ordering romidepsin
Removes contact details for 
ordering romidepsin, and 
references instructions in 
NOTIS.
NOTIS should be used for 
drug orders to avoid protocol 
amendments in case of 
changing instructions
11.5 (Data 
Management & 
Monitoring/Auditing); 
Appendix C; Appendix 
D
Referred to Appendices 
for the DSMP and data 
submission guidelines
Removes references and 
Appendix C & D, instead 
referencing the DSMP 
hyperlink and NOTIS
To align with current NU 
protocol template and policies
11.7 (Amendments to 
the Protocol)
Amendments must be 
sent to the IRB for 
approval.
Adds that amendments will 
be sent for review by “local, 
institutional, and 
governmental regulatory 
bodies, as well as by 
Celgene”. Amendments will 
also be sent to affiliates
Broader language to cover all 
required reviews and 
approvals.
Appendix C
All medications were 
listed as “not permitted”
Clarifies that QTc 
prolonging agents are 
“cautionary”; also clarifies 
that ondansetron will be 
used as a pre-medication 
unless a patient develops 
QTc prolongation
Clarification to align with 4.3.3 
Amendment 7 – July 25, 2018
SRC-approved on October 30, 2018
Section(s) Affected
Prior Version
Amendment 7 Changes
Rationale
3.1.4 (Inclusion Criteria); 
Appendix D
Organ function listed a 
cutoff for Creatinine as ≤2x 
ULN
Changes creatinine cutoff 
to Creatinine Clearance, 
where the cutoff is ≤30 
mL/min
Adds Appendix D to 
provide the formula for 
calculating Creatinine 
Clearance
To align with dose 
adjustment criteria listed in 
4.1.3 and standard of care 
criteria for lenalidomide. 
3.1.8 (Inclusion Criteria)
Patients must be free of 
any prior malignancies for 
≥1 year
Adds that “free of prior 
malignancies” is at the 
investigator’s discretion.
To clarify prior confusion as 
to the definition of 
malignancy free
3.2.6 (Exclusion Criteria)
n/a
Excludes patients who are 
receiving concurrent 
immunosuppressive 
medications post-transplant 
To address clarification 
brought up by an affiliate 
site. It is not clinically 
appropriate to treat patients 
on immunosuppressive 
medications with the study 
treatment. 
4.2 (Toxicities, Dosing 
Delays, and Dose 
Modifications)
n/a
Adds: “If study drug is 
delayed more than 21 days 
(1 treatment cycle), 
Clarification; there was 
previously no language 
about maximum length of 
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Version: November 17, 2021 (Amendment 11)
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treatment may be 
discontinued after 
discussion with the PI.”
holding patients for toxicity.
4.3.2 (Permitted 
Concomitant 
Medications)
n/a
Transfusions and growth 
factor are clarified to be 
permitted at physician 
discretion and per 
institutional guidelines
Clarification requested by 
affiliate site; transfusion and 
growth factor were not 
previously mentioned  
4.3.3 (Prohibited 
Concomitant 
Medications & 
Treatments)
Concurrent radiotherapy 
was generally prohibited
Adds a stipulation that 
radiotherapy is permitted to 
treat a single non-target 
lesion for symptom control
Clarification resulting from a 
clinical situation. Patients 
should be permitted to 
receive radiotherapy 
separate from the disease 
target lesions as it does not 
affect disease assessments 
or study endpoints 
4.6 (Patient 
Replacement); 4.7 
(Suspension of Accrual); 
7.3 (Expedited 
Reporting of SAEs) 
11.10 (Publication 
Policy); 11.11 (Criteria 
for Suspension in 
Accrual)
Referenced Data 
Monitoring Committee 
(DMC)
Updates to reference Data 
and Safety Monitoring 
Committee (DSMC)
Administrative update to 
align with internal policies
5.0 (Study Procedures, 
#8)
n/a
SAE’s are to be collected 
from the time of consent 
until 30 days after treatment
Clarification for easier 
referencing to align with 
SAE timelines within the 
protocol
7.2.3 (Serious Adverse 
Events)
SAE’s were to be collected 
during the study and for 30 
days after treatment
Adds that SAE’s will be 
collected from the time of 
consent until 30 days after 
treatment
Clarification requested by 
affiliate site
Amendment 8 – July 5, 2019
SRC-approved on December 6, 2019
Section(s) Affected
Prior Version
Amendment 8 Changes
Rationale
Cover Page
Listed Alfred Rademaker 
as the Biostatistician
Updates to Borko Jovanovic 
as the new Biostatistician
Administrative update to 
account for staffing change
Cover Page and 
Throughout
Coordinating Center was 
listed as the Clinical 
Research Office (CRO) at 
Northwestern
Updates the name of the 
coordinating center to the 
Clinical Trials Office (CTO) 
at Northwestern
Administrative update to 
account for a change in the 
coordinating center’s name; 
the coordinating center 
itself will remain the same.
Study Summary, 
Section 1.4 (Study 
Rationale), Section 3.0 
(Patient Eligibility), and 
Section 10.0 (Statistical 
Listed an accrual goal of 
32 evaluable subjects
Updates to an accrual goal 
of 20 evaluable subjects 
and provides a new 
statistical plan in Section 
10.0.
The study has been slow to 
accrue, and reducing the 
sample size will increase 
the feasibility of completing 
the trial in a timely manner. 
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Version: November 17, 2021 (Amendment 11)
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Considerations)
Modification requested by 
the lead site after receiving 
support from Celgene to 
reduce sample size.
Section 4.0 (Treatment 
Plan)
N/A
Adds the following:
With PI approval, dose 
modifications (interruptions 
and reductions) may be 
permitted for any grade AE 
deemed intolerable by the 
patient, or per treating 
investigator discretion (with 
PI approval) if thought to be 
in the best interest of the 
patient.
Modification requested by 
the DSMC to align with best 
interests of participating 
patients.
Section 4.6 (Patient 
Replacement)
Stated:
Any patient who completes 
fewer than 2 total cycles of 
therapy and is withdrawn 
for any reason except POD 
or toxicity will still be 
considered evaluable for 
toxicity endpoints; 
however, for the purpose of 
efficacy endpoints, another 
patient may be added to 
the accrual goal with the 
approval of the Data and 
Safety Monitoring 
Committee (DSMC) at NU.
Updates language to 
include the bolded text:
Any patient who completes 
fewer than 2 total cycles of 
therapy and is withdrawn 
for any reason except POD 
or toxicity will still be 
considered evaluable for 
toxicity endpoints but will 
not be evaluable for 
efficacy endpoints; for the 
purpose of efficacy 
endpoints, another patient 
may be added to the 
accrual goal with the 
approval of the Data and 
Safety Monitoring 
Committee (DSMC) at NU.
Language clarification 
requested by the Quality 
Assurance Monitor to clarify 
replacement of non-
evaluable patients
Section 5, Table 4 (Time 
and Events)
N/A
Adds a -1 day window to D8 
and D15 assessments
To allow flexibility in patient 
schedules
Section 7.2.1 (Adverse 
Events)
N/A
Now includes standard 
language describing 
examples of AE 
classification
To align with current NU 
protocol template
Section 11.6.2 (Protocol 
Deviations)
N/A
Now includes standard 
language describing 
Reportable New Information 
(RNI)
To align with current NU 
protocol template
Throughout
N/A
Corrects minor 
grammatical/typographical 
errors and formatting
Administrative change
Amendment 9 – December 9, 2019
SRC-approved on March 3, 2020
Section(s) Affected
Prior Version
Amendment 9 Changes
Rationale
Cover Page and 
Protocol version dated July 
Updates version date to 
Administrative update
IRB #: STU00097620-CR0005 Approved by NU IRB for use on or after 3/21/2022 through 3/20/2023.

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Version: November 17, 2021 (Amendment 11)
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Throughout
5, 2019 (Amendment 8)
December 9, 2019 
(Amendment 9)
Table of Contents
N/A
Updates page numbers
Administrative update
Inclusion Criterion 3.1.4
Required creatinine 
clearance of ≤ 30 mL/min
Requires creatinine 
clearance of ≥ 30 mL/min
Corrects typographical 
error.  Replaces “≤ 30 
mL/min” with “≥ 30 mL/min”
Section 7.2.4 (UPIRSO)
Section 7.2 (Expedited 
Reporting of SAEs)
Section 11.6 
(Adherence to the 
Protocol)
Section 11.7 
(Amendments to the 
Protocol)
Section 11.10 
(Publication Policy)
N/A
Updates standard language 
to align with new 
Northwestern University 
protocol template
Administrative update
Section 9.3.2 
(Tissue Collection)
Construction of the TMA 
will require minimum of 
five unstained slides of 
tissue for proper analysis.
Construction of the TMA will 
require 1.0 to 1.5 mm 
punch cores for proper 
analysis.
Updates for flexibility in 
tissue collection procedures
Appendix E
(Protocol History of 
Changes)
N/A
Adds SRC-approval date 
for protocol amendment 8
Summarizes revisions for 
protocol amendment 9
Administrative update
Amendment 10 – May 22, 2020
Section(s) Affected
Prior Version
Amendment 9 Changes
Rationale
Cover Page and 
Throughout
Protocol version dated 
December 9, 2019 
(Amendment 9)
Updates version date to 
May 22, 2020 (Amendment 
10)
Administrative update
Table of Contents
N/A
Updates page numbers
Administrative update
Section 4.1.2 
(Lenalidomide);
Section 4.1.3 
(Treatment Regimen & 
Supportive Therapies);
Table 1b
The dose should be 
adjusted in patients with 
moderate or severe renal 
impairment…
Table heading:
Dose
Addition of bolded text:
The dose and schedule 
should be adjusted in 
patients with moderate or 
severe renal impairment…
Table heading:
Dose and Schedule
Clarification.
Clarifies language to align 
with the contents of Table 
1b, which describes the 
adjusted dose and 
schedule for lenalidomide 
for patients with moderate 
or severe renal impairment.
Table 1b
N/A
Addition of bolded text in 
footnote.
1 Creatinine clearance 
(CrCl) will be measured 
and calculated prior to 
Clarification. 
Adds footnote 1 to Table 1b 
to clarify the process to 
calculate creatinine 
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Version: November 17, 2021 (Amendment 11)
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initiating each cycle as 
described in the Study 
Procedures Table in 
Section 5.0.  (Refer to 
Appendix D for 
instructions on 
calculating CrCl). The 
dose of lenalidomide will 
be adjusted per Table 1b. 
Any questions regarding 
dose calculations/ 
adjustments should be 
directed to the Lead PI.
clearance to determine 
lenalidomide dosing.
Section 5.0 
(Study Procedures)
16 Romidepsin will be 
administered intravenously 
on days 1, 8, and 15 of 
each cycle. The dose for 
the first 2 cycles (6 doses 
total) will be 10 mg/m2; in 
some cases, patients may 
be escalated to a dose of 
14 mg/m2 for remaining 
cycles (see Section 4.1.1 
for specific criteria). A 
window is allowed for 
romidepsin infusion visits 
(within ±3 days of day 1, 
and within +3 days of days 
8 and 15).
Addition of bolded text to 
footnote:
16 Romidepsin will be 
administered intravenously 
on days 1, 8, and 15 of 
each cycle. The dose for 
the first 2 cycles (6 doses 
total) will be 10 mg/m2; in 
some cases, patients may 
be escalated to a dose of 
14 mg/m2 for remaining 
cycles (see Section 4.1.1 
for specific criteria). A 
window is allowed for 
romidepsin infusion visits 
(within ±3 days of day 1, 
and within -1 to +3 days of 
days 8 and 15).
Corrects discrepancy. 
Modifies footnote 16 to 
revise the window for D8 
and D15 to be -1 to +3 days 
to align with footnote 11. 
Footnote 11 states that, 
“Day 8 and 15 each have a 
window of -1 to +3 days.”
Section 5.0 
(Study Procedures)
N/A
Adds “creatinine clearance 
check” to the Study 
Procedure’s Table with a 
corresponding footnote.  
Addition of bolded text 
below:
Clarification. 
Clarifies the process to 
calculate creatinine 
clearance to determine 
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Version: November 17, 2021 (Amendment 11)
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20 Creatinine clearance 
will be measured and 
calculated prior to 
initiating each cycle 
(Refer to Appendix D for 
instructions on 
calculating creatinine 
clearance). The dose of 
lenalidomide will be 
adjusted per Table 1b. 
Any questions regarding 
dose calculations/ 
adjustments should be 
directed to the Lead PI. 
Refer to Section 4.1.3 for 
additional information.
lenalidomide dosing.
Appendix C;
Appendix D
Appendix C and Appendix 
D did not appear in the 
Table of Contents.
Appendix D did not have a 
title. 
Revises formatting and 
adds title to appendix so 
both appendices appear in 
the Table of Contents 
appropriately. 
Administrative update
Appendix E
(Protocol History of 
Changes)
N/A
Adds SRC-approval date 
for protocol amendment 9.
Summarizes revisions for 
protocol amendment 10.
Administrative update
Throughout
N/A
Minor formatting 
adjustments.
Administrative update
Amendment 11 – November 17, 2021
Section(s) Affected
Revision
Rationale
Cover page & 
Throughout
Updates the principal investigator from Dr. Barbara Pro to 
Dr. Jonathan Moreira and provides contact information
Administrative revision
Throughout
Editorial revisions: Updates the protocol version/date and 
Appendix E (Protocol History of Changes)
Administrative revision
IRB #: STU00097620-CR0005 Approved by NU IRB for use on or after 3/21/2022 through 3/20/2023.