Clinical trial NCT02341014
Conditions: T-cell Lymphomas Relapsed or Refractory
Keywords: Carfilzomib Romidepsin Lenalidomide Lymphomas 14-179
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2015-01-02; Completion date: 2023-01-11
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label phase Ib/IIa study of patients with relapsed/refractory B- and T-cell lymphomas who are treated with carfilzomib, lenalidomide and romidepsin.

Detailed description:

Arms: arm 1: All patients will be treated with romidepsin administered intravenously on days 1 and 8 of a 21-day cycle. Lenalidomide will be taken orally daily for days 1-14 of a 21-day cycle. The carfilzomib will be given weekly on days 1, and 8 of a 21-day cycle.
Interventions: intervention 1: Carfilzomib intervention 2: Romidepsin intervention 3: Lenalidomide
Intervention descriptions: intervention 1: The initial dose of carfilzomib (cycle 1, day 1) given to any patient must be 20mg/m2 . intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Page 1 of 90 
 
 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
A Phase Ib/IIa Study of Combination therapy with Carfilzomib, Ro 
in Patients with Relapsed or Refractory B- and T-cell 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTO 
Principal Investigator/Department: 
Steven M. Horwitz, MD 
midepsin, Lenalidomide 
Lymphomas 
COL 
Medicine 
Co-Principal 
Alison Moskowitz, M.D. 
Investigator(s)/Department: 
Medicine 
Investigator(s)/Department: 
Anas Younes, M.D.  
Craig H. Moskowitz, M.D. 
Paul Hamlin, M.D. 
Lia Palomba, M.D. 
Andrew D. Zelenetz, M.D., Ph.D. 
David J. Straus, M.D. 
Ariela Noy, M.D. 
Matthew Matasar, M.D. 
Anita Kumar, M.D. 
Theresa Davey, PA 
Jurgen Rademaker, M.D. 
Ravinder Grewal, M.D. 
Patricia Myskowski, M.D. 
Meenal Kheterpal, M.D. 
Nadia Kralovic, MSPA 
Neha S. Korde, M.D. 
Audrey Hamilton, M.D. 
Afsheen Iqbal, M.D. 
Stuart Lichtman, M.D. 
Hani Hassoun, M.D. 
Parisa Momtaz, M.D. 
Oscar Lahoud, M.D. 
Susan McCall, NP 
Teresa Scardino, PA 
Michelle Wisniewski, PA 
Jason Carter, PA 
Pamela Drullinsky, M.D. 
Philip Caron, M.D., Ph.D. 
Colette N. Owens 
Jillian Soloman, MSPA 
Mila Gorsky, MD 
Karen Louw, NP 
Regina Byrne, NP 
Helen Hancock, NP 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Radiology 
Radiology 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Consenting  Professional(s)/Department: 
Anas Younes, M.D. 
Craig H. Moskowitz, M.D. 
Paul Hamlin, M.D. 
Lia Palomba, M.D. 
Andrew D. Zelenetz M.D., Ph.D. 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 


Page 2 of 90 
Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
 
 
 
 
David J. Straus, M.D. 
Medicine 
Ariela Noy, M.D. 
Medicine 
Matthew Matasar, M.D. 
Medicine 
Alison Moskowitz, M.D. 
Medicine 
Steven M. Horwitz, M.D. 
Medicine 
Anita Kumar, M.D. 
Medicine 
Neha S. Korde, M.D. 
Medicine 
Audrey Hamilton, M.D. 
Medicine 
Afsheen Iqbal, M.D. 
Medicine 
Stuart Lichtman, M.D. 
Medicine 
Hani Hassoun, M.D. 
Medicine 
Parisa Momtaz, M.D. 
Medicine 
Pamela Drullinsky,M.D. 
Medicine 
Philip Caron, M.D., Ph.D. 
Medicine 
Colette N. Owens, M.D. 
Medicine 
Oscar Lahoud, M.D. 
Medicine 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
 
OneMSK Sites 
Manhattan 
Basking Ridge 
Commack 
MSK Westchester 
Rockville Centre 
 
 
Participating Institutions – If multicenter 
study coordinated by MSK: 
PI's Name 
Site's Role 
University of Nebraska 
Matthew A  Lunning, M.D. 
Data Collection 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 3 of 90 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
7 
3.0 
BACKGROUND AND RATIONALE 
7 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
13 
4.1 
Design ............................................................................................................................... 13 
4.2 
Intervention .............................................................................................................................. 14 
5.0 
THERAPEUTIC/DIAGNOSTIC  AGENTS 
14 
5.1 
REVLIMID® .................................................................................................................................. 14 
5.2 
Romidepsin ....................................................................................................................... 17 
5.3 
Carfilzomib......................................................................................................................... 19 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
22 
6.1 
Subject Inclusion Criteria ................................................................................................... 22 
6.2 
Subject Exclusion Criteria ................................................................................................. 23 
7.0 
RECRUITMENT PLAN 
25 
8.0 
PRETREATMENT  EVALUATION 
25 
9.0 
TREATMENT/INTERVENTION  PLAN 
26 
9.1 
Pretreatment electrolyte assessment and drug management .......................................... 26 
9.2 
Treatment plan carfilzomib/romidepsin/lenalidomide Phase Ib ............................................... 26 
9.3 
Prophylactic Measures ...................................................................................................... 29 
9.4 
Concomitant Medications ........................................................................................................... 29 
9.5 
Dose Continuation, Modification and Interruption (Cycle 2 and beyond) ........................... 30 
9.6 
Treatment Adherence............................................................................................................. 36 
9.7 
Concomitant Therapy ............................................................................................................. 36 
9.7.1 
Recommended Concomitant Therapy ........................................................................... 36 
10.0  EVALUATION DURING TREATMENT/INTERVENTION 
37 
10.1 
Assessments During the First Cycle .............................................................................. 37 
10.2 
Required Blood Parameters and Other Investigations Prior to Each Treatment .............. 39 
10.3 
Cardiac Monitoring ................................................................................................................. 40 
10.4 
Cardiac Alert Findings ....................................................................................................... 40 
10.5 
Electrocardiograms ............................................................................................................ 40 
10.6 
Pregnancy Testing ............................................................................................................ 41 
10.7 
Follow-Up ...................................................................................................................................... 41 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 4 of 90 
 
 
11.0  TOXICITIES/SIDE EFFECTS 
42 
12.0  CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
47 
13.0  CRITERIA FOR REMOVAL FROM STUDY 
49 
13.1 
Discontinuation of Study Treatment ............................................................................... 49 
14.0  BIOSTATISTICS 
50 
15.0   RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES. 51 
15.1 
Research Participant Registration ..................................................................................... 51 
15.2 
Randomization ................................................................................................................... 52 
16.1 DAT A M ANAGEMENT ISSUES 
52 
16.1.1 
Data and Source Documentation for Participating Sites ............................................ 52 
16.1.2 
Data and Source Documentation Submission for Participating Sites ........................ 53 
16.1.3 
Data and Source Documentation Submission Timelines for Participating Site ......... 53 
16.1.4 
Data Review and Queries for Participating Site Data ................................................ 54 
16.1 
Quality Assurance ............................................................................................................. 54 
16.1.1 
Quality Assurance for Participating Sites ................................................................... 54 
16.1.2 
Response Review ........................................................................................................... 55 
16.2 
Data and Safety Monitoring ................................................................................................... 55 
16.3 
Regulatory Documentation ................................................................................................ 56 
16.4 
Noncompliance .................................................................................................................. 58 
17.0  PROTECTION OF HUMAN SUBJECTS 
58 
17.1 
Privacy ............................................................................................................................... 59 
17.2 
Serious Adverse Event (SAE) Reporting .............................................................................. 59 
17.2.1 
Serious Adverse Event (SAE) Definition .................................................................... 61 
17.2.2 
Pregnancies ..................................................................................................................... 63 
17.2.3 
Expedited Reporting by MSK to Celgene ...................................................................... 64 
17.2.4 
Expedited Reporting by MSK to NCCN/Onyx ............................................................ 64 
17.3 
Serious Adverse Event (SAE) Reporting for Participating Sites ...................................... 66 
17.4 
Safety Reports ................................................................................................................... 67 
18.0  INFORMED CONSENT PROCEDURES 
68 
18.1 
For Participating Sites ....................................................................................................... 68 
19.0  REFERENCES 
69 
20.0  APPENDICES 
74 
Appendix A – Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods........................................................................................................................... 74 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 5 of 90 
 
 
Appendix B – Canadian Cardiovascular Society Angina Classification .......................................... 78 
Appendix C – New York Heart Association Classification of Cardiac Disease .............................. 79 
Appendix D – Grading Scales for modified Severity-Weighted Assessment Tool mSWAT .......... 80 
Appendix E – Medications That May Cause QTc Prolongation ....................................................... 82 
Appendix F – Medications That May Inhibit CYP3A4 .................................................................. 86 
Appendix G – Study Calendar ............................................................................................................ 88 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 6 of 90 
 
 
 
1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Title: A Phase Ib/IIa Study of Combination therapy with Carfilzomib, Romidepsin, 
Lenalidomide in Patients with Relapsed or Refractory B- and T-cell Lymphomas 
Objectives: The primary endpoint of the phase Ib and IIa portion of the study is to 
determine the MTD (phase Ib) and characterize the safety and toxicity profile of 
extended treatment with the combi nation carfi lzomib, romidepsin, lenalidomide in 
patients with relapsed and refractory B- and T-cell lymphomas.  The secondary 
objectives of this study are to a) assess the overall response rate (ORR) of 
carfilzomib, romidepsin, and lenalidomide in B- and T-cell lymphoma; b) to assess 
the complete response (CR) and partial response (PR) rate; c) to assess the time 
to response (TTR), duration of response (DOR) and event free survival (EFS). 
Patient Population:  Patients with relapsed or refractory B-cell and T-cell 
lymphomas. 
Expected Number of Patients:  30 
 
Study Design and Methodology:  This will be a multicenter, open label, phase 
Ib/IIa trial carfilzomib, romidepsin and lenalidomide in patients with relapsed or 
refractory lymphomas. 
Treatments Administered:  Romidepsin will be administered intravenously on 
days 1 and 8 of a 21-day cycle. Lenalidomide will be taken orally daily for days 1- 
14 of a 21-day cycle. Carfilzomib will be given intravenously weekly on days 1 and 
8, of a 21 day cycle. Maximum tolerated dose (MTD) to be determined in the 
phase Ib portion. A cycle of carfilzomib, romidepsin, and lenalidomide will be 21- 
days. 
Safety Data Collected: The following evaluations will be conducted to assess the 
safety of the combination of romidepsin, carfilzomib, and lenalidomide: 
Phase Ib: Determine the MTD by NCI-CTCAE v4.0. 
 
Phase IIa: Further assess the combination‟s toxicity profile by NCI-CTCAE v4.0. 
 
Efficacy Data Collected: Disease specific evaluations will be conducted to assess 
the efficacy of the combi nation of carfilzomib, romidepsin, and lenalidomide: 
• Phase IIa portion (including phase Ib treated at MTD) - overall 
response rate, complete response rate, partial response rate, time to 
response, duration of response, and event-free survival. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 7 of 90 
 
 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
We hypothesize that therapy with carfilzomib in combi nation with romidepsin and 
lenalidomide will be a well-tolerated and active regimen for subjects with relapsed or 
refractory B-cell and T-cell (PTCL) lymphoma. 
a. The primary endpoint of the phase Ib and IIa portion of the study is to 
determine the MTD (phase Ib) and characterize the safety and toxicity profile of 
extended use  with the combination carfilzomib, romidepsin, lenalidomide in 
patients with B- and T-cell lymphomas. 
b. Preliminary efficacy secondary endpoints in the phase  IIa  portion (including 
those treated in the phase Ib at MTD) of the study will also be assessed: 
i. Overall response rate (ORR) of carfilzomib romidepsin, and lenalidomide 
collecti vely as well as by disease subtype 
ii. Complete response (CR) and partial response (PR) rate; 
iii. Time  to  response  (TTR),  duration  of  response  (DOR)  and  event  free 
survi val (EFS). 
iv. Based on safety and preliminary secondary endpoints further study could 
include: 
1. Addition of monoclonal antibodies or other agents to regimen 
2. Randomization against standard therapies in the relapsed and refractory 
setting 
3. Up-front therapy (PTCL only or indolent B-cell lymphoma) 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Relapsed and Refractory B- and T-cell lymphomas 
Relapsed and refractory B- and T-cell lymphomas remain an ongoing challenge 
with repeated courses of cytotoxic chemotherapy often yielding diminishing 
returns.  The 5-year overall survival (OS) in transplant ineligible patients with B- 
and T-cell lymphomas was 32%, and 20% respecti vely [Phillip, 1995; Vose J, 
2008]. There remains significant need for more acti ve therapies and combinations 
with many newer approaches now looking to long-term or maintenance treatments 
employing drugs without cumulative toxicity. 
As T-cell lymphomas have been traditionally difficult to treat, single agent overall 
response rates have generally been in the 20-35% range. Additionally, durations 
of response have been generally short lived.  Therefore, combination therapy of 
well tolerated agents may be the best approach to therapy. 
3.2 
Proteasome Inhibitors in B- and T-cell Lymphomas 
Proteasome inhibitors were initially approved for use in relapsed and/or refractory 
multiple myeloma and have been subsequently found to be effective in mantle cell 
lymphomas as well as indolent B-cell lymphomas [Goy et al. 2005, O‟Connor et al 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 8 of 90 
 
 
 
2005]. In follicular lymphoma, bortezomib, a proteasome inhibitor, carries a 55- 
70% response rate in combination with rituximab [Zinzani et al. 2012, Coiffer et al. 
2011]. Additionally, in previously untreated diffuse large B-cell lymphoma, patients 
treated with R-CHOP plus bortezomib carried a 100% response rate [Ruan et al. 
2011]. 
Bortezomib has also shown efficacy in T-cell lymphomas with a response rate of 
67% as a si ngle agent. Responses with bortezomib in these patients were durable 
lasting 7 to 14 months in a phase II study [Zinzani et al. 2007]. Furthermore, a 
phase I study of CHOP with bortezomib as first line treatment for aggressive T-cell 
lymphomas demonstrated a 61% response rate [Lee et al. 2008]. Therefore, 
proteasome inhibitors such as bortezomib have demonstrated efficacy in these 
difficult to treat disorders. 
3.2.1  Carfilzomib 
Carfilzomib is a next-generation proteasome inhibitor that exhibits a high degree of 
specificity for the catalytic domain in proteolytic active sites within the proteasome. 
Compared to bortezomib which is a slowly reversible inhibitor of the proteasome, 
carfilzomib is mechanistically irreversible.[Demo et al 2007; O‟Connor et al. 2009] 
Carfilzomib has been studied in hematologic malignancies, including multiple 
myeloma, non-Hodgkin‟s lymphomas. [O‟Connor et al. 2009] With regards to its 
use in multiple myeloma, carfilzomib was studied in a multicenter single arm study 
of 266 patients with relapsed multiple myeloma who had received at least two prior 
therapies includi ng bortezomib and an iMID.  It was administered for two 
consecuti ve days weekly for 3 weeks of a 28 day cycle. This study demonstrated 
an overall response rate of 23.7% with a median duration of response of 7.8 
months.  The most common side effects included fatigue, anemia, nausea and 
thrombocytopenia. [Seigel et al. 2012] A similar study in bortezomib naïve patients 
demonstrated an overall response rate of 64.2% and the median duration of 
response was not reached. [Vij et al. 2012] It was based on these studies that 
carfilzomib gained fast track FDA approval for the treatment of relapsed/refractory 
multiple myeloma in 2012. Carfilzomib has also been studied in combination with 
dexamethasone using a weekly dosing schedule at ≥45mg/m2 in patients with 
relapsed/refractory multiple myeloma.  In these studies, half-life was found to be 
comparable and AUC was found to be higher than on the traditional schedule.  The 
overall response rate was found to be 67%. [ Berenson et al. 2013] 
3.3. 
Histone Deacetylase Inhibitors in B- and T-cell lymphomas: Romidepsin 
Romidepsin is a potent histone deacetylase (HDAC) inhibitor which causes arrest 
of the cell cycle at both G1 and G2/M phases, induces the internucleosomal 
breakdown of chromatin, and inhibits intracellular HDAC acti vity resulting in an 
accumulation of marked amounts of acetylated histone species within M-8 cells 
[Nakajima Y, 1998]. The proposed mechanism of action in B-cell lymphomas is 
through the proto-oncogene BCL6 that is highly acti ve as a transcriptional 
repressor within the germinal B cell. Uncurbed activity of BCL6 lends to 
suppression of genes involved in lymphocyte acti vation, differentiation, cell cycle 
arrest, and apoptosis.   Moreover, accumulation of acetylated BCL6 is known to 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 9 of 90 
 
 
 
down regulate the transcriptional repressive function allowing gene transcription of 
beneficial pro-apoptotic cellular products in the otherwise malignant cell. 
[Boreschenko O, 2002] 
Romidepsin has not been cli nically studied as a single agent in B-cell lymphomas, 
but is undergoing evaluation in combi nation with lenalidomide in a phase Ia/IIb 
study in hematologic malignancies [NCTG: 01755975] However, other HDAC 
inhibitors (vorinostat, belinostat, and panobinostat) have demonstrated cli nical 
activity in early phase studies. For example, in a combined analysis of two 
consecuti ve phase I trials in hematologic malignancies performed at MSK utilizing 
vorinostat, an HDAC inhibitor, of those enrolled 32 had a B-cell non-Hodgkin 
lymphoma (NHL). Three of these patients responded with one achieving a CR. 
[O‟Connor O, 2005] Furthermore, the HDAC inhibitor panobinostat was employed 
in a phase II single agent study with 13 patients having relapse or refractory 
Hodgkin lymphoma. In this subgroup , 5 or 13 achieved a partial response. 
[Ottman O, 2008] In a more recent study the same drug was employed specifically 
for relapsed disease after autologous stem cell transplantation with an ORR of 
13%. [Younes, 2009] 
The demonstrated cli nical activity of romidepsin in T-cell lymphoma is more robust. 
Romidepsin first demonstrated acti vity in a National Cancer Institute (NC I) phase I 
study. [Sandor V, 2002] Three patients with cutaneous T-cell lymphoma (CTCL) 
and 1 with significant cutaneous involvement of peripheral T-cell lymphoma 
(PTCL) all demonstrated a response to romidepsin at varying dose levels (12.7 to 
17.8 mg/m2). The patient with PTCL experienced a complete remission after 8 
cycles of romidepsin. Subsequently, romidepsin was further evaluated in 135 
evaluable subjects with CTCL in Study GPI-04-0001 and NCI Study 1312. 
[Rasheed W, 2008] Across all 135 evaluable subjects with CTCL, the overall 
response rate (ORR) was 41% (55/135) and the complete response (CR) rate was 
7% (10/135). Subjects with advanced disease had a similar ORR as subjects with 
earlier stage disease: 42% for ≥ stage IIB and 38% for stage I or IIA disease. 
Romidepsin was active in all sites of disease, including skin, lymph nodes, viscera, 
and blood. The median duration of response was 454 days (14.9 months). 
Although the median time to response was 57 days (1.9 months), in some cases 
an objecti ve response to romidepsin was achieved after ≥6 months. Across all 135 
subjects included in the pooled evaluable subjects analysis set, median time to 
disease progression was 252 days (8.3 months). These data led to FDA approval 
of romidepsin for CTCL in September 2009. 
In the initial Phase 2 NC I-sponsored study in 48 subjects with PTCL or other T-cell 
lymphomas were enrolled in addition to the CTCL patients listed above. [Piekarz 
R, 2005] Among all 48 subjects, the ORR (CR+PR) was 31% (15/48). The CR and 
PR rates were 8% (4 /48) and 23% (11/48), respectively. When response was 
evaluated among the 34 subjects who received 2 cycles of therapy, the ORR was 
44% (15/34) and the CR and PR rates were 12% (4/34) and 32% (7/34), 
respectively. 
This acti vity of romidepsin in PTCL was confirmed in the multi-center Phase 2 
study  of  131  patients  with  relapsed  PTCL.  [Coiffier  B,  2011]    The  objecti ve 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 10 of 90 
 
 
 
response rate was 25% (33/130), including 15% (19/130) with CR/CRu. Response 
rates were not impacted by patient characteristics, prior stem-cell transplant, 
number or type of prior therapies, or response to last prior therapy. The median 
duration of response was 17 months, with the longest response ongoing at 34+ 
months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not progressed 
at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse 
events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 
19%).   This data led to FDA approval of romidepsin for PTCL in June of 2011. 
3.4 
Lenalidomide in B- and T-cell Lymphomas 
Lenalidomide is an IMiD® compound that has become a commonly used agent as 
a partner with rituximab or in multi-agent approaches in the treatment of B-cell 
malignancies. IMiD® compounds have both immunomodulatory 
and anti- 
angiogenic properties which confer antitumor effects. Although the exact antitumor 
mechanism of action of lenalidomide is unknown, a number of mechanisms are 
postulated to be responsible for lenalidomide‟s activity against B- and T-cell 
lymphoid malignancies. Lenalidomide has been demonstrated to possess anti- 
angiogenic activity through inhibition of bFGF, VEGF, and TNF-alpha induced 
endothelial cell migration, due at least in part to inhibition of Akt phosp horylation 
response to bFGF. [Dredge K, 2005] In addition, lenalidomide has a variety of 
immunomodulatory effects. Lenalidomide stimulates T-cell proliferation, and the 
production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and 
modulates IL-12 production. [Corral L, 1999] The increased level of these 
circulating cytokines augment natural killer cell number and function, and enhance 
natural killer cell activity to yield an increase in cell lysis. [Davies F, 2001] 
Upregulation of T cell derived IL-2 production is achieved at least in part through 
increased AP-1 acti vity. [Schafer P, 2003] 
Lenalidomide has been investigated in both relapsed and refractory indolent and 
aggressive non-Hodgkins lymphoma as well as Hodgkin lymphoma. In aggressi ve 
B-cell lymphomas, 49 patients were treated with the standard 25 mg dose taken 
orally for 21 days with 1 week rest. [Wiernik P, 2008] An ORR of 35% was seen 
with a complete response rate of 13%. Interestingly, a quarter of those who 
achieved a partial response at the time of first response assessment achieved 
further response with subsequent cycles. The toxicities were similar with a grade 4 
neutropenia and thrombocytopenia of 8.2%. In indolent B-cell lymphoma 
lenalidomide has been studied in a similar dosing and duration strategy. The 
outcomes in 43 patients yielded an ORR of 23% with 7% achieving a complete 
response. Importantly, at the time of publication the median duration of response 
had not been met, but was longer than 16.5 months. Toxicities were again 
predictable to include grade 4 neutropenia and thrombocytopenia of 16% and 5% 
respectively. [Witzig T, 2009] Lastly, lenalidomide has been studied in refractory 
and heavily pretreated cohort of 12 patients with Hodgkin lymphoma. [Boll B, 2009] 
While the main objecti ve of the study was to characterize the toxicity in this cohort 
50% of the patient did achieve an objective response. Interesti ngly, no grade 3 or 
4 toxicities were reported in this study. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 11 of 90 
 
 
 
Lenalidomide has also been studied in PTCL as a si ngle agent. A multicenter 
phase II study in relapsed PTCL lenalidomide when dosed at 25 mg orally for 21 
days of a 28-day cycle achieved an ORR of 30% with all responses being partial 
responses. [Deuck G, 2010] Grade 4 thrombocytopenia was seen in 33% of 
patients while grade 3 neutropenia was seen in 21%. Interestingly, development 
of a ski n rash was correlated with those who obtained a response. A smaller study 
of lenalidomide in PTCL, also showed a 30% ORR at the same dose and 
schedule. [Zinzani P, 2011] 
A small phase 2 study of lenalidomide in CTCL yielded a similar degree of activity. 
Among the 24 patients reported by Querfeld et al., the ORR was 32%. However, 
in these patients dose-limiting skin toxicity was seen at the 25 mg dose and dose 
de-escalation to 10 mg was performed. [Querfeld, 2011] In this study significant 
skin tumor flare may have confounded disease assessment among the CTCL 
patients resulting in premature withdrawal from study due to spurious progression. 
3.5 
Rationale for Combination Therapy 
Relapsed and refractory B- and T-cell lymphoid malignancies are a challenge 
faced daily. Current paradigms approaches led many patients down a path of 
multiple cytotoxic combination therapies in the hopes of long-term disease free 
control or used as a strategy towards chemosensitivity for stem cell 
transplantation. However, treatment limiting toxicities are often encountered and 
repeated courses of cytotoxic chemotherapy often yield diminishi ng returns. There 
remains significant need for more active therapies and combinations with many 
newer approaches investigating regimens that shift the paradigm to long term or 
maintenance treatment employing drugs without cumulative toxicity. 
In precli nical studies of Namalwa cells (derived from a Burkitt lymphoma), 
lenalidomide had synergistic effects with valproic acid (a known histone 
deacetylase inhibitor) by increasing apoptosis without adverse and potentially even 
beneficial effects on CD34+ progenitor cells. [Verhelle D, 2007] Furthermore, in 
multiple myeloma cells, a combination of lenalidomide with panobinostat, another 
HDAC inhibitor, has shown additive or greater activity in both in vitro and in vivo 
models. [Ocio E, 2007; Ocio E, 2010] The study of the combi nation of a HDAC 
inhibitor and lenalidomide are ongoing in patients with relapsed and refractory 
multiple myeloma. In two phase I dose finding studies, the oral HDAC inhibitor 
vorinostat has been safely combined with lenalidomide at the MTD and full 
standard approved doses (400 mg of vorinostat and 25 mg lenalidomide) of eac h 
drug alone without significant dose limiting toxicities [Siegel D 2009; Kaufman J 
2010; Richardson P, 2010]. 
Among novel, non-chemotherapeutic agents, lenalidomide and romidepsin have 
shown significant acti vity in a broad range of lymphoid malignancies with good 
safety profiles, absence of cumulative toxicities, and fundamentally different 
mechanisms of action than the chemotherapies to which most patients are initially 
exposed. Among the HDAC inhibitors, romidepsin has shown the most potent 
clinical activity when similar diseases have been studied. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 12 of 90 
 
 
 
We have been conducti ng a phase Ib/IIa study of lenalidomide with romidepsin 
among patients with B - and T-cell lymphomas. While the MTD has not been 
determined in this study (currently enrolling into the last cohort; full dose 
romidepsin with full dose lenalidomide), overall response rate among the patients 
evaluable for response (n=13) patients accrued in this study is 54% (n=7) with 
39% PR (n=5) and 15% CR (n=2). Responses by subtypes include 67% in T-cell 
lymphomas,  50%  in  B-cell  lymphomas,  and  33%  in  Hodgkin  lymphoma  with 
responses ongoing at >1 year. Thus far, patients have tolerated doses of 
lenalidomide 25mg with romidepsin 10mg/m2. Only one patient experienced dose 
limiting toxicity with pneumococcal bacteremia. Therefore, this combination 
appears to be a promising strategy for patients with relapsed/refractory B- and T- 
cell lymphomas. 
Additionally, there is evidence for the combination of HDAC with proteasome 
inhibitors. Studies in pancreatic cancer, ovarian cancer, melanoma, pancreatic 
cancer, lung cancer, multiple myeloma, acute lymphoblastic leukemia, primary 
effusion lymphoma have all shown in vivo, in vitro and early clinical synergy 
between HDAC and proteasome inhibitors. [Kikuchi et al 2013, Bhatt et al 2013, 
Bastian et al 2013, Huang et al 2012, Gatti et al 2012, Millward et al 2012] The 
synergy between HDAC and proteasome inhibitors is most likely dependent on a 
number of mechanisms. In multiple myeloma cell lines, the use of romidepsin in 
particular enhanced in vitro and in vivo acti vity of bortezomib. [Kikuchi et al 2010]. 
One proposed mechanism for this synergy was enhanced inhibition of the 
proteasome. In multiple myeloma cells previously exposed to a proteasome 
inhibitor, the addition of an HDAC inhibitor resulted in apoptosis through 
mitochondrial dysfunction and caspase mobilization [Pei et al. 2004]. Manipulation 
of the aggresome, an analogous protein degradation pathway, by HDAC and 
proteasome inhibitors may also disrupt protein folding leading to more defecti ve 
protein production [Hideshima, Richardson, Anderson 2011]. In combi nation, 
these pathways may disrupt cellular or microenvironment communication and 
result in apoptosis. However it is unlikely that these are the sole mechanisms for 
synergy between these classes of agents, which remains an area of intense 
investigation. 
It has been established in multiple myeloma that IMiDs and proteasome inhibitors 
are synergistic and the combination can often overcome refractory clones that 
have been previously been exposed to either class as a single agent. In hopes to 
expand on this synergy, a phase I study was conducted in patients with newly 
diagnosed multiple myeloma were treated with lenalidomide, bortezomib, 
dexamethasone with the addition of the HDAC inhibitor vorinostat. This study 
demonstrated that the regimen was efficacious with an overall response rate of 
100% amongst the evaluable patients (n=29) [Kaufman et al 2012]. In this study, 
the most common toxicities included thrombocytopenia, constipation, diarrhea, 
fatigue, nausea and neuropathy. Grade 3 or higher toxicity that occurred in 10% or 
greater patients was thrombocytopenia, fatigue, neutropenia, neuropathy or 
cardiovascular toxicity denoting a well tolerated up-front strategy. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 13 of 90 
 
 
 
Given the need for better tolerated and more active therapy for patients with 
relapsed and refractory B- and T-cell malignancies we propose a phase Ib/IIa 
study of carfilzomib, romidepsin, lenalidomide. This would be a strategy to build 
upon the data the will be produced from the currently accruing phase Ib/IIa with 
romidepsin and lenalidomide (not yet published). We believe that the addition of 
carfilzomib to romidepsin and lenalidomide will improve response rates and will be 
well tolerated. 
 
 
 
 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
We plan to perform an open label phase Ib/IIa study of patients with 
relapsed/refractory B- and T-cell lymphomas who are treated with carfilzomib, 
lenalidomide and romidepsin in a 3+3 design (see section 9.2).  The phase IIa 
portion of the study will involve a dose expansion at the MTD to better characterize 
the efficacy and to inform further disease specific studies. 
 
Phase Ib: The phase Ib portion of the study is designed to determine the MTD of 
carfilzomib, romidepsin and lenalidomide. All patients must have a relapsed or 
refractory B-cell or T-cell lymphoma. The design is a standard 3+3 dose escalation 
(Table 3) of carfilzomib, romidepsin and lenalidomide. The first cohort will enter at 
dose level 1.  For details please see section 9.2. 
 
Three patients will be initially treated in each cohort until the MTD is determined. 
If dose level 4 is achieved without DLT after 1 cycle that dose level will be deemed 
the optimal dose and the study will proceed to a phase IIa expansion cohort. 
Patients treated at MTD in the phase Ib portion will be counted towards the phase 
IIa accrual by disease subtype and also for all efficacy a nd toxicity endpoints 
unless they did not have measurable disease at point of study entry as allowed in 
the phase Ib portion. 
 
Phase IIa: The phase IIa portion will further assess the toxicity and safety and allow 
a preliminary assessment of the efficacy of the combination to provide background 
for a potential future subtype specific phase II study. The assessment of efficacy 
will be descripti ve. At the time of enrollment the patients will be identified as 
representing two cohorts based upon disease subtype: 1) B-cell lymphoma 2) T- 
cell lymphoma. Each cohort will enroll 10 patients including those treated at the 
MTD of the phase Ib portion. The assessment of toxicity and efficacy will be 
performed within the entire cohort evaluable at MTD. A preplanned exploratory 
analysis of the toxicity and efficacy of the disease specific cohorts will also be 
performed.  Efficacy measures which will be determined include ORR , TTR, DOR, 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 14 of 90 
 
 
 
and EFS. ORR is defined as the percentage of patients achieving a  best 
response of CR/Cru or PR at any disease assessment time point. TTR is defined 
as the time or number of cycles between study registration and documentation of 
first response (CR/Cru or PR). DOR is defined as the time or number of cycles 
between documentation of first response and progression, change of therapy, 
death, or date of last contact (if still alive without progression). EFS is defined as 
the time between study registration and documented progression, change in 
therapy, or death if no progression was observed. 
 
4.3 
Intervention 
 
All patients will be treated with romidepsin administered intravenously on days 1 
and 8 of a 21-day cycle. Lenalidomide will be taken orally daily for days 1-14 of a 
21-day cycle. The carfilzomib will be given weekly on days 1, and 8 of a 21-day 
cycle. Once a MTD is determined this dosing level will be used for the phase IIa 
portion. Cycles will be conti nued as above until the patient‟s wishes to be removed 
from the study, unacceptable toxicity develops, disease progression, treating 
physician recommends removal, or termination of study occurs. 
 
 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.2 
REVLIMID® 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory 
agent with anti-angiogenic properties. The empirical formula for lenalidomide is 
C13H13N3O3, and the gram molecular weight is 259.3. The chemical name is 3-(4- 
amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-2, 6-dione and it has the 
following chemical structure: 
O 
O 
H 
N 
N 
O 
 
NH2 
 
Lenalidomide is off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more 
soluble in organic solvents and low pH solutions. Solubility was significantly lower 
in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an 
asymmetric carbon atom and can exist as the optically acti ve forms S(-) and R(+), 
and is produced as a racemic mixture with a net optical rotation of zero. 
The mechanism of action of lenalidomide remains to be fully characterized. 
Lenalidomide possesses immunomodulatory and antiangiogenic properties. 
Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 15 of 90 
 
 
 
the secretion of anti-inflammatory cytoki nes from peripheral blood mononuclear 
cells. Lenalidomide inhibited cell proliferation with varying effectiveness (IC50s) i n 
some but not all cell lines. Of cell lines tested, lenalidomide was effective in 
inhibiting growth of Namalwa cells (a human B cell lymphoma cell line with a 
deletion of one chromosome 5) but was much less effective in inhibiting growth of 
KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 
5) and other cell lines without chromosome 5 deletions. Lenalidomide inhibited the 
expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro. 
 
 
 
5.1.1  Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed 
following oral 
administration with maximum plasma concentrations occurring between 0.625 and 
1.5 hours post-dose. Co-administration with food does not alter the extent of 
absorption (AUC) but does reduce the maximal plasma concentration (Cmax) by 
36%. The pharmacokinetic disposition of lenalidomide is linear. Cmax and AUC 
increase proportionately with increases in dose. Multiple dosing at the 
recommended dose-regimen does not result in drug accumulation. 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients 
treated in the phase I studies. Absorption was found to be rapid on both Day 1 
and Day 28 with time to maximum blood levels ranging from 0.7 to 2.0 hours at all 
dose levels (5mg, 10mg, 25mg, and 50mg). No plasma accumulation was 
observed with multiple daily dosing. Plasma lenalidomide declined in a 
monophasic manner with elimination half-life ranging from 2.8 to 6.1 hours on both 
Day 1 and 28 at all 4 doses. Peak and overall plasma concentrations were dose 
proportional over the dosi ng range of 5mg to 50mg. Exposure (AUC) in multiple 
myeloma patients is 57% higher than in healthy male volunteers. 
 
 
5.1.2 Pharmacokinetic Parameters: 
Distribution: 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
Metabolism and Excretion: 
The metabolic profile of lenalidomide in humans has not been studied. In healthy 
volunteers, approximately two-thirds of lenalidomide is eliminated unchanged 
through urinary excretion. The process exceeds the glomerular filtration rate and 
therefore is partially or entirely active. Half-life of elimination is approximately 3 
hours. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 16 of 90 
 
 
 
Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at 
no charge through Celgene‟s Revlimid Risk Evaluation and Mitigation Strategy™ 
(REMS). 
Revlimid REMS Dosage form 
Lenalidomide will be supplied as capsules for oral administration. 
 
Packaging 
Lenalidomide will be delivered to the center where the prescription will be filled 
and dispensed. Bottles will contain a sufficient number of capsules for one cycle of 
dosing. 
Labeling 
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. 
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold. 
Special Handling Instructions 
Females of childbearing potential should  not handle or administer lenalidomide 
unless they are wearing gloves. 
Unused study drug supplies 
Celgene will instruct the Investigator 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 cli nical site 
pending instructions for disposition by Celgene. Patients will be instructed to  
return empty bottles or unused capsules to the cli nic site. 
 
5.1.3 Prescribing Information 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of 
their participation in this trial at no  charge  to  them  or  their  insurance 
providers. Lenalidomide will be provided in accordance with the Revlimid REMS® 
program of Celgene Corporation. Lenalidomide will be delivered   to  the center 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 17 of 90 
 
 
 
where the prescription will be filled and dispensed. Per standard Revlimid REMS® 
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. Prescriptions must be filled within 14 days, unless the patient is a female 
of childbeari ng potential, in which case the prescription must be filled within 7 
days. Only enough lenalidomide for one cycle of therapy will be supplied to the 
patient each cycle. 
5.2     Romidepsin 
Romidepsin (ISTODAX®) is a unique bicyclic depsipeptide originally isolated from 
Chromobacterium violaceum strain 968. [Ueda H, 1994] Romidepsin is an 
antineoplastic agent that has been identified as a novel HDAC inhibitor. 
Romidepsin has been shown to induce hyperacetylation of histones and other 
nonhistone protein species resulting in a variety of phenotypic changes, induction 
of the upregulation of gene transcription, G1 and G2/M arrest of the cell cycle, 
morphological reversion of transformed cells, cell growth inhibition, apoptotic cell 
death, and inhibition of angiogenesis. 
 
 
 
CH3  HN 
H 
O 
 
S HN 
 
 
CH3 
H3C 
O H 
O S 
NH 
HN  
O 
H 
O 
CH3 
 
H 
O 
CH3 
The molecular formula of romidepsin is C24H36N4O6S2, its molecular weight is 540.71, 
and 
its 
chemical 
name 
is: 
(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1- 
methyletheyl)-2-oxa12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene- 
3,6,9,19,22-pentone. 
 
In both in vitro and in vivo systems, romidepsin has been shown to elicit a range of 
biological activities, including HDAC inhibition, induction or repression of gene 
expression, cell cycle arrest, differentiation, cell growth inhibition, apoptotic cell death, 
morphological reversion of transformed cells, and inhibition of angiogenesis. The 
manner in which romidepsin and other HDAC inhibitors exert their biological effects 
has not been fully elucidated. The current view is that these agents inhibit, to a 
greater or lesser extent, the activity of Class I (HDACs 1, 2, 3, 8), Class II (HDACs 4, 
5, 6, 7, 9, 10), and Class IV (HDAC 11) HDACs, causi ng chromatin remodeling and 
altered gene expression, which results in biological effects that are deleterious to 
tumor cell growth and survival.   There is a growing body of evidence that HDAC 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 18 of 90 
 
 
 
inhibitors can also target substrates other than histones and that the posttranslational 
modification of cellular proteins by acetylation may play an important role in the 
biological activities of HDAC inhibitors. 
 
5.2.1 Dosage Form 
 
The lyophilized, sterile finished product contains romidepsin, 10 mg/vial and 20 
mg/single use vial Povidone, USP, and hydrochloric acid to adjust pH. Romidepsin 
(for infusion) is supplied in a dual-pack configuration with a single use diluent for 
romidepsin vial that contai ns 2 mL of 80% Propylene Glycol, USP, and 20% 
Dehydrated Alcohol (ethanol), USP; steri le for use in reconstitution of romidepsin (for 
Infusion). 
 
5.2.2 Storage and Handling 
 
The dual pack is to be stored at 20 to 25ºC (68 to 77°F), excursions permitted 
between 15 to 30°C (59 to 86°F) [USP controlled room temperature]. Romidepsin 
(for infusion) is stable for at least 36 months at 25°C/60% relative humidity (RH) as 
well as for 6 months at 40°C/75% RH and is stable against heat (for 3 months at 
50°C) and humidity (for 3 months at 25°C/83% RH). Appropriately trained personnel 
using aseptic technique should reconstitute the drug. A volume of 2 mL of 
reconstitution diluent is added to the lyophilized powder and swirled until contents of 
the vial are free from visible particles. The reconstituted product stock solution at 5 
mg/mL is chemically stable for at least 8 hours at room temperature. However, 
whenever possible, drug should be prepared within 4 hours of dose administration. A 
volume of the 5 mg/mL stock solution contai ning the appropriate dose for the patient 
will be diluted in 0.9% Sodium Chloride Injection, USP (0.9% sali ne) for intravenous 
infusion, as directed by the protocol. This dilution should result in a final drug 
concentration within the demonstrated stability range of 0.02 to 0.16 mg/mL for 
reconstituted romidepsin, that is compatible with polyvinyl chloride (PVC), ethylene 
vinyl acetate (EVA), and polyethylene (PE) intravenous infusion bags; glass bottles 
may also be used.  The romidepsin infusion solution is chemically stable for at least 
24 hours at room temperature. However, whenever possible, drug should be 
prepared within 4 hours of dose administration. 
Supplier(s) 
Celgene Corporation will supply ISTODAX® (romidepsin) to study participants at no 
charge. 
 
5.2.3 
DRUGS DISPENSATION AND ACCOUNTABILITY 
 
The clinical trial supplies of romidepsin will be provided in a dual pack containing one 
vial of romidepsin for injection and one vial of diluent. The drug vial will contain a 
lyophilized powder of 10 mg of lyophilized romidepsin and 20 mg of povidone, USP 
(used as a bulking agent). The diluent vial will contai n 2 mL of a 4:1 mixture of 
propylene  glycol  and  ethanol.  Appropriately  trained  personnel  using  an  aseptic 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 19 of 90 
 
 
 
technique should reconstitute the drug. A volume of 2 mL of diluent should be added 
to the lyophilized powder and swirled until contents of the vial are free from visible 
particles. This provides a stock solution at 5 mg/mL. The stock solution will be diluted 
using aseptic technique in 500 mL 0.9% Sodium Chloride Injection, USP (0.9% 
saline) for patients with a body surface area (BSA) ranging from 1.35 to 2.79 m² and 
in 1000 mL 0.9% sali ne for patients with a BSA of 2.8 m². Reconstituted drug in 
saline is compatible with PVC, EVA, and PE IV infusion bags as well as g lass bottles. 
The vials containi ng the investigational product and the kits they are packaged in will 
be labeled according to the Good Manufacturing Practice guidelines and the local 
requirements 
Special Handling Instructions 
 
Females of childbearing potential should not handle or administer romidepsin unless 
they are wearing gloves. 
 
Record of Administration 
 
Accurate records will be kept in the source documents of all drug administration 
(includi ng prescribing and dosing). 
 
5.3 
Carfilzomib 
Carfilzomib (trade name Kyprolis®) is an analog of epoxomicin and eponemyci n, a pair 
of related natural products that were initially discovered as antitumor agents in animals, 
and later shown to inhibit the chymotrypsi n-like (CT-L) acti vity of the 20S proteasome. 
 
Carfilzomib, atetrapeptide epoxyketone proteasome inhibitor, was FDA approved for the 
treatment of relapsed and refractory multiple myeloma. Carfilzomib is a potent, selecti ve, 
and irreversible inhibitor of the CT-L acti vity of the constituti ve proteasome (the form of 
proteasome found in most cell types) and the immunoproteasome (the form of 
proteasome found in many hematopoietic cells) . In studies comparing carfilzomib to 
bortezomib, both were found to inhibit the CT-L acti vity of the proteasome with 
comparable potency [Demo 2007]. 
 
Incubation of tumor cells in culture with carfilzomib results in rapid and sustai ned  
inhibition of proteasome activity, accumulation of polyubiquiti nated proteins, and induction 
of apoptosis [Demo 2007]. The period of time required to induce apoptosis varies among 
tumor cell types and is a function of the depth and duration of proteasome inhibition, with 
cells derived from hematological tumors being the most sensitive to brief periods of 
proteasome inhibition. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 20 of 90 
 
 
 
 
 
 
The molecular formula of carfilzomib is C40H57N5O7 and its molecular weight is 719.9.  It‟s 
chemical name is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2- 
ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4- 
methylpentanamide.. 
 
Intravenous administration of carfilzomib in humans over 2 to 10 minutes results in 
suppression of proteasome CT-L activity when measured in blood 1 hour after the first 
dose. Inhibition of proteasome CT-L acti vity was comparable in whole blood and PBMCs. 
Proteasome inhibition was maintained in whole blood following the first dose of 
carfilzomib for each week of dosing, with 30-minute and bolus infusions. 
 
5.3.1 Pharmacokinetic Parameters 
Following intravenous administration of doses ≥ 15 mg/m2, carfilzomib was rapidly 
cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1. The 
systemic clearance ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, 
suggesti ng that carfilzomib was largely cleared extrahepatically. The pathways of 
carfilzomib elimination have not been characterized in humans. [Onyx 2013] 
 
 
5.3.2 Dose Administration 
 
• Carfilzomib will be diluted in 100 mL D5W and administered over approximately 30 
minutes. 
 
• The dose is calculated using the patient‟s actual body surface area (BSA) at 
baseline. Patients with a BSA greater than 2.2 m2 should receive a dose based upon 
a BSA of 2.2 m2. Dose adjustments do not need to be made for weight changes of 
less than or equal to 10%. Carfilzomib may be rounded according to local 
institutional rounding guidelines. 
 
• Prior to each dose of carfilzomib in Cycle 1, give 250  IV normal sali ne or other 
appropriate IV fluid before and after carfilzomib administration. At the discretion of 
the treating physician, give an additional 250 mL to 500 mL of IV fluids as needed 
following carfi lzomib administration. Fluids associated with Romidepsin infusion 
count toward the 250 mL to 500 mL total volume and may be used as prehydration 
for carfilzomib . Continue IV hydration, as needed, in subsequent cycles. In patients 
with chronic kidney disease or history of congesti ve heart failure, one may consider 
holding hydration in addition to the romidepsin volume. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 21 of 90 
 
 
 
• With cycle 1, pre-medicate with dexamethasone 4 mg PO or IV prior to all doses of 
carfilzomib. Additionally, if dose escalating, please also plan to premedicate with 
dexamethasone 4mg PO or IV to reduce the incidence and severity of infusion 
reactions. Reinstate dexamethasone premedication (4 mg PO or IV) if these 
symptoms develop or reappear during subsequent cycles. Dexamethasone 
premedication dosing has been increased to 8 mg PO or IV in clinical trials where 
the carfilzomib dose has exceeded 45 mg/m2. 
• It is preferred that carfilzomib is given after romidepsin. 
• The Initial dose of carfi lzomib given to any given patient (cycle 1, day 1) will be 
20mg/m2 regardless of the dose level. Subsequent doses will be based on the 
patient‟s dose level. 
 
5.3.3 Storage and Handling 
Carfilzomib for Injection is supplied as si ngle-use vials contai ning a dose of 60 mg of 
carfilzomib as a white to off-white lyophilized cake or powder. Carfilzomib vials contain no 
antimicrobial preservati ves and are intended only for si ngle use. 
 
Unopened vials of carfilzomib are stable until the date indicated on the package when 
stored in the original package at 2 °C to 8°C (36°F to 46°F). Retain carfilzomib in the 
original package to protect from light. The reconstituted solution contains carfi lzomib at a 
concentration of 2 mg/mL. 
 
5.3.4 Supplier 
Onyx will supply carfilzomib to patients at no additional charge. 
5.3.5 DRUGS DISPENSATION AND ACCOUNTABILITY 
Special Handling Instructions 
Females of childbearing potential should not handle or administer carfilzomib unless they 
are wearing gloves. 
 
Record of Administration/Accountability 
Accurate records will be kept in the source documents of all drug administration (including 
prescribing and dosing). 
Each site will also maintain records of each shipment of investigational product. The 
records will document shipment dates, method of shipment, batch numbers, and quantity 
of vials contained in the shipment. Upon receipt of the investigational product, the 
designated recipient at the study site will inspect the shipment, verify the number and 
condition of the vials, and prepare an inventory or drug accountability record. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 22 of 90 
 
 
 
Empty and partially used vials should be accounted for and destroyed at the study site in 
accordance with the internal standard operating procedures. Drug destruction records 
must be readily available for inspection by representati ves of Onyx and by regulatory 
authorities. 
Only sites that cannot destroy unused drug on-site will be required to return their unused 
supply of investigational product. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
a) 
Pathologically confirmed B- or T-cell lymphomas at the enrolling institution, 
including stage ≥ Ib  CTCL, which has relapsed or progressed after at least 
one systemic therapy. 
• Hodgkin lymphoma is allowed and will be classified as a B-cell 
lymphoma in the phase IIA portion. 
b) 
Age ≥ 18, 
c) 
Previous systemic anti-cancer therapy must have been discontinued at least 
3 weeks prior to treatment and adverse effects must have resolved to ≤Grade 
1 or baseli ne.  In the phase IIa portion, in progressing subjects a 2 week 
washout may be allowed after discussion with the MSK Principal Investigator. 
d) 
Previous radiation, hormonal therapy, and/or surgery must have been 
discontinued or completed at least 2 weeks prior to treatment in this study 
and adverse effects must have resolved. Lymph node or other diagnostic 
biopsies within 2 weeks are not considered exclusionary. 
e) 
ECOG ≤ 2 
f) 
Meet the following laboratory criteria: 
• Absolute neutrophil count  1.0/mm³, 
• Platelet count  80 K/µ (in the Phase IIa portion, if thrombocytopenia is 
due to bone marrow involvement platelet count must be  50 K/µL), 
• Phase Ib subjects must have calculated creati nine clearance  50ml/min 
by Cockcroft-Gault formula, phase IIa subjects must have calculated 
creatini ne clearance ≥ 40ml4/min by Cockcroft-Gault formula. 
• Total bilirubin  1.5 x upper limit of normal (ULN). AST (SGOT) and ALT 
(SGPT)  3 x ULN. 
g) 
Measurable disease for phase IIa portion only. 
• Lymphoma (includes CTCL patients who are without evidence of the 
disease in the ski n): CT or PET/CT by modified Cheson criteria with 
incorporation of PET. 
• CTCL: mSWAT >0, or absolute Sezary count ≥ 1000 cells/µL. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 23 of 90 
 
 
 
h) 
All study participants must be registered into the mandatory Revlimid REMS® 
program, and be willing and able to comply with the requirements of the 
REMS® program. 
i) 
Short course systemic corticosteroids for disease control, improvement of 
performance status or non-cancer indication (< 7 days) must have been 
discontinued at least 6 days prior to study treatment. Stable ongoing 
corticosteroid use (≥ 30 days) up to an equivalent dose of 15 mg of 
prednisone is permissible. 
• Topical steroids that have been used for > 3 weeks may be conti nued 
(CTCL only). 
j) 
Women of reproducti ve potential† must adhere to the scheduled  pregnancy 
testing as required in the Revlimid REMS® program. Men must agree to use 
a latex condom during sexual contact with a FCBP even if they have had a 
successful vasectomy. See Appendix A: Risks of Fetal Exposure, Pregnancy 
Testi ng Guidelines and Acceptable Birth Control Methods. 
 
† A female of reproducti ve potential is a sexually mature female who: 
1)  has not undergone a hysterectomy or bilateral oophorectomy; or 
has not been naturally postmenopausal for at least 24 consecuti ve 
months (i.e. has had menses at any time in the preceding 24 
consecuti ve months). 
 
6.3 
Subject Exclusion Criteria 
 
a) 
Patients who have a standard curative option for their lymphoid malignancy at 
current state of disease are e xc luded. For eligibility on this trial, allogeneic 
stem cell transplantation is not to be considered a standard curative option. 
b) 
Any serious medical condition, laboratory abnormality, or psychiatric illness 
that would prevent the subject from signing the informed consent form. 
c) 
Pregnant females. (Lactati ng females must agree not to breast feed while 
taking carfilzomib, lenalidomide or romidepsin). 
d) 
Known hyperse nsiti vity to thalidomide. 
e) 
The development of erythema multiforme if c haracteri zed by a desquamati ng 
rash while taking thalidomide or similar drugs. 
f) 
Prior use of lenalidomide if discontinued due to toxicity. 
g) 
Prior therapy with romidepsin if discontinued due to toxicity. 
h) 
Prior therapy with carfilzomib if disconti nued due to toxicity. 
i) 
Prior therapy with a proteasome inhibitor if discontinued due to toxicity. 
j) 
Concurrent use of other anti-cancer agents or treatments. 
k) 
Known seropositive and requiring anti-viral therapy for human 
immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus 
(HCV). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 24 of 90 
 
 
 
l) 
Concurrent malignancy requiring acti ve therapy. 
• Patients with more than one type of lymphoma may be enrolled after 
discussion with the  MSK Principal Investigator. 
m) 
Known central nervous system or meningeal involvement (in the absence of 
symptoms investigation into central nervous system involvement is not 
required). 
n) 
The following known cardiac abnormalities: 
1. Congenital long QT syndrome. 
2. QTc/QTf interval ≥ 480 milliseconds; unless secondary to pacemaker or 
bundle branch block. 
3. Myocardial infarction within 6 months of cycle one, day one 
(C1D1). Subjects with a history of myocardial infarction between 6 and 
12 months prior to C1D1 who are asymptomatic and have had a 
negative cardiac risk assessment (treadmill stress test, nuclear medicine 
stress test, or stress echocardiogram) si nce the event may participate. 
4. Other significant ECG abnormalities including 2nd degree atrio- 
ventricular (AV) block type II, 3rd degree AV block. 
5. Symptomatic coronary artery disease (CAD), e.g., angina Canadian 
Class II-IV (see Appendix B). In any patient in whom there is doubt, the 
patient should have a stress imaging study and, if abnormal, 
angiography to define whether or not CAD is present. 
6. An ECG recorded at screening showing evidence of cardiac ischemia 
(ST depression of ≥2 mm, measured from isoelectric line to the ST 
segment).  If in any doubt, the patient should have a stress imaging 
study and, if abnormal, angiography to define whether or not CAD is 
present. 
7. Congestive heart failure (CHF) that meets New York Heart Association 
(NYHA) Class II to IV definitions (see Appendix C) and/or ejection 
fraction <45% by echocardiogram, or cardiac MRI. 
8. A known history of sustained ventricular tachycardia (VT), ventricular 
fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently 
addressed with an automatic implantable cardioverter defibrillator 
(AICD). 
9. Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior 
treatment or other causes. 
10. Uncontrolled hypertension, i.e., blood pressure (BP) of ≥170/95; patients 
who have a history of hypertension controlled by medication must be on 
a stable dose (for at least one month) and meet all other inclusion 
criteria. 
11. Any cardiac arrhythmia requiring an anti-arrhythmic medication 
(excluding stable doses of beta-blockers) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 25 of 90 
 
 
 
12. Patients taking drugs that can cause  significant QTc/QTf prolongation, 
unless able to be switched to non-QTc/QTf prolonging medication or on 
a stable dose without significant QT prolongation (>470 msec) 
13. Concomitant use of significant C YP3A4 inhibitors unless able to be 
switched to a non-C YP3A4 inhibiting medication.. 
 
• 
Caution should be used when administeri ng study drugs to 
patients taking medications significantly metabolized by these 
enzymes refer to (http://medicine .iup ui.ed u/c linp harm/ddis/cli nical-  
table/ ) for clinically relevant medications  Particular attention 
should be paid to patients recei ving warfarin. Patient should have 
coagulation paramaters monitored regularly, and warfarin dose 
adjusted accordingly.  If these drugs cannot be disconti nued or 
replaced, enrollment may be allowed after discussion with MSK PI. 
 
7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by a member of the patient‟s 
treatment team, the protocol investigator, or research team. If the investigator is a 
member of the treatment team, s/he will screen their patient‟s medical records for 
suitable research study participants and discuss the study and their potential for 
enrolling in the research study. Potential subjects contacted by their treating 
physician will be referred to the investigator/research staff of the study. 
Furthermore, eligible patients from the lymphoma or myeloma service will be 
identified by individual consenti ng physicians at the time of medical disciplinary 
rounds or in clinic at Memorial Sloan Kettering Cancer Center or the University of 
Nebraska Medical Center. 
 
 
8.1 
PRETREATMENT EVALUATION 
 
8.2 Documentation of tests resulted and/or verification to be performed within 28 
days of starting treatment. 
 
1. Record prior medications and treatments 
2. Record prior anti-cancer therapy 
3. Physical examination 
4. ECOG performance status 
5. 12 lead ECG 
6. ECHO or Cardiac MRI 
7. Complete metabolic panel, including magnesium and phosphorus 
8. Lactate dehydrogenase (LDH) 
9. PET/CT or CT Chest, Abdomen, and Pelvis 
10. Register patient with Revlimid REMS® program. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 26 of 90 
 
 
 
11. mSWAT for patient with cutaneous lymphoma. 
12. Sezary panel in patients with Sezary syndrome only. 
o Sezary panel: peripheral blood flow cytometry includi ng CD2, CD3, CD4, 
CD8, CD26 and or CD7 
13. Phase  IIa  only:  patients with  suspected  or  known  prior  bone  marrow 
involvement must have a bone marrow biopsy performed. 
14. Pregnancy testing for females of childbearing potential within 10-14 days and 
again 24 hours prior to prescribing lenalidomide per the Revlimid REMS® 
program. 
 
 
8.3 Documentation of tests resulted and/or verification to be performed within 14 
days of starting treatment. 
• Complete blood count (CBC) 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 
Pretreatment electrolyte assessment and drug management 
Prior to initiation of each dose of romidepsin in cycle 1 and cycle 2 the patients level 
of potassium (K+) and magnesium (Mg) must be confirmed to be greater than or 
equal to the lower limit of normal for the testi ng laboratory, or corrected to those 
levels. In cycle 3 and beyond, magnesi um and potassi um levels may be checked 
up to 3 days before romidepsin. If within treatment range they do not need to be 
repeated prior to romidepsin administration. Intravenous (IV) supplementation with 
potassium 
chloride 
(KCL) and/or 
magnesium 
sulfate 
can be 
used. If 
supplementation is necessary, documentation of levels after IV supplementation is 
required. Supplementation with oral KCL or magnesium oxide (MgOX) or 
magnesium soy (MgSoy) can be used. These parameters apply to both the phase 
Ib and IIa portion of the study. 
9.3 
Treatment plan carfilzomib/romidepsin/lenalidomide Phase Ib 
 
9.3.1 
Lead-in Dose 
The initial dose of carfilzomib (cycle 1, day 1) given to any patient regardless of 
dose level must be 20mg/ m2 . All subsequent doses of carfilzomib will be based 
on the patient‟s dose level. 
9.3.2 
Dose Escalation 
Subjects enrolled into the phase 1b portion will enroll at dosing level 1 with three 
patients per dosi ng level (3+3 design).  A cycle will be 21-days.  Based on toxicity 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 27 of 90 
 
 
 
and activity seen during the phase Ib portion, additional dose levels and/or alternate 
28 day cycle may be explored through an amendment. The carfilzomib will be 
given intravenously weekly on days 1 and 8. The romidepsin will be given 
intravenously on days 1 and 8. The lenalidomide will be given as a once a day oral 
drug given on days 1-14. It is preferred that romidepsin be administered prior to 
carfilzomib. 
 
 
 
 
TABLE 1: Phase I Dose Escalation 
Dose 
Level 
Romidepsin 
Lenalidomide 
Carfilzomib 
(mg/m2) 
-1 
8 mg/m2 
10 mg 
20 
1 
8 mg/m2 
15 mg 
36 
2 
8 mg/m2 
15 mg 
45 
3 
10 mg/m2 
20 mg 
45 
4 
10 mg/m2 
20mg 
56 
 
If all three patients complete one cycle of therapy without a DLT at the respecti ve 
dose level then the subsequent dose level can be accrued. 
A DLT is defined in cycle 1 of the phase I portion as: 
• Non-hematologic toxicity of grade ≥3 (attributed to study drugs with the 
exception of alopecia , nausea, or grade ≥3 vomiting not responsive to 
antiemetics) 
• 
Hematologic grade 4 toxicity (attributed to study drugs) defined as grade 4 
thrombocytopenia of any duration; grade 4 neutropenia lasti ng more than 5 
days; or grade 4 anemia unexplained by the underlying disease 
• 
Grade ≥3 thrombocytopenia with cli nically significant bleeding 
• 
Febrile neutropenia of any duration (ANC <1.0K/ µL with fever 38.5oC) 
• 
Inability to receive day 1 of cycle 2 due to conti nued drug-related toxicity 
including Grade ≥ 2 toxicity that does not resolve to Grade ≤ 1 by the start of 
the next cycle. 
• 
Grade 3 thrombocytopenia or neutropenia (attributed to study drug) within 
cycle 1 that results in a) ≥ 4 day delay in any romidepsin or carfilzomib dose 
or b) missing greater than 4 days of lenalidomide. (This criteria only applies 
to the phase Ib portion and does not apply to the phase IIa stoppi ng rules). 
 
After the MTD is determined by either DLT or accrual of si x patients without DLT at 
dose level 4 in the first cycle accrual to the phase Ib portion will be considered 
closed. The MTD from the phase Ib study will be used for the phase IIa portion. 
Of note, only patients who complete ≥80% of the doses of carfilzomib, romidepsin 
and lenalidomide during the first cycle will be evaluable for MTD.  Patients who do 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 28 of 90 
 
 
 
not meet this criteria for minimum drug exposure and do not have a dose limiting 
toxicity will be replaced for determination of MTD. 
 
The treatment plan is described below for the phase Ib portion: 
• Romidepsin/Lenalidomide/Carfilz omib:  Romidepsin IVPB over 4  hours 
on days 1 and 8 
• Carfilzomib IVPB administered over approximately 30 minutes on days 1 
and 8** 
• Lenalidomide PO q days 1-14 
 
 
**1 cycle equals 21 days 
Patients will be treated until progression of disease, unacceptable toxicity, patient 
or physician choice or study closure. The study will remain open until all patients 
have discontinued therapy or 1 year from the last enrollee, whichever comes first . 
If a patient is respondi ng past the timeline listed above, the MSK Principal 
Investigator may decide to keep the trial open. 
 
Of note, if patient‟s experiences a greater than 10% change in body weight, dose 
of romidepsin and carfilzomib should be adjusted accordi ngly. Doses do not need 
to be adjusted for less than 10% changes in body weight. 
 
a. Treatment Plan: carfilzomib/romidepsin/lenalidomide Phase IIa 
The phase IIa portion is planned to include 20 patients. Each disease cohort, B- 
and T-cell lymphoma, will have 10 patients. Patients treated at MTD in the phase 
Ib cohort (if measurable disease at enrollment) will be included towards the 20 
patient total in the phase IIa. The MTD has been determined to be dose level 1; 8 
mg/m2 romidepsin on days 1 and 8, 15 mg lenalidomide from days 1 - 14, and 36 
mg/m2 carfilzomib on days 1 and 8. The phase IIa cohort will be evaluated both 
collecti vely and by disease subtype. 
 
Patients that have received long-term therapy (greater  than  one 
year) with response will be allowed to have their schedule modified 
to allow less frequent dosing per investigator and primary 
investigator discretion. 
b. 
Lenalidomide administration 
In either phase of the study patients will be asked to take the lenalidomide at 
approximately the same time each day.  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. A medication diary will be provided to the patient 
and asked to be returned prior to each cycle [See Appendix G]. Any pills not used 
must be returned and all pills must be accounted for. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 29 of 90 
 
 
 
Patients who take more than the prescribed dose of lenalidomide should be 
instructed to seek emergency medical care if needed and contact study staff 
immediately. 
9.4 
Prophylactic Measures 
• Subjects should receive prophylactic anti-emetics prior to romidepsin and 
carfilzomib administration (ondansetron preferred). 
• Subjects should receive dexamethasone 4mg PO or IVPB prior to the first two 
cycles of carfi lzomib. Dexamethasone is optional for the subsequent cycles. 
• G-CSF may be given at the discretion of the treating physician. 
• Subjects should be taki ng prophylaxis against varicella zoster per the 
institutional guidelines (e.g. acyclovir 400mg by mouth twice daily) while on this 
regimen. 
9.5 
Concomitant Medications 
 
Patients will be instructed not to take any additional medications (including over- 
the-counter products) during the trial without prior consultation with their treating 
physician. All medications taken within 30 days of screeni ng and medications and 
supporti ve therapies that are administered during the study must be recorded in 
the electronic Case Report Forms (eCRFs) and in the source documents. 
Supportive therapy, that is ongoing at baseline, will be permitted during the 
treatment phase of the study. If other  therapy  for  the  disease  is  required, 
conti nuation of the study treatment should be discussed with the MSKPrincipal 
Investigator. Concomitant medications for other medical conditions are permitted 
as clinically indicated subject to specific protocol requirements outlined below. 
9.5.1 Prohibited/monitored concurrent therapy 
• Any investigational agent other than lenalidomide or romidepsin. 
• Any medications at high risk of causing QTc/QTf prolongation or inducing 
torsades de pointes (as listed in Appendix E). 
• Concomitant use of C YP3A4 inhibitors with romidepsin should be avoided 
(excluding anti-emetics) to prevent potential increase in romidepsin 
exposure during concomitant treatment with these drugs. Should a patient 
already enrolled on this study require treatment with a drug listed in 
Appendix F romidepsin must be interrupted prior to starting these drugs 
and should not resume until a washout period of at least 5 half-lives has 
elapsed. 
Any medications that have the potential to alter serum electrolytes (e.g., diuretics) 
should be monitored very closely for electrolyte abnormalities as these can 
contribute to the risk of QTc/QTf prolongation and ventricular arrhythmias. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 30 of 90 
 
 
 
9.5 
Dose Continuation, Modification and Interruption 
Subjects will be evaluated for AEs at each visit with the NCI CTCAE v4.0 used as 
a guide for the grading of severity. DLTs as defined will be tabulated in cycle 1 of 
phase Ib and cycles 1-4 of the phase IIa portion of the study. The toxicity decision 
rule for the IIa portion is described in Section 14.0. The sections below describe 
dose reduction steps, instructions for initiation of a new cycle of therapy and dose 
modifications during a cycle of therapy. Of note, if patient‟s experiences a greater 
than 10% change in body weight, dose of romidepsin should be adjusted 
accordingly. Doses do not need to be adjusted for less than 10% changes in body 
weight. 
 
9.5.1 Instructions for Dose Modifications or Interruption During Phase 1 
Cycle 1 
There will be no dose reductions in cycle 1 phase 1. Inability to meet treatment 
criteria will result in holding the dose. 
 
9.5.2 Instructions for Dose Modifications or Interruption During Phase 1 
Cycle 2 and beyond and phase 2 all cycles 
Dose delay and dose reduction rulesare as follows and in the table below. The 
following dose modification criteria are applicable to adverse events related to 
study drugs: 
• In the event of dose reduction due to toxicity all agents will be reduced as per 
Table 2, 3, 4. If an agent is already at its lowest dose per tables 2,3,4 then the 
other agents will be reduced. If the lowest doses are not tolerated the subject 
will be removed from the study. 
• For treatment interruptions during a cycle, the 21-day schedule of each cycle 
will continue to be followed. Missed doses of lenalidomide, carfilzomib and 
romidepsin are not made up. For treatment interruptions that delay the 
scheduled start of a new cycle, when toxicity has resolved as required to allow 
the start of a new cycle, the restart day of therapy becomes Day 1 of the next 
cycle. 
• 
If a patient is at the lowest dose level and deriving benefit from therapy, they 
may continue on protocol therapy despite ≥ grade 3 hematologic toxicity or 
non-clinically significant non-hematologic toxicity after discussion with the MSK 
principal investigator. A delay of planned study therapy of greater than 21 days 
with result in removal from study. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 31 of 90 
 
 
 
 
TABLE 2: Lenalidomide Dose Modification Steps 
Current Lenalidomide Dose 
One Level Dose Reduction 
20 mg daily on Days 1-14 every 21 days 
15 mg daily on Days 1-14 every 21 days 
15 mg daily on Days 1-14 every 21 days 
10 mg daily on Days 1-14 every 21 days 
10 mg daily on Days 1-14 every 21 days 
5 mg daily on Days 1-14 every 21 days 
 
 
TABLE 3: Romidepsin Dose Modification Steps 
Current Romidepsin Dose 
One Level Dose Reduction 
10 mg/m
2 daily on Days 1,8 
8 mg/m
2 daily on Days 1,8 
8 mg/m
2 daily on Days 1,8 
5 mg/m
2 daily on Days 1,8 
5 mg/m2 daily on Days 1,8 
5 mg/m2 daily on Days 1 
Carfilzomib Dose Modification Steps 
Current Carfilzomib Dose 
One Level Dose Reduction 
56 mg/m2 
45 mg/m
2
 
45 mg/m2 
36 mg/m2 
36mg/m2 
20 mg/m2 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 32 of 90 
 
 
 
 
TABLE 4: Dose Modifications for Lenalidomide, Carfilzomib and Romidepsin for Phase 1 cycle 2 and 
beyond/ Phase 2 all cycles 
NCI CTC Toxicity Grade 
Dose Modification Instructions 
(also see Instructions for Initiation of a New Cycle above) 
 
 
 
 
≥Grade 3 neutropenia not 
associated with fever 
• 
If found on the day of romidepsin and/or carfilzomib treatment hold 
(interrupt) lenalidomide, carfilzomib and romidepsin dose. 
• 
Follow CBC at least weekly until recovery 
• 
Treatment with romidepsin/carfilzomib and lenalidomide 
may be resumed if ANC recovers to ≤ grade 2 neutropenia 
within 4 days of a planned dose (with or without G-CSF). 
• 
If ANC does not recover to ≤ grade 2 within 4 days, dose is 
missed and not made up. Reduce one dose level upon 
resolution of neutropenia to ≤ grade 2. 
• 
If found on days between romidepsin and carfilzomib dosing, 
lenalidomide may be held and G-CSF may be used at the discretion 
of the treating physician. 
 
 
≥Grade 3 
neutropeniaassociated with 
fever (temperature ≥ 38.5º C) or 
Grade 4 neutropenia 
• 
Hold (interrupt) lenalidomide, carfilzomib and romidepsin dose. 
• 
Follow CBC at least weekly until recovery. 
• 
If neutropenia has resolved to ≤ grade 2 prior to Day 14 of the current 
cycle, restart lenalidomide, carfilzomib and romidepsin at next lower 
dose level and continue through the scheduled Day 14 of the current 
cycle. Otherwise, omit for remainder of cycle and reduce the dose of 
lenalidomide, carfilzomib and romidepsin by 1 dose level at the start 
of the next cycle.  Omitted doses are not made up. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 33 of 90 
 
 
 
 
TABLE 4: Dose Modifications for 
beyond/ Phase 2 all cycles 
Lenalidomide, Carfilzomib and Romidepsin for Phase 1 cycle 2 and 
NCI CTC Toxicity Grade 
Dose Modification Instructions 
(also see Instructions for Initiation of a New Cycle above) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
≥  Grade  3 
(platelet count < 50,000/mm³) 
• 
If found on the day of romidepsin and/or carfilzomib treatment, hold 
(interrupt) lenalidomide, carfilzomib and romidepsin dose. 
• 
Follow CBC at least weekly. 
• 
Treatment with romidepsin/carfilzomib and lenalidomide 
may be resumed if thrombocytopenia recovers to ≤ grade 2 
thrombocytopenia within 4 days of a planned dose. 
• 
If thrombocytopenia does not recover to ≤ grade 2 within 4 
days, dose is missed and not made up. Reduce one dose 
level upon resolution of thrombocytopenia to ≤ grade 2. 
• 
If grade 3 thrombocytopenia found on the days between romidepsin 
and/or carfilzomib treatment, lenalidomide may be held at the 
discretion of the treating physician. 
• 
If grade 4 thrombocytopenia found on the days between romidepsin 
and/or carfilzomib treatment, hold lenalidomide 
• 
Follow CBC at least weekly. 
• 
If thrombocytopenia resolves to ≤ grade 2 prior to Day 14 
of the current cycle, lenalidomide may be restarted at the 
same dose level. Otherwise, omit for remainder of  the 
cycle and reduce the dose of romidepsin, carfilzomib, and 
lenalidomide by 1 dose level at the start of the next cycle. 
Omitted doses are not made up. 
• 
Hold prophylactic anti-coagulation, if applicable. 
• 
Restart prophylactic anti-coagulation when platelet count is ≥ 
50,000/mm³. 
• 
Platelet transfusion solely to meet treatment criteria are discouraged 
but may be considered after discussion with the MSK PI. 
Non-blistering rash 
Grade 3 
 
 
Grade 4 
• 
If Grade 3, hold (interrupt) lenalidomide, romidepsin and carfilzomib 
dose.  Follow weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to Day 14 of the current 
cycle, restart lenalidomide, carfilzomib and romidepsin at next lower 
dose level and continue through the scheduled Day 14 of the current 
cycle. Otherwise, omit for remainder of cycle and reduce the dose of 
lenalidomide, carfilzomib and lenalidomide by 1 dose level at the start 
of the next cycle.  Omitted doses are not made up. 
• 
If Grade 4, discontinue lenalidomide, romidepsin and carfilzomib. 
Remove patient from study. 
Desquamating (blistering) rash- 
any Grade 
Discontinue lenalidomide, carfilzomib and romidepsin.  Remove patient 
from study. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 34 of 90 
 
 
 
 
TABLE 4: Dose Modifications for 
beyond/ Phase 2 all cycles 
Lenalidomide, Carfilzomib and Romidepsin for Phase 1 cycle 2 and 
NCI CTC Toxicity Grade 
Dose Modification Instructions 
(also see Instructions for Initiation of a New Cycle above) 
Neuropathy 
Grade 3 
 
 
 
 
Grade 4 
• 
If Grade 3, hold (interrupt) romidepsin, lenalidomide and carfilzomib 
dose.  Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to Day 14 of the current 
cycle, restart lenalidomide, romidepsin and carfilzomib at next lower 
dose level and continue through the scheduled Day 14 of the current 
cycle. Otherwise, omit for remainder of cycle and reduce the dose of 
lenalidomide, romidepsin and carfilzomib by 1 dose level at the start 
of the next cycle.  Omitted doses are not made up. 
• 
If Grade 4, discontinue lenalidomide and carfilzomib. Remove patient 
from study. Responding patients may continue on romidepsin off of 
study. 
 
 
Venous thrombosis/embolism 
≥ Grade 3 
• 
Hold (interrupt) carfilzomib, lenalidomide and romidepsin. Start 
therapeutic anticoagulation, if appropriate. 
• 
Restart carfilzomib, lenalidomide and romidepsin at investigator‟s 
discretion after discussion with the MSK PI (reduce 1 dose level of 
each drug). 
• 
See Anticoagulation Consideration 
 
Hyperthyroidism or 
hypothyroidism 
• 
Omit lenalidomide, carfilzomib, and romidepsin for remainder of cycle, 
evaluate etiology, and initiate appropriate therapy. 
• 
See Instructions for Initiation of a new cycle and reduce the dose of 
lenalidomide by 1 dose level. 
Other related non-hematologic 
toxicity ≥ Grade 3 including 
grade 3: 
• 
Pulmonary hypertension 
• 
Congestive heart failure 
• 
Myocardial ischemia 
• 
Decreased ventricular 
function 
• 
Hepatic toxicity 
• 
Pulmonary 
complications 
• 
Renal Failure 
• 
Hold (interrupt) lenalidomide, carfilzomib romidepsin dose. Follow at 
least weekly. 
• If the toxicity resolves to ≤ grade 2 prior to Day 14 of the current cycle, 
restart lenalidomide, carfilzomib and romidepsin at one dose level 
lower and continue through the scheduled Day 21 of  the  current 
cycle. Otherwise, omit for remainder of cycle. Omitted doses are not 
made up. Otherwise, omit for remainder of cycle and reduce the 
dose of lenalidomide, carfilzomib and romidepsin by 1 dose level at 
the start of the next cycle. 
• 
For patients with ≥ grade 3 nausea or vomiting, dose reductions are 
only required for patients who had persistent ≥grade 3 vomiting 
despite use of oral and/or IV antiemetics. 
 
9.5.2 Romidepsin Dose Modification in Case of Cardiac Toxicity 
 
The guidelines for cardiac monitoring and timing of ECG assessments are 
presented in Table 5. Prolongation of QTc/QTf ≥ 500 msec is considered to be an 
alert associated with romidepsin administration. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 35 of 90 
 
 
 
 
Table 5: Dose alteration based on cardiac abnormalities 
Parameter/Symptoms 
Change 
Action 
Dosing/ 
Continuation 
Sinus tachycardia 
Pulse 
>140/min  after 
recumbency 
Hold further dosing 
and treat 
appropriately.  If 
desired, a local 
cardiologist may be 
consulted. 
If resolved, restart romidepsin at 
reduced dose as per table 3. 
If not resolved, take off study. 
Atrial dysrhythmia (SVT, 
atrial fibrillation, or atrial 
flutter) 
New 
occurrence 
Prolongation of  QTc/QTf 
compared to baseline 
To  ≥500 msec 
Heart rate 
> 
120 
bpm 
with > 20 bpm 
increase from 
previous 
evaluation; 
Ventricular tachycardia 
≥3  beats  in  a 
row 
Ventricular 
fibrillation; 
Torsade de Pointes 
New 
occurrence 
Hold further dosing 
and treat 
appropriately.  The 
MSK PI should be 
notified immediately 
and local 
cardiologist should 
be consulted. 
Hold further dosing until MSK  PI 
and cardiologist evaluation is 
complete 
A subsequent  episode  of  any of  the 
above, despite dose reduction 
Take off study 
T-wave morphology 
Inversion 
of 
≥4 mm
a
 
Hold further dosing 
and treat 
appropriately.  If 
desired, a local 
cardiologist may be 
consulted. 
If resolved, restart romidepsin at 
reduced dose of 10 mg/m² 
In some patients, ST segment and 
T-wave morphology changes may 
recur despite a dose reduction to 
10mg/m2.  In such cases, further 
treatment should be held until the 
ECG changes resolve.  If the patient 
experiences no concomitant clinical 
events, treatment may be resumed 
at the reduced dose of 10 mg/m2 
If not resolved, take off study 
ST-segment 
Depression   of 
≥2 mmb 
 
NOTE: Cardiac findings that require dose modification should be reported as 
AEs or SAEs as appropriate. 
a Measured from isoelectric line to peak of T-wave. 
b Measured from isoelectric line to ST segment. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 36 of 90 
 
 
 
 
 
9.5.3 Other Non-Hematologic and Hematologic Toxicities 
All previously established or new toxicities observed any time, with the exception 
of those mentioned above, are to be managed as summarized in Table 5: 
 
• Dose interruption or study discontinuation is  not required  for lymphopenia of any 
grade. 
• In general, if study drug has been held and the toxicity does not resolve, as defined 
above, then drug must be discontinued. 
• Dose reductions should not be performed for alopecia or for non-infectious diarrhea, 
nausea, or vomiting that was not treated with aggressive anti-diarrheal or anti-emetic 
support. 
9.6 
Treatment Adherence 
Research personnel will review the dosing instructions with patients. Patients will 
be provided with a medication diary and asked to record the drug administration. 
Patients will be asked to bring any unused drug and empty drug containers to the 
research personnel at the beginning of each cycle. Site staff will count and record 
the number of used and unused drug at the beginning of each cycle and reconcile 
with the patient diary. 
Any unused Revlimid® (lenalidomide) should be returned to the patient for 
disposition in accordance with the Revlimid REMS program. 
 
9.7 
Concomitant Therapy 
 
9.7.1 Recommended Concomitant Therapy 
Subjects will receive full supportive care, including transfusions of blood and blood 
products, antibiotics, analgesics, and antiemetics when appropriate. Subjects 
should take prophylaxis against varicella zoster as per their institutional guidelines 
while on this regimen (e.g. acyclovir 400mg by mouth twice daily). 
 
9.7.2 Anticoagulation Consideration 
Lenalidomide increases the risk of thrombotic events in patients who are at high 
risk or with a history a thrombosis, in particular when combined with other drugs 
known to cause thrombosis. When lenalidomide was combined with other agents 
such as steroids (e.g. dexamethasone, prednisone), anthracyclines (Doxil, 
Adriamycin) and erythropoietin the risk of thrombosis is increased. For information 
on the risk of venous thromboembolism with combined oral contraceptio n see 
Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods. 
Consideration should be given to the optional use of aspiri n (81 or 325 mg) or 
some other form of prophylaxis as deemed appropriate. Low molecular weight 
heparin may be utilized in patients that are intolerant to ASA. Coumadin should be 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 37 of 90 
 
 
 
used with caution and close monitoring of INR. Carefully monitor prothrombin time 
(PT) and 
International Normalized Ratio (INR) 
in patients 
concurrently 
administered ISTODAX® and Coumadin derivatives. 
If prophylactic anti-coagulation is used, it will be held for platelet counts < 50,000, 
and then restarted when platelet counts are above this level. 
 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
10.2 Assessments During Treatment: Phase 1, cycle 1 and cycle 2; phase 
2, cycle 1 
 
A patient may recei ve treatment on day 1 or day 8 of the first cycle if he or she 
meets the following parameters on the day of treatment: 
• ANC is ≥ 1.0 K/µL Platelet count is ≥ 80 K/µL or within 10 K/µL of baseli ne for 
cycle 1 day 1 and platelet count ≥ 50 K/µL for cycle 1 day 8. (In the Phase II 
portion, if thrombocytopenia is due to bone marrow involvement platelet count 
must be  50 K/µL), 
• Serum creatinine concentration ≤ 2.0 × ULN or ≤ baseline 
Serum potassium must be confirmed to be greater than or equal to the lower 
limit of normal for the testing laboratory, or corrected to those levels. 
o Supplements must be given to patients whose potassi um and/or 
magnesium are below the aforementioned range. 
▪ Magnesium supplementation: If levels are below normal range, 
but within 0.5 units of the lower limit of normal, patients can 
receive at least 2gm magnesium IV and proceed to treatment 
without re-checki ng labs. Patients can be treated if magnesium 
levels are above normal range. 
• Potassium supplementation: If levels are below normal range, but within 0.3 
units of the lower limit of normal, patients can recei ve at least 20mEq 
potassium and proceed to treatment without re-checking labs. Any drug-related 
rash or neuropathy that may have occurred has resolved to ≤ grade 1 severity 
• Any other drug-related adverse events that may have occurred have resolved 
to ≤ grade 2 severity. 
Within 7 days of treatment: 
 
• AST (SGOT) and ALT (SGPT) ≤ 3.0 × ULN . 
o Liver function analysis should be assessed on the day of treatment but 
does not have to be resulted prior to initiating treatment if the most 
recent assessment meets the above criteria and was performed within 
the last 7 days. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 38 of 90 
 
 
 
If these conditions are not met on Day 1 of a new cycle, the subject will be 
evaluated at least weekly and a new cycle of treatment will not be in itiated 
until the toxicity has resolved as described above. 
 
10.2.1 Assessments During Treatment: Phase 1, cycle 3 and beyond; phase 
2, cycle 2 and beyond 
 
A patient may initiate a new cycle if he or she meets the following parameters 
on the day of treatment: 
o ANC is ≥ 1.0 K/µL 
o Platelet count is ≥ 80 K/µL or within 10 K/µL of baseline. (In the Phase II 
portion, if thrombocytopenia is due to bone marrow involvement platelet 
count must be  50 K/µL) 
 
The following parameters may be checked within 3 days of initiating a cycle: 
o Serum creatinine concentration ≤ 2.0 × ULN or ≤ baseline 
o Serum potassium and magnesium is ≥ the lower limit of normal for the 
testing laboratory, or corrected to those levels for the testing laboratory. 
o If levels are within range romidepsin may be administered without repeat 
testing on day of treatment unless clinically indicated (such as vomiting, 
diarrhea, or initiation of medications that may affect electrolytes). 
o Supplements must be given to patients whose potassi um and/or 
magnesium are below the aforementioned range: 
▪ Magnesium supplementation: If levels are below normal range, 
but within 0.5 units of the lower limit of normal, patients can 
receive at least 2gm magnesium IV and proceed to treatment 
without re-checking labs. 
Potassium supplementation: If levels are below normal range, but within 
0.3 units of the lower limit of normal, patients can receive at least 20mEq 
potassium and proceed with treatment without re-checki ng labs. 
• Any drug-related rash or neuropathy that may have occurred has resolved to 
≤ grade 1 severity 
• Any other drug-related adverse events that may have occurred have resolved 
to ≤ grade 2 severity. 
• ECG schedule as specified in Table 7. 
Within 14 days of treatment: 
• AST (SGOT) and ALT (SGPT) ≤ 3.0 × ULN. 
o Liver function analysis should be assessed on the day of treatment but 
does not have  to be  resulted prior to initiating  treatment if the most 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 39 of 90 
 
 
 
recent assessment meets the above criteria and was performed within 
the last 14 days. 
 
If these conditions are not met on Day 1 of a new cycle, the subject will be 
evaluated at least weekly and a new cycle of treatment will not be initiated until the 
toxicity has resolved as described above. 
 
10.3 Required Blood Parameters and Other Investigations Prior to Romidepsin 
Day 8 
The following criteria must be fulfilled: 
• ANC is ≥1.0 K/µL. 
• Platelet count is ≥ 50 K/µL. 
o Serum potassium and magnesium is ≥ the lower limit of normal for the 
testing laboratory, or corrected to those levels for the testing laboratory. 
o If levels are within range romidepsin may be administered without repeat 
testing on day of treatment unless clinically indicated (such as vomiting, 
diarrhea, or initiation of medications that may affect electrolytes). 
o Supplements must be given to patients whose potassi um and/or 
magnesium are below the aforementioned range. 
▪ Magnesium supplementation: If levels are below normal range, 
but within 0.5 units of the lower limit of normal, patients can 
receive at least 2gm magnesium IV and proceed to treatment 
without re-checking labs. 
▪ Potassium supplementation: If levels are below normal range, but 
within 0.3 units of the lower limit of normal, patients can recei ve at 
least 20 mEq potassium and proceed with treatment without re- 
checking labs. 
• Recovery of any drug-related  non-hematological toxicity to Grade 2 or less, 
unless otherwise indicated. 
• ECG schedule as specified in Table 7. 
• If any of these criteria are not fulfilled, then administration of study drugs should 
be delayed as detailed in Section 9.0. 
 
Within 7 days of treatment: 
 
• AST (SGOT) and ALT (SGPT) ≤ 3.0 × ULN. 
o Liver function analysis should be assessed on the day of treatment but 
does not have to be resulted prior to initiating treatment if the most 
recent assessment meets the above criteria and was performed within 
the last 7 days. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 40 of 90 
 
 
 
10.4 Cardiac Monitoring 
Minor ECG changes are expected following romidepsin administration (refer to 
current Investigator‟s Brochure). Cardiac assessments must be performed for all 
study patients. The treating investigator must perform the primary assessment 
and is responsible for the cardiac safety of the patients. 
10.5 Cardiac Alert Findings 
In the event of an alert finding, the individual decision about a delay of 
administration, dose reduction, or withdrawal from the study will be made by the 
Investigator (in association with local cardiologist, if preferred). All alerts must be 
confirmed via manual read of the patients ECG; the machine reading alone is not 
adequate. The following findings are considered to be cause for alert and if they 
occur, should be reported as AEs or SAEs, as appropriate: 
• QTc or QTf is ≥ 500 msec: 
o Either QTc or QTf formulas can be used; the lesser of the two values will 
be recorded. 
o If the patient has a known incomplete or complete right bundle branch 
block (RBBB) or left bundle branch block (LBBB) a change in QTc/QTf of 
> 60 msec from the post antiemetic ECG will be used as criteria for and 
adverse event and would be graded as a grade 3 adverse event. 
o If the patient has a single or dual chamber pacemaker a change in 
QTc/QTf of > 60 msec from the post antiemetic ECG in either the native 
rhythm or paced rhythm will be used as a criteria for an adverse event 
and would be graded as a grade 3 adverse event. 
• Ventricular arrhythmia: VT (≥ 3 beats in a row) or VF. 
• Sinus tachycardia (pulse >140/min after recumbency). 
• Heart rate is > 120 bpm with > 20 bpm increase from previous evaluation. 
• New occurrence of atrial dysrhythmias (SVT, atrial fibrillation, or atrial flutter). 
• Abnormal ST and/or T-wave changes includi ng ST depression of  2 mm (as 
measured from isoelectric line to the ST segment at a point 60 msec at the end 
of the QRS complex); T-wave inversion of  4 mm (measured from isoelectric 
line to peak of T-wave) as long as the main QRS vector is positive . 
• Ventricular tachycardia, including Torsade de Pointes. 
See Table 5 in Section 9 for recommended dose reductions, etc., in the above 
situations. 
10.6 Electrocardiograms 
An ECG must be performed within 1 hour (after administration of antiemetic 
premedication) prior to romidepsin and after completion of each romidepsin 
infusion for cycles 1 and 2. If no QTc/QTf value greater than 480 msec is 
demonstrated by auto-read or manual read then further ECGs may be omitted for 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 41 of 90 
 
 
 
the duration of study. If a QTc/QTf value greater than 480 but less than 500 msec 
is encountered then ECGs should be performed within 1 hour prior to romidepsin 
infusion for the first dose of each subsequent cycle. 
 
If a QTc/QTf is ≥ 500 msec is encountered, ECGs should be repeated twice more 
for a mean of three QTc/QTf values. If the mean is > 500 msec, follow dose 
modification guidelines in table 6. 
Note to Investigators: At the Investigator‟s discretion, more intensive ECG 
monitoring can be performed for all romidepsin administrations. 
10.7 Pregnancy Testing 
Pregnancy tests for females of childbearing potential. A female of chi ldbearing 
potential (FCBP) is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e. has had menses at any 
time in the preceding 24 consecuti ve months). 
 
Pregnancy tests will be required by the Revlimid REMS® program and will occur 
within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide for 
Cycle 1 (prescriptions must be filled within 7 days). FCBP with regular or no 
menstruation must have a pregnancy test weekly for the first 28 days and then 
every 28 days while on therapy (including breaks in therapy); at disconti nuation of 
lenalidomide and at Day 28 post the last dose of lenalidomide. Females with 
irregular menstruation must have a pregnancy test weekly for the first 28 days and 
then every 14 days while on therapy (including breaks in therapy), at 
discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of 
lenalidomide (see Appendix A: Risks of Fetal Exposure, Pregnancy Testi ng 
Guidelines and Acceptable Birth Control Methods). 
 
10.8 Follow-Up 
Patients, who disconti nue treatment for any reason, will be followed for 1 month or 
until resolution of all treatment related AEs or initiation of alternate cancer therapy, 
whichever is longer. At treatment disconti nuation, patients will undergo a safety 
assessment approximately 1 month after the last dose of protocol therapy. In 
addition, off study evaluations per the end of study assessments will be done. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 42 of 90 
 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
Side Effects of Romidepsin 
Likely 
• Nausea 
• Vomiting 
• Loss of appetite 
• Fatigue 
• Constipation 
• Diarrhea 
• Altered sensation of taste 
• Fever 
 
Side effects related to levels of substances found in the blood: 
• Thrombocytopenia 
• 
Anemia 
• Leukopenia 
• Hyperglycemia 
• Hypocalcemia 
• Hypomagnesemia 
• Hypoalbuminemia 
 
Less Likely 
• Swelling 
• Decreased weight 
• Heart traci ng irregularities 
• Weakness 
• Joint pain 
• Itching 
• Back pain 
• Dizziness 
• Abdominal pain 
• Dehydration 
• Changes in heart function 
• Heartburn 
• Low blood pressure 
• Cough 
• Skin infections 
• Shortness of breath 
• Headache 
• Feeling of discomfort or uneasiness 
• Insomnia 
• Burning or tingling sensations 
• Headache 
• Feeling of discomfort or uneasiness 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 43 of 90 
 
 
 
 
 
 
Side effects related to levels of substances found in the blood: 
• Hyperbilirubinemia 
• Hypokalemia 
• Lymphopenia 
• Hyponatremia 
• Hypermagnesemia 
• Increased creati nine 
• Hypophosphatemia 
• Elevated transaminases 
• Elevated alkaline phosphatase 
 
Rare but serious 
• Anxiety 
• Infections 
• Bleeding 
• Increased heart rate 
• Hyperkalemia 
• Hyperuricemia 
• Pancreatitis 
• Deep venous thrombosis 
• Syncope 
 
Side Effects of Lenalidomide 
Likely: 
• Fatigue or feeling tired 
• Lack or loss of strength 
• Anemia or a decrease in red blood cells that can cause tiredness 
• Decrease in white blood cells that can make you more prone to infections 
(Neutropenia) 
• Decrease in platelets which can cause you to bruise or bleed easily 
(Thrombocytopenia) 
• Blood clot in lower extremities 
• Vision blurred 
• Nosebleed 
• Constipation or difficulty moving your bowels 
• Diarrhea or loose/frequent bowel movements 
• Nausea or vomiting 
• Loss of appetite 
• Joint pain 
• Swelling of the arms and legs 
• Fever 
• Cough 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 44 of 90 
 
 
 
• Shortness of breath or difficulty catchi ng your breath 
• Upper respiratory infection (infection of nose, sinus, and throat) 
• Allergic reaction 
• Itching and dry ski n 
• Dizziness 
• Headache 
• Altered sense of taste 
• Abnormal sense of touch 
• Pain and decreased sensation in nerves 
• Pneumonia 
 
Less Likely: 
• Problem with moving food through digesti ve system (gastrointesti nal motility 
disorder) 
• Dry mouth 
• Indigestion (dyspepsia) 
• Muscular weakness 
• Stroke 
• Tingling sensation (paresthesia) 
• Fainting (syncope) 
• Drowsiness 
• Difficulty breathing (respiratory distress) 
• Excessive sweati ng (hyperhidrosis) 
• Fever with a decrease in white blood cells that help fight infections (febrile 
neutropenia) 
• Shortage of all types of blood cells includi ng red blood cells, white blood cells, and 
platelets (pancytopenia) 
• Excessive loss of body water (dehydration) 
• High blood sugar (hyperglycemia) 
• Uncontrolled blood sugar (diabetes mellitus) 
• Higher than normal blood uric acid (hyperuricemia) 
• Higher than normal level of iron in body (iron overload) 
• Lens of eye becomes cloudy (cataracts) 
• High blood pressure (hypertension) 
• Low blood pressure (hypotension) 
• Bleeding 
• Altered mood 
• Depression 
• Irregular heartbeat (atrial fibrillation) 
• Failure of the heart (cardiac failure) 
• Heart attack (acute myocardial infarction) 
• Fast heartbeat (tachycardia) 
• Not enough blood flow to heart muscle (myocardial ischemia) 
• Secondary cancer 
• Kidney damage (renal failure) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 45 of 90 
 
 
 
• Abnormal liver function tests 
• Tumor lysis syndrome 
 
 
Rare but Serious 
• Fever with a decrease in white blood cells that help fight infections (Febrile 
neutropenia) 
• Blood clot in or around the lungs (Pulmonary embolism) 
• Deep vein thrombosis or blood clots in larger blood vessels 
• Atrial fibrillation or irregular heartbeat 
• Pneumonia or an infection of the lungs 
• Sepsis or an infection of the blood 
• Kidney failure or inability of the kidneys to remove waste from the body 
• Muscle breakdown (rhabdomyolysis) 
• Swelling of the lungs 
• Severe ski n rash (Stevens-Johnson syndrome) 
 
Side Effects of Carfilz omib 
 
Likely Side Effec ts: 
• Fatigue (tiredness) 
• Fever 
• Headache 
• Cough 
• Cough with phlegm 
• Shortness of breath (at rest or with exertion) 
• Nausea 
• Vomiting 
• Diarrhea 
• Constipation 
• Decreased red blood cell count which may lead to feeling tired 
• Decreased platelet counts which may lead to increase bleeding or bruising 
• Decreased white blood cell count 
• Upper respiratory tract infection 
• Mild decreases in kidney function which are generally reversible 
• Swelling of the arms or legs 
• Back pain 
• High blood pressure 
• Pneumonia or other lower respiratory tract infections 
 
 
Less Likely Side Effects: 
• Flu-like symptoms such as fever, chi lls, or shaking that may occur at any time but 
are more likely to occur on the day of or the day after carfilzomib infusion. 
• Loss of or decreased appetite which may lead to weight loss 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 46 of 90 
 
 
 
• Insomnia (difficulty sleeping) 
• Anxiety 
• Dizziness 
• Confusion or changes in mental state 
• Blurred or double vision 
• Numbness, tingling, or decreased sensation in hands and/or feet 
• Blood chemistry and electrolyte alterations 
• Rash and/or itching, or dry ski n 
• Pain, burning, or irritation at the infusion site 
• Generalized pain 
• Pain in the bones or joint pain 
• Muscle spasm, pain, or weakness 
• General weakness, or lack of energy or strength 
• Abdominal pain, discomfort, or swelli ng 
• Indigestion (upset stomach) 
• Inflammation of the li ver (mild, reversible changes in liver function tests) 
• Increase or decrease in blood pressure 
• Urinary tract infection 
• Nosebleeds 
• Dehydration 
• Sore throat, inflammation of the nose and throat, runny nose or nasal congestion 
• Blood clots in the leg or lungs 
• Change in voice or hoarseness 
• Toothache 
• Low white blood cell count which may be associated with fever 
• Low blood pressure 
 
Rare and/or Potentially Serious Side Effects: 
• Infusion reactions (which can occur during or shortly after carfilzomib infusion) 
including flushi ng or feeling hot, fever, shakes, nausea, vomiting, weakness, 
shortness of breath, swelling of the face, pain in the muscles or joints, tightness or 
pain in the chest, and low blood pressure 
• Allergic reaction includi ng total body rash, hives, and difficulty breathing 
• Inflammation of the pancreas (pancreatitis) 
• Kidney failure which can lead to dialysis 
• Worseni ng liver function up to and includi ng liver failure 
• Decreased or worseni ng of heart function including chest pain, abnormal heart 
rhythm, heart attack, and heart failure 
• Severe shortness of breath leading to hospitalization or death 
• Increase in the blood pressure in the arteries of the lungs 
• Infections in the blood 
• Thrombotic thrombocytopenic purpura (TTP) 
o TTP is a rare blood disorder. In TTP, blood clots form in small blood 
vessels throughout the body. The clots can limit or block the flow of 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 47 of 90 
 
 
 
oxygen-rich blood to the body's organs, such as the brain, kidneys, and 
heart. 
• Hemolytic-uremic syndrome (HUS) 
o HUS is a disorder that usually occurs when an infection in the digestive 
system produces toxic substances that destroy red blood cells, causi ng 
kidney injury. 
 
• Secondary cancers such as myelodysplastic syndrome (MDS) / Acute Myeloid 
Leukemia 
o Myelodysplastic syndromes refers to disorders that develop when the cells 
in the bone marrow (the soft inner part of the bones, where new blood cells 
are made) do not work properly and have problems making new blood 
cells. 
 
• Posterior Reversible Encephalopathy Syndrome (PRES) 
o PRES is a rare, neurological disorder, which can present with seizure, 
headache, lethargy, confusion, blindness, altered consciousness, and 
other visual and neurological disturbances, along with hypertension. 
• Tumor lysis syndrome (TLS) 
o Tumor lysis syndrome is caused by rapid killi ng of tumor cells during 
treatment. When the tumor cells die, they release their contents into the 
bloodstream. If cell killing is very rapid, this can affect blood chemistries 
and the kidneys. In severe cases, this can lead to shutdown of kidney 
function requiring dialysis. 
• Pulmonary hemorrhage ( bleeding in the lungs) 
• Brain Hemorrhage 
• Bleeding in the stomach and bowels 
 
 
12.1 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Response and progression of disease will be evaluated in this study using a 
modification of the international criteria proposed by the modified Cheson criteria with 
incorporation of PET/CT. [Cheson B, 2007]. The imaging modality for evaluation will 
be dependent on disease subtype. For aggressi ve lymphomas (e.g. DLBCL, PTCL, 
HL), PET/CT will be used for evaluation of response. For indolent lymphomas, CT 
alone or PET/CT may be used at the discretion of the treating physician. For CTCL, 
please see Section 12.0.2. 
 
Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 15 mm 
with conventional techniques (PET, CT, MRI, x-ray). All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Non-measurable disease: All other lesions (or sites of disease), includi ng small 
lesions (longest diameter < 15 mm), are considered non-measurable disease. Bone 
lesions,  leptomeningeal  disease, ascites,  pleural/pericardial  effusions,  lymphoma 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 48 of 90 
 
 
 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT 
or MRI), and cystic lesions are all non-measurable. 
 
 
12.1.1 Extracutaneous Response Criteria 
Response criteria will be based on assessment following 2 cycles and subsequent 
assessments will be made every 3 cycles thereafter (e.g. after cycle 5, 8, 11 etc). The 
criteria are as follows (GTD = Greatest Transverse Diameter; SPD = Sum of the 
Products of the Greatest Diameter): 
 
Complete Remission (CR): 
 
• No cli nical, radiographic or diagnostic evidence of disease. 
• No disease related symptoms. 
• Abnormal biochemical  values  (e.g., LDH) clearly attributable  to  lymphoma 
must have normalized. 
• Lymph nodes, nodal masses regressed to “normal” size: 
• If > 1.5 cm before treatment regressed to ≤ 1.5 cm in GTD. 
• If 1.1 to 1.5 cm before treatment, regressed to ≤ 1 cm in GTD (or >75% in 
SPD). 
• Spleen and all previously enlarged organs decreased in size. Spleen must not 
be palpable on exam 
• Bone marrow free of disease on repeat aspirate and biopsy if initially positi ve. 
• Normalization of PET scan. 
 
Complete Remission/unconfirmed (CRU): 
 
Patients meeting the above criteria for CR with the following exceptions: 
• Residual node mass of >1.5 cm in GTD regressed by > 75% in SPD. 
• Individual nodes previously confluent regressed by >75% in SPD 
• Indeterminate bone marrow (increased number or si ze of lymphoid aggregates 
without cytologic or architectural atypia). 
 
Partial Remission (PR): 
• Greater than or equal to 50% decrease in SPD of the si x largest dominant 
nodes/nodal masses. 
• No increase in size of other nodes, liver or spleen. 
• Splenic and hepatic nodes regressed at least 50% in SPD. 
• No new sites of disease. 
• Bone marrow and organs other than the spleen and liver cannot be 
considered for evaluation for PR because involvement at these sites is 
considered evaluable but not measurable. 
 
PET negative Partial Remission (PET- PR): 
• 
Patient meets above criteria for PR with resolution of previous PET positive 
lesions. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 49 of 90 
 
 
 
 
 
Stable Disease (SD): 
• Patients who have achieved less than a partial remission but who have not 
developed findings consistent with progressive disease. 
 
Progressive Disease (PD): 
• In patients previously CR, CRUCRU, PR or SD. 
• Greater than or equal to 50% increase in SPD of any previously identified 
abnormal node. 
• Appearance of any new lesion during or at the end of therapy 
 
12.1.2 Cutaneous T-cell Lymphoma (CTCL) Response Criteria 
 
Dermatologic responses will be determined by the modified Severity-Weighted 
Assessment Tool (mSWAT), a standardi zed approach to measuring the extent and 
severity of overall skin disease in patients with CTCL. It will be briefly described and 
full details are provided in Appendix D. The purpose of this description is to optimize 
intra-observer objectivity and to minimize the potential for intra-observer and inter- 
observer variability in the measurement of overall ski n disease. Only physicians who 
received training will be permitted to conduct mSWAT assessments during the 
clinical study. It is essential that physicians adhere as closely as possible to the 
prescribed procedures so as to reduce measurement error and variability. All efficacy 
assessments should be performed by the same physician for each patient whenever 
possible. Physicians will be instructed not to examine previous mSWAT assessments 
and full body photographs prior to conducting the current mSWAT assessment. 
 
13.1 CRITERIA FOR REMOVAL FROM STUDY 
 
13.2 
Discontinuation of Study Treatment 
Treatment will conti nue until the occurrence of any of the following events. 
• Disease progression 
• Institution of alternate therapy or planned stem cell transplantation. 
• Adverse event(s) that, in the judgment of the Investigator, may cause severe 
or permanent harm or which rule out continuation of the treatment regimen. 
• Discontinuation of lenalidomide, carfilzomib or romidepsin for any reason. 
• Major violation of the study protocol. 
• Withdrawal of consent 
• Lost to follow up 
• Death 
• Pregnancy or a positive pregnancy test 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 50 of 90 
 
 
 
 
 
14.0 
BIOSTATISTICS 
 
The standard dose-escalation scheme for this study is as follows. Patients will be 
accrued to the study in cohorts of 3. For any given dose an initial cohort of 3 patients 
will be treated at that dose. The dose level will be escalated if none of the 3 patients 
exhibits any DLT in the first cycle as defined above. If a DLT is observed in one 
patient, an additional cohort of 3 patients will be treated at that dose. The dose will be 
escalated if none of the additional 3 patients exhibits any DLT. Dose-escalation stops 
and the previous dose will be considered the MTD if 2 or more patients have a DLT. 
If the previous dose level has been administered to only 3 patients, an additional 3 
patients will be enrolled to confirm the result. For this design the probability of 
escalation is as follows: 
 
 
True toxicity 
rate 
5% 
10% 
15% 
20% 
25% 
30% 
40% 
50% 
Probability of 
escalation 
0.97 
0.91 
0.81 
0.71 
0.60 
0.49 
0.31 
0.17 
 
Dose escalation will start with dose level 1. A dose level -1 is also added to the 
design to ensure a minimum level of toxicity (we expect this dose level will be quite 
tolerable for patients based on the phase I data of romidepsin and lenalidomide). The 
maximum number of patients needed for this dose escalation design is 30. We 
estimate accrual to be 2 patients per month. Patients with measurable disease 
treated at MTD in the phase Ib will be analyzed in phase IIa to further characterize 
the toxicity of carfilzomib, romidepsin and lenalidomide in combination at the MTD 
determined by phase Ib. In phase IIa, we plan to enroll patients so that the total 
number of patients enrolled in each disease type cohort (B-cell lymphoma and T-cell 
lymphoma) will include 10 patients at the MTD. We estimate accrual to be 1 patient 
per month in each disease type cohort. To consecuti vely monitor the safety primary 
endpoint in the phase IIa portion, we will employ a sequential probability stopping 
rule for the predefined DLT in the phase Ib portion of cycles 1 -4. This stoppi ng rule 
specifies that the study will be terminated if DLT occur in: ≥3/first 6; ≥6/first 12; or if 
more than 10 patients when the last (20th) evaluable patient has completed the trial 
have any DLT. This rule has the following stopping probability: 
 
 
 
 
S 
e 
condary objecti ves of this study aim at examining many cli nical endpoints (see above 
section for detailed definitions). Our assessment of efficacy will remain descriptive 
and we will evaluate the following measures. Overall response rate (ORR), complete 
response  rate, partial  response  rate  will  be  summarized  usi ng  proportions  and 
True toxicity rate 
5% 
10% 
15% 
20% 
25% 
30% 
35% 
40% 
50% 
Stopping prob. 
0.002 
0.016 
0.049 
0.104 
0.184 
0.289 
0.413 
0.548 
0.797 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 51 of 90 
 
 
 
confidence intervals will be provided. ORR will be calculated based on the best 
response at any time during the course of treatment on this protocol. Response rates 
will be calculated based on the first time point at which that degree of response was 
noted. Time to response, duration of response and event free survival will be 
analyzed by routine survival analysis tools such as Kaplan-Meier estimation or 
competing risks method. In this portion of the study, the disease subtypes (B-cell and 
T-cell lymphoma) will be grouped together includi ng those from the phase Ib that 
were treated at MTD. To preliminarily collect the data, subset analyses will also be 
conducted to evaluate the ORR (CR +PR), TTR, DOR, and EFS for each disease 
subtype. 
Dr. Fausto Loberiza, and Dr. Fang Yu from the University of Nebraska provided the 
Biostatistical plan for this trial. Dr. Fang Yu will be involved in study analysis during 
the study. The statistician will have access to the data in Medidata which will allow for 
a secure transfer of information. 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.2 Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration proc ess registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility 
Checklist is confirm ing whether or not the participant is eligible to enroll in the study. 
Study staff are responsible for ensuring that all institutional requirem ents necessary to 
enroll a participant to the study have been completed. See related Clinical Researc h 
Policy and Procedure #401 (Protocol Participant Registration). 
 
. 
 
15.1. Registration for Participating Sites 
 
Central registration for this study will take place at MSK. 
 
To complete registration and enroll a participant from another institution, the site must 
contact the MSK study coordinator to notify him/her of the participant registration. 
The  following  documents  must be  sent to  the  MSK  study coordinator  for each 
enrollment within 24 hours of the informed consent form being signed: 
• The completed or partially completed MSK eligibility checklist 
• The signed informed consent and HIPAA Authorization form 
• Supporting source documentation for eligibility questions (e.g. labora tory 
results, pathology report, radiology reports, MD notes, physical exam sheets, 
medical history, prior treatment records, and EKG report). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 52 of 90 
 
 
 
Upon receipt, the MSK study coordinator will conduct an interim review of all 
documents and will associate the participant to the study in MSK‟s Clinical Trials 
Management System (CTMS). The participant will be assigned a protocol participant 
number in CTMS. This number will be relayed back to the study staff at the 
registering participating site via e-mail and will serve as enrollment confirmation. The 
number is unique and must be written on all data and correspondence for the 
participant. 
If the eligibility checklist is not complete or source documentation is missing, the 
participating site will be responsible for sending the completed registration 
documents within 30 days of the consent. 
Once the external registration submission is complete, if the participating site IRB has 
granted approval for the protocol and the participating site is in good standing, the 
MSK study coordinator will fully register the participant in CTMS. The participating 
site will be notified by the MSK study coordi nator when registration is complete. 
 
 
15.3 Randomization 
 
There is no randomization in this study. 
 
16.1 DATA MANAGEMENT ISSUES 
 
A MSK Research Study Assistant (RSA) will be assigned to the study. The 
responsibilities of the RSA include project compliance, data collection, abstraction 
and data entry, data reporting, regulatory monitoring, problem resolution and 
prioritization, and coordi nation of the activities of the protocol study team. 
 
The data collected for this study will be entered into a secure electronic Case Report 
Forms (eCRFs) by the assigned MSK RSA (for MSK patients only). Source 
documentation will be available to support the computeri zed patient record. 
 
 
 
 
 
 
 
 
16.1.1 Data and Source Documentation for Participating Sites 
 
 
Data 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 53 of 90 
 
 
 
The participating site(s) will enter data remotely into electronic Case Report Forms 
(eCRFs) using the internet based system, Medidata Rave. Data entry guidelines 
have been generated for this study and site staff will recei ve database training prior 
to enrolling its first participant. The participating site PI is responsible for ensuring 
these forms are completed accurately and in a timely manner. A schedule of required 
forms is shown in section 16.0.3. 
 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should 
be consistent with data entered into eCRFs. Relevant source documentation to be 
submitted throughout the study includes: 
o Baseline measures to assess pre–protocol disease status (ex. CT, PSA, bone 
marrow) 
o Treatment records 
o Toxicities/adverse events of grades that meet study reporting requirements 
and have not been previously submitted with a SAE Report 
o Response designation 
o Any other forms of source documentation required per protocol 
 
Source documentation should include a minimum of two identifiers to allow for data 
verification. MSK will maintain the confidentiality of any subject-identifiable 
information it may encounter. 
16.1.2 Data and Source Documentation Submission for Participating Sites 
Participating sites should enter data directly into Medidata Rave. Source 
documentation should be sent to MSK to the contact information provided by the 
MSK study coordinator. Submissions should include a cover page listi ng relevant 
records enclosed per participant. 
16.1.3 Data and Source Documentation Submission Timelines for Participating 
Site 
Data and source documentation to support data should be transmitted via MediData 
Rave according to following chart: 
 
 
 
 
 
 
 
 
 
Time point 
Data 
Source Documentation 
Baseline 
Within 24 hours of consent 
(see section 4.0) 
Within 24 hours of consent 
(see section 4.0) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 54 of 90 
 
 
 
 
Study Visits 
Within 14 days of the study visit 
Within 14 days of the study visit 
Serious Adverse 
E vents 
Within 3 days of event(see section 17.3); 
Updates to be submitted as available 
Within 3 days of event (see section 
16.1.1) 
 
 
*Toxicities/adverse events that meet reporting requirement as outlined in section 11. 
 
16.1.4 Data Review and Queries for Participating Site Data 
 
Research staff at MSK will review data and source documentation as it is submitted. 
Data will be monitored against source documentation and discrepancies will be sent 
as queries to the participating sites. Queries will be sent by MSK Research staff twice 
a month. 
 
Participating sites should respond to data queries within 14 days of receipt. 
 
16.2 Quality Assurance 
 
Registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing 
data and inconsistencies. Accrual rates and extent and accuracy of evaluations and 
follow-up will be monitored periodically throughout the study period and potential 
problems will be brought to the attention of the study team for discussion and action. 
 
16.2.1 Quality Assurance for Participating Sites 
 
Monitoring 
 
Each data collection site will be monitored periodically by MSK. Monitoring visits will 
be conducted every 4-8 weeks, dependent upon the protocol and patient accrual and 
activity. The monitor and the participating site will identify a mutually agreeable time 
for each monitoring visit. At least 10 busi ness days ahead of the visit, the monitor will 
send the site a notification letter that details the date and expectations of the visit. 
Monitoring may be conducted remotely or in-person. The monitor must be allowed 
access to all protocol regulatory and source documents to assess compliance with 
the protocol, federal regulations and GCPs. The monitor will assess all data for 
completeness of source documents and to confirm data being recorded in the eCRFs 
is accurate. If monitoring will be done remotely, sites must agree in advance to 
provide source documents as required. During onsite visits, the monitor will also 
inspect and review the facilities and investigational product storage area. The 
participating site will maintain accurate records of dispensing of study drugs for drug 
accountability. Drug accountability will be reviewed at monitoring visits. Study drug 
and bottles must be retained until the monitor performs drug accountability of the 
study drug(s). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 55 of 90 
 
 
 
The site Investigator(s) and/or an authorized member of the Investigator‟s staff 
should allow sufficient time during monitoring visits to discuss findings. The 
Investigator(s) or an authorized  member of the Investigator‟s staff will make any 
necessary corrections during and between monitoring visits. 
 
 
Auditing 
 
Each participating site accruing participants to this protocol may be audited by MSK 
for protocol and regulatory compliance, data verification and source documentation. 
Audits of selected participant records may be conducted on-site or remotely. 
 
Each audit will be summarized and a final report will be sent to the PI at the audited 
participating site within 30 days of the audit. The report will include a summary of 
findings, participant-specific case review, recommendations on any performance 
and/or shortcomings and request for corrective action, when necessary. When 
corrective action is required, the participating site must reply within 45 days of receipt 
of the audit report with their correcti ve action plan. 
 
 
16.1.2 Response Review 
Since therapeutic efficacy is a stated primary objective, all sites participant‟s 
responses are subject to review by MSK‟s Therapeutic Response Review Committee 
(TRRC). Radiology, additional lab reports and possibly bone marrow biopsies and/or 
aspirates will need to be obtained from the participating sites for MSK TRRC review 
and confirmation of response assessment. These materials must be sent to MSK 
promptly upon request. 
 
 
16.2 Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer 
Center were approved by the National Cancer Institute in September 2001. The plans 
address the new policies set forth by the NCI in the document entitled “Policy of the 
National Cancer Institute for Data and Safety Monitoring of Clinical Trials” which can 
be found at: http://ca ncertrials.nci.ni h.go v/researc hers/ds m/inde x.html. The DSM 
Plans at MSK were established and are monitored by the Office of Clinical Research. 
The MSK Data and Safety Monitoring Plans can be found on the MSK Intranet at:  
http://i nside2/clinresearc h/Documents/MSKCC%20Data%20and%20 Safety%20 Monit  
oring%20Pla ns.pdf. 
There are several different mechanisms at MSK by which clinical trials are monitored 
for data, safety and quality.  There are institutional processes in place for quality 
assurance (e.g., protocol monitoring, compliance and data verification audits, 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 56 of 90 
 
 
 
therapeutic response, and staff education on clinical research QA) and departmental 
procedures for quality control, plus there are two institutional committees that are 
responsible for monitoring the activities of our cli nical trials programs. The 
committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III cli nical 
trials, report to the Center‟s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed 
for its level of risk and degree of monitoring required. Every type of protocol (e.g., 
NIH sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, 
etc.) will be addressed and the monitoring procedures will be established at the time 
of protocol activation. 
16.3 Regulatory Documentation 
 
Site Activation 
 
Prior to implementing this protocol at MSK, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be 
approved by the MSK Institutional Review Board/Privacy Board (IRB/PB).  There will 
be one protocol document and each participating site will utilize that document. 
 
The following documents must be provided to MSK before the participating site can 
be initiated and begin enrolling participants: 
• Participating Site IRB approval(s) for the protocol, appendices, informed consent 
form and HIPAA authorization 
• Participating Site IRB approved informed consent form and HIPAA authorization 
• Participating Site 1572 
• Conflict of Interest forms for Participating Site Investigators on the 1572 
• Participating Site IRB membership list 
• 
Participating Site IRB‟s Federal Wide Assurance number and OHRP Registration 
number 
• Curriculum vitae and medical license for each investigator and consenting 
professional 
• Documentation of Human Subject Research Certification training for investigators 
and key staff members at the Participating Site 
• Documentation of Good Clinical Practice (GCP) training for the PI and co-PI at 
each participating site. 
• Participating site laboratory certifications and normals 
 
Upon receipt of the required documents, MSK will formally contact the site and grant 
permission to proceed with enrollment. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 57 of 90 
 
 
 
16.3.1 Amendments 
 
Each change to the protocol document must be organized and documented by MSK 
and approved first by the MSK IRB/PB. Protocol amendments that affect MSK only 
(e.g. change in MSK Co-Investigator, MSK translation, etc.) do not require IRB review 
at the participating site(s). All other protocol amendments will be immediately 
distributed to each participating site upon receipt of MSK IRB/PB approval. 
Each participating site must obtain IRB approval for all amendments within 45 
calendar da ys of MSK IRB/PB approval. If the amendment is the result of a safety 
issue or makes eligibility criteria more restricti ve, participating sites will not be 
permitted to conti nuing enrolling new participants until site IRB approval of the 
revised protocol documents is granted and submitted to MSK. 
 
16.3.2 Additional IRB Correspondence 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site‟s IRB and the most 
current approved version of the informed consent form should be submitted to MSK 
within 7 days of expiration. Failure to submit the re-approval in the stated timeline will 
result in suspension of new participant enrollment. 
 
Deviations 
 
A protocol deviation on this study is defined as any incident involving non-adherence 
to an IRB approved protocol. Deviations typically do not have a significant effect on 
the rights, safety, or welfare of research participants or on the integrity of the 
resultant data. Deviations that represent unanticipated problems involving risks to 
participants or others, or serious adverse events should be reported. 
 
Deviations that do not adversely affect the rights and/or welfare of the participant or 
the scientific validity of the study and are related to protocol scheduling changes 
outside of the allowed window due to a holiday (e.g., New Year‟s, Thanksgiving, etc.) 
and/or inclement weather or other natural event do not require reporting to the MSK 
IRB/PB. However, they must be clearly documented in the patient‟s medical record. 
Prospective De viations 
 
Deviations to the research protocol that involve an informed consent procedure 
change and/or treatment/pharmacy alterations that are not allowed by the protocol 
require prospective approval from the MSK IRB/PB prior to the change being carried 
out. Participating sites should contact the MSK PI who will in turn seek approval from 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 58 of 90 
 
 
 
the MSK IRB/PB. Deviations to the research protocol that involve patient eligibility wi ll 
not be permitted. 
Retrospecti ve De viations 
 
Deviations that include a change or departure from the research protocol without 
prior approval from the MSK IRB/PB are considered retrospecti ve deviations. 
Retrospecti ve deviations should be reported to the MSK PI as soon as possible, who 
will in turn report the deviation to the MSK IRB/PB as per MSK g uidelines. 
 
Participating Site IRB Reporti ng 
 
Participating sites should report all deviations to their institution‟s IRB per local 
guidelines. Approvals/acknowledgments from the participating site IRB for protocol 
deviations should be submitted to MSK upon receipt. 
 
Other co rrespo ndence 
 
Participating sites should submit other correspondence to their institution‟s IRB 
according to local guidelines, and submit copies of official site IRB correspondence, 
including approvals and acknowledgements, to MSK. 
 
 
16.3.4 Document maintenance 
 
The MSK PI and participating site PI will maintain adequate and accurate records to 
enable the implementation of the protocol to be fully documented and the data to be 
subsequently verified. 
 
The participating sites will ensure that all regulatory documents and participating site 
IRB correspondences are maintained in an on-site regulatory binder and sent to MSK 
as outlined within the protocol. The regulatory binder on site will be reviewed by the 
MSK designated study monitor at monitoring visits. A regulatory binder for each site 
will also be maintained at MSK; this binder may be paper or electronic. 
 
After study closure, the participating sites will maintain all source documents, study 
related documents and CRFs for 7 years. 
16.4 
Noncompliance 
If a participating site is noncompliant with the protocol document, accrual privileges 
may be suspended and/or contract payments may be withheld, until the outstanding 
issues have been resolved. 
 
17.1 PROTECTION OF HUMAN SUBJECTS 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 59 of 90 
 
 
 
MSK affirms the subject‟s right to protection against invasion of privacy. In 
compliance with United States federal regulations, Celgene requires the Investigator 
to permit representati ves of Celgene Corporation and, when necessary, 
representati ves of the FDA or other regulatory authorities to review and/or copy any 
medical records relevant to the study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate 
from the  subject‟s statement of informed consent, it is the responsibility of the 
Investigator to obtain such permission in writing from the appropriate individual. 
 
MSK‟s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The 
use and disclosure of protected health information will be limited to the individuals 
described in the Research Authorization form. A Research Authorization form must 
be completed by the Principal Investigator and approved by the IRB and Privacy 
Board (IRB/PB). 
17.2 Privacy 
 
MSK‟s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The 
use and disclosure of protected health information will be limited to the individuals 
described in the Research Authorization form. A Research Authorization form must 
be completed by the Principal Investigator and approved by the IRB and Privacy 
Board (IRB/PB). 
 
 
17.3 Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of 
existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitali zation may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not 
considered an SAE. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 60 of 90 
 
 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant‟s last investigational treatment or 
intervention. Any events that occur after the 30-day period and that are at least 
possibly related to protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of 
Serious Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar 
days of the event. The IRB requires a Clinical Research Database (CRDB) SAE 
report be submitted electronically to the SAE Office as follows: 
Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All 
other reports should be sent to saemskind@mskcc.org. 
 
The report should contai n the following information: 
Fields populated from CRDB: 
• Subject‟s initials 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and ti tle 
 
 
Data needing to be entered: 
 
• The date the adverse event occurred 
• The adverse event 
• The grade of the event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject‟s condition 
o Indication if the subject remains on the study 
• If an amendment will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated Problem 
 
The PI‟s signature and the date it was signed are required on the completed report. 
The CRDB SAE report should be completed as per above instructions.  If 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 61 of 90 
 
 
 
appropriate, the report will be forwarded to the FDA by the SAE staff through the IND 
Office 
17.3.1 Serious Adverse Event (SAE) Definition 
 
A serious adverse event is one that at any dose (including overdose): 
• Results in death 
• Is life-threatening1 
• Requires inpatient hospitalization or prolongation of existi ng hospitali zation 
• Results in persistent or significant disability or incapacity2 
• Is a congenital anomaly or birth defect 
• Is an important medical event3 
• Pregnancy 
 
1“Life-threatening” means that the subject was at immediate risk of death at the time 
of the serious adverse event; it does not refer to a serious adverse event that 
hypothetically might have caused death if it were more severe. 
 
2“Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person‟s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above 
occurred. Important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above should 
also usually be considered serious. Examples of such events include allergic 
bronchospasm requiring intensi ve treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. A new diagnosis of cancer during 
the course of a treatment should be considered as medically important. 
In addition, an important medical event that may not result in death, be life- 
threatening, or require/prolong hospitali zation may be considered a SAE, when, 
based upon appropriate medical judgment, it may jeopardize the subject and/or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
 
Adverse Event Definition 
 
An adverse event (“AE”) is any untoward medical occurrence in a Study subject 
administered an investigational Study drug and that does not necessarily have a 
causal relationship with this treatment. An AE therefore can be any unfavorable and 
unintended sign (including laboratory finding), symptom or disease temporally 
associated with participation in a study, whether or not considered drug-related. In 
addition to new events, any increase in the severity or frequency of a pre -existing 
condition that occurs after the subject signs a consent form for participation is 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 62 of 90 
 
 
 
considered an AE. This includes any side effect, injury, toxicity, or sensiti vity 
reaction. 
 
A suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes of 
expedited safety reporting, „reasonable possibility‟ means there is evidence to 
suggest a causal relationship between the study drug and the adverse event. An 
adverse reaction (AR) means any adverse event caused by a study drug. This means 
there is reason to conclude that the study drug caused the event. 
 
An unexpected AE is any AE, the specificity or severity of which is not consistent with 
the current labeling for the Study drug. „Unexpected‟ also refers to adverse events or 
suspected adverse reactions that are mentioned in the Investigator Brochure as 
occurri ng with a class of drugs or as anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurri ng with the particular drug 
under investigation. 
Adverse Event Reporting 
 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event 
reporting. A copy of the CTCAE Version 4.0 can be downloaded from the CTEP 
homepage (http://ctep .info.nih.go v).http ://c tep.i nfo.ni h.go v). All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. All adverse clinical 
experiences, whether observed by the investigator or reported by the patient, must 
be recorded, with details about the duration and intensity of each patient‟s outcome. 
The investigator must evaluate each adverse experience for its relationship to the 
test drug and for its seriousness. Adverse experiences (AE) should be defined with 
regards to the toxicity attribution scale as follows: 
• Unrelated: The AE is clearly not related to the intervention. 
• Unlikely: The AE is doubtfully related to the intervention. 
• Possible: The AE may be related to the intervention. 
• Probable: The AE is likely related to the intervention. 
• Definite: The AE is clearly related to the intervention. 
 
The investigator must appraise all abnormal laboratory results for their cli nical 
significance.  If any abnormal laboratory result is considered cli nically significant, the 
investigator must provide details about the action taken with respect to the test drug 
and about the patient‟s outcome. 
 
AEs should be reported from the date of signed consent through 30 days post-last 
dose of Study drug or initiation of a new anti-cancer therapy, whichever occurs first. 
All AEs must be followed to resolution or to stabili zation if improvement or resolution 
is not expected.  Recording should be done in a concise manner using standard, 
acceptable medical terms.  The AE recorded should not be a procedure or a cli nical 
measurement (i.e., a laboratory value or vital sign) but should reflect the reason for 
the procedure of the diagnosis based on the abnormal measurement. Further, a 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 63 of 90 
 
 
 
procedure or surgery is not itself an AE; rather, the event leading to the procedure or 
surgery is considered an AE. 
 
If, in the Site Principal Investigator‟s judgment, a clinically significant worsening from 
baseline 
is 
observed 
in 
any 
laboratory or 
other 
test parameter 
(e.g., 
electrocardiogram “ECG” or angiogram), physical exam finding, or vital sign, a 
correspondi ng clinical AE should be recorded. If a specific medical diagnosis has 
been made, then that diagnosis should be recorded. 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). 
 
17.3.2 Pregnancies and Lactation Exposure 
Pregnancies ,lactation exposure and suspected pregnancies (including a positive 
pregnancy test regardless of age or disease state) of a female subject occurring 
while the subject is on lenalidomide and carfilzomib, or within 28 days of the 
subject‟s last dose of the study drugs, are considered immediately reportable events. 
Lenalidomide and carfilzomib are to be disconti nued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug 
Safety immediately by facsimile or email using the Pregnancy Initial Report Form. 
The pregnancy, lactation exposure, suspected pregnancy, or positi ve pregnancy test 
must be reported to Onyx within ten (10) calendar days by facsimile or email. The 
female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproducti ve toxicity for further evaluation and counseli ng. 
The Investigator will follow the female subject until completion of the pregnancy, and 
must notify Celgene Drug Safety and Onyx immediately about the outcome of the 
pregnancy (either normal or abnormal outcome) usi ng the Pregnancy Follow-up 
Report 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 and Onyx immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator‟s knowledge of the event using the 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 and Onyx immediately by facsimile, or other 
appropriate method, within 24 hours of the Investigator‟s knowledge of the event 
using the SAE Report Form. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 64 of 90 
 
 
 
Male S ubjec ts 
If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taki ng lenalidomide and/ or carfilzomib should notify the 
Investigator, and the pregnant female partner should be advised to call their 
healthcare provider immediately. 
In the case of a live “normal” birth, Celgene Drug Safety and Onyx should be advised 
as soon as the information is available. 
17.3.3 Expedited Reporting by MSK to Celgene 
Serious adverse events (SAE) are defined in Section 17.2.1. The MSK investigator 
must inform Celgene i n writing using a Celgene SAE form of any SAE within 24 ho urs 
of being a ware of the e vent. The written report must be completed and supplied to 
Celgene by facsimile within 24 -ho urs/1 b usiness da y. The initial report must be as 
complete as possible, including an assessment of the causal relationship between 
the event and the investigational product(s). 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 Celge ne tracking number (RV-NHL- 
PI-637) a nd the institutiona l p rotocol number s ho uld be i ncluded o n SAE reports (or 
on the fa x co ver letter) se nt to Celge ne. A copy of the fax transmission confirmation 
of the SAE report to Celgene should be attached to the SAE and retained with the 
patient records. 
 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr.  Suite 6000 
Berkeley Heights, NJ  07922 
 
Fax: 
(908) 673-9115 
E- mail:          drugsafe ty@celge ne .com 
 
 
17.3.4 Expedited Reporting by MSK to NCCN/Onyx 
Serious adverse events (SAE) are defined in Section 17.2.1. All SAEs that are judged 
to be unexpected according to the Investigator‟s Brochure and drug related must be 
considered for reporting and/or reported by Onyx (an Amgen subsidiary) to the 
relevant Regulatory Authority (ies) in accordance to IC H E2B guidelines: Clinical 
Safety Data Management Data Elements for Transmission of Individual Case Safety 
Reports and any applicable local regulations (e.g. 21 CFR 312, EU Clinical Trial 
Directive).  The Site Principal Investigator is also responsible for notifying the 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 65 of 90 
 
 
 
Institutional Review Board (“IRB”) or Independent Ethics Committee (“IEC”) in 
accordance with local regulations, of all appropriate SAEs. 
The MSK Principal Investigator must inform MSK‟s Safety Department of all 
expedited safety reports submitted to the relevant Regulatory Authorities via the 
contact information listed below. These notifications should be performed in parallel 
to the Regulatory Authority submissions (e.g., within seven (7) calendar days for any 
fatal or life-threatening SUSARs and within fifteen (15) calendar days for all other 
SUSARs, but in no case any later than 24 hours one (1) busi ness day from the 
submission date.  This report must be completed on a MSK SAE report form and 
provided to Onyx Drug Safety in English. All safety submissions to Onyx (via fax or 
email) must be accompanied by a completed SAE Report Cover Page. 
All other SAEs shall be reported and provided to MSK‟s Safety Department as 
described in section 17.2. All other SAEs (non-SUSARs) will be batched and 
submitted to Onyx as line listings on a monthly basis. Onyx Drug Safety reserves the 
right to review the eCRFs or source documents in response to any inquiries by 
Regulatory Authorities that the Institution may receive. 
 
The initial report must be as complete as possible, at a minimum including the 
serious adverse event term (s), subject identifier, date of awareness of the event, an 
assessment of the causal relationship between each event and the investigational 
Study drug(s), and name of the reporter (Principal Investigator or sub-investigator). 
Information not available at the time of the initial report (e.g., an end date for the 
adverse event or laboratory values recei ved after the report) must be documented on 
a follow-up MSK SAE (only for non-expedited SAEs) form, and submitted to Onyx in 
the same timelines as outlined above. Additional information shall also include SAE 
onset date, SAE stop date, outcome, date of first dose of Study drug(s), date of last 
dose of Study drug(s) prior to event onset, action taken with Study drug(s), Relevant 
history (including diagnostics, laboratory values, radiographs, concomitant 
medications, and event treatment and Site Principal Investigator‟s causality 
assessment to each event.  The Institutional protocol number should be included on 
all reports to Onyx Drug Safety.  MSK is responsible for creati ng an annual safety 
report of the overall conduct of the specific Study for distribution to the EC(s) and 
applicable Regulatory Authorities. Onyx, in addition, shall create an annual safety 
report includi ng listi ngs of all serious adverse drug reactions from both Onyx 
sponsored research and Investigator-Sponsored Trials, and Onyx will submit this 
report to the Regulatory Authorities in any country where there is cli nical 
development of the Study drug or where the Study drug is marketed. Additionally, 
the Institution is responsible for reporting SAEs to Onyx Drug Safety as described 
above to the following: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 66 of 90 
 
 
 
To report a Serious Adverse Event or other safety related information to Onyx 
Drug Safety please use: 
 
Drug Safety Hotline: 
650.266.2501 
Drug Safety Fax: 
888-814-8653 
Drug Safety E-mail: 
svc-ags-in-us@a mgen.com 
 
AND 
 
To report a Serious Adverse Event or other safety related information to the 
NCCN please use: 
NCCN Fax: 
(215) 358-7699 
 
NCCN Email: 
ORPReports@ncc n.org 
 
 
 
17.4 Serious Adverse Event (SAE) Reporting for Participating Sites 
Responsibilities of Partic ipating Sites 
• Participating sites are responsible for reporting all SAEs to their local IRB per 
local guidelines. Site IRB approvals/acknowledgments must be sent to MSK 
upon receipt. 
• Participating sites are responsible for submitting the SAE Report Form to MSK 
within 3 calendar days  of learning of the event. 
• When a  life-threatening event or death is unforeseen and indicates 
participants or others are at increased risk of harm, participating sites should 
notify the MSK PI as soon as possible but within 24 hours of the time the site 
becomes aware of the event. 
 
SAE contact information for the Coordinating Center is listed below: 
 
E- mail MSK Research Staff to the attention of MSK IRB# 14-179 
 
AND 
 
MSK PI: Steven Horwitz, MD Memorial Sloan Kettering Center 
Email: horwitzs@mskcc .org 
 
Respo nsibility of MSK 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 67 of 90 
 
 
 
• MSK Research Staff are responsible for submitting all SAEs to the MSK 
IRB/PB and funding entities  ( if applicable) as specified in 17.2, to Celgene 
as specified in 17.2.3 , and to Onyx/NCCN as specified in 17.2.4. 
• 
MSK is responsible for informing all participating sites about all unexpected 
SAEs that are either possibly, probably or definitely related to the study 
intervention within 15 days of recei ving the stamped SAE from the MSK 
IRB/PB. 
• 
MSK is responsible for informing all participating sites within 24 hours or 
on the next busi ness day about a life-threatening event or death that is 
unforeseen and indicates participants or others are at increased risk of 
harm. 
 
17.5 Safety Reports 
 
 
MSK must submit external safety reports to the MSK IRB/PB accordi ng to institutional 
guidelines. All external safety reports will be made available to the participating sites. 
Outside safety reports that are reportable to the MSK IRB/PB will be distributed to the 
participating sites immediately upon recei ving a stamped copy from the MSK IRB/PB. 
Participating sites will receive a special alert for any outside safety reports that warrant a 
significant change to the conduct of the study. Outside safety reports that are not reportable 
to the MSK IRB/PB, will be sent to the participating sites monthly. 
Participating sites are responsible for submitting safety reports to their local IRB per their 
local IRB guidelines. All local IRB approvals/acknowledgments of sa fety reports must be 
sent to MSK upon receipt. 
 
 
17.6 Unanticipated Problems 
 
Unanticipated problems involving risks to participants or others (UPs) are defined as 
any incident, experience or outcome that meets all of the following criteria: 
• Unanticipated (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent document; 
and (b) the characteristics of the subject population being studied; and 
• Related or possibly related to participating in the research (possibly related 
means there is a reasonable probability that the incident, experience or 
outcome may have been caused by procedures involved in the researc h); and 
• Suggests that the research place participants or others at a greater risk of 
harm (includi ng physical, psychological, economic, or social harm) than was 
previously known or recognized. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 68 of 90 
 
 
 
Participating sites are responsible for reporting all UPs to MSK as soon as possible 
but within 3 ca le ndar da ys of learning of the event. UPs that are SAEs should be 
reported to MSK via SAE Report form as per section 17.3 of this protocol. All other 
UPs should be reported to MSK in a memo signed by the site PI. 
MSK is responsible for submitti ng UPs to the MSK IRB/PB accordi ng to institutional 
guidelines. In addition, MSK is responsible for notifying participating sites of all non- 
SAE UPs that may affect the sites. 
 
 
18.1 INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenti ng professionals will 
explain full details of the protocol and study procedures as well as the risks involved 
to participants prior to their inclusion in the study. Participants will also be informed 
that they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicati ng their consent to participate. This consent 
form meets the requirements of the Code of Federal Regulations and the Institutional 
Review Board/Privacy Board of this Center. The consent form will include the 
following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supporti ve care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/i nteractions 
and to withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenti ng 
professional will fully explain the aspects of patient privacy concerni ng research 
specific information.  In addition to signing the IRB Informed Consent, all patients 
must agree to the Research Authorization component of the informed consent form. 
Each participant and consenti ng professional will sign the consent form. The 
participant must receive a copy of the signed informed consent form. 
 
18.2 Inform Consent Procedures for Participating Sites 
 
The investigators listed on the Consenting Professionals Lists at each participating 
site may obtain informed consent and care for the participants accordi ng to good 
clinical practice and protocol guidelines. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 69 of 90 
 
 
 
A note will be placed in the medical record documenting that informed consent was 
obtained for this study, and that the participant acknowledges the risk of participation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.0 
REFERENCES 
 
1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous 
lymphomas. Blood 105: 3768-85, 2005 
2. Querfeld C, Guitart J, Kuzel TM, Rosen ST. Primary cutaneous lymphomas: a review 
with current treatment options. Blood Rev 17: 131-42, 2003 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 70 of 90 
 
 
 
3. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 
patients with mycosis fungoid and Sezary syndrome cli nical prognostic factors and risk 
for disease progression. Arch Dermatol 139: 857-66, 2003 
4. Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S, et al. Survival 
outcomes and prognostic factors in mycosis fungoides/ Sezary syndrome: validation of 
the revised International Society for Cutaneous Lymphomas/European Organisation for 
Research and Treatment of Cancer staging proposal. J Clin Oncol 2010;28:4730–9. 
5. Talpur R, Singh L, Daulat S, et al. Long-term outcomes of 1263 patients with mycosis 
fungoides and sezary syndrom from 1982-2009. Clin Cancer Res: 18, 5051–60. 
6. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T- 
cell lymphoma study: pathology findings and cli nical outcomes [Multicenter Study]. 
Journal of cli nical oncology: official journal of the American Society of Clinical Oncology. 
2008;26(25):4124-4130. 
7. O'Connor OA, Wright J, Moskowitz C, et al Phase II cli nical experience with the novel 
proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and 
mantle cell lymphoma. J Clin Oncol 2005;23:676–84. 
8. Goy A, Younes A, McLaughli n P, et al. Phase II study of proteasome inhibitor bortezomib 
in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol2005; 23:667–75. 
9. Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib 
in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin 
Oncol 2007;25:4293–7. 
10. Zinzani PL, Khuageva NK, Wang et al. Bortezomib plus rituximab versus rituximab in 
patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular 
lymphoma: subgroup analysis of a randomized phase 3 trial. J Hematol Oncol 2012; 
22:67. 
11. Coiffier B, Osmanov EA, Hong X, et al Bortezomib plus rituximab versus rituximab alone 
in patients with relapsed, rituximab-naive or rituximab-sensiti ve, follicular lymphoma: a 
randomised phase 3 trial. Lancet Oncol 2011;12:773-784. 
12. Ruan J, Martin P, Furman RR, et al. Bortezomib plus CHOP-rituximab for previously 
untreated diffuse large B-cel lymphoma and mantle cell lymphoma. J Clin Oncol 2011; 
690-7. 
13. Lee J, Suh C, Kang HJ, et al. Phase I study of proteasome inhibitor bortezomib plus 
CHOP in patients with advanced, aggressi ve T-cell or NK/T-cell lymphoma. Ann 
Oncol 2008;19:2079–83. 
14. Dunleavy K, Piekarz RL, Zain J, Janik JE, Wilson WH, O'Connor OA, Bates SE. New 
strategies in peripheral T-cell lymphoma: understanding tumor biology and developing 
novel therapies. Clin Cancer Res. 2010 Dec 1;16(23):5608-17. 
15. Lee J, Suh C, Kang HJ, Ryoo BY, Huh J, Ko YH, Eom HS, Kim K, Park K, Kim WS. 
Phase I study of proteasome inhibitor bortezomib plus CHOP in patients with advanced, 
aggressive T-cell or NK/T-cell lymphoma. Ann Oncol. 2008 Dec;19(12):2079-83. 
16. Juvekar A, Manna S, Ramaswami S, Chang TP, Vu HY, Ghosh CC, Celiker 
MY, Vancurova I. Bortezomib induces nuclear translocation of IκBα resulting in gene- 
specific suppression of NF-κB--dependent transcription and induction of apoptosis in 
CTCL. Mol Cancer Res. 2011 Feb; 9(2):183-94. 
17. CarfilzomibcarfilzomibRasheed W, Bishton M, Johnstone R, et al. Histone deacetylase 
inhibitors in lymphoma and solid malignancies. Exp Rev Anticancer Ther 2008; 
8(3):413-432. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 71 of 90 
 
 
 
18. Sandor V, Bakke S, Robey R, et al. Phase I trial of the histone deactylase inhibitor, 
depsipeptide (FK901228, NSC 630176), in patients with refractory neoplasms. Clinical 
Cancer Research. 2002; 8:718-728. 
19. Piekarz RL. Responses and molecular markers in patients with peripheral T-cell 
lymphoma treated on a phase II trial of depsipeptide, FK228 [abstract]. ASCO. 2005. 
Abstract 3061. 
20. Querfeld C, Rosen S, Guitart J, et al. Phase II multicenter trial of lenalidomide: Clinical 
and immunomodulatory effects in patients with CTCL [Abstract]. Blood. 2011; 118:1638. 
21. Coiffier B, Pro B, Prince M et al. Results from a Pivotal, Open Label, Phase II Study of 
Romidepsin in Relapsed and Refractory Peripheral T-Cell Lymphoma After Prior 
Systemic Therapy. J Clin Oncol, 2011 ; 30(6) : 631-636. 
22. Corral LF, Haslett PAJ, Muller FW, Chen R, Wong LM, O‟campo CJ, Patterson RT, 
Stirling DI, Kaplan G. Differential cytokine modulation and T cell acti vation by two 
distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J 
Immunology. 1999; 163:380-386. 
23. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, Gupta 
D, Chauhan D, Treon SP, Richarson PG, Schlossman RL, Morgan GJ, Muller GW, 
Stirling DI, Anderson KC. Thalidomide and immunomodulatory derivatives augment 
natural ki ller cell cytotoxicity in multiple myeloma. Blood. 2001;98:210-216. 
24. Nakajima Y, Kim YB, Terano H. FR901228, a potent antitumor antibiotic, is a novel 
histone deacetylase inhibitor. Exp Cell Res. 1998;241:126-133. 
25. Zinzani P, Pellegrini C, Broccolli A, et al. Lenalidomide monotherapy for 
relapsed/refractory peripheral T-cell lymphoma not otherwise specified.  Leukemia & 
Lymphoma. 2011;52(8):1585-1588 
26. Dredge K, Horsfall R, Robinson S, Zhang L-H, Lu L, et al. Orally administered 
lenalidomide (lenalidomide) is anti-angiogenic in vivo and inhibits endothelial cell 
migration and Akt phosphorylation in vitro. Microvascular Research 69 (2005) 56-63. 
27. Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man H-W, et al. Enhancement of 
cytoki ne production and AP-1 transcriptional acti vity in T cells by thalidomide-related 
immunomodulatory drugs. J of Pharmacology and Exp Therapeutics. 2003 305:1222- 
1232. 
28. Deuck G, Chua N, Prasad A, et al. Interim report of a phase II cli nical trial of 
lenalidomide for T-cell non Hodgkin lymphoma. Cancer 2010; 116: 4541-8. 
29. Ocio  EM,  Vilanova  D,  San-Segundo  L  et  al.  Triple  combinations  of  the  HDAC 
inhibitor panobinostat (LBH589) and dexamethasone with either lenalidomide or 
bortezomib are highly effecti ve in a multiple myeloma mouse model. Blood, ASH Annual 
Meeting Proceedings 2007 (Abstr 1514) 
30. Ocio EM, Vilanova D, Atadja P et al. In vitro and in vivo rationale for the triple 
combination of panobinostat (LBH589) and dexamethasone with either bortezomib or 
lenalidomide in multiple myeloma.  Haemato logica. 2010 May; 95(5):794-803. 
31. Verhelle D, Corral LG, Wong et al. Lenalidomide and CC-4047 inhibit the proliferation of 
malignant B cells while expanding normal CD 34+ progenitor cells. Cancer Res 2007; 
67(2): 746-55. 
32. Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human 
multiple myeloma cells by proteasome inhibitor bortezomib and histone deacetylase 
inhibitors. Clin Cancer Res 2004; 10:3839-52. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 72 of 90 
 
 
 
33. Richardson P, Weber D, Mitsiades C, et al. A phase I study of Vorinostat, Lenalidomide, 
and Dexamethasone in patients with relapsed or relapsed and refractory multiple 
myeloma: Excellent tolerability and promising acti vity in a heavily pretreated population. 
Blood. 2010;116:813 Abs #1951 
34. Kaufman J, Shah J, Laubach J et al. Lenalidomide, Bortezomib, and Dexamethasone 
(RVD) in combination with vorinostat as front-line therapy for patients with multiple 
myeloma (MM): Initial results of a phase 1 trial.  Blood. 2010;116(21):1251 Abs #3034. 
35. Siegel D, Weber D, Misiades C, et al. Combined Vorinostat, Lenalidomide, and 
Dexamethasone therapy in patients with relapsed or refractory multiple myeloma: A 
Phase I study. Siegel D, et al. Blood. 2009;114(22):129 Abs #305 
36. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome 
inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple 
myeloma. Mol Cancer Ther November 201110; 2034-42. 
37. Kikuchi J, Wada T, Shimi zu R, Izumi T, Akutsu M, Mitsunaga K, et 
al. Histone 
deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple 
myeloma.Blood 2010;116:406–17. 
38. Kikuchi   J,   Yamada   S,   Koyama   D,   Wada   T,   et   al.   The   Novel   Orally 
Active Proteasome Inhibitor K-7174 Exerts Anti-myeloma Acti vity in Vitro and in Vivo by 
Down-regulating the Expression of Class I Histone Deacetylases. J Biol Che m. 2013 
39. Bhatt   S, Ashlock    BM, Toome y    NL, et    al.    Efficacious proteasome/HDAC 
inhibitor combination therapy for primary effusion lymphoma. J Cli n Inves t. 2013 Jun 
3;123(6):2616-28. 
40. Bastian L, Hof J, Pfa u  M, Fichtner  I, Eckert  C, He nze  G, Prada  J, vo n  Stackelberg  
A, Seeger K, Sha lapour S.Synergistic acti vity of bortezomib and HDACi in preclinical 
models of B-cell precursor acute lymphoblastic leukemia via modula tion of p53, 
PI3K/AKT, and NF-κB. Clin Cancer Res . 2013 Mar 15;19(6):1445-57 
41. Hua ng H, Li u N, Ya ng C, Liao S, Guo H, Zhao K, Li X, Li u S, Gua n L, Li u C, Xu L, Zha ng  
C, Song    W, Li    B, Ta ng    P, Dou    QP, Liu    J.     HDAC     inhibitor L-carnitine 
and proteasome inhibitor bortezomib synergistically exert anti-tumor acti vity in vitro and 
in vivo. PLoS One . 2012;7(12):e52576.. 
42. Gatti L, Be nedetti V, De Cesare M, Corna E, Cincine lli R, Zaffa roni N, Zunino F, Perego 
P. Synergistic interaction between the novel histone deacetylase inhibitor ST2782 and 
the proteasome inhibitorbortezomib in platinum-sensiti ve and resistant ovarian 
carcinoma cells. J Inorg Biochem. 2012 Aug;113:94-101. 
43. Millward M, Price T, To wnsend A, Swee ney C, Spencer A, S uk umara n S, Longe necker  
A, Lee   L, La y   A, Sha rma   G, Gemmill   RM, Drabkin    HA, L lo yd    GK,Ne uteboom  
ST, McConke y DJ, Palladino MA, Spear MA.Phase 1 clinical trial of the novel 
proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in 
patients with melanoma, pancreatic and lung cancer based on in vitro assessments of 
the combination. Inves t New Drugs . 2012 Dec;30(6):2303-17. 
44. Kaufman JL, Shah JJ, Laubach JP, et al. Lenalidomide, bortezomib, and 
dexamethasone (RVD) in combination with vorinostat as front-line therapy for patients 
with multiple myeloma (MM): results of a phase I study. Blood. 2012;120 (abstract 336) 
45. Demo SD, Kirk CJ, Aujay MA, et al. Anti-tumor acti vity of PR-171, a novel irreversible 
inhibitor of the proteasome. Cancer Res. 2007;67:6383–91. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 73 of 90 
 
 
 
46. Meiners S, Heyken D, Weller A, et al. Inhibition of proteasome activity induces concerted 
expression of proteasome genes and de novo formation of mammalian proteasomes. J 
Biol Chem. 2003 Jun 13; 278(24):21517–25. 
47. Sandor V, Senderowicz, Mertins, et al. P21-dependent G1 arrest with downregulation of 
cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. 
British Journal of Cancer. 2000; 83(6): 817-825. 
48. Sandor V, Bakke S, Robey R, et al. Phase I trial of the histone deactylase inhibitor, 
depsipeptide (FK901228, NSC 630176), in patients with refractory neoplasms. Clinical 
Cancer Research. 2002; 8:718-728. 
49. Ueda H, Nakajima H, Hori Y, Goto T, et al. Action of FR901228, a novel antitumor 
bicyclic depsipeptide produced by chromobacteri um violaceum no. 968, on Ha-ras 
transformed NIH3T3 cells. Biosci Biotech Biochem. 1994;58:1579-1583. 
50. Fecteau K, Mei J, Wang HC, et al. Differential modulation of signali ng pathways and 
apoptosis of ras transformed lOTl/2 cells by the depsipeptide FR901228. J Pharmacol 
Exp Ther. 2002; 300:890-899. 
51. Onyx Pharmaceuticals. Investigator‟s Brochure for Carfilzomib. Version 12.0. August 28, 
2013. 
52. Ottmann OG, Spencer A, Prince HM, et al., Phase IA/II Study of Oral Panobinostat 
(LBH589), a Novel Pan-Deacetylase Inhibitor (DACi) Demonstrati ng Efficacy in Patients 
with Advanced Hematologic Malignancies. Blood, 2008. 112(11): 352-353. 
53. Younes A,Ong TC, Ribrag V. Efficacy of Panobinostat in Phase II Study in Patients with 
Relapsed/Refractory Hodgkin Lymphoma (HL) After High-Dose Chemotherapy with 
Autologous Stem Cell Transplant. Blood, 2009. 114(22): 380-381. 
54. Philip T, Guglielmi C, Hagenbeek A, et al., Autologous bone marrow transplantation as 
compared with salvage chemotherapy in relapses of chemotherapy-sensitive non- 
Hodgkin's lymphoma. N Engl J Med, 1995. 333(23): 1540-5. 
55. Bereshchenko OR, Gu W, Dalla-Favera R. Acetylation inacti vates the transcriptional 
repressor BCL6. Nat Genet, 2002. 32(4): 606-13. 
56. Witzig TE, Wiernik PH, Moore T, et al., Lenalidomide Oral Monotherapy Produces 
Durable Responses in Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma. 
Journal of Clinical Oncology, 2009. 27(32): 5404-5409. 
57. Boll B, Borchmann P, Topp MS et al., Lenalidomide in patients with refractory or multiple 
relapsed Hodgki n lymphoma. Br J Haematol, 2010. 148(3): 480-2. 
58. O'Connor, O. A. et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the 
novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin 
Cancer Res 15, 7085-7091, doi:10.1158/1078-0432.CCR-09-0822 (2009). 
59. Siegel, D. S. et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients 
with relapsed and refractory multiple myeloma. Blood 120, 2817-2825, doi:10.1182/blood- 
2012-05-425934 (2012). 
60. Vij, R. et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib 
in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 119, 
5661-5670, doi:10.1182/blood-2012-03-414359 (2012). 
61. Berenson, J. R. et al. A Phase 1, Dose-Escalation Study (CHAMPION-1) Investigating Weekly 
Carfilzomib In Combination With Dexamethasone For Patients With Relapsed Or Refractory 
Multiple Myeloma. Blood 122 (2013). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 74 of 90 
 
 
 
20.0 
APPENDICES 
 
Appendix A – Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods 
Risks Associated with Pregnancy 
 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor 
has the effect of the lenalidomide on human eggs and sperm. Lenalidomide is structurally 
related to thalidomide. Thalidomide is a known human teratogenic acti ve substance that 
causes severe life-threatening birth defects. An embryofetal development study in animals 
indicates that lenalidomide produced malformations in the offspring of female monkeys who 
received the drug during pregnancy. The teratogenic effect of lenalidomide in humans 
cannot be ruled out. Therefore, a risk minimization plan to prevent pregnancy must be 
observed. 
All study participants must be registered into the mandatory Revlimid REMS™, and be 
willing and able to comply with the requirements of REMS™.. 
Criteria for females of c hildbeari ng pote ntial (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female who: 1) 
has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecuti ve months). 
The inves tigator must e ns ure tha t: 
• Females of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that she has an adequate level of understanding 
• Females NOT of childbearing potential acknowledge that she understands the 
hazards and necessary precautions associated with the use of lenalidomide 
• Male patients taking lenalidomide acknowledge that he understands that traces of 
lenalidomide have been found in semen, that he understands the potential 
teratogenic risk if engaged in sexual acti vity with a female of childbearing potential, 
and that he understands the need for the use of a condom eve n if he has had a 
vasectomy, if engaged in sexual activity with a female of childbearing potential. 
Contraceptio n 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete absti nence from 
heterosexual intercourse during the following time periods related to this study: 1) for at 
least 28 days before starting lenalidomide; 2) throughout the entire duration of lenalidomide 
treatment; 3) during dose interruptions; and 4) for at least 28 days after lenalidomide 
discontinuation. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 75 of 90 
 
 
 
The two methods of reliable contraception must include one highly effecti ve method and 
one additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effecti ve and 
additional effecti ve methods of contraception: 
o Highly effecti ve methods: 
▪ Intrauterine device (IUD) 
▪ Hormonal (birth control pills, injections, implants) 
▪ Tubal ligation 
▪ Partner‟s vasectomy 
o Additional effective methods: 
▪ Male condom 
▪ Diaphragm 
▪ Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are not 
recommended. If a patient is currently usi ng combined oral contraception the patient should 
switch to one of the effective method listed above. The risk of venous thromboembolism 
continues for 4−6 weeks after discontinuing combined oral contraception. The efficacy of 
contraceptive steroids may be reduced during co-treatment with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased 
risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic 
antibiotics should be considered particularly in patients with neutropenia. 
Pregna nc y tes ting 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of chi ldbearing potential, including females of childbearing potential 
who commit to complete absti nence, as outlined below. 
Before starting lenalidomide 
Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
prescribing lenalidomide. The first pregnancy test must be performed within 10-14 days 
prior to prescribing lenalidomide and the second pregnancy test must be performed within 
24 hours prior to prescribing lenalidomide. The patient may not receive lenalidomide until 
the Investigator has verified that the results of these pregnancy tests are negative. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 76 of 90 
 
 
 
Male Patients: 
Must agree to practice complete abstinence or agree to use a condom during sexual contact 
with pregnant females or females of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 28 days following 
lenalidomide disconti nuation, even if he has undergone a successful vasectomy. 
During study participation and for 28 days following lenalidomide discontinuation 
Female Patients: 
• FCBP with regular or no menstrual cycles must agree to have pregnancy tests 
weekly for the first 28 days of lenalidomide treatment, including dose interruptions 
and then every 28 days throughout the remaining duration of lenalidomide treatment, 
including dose interruptions, at lenalidomide disconti nuation, and at Day 28 following 
lenalidomide discontinuation. If menstrual cycles are irregular, the pregnancy testing 
must occur weekly for the first 28 days of lenalidomide treatment, including dose 
interruptions, and then every 14 days throughout the remaining duration of 
lenalidomide treatment, including dose interruptions, at lenalidomide discontinuation, 
and at Day 14 and Day 28 following lenalidomide disconti nuation. 
• At each visit, the Investigator must confirm with the FCBP that she is continui ng to 
use two reliable methods of birth control at each visit during the time that birth control 
is required. 
• If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide 
must be immediately discontinued. 
• Pregnancy testi ng and counseli ng must be performed if a patient misses her period 
or if her pregnancy test or her menstrual bleeding is abnormal. Lenalidomide 
treatment must be temporarily discontinued during this evaluation. 
• Females must agree to abstai n from breastfeedi ng during study participation and for 
at least 28 days after lenalidomide disconti nuation. 
Male Patients: 
• Must practice complete abstinence or use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire duration 
of lenalidomide treatment, during dose interruptions and for at least 28 days following 
lenalidomide disconti nuation, even if he has undergone a successful vasectomy. 
• If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 
Additional preca utio ns 
• Patients should be instructed never to give lenalidomide to another person. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 77 of 90 
 
 
 
• Female patients should  not donate blood during therapy and for at least 28 days 
following disconti nuation of lenalidomide. 
• Male patients should not donate blood, semen or sperm during therapy or for at least 
28 days following discontinuation of lenalidomide. 
• Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle 
of therapy. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 78 of 90 
 
 
 
 
Appendix B – Canadian Cardiovascular Society Angina Classification 
 
Class I 
Ordinary physical acti vity, (e.g., walking and climbing stairs) does not cause 
angina; angina occurs with strenuous, rapid, or prolonged exertion at work or 
recreation. 
Class II 
Slight limitation of ordinary activity; angina occurs on walking or climbi ng stairs 
rapidly; walking uphill; walking or stair climbing after meals, in cold, in wind, or 
under emotional stress; or only during the few hours after awakening; when 
walking > 2 blocks on level ground; or when climbing more than 1 flight of stairs 
at a normal pace and in normal conditions. 
Class III 
Marked limitation of ordinary physical activity; angina occurs on walking 1 to 2 
blocks on level ground or climbi ng 1 flight of stairs at a normal pace in normal 
conditions. 
Class IV 
Inability to perform any physical activity without discomfort; anginal symptoms 
may be present at rest. 
Campeau L. Grading of angina pectoris. Circulation 1975; 54:522-3. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 79 of 90 
 
 
 
Appendix C – New York Heart Association Classification of Cardiac Disease 
 
NYHA Classification of Cardiac Disease 
 
Class 
Functional Capacity 
Objective 
Assessment 
I 
Patients with cardiac disease but without resulti ng 
limitations of physical activity. Ordinary physical acti vity 
does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
No objective 
evidence of 
cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation 
of physical acti vity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain. 
Objecti ve evidence 
of minimal 
cardiovascular 
disease. 
III 
Patients with 
cardiac disease resulting in marked 
limitation of physical acti vity. They are comfortable at 
rest. Less than 
ordinary 
activity 
causes fatigue, 
palpitation, dyspnea, or anginal pain. 
Objecti ve evidence 
of moderately 
severe 
cardiovascular 
disease. 
IV 
Patients with cardiac disease resulting in inability to carry 
on any physical activity without discomfort. Symptoms of 
heart failure or the anginal syndrome may be present 
even at rest. If any physical acti vity is undertaken, 
discomfort is increased. 
Objecti ve evidence 
of severe 
cardiovascular 
disease. 
Source: The Criteria Committee of New York Heart Association. Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: 
Little, Brown & Co; 1994:253-256. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 80 of 90 
 
 
 
Appendix D – Grading Scales for modified Severity-Weighted Assessment Tool 
mSWAT 
 
1. 
Total Body Surface Area (TBSA) Involve ment b y Skin Disease 
The body is divided into 12 regions with pre-assigned %TBSA based on the burn 
literature. The extent of ski n disease in each region is quantified by using the 
patient‟s palm to measure the %TBSA involvement within region: patient‟s palm with 
4 fingers (excluding the thumb) is 1% of TBSA. Patient‟s palm without fingers is 0.5% 
of TBSA. The patient‟s palm with 4 fingers is traced on a transparency sheet at the 
baseline visit, usi ng a permanent marker that will not rub off or smear. The 
transparency of the patient‟s palm should be used in all mSWAT assessments during 
the course of the cli nical study. The transparency will be labeled with the patient‟s 
study ID number kept in the patient‟s study fi le on site. Using the baseli ne visit 
transparency of the patient‟s palm, the investigator will measure and record on the 
electronic case report form (Example of table from eCRF is given below) the %TBSA 
for each lesion type within each of the 12 regions. 
 
2. 
Seve rity Weighting Factor 
The severity weighting factors will be the following: 
1= patch (flat erythema or erythema with mild infiltration) 
2=plaque (elevated erythema or erythema with moderate infiltration) 
4= tumor or ulceration (erythema with fissuri ng, ulceration or tumor) 
Patch is defined as abnormal skin not elevated from normal ski n. A 
plaque is defined as abnormal skin elevated from normal skin by < 5 
mm. A plaque elevated ≥ 5 mm is a tumor. 
 
3. 
Calc ula ting Ski n Scores 
The sum of %TBSA by lesion is derived by summing the %TBSA from all regions 
affected by the lesion. The sum of %TBSA across lesion types (patches, plaques and 
tumors) within each region cannot exceed the %TBSA for the region. For example, 
the %TBSA for the head region is 7%. The sum of %TBSA across lesion types from 
head can only range from 0-7%. The ski n score subtotal by lesion type are derived by 
multiplying the sum of %TBSA for patches from all regions by 1, sum of %TBS of 
plaques from all regions by 2, and the sum of %TBSA of tumors or ulcers from all 
regions by 4. The ski n score total is derived from summing the skin score subtotals  
for patches, plaques and tumors or ulcers. The ski n score total is dimensionless with 
a scale of 0 to 400. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 81 of 90 
 
 
 
 
 
 
Responses will be determined by the criteria described in the table below. 
Progression of disease while on treatment should be confirmed by a second 
assessment 1-4 weeks later so that patients who experience a temporary flare of 
disease due to skin infection or other intercurrent illnesses are not removed from the 
study prematurely. 
Assessment 
Description 
Status
Completely clear 
No evidence of disease; 100% improvement 
CR 
Marked Improvement 
Greater than or equal to 50% decrease in ski n scores 
compared 
PR 
Slight Improvement 
Less than 50% decrease in skin scores compared to 
baseline 
SD 
Worse 
≥ 25% increase in skin scores compared to baseline while 
the patient is actively taki ng the study drug 
or 
≥ 50% increase in the sum of the products of the greatest 
diameters of pathologically positi ve lymph nodes (should 
be documented by biopsy) compared to baseli ne while the 
patent is actively taki ng the study drug. 
PD 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 82 of 90 
 
 
 
Appendix E – Medications That May Cause QTc Prolongation 
 
The following table presents a list of drugs that may prolong the QTc.  These drugs are 
prohibited during the study.  Romidepsin may be administered after a 5 half-life washout 
period elapses following the use of these drugs.  Washout period is based on roughly 
5 half-lives and rounded to a convenient interval. Patients taking lower risk drugs not known 
to interact with the study drug will be monitored and may be allowed on study. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 83 of 90 
 
 
 
Medications That May Cause QTc Prolongation 
 
Compound 
(Brand Name) 
Compound Half-Life 
Possible 
Washout 
Period 
(Hours) 
Possible 
Washout 
Period 
(Days) 
Antiarrhythmics 
Amiodarone (Cordarone, Pacerone) 
58 
days 
(15-142) 
36 days (active metabolite) 
180 
Disopyramide (Norpace, Norpace CR) 
6.7 hr (4-10) 
36 
Dofetilide (Tikosyn) 
10 hr 
48 
Flecainide (Tambocor) 
20 hr (12-27) 
5 
Ibutilide (Corvert) 
6 hr (2-12) (variable among patients) 
36 
Procainamide 
(Pronestyl, 
Procanbid, 
Procan) 
3-4 
hr 
for 
PA and 
NAPA 
(active 
metabolite) 
24 
Quinidine 
(Quinaglute, 
Cardioquin, 
Quinidex) 
6-8 hr in adult; 3-4 hr in children 
36 
Sotalol (Betapace, Sorine) 
12 hr 
72 
Antibiotics 
Azithromycin  (Zithromax,   Zithromax  Tri- 
Pack, Zithromax Z-Pak, Zmax) 
Immediate  release:  68-72  hr,  extended 
release 59 hr 
12-15 
Clarithromycin (Biaxin, Biaxin XL) 
Nonlinear 
PK 3-4 hr (250 mg Q12) 
5-7 hr (500 mg Q12) 
36 
Erythromycin 
(Benzamycin,  Eyrc, E-
glades, Erygel, E-solve 2, Akne-Mycin, 
Eryderm, Sansac, Erythro-Statin, Erymax, 
Staticin, T-Stat, C-solve-2, Erycetter, PCE, 
Ery-Tab, 
E-Mycin, 
E-Base, 
 
E.E.S., 
Eryped,      E.E.S      200,      E.E.S      400, 
Pediamycin, Eryzole, Erythrocin) 
Each salt form has different half-life 
Gatifloxacin (Tequin, Tequin Teqpaq) 
7-14 hr 
48 
Grepafloxacin (Raxar) 
16 hr 
3 
Antibiotics (cont’d) 
Levofloxacin (Levaquin, Quixin, Elequin) 
6-8 hr 
48 
Moxifloxacin (Avelox, Vigamox) 
12 ± 1.3 hr 
72 
Sparfloxacin (Zagam) 
20 hr (16-30) 
4 
Telithromycin (Ketex) 
2-3 hr 
24 
Anticonvulsants 
Felbamate (Felbatol) 
20-23 hr 
5 
Fosphenytoin (Cerebyx) 
12-29 hr 
6 
Antidepressants 
Venlafaxine (Effexor) 
5 
± 
2 
hr 
for 
parent 
comp. 
11± 2 hr for OVD (active metabolite) 
60 
Antidiarrheals 
Octreotide (Sandostatin) 
1.7 hr 
12 
Antiemetics 
Dolasetron (Anzemet) 
8.1 hr 
Droperidol (Inapsin) 
2.2 hr 
10 
Domperidone (Motilium) 
7-8 hr 
48 
Palonosetron (Aloxi) 
40 hr 
10 
Antihypertensives 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 84 of 90 
 
 
 
 
Compound 
(Brand Name) 
Compound Half-Life 
Possible 
Washout 
Period 
(Hours) 
Possible 
Washout 
Period 
(Days) 
Moexipril/Hydrochlorothiazide  (Uniretic) 
2-9 
hr(include 
active 
moexipril; 
5.6-14.8 hr for HCTZ 
metabolite) 
for 48 
Antimalarials 
Halofantrine (Halfan) 
6-10 days (variable among individuals) 
45 
Quinidine 
(Quinaglute, 
Quinidex) 
Cardioquin, 
6-8 hr in adult; 3-4 hr in children 
36 
Antimanics 
Lithium (Eskalith, Lithobid, Lithonate) 
24 hr (10-50) 
7 
Antineoplastics 
Arsenic trioxide (Trisenox) 
Not characterized 
Tamoxifen (Nolvadex) 
5-7 days (biphasic) 
30 
Antiprotozoals 
Pentamidine (NebuPent, Pentam) 
6.4 ± 1.3 hr 
36 
Antipsychotic agents 
Chlorpromazine (Thorazine) 
30 ± 7 hr 
7 
Haloperidol (Haldol) 
18 ± 5 hr 
5 
Mesoridazine (Serentil) 
24-48 hr (animal study) 
10 
Pimozide (Orap) 
55 hr 
14 
(Continued from previous page) 
Antipsychotic agents (cont’d) 
Quetiapine (Seroquel) 
6 hr 
36 
Risperidone (Risperdal, Risperdal Consta) 
3-20  hr  (extensive  to  poor  metabolizer) 
9-hydroxyrisperidone (active metabolite) T 
½ 
= 
21-30 
hr 
(extensive 
to 
poor 
metabolizer) 
4 
Thioridazine (Mellaril) 
20-40 hr (Phenothiazines) 
7 
Ziprasidone (Geodon, Zeldox) 
7 hr 
36 
Antispastics 
Tizanidine (Zanaflex) 
2.5 hr 
12 
Antivirals 
Amantadine (Symadine, Symmetrel) 
17 ± hr (10-25) 
4 
Foscarnet (Foscavir) 
87.5 
± 
41.8 
(distribution and release from bone) 
hr 
20 
Analgesics 
Levomethadyl (Orlaam) 
Multiple compartment 
metabolite 
2.6 
day 
2 
day 
for 
4 day for dinor-LAAM 
PK 
for 
with active 
LAAM, 
nor-LAAM, 
20 
Asthma medications 
Salmeterol 
(Advair 
Serevent Diskus) 
Diskus, 
Serevent, 
5.5 hr (only one datum) 
36 
Calcium channel blockers 
Bepridil (Vascor) 
42 hr (26-64) 
10 
Isradipine (DynaCirc) 
8 hr (multiple metabolites) 
48 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 85 of 90 
 
 
 
 
Compound 
(Brand Name) 
Compound Half-Life 
Possible 
Washout 
Period 
(Hours) 
Possible 
Washout 
Period 
(Days) 
Nicardipine (Cardene) 
~2 hr post IV infusion 
12 
Cholinergic enhancers 
Cisapride (Propulsid) 
6-12 hr, up to 20 hr 
60 
Diuretics 
Indapamide (Lozol) 
14 hr (biphasic elimination) 
3 
Immunosuppressants 
Tacrolimus (Prograf, Protopic) 
~34  hr  in  healthy  patients  ;  ~19  hr  in 
kidney transplant 
7 
Migraine medications 
Naratriptan (Amerge) 
6 hr 
36 
Sumatriptan (Imitrex) 
2.5 hr 
12 
Zolmitriptan (Zomig) 
2.8-3.7 hr (higher in female) 
18 
Narcotic pain relievers 
Methadone (Dolophine, Methadose) 
15-30 hr 
7 
Sedatives 
Chloral hydrate 
Readily 
converted 
to 
Trichloroethanol 
(active metabolite T½= 7-10 hour) 
48 
References: 
Physician‟s Desk Reference 2002 
Facts and Comparisons (update to June, 2000) 
The Pharmacological Basis of Therapeutics 9th Edition, 1996 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 86 of 90 
 
 
 
Appendix F – Medications That May Inhibit CYP3A4 
The following table presents a list of drugs that may inhibit C YP3A4. As romidepsin is 
predominately metabolized by C YP3A4, inhibition of this enzyme could result in elevated 
plasma levels or increased exposure to romidepsin. Romidepsin may be administered after 
a 5 half-life washout period elapses following the use of these drugs. Washout period is 
based on roughly 5 half-lives and rounded to a convenient interval. 
 
Medications That May Inhibit CYP3A4 
Compound 
(Brand Names) 
Compound 
Half-Life 
Possible 
Washout 
Period 
-
Hours 
Possible 
Washout 
Period 
-
Days 
Azole Antifungals 
Clotrimazole (Mycelex, Lotrimin, Lotrisone) 
Not available 
Ketoconazole (Nizoral, Ketozole) 
6 hr (2-8 hr) 
30 hr 
Itraconazole (Sporanox) 
21 hr 
5 days 
Fluconazole (Diflucan) 
3 hr 
15 hr 
Miconazole (Monistat) 
57 hr 
11 days 
HIV Protease Inhibitors 
Ritonavir (Norvir, Kaletra) 
4 hr 
20 hr 
Indinavir (Crixivan) 
2 hr 
10 hr 
Saquinavir (Invirase, Fortovase) 
5 hr 
25 hr 
Nelfinavir (Viracept) 
4 hr 
20 hr 
Delavirdine (Rescriptor) 
6 hr 
30 hr 
Macrolide Antibiotics 
Troleandomycin (Tao) 
Not available 
Erythromycin (Benzamycin, Eyrc, E-glades, Erygel, E- 
solve 2, Akne-Mycin, Eryderm, Sansac,  Erythro- 
Statin, Erymax, Staticin, T-Stat, C-solve-2, Erycetter, 
PCE,  Ery-Tab,  E-Mycin,  E-Base,  E.E.S.,  Eryped, 
E.E.S 
200, 
E.E.S 
400, 
Pediamycin, 
Eryzole, 
Erythrocin) 
2 hr 
10 hr 
Clarithromycin (Prevpac, Biaxin) 
5 hr 
25 hr 
Other Antibiotics 
Chloramphenicol (Chloromycetin, Chloroptic) 
4 hr 
20 hr 
Ciprofloxacin (Ciprodex, Cipro, Ciloxan) 
4 hr 
20 hr 
Norfloxacin (Noroxin, Chibroxin) 
4 hr 
20 hr 
Serotonin Reuptake Inhibitors (SSRI’s) 
Fluoxetine (Prozac, Sarafem, Symbyax) 
Fluoxetine  5 
days 
Norfluoxetine 
(active 
metabolite) 
12  days  (4- 
16 days) 
60 days 
Nefazodone (Serzone) 
3 hr 
15 hr 
Fluvoxamine (Luvox) 
16 hr 
3 days 
Antiemetics 
Aprepitant (Emend) 
11 
hr 
(9-13 hr) 
2 days 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 87 of 90 
 
 
 
 
Compound 
(Brand Names) 
Compound 
Half-Life 
Possible 
Washout 
Period 
-
Hours 
Possible 
Washout 
Period 
-
Days 
Oral Contraceptives 
Ethinyl-estradiol  (Kariva,  Velivet,  Mircette,  Desogen, 
Cyclessa, 
Ortho-Cept, 
Yasmin, 
Demulen, 
Zovia, 
NuvaRing, 
Seasonale, 
Lessina, 
Portia, 
Levlite, 
Nordette, Aviane, Enpresse, Trivora, Levora, Alesse, 
Triphasil, Ortho Evra, Ovcon, Nortrel, Gencept, 
Balziva, Brevicon, Norinyl, Norethin, Aranelle, Ortho- 
Novum, Modicon, Tri-Norinyl, Femhrt, Junel, Loestrin, 
Estrostep, Microgestin, Tri-Previfem, Previfem, Tri- 
Sprintec, Sprintec, Ortho Tri-Cyclen, Cryselle, Low- 
ogestrel, Ogestrel, Lo/Ovral, Ovral) 
15 hr 
3 days 
Oral Contraceptives (cont’d) 
Mifepristone (Mifeprex, RU-486) 
18 hr 
4 days 
Gestodene 
20-22 hr 
5 days 
Histamine H2-Receptor Antagonists 
Cimetidine (Tagamet) 
2 hr 
10 hr 
Antiarrhythmic Drugs 
Quinidine (Quinaglute, Cardioquin, Quinidex) 
7 hr 
35 hr 
Amiodarone (Cordarone, Pacerone) 
53 
days 
(15-142 
days) 
265 days 
Antihypertensives 
Diltiazem (Taztia, Cartia, Cardizem, Dilt-CD, Dilacor, 
Teczem, Tiamate. Trizac) 
3 
hr 
[7 
hr 
for 
extended 
release 
(Trizac)] 
15 
hr 
35 hrs 
Verapamil 
(Tarka, 
Verelan, 
Isoptin, 
Covera-HS, 
Calan) 
8 hr 
40 hr 
Calcium Channel Blocker 
Mibefradil (Posicor) 
21 
hr 
(17-25 hr) 
5 days 
Others 
Grapefruit juice 
Not available 
Star fruit 
Not available 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 88 of 90 
 
 
 
 
 
Appendix G – Study Calendar 
 
Table 6: Study Evaluation Schedule 
Procedure 
Screening 
Cycle 1 
Cycle 2 and beyond 
End of 
study 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
End of 
cycle 
Record prior medications, treatments 
X 
Record prior anti-cancer therapies 
X 
Physical  examination1 
X 
X 
X 
X10 
X 
X 
ECOG performance status1 
X 
X 
X 
X 
12 Lead ECG2 
X 
X 
X 
X 
X 
ECHO or cardiac MRI 
X 
Hematology 
X 
X 
X 
X10 
X12 
X12 
X 
LDH3 
X 
X12 
Electolytes3 
X 
X 
X 
X10 
X12 
X12 
X 
Li ver function analysis3 
X 
X 
X 
X10 
X12 
X 
Pregnancy  testing4 
X 
X 
X 
X10 
X12 
X 
REMS™ program (patient 
enrollment) 
X 
Start lenalidomide5 
X 
X 
Carfilzomib* 
X 
X 
X 
X 
Romidepsin* 
X 
X 
X 
X 
Disease/ Response assessment 6,7 
X 
X9,14 
X11 
Record adverse events8 
X 
X 
X10 
X 
X 
X13 
X 
Record concomitant  medications 
X 
X 
X 
X10 
X 
X 
X13 
X 
Table 7 Leg en d 
* For cycle 1, study assessments and/or romidepsin and carfilzomib dosing may be delayed a) up to 3 days in the 
setting  of  grade  3  thrombocytopenia  or  neutropenia  that  recovers  or    b)  up  to  1  day  for  other  scheduling 
considerations. 
 
*For cycle 1, labs may be performed up to 1 day prior to treatment. After completion of cycle 1, labs may be 
performed up to 3 days prior to treatment. For cycle 2 and beyond, romidepsin and carfilzomib dosing may be 
delayed up to 3 days or given up to one day ahead of the scheduled dosing. Romidepsin doses must be given at 
least 6 days apart. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 89 of 90 
 
 
 
1If Physical examination, vital signs, weight and ECOG performance status were done within 7 days of Day 1, they 
do not need to be repeated at study cycle X, Day 1 (excluding cycle 1 in the phase Ib portion). An unscheduled visit 
can occur at any time during the study. 
2The schedule for ECG monitoring is found in section 10.5 and romidepsin dose modifications in Table 5. After 
cycle 2 the schedule can be amended as clinically indicated in section 1 0.5. 
3Sodium, potassium, chloride, bicarbonate, BUN, creatinine, calcium, and glucose are part of the electrolyte 
assessment at every time point. Magnesium will be added to the electrolyte panel at screening, days 1, and 8 of 
the treatment cycle, and at the end of study visit. Liver function analysis (at least total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin) is nece ssary on day 1 of each cycle but doe s not have to be resulted 
to initiate treatment.  Liver function analysis must be re sulted within 7 days of cycle 1 day 1 and cycle 2 day 
1 to proceed with treatment. Liver function analysis must be re sulted within 14 days of day 1 of cycle 3 and 
beyond to proceed with treatment 
4Pregnancy tests for females of  childbearing potential  are  required  through  the  Revlimid  REMS®  program.  A 
female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal  for at least 24 consecutive months (i.e., has 
had menses at any time in the preceding 24 consecutive months). Pregnancy tests must occur within 10 – 14 days 
and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days). 
FCBP with regular or no menstruation must have a pregnancy test weekly for the fi rst 28 days and then every 28 
days while on therapy (including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last 
dose of lenalidomide. Females with irregular menstruation must have a pregnancy test weekly for the first 28 days 
and then every 14 days while on therapy  (including breaks  in therapy), at  discontinuation of lenalidomide and at 
Day 14 and Day 28 post the last dose of lenalidomide  (see  Appendix  C:  Risks  of Fetal  Exposure,  Pregnancy 
Testing Guidelines and Acceptable Birth Control Meth ods). 
5Lenalidomide must be prescribed through and in compliance with the REMS™ program of Celgene Corporation. 
Prescriptions must be filled within 7 days. Consideration should be given to prescribing lenalidomide 5 to 7 days in 
advance of Day 1 of each cycle to allow time for required patient and prescriber surveys, and drug shipment  to 
patient. Any unused Revlimid® (lenalidomide) should be returned to Biologics for disposal in accordance with the 
REMS™ program. 
6Baseline disease assessments must be performed after discontinuation of most recent anti-cancer  therapy 
including systemic steroids.  Outside scans are acceptable if performed within 28 days. 
7 The imaging modality for evaluation will be dependent on disease subtype. For aggressi ve lymphomas (e.g. 
DLBCL, PTCL, HL), PET/ CT will be used for evaluation of response. For indolent lymphomas, CT alone or PET/CT 
may be used at the discretion of the treating physician. A bone marrow will only be repeated to confirm a complete 
response if previously known to be involved. Cutaneous T-cell lymphoma patients (CTCL) will have an mSWAT 
(Appendix D) performed at these time points and imaging at baseline. In CTCL patient‟s, imaging will be repeated i f 
appropriate (patients with known nodal or visceral disease) every other cycle. Sezary panel in patients with Sezary 
syndrome. Cutaneous lymphoma patients without nodal or visceral disease  will  have  imaging  repeated  only  to 
confirm a complete response. 
8 An additional safety assessment will be done 28 days (+/- 7 days) following the last dose of protocol therapy. 
9Response assessment will be performed at the end of cycles 2. Thereafter, response assessment will occur at the 
end of every third cycle (5,8,11, etc..) until disease progression or removal from study. 
10 +/- 3 days 
11if not performed within 28 days 
12For cycle 3 and beyond,  laboratory assessments performed up to three days prior to the day of treatment  are 
adequate for treatment as long as they are within the treatment parameters. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-179 A(6) 
Approval date: 12-Dec-2017 
Administrative Update 1 : 06-Dec-2018 
Page 90 of 90 
 
 
 
13  For cycles 2, 3 and 4, concomitant medications and adverse events may be performed via an assessment 
by telephone +/- 3 days of day 15 of the cycle.  Beyond cycle 4, day 15 assessments are not required. 
14    5 
days to + 3 days.