Conditions: Follicular Lymphoma Marginal Zone B-Cell Lymphoma MALT Lymphoma Lymphoma of Mucosa-Associated Lymphoid Tissue Lymphoma, Small Lymphocytic Waldenstrom Macroglobulinemia Mantle-Cell Lymphoma
Keywords: Revlimid Celgene brand of lenalidomide lenalidomide Rituxan CD20 antibody, rituximab rituximab Follicular Lymphoma Marginal Zone B-Cell Lymphoma Lymphoma, Small Lymphocytic Waldenstrom Macroglobulinemia Mantle-Cell Lymphoma Antigens, CD20 refractory resistantRefractory/progressive lymphoma less than 6 months from first rituximab dose of previous rituximab-containing regimen Previously treated Treated with rituximab
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 50
Healthy volunteers: no

Brief summary:
Pre-clinical data and recently published clinical data suggest a synergistic effect between lenalidomide and dexamethasone. We hypothesize that a combination of lenalidomide-dexamethasone can overcome rituximab resistance. To determine the response rate to lenalidomide and dexamethasone plus rituximab therapy in subjects with recurrent small B-cell non-Hodgkin lymphoma who have had lymphoma progression within 6 months of being treated with rituximab alone or with a rituximab-containing regimen, we propose initial treatment with both drugs for two 28-day treatment cycles (Part I). After response assessment following two cycles of lenalidomide-dexamethasone, patients will enter Part II of the study. In Part II, patients will receive lenalidomide-dexamethasone and rituximab to evaluate the potential reversal of rituximab resistance as measured by response to rituximab and progression-free survival following rituximab.

Detailed description:

Arms:
arm 1: Lenalidomide-low dose dexamethasone plus rituximab

Interventions: intervention 1: Lenalidomide intervention 2: Dexamethasone intervention 3: Rituximab
Intervention descriptions: intervention 1: Lenalidomide: 10mg capsules, orally, once daily for each 28 day cycle for the duration of the study intervention 2: Dexamethasone: 8mg tablets, orally, once weekly on days 3, 10, 17, 24 of each 28 day cycle for the duration of the study; intervention 3: Rituximab: 375mg/m2 IV (in the vein), once weekly on days 1, 8, 15, 22 during month 3 of therapy

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 66 
 
 
 
  
Version: August 24, 2018 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor 
 
University of Pennsylvania  
 
 
 
UPenn # UPCC 02408 
 
 
A Phase II Trial of Lenalidomide (Revlimid®) + Rituximab with and without Dexamethasone in 
Recurrent Small B-Cell Non-Hodgkin Lymphomas (NHL) Resistant to Rituximab  
 
 
Supporter: 
Celgene Corporation 
86 Morris Ave, 
Summit, NJ   07901 
1-800-742-3107 
 
Study Product: 
Lenalidomide (Revlimid®) 
Protocol Number: 
Celgene # RV-NHL-PI-296 
UPenn # UPCC 02408 
NCT00783367 
 
IND Number: 
Exempt 
 
 
 
 
 
Date: 
3/24/2014 
Updated 8/24/2018 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of the University of Pennsylvania.  No part 
of it may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the study sponsor. 


Page 2 of 66 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Principal Investigator: 
 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
Printed Name of Investigator 
Stephen J. Schuster, MD 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, 
IRB/EC procedures, instructions from Celgene 
representatives, the Declaration of Helsinki, ICH 
Good Clinical Practices guidelines, and the applicable 
parts of the United States Code of Federal Regulations 
or local regulations governing the conduct of clinical 
studies. 


Page 3 of 66 
 
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Supporter: 
 
Celgene Corporation 
86 Morris Ave, 
Summit,  NJ   07901 
1-800-742-3107 
 
 
 
Study Location: 
 
University of Pennsylvania  
 
Principal Investigator: 
 
Stephen J. Schuster, MD 
Research Nurse: 
Research Coordinator: 
 
 
Ellen Napier, CRNP 
 
Kristy Walsh 
Study Sub-Investigators:  
Jakub Svoboda, MD 
Sunita Nasta, MD 
Daniel Landsburg, MD 
James Gerson, MD 
Elise Chong, MD 
 


Page 4 of 66 
 
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Table of Contents 
STUDY SUMMARY ............................................................................................................................................... 9 
1 
INTRODUCTION ............................................................................................................................... 10 
1.1  
BACKGROUND 
10 
1.1.1  
Fc Receptor Polymorphisms ...................................................................................................................... 10 
1.1.2  
Complement-dependent cell Lysis.............................................................................................................. 11 
1.1.3  
CD20 signaling and direct pro-apoptotic effect ........................................................................................ 11 
1.1.4 
Enhancing ADCC and targeting the microenvironment ............................................................................ 11 
1.1.5 
Lenalidomide: an immunomodulator ......................................................................................................... 11 
1.2  
PRECLINICAL DATA 
12 
1.3  
CLINICAL DATA 
13 
1.4 
 RATIONALE 
13 
2 
STUDY OBJECTIVES........................................................................................................................ 14 
2.1  
PRIMARY OBJECTIVES 
14 
2.2 
SECONDARY OBJECTIVES 
14 
3 
STUDY DESIGN ................................................................................................................................. 15 
3.1  
GENERAL DESIGN 
15 
3.2  
REQUIRED DATA 
17 
3.3  
TABLE OF EVENTS 
18 
3.4   
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
19 
3.5    
CORRELATIVE SCIENCE 
19 
3.5.1  
FcR Polymorphism .................................................................................................................................... 19 
3.5.2  
Peripheral Blood FACS Analysis............................................................................................................... 19 
3.5.3  
Plasma Cytokine Analysis .......................................................................................................................... 20 
3.6 
CORRELATIVE SCIENCE SAMPLE SUBMISSION 
20 
3.6.1  
FcR Polymorphism Sample Procurement (Cohort 1 Only) ....................................................................... 20 
3.6.2  
FcR Polymorphism Sample Submission ..................................................................................................... 20 
3.6.3  
Peripheral Blood and Plasma Sample Procurement ................................................................................. 21 
3.6.4  
Peripheral Blood Sample Submission ........................................................................................................ 21 
3.6.5  
Paraffin-embedded tissue block submission .............................................................................................. 21 
4 
SUBJECT SELECTION AND WITHDRAWAL ............................................................................. 22 
4.1  
INCLUSION CRITERIA 
22 
4.2  
EXCLUSION CRITERIA 
23 
4.3 
SUBJECT RECRUITMENT AND SCREENING 
24 
4.4 
EARLY WITHDRAWAL OF SUBJECTS 
25 
5 
DRUG FORMULATION, AVAILABILITY AND PREPARATION............................................. 26 
5.1  
LENALIDOMIDE 
26 
5.1.1  
Mechanism of Action ................................................................................................................................. 26 
5.1.2 
Pharmacokinetics and Drug Metabolism .................................................................................................. 26 
5.1.3   
Supplier ...................................................................................................................................................... 27 
5.1.4  
Dosage form .............................................................................................................................................. 27 
5.1.5 
 Packaging ................................................................................................................................................. 27 
5.1.6 
 Storage ...................................................................................................................................................... 27 
5.1.7 
 Prescribing Information ........................................................................................................................... 27 
5.1.8 
Special Handling Instructions ................................................................................................................... 28 
5.2  
RITUXIMAB (RITUXAN®, IDEC-C2B8) 
28 
6 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITIES .......................................... 29 
6.1 
LENALIDOMIDE AND DEXAMETHASONE 
29 
6.1.1 
Dose Continuation, Modification and Interruption ................................................................................... 29 
6.1.2 
Instructions for initiation of a New Cycle .................................................................................................. 30 


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6.1.3 
Instructions for dose modifications or interruption during a cycle ........................................................... 31 
6.2  
RITUXIMAB 
34 
6.2.1  
Infusion and Hypersensitivity reactions ..................................................................................................... 34 
6.2.2 
Dermatology Toxicity ................................................................................................................................ 34 
6.3  
ANCILLARY THERAPY 
34 
7 
RESPONSE DEFINITION (SEE APPENDIX D + E) ...................................................................... 36 
7.1   
COMPLETE RESPONSE (CR) 
36 
7.2   
COMPLETE RESPONSE/UNCONFIRMED (CRU) 
36 
7.3   
PARTIAL RESPONSE (PR) 
37 
7.4  
STABLE DISEASE (SD) 
37 
7.5   
RELAPSED DISEASE (RD) 
38 
7.6   
PROGRESSIVE DISEASE (PD) 
38 
7.7   
MOLECULAR COMPLETE RESPONSE (MCR) 
38 
7.8   
RESPONSE RATES 
38 
7.9   
TIME TO PROGRESSION (TTP) 
39 
7.10   
PROGRESSION FREE SURVIVAL (PFS) 
39 
7.11    
OVERALL SURVIVAL (OS) 
39 
8 
STATISTICAL PLAN ......................................................................................................................... 39 
9 
SAFETY AND ADVERSE EVENTS ................................................................................................. 41 
9.1 
DEFINITIONS 
41 
9.2 
RECORDING OF ADVERSE EVENTS 
43 
9.3 
REPORTING OF ADVERSE EVENTS 
43 
9.3.1  
Pregnancies ............................................................................................................................................... 43 
9.3.2  
Adverse Event Reporting Period ................................................................................................................ 44 
9.4     
REPORTING OF SERIOUS ADVERSE EVENTS 
45 
9.4.1 
Study Supporter Notification by Investigator............................................................................................. 45 
9.4.2 
DSMC /IRB Notification by Investigator ................................................................................................... 45 
9.4.3 
FDA Notification by Investigator............................................................................................................... 46 
10 
DATA HANDLING AND RECORD KEEPING .............................................................................. 47 
10.1   
ANALYSES AND REPORTING 
47 
10.2   
CONFIDENTIALITY 
47 
10.3   
SOURCE DOCUMENTS 
47 
10.4   
CASE REPORT FORMS 
47 
10.5   
RECORDS RETENTION 
48 
10.6   
EXCEPTIONS AND DEVIATIONS 
48 
10.7   
PROTOCOL AMENDMENTS 
49 
10.8   
PREMATURE DISCONTINUATION OF STUDY 
49 
11 
STUDY MONITORING, AUDITING, AND INSPECTING ........................................................... 49 
11.1 
STUDY OVERSIGHT 
49 
11.2 
MEDICAL MONITOR 
50 
11.3 
SAFETY MONITORING 
50 
11.4 
AUDITING AND INSPECTING 
51 
12 
ETHICAL CONSIDERATIONS ........................................................................................................ 51 
13 
STUDY FINANCES ............................................................................................................................ 52 
13.1   
FUNDING SOURCE 
52 
13.2   
CONFLICT OF INTEREST 
52 
14 
PUBLICATION PLAN ....................................................................................................................... 52 
15 
REFERENCES .................................................................................................................................... 53 
16       
APPENDIX ........................................................................................................................................... 57 


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APPENDIX A: RISKS OF FETAL EXPOSURE, PREGNANCY TESTING GUIDELINES AND ACCEPTABLE BIRTH 
CONTROL METHODS 
57 
APPENDIX B: ECOG PERFORMANCE STATUS SCALE 
60 
APPENDIX C: NCI CTCAE VERSION 5.0 
61 
APPENDIX D:  INTERNATIONAL WORKSHOP RESPONSE CRITERIA (IWRC) FOR NON HODGKIN’S LYMPHOMA
 
62 
APPENDIX E: RESPONSE CRITERIA FOR NHL 
64 
APPENDIX F:  WHO CLASSIFICATION OF B-NHL 
65 
APPENDIX G:  ANN ARBOR STAGING SYSTEM OF LYMPHOMA 
66 
 


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List of Abbreviations 
 
AE 
 
Adverse event 
ADCC  
Antibody-dependent cell cytotoxicity 
ALT (SGPT) Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC  
Absolute neutrophil count 
AST (SGOT) Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
BUN  
Blood urea nitrogen 
CDC  
complement-dependent cell cytotoxicity 
CFR 
 
Code of Federal Regulations 
CLL 
 
Chronic Lymphocytic Leukemia 
CR 
 
Complete response 
CRF 
 
Case report form 
CT 
 
Computed tomography 
CTC 
 
Common toxicity criteria 
DMC  
Data Monitoring Committee 
EC 
 
Ethics Committee 
ECG  
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
EMEA  
European Agency for Evaluation of Medicinal Products 
FCBP   
Female of child bearing potential 
FDA  
Food and Drug Administration 
G-CSF  
Granulocyte colony stimulating factor, filgrastim (Neupogen®) 
GCP  
Good clinical practice 
IB 
 
Investigator’s Brochure 
ICH 
 
International Conference on Harmonization 
IFN 
 
Interferon 
Ig 
 
Immunoglobulin 
IL- 
 
Interleukin- 
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review Board 
ITT 
 
Intent-to-treat 
IVRS  
Interactive Voice Response System 
IWRC  
International Workshop Response Criteria for NHL 
LD 
 
Longest diameter 
LDH  
Lactate dehydrogenase 
MCH  
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV  
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activity 
MRI 
 
Magnetic resonance imaging 
MTD  
Maximum tolerated dose 
NCI 
 
National Cancer Institute 
NHL  
Non-Hodgkin Lymphoma 
OS 
 
Overall survival 
PBMC  
Peripheral Blood monocytic cell 
PD 
 
Progressive disease 


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PR 
 
Partial response 
RBC  
Red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RR 
 
Response rate 
SAE 
 
Serious adverse event 
SD 
 
Stable disease 
TPP 
 
Therapeutics Product Program 
TSH 
 
Thyroid stimulating hormone 
TTP 
 
Time to progression 
WBC  
White blood cell (count) 
WHO   
World Health Organization  
 


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Study Summary 
Title 
Phase II Trial of Lenalidomide (Revlimid®)+ Rituximab  with and 
without Dexamethasone in Recurrent Small B-cell Non-Hodgkin 
Lymphomas (NHL) Resistant to Rituximab  
Protocol Number 
Celgene# RV-NHL-PI-296 
UPenn # UPCC 02408 
Phase 
Phase II 
Methodology 
Open label 
Study Duration 
Patients will receive therapy until disease progression, development of 
unacceptable toxicity, or voluntary withdrawal, whichever occurs first 
Study Center(s) 
Single 
Objectives 
To evaluate the potential of Revlimid to overcome resistance to 
Rituximab 
Number of Subjects 
45 evaluable subjects 
Diagnosis and Main 
Inclusion Criteria 
• Previously treated, histologically confirmed follicle center 
lymphoma (grades 1, 2 and 3a), marginal zone lymphoma, SLL 
with <5,000 lymphocytes/ mm³, lymphoplasmacytic lymphoma 
with <3gm/ml IgM, or mantle cell lymphoma. 
 
• Flow cytometry or immunohistochemistry must confirm CD20 
antigen expression. 
 
• Patients must have been treated with rituximab in combination 
with chemotherapy or as monotherapy and must have had less 
than a partial response or progressive disease within 6 months of 
any dose of rituximab. 
 
• ECOG 0-2 
 
• Age>18 
 
• Measurable disease 
 
Study Product  
For study participants, Celgene Corporation will provide lenalidomide 
at no charge through the Revlimid REMS® program.   
Duration of 
administration 
Lenalidomide will be given until withdrawal from trial, i.e either until 
disease progression with <3 months estimated life expectancy in Part I 
or any progression of disease after rituximab component of protocol 
therapy (part II). 
Statistical 
Methodology 
Fisher’s exact test for response rate. Paired comparisons of time to 
progression (TTP) of previous, rituximab-containing treatment regimen 
to TTP in this study for each individual patient. McNemar's test for 
comparison of response rates in previous treatment to response rate in 
this study. 


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1 Introduction 
 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
1.1  
Background 
Although there is a wide array of treatment modalities available and initial response rates are 
high, most patients with small B-cell, or so-called “low grade”, non-Hodgkin lymphomas (NHL) 
will eventually develop recurrent or refractory disease and many ultimately die from lymphoma-
related complications. Chemotherapy and radiation therapy have clearly provided benefits to 
patients with these disorders, yet the potential for cure is limited and thus new approaches are 
under investigation. The monoclonal antibody rituximab (directed against the B-cell antigen CD 
20) has received Food and Drug Administration (FDA) approval for patients with relapsed low-
grade NHL. In a pivotal trial of 166 patients with relapsed low grade NHL, a response rate of 
48% was observed with a median time to progression (TTP) of 12 months in responders. 1 A 
higher response rate was observed in patients receiving rituximab as second-line therapy 
compared to those patients following three or more prior chemotherapy regimens. In low-grade 
NHL patients who initially respond (time to progression of at least 6 months) and then relapse 
after single agent rituximab therapy, an overall response rate of 40% has been reported following 
re-treatment with median TTP of about 18 months after second administration. 2 However, 
approximately 50% of patients may not respond to initial treatment and almost all patients with 
low-grade B-cell lymphomas will experience disease progression at some point following 
rituximab therapy. To overcome rituximab resistance, it is paramount to thoroughly understand 
the mechanisms involved. Multiple mechanisms have been proposed for the activity of 
rituximab, including antibody-dependent cellular cytotoxicity (ADCC)  3-5, complement-
dependent cytotoxicity (CDC) 5,6, and a direct pro-apoptotic effect 7,8.  
1.1.1  Fc Receptor Polymorphisms 
Although F(ab’)2 rituximab homodimers were shown effective in inducing apoptosis of B-cell 
lymphoma cell lines in vitro 8, other works have recently established the importance of ADCC as 
a predominant mechanism of lymphoma cell clearance and that Fcγ receptors (R) are critical for 
the in vivo actions of rituximab in NHL. In a xenograft model of human lymphoma, knocking 
out the Fcγ R-loci in mice resulted in complete abrogation of response to rituximab. In contrast, 
knocking out the inhibitory Fcγ RIIb in mice resulted in enhanced response to rituximab in the 
same xenograft model. 9 In addition, the recent demonstration in NHL patients that response to 
rituximab is dependent on specific Fcγ RIIIa polymorphisms supports the importance of ADCC 
in the in vivo activity of rituximab. 10The activating Fcγ R on natural killer (NK) cells and 
monocytes (Fc γ RIIIA) and on monocytes (Fc γ RIIa) mediates ADCC. Genomic 
polymorphisms corresponding to phenotype expression of valine (V) or phenylalanine (F) at 
amino acid 158 on the Fcγ RIIIa greatly influences the affinity of IgG1 to the Fcγ receptor. 
Stronger binding of antibody to homozygous FcRIIIa-158V has been demonstrated. Similarly, 
polymorphism related to expression of histidine (H) or arginine (R) at amino acid 131 in Fcγ 
RIIa affects the binding of IgG1. In the abovementioned study of 49 patients with previously 
untreated follicular lymphoma, patients homozygous for the Fcγ Ra-158V (V/V) had a 


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significantly higher response rate to rituximab than those with the phenylalanine (F/F) genotype 
(67%). 10Furthermore, polymerase chain reaction (PCR) detection of bcl-2 re-arranged cells was 
significantly lower in the homozygous V/V group. In contrast, Fcγ RIIa-131 polymorphisms 
were not associated with response to rituximab. In a second study, both Fcγ RIIIa-158 (V/V) and 
Fcγ RIIa-131 (H/H) correlated with response and progression-free survival following treatment 
with rituximab. 11This study will describe any prognostic significance observed for different Fcγ 
RIIIa receptor polymorphisms on response to combination rituximab – lenalidomide therapy. 
1.1.2  Complement-dependent cell Lysis 
Rituximab is capable of binding C1q and in vitro studies indeed have demonstrated the ability of 
the antibody to mediate complement-dependent cell Lysis (CDC) of human B-lymphoid cell 
lines. 12 These findings are corroborated by the observation that complement is consumed during 
treatment with rituximab and levels of side effects correlate with severity of the side effects 
associated with rituximab-infusion. 13 The precise role of CDC in rituximab therapy and its 
potential contribution to rituximab resistance are unclear and require further study. 
1.1.3  CD20 signaling and direct pro-apoptotic effect 
In addition to CDC, binding of rituximab appears to induce CD20-dependent caspase activation 
through increased calcium conductivity with subsequent IL-10 down regulation, invoking several 
signaling pathways. 14  Gene expression profiling of rituximab resistant follicular lymphoma 
revealed differential expression of genes involved in cellular immune response, including 
cytokines, complement and T-cell receptor signaling, suggesting a more profound role of the 
microenvironment than the malignant cells in rituximab resistance. 15,16 This is further supported 
by observations that loss of CD20 expression is not an important mechanism of rituximab 
resistance. This is corroborated by the effectiveness of CD20 radio-immunoconjugates in this 
setting. 17 
1.1.4 Enhancing ADCC and targeting the microenvironment 
With our current understanding highlighting the apparent role of ADCC and the immunological 
microenvironment in the response to rituximab, several approaches to stimulate effector cell 
function have been suggested to augment the response to rituximab and overcome resistance. For 
instance, various human studies have evaluated the role of cytokines in combination with 
rituximab, including IFN-α, Il-12, and Il-2, demonstrating safety and effector cell 
enhancement.18   For example, IFN-α, an immunomodulatory cytokine that induces antigen 
expression and enhances cytotoxicity, has been combined with rituximab in a phase II trial with 
38 patients. While the overall survival did not differ significantly from that expected with 
rituximab alone, time to progression in responding patients appeared prolonged. 19 Trials 
combining IL-2 with rituximab suggested prolonged time to progression in patients with 
follicular lymphoma.20,21 These trials suggest that targeting the microenvironment to modulate 
antigen expression as well as enhance cytotoxicity could potentially overcome resistance to 
rituximab. 
1.1.5 Lenalidomide: an immunomodulator 
One agent, which may potentially augment the activity of rituximab in NHL and thus potentially 
overcome rituximab resistance, is lenalidomide (Revlimid®), a proprietary IMiD™ compound of 
Celgene Corporation.  Lenalidomide is a potent thalidomide derivate with immunomodulatory 
properties including stimulation of T-cell proliferation as well as production of IL-2 and 


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interferon-gamma in addition to other cytokines. The biological effects of IMiD™ compounds 
are presumed to be mediated by: (1) activation of the innate (e.g., NK cells) and adoptive (e.g., 
T-cells) immune systems, and (2) inhibition of angiogenesis. Treatment of lymphoma-bearing 
SCID mice with a combination of Rituximab and IMiD™ compounds demonstrated 
augmented/synergistic anti-tumor activity compared to monotherapy of either agent alone. This 
synergistic activity was attributed to an NK cell expansion (demonstrated by flow cytometric 
analysis) and further confirmed by in vivo NK cell depletion studies. 22,23 Moreover, increased 
production of IFN α, IL-2, and IL-12 enhanced NK cell- and monocyte-mediated tumor cell 
ADCC.24 Lenalidomide-mediated enhancement of chemokine production by NK cells in the 
context of NK cell-mediated ADCC of tumor cells suggests the concomitant promotion of 
chemoattraction and potential infiltration of tumor-specific T-cells.25 Interestingly, Lenalidomide 
strongly inhibits T-regulatory cell proliferation and suppressor-function. It inhibits IL-2-
mediated generation of FOXP3 positive CTLA-4 positive CD25
high 
CD4
+ 
T-regulatory cells from 
PBMCs by up to 50%. Furthermore, suppressor function of pre-treated T-regulatory cells against 
autologous responder-cells is abolished or markedly inhibited without drug related cytotoxicity.26 
These results provide a strong rationale for combination of lenalidomide with IgG1 antibodies to 
tumor-specific surface antigens in cancer patients. 
1.2  
Preclinical Data 
Lenalidomide inhibits the proliferation of Namalwa (Burkitt’s lymphoma derived) and 
Jeko-1 and Rec-1 (both mantle cell lymphoma derived) NHL cell lines, and this was associated 
with G0/G1 phase arrest. When lenalidomide and dexamethasone were combined simultaneously 
a clear synergistic interaction was observed related to hypophosphorylation of the Rb protein and 
activation of caspase-3 and -8, leading to extensive apoptosis. 
 
Non anti-proliferative concentrations of lenalidomide markedly inhibited the production 
of the pro-angiogenic factors VEGF, IL-8 and PDGF. The inhibition of VEGF production by 
Lenalidomide appears to be through the down-regulation of VEGF gene transcription. 
The up-regulation of p21 gene expression may partially explain the anti-proliferative effect of 
lenalidomide on NHL cells. However, lenalidomide had no effect on cyclin D1 and p53 
gene expression. These anti-proliferative and anti-angiogenic activities of lenalidomide on a 
variety of NHL cells support the potential study of lenalidomide in patients with NHL. 3 22,23  
 In particular, the anti-proliferative data provide a rationale for combination with dexamethasone. 
 
Lenalidomide is a potent enhancer of NK cell and monocyte-mediated tumor cell ADCC. There 
were similar enhancing effects on various tumor cells using trastuzumab (Her-2+ breast cancer), 
cetuximab (EGFR+ colorectal cancer), and rituximab (CD20+ NHL cells). There was no 
enhancing effect with the non-ADCC inducing IgG2a-isotype antibody panitumumab. 
Enhancement of NK cell-mediated ADCC requires both antibody binding to Fc-γ receptors plus 
IL-2 or IL-12 signaling (i.e., lenalidomide alone does not cause an effect). The NK cell 
stimulatory effect is due to enhanced Fc-γ receptor signaling, likely via inhibition of phospho-
SHIP-1, leading to enhanced granzyme B and Fas-L expression. Enhancement of chemokine 
production by IgG-stimulated NK cells suggests the concomitant promotion of chemoattraction 
and potential infiltration of tumor-specific T-cells. Lenalidomide enhances monocyte-mediated 
ADCC of antibody-coated tumor cells, which is completely blocked by a neutralizing anti-IL-12 
monoclonal antibody. 24,25  These results provide a strong rationale for combination of 
lenalidomide with IgG1 antibodies to tumor-specific surface antigens in cancer patients. 


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Lenalidomide inhibits IL-2-mediated generation of FOXP3 positive CTLA-4 positive CD25
high 
CD4
+ 
T-regulatory cells from PBMCs by up to 50%. Furthermore, the suppressor function of 
pre-treated T-regulatory cells against autologous responder-cells is abolished or markedly 
inhibited without drug related cytotoxicity. Also, Balb/C mice exhibit 25% reduction of lymph 
node T-regulatory cells after lenalidomide treatment. Inhibition of T-regulatory cell function was 
not due to changes in TGF-beta or IL-10 production but was associated with decreased T-
regulatory cell FOXP3 expression. 26 In conclusion, these data provide one explanation for the 
adjuvant properties of lenalidomide and suggests that they may help overcome an important 
barrier to tumor-specific immunity in cancer patients. 
1.3  
Clinical Data 
A phase I/II study evaluating lenalidomide with rituximab for the treatment of 
relapsed/refractory mantle cell lymphoma was presented in 2007 at the 49th Annual Meeting of 
the American Society of Hematology (ASH). 18 patients were enrolled in this trial, all of which 
had previously been treated with rituximab. The study indicated that 70% of patients achieved 
responses with 30% of patients achieving complete responses when given the combination 
therapy. 27 The most common Grade 3/4 adverse events observed were neutropenia, febrile 
neutropenia, thrombocytopenia and myalgia. A separate study evaluated lenalidomide oral 
monotherapy for relapsed/refractor mantle-cell NHL in 15 patients. Objective response was 
noted in 53% with manageable side effects. 28 A study of 45 high-risk patients with relapsed or 
refractory CLL, treated with lenalidomide oral monotherapy, showed an overall response rate of 
47%, with 9% of the patients attaining a complete remission. Fatigue, thrombocytopenia, and 
neutropenia were the most common adverse effects noted in 83%, 78%, and 78% of the patients, 
respectively. 29 
1.4 
 Rationale  
Based on these vitro and in vivo studies, we propose to evaluate the potential of lenalidomide to 
overcome rituximab resistance. As pre-clinical data and published clinical data suggest a 
synergistic effect between lenalidomide and dexamethasone, we propose initial treatment with 
both drugs for two 28-day treatment cycles (Part I or “priming”) for subjects enrolled to Cohort 
1. This combination in itself should have clinical efficacy.  The priming phase in Part I will 
allow the study of immune-modulatory effects on T-cell subsets and cytokine milieu induced by 
the combination of lenalidomide and dexamethasone prior to the addition of rituximab.  A 
reduced dose of lenalidomide 10 mg daily was chosen as the starting dose, given the heavily pre-
treated patient population and the potential for lenalidomide-related myelosuppression. After the 
first lenalidomide – dexamethasone treatment cycle, the lenalidomide dose can be increased by 
one dose level based on patient-specific tolerance (see Section 6 for full details). After response 
assessment following two cycles of lenalidomide – dexamethasone, patients with responsive or 
stable disease, and patients with progressive disease with an estimated life expectancy of > 3 
months will enter Part II with lenalidomide - dexamethasone and rituximab to evaluate the 
potential reversal of rituximab resistance as measured by response to rituximab and progression-
free survival following rituximab.   
 
Subjects enrolled to Cohort 2 of protocol treatment will receive treatment on the same schedule 
as those subjects in Cohort 1 (10 mg lenalidomide daily, weekly rituximab during Cycle 3), but 


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weekly dexamethasone will be eliminated from the study treatment plan.  Response assessments 
will be conducted at the same timepoints (at the end of cycles 2 and 5).  
 
To study the immunomodulatory effect of lenalidomide, as well as its possible role in host-
associated rituximab resistance, we will analyze changes in peripheral blood mononuclear cells 
(PBMC) constitution (e.g., changes in NK cell, activated NK cell, activated T cell and Treg 
numbers) following exposure to lenalidomide and correlate various cell subtype levels and 
changes to the objective response rates to therapy with rituximab + lenalidomide with and 
without dexamethasone, compared to Part I with lenalidomide with and without dexamethasone 
alone. In addition, plasma samples both pre- and post-therapy will be tested for changes in 
plasma cytokines (i.e., interferon-gamma, GM-CSF, sIL-2R, IL-2, IL-10, IL-12, Rantes) in an 
attempt to correlate anti-tumor activity to lenalidomide-associated immunomodulatory effects on 
these cytokines. It is hypothesized that at least some of the immunomodulatory effects of 
lenalidomide may be mediated through the release of immunostimulatory cytokines. The 
proposed correlative studies seek to assay plasma cytokine levels pre- and post-therapy and 
correlate values with clinical outcome. 
 
2 Study Objectives 
2.1  
Primary Objectives 
2.1.1  To determine the response rate to lenalidomide + rituximab therapy with and 
without dexamethasone in relapsed small B-cell lymphomas with rituximab 
resistance. 
2.2 
Secondary Objectives 
2.2.1 To determine time to progression after lenalidomide + rituximab therapy with and 
without dexamethasone in relapsed small B-cell lymphomas with rituximab 
resistance and compare the time to progression for the previous rituximab-
containing regimen 
 
2.2.2 To compare the response rate for the previous rituximab-containing regimen to 
that obtained subsequently to lenalidomide + rituximab therapy with and without 
dexamethasone. 
 
 
2.2.3 To determine the toxicity profile of lenalidomide + rituximab therapy with and 
without dexamethasone in patients who have received a previous rituximab-
containing combination regimen. 
 
2.2.4 To correlate FcγRIIIa receptor polymorphism profiling with response to 
lenalidomide - dexamethasone + rituximab therapy in relapsed small B-cell 
lymphomas with rituximab resistance (Cohort 1 only). 
 
2.2.5 To evaluate changes in NK cells, activated NK cells, activated T cells, T regs, and 
several plasma cytokines following exposure to lenalidomide - dexamethasone 
and lenalidomide - dexamethasone + rituximab therapy and correlation of 
observed changes to objective response rates. 


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2.2.6 To determine the presence or absence of minimal residual disease after Part I and 
Part II of protocol therapy using a PCR-based assay of DNA.  
 
2.2.7 To determine whether 1) a decrease in serum albumin by > 0.3 g/dL at 
commencement of cycle 2 from baseline predicts a response (CR/PR)to protocol 
therapy and whether 2) a baseline serum albumin < 4.1 g/dL predicts no response 
(SD/PD) to protocol therapy.   
 
3 Study Design 
3.1  
General Design 
Phase II Trial of Lenalidomide (Revlimid®) + Rituximab with and without Dexamethasone in 
recurrent small B cell non-Hodgkin lymphomas (NHL) resistant to Rituximab: 
 
^ Close monitoring for tumor lysis syndrome (TLS) should be initiated concurrent with the initiation of lenalidomide-dexamethasone in Part I 
(see Section 3.2).  Subjects will receive tumor lysis prophylaxis if clinically indicated.  All subjects should remain well hydrated during at least 
the first 7 days of Cycle 1.  Close monitoring for TLS and the need for TLS prophylaxis should be repeated during at least the first 7 days of Part 
II treatment.  Additional TLS monitoring and prophylaxis may be employed at any time at the investigator’s discretion.  Tumor flare occurring 
during the first 1-2 weeks of Cycles 1, 2 and 3 should be recorded as AEs and not as progressive disease (PD).  Tumor flare should be treated 
symptomatically with non-steroidal anti-inflammatory agents (NSAIDs) and other measures as needed 
* Follow-up staging 3 months after first dose of Rituximab (i.e after 5 months) then after months 12, 18 and 24 (as counted from enrollment of 
trial), then yearly until disease progression , development of unacceptable toxicity, or voluntary withdrawal, whichever occurs first. 
‡ In patients with absolute lymphocyte count>20,000/ul, prior to rituximab infusion, close monitoring for tumor lysis syndrome should be 
initiated and those patients should receive appropriate supportive care (e.g., allopurinol, intravenous hydration, additional laboratory test 
monitoring, etc.). A modified dosing scheme is suggested for those patients with absolute lymphocyte count>20,000/ul (see 6.2) 
# At time of progression or relapse, a biopsy is recommended. If a biopsy is performed, and the patient consented to allow their tissue to be kept 
for future unknown use, the pathology specimen will be asservated at the U Penn Tissue Core facility. 
≠ Subjects with CR, PR, SD or PD with an estimated life expectancy of >3 months will continue to Part II of the trial 
% The lenalidomide dose may be escalated to 15mg daily at the beginning of Cycle 2 of Part I based on patient-specific tolerance as defined in 
Section 6.  The lenalidomide dose during Part II will be determined by dose modification guidelines in Section 6.  For patients in Cohort I, the 
dexamethasone dose during Part II may also be adjusted due to toxicities experienced during Part I.  After Part II, patients with SD, PR or CR 
will continue to receive study treatment as per the schedule above in 28-day cycles until disease progression, development of unacceptable 
toxicity, or voluntary withdrawal, whichever occurs first. 
 
 
RESTAG I NG # ≠ 
REG I STRAT ION 
RESTAG I NG * # 
Part I: Lenalidomide w/ or 
w/o Dexamethasone^%:   
Cohort 1: Lenalidomide 
starting at 10 mg PO on 
days 1-28 for two 28 day 
cycles,  dexamethasone 8 
mg PO on Days 3, 10, 17 
and 24 for two 28 day 
cycles.  
Cohort 2: Lenalidomide 
starting at 10 mg PO on 
days 1-28 for two 28 day 
cycles.   
Restaging after Cycle 2 
Part II: Lenalidomide + 
Rituximab w/ or w/o 
Dexamethasone^%:   
Cohort 1: Lenalidomide PO 
daily on days 1-28 of each 
28 day cycle, 
dexamethasone 8 mg PO 
on Days 3, 10, 17 and 24 of 
each 28 day cycle.  
Rituximab ‡ 375 mg/m2 IV 
once weekly during Cycle 3 
Cohort 2: Lenalidomide on 
days 1-28 of each 28 day 
cycle. Rituximab ‡ 375 
mg/m2 IV once weekly 
during Cycle 3 
Restaging after Cycle 5 
Study 
Continuation: 
Cohort 1: 
Subjects 
continue to take 
daily 
lenalidomide 
and weekly 
dexamethasone 
until withdrawal 
from study 
Cohort 2: 
Subjects 
continue to take 
daily 
lenalidomide 
until withdrawal 
from study 


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We plan to include previously treated, histological confirmed follicular lymphoma, marginal 
zone lymphoma, small lymphocytic lymphoma with <5000 lymphocytes / mm³, 
lymphoplasmacytic lymphoma with < 3gm/ml IgM or mantle cell lymphoma with confirmation 
of CD20 antigen expression by flow cytometry or immunohistochemistry on the diagnostic 
biopsy. Paraffin blocks and/or frozen material from the initial biopsy or biopsy at relapse will be 
requested in all cases, but are not required for protocol eligibility. 
 
Subjects must have been treated with rituximab in combination with chemotherapy or as 
monotherapy and must have refractory or progressive lymphoma.  Subjects must have had less 
than a partial response or progressive disease within 6 months of any dose of rituximab. 
 
Subjects must have measurable disease (see Section 3.3).  Subjects will need staging to be 
completed within 60 days prior to registration. 
 
Forty-five subjects will be enrolled to this study.  The first twenty-five evaluable subjects will be 
enrolled to Cohort 1 of study treatment, which will consist of daily dosing of lenalidomide, 
weekly dosing of dexamethasone and weekly dosing of rituximab during Cycle 3, as described 
below.  Cohort 2 will consist of twenty subjects.  These subjects will follow the same treatment 
schedule as those in Cohort 1, but will not receive weekly dexamethasone.   
 
In Part I of the study, subjects in both cohorts will receive lenalidomide 10 mg PO once daily on 
Days 1-28 every 28 days for two 28-day cycles.  Subjects in Cohort 1 will also receive 
dexamethasone 8 mg PO once weekly (dosing on Days 3, 10, 17 and 24 is suggested, but not 
required) for two 28-day cycles. Serum and plasma samples for ancillary studies will be 
collected for all subjects upon entry into the trial, after 2 cycles of study therapy, and at the 
investigator’s discretion in subjects with extended remissions. Subjects will be restaged after the 
first 2 cycles (Part I) prior to Part II and will continue with Part II (with rituximab) unless 
progression of disease is documented with life expectancy estimated to be <3 months during Part 
I.  
 
In Part II, all subjects will receive lenalidomide once daily Days 1-28 over 28 days as well as 
Rituximab 375mg/m2 IV once weekly during cycle 3.  Subjects enrolled in Cohort 1 will also 
receive dexamethasone PO once weekly during each 28 day treatment cycle.  The doses of 
lenalidomide and dexamethasone (for subjects in Cohort 1) during Part II will be determined by 
dose modification guidelines in Section 6.  All subjects will be restaged 3 months after first 
rituximab infusion (prior to cycle 6). Again, serum and plasma samples for ancillary studies will 
be collected at this point. Following Part II, subjects in Cohort 1 will continue on lenalidomide 
once daily on Days 1-28 every 28 days and dexamethasone once weekly until disease 
progression, development of unacceptable toxicity, or voluntary withdrawal, whichever occurs 
first.     
 
Subjects in Cohort 2 will continue on lenalidomide once daily on days 1-28 of each 28 day cycle. 
Restaging for all subjects will be performed on months 12, 18 and 24 (as counted from 
enrollment of trial) and then yearly until disease progression, development of unacceptable 
toxicity, or voluntary withdrawal, whichever occurs first.  These restaging assessments may be 
performed +/- 2 months from these timepoints, or at the clinical discretion of the treating 
physician. 


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Subjects are required to receive prophylactic anti-coagulation with aspirin, Coumadin or low 
molecular weight heparin due to the increased risk of thrombosis reported with lenalidomide 
therapy.  Coumadin should only be used with caution and close monitoring of INR.  Prophylactic 
anti-coagulation should be held for platelet counts < 50,000/mm3 and restarted when platelet 
counts are ≥ 50,000/mm3.   
 
3.2  
Required Data 
 
Guidelines for pre-study testing 
 
To be completed within 60 days before registration: 
• Radiological imaging (e.g., CT or MRI) which is utilized for tumor measurement.  If a 
fusion PET-CT has been obtained and is deemed satisfactory for anatomic evaluation of 
lesions, a separate diagnostic contrasted CT study will not be required. 
 
• Review of diagnostic pathology material to confirm the diagnosis 
 
• Paraffin blocks and/or frozen material from the initial biopsy or biopsy at relapse will be 
requested in all cases, but are not required for protocol eligibility.   
 
To be completed within 28 days before registration, or on date of registration 
• All blood studies 
• History and physical exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.3 Table of Events  
 
 
Tests & Observations  
(see footnote M) 
Prior to 
study 
Prior to 
starting 
Cycles 1-6  
Restaging after  
Part I 
Restaging after Part II 
and subsequent follow-
up* 
History 
Physical Examination 
Height 
Weight, BSA** 
Performance Status 
Tumor measurements 
Drug toxicity Assessment 
Register into Revlimid REMS® 
program 
EKG 
 
Laboratory Studies (see footnote M) 
    X 
    X 
    X 
    X 
    X 
    X 
 
    X,O 
     
    X 
        
       X 
 
        
       X 
       A 
       X 
 
   
             
            X 
 
            X 
            X 
            X 
            X 
                     
                    X 
 
 
                    X 
                    X       
                    X,N 
 
        
CBC, Differential, Platelets 
Serum Creatinine, BUN 
Serum Electrolytes 
Total Protein, Albumin 
AST,ALT, Alk. Phos., Bilirubin 
ESR, CRP, Fibrinogen 
Uric acid/Phosphate/LDH/Ca++ 
Serum or urine b-HCG*** 
Serum IgG, IgA, IgM 
FCR Polymorphism Sample (see 3.5) 
Blood and Plasma Sample (see 3.5) 
HACA 
HBsAg, HepCAb, HBcAb 
TSH (repeat only if clinically 
indicated) 
 
Staging  (see footnote M) 
    X 
    X 
    X 
    X 
    X 
    X^ 
    X 
    X, B 
    X^ 
    X^ 
    X 
 
    F 
    X 
 
      X,H 
      X, 
      X, 
       X 
       X 
       X, ^ 
      X,J 
       B 
       X,C^ 
 
        
 
 
        
            X 
            X 
            X 
            X 
            X 
            X^ 
            X 
            X 
            X^ 
    
            X  
 
 
 
  
 
                    X 
                    X 
                    X 
                     
                    X 
                    X,C^ 
                    X,C 
B 
                    C^ 
 
                   D 
                   E^ 
                   F             
CT / MRI (chest/abd/pelvis) / PET-CT 
CT Scan/MRI (neck) 
Bone Marrow Asp& BX (unilateral) 
Histologic Review 
    X 
    G 
    P 
    X 
 
            X 
            G  
            K 
            L 
                   X 
                   G 
                   K 
                   L 
* Follow-up staging on months 12, 18 and 24 as counted from enrollment, then yearly until disease progression, development of unacceptable 
toxicity, or voluntary withdrawal, whichever occurs first.  Physical exams and study labs should be done monthly for the first 6 months, every two 
months for cycles 7-13 and every three months thereafter (+/- 2 weeks). After the first 6 months of weekly labs, subjects will continue to have a 
CBC monthly while on-study. 
**   Although doses are recalculated prior to each treatment, the actual dose of rituximab to be given need not change unless the calculated dose 
changes by > 10%. NOTE THAT LENALIDOMIDE DOSES ARE NOT BASED ON WEIGHT OR BSA. 
*** Pregnancy tests for females of childbearing potential.  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).    
^ Subjects enrolled into Cohort 1 only.  Not applicable for subjects enrolled into Cohort 2. 
A       If accessible to physical examination, please record measurements 
B 
Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide (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 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 A: Risks 
of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods). 
C 
Perform for the first 6 cycles  
D 
Obtained prior to beginning Cycle 6 and at the investigator’s discretion in subjects with durable remissions. 
E 
Perform upon completion of rituximab therapy (before initiation of Cycle 4) and at the End of Cycle 10 
F 
Patients with known hepatitis B or C are not eligible for this study.  Negative results are required for participation.  This will be based on 
the subject’s medical history. Note: Baseline Hepatitis B/C testing is not required.  
G 
Perform if nodes are palpable. 


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H 
Weekly throughout cycles 1-6, monthly thereafter. 
J 
During Cycles 1 on Day 3, 4, or 5 and on Day 8.  During the cycle of rituximab therapy (cycle 3) on Days 3, 4, or 5, and on Days 8 to 
monitor for tumor lysis syndrome.  Additional assessments may be done at any time. 
K 
If initially positive, repeat only in patients who are demonstrated to be in CR/Cru by all other criteria. 
L 
At time of progression or relapse, a biopsy is recommended to be performed. If a biopsy is performed, patients may separately consent to 
allow their tissue to be kept for future unknown research. 
M 
If 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 Day 1.An unscheduled visit can occur at any time during the study.  Source must be maintained for these unscheduled 
visits. The date for the visit and any data generated must be recorded on the appropriate CRF.  Source documents for these unscheduled 
visits must also be maintained. 
N 
An additional safety assessment will be done 30 days (+/- 7 days) following the last dose of study drug. 
O 
Lenalidomide must be prescribed through and in compliance with the Revlimid 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 the patient for disposition in accordance with the Revlimid REMS® program. 
P 
If patient has a history of bone marrow involvement at baseline. 
 
 
3.4  Guidelines for Evaluation of Measurable Disease 
 
• Clinical lesions will only be considered measurable when they are superficial ( e.g skin 
nodules, palpable lymph nodes). 
• Chest X-ray lesions are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable. 
• Conventional CT and MRI should be performed with cuts of 10mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5mm contiguous 
reconstruction algorithm. This applies to the chest, abdomen, and pelvis. Head & neck 
and extremities usually require specific protocols. 
• Ultrasound should not be used to measure tumor lesions that are clinically not easily 
accessible when the primary endpoint of the study is objective response evaluation. It is a 
possible alternative to clinical measurements of superficial palpable nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination 
• PET/CT may be performed as an alternative to CT or MRI at the investigator’s 
discretion 
3.5   Correlative Science 
 
All correlative studies will be performed upon completion of the trial as a batch run. 
The correlative studies detailed below may be altered at the discretion of the Principal 
Investigator. 
3.5.1 FcR Polymorphism 
Genomic polymorphisms corresponding to phenotype expression of valine (V) or phenylalanine 
(F) at amino acid 158 on the Fcγ RIIIa will be analyzed fluorescent automated cycle sequencing 
of Taq PCR products      
 
3.5.2 Peripheral Blood FACS Analysis  
PBMCs will be subjected to FACS analysis for expression of CD3, CD4, CD8, CD25, CD39, 
CD73, CD127, FOXP3, CD122, CD212 (IL-12R), HLA-DR, CD14, CD19, CD56, CD69, FAS-
L and granzyme B as well as additional antigens as indicated. Flow cytometry to detect 


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intracellular cytokine production in individual cells in peripheral blood, or from cells in the 
ELISA assays will also be performed to test production of IL-2, IL-10, interferon-γ, TGF-β and 
other cytokines as indicated. 
 
Treg function will be determined following isolation of CD4+CD25+ cells from PBMC using 
published criteria. CD 39 and CD73 will be used to identify memory T reg cells. Functional tests 
include inhibition of T cell proliferation driven by α-CD3 plus α-CD28 mAb exposure, reduction 
in T cell IL-2 or interferon-γ production and reduced cytolytic activity. Sorting of cells into 
additional populations (LAG3+/-, CD27+/-, CD8+/-, Ki-67+/-) may also be attempted prior to 
suppression testing. Foxp3 message will be ascertained by flow cytometry. If primary tissue is 
available, IHC for CD3, CD4, CD8, FOXP3, and CD56 will be performed. 
 
3.5.3 Plasma Cytokine Analysis  
Samples will be saved until the end of study for a batch run. At that time, cytokines will be tested 
using commercial ELISA kits (R&D Systems, Minneapolis, MN). Cytokines to be tested include 
interferon-γ, GM-CSF, sIL-2R, IL-2, IL-4, IL-10, IL-12, Rantes and TGF-β. 
 
3.5.4 Minimal Residual Disease Analysis 
If a paraffin embedded diagnostic tissue specimen is available, this material will be used to 
generate patient specific probes for detection of minimal residual disease in blood at baseline and 
during protocol therapy (at the end of Part I, prior to starting Cycle 6, and at the investigator’s 
discretion in subjects who experience a durable remission) using a PCR assay. This assessment 
will be performed using a portion of the peripheral blood collected for ancillary studies (see 
Section 3.5.3) and will not require blood collection beyond that performed during the study for 
other analyses.    
 
3.6 
Correlative Science Sample Submission 
3.6.1 FcR Polymorphism Sample Procurement (Cohort 1 Only) 
If a patient has consented and agreed to allow their blood to be used for research studies  
(Research related Studies Consent Form, see Appendix J), Peripheral blood will be collected 
prior to treatment for analysis of FcR polymorphisms. 20ml of peripheral blood in two yellow 
(ACD) or purple (EDTA) top Vacutainer® tubes. The tubes should be inverted 8-10 times to mix 
the tube additive and then refrigerated until shipped. Samples should be labeled with the 
patient’s initials, study number, patient study ID# and date and time of collection. A log sheet 
(Correlative Science Form A) must be sent with the specimen and a copy retained in the 
investigator’s file.  This sample can be obtained at baseline, or at any time during a subject’s 
participation in this study. 
3.6.2 FcR Polymorphism Sample Submission 
Blood samples should be send to: 
 
Kathakali Addya, PhD 
Molecular Diagnosis and Genotyping Facility 
7 Gates West 
3400 Spruce Street 
Philadelphia, PA 19104 


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3.6.3 Peripheral Blood and Plasma Sample Procurement 
If a patient has consented and agreed to allow their blood to be used for research studies 8 green 
top (heparin) tubes and 1 red top tube will be collected at the following timepoints: prior to 
treatment, prior to beginning Cycle 3 of treatment, and prior to beginning Cycle 6.   If the 3rd 
blood/plasma sample is missed (i.e. prior to beginning Cycle 6), it can be drawn at a later time 
point.  Samples should be labeled with the patient’s initials, study number, patient study ID# and 
date and time of collection. A completed “Clinical Research Sample – Information and 
Processing Record” from the Human Immunology Core must be sent with the specimen and a 
copy of Correlative Science Form B should be retained in the patient’s study chart. 
 
Peripheral blood for MRD analysis in subjects with extended remissions will be collected as 
3mL in EDTA tube.  This will be performed during a routine blood draw.  This will only be 
performed if the patient has consented and agreed to allow their blood to be used for research 
studies. 
 
3.6.4 Peripheral Blood Sample Submission 
Samples for ancillary studies should be sent on the same day they are obtained to: 
 
Nicole Aqui MD 
Division of Transfusion Medicine 
University of Pennsylvania 
272 John Morgan 
3620 Hamilton Walk 
Philadelphia, PA 19104 
Office: 215 746-1195 
Lab: 215 746-1199 
Fax: 215 746-1100 
 
Samples for MRD testing will be sent to: 
Adaptive Biotechnologies 
Attention: Clinical Lab 
1551 Eastlake Ave E, Ste 200 
Seattle, WA 98102 
 
3.6.5 Paraffin-embedded tissue block submission 
If a patient has consented to allow their tissue to be kept for future unknown use, only one tissue 
block will be needed to accommodate both histological confirmation and future correlative 
science studies. At time of progression or relapse, if a patient has consented to allow their tissue 
to be kept for future unknown use, and if a biopsy has been performed, these pathology 
specimens will be sent for pathology review and future correlative science studies to: 
 
Tumor Tissue Bank Core Facility 
Hospital of the University of Pennsylvania 
Department of Pathology & Laboratory Medicine 
6.119 Founders Pavilion, 3400 Spruce Street 
Philadelphia, PA 19104  


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Phone: 215-615-1673 
Fax: 215-349-5910 
4 Subject Selection and Withdrawal 
4.1  
Inclusion Criteria  
 
• Documentation of disease 
 
o Previously treated, histological confirmed follicle center lymphoma, grade 1-3a, 
marginal zone lymphoma, small lymphocytic lymphoma with < 5000 
lymphocytes /mm³ or lymphoplasmacytic lymphoma with <3gm/ml IgM, mantle 
cell lymphoma by WHO classification (see Appendix F). 
 
o Bone marrow biopsies as sole means of diagnosis are not acceptable. Fine needle 
aspirates are not acceptable. 
 
o Institutional flow cytometry or immunohistochemistry must document CD20 
antigen expression. Past documentation of CD20 antigen expression is admissible. 
 
• Prior treatment 
 
o Patients must have been treated with rituximab in combination with chemotherapy 
or as monotherapy and must have refractory or progressive disease.  Subjects 
must have had less than a partial response or progressive disease within 6 months 
of any dose of rituximab. 
 
• Age > 18 
 
• ECOG performance status 0-2 (see Appendix B) 
 
• Measurable disease must be present either on physical examination or imaging studies. 
Non-measurable disease alone is not acceptable. Any tumor mass > 2cm is considered 
measurable. 
 
• Lesions that are considered non-measurable, but assessable include the following: 
 
o Bone lesions (lesions if present should be noted) 
o Ascites 
o Pleural/pericardial effusion 
o Lymphangitis cutis/pulmonis 
o Bone marrow (involvement by non-Hodgkin lymphoma should be noted) 
 
• Patients with a history of intravenous drug abuse or any behavior associated with 
increased risk of HIV infection should be tested for exposure to the HIV virus. 
 


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• Understand and voluntarily sign an informed consent form. 
 
• Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation. Patients 
intolerant to ASA may use warfarin or low molecular weight heparin 
 
• Laboratory test results within these ranges: 
o Absolute neutrophil count ≥ 1000/mm³  
o Platelet count ≥ 75,000 /mm³  
o Serum creatinine ≤ 2.0 mg/dL 
o Total bilirubin ≤ 1.5 mg/dL (unless due to Gilbert’s syndrome) 
o AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN if hepatic metastases 
are present. 
• Disease free of prior malignancies for ≥ 5 years with exception of currently treated basal 
cell or squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix or breast.  
• All study participants must be registered into the mandatory Revlimid REMS® program, 
and be willing and able to comply with the requirements of Revlimid REMS®. 
• Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to and 
again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 
days) and must either commit to continued abstinence from heterosexual intercourse or 
begin TWO acceptable methods of birth control, one highly effective method and one 
additional effective method AT THE SAME TIME, at least 28 days before she starts 
taking lenalidomide.  FCBP must also agree to ongoing pregnancy testing.  Men must 
agree to use a latex condom during sexual contact with a FCBP even if they have had a 
successful vasectomy.  See Appendix: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods. 
 
 
4.2  
Exclusion Criteria 
 
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from following study procedures. 
                                                 
 
† A female of childbearing potential is a sexually mature woman 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). 
 
 


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• Pregnant or breast-feeding females. (Lactating females must agree not to breast feed 
while taking lenalidomide). 
• Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study or confounds the 
ability to interpret data from the study. 
• Use of any other experimental drug or therapy within 28 days of baseline. 
• Known hypersensitivity to thalidomide. 
• The development of erythema nodosum if characterized by a desquamating rash while 
taking thalidomide or similar drugs. 
• Any prior use of lenalidomide. 
• Known positive for HIV or active infectious hepatitis, type A, B or C.  Patients who test 
positive or who are known to be infected are not eligible due to an increased risk of 
infection with this regimen. An HIV test is not required for entry in this protocol, but is 
required if the patient is perceived to be at risk. 
• Known CNS involvement by lymphoma. 
 
4.3 
Subject Recruitment and Screening 
 
This clinical trial can fulfill its objectives only if patients appropriate for the trial are enrolled. 
All relevant medical and other considerations should be taken into account deciding whether this 
protocol is appropriate for a particular patient. Physicians should consider the risks and benefits 
of any therapy and therefore only enroll patients for whom the agents administered are 
appropriate. Although they will not be considered as formal eligibility (exclusion) criteria, as 
part of the decision-making process physicians should recognize that the following might 
increase the risk to the patients entering this protocol: 
 
Serious medical illness or psychiatric condition, which would prevent compliance with treatment 
or informed consent. 
 
Medical conditions such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac 
disease, which, in the opinion of the treating physician, would make this protocol unreasonably 
hazardous for the patient. 
 
Patients at high risk of hepatitis B infection should be screened before starting treatment. 
Carriers of hepatitis B should be closely monitored for evidence of active HBV infection and 
hepatitis during and for several months after rituximab treatment. 
 
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 is combined with other agents such as steroids (e.g. dexamethasone, 


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prednisone), anthracyclines (Doxil, Adriamycin) and erythropoietin the risk of thrombosis is 
increased.  Due to the known increased risk of thrombotic events associated with the 
combination of lenalidomide and dexamethasone subjects will receive aspirin (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 used with caution and close 
monitoring of INR. 
 
Patients with absolute lymphocyte count >20,000/ul should be closely monitored for tumor lysis 
syndrome.  These patients should receive appropriate supportive care and prophylaxis (e.g., 
allopurinol, intravenous hydration, additional laboratory test monitoring, etc.) prior to rituximab 
infusion.  A modified dosing scheme is suggested for those patients with absolute lymphocyte 
count>20,000/ul (see 6.2). 
 
 
4.4 
Early Withdrawal of Subjects 
 
Subjects will be removed from protocol for any of the following reasons: 
 
• Any clinical adverse event, laboratory abnormality or inter-current illness, which, in the 
opinion of the investigator, indicates that, continued treatment with study therapy is not 
in the best interest of the subject. 
 
• Any toxicity requiring discontinuation as outlined in the dose modifications criteria in 
Table 2, Section 6.1.3. 
 
• The subject declines further therapy. 
 
• The subject experiences progression of disease after the first 2 cycles of study treatment 
(Part I) with estimated life expectancy < 3 months or relapse of lymphoma/progression of 
disease after having received rituximab (see also Section 7). 
 
• It is deemed in the best interest of the subject.  In this instance, the Principal Investigator 
should be notified. 
 
• Termination of the study by the supporter, Celgene. 
 
• Pregnancy 
 
• The reason(s) for withdrawal should be noted in the case report form and in the subject’s 
medical record. Survival data on patients that withdraw from the trial will be recorded.  
Statistical analysis will be performed on an intent-to-treat basis. 
 
 


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5 Drug Formulation, Availability and Preparation 
5.1 Lenalidomide  
REVLIMID®  (Lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti-
angiogenic properties.  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:  
Chemical Structure of Lenalidomide 
 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.  
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 
active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero. 
5.1.1 Mechanism of Action 
The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide 
possesses immunomodulatory and anti-angiogenic properties.  Lenalidomide inhibited the 
secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory 
cytokines from peripheral blood mononuclear cells.  Lenalidomide inhibited cell proliferation 
with varying effectiveness (IC50s) in 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.   
5.1.2 Pharmacokinetics and Drug Metabolism 
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. 


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Pharmacokinetic sampling in myelodysplastic syndrome (MDS) patients was not performed. In 
multiple myeloma patients, maximum plasma concentrations occurred between 0.5 and 4.0 hours 
post-dose both on Days 1 and 28.  AUC and Cmax values increase proportionally with dose 
following single and multiple doses. Exposure (AUC) in multiple myeloma patients is 57% 
higher than in healthy male volunteers.  
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.  
5.1.3   Supplier 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through the Revlimid REMS® program.  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 Celgene’s Revlimid REMS® program. 
5.1.4  Dosage form 
Lenalidomide will be supplied as capsules for oral administration.   
5.1.5  Packaging 
Lenalidomide will be shipped directly to patients.   Bottles will contain a sufficient number of 
capsules for one cycle (28 days) of dosing.    
5.1.6  Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold.     
5.1.7  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.  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 Celgene’s Revlimid REMS® program.  Prescriptions must be filled within 7 
days.  Only enough lenalidomide for one cycle of therapy will be supplied to the patient each 
cycle. 
 


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5.1.8 Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 
5.2  
Rituximab (Rituxan®, IDEC-C2B8)  
Rituximab is clinically indicated for the treatment of CD20+ non-Hodgkin lymphomas, and will 
be billed to the patient and/or insurance.  Please refer to the agent’s package insert for additional 
information. 
5.2.1 Availability 
Rituximab is commercially available in 10ml and 50ml single-use vials containing 100 or 500 
mg of antibody, respectively at concentration of 10 mg/ml.   
5.2.2 Storage and Stability 
Intact vials should be stored under refrigeration. Dilute solutions for infusion (1-4mg/ml) are 
stable for 24 hours under refrigeration, and for an additional 24 hours at room temperature. 
 
5.2.3 Preparation 
The desired dose of rituximab should be diluted in 0.9% NaCL or D5W to a final concentration 
of 1-4mg/ml. Mix by inverting the bag gently. 
 
5.2.4 Administration 
Rituximab will be administered by IV infusion as described in 6.2. Patients must be pretreated 
with acetaminophen and diphenhydramine prior to each dose of rituximab. 
 
5.2.5 Toxicity 
The most serious adverse events associated with rituximab include severe infusion reactions, 
Tumor Lysis syndrome and severe muco-cutaneus reactions. Severe infusion reactions consisting 
of hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation or cardiogenic shock may be fatal. Most reported fatal reactions occurred 
within 24 hours of the first dose of rituximab. If a reaction occurs, the infusion should be stopped 
until the symptoms resolve, and then restarted at a 50% slower rate. Because severe infusion 
reactions have been noted more frequently in patients with high leukocyte counts, such patients 
should be observed closely. 
 
Tumor Lysis syndrome resulting in renal failure has been described and occasional fatalities 
noted. Tumor Lysis syndrome is more likely in patients with high numbers of circulating 
malignant cells.  These patients should receive appropriate supportive care and prophylaxis (e.g., 
allopurinol, intravenous hydration, additional laboratory test monitoring, etc.) prior to rituximab 
infusion. 
 
Severe muco-cutaneus reactions associated with rituximab include Stevens-Johnson syndrome 
and toxic epidermal necrolysis. The onset of these reactions has been from 1-3 weeks. 
 
Less severe infusion reactions are common with rituximab. These include fever, chills and 
dyspnea. The mechanism of rituximab infusion reactions is thought to be the release of 
cytokines. Infusions should be interrupted until symptoms resolve, and restarted at a 50% slower 


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rate. Pretreatment with acetaminophen and diphenhydramine before each dose of rituximab may 
minimize the likelihood/severity of infusion reactions. 
 
Recent reports describe hepatitis B reactivation with fulminant hepatitis, hepatic failure and 
death in some patients receiving rituximab in combination with chemotherapy. The median time 
to diagnosis of hepatitis was approximately 4 months after starting rituximab and approximately 
1 month after last dose. 
 
A report in the literature described an increase in fatal infection in HIV-related lymphoma 
patients when rituximab was used in combination with CHOP chemotherapy, as compared to 
CHOP alone. Patients with HIV infection are not eligible for entry on this research study. 
 
6 Dose Modifications and Management of Toxicities 
6.1 
Lenalidomide and Dexamethasone 
Administration:  For subjects in both Cohorts 1 and 2 with baseline creatinine clearance of >30 
ml/min, the initial dose of lenalidomide for investigation is 10 mg/day, orally on days 1 - 28, 
repeated every 28 days (28 day cycle).  The initial dose for subjects with a baseline creatinine 
clearance of <30 ml/min will be 5 mg orally on days 1 – 28 of each 28 day cycle.  Dosing will be 
at approximately the same time each day.  Prescriptions must be filled within 7 days. 
For patients in Cohort 1 only, the initial dexamethasone dose will be 8mg PO once weekly 
(dosing on days 3, 10, 17 and 24 are suggested but not required), repeated every 28 days.  
Subjects enrolled to Cohort 2 will not receive dexamethasone as part of protocol therapy. 
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. 
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. 
Subjects experiencing adverse events may need study treatment modifications (See 6.1.3). 
 
Lenalidomide Dose Escalation Evaluation and Instruction:  All subjects shall be evaluated 
after first cycle of lenalidomide for dose escalation. If no drug-related toxicity of ≥ Grade 3 was 
noted, dose escalation to the next dose level is permissible at the start of Cycle 2 during Part I 
(see Section 6.1.1 for lenalidomide dose levels). No dose escalation shall be permitted upon 
entry into Part II of the trial or at any other time except at the start of Cycle 2 during Part I.   
Record of administration: Accurate records of all study drug administration (including 
prescribing and dosing) will be made in the source documents. 
6.1.1 Dose Continuation, Modification and Interruption    
Subjects will be evaluated for AEs at each visit with the NCI CTCAE v5.0(Appendix C: NCI 
CTCAE v5.0) used as a guide for the grading of severity.  Refer to the Dose Modification Steps 
below, and to Sections 6.1.2 and 6.1.3 for full instruction on initiation of a new cycle of therapy 
and dose modifications during a cycle of therapy.    


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Dose Modification Steps 
 
Table 1: LENALIDOMIDE Dose Reduction Steps 
Dose Level +1 
15 mg daily on Days 1-28 every 28 days 
Starting Dose 
10 mg daily on Days 1-28 every 28 days 
 
 
Dose Level – 1 
 
 
5 mg daily on Days 1-28 every 28 days 
Dose Level – 2 
5 mg every other day during Days 1-28 every 28 
days 
Dose Level - 3 
Subjects with extended remissions (response > 
1 year) may have their dose adjusted at the 
discretion of the Principal Investigator; any dose 
adjustments at Dose Level -3 must be approved 
in writing by the Medical Monitor.  
 
6.1.2 Instructions for initiation of a New Cycle  
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
• The ANC is ≥ 1000 /mm³ 
• The platelet count is ≥ 50,000 /mm³;  
• 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.  
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly and 
a new cycle of treatment will not be initiated until the toxicity has resolved as described above.  
If lenalidomide dosing was halted during the previous cycle and was restarted with a one-level 
dose reduction without requiring an interruption for the remainder of the cycle, then that reduced 
dose level will be initiated on Day 1 of the new cycle. If lenalidomide dosing was omitted for 
the remainder of the previous cycle or if the new cycle is delayed due to toxicity newly 
encountered on the scheduled Day 1, then the new cycle will be started with a one-level 
dose reduction of lenalidomide. 
 
If subjects experience cytopenias and do not meet study requirements to resume lenalidomide, 
they may proceed with rituximab as described in the protocol.   


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6.1.3 Instructions for dose modifications or interruption during a cycle 
Table 2: Lenalidomide Dose Modifications  
 
NCI CTC Toxicity Grade 
Onset Day 2-21 of Cycle 
Onset ≥ Day 22 of Cycle 
Grade 
3 
neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia 
• 
Hold (interrupt) lenalidomide dose 
(missed doses of lenalidomide are 
not made up). 
• 
Follow CBC weekly. 
• 
If neutropenia has resolved to ≤ 
grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue the cycle 
through Day 28.  If neutropenia is 
the only toxicity for which a dose 
reduction is required, G-CSF may 
be used and the lenalidomide dose 
maintained. 
• 
Omit lenalidomide for 
remainder of cycle 
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level.  If 
neutropenia is the 
only toxicity for which 
a dose reduction is 
required. G-CSF may 
be used and the 
lenalidomide dose 
maintained for the 
next cycle at the 
investigators 
discretion. 
Thrombocytopenia 
≥Grade 3 (platelet count 
< 50,000/mm³) 
• 
Hold (interrupt) lenalidomide dose 
and prophylactic anti-coagulation, if 
applicable. 
• 
Follow CBC weekly. 
• 
If thrombocytopenia resolves to ≤ 
grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue the cycle 
through Day 28.  See Section 6.3 
for instructions for restarting 
prophylactic anti-coagulation. 
 
• 
Omit lenalidomide for 
remainder of cycle 
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level. 
Non-blistering rash 
Grade 3 
 
 
 
Grade 4 
• 
If Grade 3, hold (interrupt) 
lenalidomide dose.  Follow weekly. 
• 
If the toxicity resolves to ≤ grade 1 
prior to Day 21, restart lenalidomide 
at next lower dose level and 
continue the cycle through Day 28. 
 
 
 
• 
Discontinue lenalidomide.  Remove 
patient from study. 
• 
Omit lenalidomide for 
remainder of cycle.  
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level. 
 
 
 
• 
Discontinue 
lenalidomide.  
Remove patient from 
study. 
Desquamating 
(blistering) rash- any 
Grade  
• 
Discontinue lenalidomide.  Remove 
patient from study. 
• 
Discontinue 
lenalidomide.  
Remove patient from 
study. 


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Table 2: Lenalidomide Dose Modifications  
 
NCI CTC Toxicity Grade 
Onset Day 2-21 of Cycle 
Onset ≥ Day 22 of Cycle 
Neuropathy 
 
Grade 3 
 
 
 
 
 
 
Grade 4 
 
• 
Hold (interrupt) lenalidomide dose.  
Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 1 
prior to Day 21, restart lenalidomide 
at next lower dose level and 
continue the cycle through Day 28. 
 
 
 
 
• 
Discontinue lenalidomide.  Remove 
patient from study. 
• 
Omit lenalidomide for 
the remainder of the 
cycle. 
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level. 
 
 
 
• 
Discontinue 
lenalidomide.  
Remove patient from 
study. 
Venous 
thrombosis/embolism 
≥ Grade 3 
• 
Hold (interrupt) lenalidomide and 
start anticoagulation; restart 
lenalidomide at investigator’s 
discretion (maintain dose level). 
• 
Omit lenalidomide for 
remainder of cycle.  
Hyperthyroidism 
or 
hypothyroidism 
• 
Omit lenalidomide 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. 
• 
Omit lenalidomide 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 non-hematologic 
toxicity ≥ Grade 3 
attributable to 
lenalidomide  
• 
Hold (interrupt) lenalidomide dose.  
Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 2 
prior to Day 21, restart lenalidomide 
at next lower dose level and 
continue the cycle through Day 28. 
• 
Omit lenalidomide for 
remainder of cycle.  
• 
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level. 
 
NOTE: If subjects do not have adequate hematological recovery within 28 days of their last 
study treatment, lenalidomide will be discontinued and not restarted.  However, the subjects will 
still be followed for response assessment and included in endpoint analyses. 
 
Table 3: Dose Modification for Dexamethasone (Cohort 1 Patients Only) 
Use Common Terminology Criteria for Adverse Events (CTCAE) v5.0 unless otherwise specified  
CTCAE 
CATEGORY 
ADVERSE EVENT 
DOSAGE CHANGE 
Gastrointestinal 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1-2 (requiring 
medical management) 
Treat with H2 blockers, sucralfate, or 
omeprazole.   
 
If symptoms persist despite above measures, 
consider dexamethasone dose reduction 
and/or schedule modification. 


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Table 3: Dose Modification for Dexamethasone (Cohort 1 Patients Only) 
Use Common Terminology Criteria for Adverse Events (CTCAE) v5.0 unless otherwise specified  
CTCAE 
CATEGORY 
ADVERSE EVENT 
DOSAGE CHANGE 
 
≥Grade 3 (requiring 
hospitalization or 
surgery) 
Hold dexamethasone until symptoms 
adequately controlled.  Restart 
dexamethasone at reduced dose along with 
concurrent therapy with H2 blockers, 
sucralfate, or omeprazole.  If toxicity recurs, 
discontinuation of dexamethasone may be 
considered. 
 
Acute pancreatitis 
Discontinue dexamethasone and do not 
resume 
Cardiovascular 
Edema 
≥Grade 3 (limiting 
function and 
unresponsive to therapy 
or anasarca) 
Hold dexamethasone until symptoms 
adequately controlled.  Use diuretics as 
needed.   Restart dexamethasone with 
consideration of dexamethasone dose 
reduction and/or schedule modification.  If 
toxicity recurs, discontinuation of 
dexamethasone may be considered. 
Neurology 
Confusion or Mood 
alteration  
≥ Grade 2 (interfering 
with function +/- 
interfering with activities 
of daily living) 
Hold dexamethasone until symptoms 
adequately controlled.  Restart 
dexamethasone with consideration of 
dexamethasone dose reduction and/or 
schedule modification.  If toxicity recurs, 
discontinuation of dexamethasone may be 
considered. 
Musculoskeletal 
Muscle weakness  
≥ Grade 2 (symptomatic 
and interfering with 
function +/- interfering 
with activities of daily 
living) 
Hold dexamethasone until symptoms 
adequately controlled.  Restart 
dexamethasone with consideration of 
dexamethasone dose reduction and/or 
schedule modification. If weakness persists, 
consider further dexamethasone dose 
reduction and/or schedule modification, or 
discontinuation.  
Metabolic 
 
Hyperglycemia 
≥ Grade 3 or higher 
Treatment with insulin or oral 
hypoglycemics as needed.  If uncontrolled 
despite above measures, consider 
dexamethasone dose modification and/or 
schedule modification, or discontinuation. 
Any  Other Toxicity 
Attributed to 
Dexamethasone   
≥ Grade 3 or higher  
Hold dexamethasone until symptoms 
adequately controlled.  Restart 
dexamethasone with consideration of 
dexamethasone dose reduction and/or 
schedule modification.  If toxicity recurs, 
discontinuation of dexamethasone may be 
considered. 
 
 


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6.2  
Rituximab  
 
Rituximab 375mg/m2 will be administered by IV infusion once weekly during cycle 3. The 
initial rate during the first infusion should be 50mg/hr. The infusion rate may be increased, if 
tolerated, by 50mg/hr increments every 30 minutes to a maximum of 400mg/hr. If administration 
is well tolerated during the first infusion, subsequent infusions of therapy may begin at a rate of 
100 mg/hr. If tolerated, the rate may be increased by 100 mg/hr increments every 30 min to a 
maximum rate of 400 mg/h.  
 
  Close monitoring for tumor lysis syndrome (TLS) and TLS prophylaxis should be initiated 
during Cycles 1 on Day 3, 4, or 5 and on Day 8. During the Cycle 3, tumor lysis labs should be 
drawn at one timepoint between days 3-5 and on day 8 after each subject’s first dose of 
rituximab. .  Additional assessments may be done at any time (see Sections 3.2 and 6.3).  Extra 
care should be taken with TLS monitoring and with TLS prophylaxis in patients with an absolute 
lymphocyte count>20,000/ul, and those patients should receive appropriate supportive care (e.g., 
allopurinol, intravenous hydration, additional laboratory test monitoring, etc.).  
6.2.1 Infusion and Hypersensitivity reactions 
In subjects with absolute lymphocyte count >20,000/ul, special attention will be given to TLS 
monitoring and TLS prophylaxis (Section 6.2) and the rituximab infusion shall be modified as 
follows: 50 mg absolute dose on Day 1, 150 mg absolute dose on Day 2 and (375mg/m2-200mg) 
on Day 3. 
 
Rituximab infusions must be interrupted if any infusion reactions (e.g., fever, chills, dyspnea 
etc.) > grade 1 occur. When the symptoms have resolved completely, the infusion may be 
restarted at half the previous rate. If tolerated, rituximab may be gradually re-escalated to the 
initial infusion rate. If patients experience a second infusion reaction, the rituximab infusion 
should be stopped. At the investigator’s discretion, patients unable to complete the full dose of 
rituximab may resume the incomplete treatment on the following day after dexamethasone 20 
mg po is given the night before and the morning of retreatment. 
 
Infusion reactions are distinct from hypersensitivity reactions, but they may have overlapping 
manifestations. Hypersensitivity reactions to rituximab are non-IgE mediated and may also 
respond to decreases in infusion rates. For hypersensitivity reactions>grade1, rituximab should 
be interrupted and the reaction treated with antihistamines, steroids and/or epinephrine. 
Following complete resolution of grade 1or 2 reactions, rituximab may be restarted at half the 
previous rate and re-escalated as above. For grade 3 or 4 hypersensitivity reactions, rituximab 
should be discontinued. 
6.2.2 Dermatology Toxicity 
In the instance of > grade 3 erythema multiforme, remove patient from the protocol therapy. 
 
6.3  
Ancillary Therapy 
 


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Patients should receive full supportive care, including transfusion of blood and blood products, 
epoietin, antibiotics, antiemetics etc, when appropriate. The reasons for treatment, dosage and 
dates of treatment should be recorded.  
 
 
6.3.1 Tumor Lysis Prophylaxis 
Close monitoring for tumor lysis syndrome (TLS) should be initiated concurrently with the 
initiation of study treatment in Part I for all subjects.  Subjects may receive tumor lysis 
prophylaxis if clinically indicated.  All subjects should remain well hydrated during at least the 
first 7 days of Cycles 1.  Close monitoring for TLS and the need for TLS prophylaxis should be 
repeated during at least the first 7 days of Part II of treatment (the first 7 days of Cycle 3).  
Additional TLS monitoring and prophylaxis may be employed at any time at the investigator’s 
discretion.   
 
Subjects who are felt to be at high risk for tumor lysis syndrome should receive prophylaxis with 
allopurinol.  Other subjects should receive tumor lysis prophylaxis if clinically indicated.  All 
subjects should be instructed to maintain adequate hydration and maintain urinary output.  To 
maintain fluid intake, subjects should be instructed to drink 8 to 10 eight ounce glasses of water 
each day for at least the first 7 days of Cycle 1.  Hydration levels should be adjusted according to 
age and clinical status, and lowered if the subject’s cardiovascular status indicates the possibility 
of volume overload.  Close monitoring for TLS and TLS prophylaxis (allopurinol, if possible, 
and oral hydration as above) should be repeated during at least the first 7 days of Part II 
treatment (the cycle including rituximab).  Additional TLS monitoring and prophylaxis may be 
employed at any time at investigator discretion.   
 
6.3.2 Tumor Flare Reaction 
Tumor flare occurring during the first 1-2 weeks of Cycles 1, 2 and 3 should be recorded as AEs 
and not as progressive disease (PD).  Tumor flare should be treated symptomatically with non-
steroidal anti-inflammatory agents (NSAIDs) and other measures as needed. 
 
6.3.3 Prophylactic Anti-coagulation  
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 is combined with other agents such as steroids (e.g. dexamethasone, 
prednisone), anthracyclines (Doxil, Adriamycin) and erythropoietin the risk of thrombosis is 
increased.  Due to the known increased risk of thrombotic events associated with the 
combination of lenalidomide and dexamethasone subjects will receive aspirin (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 used with caution and close 
monitoring of INR.  Prophylactic anti-coagulation should be held for platelet counts < 
50,000/mm3 and restarted when platelet counts are ≥ 50,000/mm3.  Prophylactic anti-coagulation 
may be discontinued if dexamethasone is discontinued unless subjects are receiving 
erythropoietin.   
6.3.4 Prohibited concomitant therapy 


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Concomitant use of sargramostim (GM-CSF), other anti-cancer therapies, including radiation, 
thalidomide, or other investigational agents is not permitted while subjects are receiving study 
drug during the treatment phase of the study. 
7  
Response Definition (see Appendix D + E) 
7.1   Complete Response (CR) 
 
7.1.1 Complete disappearance of all detectable clinical and radiographic evidence of 
disease and disappearance of all-disease related symptoms if present before 
therapy, and normalization of those biochemical abnormalities (e.g., lactate 
dehydrogenase [LDH] definitely assignable to NHL. 
 
7.1.2 All lymph nodes and nodal masses must have regressed to normal size (≤ 1.5 cm 
in their greatest transverse diameter for nodes > 1.5 cm before therapy).  
Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse 
diameter before treatment must have decreased to ≤ 1 cm in their greatest 
transverse diameter after treatment, or by more than 75% in the sum of the 
products of the greatest diameters (SPD). 
 
7.1.3 The spleen, if considered to be enlarged before therapy on the basis of a CT scan, 
must have regressed in size and must not be palpable on physical examination. 
However, no normal size can be specified because of the difficulties in accurately 
evaluating splenic and hepatic size.  For instance, spleens thought to be of normal 
size may contain lymphoma, whereas an enlarged spleen may not necessarily 
reflect the presence of lymphoma but variations in anatomy, blood volume, the 
use of hematopoietic growth factors, or other causes.  The determination of 
splenic volume or splenic index by CT scan is cumbersome and not widely used.   
Any macroscopic nodules in any organs detectable on imaging techniques should 
no longer be present.  Similarly, other organs considered to be enlarged before 
therapy due to involvement by lymphoma, such as liver and kidneys, must have 
decreased in size. 
 
7.1.4 If the bone marrow was involved by lymphoma before treatment, the infiltrate 
must be cleared on repeat bone marrow aspirate and biopsy of the same site.  The 
sample on which this determination is made must be adequate (>20 mm biopsy 
core).   Flow cytometry, molecular, or cytogenetic studies are not considered part 
of routine assessment to document persistent disease at the present time.  
 
7.2   Complete Response/Unconfirmed (Cru)  
 
CR/unconfirmed (CRu) includes those subjects who fulfill criteria 1 and 3 above, but 
with one or more of the following features: 
 


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7.2.1 A residual lymph node mass greater than 1.5 cm in greatest transverse diameter 
that has regressed by more than 75% in the SPD.  Individual nodes that were 
previously confluent must have regressed by more than 75% in their SPD 
compared with the size of the original mass. 
 
7.2.2 Indeterminate bone marrow (increased number or size of aggregates without 
cytological or architectural atypia). 
 
7.3   Partial Response (PR) 
 
7.3.1 >50% decrease in SPD of the six largest dominant nodes or nodal masses.  These 
nodes or masses should be selected according to the following features: (a) they 
should be clearly measurable in at least two perpendicular dimensions, (b) they 
should be from as disparate regions of the body as possible, and (c) they should 
also include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved. 
 
7.3.2 No increase in the size of the other nodes, liver, or spleen. 
 
7.3.3 Splenic and hepatic nodules must regress by at least 50% in the SPD. 
 
7.3.4 With the exception of splenic and hepatic nodules, involvement of other organs is 
considered assessable and not measurable disease. 
 
7.3.5 Bone marrow assessment is irrelevant for determination of a PR because it is 
assessable and not measurable disease; however, if positive, the cell type should 
be specified in the report, e.g., large-cell lymphoma or low-grade lymphoma (i.e., 
small, lymphocytic small cleaved, or mixed small and large cells.) 
 
7.3.6 No new sites of disease. 
7.4  
Stable Disease (SD)  
 
7.4.1 Stable disease is defined as less than a PR (see above) but is not progressive 
disease (see below). 
 


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7.5   Relapsed Disease (RD)  
 
7.5.1 Appearance of any new lesion or increase by >50% in the size of previously 
involved sites. (only applies to subjects that achieve a CR). 
 
7.5.2 >50% increase in greatest diameter of any previously identified node greater than 
1 cm in its short axis or in the SPD of more than one node. 
 
7.6   Progressive Disease (PD)  
 
7.6.1 >50% increase from nadir in the SPD of any previously identified abnormal node 
for PRs or non-responders. 
 
7.6.2 Appearance of any new lesion during or at the end of therapy which is >1.5 cm by 
radiologic evaluation or greater than 1 cm by physical examination. 
 
7.7   Molecular Complete Response (MCR)  
 
7.7.1 For subjects with clonal immunoglobulin heavy chain gene rearrangement, or 
Bcl2/IgH rearrangement by PCR, MCR will be defined as the inability to detect a 
previously detectable malignant clonal population of cells using a PCR-based 
assay on bone marrow and/or peripheral blood specimens. 
 
7.8   Response Rates  
 
7.8.1 Response to Lenalidomidewith and without Dexamethasone:  Response rate is 
defined as the percentage of subjects who attain complete response (CR), 
complete response unconfirmed (CRu), or partial response (PR) after two cycles 
of –study treatment (lenalidomide-dexamethasone for Cohort 1 subjects; 
lenalidomide monotherapy for Cohort 2 subjects.  Subjects may be scored as 
having progressive disease (PD) after 2 cycles of –study treatment and will be 
removed from the study if the estimated life expectancy is < 3 months at that time.  
Following an intent-to-treat analysis plan, all subjects who receive one day of 
chemotherapy will be included in the denominator for this response rate. 
 
7.8.2 Response to Lenalidomide + Rituximab with and without Dexamethasone:  
Response to lenalidomide plus rituximab with and without dexamethasone is 
defined as the percentage of subjects in complete remission (CR), complete 
remission unconfirmed (CRu), partial response (PR), or with stable disease (SD) 
at the 3 months post-rituximab evaluation.  Only subjects who receive rituximab 
are included in the denominator for this secondary response rate. 
 


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7.9   Time to progression (TTP) 
 
 
TTP is defined as the time from the first day of protocol therapy to the first event 
defining progression of disease or last subject contact.  TTP is defined for all 
subjects receiving protocol therapy, following an intent-to-treat analysis plan. 
TTP from rituximab is defined for patients receiving rituximab (Part II) from the 
first day of rituximab therapy to the first event defining treatment failure. 
 
7.10   Progression free survival (PFS)  
 
 
PFS is defined as the time from first day of protocol therapy to disease 
progression, death due to any cause or last subject contact.  PFS is defined for all 
subjects entered on the study, following an intent-to-treat analysis plan.  A 
secondary analysis will also include a calculation of PFS from day of rituximab 
infusion. 
 
7.11   Overall Survival (OS)  
 
Overall survival is defined as the time from first day of protocol therapy to death 
due to any cause or last subject contact.  
 
7.12 Safety evaluation 
 
Data from all subjects who receive any study drug will be included in the safety 
analyses. Subjects who entered the study and did not take any of the study drug(s) 
and had this confirmed, will not be evaluated for safety. 
 
The severity of the toxicities will be graded according to the NCI CTCAE v3.0 
whenever possible. 
 
8 
Statistical Plan 
 
Statistical design and analysis 
Design.  This study will enroll 45 evaluable subjects, all of whom have had lymphoma 
progression or failure to respond within six months of being treated with rituximab alone or with 
a rituximab-containing regimen.  Twenty-five patients will be enrolled into Cohort 1, which will 
consist of daily dosing of lenalidomide and weekly dosing of dexamethasone.  An additional 
twenty patients will be enrolled into Cohort 2, in which patients will receive daily dosing of 
lenalidomide, but will not be treated with weekly dexamethasone. Subjects with documented 
Rituxan-refractory disease will be enrolled to the study and treated for two 28-day cycles with 
lenalidomide – dexamethasone (Cohort 1) or lenalidomide alone (Cohort 2).  After this first 
treatment period, termed Part I, subjects will be re-evaluated and subsequently treated with 


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lenalidomide – dexamethasone and rituximab (Cohort 1) or lenalidomide and rituximab (Cohort 
2) in combination. A subject who does not complete rituximab therapy as part of this study will 
be considered non-evaluable and may be replaced by enrolling an additional subject.  However, 
all subjects will be included in the intent-to-treat analysis. 
 
Power to detect adverse effects.  With 45 subjects, we will have 90% power to detect any 
unforeseen toxicity whose prevalence is at least 5.0%.  The half-width of the confidence interval 
for any fraction (toxicity or response) will extend no more than +/- 15% around the estimate. 
 
Treatment response.  We will use McNemar’s test to compare the fractions of patients  
responding to rituximab therapy without (baseline) and with revlimid.  In the baseline period, we 
estimate that 10% of patients will have responded to rituximab, although all will ultimately fail 
within 6 months.  Assuming a modest kappa (intra-subject correlation) of 10%, with 45 patients 
we have 87% power to detect a significant effect of revlimid treatment if the treatment-period 
response rate is 35%. 
 
Time to progression.  We will compute a 95% confidence interval for the ratio of median TTP 
under revlimid+rituximab to the median TTP under rituximab alone, using the nonparametric 
method of Jung and Su (1995).  If the interval excludes 1, we will declare the difference to be 
statistically significant. 
 
To evaluate the power of this design, we assumed that TTP in the baseline (rituximab only) 
period would be statistically independent of TTP in the follow-up (combination treatment) 
period.  This will lead to a conservative estimate of the power, as positive correlation of failure-
time endpoints generally increases power for paired comparisons (e.g., see Mick et al. 2000).  
Assuming that median TTP in the baseline period is 3 months, we calculated the power to detect 
significance in a test of the null hypothesis that median TTP is the same in both periods.  If the 
median TTP in the follow-up period is doubled, to 6 months, then the power is 83%; if the 
median TTP is tripled, to 12 months, then the power is essentially 100%.  Thus power is 
satisfactory if there is a substantial increase in the median TTP.  
 
Design and analysis of correlative studies.  In correlative studies, we will compare mean changes 
in immunologic phenotype parameters (fraction Th2+ cells, NK cells and Treg cells) between the 
subjects who experience a remission (expected to be up to 80%, or 36 of 45 subjects) and those 
who do not (as few as 20%, or 9 of 45 subjects).  As we do not yet know the likely values of 
these immunologic parameters, we estimate the power in terms of the difference in means as a 
fraction of the common standard deviation (SD).  The basic analysis is a t test comparing mean 
change in the two groups.  Calculations show that if the standardized difference is equal to 1 SD, 
then the power is 75%, whereas if the standard difference is 1.25 SDs, then the power is 91%.  
Thus the power of this correlative analysis is reasonable as long as there is a reasonably large 
difference in mean change between the remission and non-remission groups. 
Analysis of serum albumin as a biomarker. We will test the hypotheses that 1) a decrease in 
serum albumin by > 0.3 g/dL at commencement of cycle 2 from baseline predicts a response 
(CR/PR)to protocol therapy and that 2) a baseline serum albumin < 4.1 g/dL predicts no response 
(SD/PD) to protocol therapy.  From preliminary analysis of our first eleven patients, we will 
assume the same breakdown of responses (3 non-responders: 8 responders).  Using this 


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assumption, we will have 80% power with a two-tailed alpha of 0.05 to detect an odds ratio of 
2.6; this is 10 times less than expected. 
9 Safety and Adverse Events 
9.1 
Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries should 
be regarded as adverse events.  Abnormal results of diagnostic procedures are considered to 
be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
• fatal 
• life-threatening1 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity2 
• a congenital anomaly or birth defect 
• an important medical event3 
• positive pregnancy 
 
1 “Life-threatening” as defined by CTCAE Version 5.0. 
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. 
3 Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in situations where none of the outcomes listed above occurred.  Important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above should also usually be 
considered serious.  Examples of such events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.  A new diagnosis of cancer during the course of a 
treatment should be considered as medically important. 
 
Note: Hematologic toxicities will not be captured as serious adverse events. 
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
 
Unexpected adverse events 
An adverse event related to therapy is considered unexpected (or unanticipated) if the event 
severity and/or frequency is not described in the investigator brochure and/or protocol.   


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Related adverse events 
An adverse event is considered related to participation in the research if there is a 
reasonable possibility that an event was caused by an investigational product, intervention 
or research-required procedures.  For the purposes of this study, "reasonable possibility" 
means there is evidence to suggest a causal relationship.  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as an 
adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At 
the last scheduled visit, the investigator should instruct each subject to report any 
subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study.  The investigator should notify the study 
sponsor (S. Schuster) of any death or adverse event occurring at any time after a subject 
has discontinued or terminated study participation that may reasonably be related to this 
study.  The sponsor (S. Schuster) should also be notified if the investigator should become 
aware of the development of cancer or of a congenital anomaly in a subsequently 
conceived offspring of a subject that has participated in this study.  
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of 
the following conditions is met:  
• All Grade 3 and 4 lab abnormalities not present at baseline should be captured as 
adverse events*.   
• Any lab abnormality requiring clinical intervention or dose modification will also 
be captured as an adverse event*.  
* This excludes lymphopenia.  
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise 
in this protocol.  Any condition responsible for surgery should be documented as an 
adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: 


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• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or diagnostic 
and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 
9.2 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be grouped 
under one diagnosis. 
 
All treatment-emergent adverse events occurring during the study period (after initiation of study 
treatment) must be recorded.  The clinical course of each event should be followed until 
resolution, stabilization, or until it has been determined that the study treatment or participation 
is not the cause.  Serious adverse events that are still ongoing at the end of the study period must 
be followed up to determine the final outcome.  Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation 
should be recorded and reported immediately. 
 
Toxicity will be scored using CTCAE Version 5.0 for toxicity and adverse event reporting.  A 
copy of the CTCAE Version 5.0 can be downloaded from the CTEP homepage 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0.  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 episode, the action taken with respect to the 
test drug, and the patient’s outcome.  The investigator must evaluate each adverse experience for 
its relationship to the test drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical significance.  If 
any abnormal laboratory result is considered clinically significant, the investigator must provide 
details about the action taken with respect to the test drug and about the patient’s outcome. 
 
9.3 
Reporting of Adverse Events 
9.3.1 Pregnancies 
Pregnancy of a female subject or the female partner of a male subject occurring while the subject 
is on lenalidomide or within 4 weeks after the subject’s last dose of lenalidomide are considered 
expedited reportable events.  If the subject is on lenalidomide, it is to be discontinued 


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immediately and the subject is to be instructed to return any unused portion of lenalidomide to 
the Investigator.  The pregnancy must be reported to Celgene Corporation Worldwide Drug 
Safety Surveillance (WWDSS) within 24 hours of the Investigator’s knowledge of the pregnancy 
by phone and facsimile using the SAE Form. 
 
The Investigator will follow the pregnant female until completion of the pregnancy, and must 
notify Celgene Corporation Safety Surveillance of the outcome as specified below.  The 
Investigator will provide this information as a follow-up to the initial SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the procedures 
for Expedited Reporting of SAEs to Celgene (i.e., report the event to Celgene Corporation Drug 
Safety Surveillance by facsimile within 24 hours of the Investigator’s knowledge of the event). 
 
Any suspected fetal exposure to lenalidomide must be reported to Celgene within 24 hours of 
being made aware of the event. The pregnant female should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Investigator suspects is 
related to the in utero exposure to lenalidomide should also be reported. 
In the case of a live “normal” birth, Celgene Corporation Drug Safety Surveillance should be 
advised as soon as the information is available. 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Drug Safety Surveillance  
86 Morris Avenue 
Summit, N.J. 07901 
 
Toll Free:   
(800)-640-7854 
Phone:  
(908) 673-9667 
Fax: 
 
(908) 673-9115 
e-mail:  
drugsafety@celgene.com 
 
9.3.2 Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures to the end of the study treatment follow-up.  For this 
study, the study treatment follow-up is defined as 30 days following the last administration of 
study treatment. 
 


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9.4    Reporting of Serious Adverse Events 
9.4.1 Study Supporter Notification by Investigator 
All serious adverse events must be reported to the study supporter, Celgene, by telephone 
or FAX within 24 hours of being aware of the event.  A Serious Adverse Event (SAE) 
form on a FDA 3500A or MEDWATCH form with the Celgene Reference Number #RV-
NHL-PI-296 must be completed by the investigator and faxed to the study supporter 
within 24 hours of being aware of the event.  The initial report must be as complete as 
possible, including details of the causal relationship between the event and the 
investigational product(s) if available.  Information not available at the time of the initial 
report (e.g., an end date for the adverse event or laboratory values received after the 
report) must be documented on a follow-up MEDWATCH.  A final report to document 
resolution of the SAE is required.  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. Report serious adverse events by phone and facsimile to: 
 
Celgene Corporation 
Drug Safety Surveillance  
86 Morris Avenue 
Summit, N.J. 07901 
 
Toll Free:   
(800)-640-7854 
Phone:  
(908) 673-9667 
Fax: 
(908) 673-9115 
e-mail:  
 
 
 
drugsafety@celgene.com 
 
At the time of the initial report, the following information should be provided: 
 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was 
discontinued 
• The reason why the event is 
classified as serious 
• Investigator assessment of the 
association between the event and 
study treatment 
 
Within the following 48 hours, the investigator must provide further information to 
Celgene on the serious adverse event in the form of a written narrative.  This should 
include a copy of the completed Serious Adverse Event form, and any other diagnostic 
information that will assist the understanding of the event.  Significant new information 
on ongoing serious adverse events should be provided promptly to Celgene.   
 
9.4.2 DSMC /IRB Notification by Investigator 
DSMC and IRB Notification: 


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Report events to local regulatory review committees per institutional requirements.   
 
9.4.3 FDA Notification by Investigator 
Adverse drug reactions that are Serious, Unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the 
Food and Drug Administration (FDA) in writing.  A clear description of the suspected 
reaction should be provided along with an assessment as to whether the event is drug or 
disease related.   
 
The investigator shall notify the FDA by telephone or by facsimile transmission of any 
adverse drug reactions that are Serious, Unlisted/unexpected, and at least possibly 
associated to the drug, including unexpected fatal or life-threatening experience 
associated with the use of the drug, as soon as possible but no later than 7 calendar days 
from the sponsor’s (investigator’s) original receipt of the information. 
 
If a previous adverse event that was not initially deemed reportable is later found to fit 
the criteria for reporting, the study sponsor (investigator) will submit the adverse event in 
a written report to the FDA as soon as possible, but no later than 7 calendar days from the 
time the determination is made. 
 
Each phone call or fax shall be transmitted to the FDA new drug review division in the 
Center for Drug Evaluation and Research or the product review division in the Center for 
Biologics Evaluation and Research that has responsibility for review of the IND if 
applicable. 
 
 
9.4.4    Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following 
information: 
  
• Any AE associated with the use of study drug in this study or in other studies that 
is both serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human 
subjects 
including 
reports 
of 
mutagenicity, 
teratogenicity, 
or 
carcinogenicity. 
  
Events that are found to be unexpected and probably/definitely related, or that may pose 
significant risks to subjects, should be submitted to the IRB/CTSRMC within 10 working 
days of notification.   
  
The Investigator must keep copies of all SAE information, including correspondence with 
Celgene and the IRB/DSMC, in the Study Regulatory Binder.  
 


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10 
  Data Handling and Record Keeping 
10.1  Analyses and Reporting 
Data will initially be analyzed and reported 3 months after the twenty-fifth patient completes 
dose four of rituximab. All subsequent data collected will be analyzed and reported in a follow-
up clinical report. 
10.2  Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 
 
Celgene affirms the subject’s right to protection against invasion of privacy.  In compliance with 
United States federal regulations, Celgene requires the Investigator to permit Celgene’s 
representatives and, when necessary, representatives 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. 
10.3  Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents   Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
10.4  Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 


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printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
10.5  Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period if required by an agreement.  In such an instance, it is the 
responsibility of the sponsor to inform the institution as to when these documents no longer need 
to be retained.  The Investigator agrees to adhere to the document/records retention procedures 
by signing the protocol. 
 
10.6  Exceptions and Deviations 
 
Exceptions (prospective action): 
An exception is defined as a one-time, unintentional action or process that departs from the IRB 
and CTSRMC approved study protocol, intended for one occurrence. If this action disrupts the 
study progress, such that the study design or outcome (endpoints) may be compromised, or the 
action compromises the safety and welfare of study subjects, advance documented approval from 
the local regulatory review committees, per institutional guidelines, is required.  Exceptions will 
not be allowed unless reviewed and approved first by the Study Medical Monitor and the Study 
Principal Investigator, and then subsequently by the ACC DSMC, and IRB.  Principal 
Investigator and Medical Monitor approval must be received first and included in with the 
IRB/DSMC submission. All entities should be given sufficient time to evaluate this request. 
 
Deviation (retrospective action): 
A deviation is defined as a one-time, unintentional action or process that departs from the 
approved study protocol, involving one incident and identified retrospectively.  If the deviation 
disrupts study progress, such that the study design or outcomes may be compromised, or the 
deviation compromises the safety and/or welfare of study subjects, the deviation must be 
reported within 48 hours of PI knowledge to local regulatory review committees per institutional 
guidelines.  
Reports should include the following information the following information:  
• Protocol number 
• Subject number 
• Description of the exception or deviation 
• Impact on subject safety 
• Impact on data integrity  
Deviations that are assessed by the PI to not disrupt the study progress, such as not affecting the 
study design or outcome, or compromising the safety and/or welfare of study subjects, should be 
documented in site records and contain documentation of the PI’s assessment. 
 


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Reportable Deviations 
Any accidental or unintentional deviation from the approved protocol, identified retrospectively, 
that in the opinion of the investigator or as defined by the protocol, placed one or more 
participants at increased risk, compromises the rights or welfare of subjects, and/or disrupts the 
study design, is considered a reportable event and must be reported to the Study Principal 
Investigator, Study Medical Monitor, IRB, and ACC DSMC within 10 working days of 
notification. Principal Investigator and Medical Monitor approval/acknowledgement must be 
received first and included in with the IRB/DSMC submission. Deviations to protect subjects 
from immediate harm/danger should be reported immediately following the event to the entities 
outlined above. 
 
10.7  Protocol amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and reviewed by 
Celgene.  Amendments should only be submitted to IRB/EC after consideration of Celgene 
review.  Written verification of IRB/EC approval will be obtained before any amendment is 
implemented. 
 
10.8  Premature discontinuation of study 
The responsible local clinical Investigator as well as Celgene have the right to discontinue this 
study at any time for reasonable medical or administrative reasons.  Possible reasons for 
termination of the study could be but are not limited to: 
• Unsatisfactory enrollment with respect to quantity or quality. 
• Inaccurate or incomplete data collection. 
• Falsification of records. 
• Failure to adhere to the study protocol. 
Any possible premature discontinuation would be documented adequately with reasons being 
stated, and information would have to be issued according to local requirements (e.g., IRB/EC, 
regulatory authorities, etc.). 
11 
Study Monitoring, Auditing, and Inspecting 
11.1 Study Oversight 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan.  This will include a regular assessment of the number and type of serious 
adverse events. 
The investigator will permit study-related monitoring, audits, and inspections by the DSMC, 
IRB, government regulatory bodies, and University compliance and quality assurance groups of 
all study related documents (e.g. source documents, regulatory documents, data collection 


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instruments, study data etc.). The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).  
This study will be audited by the Data and Safety Monitoring Committee (DSMC) six months 
from the first subject enrolled and every six month thereafter for the duration of the study.  This 
schedule may be changed at the discretion of the DSMC. The study team will ensure all study 
related regulatory documents and subject charts are available and organized prior to the arrival of 
the auditor.  Issues identified by the auditors will be addressed within 10 days of receipt of the 
letter of findings.   
 
On-going Monitoring:  During the course of the trial, safety and data quality monitoring will be 
performed in an on-going manner by the Research Nurse (Ellen Napier, CRNP) and the 
PI(Stephen Schuster).  The PI will review all Adverse Events in “real-time” to ensure 
appropriateness of the data and timeliness of reporting.  The PI will ensure that all amendments 
to the protocol and consent form are distributed to the IRB and CTSRMC prior to implementing 
any changes that may be required as a result of on-going monitoring. The PI will also ensure that 
all renewals are received in a timely manner and all IRB correspondences are maintained. 
 
11.2 Medical Monitor 
The Medical monitor for this study will be Adam Waxman M.D.  Dr. Waxman is not directly 
involved in the trial and is not collaborating with the sponsor/investigator in any other trial.  In 
this role, Adam Waxman, M.D.  will review all AEs including grading, toxicity assignments, all 
other safety data and activity data observed at each dose level prior to escalating to the next dose. 
Adam Waxman, M.D.  may recommend reporting of adverse events and relevant safety data not 
previously reported and may recommend suspension or termination of the trial.   The Medical 
Monitor will be asked to review study data at least quarterly (every 3 months) or more frequently 
depending on enrollment. 
 
11.3 Safety Monitoring 
Interim analyses of toxicity are to be performed quarterly or every three patients on-study.  
 
This investigator initiated protocol is considered high risk as per the Abramson Cancer Center 
Data and Safety Monitoring Plan. As such, high risk protocols are audited approximately six 
months from their first subject accrual and approximately every six month thereafter for the 
duration of the study. However, this schedule may be changed at the discretion of the DSMC. 
The PI will be notified in advance of the selection of their protocol for review and cases are 
randomly selected. A formal report is written to the PI by the DSMC.  The committee may alter 
the frequency of re-monitoring based on the audit findings and degree of deficiencies. If an audit 
is unacceptable due to major deficiencies, representatives from the DSMC meet with the PI to 
discuss the findings of the audit and necessary corrective actions. If the deficiencies involve 
subject safety or serious regulatory violations, the Cancer Center Director, DSMC Chair, and 
DSMC Administrative Director will meet to discuss necessary actions concerning study status. 
The PI is given five business days to respond to these findings. An evaluation of the deficiencies 
will be re-evaluated upon receiving the PI’s response. At this time, if the DSMC Chair and the 


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Administrative Director do not find the response satisfactory, the IRB and OHR will be alerted 
of the actions taken by the ACC. 
 
Quarterly team meetings will also be held throughout the course of this study in order to discuss 
the protocol, ongoing patients, toxicity data, and recruitment issues. 
11.4 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
supporter, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
The Investigator will permit study-related audits by Celgene or its representatives providing 
direct access to the facilities where the study took place, to source documents, to CRFs, and to all 
other study documents. 
 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during audits to review data and resolve any queries and to allow direct access to the 
subject’s records (e.g., medical records, office charts, hospital charts, and study related charts) 
for source data verification.  The data collection must be completed prior to each visit and be 
made available to the Celgene representative so that the accuracy and completeness may be 
checked. 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
12    Ethical Considerations 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki.  This study is to be conducted according to US and 
international standards of Good Clinical Practice (FDA Title 21 part 312 and International 
Conference on Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures.   
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the supporter before commencement of this study.  The investigator should 
provide a list of EC/IRB members and their affiliate to the supporter. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the 
EC/IRB for the study.  The formal consent of a subject, using the EC/IRB-approved consent 
form, must be obtained before that subject is submitted to any study procedure.  This consent 


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form must be signed by the subject or legally acceptable surrogate, and the investigator-
designated research professional obtaining the consent.  Documentation of the informed consent 
process should be recorded in the subject’s source documents.  The original consent form signed 
and dated by the subject and by the person consenting the subject prior to the subject’s entry into 
the study, must be maintained in the Investigator’s study files. 
 
13 
Study Finances 
13.1  Funding Source 
The study and ancillary research will be in part funded through financial support from Celgene 
Corporation. 
13.2  Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study 
supporter prior to participation in this study.  All University of Pennsylvania investigators will 
follow the University conflict of interest policy. 
14 
Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the supporter for the purposes of performing the study, will 
be published or passed on to any third party without the consent of the study supporter.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 
 
 
 
 


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15 
References 
 
1.  McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman 
MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, 
Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent 
lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 
1998;16:2825-2833 
 
2.  Davis TA, Grillo-Lopez AJ, White CA, McLaughlin P, Czuczman MS, Link BK, Maloney 
DG, Weaver RL, Rosenberg J, Levy R. Rituximab anti-CD20 monoclonal antibody therapy in 
non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol. 2000;18:3135-3143 
 
3.  Zhang L, Schafer P, Muller G, Stirling D, Bartlett J. Lenalidomide and dexamethasone 
synergize to greatly enhance direct anti-proliferative effects 
on non-Hodgkin’s lymphoma cells in vitro. Haematologica. 2007;92[suppl.2]:0737 
 
4.  Golay J, Lazzari M, Facchinetti V, Bernasconi S, Borleri G, Barbui T, Rambaldi A, Introna 
M. CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell 
chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood. 2001;98:3383-
3389 
 
5.  Golay J, Zaffaroni L, Vaccari T, Lazzari M, Borleri GM, Bernasconi S, Tedesco F, Rambaldi 
A, Introna M. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody 
rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood. 
2000;95:3900-3908 
 
6.  Harjunpaa A, Junnikkala S, Meri S. Rituximab (anti-CD20) therapy of B-cell lymphomas: 
direct complement killing is superior to cellular effector mechanisms. Scand J Immunol. 
2000;51:634-641 
 
7.  Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and 
resistance. Oncogene. 2003;22:7359-7368 
 
8.  Hofmeister JK, Cooney D, Coggeshall KM. Clustered CD20 induced apoptosis: src-family 
kinase, the proximal regulator of tyrosine phosphorylation, calcium influx, and caspase 3-
dependent apoptosis. Blood Cells Mol Dis. 2000;26:133-143 
 
9.  Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo 
cytoxicity against tumor targets. Nat Med. 2000;6:443-446 
 
10.  Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. 
Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc 
receptor FcgammaRIIIa gene. Blood. 2002;99:754-758 
 


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11.  Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms 
independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 
2003;21:3940-3947 
 
12.  Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, 
Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to 
CD20. Blood. 1994;83:435-445 
 
13.  van der Kolk LE, Grillo-Lopez AJ, Baars JW, Hack CE, van Oers MH. Complement 
activation plays a key role in the side-effects of rituximab treatment. Br J Haematol. 
2001;115:807-811 
 
14.  Alas S, Emmanouilides C, Bonavida B. Inhibition of interleukin 10 by rituximab results in 
down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. Clin 
Cancer Res. 2001;7:709-723 
 
15.  Bohen SP, Troyanskaya OG, Alter O, Warnke R, Botstein D, Brown PO, Levy R. Variation 
in gene expression patterns in follicular lymphoma and the response to rituximab. Proc Natl 
Acad Sci U S A. 2003;100:1926-1930 
 
16.  Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, Fisher RI, Braziel RM, 
Rimsza LM, Grogan TM, Miller TP, LeBlanc M, Greiner TC, Weisenburger DD, Lynch JC, 
Vose J, Armitage JO, Smeland EB, Kvaloy S, Holte H, Delabie J, Connors JM, Lansdorp PM, 
Ouyang Q, Lister TA, Davies AJ, Norton AJ, Muller-Hermelink HK, Ott G, Campo E, 
Montserrat E, Wilson WH, Jaffe ES, Simon R, Yang L, Powell J, Zhao H, Goldschmidt N, 
Chiorazzi M, Staudt LM. Prediction of survival in follicular lymphoma based on molecular 
features of tumor-infiltrating immune cells. N Engl J Med. 2004;351:2159-2169 
 
17.  Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN, Cripe L, 
Wiseman G, Olejnik T, Multani PS, White CA. Treatment with ibritumomab tiuxetan 
radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J 
Clin Oncol. 2002;20:3262-3269 
 
18.  Ansell SM, Ristow KM, Habermann TM, Wiseman GA, Witzig TE. Subsequent 
chemotherapy regimens are well tolerated after radioimmunotherapy with yttrium-90 
ibritumomab tiuxetan for non-Hodgkin's lymphoma. J Clin Oncol. 2002;20:3885-3890 
 
19.  Davis TA, Maloney DG, Grillo-Lopez AJ, White CA, Williams ME, Weiner GJ, Dowden S, 
Levy R. Combination immunotherapy of relapsed or refractory low-grade or follicular non-
Hodgkin's lymphoma with rituximab and interferon-alpha-2a. Clin Cancer Res. 2000;6:2644-
2652 
 
20.  Friedberg JW, Kim H, McCauley M, Hessel EM, Sims P, Fisher DC, Nadler LM, Coffman 
RL, Freedman AS. Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and 
rituximab in patients with non-Hodgkin lymphoma: increased interferon-alpha/beta-inducible 
gene expression, without significant toxicity. Blood. 2005;105:489-495 


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21.  Gluck WL, Hurst D, Yuen A, Levine AM, Dayton MA, Gockerman JP, Lucas J, Denis-Mize 
K, Tong B, Navis D, Difrancesco A, Milan S, Wilson SE, Wolin M. Phase I studies of 
interleukin (IL)-2 and rituximab in B-cell non-hodgkin's lymphoma: IL-2 mediated natural killer 
cell expansion correlations with clinical response. Clin Cancer Res. 2004;10:2253-2264 
 
22.  Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. 
Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a 
severe combined immunodeficient mouse lymphoma model. Clin Cancer Res. 2005;11:5984-
5992 
 
23.  Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, Roth M, Vaughn M, Knight J, Wallace P, 
Czuczman MS. Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine 
production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of 
rituximab in vivo. Br J Haematol. 2008;140:36-45 
 
24.  Wu L, Adams M, Schafer P, Muller G, Stirling D, Bartlett J. Lenalidomide strongly 
enhances natural killer (NK) cell and monocyte mediated antibody-dependent cellular 
cytotoxicity (ADCC) of rituximab treated CD20+ VE cancer cells in vitro. Haematologica. 
2007;92[suppl.2]:0314 
 
25.  Bartlett J, Wu L, Adams M, Schafer P, Muller G, Stirling D. Lenalidomide and 
pomalidomide strongly enhance tumor cell killing in vitro during antibody-dependent cellular 
cytotoxicity (ADCC) mediated by trastuzumab, cetuximab and rituximab. JCO. 2007;25:3023 
 
26.  Galustian C, Klaschka D, Meyer B, Labarthe M, Bartlett J, Dalgleish A. Lenalidomide 
(Revlimid®, CC-5013) and ActimidTM (CC-4047) inhibit the function and expansion of T 
regulatory (Treg) cells in vitro: Implications for anti-tumor activity in vivo. Proc Amer Assoc 
Cancer Res. 2006;47:4882 
 
27.  Wang M, Fayad L, Hagemeister F, Neelapu S, Samuels B, Samanigo F, Pro B, Yi Q, Bell N, 
Byrne C, Weaver P, Hartig K, Knight R, Zeldis J, Kwak L, Romaguera J. Lenalidomide (Len) in 
Combination with Rituximab (R) Demonstrated Early Evidence of Efficacy in a Phase I/II Study 
in Relapsed/Refractory Mantle Cell Lymphoma (MCL). Blood. 2007;110:#2562 
 
28.  Tuscano J, Lossos I, Justice G, Vose J, Takeshita K, Ervin-Hayes A, Pietroniga D, Zeldis J, 
Habermann T. Lenalidomide oral monotherapy produces a 53% response rate in patients with 
relapsed/refractory mantle-cell Non-Hodgkin's Lymphoma. Blood. 2007;110:#2563 
 
29.  Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter 
CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-
Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in 
patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J 
Clin Oncol. 2006;24:5343-5349 
 
30.  Jung SH, Su JQ. Non-parametric estimation for the difference or ratio of median failure 
times for paired observations. Stat Med. 1995;14:275-281 


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31.  Mick R, Crowley JJ, Carroll RJ. Phase II clinical trial design for noncytotoxic anticancer 
agents for which time to disease progression is the primary endpoint. Control Clin Trials. 
2000;21:343-359 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16      Appendix 
 
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.  The risks to a fetus are not known.  
However, lenalidomide is structurally related to thalidomide.  Thalidomide is a known human 
teratogenic active substance that causes severe life-threatening birth defects.  An embryofetal 
development study in animals indicates that lenalidomide produced malformations in the 
offspring of female monkeys who received the drug during pregnancy.  The teratogenic effect of 
lenalidomide in humans cannot be ruled out.  Therefore, a risk minimization plan to prevent 
pregnancy must be observed. 
All study participants must be registered into the mandatory Revlimid REMS® program, and be 
willing and able to comply with the requirements of Revlimid REMS®. 
Criteria for Females of Childbearing potential:  
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 consecutive months). 
The investigator must ensure that: 
• 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 activity with a female of childbearing potential, and that he 
understands the need for the use of a condom even if he has had a vasectomy, if engaged 
in sexual activity with a female of childbearing potential.   


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Females of childbearing potential (FCBP)† must agree to use two reliable forms simultaneously 
or to practice complete abstinence from heterosexual intercourse during the following time 
periods related to this study: 1) for at least 28 days before starting study drug; 2) while 
participating in the study; 3) during dose interruptions and 4) for at least 28 days after 
discontinuation from the study. The two methods of reliable contraception must include one 
highly effective method (i.e. intrauterine device (IUD), hormonal [birth control pills, injections, 
or implants], tubal ligation, partner’s vasectomy) and one additional effective (barrier) method 
(i.e. latex condom, diaphragm, cervical cap).  FCBP must be referred to a qualified provider of 
contraceptive methods if needed.   
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 using 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.  
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below. 
Before starting study drug:   
Female Subjects:   
• 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 (prescriptions must be filled within 7 
days).  The subject may not receive study drug until the Investigator has verified that the 
results of these pregnancy tests are negative.of contraception  
Male Subjects:   
• Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following 
discontinuation from the study even if he has undergone a successful vasectomy.  
                                                 
 
† A female of childbearing potential is a sexually mature woman 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). 
 
 


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During study participation and for 28 days following discontinuation from the study: 
All Subjects: 
• If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a 
male study subject during study participation, lenalidomide must be immediately 
discontinued. 
Female Subjects:   
• FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, at study 
discontinuation, and at day 28 following discontinuation from the study. If menstrual 
cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and 
then every 14 days while on study, at study discontinuation, and at days 14 and 28 
following discontinuation from the study.   
• In addition to the required pregnancy testing, the Investigator must confirm with FCBP 
that she is continuing to use two reliable methods of birth control at each visit.   
• If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide must 
be immediately discontinued. 
• 
Pregnancy testing and counseling must be performed if a subject misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Study drug treatment must be 
discontinued during this evaluation. 
• Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after lenalidomide discontinuation. 
Male Subjects: 
• Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following 
discontinuation from the study even if he has undergone a successful vasectomy. 
 Additional precautions 
• Patients should be instructed never to give lenalidomide to another person. 
• Female patients should not donate blood during therapy and for at least 28 days following 
discontinuation 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.  


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Appendix B: ECOG Performance Status Scale 
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light house 
work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
 


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Appendix C: NCI CTCAE Version 5.0 
 
Toxicity will be scored using NCI  CTCAE Version 5.0 for toxicity and adverse event reporting.  
A copy of the NCI CTC Version 5.0 can be downloaded from the CTEP homepage: 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  All appropriate 
treatment areas have access to a copy of the CTCAE Version  
 
 
 
 
 


Pa ge 6 2  of 6 6  
 
V ersi o n: A u g ust 2 4, 2 0 1 8  
C O N FI D E N TI A L  
T his material is t he pr o pert y of t he U ni versit y of Pe n ns yl va nia.  D o n o t discl ose or use e xc e pt as a ut h orize d i n writi n g b y t he st u d y s p o ns or 
A p pe n di x D:  I nter n ati o n al W or ks h o p Res p o nse Criteri a (I W R C) f or N o n 
H o d g ki n’s L y m p h o m a  
 
C o m plete R es p o nse ( C R)  
C o m plete disa p peara n ce of all detecta bl e cli nical a n d ra di o gra p hic e vi de n ce of disease a n d 
disa p pear a nce of all -disease rel ate d  s y m pt o ms if prese nt bef ore t hera p y, a n d n or malizati o n of 
t h ose bi oc he mical a b n or malities (e. g., l actate d e h y dr o ge nase [ L D H] defi nitel y assi g na bl e t o 
N H L.  
 
All l y m p h n o d es a n d n o d al masses m ust ha ve re gresse d t o n or mal size (  1. 5 c m i n t heir great est 
tra ns verse di a meter f or n o des > 1. 5 c m bef ore t hera p y).  Pre vi o usl y i n v ol ve d n o des t hat were 1. 1 
t o 1. 5 c m i n t heir gr eatest tra ns verse di a meter b ef ore treat me nt m ust ha ve d ecrease d t o  1 c m i n 
t heir great est tra ns vers e dia meter after treat me nt, or b y m ore t ha n 7 5 % i n t he s u m of t he pr o d ucts 
of t he greatest dia meters ( S P D).  
 
T he s plee n, if c o nsi d ere d t o be e nlar ge d b ef ore t hera p y o n t he basis of a C T sca n, m ust ha ve of 
t he diffic ulties i n acc urat el y e val uati n g s ple nic a n d he patic size.  F or i nsta n ce, s plee ns th o u g ht t o 
be of n or mal size ma y c o ntai n l y m p h o ma, w hereas a n e nlar ge d s plee n ma y n ot necessaril y 
reflect t he pres e nce of l y m p h o ma b ut variati o ns i n a nat o m y, bl o o d v ol u me, t he use of 
he mat o p oietic gr o wt h f act ors, or ot her ca uses.  T h e deter mi nati o n of s ple ni c v ol u me or s ple nic 
i n de x b y C T sca n is c u m bers o me a n d n ot wi del y use d.   A n y macr os c o pic n o d ules i n a n y or ga ns 
detecta ble o n i ma gi n g tec h ni q ues s h o ul d n o l o n ger be pres e nt.  Si milarl y, ot her or ga ns 
c o nsi dere d t o be e nlar ge d bef ore t h era p y d u e t o i n v ol ve me nt b y l y m p h o m a, s uc h as li ver a n d 
ki d ne ys, m ust ha ve d ecr ease d i n size. 
 
If t he b o ne marr o w w as i n v ol ve d b y l y m p h o ma bef ore treat me nt, t he i nfiltrate m ust be cleare d 
o n re peat b o n e marr o w as pirate a n d bi o ps y of t he sa me site.  T he sa m ple o n w hic h t his 
det er mi nati o n is ma de m ust be a de q uate ( > 2 0 m m bi o ps y c ore).   Fl o w c yt o metric, m olec ular, or 
c yt o ge netic st u dies ar e n ot c o nsi dere d part of r o uti ne assess me nt t o d oc u m e nt persiste nt disease 
at t he prese nt ti me.   
 
C o m plete R es p o nse/ U nc o nfir me d ( C r u)  
C R/ u nc o nfir me d ( C R u) i ncl u des t h ose s u bjects w h o f ulfill criteria 1 a n d 3 a b o ve, b ut wit h o ne or 
m ore of t he f oll o wi n g f eat ures: 
 
A resi d ual l y m p h n o d e m ass greater t ha n 1. 5 c m i n greatest tra ns v erse di a meter t hat has 
re gress e d b y m ore t ha n 7 5 % i n t he S P D.  I n di vi d u al n o des t hat were pre vi o usl y c o nfl u e nt m ust 
ha ve re gresse d b y m ore t ha n 7 5 % i n t heir S P D c o m pare d wit h t he size of t he ori gi n al mass. 
 
I n d eter mi nate b o n e marr o w (i ncrease d n u m ber or size of a g gre gates wit h o ut c yt ol o gical or 
arc hitect ural at y pia).  
 


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Partial Response (PR) 
>50% decrease in SPD of the six largest dominant nodes or nodal masses.  These nodes or 
masses should be selected according to the following features: (a) they should be clearly 
measurable in at least two perpendicular dimensions, (b) they should be from as disparate 
regions of the body as possible, and (c) they should also include mediastinal and retroperitoneal 
areas of disease whenever these sites are involved. 
 
No increase in the size of the other nodes, liver, or spleen. 
 
Splenic and hepatic nodules must regress by at least 50% in the SPD. 
 
With the exception of splenic and hepatic nodules, involvement of other organs is considered 
assessable and not measurable disease. 
 
Bone marrow assessment is irrelevant for determination of a PR because it is assessable and not 
measurable disease; however, if positive, the cell type should be specified in the report, e.g., 
large-cell lymphoma or low-grade lymphoma (i.e., small, lymphocytic small cleaved, or mixed 
small and large cells.) 
 
No new sites of disease. 
 
Stable Disease (SD)  
Stable disease is defined as less than a PR (see above) but is not progressive disease (see below). 
 
Relapsed Disease (RD)  
Appearance of any new lesion or increase by >50% in the size of previously involved sites. (only 
applies to subjects that achieve a CR). 
 
>50% increase in greatest diameter of any previously identified node greater than 1 cm in its 
short axis or in the SPD of more than one node. 
 
Progressive Disease (PD)  
 
>50% increase from nadir in the SPD of any previously identified abnormal node for PRs or 
nonresponders. 
 
Appearance of any new lesion during or at the end of therapy which is >1.5 cm by radiologic 
evaluation or greater than 1 cm by physical examination 


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Appendix E: Response Criteria for NHL 
 
 


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Appendix F:  WHO classification of B-NHL 
 
 
 
 
  
 
 
o Chronic lymphocytic leukemia/Small lymphocytic lymphoma  
o B-cell prolymphocytic leukemia  
o Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia  
o Splenic marginal zone lymphoma  
o Plasma cell neoplasms  
 
Plasma cell myeloma  
 
Plasmacytoma  
 
Monoclonal immunoglobulin deposition diseases  
 
Heavy chain diseases  
o Extranodal marginal zone B cell lymphoma (MALT lymphoma)  
o Nodal marginal zone B cell lymphoma  
o Follicular lymphoma  
o Mantle cell lymphoma  
o Diffuse large B cell lymphoma  
o Mediastinal (thymic) large B cell lymphoma  
o Intravascular large B cell lymphoma  
o Primary effusion lymphoma  
o Burkitt lymphoma/leukemia  
o Lymphomatoid granulomatosis 


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Appendix G:  Ann Arbor Staging System of Lymphoma 
 
Stage I  
 
Involvement of a single lymph node region (I) OR involvement of a single extra-
lymphatic organ or site (IE).  
 
Stage II  
 
Involvement of two or more lymph node regions on the same side of the 
diaphragm (II) OR localized involvement of an extra-lymphatic organ or site and 
of one or more lymph node regions on the same side of the diaphragm (IIE).  
 
Stage III  
 
Involvement of lymph nodes regions on both sides of the diaphragm (III) which 
may also be accompanied by localized involvement of extra-lymphatic organ or 
site (IIIE) or by involvement of the spleen (IIIS) or both (IIISE).  
 
Stage IV  
Diffuse or disseminated involvement of one or more extra-lymphatic organs or 
tissues with or without associated lymph node involvement.  
Identification of the presence or absence of symptoms should be noted with each 
stage designation:  
A = asymptomatic  
B = fever (>38°C), drenching night sweats, or weight loss greater than 10% of 
body weight