Phase II Study of Lenalidomide and Rituximab in Subjects With Previously Untreated Indolent Non Hodgkin's Lymphoma
Phase: PHASE2
Conditions: Non Hodgkin's Lymphoma
Sponsor: University of California, Davis

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Phase II Study of Lenalidomide and Rituximab in Subjects with 
Previously Untreated Indolent Non Hodgkin’s Lymphoma 
 
STUDY DRUG   
Revlimid®, lenalidomide and 
Rituxan®, rituximab 
PROTOCOL NUMBER:  
UCDCC# 224 
Celgene # RV--NHL-PI-0488 
VERSION DATE:  
09/10/18 
AMENDMENT:   
16 
PROTOCOL HISTORY:   
4;  05/04/10 
5;  12/09/10 
6;  04/22/11 
7;  08/01/11 
8;  04/09/12 
9;  12/26/12 
10; 03/26/13 
11; 11/25/13 
12; 3/14/14 
13: 06/19/15 
14: 02/08/16 
15: 09/08/17 
IND:   
108,415 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 

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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
______________________________________________________ 
Signature of Site Principal Investigator 
 
 
__________________________ 
Date  
 
 
______________________________________________________ 
Printed Name of  Site Principal Investigator 
 
Institution Name: __________________________________________________ 
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. 
 
 
 
 
 
 
 
 
 
 
 
 

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TRIAL DESIGN 
 
 
__________________________________________    _______
Informed 
Consent 
signed 
Revlimid d1-21
<28 
day 
Weekly Rituximab 
Revlimid d1-21
Cycle 1 
Restaging 
scans, 
repeat 
every 2 
cycles  
Cycle 2 
Enrollment 
CR-> Continue therapy until progression or 
toxicity, may discontinue after cycle 12 if 
CR maintained 
PR or SD ->Continue therapy, if CR not 
achieved after cycle 4, additional course of 
Rituximab during cycle 5- days 1,8,15,22. 
Progression -> Discontinue trial or Go on 
to optional radiotherapy cohort (see below) 

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Optional Radiotherapy Cohort 
 
 
 
 
 
 
 
 
 
 

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Table of Contents  
Protocol Synopsis ............................................................................... 8 
Schedule of Study Assessments ......................................................... 14 
Glossary of Abbreviations .................................................................. 17 
Background and Rationale ................................................................. 19 
Study Objectives and Endpoints ........................................................ 28 
Treatment Assignments ...................................................................... 36 
Adverse Events ................................................................................... 44 
Response Criteria ............................................................................... 49 
Data Management ............................................................................... 54 
Data and Safety Monitoring ............................................................... 54 
Biostatistical Analysis ........................................................................ 56 
Regulatory Considerations ................................................................. 62 
Registration Guidelines ...................................................................... 63 
Records to be Kept and Data Submission Schedule………………..64 
Minorities and Gender Statement ....................................................... 65 
References .......................................................................................... 65 
 
 
 
 
 

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Appendices ......................................................................................... 70 
I. Lenalidomide Risk of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods 
II. ECOG Performance Status 
III. Cockcroft-Gault estimation of CrCl 
IV. NCI CTC Version 4.0 
V. Rituximab Package Insert 
VI. Lenalidomide (Revlimid®) Package Insert 
VII. Registration Procedures for Phase II trials 
VIII. Data Collection Forms and Submission Schedule 
IX. Correlative Studies (Sutter Pacific Medical Foundation) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Synopsis 
1
PROTOCOL TITLE: Phase II study of Lenalidomide and Rituximab in Patients with Previously 
Untreated Indolent Non-Hodgkin’s Lymphoma 
PROTOCOL NUMBER: 
UCDCC# 224 
Celgene # RV-NHL-PI-0488 
DATE PROTOCOL FINAL: 
05/04/10 
STUDY DRUG: 
Revlimid® (lenalidomide) and Rituximab 
INDICATION: 
Previously Untreated  Indolent Lymphoma 
STUDY PHASE: 
Phase II 
BACKGROUND AND RATIONALE:   
Non-Hodgkin’s lymphomas (NHL) are a very heterogeneous group of malignancies.  Depending 
on their pathologic diagnosis, each subtype of NHL can behave differently. Indolent lymphomas 
are generally incurable with standard therapeutic approaches and typically have a chronic course 
with repeated relapses and progression despite therapy. There is no standard of care for patients 
with indolent lymphoma and no treatment approach has consistently demonstrated a survival 
advantage. In general, the treatment strategy is to monitor the patient closely and initiate therapy 
when there are indications.  The majority of patients with NHL are elderly. In fact, the greatest 
increase in incidence of NHL is in the elderly male population over the past 20 years.  There is 
little question that the magnitude and duration of response in patients who cannot maintain dose 
intensity or receive standard chemotherapeutics is often inferior.  Therefore, development of 
regimens that are more tolerable and exploit unique and different mechanisms of action are 
needed. 
 
Lenalidomide is currently approved by the FDA for multiple myeloma and myelodysplastic 
syndrome and is being studied in other hematological conditions including lymphomas. Although 
the exact anti-tumor mechanism of action of lenalidomide is unknown, a number of mechanisms 
are postulated to be responsible for lenalidomide’s anti-tumor activity. In laboratory models, 
lenalidomide can enhance T- and NK-cell synapse formation with tumor B cells to enhance 
immune-mediated cytotoxicity.  Lenalidomide has also been shown to reverse the impaired ability 
of T cells to form immunological synapses, a process that appears to be defective in lymphomas 
and leukemias. Lenalidomide also exerts antiproliferative activity via upregulation of tumor-
suppressor genes (including p21 and SPARC) that results in G1 cell-cycle arrest, caspase 
activation, and apoptosis. 
 
Multiple clinical studies have established that lenalidomide is a promising agent in the treatment of 
lymphomas. NHL-003 study by Czuczman et al evaluated the role of lenalidomide as monotherapy 
in 217 patients with relapsed/refractory aggressive Non-Hodgkin’s Lymphoma. Among these, 
50% patients had Diffuse large B cell Lymphoma, 26% Mantle Cell Lymphoma, 9% Follicular 

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Lymphoma Grade III, and 15% transformed lymphoma. The ORR for all 217 patients was 35%, 
with 13% complete response, 22% partial response, and 21% had stable disease. Responses were 
observed in all histological types. Median progression-free survival for all patients was 3.5 months 
and the median duration of response for the 77 responders was 11.6 months. The primary side 
effect of lenalidomide was reversible myelosuppression.  
   
The efficacy and safety of lenalidomide was also shown in relapsed/refractory mantle cell 
lymphoma [3,4, 5]. Czuczman et al evaluated lenalidomide monotherapy with an overall response 
rate of 41%. Zaja et al studied lenalidomide in combination with dexamethasone, with a 50% 
overall response rate. Wang et al reported an overall response rate of 53% for the combination of 
lenalidomide with rituximab. These studies also demonstrated a favorable toxicity profile for 
lenalidomide and the combinations. 
 
Rituximab has known clinical activity in patients with CLL and NHL.  A monoclonal antibody 
directed against CD20 antigen on B-lymphocytes, rituximab binds to the antigen on the cell 
surface (activating complement-dependent cytotoxicity) and to human Fc receptors which 
mediates cell killing through an antibody-dependent cellular toxicity.   
 
The rationale for combining these two agents originates from the hypothesis that enhancement of 
host immune effector mechanisms may augment the clinical efficacy of rituximab without 
significantly increasing toxicity. In fact, in animal models and human trials improved efficacy has 
been observed when various biologics have been combined with rituximab. The improved efficacy 
often correlated with various measures of host immune function including IL-2, IL-21, GM-CSF, 
and INF.  
 
We at UC Davis have studied the combination of lenalidomide and rituximab in relapsed/ 
refractory indolent NHL, and it appears to be safe and active with an acceptable side effect profile. 
16 patients have been enrolled as of December 2009. 10 of the 16 patients were considered heavily 
pre-treated, and 7 rituximab refractory. Overall response rate in a preliminary analysis was 
remarkable at 75%, with 31% CR and 44% PR [6]. The toxicity profile was safe, with the most 
common grade 3 and 4 events being fatigue, neutropenia and lymphopenia. The protocol was 
amended after two patients developed tumor lysis syndrome, to include tumor lysis prophylaxis 
with allopurinol and reducing the initial dose of lenalidomide from 25 to 20 mg. No additional 
patients developed tumor lysis after this modification. 
 
Fowler et al also recently presented their data on front-line therapy of indolent B-cell non-
Hodgkin’s lymphoma with a combination of lenalidomide and rituximab. Patients received 
lenalidomide at a dose of 20 mg orally on days 1-21 and rituximab 375 mg/m2 IV on day 1 of each 
cycle, for up to 6 cycles of therapy. Among the 28 patients enrolled, overall response rate was 
86%, with a complete response in 75%. The combination was well tolerated with the most 
common grade 3 and 4 adverse events being myalgia, neutropenia and rash.[7] 
 
These results are encouraging and further studies are warranted to explore the combination of 
lenalidomide and rituximab in front-line treatment of previously untreated indolent lymphoma. 
 

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Radiotherapy is frequently employed as a treatment strategy for indolent lymphoma, either as 
curative intent therapy for early stage (I/II) disease, or a palliation for symptomatic advanced 
disease. Low grade lymphoma is typically exquisitely sensitive to radiotherapy, with palliative 
responses identified in high percentage of patients treated with doses as low as 4 Gy over 2 
fractions [8-9]. Local radiotherapy is consistently well-tolerated in this patient population with low 
rates of grade 3+ toxicity [8]. 
 
Emerging clinical data suggest local radiotherapy may exhibit potent systemic immunomodulatory 
effects when delivered in combination with systemic immunotherapy agents, and in select cases 
may generate a systemic response (in non-radiotherapy target lesions) in patients previously 
refractory to immunotherapy alone. Case reports/series in melanoma patients describe impressive 
systemic effects following local radiotherapy in patients previously refractory to the immune 
checkpoint (CTLA-4) inhibitor ipilimumab [10-11]. Such effects are not well-studied yet for 
lenalidomide, However, lenalidomide is a potent immunomodulatory agent that exhibits both 
tumoricidal and anti-proliferative effects. There is evidence that lenalidomide may exert its 
antitumor effects by reversing the defective ability of T cells and NK cells to form synapses with 
malignant B cells thereby enhancing immune-mediated cytotoxicity. We hypothesize that in the 
presence of tumor antigens that are released as a result of local tumor irradiation, lenalidomide will 
mediate a response at distant sites in patients that were previously refractory to lenalidomide. 
 
We propose employing this strategy in patients who progress on the combination of lenalidomide 
and rituximab. Patients will continue lenalidomide while undergoing local radiotherapy to a single 
site of disease, with re-staging every 2 months to assess for local and distant response. 
Lenalidomide will then be continued until disease progression.  
 
1. Corral LF, Kaplan G et al.  Differential cytokine modulation and T cell activation by two 
distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha.  J Immunol. 
1993;163:380-386. 
 
2. Witzig T, Czuczman M, et al. Durable Responses After Lenalidomide Oral Monotherapy in 
Patients with Relapsed or Refractory (R/R) Aggressive Non-Hodgkin’s Lymphoma (a-NHL): 
Results From An International Phase 2 Study (CC-5013-NHL-003)  
Blood (ASH Annual Meeting Abstracts) 2009: Abstract 1676 
  
3. Zaja F, Fanin R, et al. Salvage Treatment with Lenalidomide and Dexamethasone in Patients 
with Relapsed Refractory Mantle Cell Lymphoma.  Blood (ASH Annual Meeting Abstracts) 2009: 
Abstract 1713 
 
4. Wang L, Romaguera J et al. A Phase I/II Study of Lenalidomide in Combination with 
Rituximab in Relapsed/Refractory Mantle Cell Lymphoma. Blood (ASH Annual Meeting 
Abstracts) 2009: Abstract 2719. 
 
5. Zinzani PL, Czuczman MS et al. Confirmation of the Efficacy and Safety of Lenalidomide Oral 
Monotherapy in Patients with Relapsed or Refractory Mantle-Cell Lymphoma: Results of An 
International Study (NHL-003) Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract 262 

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 6. Dutia M, Tuscano JM et al. R2: Preliminary Results of a Phase II Study of Lenalidomide and 
Rituximab in Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma (NHL) Blood (ASH 
Annual Meeting Abstracts) 2009: Abstract 1679 
 
7. Fowler N, Sananeigo F et al. A Biologic Combination of Lenalidomide and Rituximab for 
Front-Line Therapy of Indolent B-Cell Non-Hodgkin's Lymphoma. Blood (ASH Annual Meeting 
Abstracts) 2009: Abstract 1714. 
 
8. Hoskin, P.J., et al., 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma 
(FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol, 2014. 15(4): p. 457-63. 
 
9. Rossier, C., et al., Low-dose radiotherapy in indolent lymphoma. Int J Radiat Oncol Biol Phys, 
2011. 81(3): p. e1-6. 
 
10. Grimaldi, A.M., et al., Abscopal effects of radiotherapy on advanced melanoma patients who 
progressed after ipilimumab immunotherapy. Oncoimmunology, 2014. 3: p. e28780. 
 
11. Hiniker, S.M., D.S. Chen, and S.J. Knox, Abscopal effect in a patient with melanoma. N Engl J 
Med, 2012. 366(21): p. 2035; author reply 2035-6. 
STUDY OBJECTIVES: 
Primary:   
Response rate (overall and complete) to the combination of lenalidomide and rituximab in patients 
with previously untreated indolent Non-Hodgkin’s Lymphoma. 
Secondary:   
Time to progression, safety, tolerability, duration of response, overall survival, cytokine profile 
changes. 
 
Response rate (overall and complete) in non-target lesions following local radiation with 
concurrent lenalidomide in patients previously refractory to the combination of lenalidomide and 
rituximab. 
STUDY DESIGN: 
The study will be a multi-institution, phase II clinical trial in patients with previously untreated 
indolent Non-Hodgkin’s lymphoma. Patients will receive lenalidomide 20 mg daily, on days 1-21 
of a 28 day cycle. Rituximab 375 mg/m2 will be administered weekly for 4 doses starting day 15 
of cycle 1, to be repeated if patient does not achieve a complete response after cycle 4, on days 1, 
8, 15 and 22 of cycle 5. Therapy with lenalidomide may be discontinued after twelve cycles if the 
patient achieves a complete response. 
Patients progressing on lenalidomide and rituximab will be offered treatment in a radiotherapy 
cohort. Patients will continue lenalidomide at the current dose, on days 1-21 of a 28 day cycle. 
Local fractionated radiotherapy will be delivered to a single site of disease days 1-5 of a 28 day 

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cycle to 20 Gy in 4 Gy fractions. Re-staging will be performed every 2 months, and lenalidomide 
will be continued until disease progression or intolerance. 
STUDY ENDPOINTS: 
Primary: 
Complete response (CR), near complete response (CRu), or partial response (PR), stable disease 
(SD) of 4 months. 
 
Secondary: 
Time to disease progression, tolerability, duration of response, overall survival, and tumor control 
rate from the start of treatment. 
 
Measurement of immune profile 
STUDY DURATION:  
Patients will be enrolled over 2yrs. 
TOTAL SAMPLE SIZE:  
Approximately 30 patients  
Of the 30 total patients 10 progressing 
patients will be offered optional treatment on 
the radiotherapy arm 
DOSING REGIMEN(S): 
Lenalidomide will be initiated at 20 mg daily, days 
1-21 of a 28 day cycle, to be continued until 
disease progression, unacceptable toxicity or after 
twelve cycles if the patient has achieved a 
complete response.   
 
Rituximab 375 mg/m2/wk x 4 weeks, to begin Day 
15 of cycle 1. After 4 cycles of therapy if patient 
does not achieve CR, the patient will receive a 
second course of Rituximab. 
 
Blood samples for companion study to assess 
immune profiles will be obtained within 1 week 
prior to starting treatment & then on days 15, 30, 
60 and 120, and then at the end of treatment or 
when treatment is discontinued for any reason. 
Additional blood draws for immunologic profiling 
at day 15, 30 after starting radiation therapy and at 
the time of progression for patients taking part in 
the additional radiation therapy cohort. If the 
patient progresses within 8 weeks, the blood draw 
STUDY DRUG SUPPLIES: 
Celgene Corporation will supply 
lenalidomide as 5 mg capsules.   

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at progression will not be done. 
 
After progression: Lenalidomide will be continued 
at the current dose, days 1-21 of a 28 day cycle. 
Radiotherapy will be delivered in a single course 
of 20 Gy in 5 daily fractions of 4 Gy each, day 1-5 
of a 28 day cycle. Lenalidomide will be continued 
until disease progression, unacceptable toxicity or 
after twelve cycles if the patient has achieved a 
complete response.   
 

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Procedure 
Screening 
≤ 28days from 
Baseline (First 
day study drug 
administration) 
Cycle 1 
Cycle 2  
All 
other 
cycles 
At  
Progression18 
Discontinuation 
From Study 
Drug 
Follow-
Up Phase 
Post-
Progression 
Radiation19 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 1 
 
 
Every 3 
months 
 
testing and counseling should be performed if a patient misses her period or if there is any abnormality in her pregnancy test or in her menstrual bleeding.    
7 Complete after every 2 cycles. All PRs and CRs must be confirmed by repeat scans no less than 4 weeks after the criteria for response are first met. Timing of 
alternate cycle efficacy assessments will be reset following a confirmation or response assessment.  After CR is confirmed scans may be repeated every four 
cycles. If the subject is in remission for more than 1 year then follow-up will be every four months unless there are clinical indications. 
8Repeat all evaluations necessary to document known (+ at baseline) or suspected sites of disease.  
9Rituximab administration four weekly doses days 15, 22 of cycle 1 and days 1 and 8 of cycle 2. To be repeated for 4 weekly doses if no CR attained post cycle 4. 
10 For patient providing consent.  Blood samples for companion study to assess immune profiles will be obtained within 1 week prior to starting treatment,  on 
days 15, 30, 60 and 120, and then at the end of treatment or when treatment is discontinued for any reason. See section 11.5 
11 Lenalidomide must be prescribed through and in compliance with the Revlimid REMS™ program.  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 UC Davis pharmacy or participating site’s pharmacy that will dispose the drug to the patient.  Any unused Revlimid® (lenalidomide) should be 
returned to the pharmacy for disposition in accordance with the Revlimid REMS™ program 
12 An additional safety assessment will be done 30 days (+/- 2 days) following the last dose of study drug. 
13 Results must be available prior to initiation of cycle, thus procedures should be ordered to ensure results are available on day 1. Procedures may be done up to 3 
days before day 1.  
14If PET/CT is ordered, CT scan must be of “diagnostic” quality in order to allow radiology to provide tumor measurements for response assessment by IWGR 
criteria. 
15 Tumor lysis prophylaxis with allopurinol starting 24 hours before treatment & then continued daily for the first cycle 
16  Peripheral blood will be tested for quantitative PCR to detect t(14,18) prior to starting the study, as part of the correlative studies for patients providing consent. 
If positive, this will be repeated if patient achieves a CR with labs every cycle thereafter.   
17 If HIV status is unknown. 
18. At the time of progression the patient will be offered local radiation therapy and continued treatment with the most recent dose of lenalidomide (section 5.3 and 
6.5) 
19 Optional radiation therapy phase at the time of progression. Patients have 4 weeks from the time of progression to start radiation. Lenalidomide will be 
continued throughout. 
20 CT or PET/CT will be done to document progression and repeated 2 months after completion of radiation therapy. Re-imaging will continue every 2 months 
until CR or progression 
21 Response assessment will be every 2 months until progression or CR 
22 Additional blood draws for immunologic profiling at day 15, 30 after starting radiation therapy and at the time of progression for patients taking part in the 
additional radiation therapy cohort. See section 11.5.  If the patient progresses within 8 weeks, the blood draw at progression will not be done. 

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Glossary of Abbreviations 
3
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CR 
Complete response 
CRF 
CRu 
Case report form 
Complete response unconfirmed 
CT 
Computed tomography 
CTC 
Common toxicity criteria 
DMC 
Data Monitoring Committee 
DTIC 
Dacarbazine 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMEA 
European Agency for Evaluation of Medicinal Products 
FDA 
Food and Drug Administration 
G-CSF 
Granulocyte colony stimulating factor, filgrastim (Neupogen) 
GM-CSF 
Granulocyte/macrophage colony stimulating factor, sargramostim, 
(Leukine, Prokine) 
GCP 
Good clinical practice 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IFN 
Interferon 
IL-2 
Interleukin-2 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVRS 
Interactive Voice Response System 
IWGRC 
International Working Group Response Criteria 
LD 
Longest diameter 
LDH 
Lactate dehydrogenase 
MCH 
Mean corpuscular hemoglobin 

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MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activity 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
OS 
Overall survival 
PD 
Progressive disease 
PR 
Partial response 
RBC 
Red blood cell (count) 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
TCR 
Stable disease 
Tumor control rate 
TPP 
Therapeutics Product Program 
TSH 
Thyroid stimulating hormone 
TTP 
Time to progression 
WBC 
White blood cell (count) 
WCBP 
Women of child bearing potential 
WHO 
World Health Organization 
 
 

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Background and Rationale 
4
4.1 Introduction 
Despite the availability of multiple therapeutic modalities and a high response rate to initial 
therapy, most patients with low grade non-Hodgkin lymphoma (NHL) will develop recurrent 
or refractory disease and most ultimately die from lymphoma-related complications. 
Chemotherapy and radiation therapy have clearly provided benefit to patients with these 
disorders. It is evident, however, that these agents are limited in their potential for cure of 
patients with indolent lymphoma, and thus new approaches are under investigation. The 
monoclonal antibody rituximab (directed against the B-cell antigen CD20) has been shown to 
be useful in the treatment of relapsed patients with low grade NHL for which it received Food 
and Drug Administration (FDA) approval. In a pivotal trial of 166 patients with relapsed low 
grade NHL, a response rate of 48% was observed (approximately 60% in the follicular 
histologies), with a median time to progression (TTP) of 12 months in responders. 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 
retreatment, with median TTP of about 18 months after the second administration. Subsequent 
studies of rituximab have evaluated its utility as a single agent in various other subtypes of 
NHL, such as diffuse large B-cell and mantle cell, as well as in combination with numerous 
chemotherapy regimens. Rituximab has been widely adopted by oncologists as a well-tolerated 
and active agent in NHL, and most lymphoma patients receive it at some point in their course 
either as a single agent, or in combination with chemotherapy. 
 
Current research directions include ways of enhancing the activity of rituximab. In addition to 
chemotherapy, numerous “biologic” agents are under development and are being evaluated in 
combination with rituximab in order to explore the possibility of synergistic activity. These 
include cytokines (interferon, IL-2, GM-CSF), other antibodies (epratuzumab or anti-CD22, 
anti-CD80, and Hu1D10 or anti-HLA-DR) and Bcl-2 antisense. Phase I or II trials with these 
agents in combination with rituximab have been developed, and in some cases have 
demonstrated promising initial results. These combination regimens are particularly attractive 
to patients and clinicians who wish to avoid toxicities more typically associated with 
chemotherapy, and offer alternative mechanisms of action against chemotherapy-resistant 
disease. 
 
One agent which has been shown to augment the activity of rituximab in NHL is lenalidomide 
(Revlimid®). It is a potent thalidomide derivative with immunomodulatory activity including 
stimulation of T cell proliferation as well as production of IL-2 and interferon-gamma in 
addition to other cytokines. Phase I trials with doses up to 50 mg/day have been conducted in 
multiple myeloma and myelodysplastic syndrome (MDS). The maximum tolerated dose has 
been determined to be in the range of 25 mg/day administered orally, with dose-limiting 
toxicity principally myelosuppression. Grade 1-2 scalp pruritus, diarrhea and urticaria have 
also been noted, while symptoms of constipation, somnolence and neuropathy as associated 

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with thalidomide are generally not observed. This dose has achieved concentrations associated 
with modulation of cytokine production in vitro, and has provided clinical responses in both 
myeloma and MDS. Regimens with 21 days of treatment cycled every 28 days have been 
associated with less myelosuppression. Lenalidomide has activity against lymphoid cell lines 
in vitro, and xenograft studies using Raji lymphoma cell lines in SCID mice have demonstrated 
that the addition of lenalidomide to rituximab augments anti-tumor effects. These preclinical 
studies provide evidence that the combination of lenalidomide and rituximab warrants further 
evaluation in NHL. The favorable toxicity profile of rituximab does not overlap with 
lenalidomide, and suggests that they can be safely employed together (with appropriate dose 
modification guidelines for lenalidomide, if necessary). Preclinical studies, as well as several 
clinical trials in B cell malignancies, suggest that not only may lenalidomide augment the 
activity of rituximab. Given the importance of rituximab and the promise of rituximab-based 
combinations in indolent lymphoma, rational assessment of these regimens in a series of 
studies is a priority. We have an ongoing clinical trial studying the combination of 
lenalidomide and rituximab in relapsed/ refractory indolent NHL. In this a Phase II trial, and 
the combination appears to be safe and active with an acceptable side effect profile. The 
preliminary results from this study have been encouraging and hence this therapy is being 
tested as upfront treatment of indolent NHL. 
 
Lenalidomide belongs to a proprietary class of Celgene compounds called IMiDs®.   IMiDs®, 
of which thalidomide is the parent compound, have both immunomodulatory and anti-
angiogenic properties which could confer antitumor and antimetastatic effects.  Lenalidomide 
has been demonstrated to possess anti-angiogenic activity through inhibition of bFGF, VEGF 
and TNF-alpha induced endothelial cell migration, due at least in part to inhibition of Akt 
phosphorylation response to bFGF [1]..  Lenalidomide stimulates T cell proliferation, and the 
production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates IL-12 
production [2].0  Upregulation of T cell derived IL-2 production is achieved at least in part 
through increased AP-1 activity [3].  In laboratory models, lenalidomide can enhance T- and 
NK-cell synapse formation with tumor B cells to enhance immune-mediated cytotoxicity.  
Lenalidomide has also been shown to reverse the impaired ability of T cells to form 
immunological synapses, a process that appears to be defective in lymphomas and 
leukemias. Lenalidomide also exerts antiproliferative activity via upregulation of tumor-
suppressor genes (including p21 and SPARC) that results in G1 cell-cycle arrest, caspase 
activation, and apoptosis. To date, lenalidomide has been evaluated in multiple malignant cell 
types, both solid and hematologic tumors.  Significant activity has been demonstrated in 
multiple myeloma and myelodysplastic syndrome.  There are some early clinical studies 
confirming the activity of lenalidomide in other hematologic malignancies including non-
Hodgkin’s lymphoma[4].   
Rituximab is a monoclonal antibody directed towards CD20, a receptor found on B-cells.  It 
has shown clinical activity, both as a single agent and in combination with chemotherapy, in 
multiple B-cell based malignancies.  Rituximab binds to the antigen on the cell surface 
(activating complement-dependent cytotoxicity) and to human Fc receptors which mediates 
cell killing through an antibody-dependent cellular toxicity. 
 

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Radiotherapy is commonly employed in both the definitive and palliative management of 
indolent lymphoma. Stage I/II indolent NHL may be treated with modest doses of radiotherapy 
alone or with rituximab with curative intent [5, 6], which palliative radiotherapy is frequently 
used in advanced symptomatic indolent NHL with high rates of response. Due to the exquisite 
sensitive of indolent NHL to radiotherapy, modest doses ranging from 4-30 Gy with 
conventional fractionation are successfully used [7, 8]. Depending on the field toxicity from 
local radiotherapy for indolent NHL is typically quite minimal [8]. 
 
4.2 Correlative Studies 
 
The biological effects of the thalidomide derivatives, lenalidomide and CC-4047 (IMiDs®) 
have been shown to be up to 10,000 times more potent than thalidomide. The biological effects 
of IMiDs® are presumed to be mediated by: (1) activation of some components of the innate 
(e.g., NK cells) or adoptive immune system (e.g., T-cells), (2) modification of the cytokine 
micro-environment of the tumor bed, or (3) inhibition of angiogenesis. Laboratory studies 
using lenalidomide demonstrated inhibition of DNA synthesis of NHL cell lines). In addition, 
treatment of lymphoma-bearing SCID mice with a combination of rituximab + IMiDs® 
demonstrated augmented/synergistic anti-tumor activity compared to monotherapy of either 
agent alone. This synergistic activity has been hypothesized to be attributed to NK cell 
activation and expansion as well as changes in the cytokine milieu. Based on this hypothesis 
we propose to assay PBMC and plasma samples pre-, during and post- therapy by various 
immune assays (please see correlative studies section 11.6) in an attempt to correlate anti-
tumor activity to lenalidomide associated immunomodulatory effects. 
Additionally, peripheral blood samples will be tested for quantitative polymerase chain reaction 
(q-PCR) analysis for t(14;18) (q32;q21) translocation, which juxtaposes the bcl-2 oncogene on 
chromosome 18 and the JH segment of the immunoglobulin heavy chain (IgH) genes on 
chromosome 14. This is found frequently in follicular lymphomas and has been shown to 
predict treatment response and long-term clinical outcome of patients with FL. [9] 
 
4.3 Clinical experience with lenalidomide in solid tumors 
Twenty patients with varying types of solid tumors (13 with malignant melanoma, 2 each with 
carcinoma of the pancreas and non-small-cell lung cancer [NSCLC], 1 each with renal 
carcinoma, breast carcinoma, and carcinoid-unknown primary) were enrolled in a Phase 1 
study of lenalidomide conducted at the St. George Hospital, London, UK.  This was a non-
randomized, open-label with-in patient dose-escalation design, where patients started on 5 
mg/day for 7 days and then increased their dose every 7 days to 10 mg/day, 25 mg/day, and 50 
mg/day for a total of 4 weeks on therapy [10]. 
Investigators at the NCI have enrolled 20 patients, including 18 patients with recurrent high-
grade gliomas and 2 with other refractory CNS malignancies (1 recurrent atypical meningioma 
and 1 multiple recurrent spinal hemangioblastomas) into a phase I trial of lenalidomide given 
on Days 1 through 21 every 28 days.  Treatment has been well tolerated with 1 grade 2 
myelosuppression as the only toxicity > grade 1 [11]. 

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In an ongoing phase I trial in patients with refractory metastatic cancer conducted through the 
NCI, 12 patients with metastatic androgen independent prostate cancer have been enrolled.  
Lenalidomide was administered in daily doses of 5mg (3 patients), 10mg (3 patients) and 20mg 
(6 patients).  Dose limiting toxicity was seen at 20mg/day (1 grade 3 thrombosis and 1 grade 3 
hypotension).  Stable PSA values for at least 8 weeks were observed in 6 patients [12]. 
In a phase III, multi-center, randomized parallel group study comparing two dose regimens of 
lenalidomide, 293 patients with malignant melanoma were enrolled.  Subjects were 
randomized to receive treatment with lenalidomide at a dose of 5 mg per day orally for 28 days 
or to 25 mg per day orally for 21 days with a 7 day rest (28 day cycle).  Treatment continued 
until the patient developed disease progression or intolerable adverse events occurred.  Interim 
analysis failed to show an advantage of one regimen over the other with respect to survival.  
Analyses of response rates are pending.  The toxicity profile was similar in both dose groups 
and the most frequent adverse events were fatigue, seen in 32% of patients, followed by nausea 
and diarrhea, seen in 24% and 20% of patients respectively.  Neutropenia and 
thrombocytopenia were seen in 2.4% and 2.0% of patients respectively.  Grade 3 and 4 
toxicities were seen infrequently (<15%). 
A second phase III randomized trial compared a lenalidomide dose of 25 mg daily orally for 21 
days with a 7 day rest (28 day cycle) to placebo in patients with metastatic melanoma.  Three 
hundred and five patients enrolled on this study and a preplanned interim analysis failed to 
demonstrate a survival advantage.  Response rates are being analyzed.  The toxicity profile was 
favorable and similar to the previous phase III study [13].  
4.4 Clinical experience in multiple myeloma with lenalidomide 
In 2 phase I studies in multiple myeloma, a total of 41 patients have been treated with 
lenalidomide.  In one study at the University of Arkansas, 15 patients who relapsed or were 
refractory to high dose melphalan therapy with stem cell transplant were treated for 4 weeks in 
an open-label safety study and were permitted to continue therapy in an extension phase of the 
trial.  Patient cohorts were treated at the following daily doses: 5mg, 10mg, 25mg, and 
50mg (12).  In a similar study at the Dana Farber Cancer Institute, 27 patients with rapidly 
advancing refractory multiple myeloma were enrolled [14].   
Anti-myeloma activity was observed in each of these 2 phase I studies.  Decreases in 
neutrophil and platelet counts were the dose-limiting toxicities associated with lenalidomide.  
The maximum tolerated dose (MTD) was not reached within 28 days.  Due to dose 
modifications associated with myelosuppression observed beyond Day 28 at the 25mg and 
50mg daily dose levels, the dose schedule most widely used in future studies has been 
lenalidomide 25 mg on Days 1-21, repeated every 28 days.   
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the 
phase I studies.  Absorption was found to be rapid on both Day 1 and Day 28 with time to 
maximum blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, and 
50mg).  Plasma lenalidomide declined in a monophasic manner with elimination half-life 
ranging from 2.8 to 6.1 hours on both Day 1 and 28 at all 4 doses.  No plasma accumulation 
was observed with multiple daily dosing.  Peak and overall plasma concentrations were dose 
proportional over the dosing range of 5mg to 50mg [15]. 

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A multicenter, randomized, phase II trial compared 2 syncopated dose schedules of 
lenalidomide used alone or in combination with dexamethasone in the treatment of relapsed or 
refractory multiple myeloma.  All patients were treated on Days 1-21 of a 28-day cycle.  
Patients treated with 15mg BID experienced more myelosuppression and dose reductions 
compared with patients treated with 30mg daily.  Anti-myeloma activity was observed with 
each dose and schedule of single agent lenalidomide.  The addition of dexamethasone to 
lenalidomide yielded responses in some patients who had not responded to lenalidomide alone 
[16]. 
A recent phase II trial utilizing lenalidomide plus dexamethasone for newly diagnosed multiple 
myeloma patients was recently reported by the Mayo Clinic. Lenalidomide was given orally 25 
mg daily on days 1-21 of a 28-day cycle. Dexamethasone was given orally 40 mg daily on days 
1-4, 9-12, 17-20 of each cycle. Objective response was defined as a decrease in serum 
monoclonal protein by 50% or greater and a decrease in urine M protein by at least 90% or to a 
level less than 200 mg/24 hours, confirmed by two consecutive determinations at least 4 weeks 
apart. Thirty-one of 34 patients achieved an objective response, including 2 (6%) achieving 
complete response (CR), and 11 (32%) meeting criteria for both very good partial response and 
near complete response, resulting in an overall objective response rate of 91%. Of the 3 
remaining patients not achieving an objective response, two had minor response (MR) and one 
stable disease. Forty-seven percent of patients experienced grade 3 or higher non-hematologic 
toxicity, most commonly fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis 
(6%) and rash (6%). Rev/Dex is a highly active regimen with manageable side-effects in the 
treatment of newly diagnosed myeloma [17]. 
A phase I/II trial of Liposomal doxorubicin (Doxil®), vincristine, dexamethasone (DVd) and 
lenalidomide in heavily pretreated relapsed/refractory multiple myeloma patients is ongoing.  
The MTD of lenalidomide was 10mg on Days 1-21 in combination with Doxil® 40mg/m2 
IVPB on Day 1, vincristine 2mg IVP on Day 1 and dexamethasone 40mg PO on Days 1-4 
cycled every 28 days.  All patients received amoxicillin, acyclovir and aspirin 81mg 
prophylactically.  The dose limiting toxicity with lenalidomide 15mg on Days 1-21 in 
combination with DVd was sepsis/septic shock [18].  Additional phase I trials of lenalidomide 
with chemotherapy in advanced malignancies are in progress. 
There have been 2 multicenter, randomized, double-blinded, placebo-controlled phase III trials 
[1 U.S. (MM-009) and 1 international (MM-010)] in patients with relapsed or refractory 
multiple myeloma [19].  More than 350 patients were enrolled into each of these studies.  All 
patients had to be considered sensitive to dexamethasone and were treated with dexamethasone 
40mg qd, Days 1-4, 9-12 and 17-20.  In addition to receiving dexamethasone, patients were 
randomized to lenalidomide 25mg qd or placebo, Days 1-21.  Cycles were repeated every 28 
days.   After 4 cycles, there was a predetermined reduction of the dexamethasone dose to 40mg 
qd, Days 1-4 repeated every 28 days.  In both studies, a pre-specified interim analysis 
conducted by an Independent Data Monitoring Committee demonstrated that subjects receiving 
the combination of lenalidomide (Len) plus dexamethasone (Dex) had significantly longer 
times to progression and higher response rates than those treated with single-agent 
dexamethasone.   
 
 

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MM-009  
Len/Dex 
MM-010 
Len/Dex 
MM-009 
Placebo/Dex 
MM-010 
Placebo/Dex 
 
CR+PR (%) 
61.2 
58.0 
22.8 
21.7 
P < 0.001 
CR (%) 
26.5 
13.6 
4.1 
4.0 
 
PR (%) 
34.7 
44.3 
18.7 
17.7 
 
SD (%) 
28.2 
33.5 
57.9 
64.6 
 
PD (%) 
2.9 
2.8 
12.3 
7.4 
 
Median TTP 
(mos)  
15.0 
13.3 
5.1 
5.1 
P <0.000001 
4.5 Clinical experience in myelodysplastic syndromes (MDS) with lenalidomide 
An exploratory trial in 43 MDS patients with transfusion dependent or symptomatic anemia 
was conducted at the University of Arizona [20].  Patients received lenalidomide at doses of 
25mg or 10mg per day, or of 10mg on Days 1-21, repeated every 28 days.  All patients had had 
no response to erythropoietin or had a high endogenous erythropoietin level.  Response rates 
were similar across the 3 dose schedules used.  Responses were observed in 24 patients overall 
(56%) including 21 patients with a major response and 20 patients with sustained transfusion 
independence.  Patients with a major response reached a median hemoglobin level of 13.2 
grams per deciliter, with a corresponding 5.3 grams per deciliter median increase from 
baseline.  After a median follow-up of 81 weeks, the median duration of major response had 
not been reached and was more than 48 weeks.  Of 20 patients with karyotypic abnormalities, 
10 (50%) patients had a complete cytogenetic remission.  The response rate was highest in 
patients with a clonal interstitial deletion involving chromosome 5q31.1 (10 out of 12, 83%).  
Neutropenia and thrombocytopenia were the most common adverse events, and resulted in 
dose delays or reductions in 25 patients (58%). 
A multi-center trial (MDS-003) of 148 MDS patients with a clonal interstitial deletion 
involving chromosome 5q31.1 where lenalidomide was given: 10mg on Days 1-21 repeated 
every 28 days to 44 patients and 10mg daily to the other 104 patients.  Transfusion 
independence was achieved in 93 patients (64%), with a median hemoglobin increase of 
3.9g/dl. Cytogenetic response was achieved in 76% of transfusion independent patients with 
55% achieving a cytogenetic complete response. Pathologic complete response was 
documented in 32 out of 110 (29%) evaluable patients.  With a median follow-up of 9.3 
months, the median response duration had not been reached.  Neutropenia (39%) and 
thrombocytopenia (35%) were the most common adverse events requiring dose delays or 
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Another trial (MDS-002) studied patients with low to intermediate-1 risk MDS.  215 patients, 
of whom, 166 were documented to have low to intermediate-1 risk MDS were enrolled.  
Among the patients with documented low to intermediate-1 risk MDS, 84 patients (51%) 
responded to treatment.  Transfusion independence was achieved in 54 patients (33%) and 30 
patients (18%) achieved a minor response, defined as a 50% or greater decrease in blood 
transfusion requirement.  The median duration of transfusion-independence was 41 weeks.  
The median baseline hemoglobin level was 8.0g/dl, which increased by 3.2g/dl in responding 
patients.  Among 20 patients evaluable for cytogenetic response, 9 patients (45%) experienced 
a cytogenetic remission [22]. 
REVLIMID® (lenalidomide) is now indicated for the treatment of patients with transfusion-
dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated 
with a deletion 5q cytogenetic abnormality with or without additional cytogenetic 
abnormalities and in combination with dexamethasone for patients with multiple myeloma that 
have received at least one prior therapy. 
4.6 Clinical experience of thalidomide and lenalidomide in other hematologic 
malignancies 
Hernandez-Ilizaliturri et al showed in early pre-clinical trials the activity of thalidomide 
derivaties in other NHL.  Treatment of NHL cells with lenalidomide resulted in a 40-70% 
growth inhibition when compared with controls [4].  In vitro studies in severe combined 
immunodeficient mice showed some synergistic activity between lenalidomide and rituximab 
compared to rituximab monotherapy-treated animals.  Kaufmann et al treated 16 patients with 
relapsed/refractory mantle cell lymphoma with rituximab in combination with thalidomide.  13 
patients (81%) showed an objective response with 5 CRs and median progression free survival 
of 20.4 months.[23]  These two studies outline the potential therapeutic roles IMiDs® have in 
this patient population. 
 
Clinical experience of lenalidomide in Non Hodgkin’s Lymphomas 
Aggressive NHL 
NHL-003 study by Czuczman et al evaluated the role of lenalidomide as monotherapy in 217 
patients with relapsed/refractory aggressive Non-Hodgkin’s Lymphoma. Among these, 50% 
patients had Diffuse large B cell Lymphoma, 26% Mantle Cell Lymphoma, 9% Follicular 
Lymphoma Grade III, and 15% transformed lymphoma. The ORR for all 217 patients was 
35%, with 13% complete response, 22% partial response, and 21% had stable disease. 
Responses were observed in all histological types. Median progression-free survival for all 
patients was 3.5 months and the median duration of response for the 77 responders was 11.6 
months. The primary side effect of lenalidomide was reversible myelosuppression [24].  
Indolent NHL 
 
Witzig et al reported a phase II study of lenalidomide (25 mg/d for 21 of 28 days) in patients 
with relapsed or refractory indolent NHL. Among 27 assessable patients with a median of three 

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(range, one to 17) prior therapies, the ORR was 26% (n = 7) including two CRs, whereas the 
overall clinical benefit (stable disease or better response) was observed in 59% of the patients. 
A large, randomized, multicenter clinical trial conducted by the Cancer and Leukemia Group B 
(CALGB) is investigating the clinical benefit of lenalidomide versus lenalidomide/rituximab in 
patients with relapsed follicular NHL [25].  
We at UC Davis have studied the combination of lenalidomide and rituximab in relapsed/ 
refractory indolent NHL, and it appears to be safe and active with an acceptable side effect 
profile. 16 patients have been enrolled as of December 2009. 10 of the 16 patients were 
considered heavily pre-treated, and 7 rituximab refractory. Overall response rate in a 
preliminary analysis was remarkable at 75%, with 31% CR and 44% PR. The toxicity profile 
was safe, with the most common grade 3 and 4 events being fatigue, neutropenia and 
lymphopenia. The protocol was amended after two patients developed tumor lysis syndrome, 
to include tumor lysis prophylaxis with allopurinol and reducing the initial dose of 
lenalidomide from 25 to 20 mg. No additional patients developed tumor lysis after this 
modification. 
 
Fowler et al also recently presented their data on front-line therapy of indolent B-cell non-
hodgkins lymphoma with a combination of lenalidomide and rituximab. Patients received 
lenalidomide at a dose of 20 mg orally on days 1-21 and rituximab 375 mg/m2 IV on day 1 of 
each cycle, for up to 6 cycles of therapy. Among the 28 patients enrolled, overall response rate 
was 86%, with a complete response in 75%. The combination was well tolerated with the most 
common grade 3 and 4 adverse events being myalgia, neutropenia and rash [26]. 
 
Mantle-Cell Lymphoma 
 
Kaufman et al first reported the clinical efficacy of thalidomide combined with rituximab in 
patients with relapsed/refractory mantle-cell lymphoma (MCL). The ORR and CR rate in this 
study was 81% and 31%, respectively with a median progression-free survival of 20.4 months 
[23]. On the basis of these findings, a phase I clinical trial of lenalidomide (5 to 25 mg) in 
combination with rituximab was initiated for MCL. The MTD was 20 mg/d, 21 of 28 days. 
Overall response rate of 41% was reported. Zaja et al studied lenalidomide in combination with 
dexamethasone, with a 50% overall response rate [27]. Wang et al reported an overall response 
rate of 53% for the combination of lenalidomide with rituximab. These studies also 
demonstrated a favorable toxicity profile for lenalidomide and the combinations. 
4.7 Clinical Rationale for Combination of Lenalidomide and Radiotherapy in 
Indolent NHL 
Recent preclinical and early clinical data suggest radiotherapy may act as a potent 
immunostimulatory agent in the appropriate setting, and may be a promising partner therapy 
for systemic immunotherapy agents such as lenalidomide. Radiotherapy may exert 
immunostimulatory effects via multiple mechanisms, including tumor vasculature 
normalization [28], improved T-cell homing to tumors [28], destruction of immunosuppressive 
stromal cells [29], induction of immune mediated tumor cell death [30], and tumor antigen 
exposure in the presence of immune modulation, among others. Small case series and case 
reports in melanoma patients describe impressive systemic abscopal (ab-scopus – away from 

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the target) responses distant from the radiation target lesion in patients irradiated after failing 
therapy with the immunotherapy agent ipilimumab, an inhibitor of the immune checkpoint 
CTLA-4. Grimaldi et al describe 21 patients who progressed through ipilimumab treatment and 
subsequently underwent palliative radiotherapy to any site [31]. The authors identified a 
remarkable 52% systemic response rate, with a median time to response of 1 month. Other case 
reports have suggested similar phenomena in melanoma patients receiving palliative radiation 
following failure to respond to immunotherapy [32, 33].  
The specific interplay between lenalidomide and radiotherapy and the potential for radiation-
induced augmentation of systemic anti-tumor response is not well-studied. However, several 
case reports detailing heavily pre-treated lymphoma and myeloma patients with impressive 
systemic responses following treatment with lenalidomide and local radiation support possible 
synergism between these modalities [34, 35]. Additionally, several preliminary clinical trials 
have provided preliminary evidence of synergistic anti-tumor responses when combining 
immunotherapy and local radiation for lymphoma patients. Investigators from Stanford 
University enrolled 15 patients with low grade B cell lymphoma and delivered low dose local 
radiotherapy (4 Gy in 2 fractions) with concurrent intratumoral injection of C-G enriched, 
synthetic oligodeoxynucleotide (CpG) TLR9 agonist PF-3512676 [36]. Systemic responses 
were identified in 6 patients, including one complete response. Similarly, Kim et al evaluated 
the same approach in 15 patients with mycosis fungoides, with 5 systemic responses identified 
[37]. Investigators at the Oslo University Hospital completed a 14 patient pilot trial enrolling 
stage III/IV follicular lymphoma patients. Treatment consisted of low-dose intratumoral 
rituximab injections with immature autologous dendritic cells and granulocyte-macrophage 
colony-stimulating factor with a single dose of 8 Gy to the injected site. This regimen was 
completed to 3 separate sites for each patient: weeks 1, 3, and 5. A 34% objective clinical 
response rate was identified, with 2 durable complete remissions [38].   
4.8 Adverse Events 
Most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal 
pain, nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, 
UTI, Upper respiratory infection, cellulitis, atrial fibrillation, congestive heart failure, 
myocardial infarction, chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back 
pain, bone pain, generalized pain, dizziness, mental status changes, syncope, renal failure, 
dyspnea, pleural effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, 
dizziness, spinal cord compression, syncope, disease progression, tumor lysis syndrome, death 
not specified and fractures.  
Second new cancers  
According to researchers, patients with cancer have a higher risk of developing a second new 
cancer when compared to people without cancer. In clinical studies of newly diagnosed 
multiple myeloma, a higher number of second cancers were reported in patients treated with 
induction therapy (treatment as first step to reducing number of cancer cells) and/or bone 
marrow transplant then lenalidomide for a long period of time compared to patients treated 
with induction therapy and/or bone marrow transplant then placebo (a capsule containing no 

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lenalidomide). Patients should make their doctors aware of their medical history and any 
concerns they may have regarding their own increased risk of other cancers.  
Complete and updated adverse events are available in the Investigational Drug Brochure and 
the IND Safety Letters.  
The most frequent adverse events associated with rituximab include: infusion-related toxicities 
(fevers/chills, rigors, hypertension/hypotension, bronchospasm, angioedema, nausea/vomiting, 
myalgias, and rigors), cytopenias (neutropenia with a mean duration of 13 days, leucopenia, 
lymphopenia with a mean duration of 14 days), and generalized weakness.  Rare reports of 
hepatitis B reactivation have been associated with rituximab. 
4.9 Rationale for Treatment in this Setting 
The rationale for combining lenalidomide and rituximab originates from the hypothesis that 
enhancement of host immune effector mechanisms may augment the clinical efficacy of 
rituximab without significantly increasing toxicity. Recent studies as above have shown this to 
be effective and safe in patients with relapsed/refractory as well as upfront treatment of 
indolent non-Hodgkin’s lymphoma.  
 
Study Objectives and Endpoints 
5
5.1 Objectives 
5.1.1 Primary objectives     
• To determine the response rates to treatment with the combination of lenalidomide and 
rituximab in patients with previously untreated indolent NHL. 
5.1.2 Secondary study objectives 
• Time to disease progression, safety, tolerability, duration of response, and overall 
survival.  
• To assess changes in serum cytokines as well as cellular immune phenotypic and 
functional changes before and after treatment, and correlate these changes with 
response. 
• Examine immune correlates after local radiotherapy 
5.2 Endpoints 
5.2.1 Primary Endpoint 
• Complete response (CR), near complete response (CRu), or partial response (PR), 
stable disease (SD) of 4 months 
5.2.2 Secondary Endpoints 
• Time to disease progression 

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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 an 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. 
REVLIMID®  (lenalidomide) is available in 5 mg and 25 mg capsules for oral administration. 
Each capsule contains lenalidomide as the active ingredient and the following inactive 
ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. 
5.3.1.1 
CLINICAL PHARMACOLOGY  
Mechanism of Action:  
The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide 
possesses immunomodulatory and antiangiogenic properties.  Lenalidomide inhibited the 
secretion of pro-inflammatory cytokines and increased 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.   
5.3.1.2 
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. 
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.  
Pharmacokinetic Parameters: 
Distribution: 

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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.  
5.3.1.3 
Supplier(s) 
Celgene Corporation will supply Revlimid®, lenalidomide to study participants at no charge 
through Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) (formerly 
known as RevAssist® Program). .  
5.3.1.4 
Dosage form 
Lenalidomide will be supplied as 5 mg capsules for oral administration.   
5.3.1.5 
Packaging 
Lenalidomide will be shipped directly to patients or to the clinic site for IND studies. Bottles 
will contain a sufficient number of capsules for one cycle of dosing.    
5.3.1.6 
Labeling 
Lenalidomide investigational supplies are dispensed to the patients in individual bottles of 
capsules.  Each bottle will identify the contents as study medication and bear Celgene’s name, 
quantity contained, and the standard caution statement as follows:  Caution: New drug - 
Limited by Federal law to investigational use.   
 
The study drug label must be clearly visible.  For appropriate drug accountability, it is 
recommended that each bottle be marked with the institutional or Celgene protocol number 
(RV-NHL-PI-0448) upon receipt.  Additional labels must not cover the Celgene label.  
Additional labels must not cover the Celgene label. 
5.3.1.7 
Receipt of study drug 
The Investigator or designee is responsible for taking an inventory of each shipment of study 
drug received, and comparing it with the accompanying study drug accountability form.  The 
Investigator will verify the accuracy of the information on the form, sign and date it, retain a 
copy in the study file, and return a copy to Celgene or its representative.   
5.3.1.8 
Storage 
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent 
unauthorized access. 
The study drug should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold. 

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5.3.1.9 
Unused study drug supplies 
Any unused Revlimid® (lenalidomide) should be returned as instructed through the Revlimid 
REMS™ program. 
5.3.1.10 Prescribing Information 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide will 
be provided in accordance with the Revlimid REMS ™ program of Celgene Corporation.  Per 
standard Revlimid REMS™ program requirements, all physicians who prescribe lenalidomide 
for research subjects enrolled into this trial, and all research subjects enrolled into this trial, 
must be registered in and must comply with all requirements of the Revlimid REMS™ 
program.  Drug will be shipped on a per patient basis by the contract pharmacy to the clinic 
site for IND studies. Only enough lenalidomide for one cycle of therapy will be supplied to 
the patient each cycle. 
 
Further 
information 
about 
the 
Revlimid 
REMS® 
program 
is 
available 
at www.celgeneriskmanagement.com. 
 
5.3.1.11 Pregnancy Testing 
 
Females must follow pregnancy testing requirements as outlined in the Revlimid REMS® 
program. 
 
5.3.2 DESCRIPTION of Rituximab 
Rituxan® (rituximab) is a monoclonal antibody directed against the CD20 antigen on B-
lymphocytes. CD20 regulates cell cycle initiation; and, possibly, functions as a calcium 
channel.  
5.3.2.1 
CLINICAL PHARMACOLOGY 
Mechanism of Action:  
Rituximab binds to the antigen on the cell surface, activating complement-dependent 
cytotoxicity; and to human Fc receptors, mediating cell killing through an antibody-dependent 
cellular toxicity. 
5.3.2.2 Pharmacokinetics and Drug Metabolism: 
Absorption: 
Rituximab is administered intravenously. 
Pharmacokinetic Parameters: 
Metabolism and Excretion: 
Rituximab remains detectable in the serum for 3-6 months after completion of treatment with 
B-cell recovery beginning about 6 months following completion of treatment.  Median B-cell 
levels return to normal by 12 months after completion of therapy.  Once infused, absorption is 

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immediate and results in rapid and sustained depletion of circulating and tissue-based B cells.  
The half-life of rituximab at doses >100 mg/m2 is 4.4 days (range of 1.6-10.5 days).  At doses 
of 375 mg/m2, the half life is 50 hours following the first dose to 174 hours following the 
fourth dose).  The mechanism of clearance for rituximab is uncertain although phagocytosis 
and catabolism in the reticuloendothelial system is suspected. 
5.3.2.3 
Supplier(s) 
Genentech Pharmaceuticals, Inc. Commercial rituximab for intravenous administration will be 
obtained from the UC Davis Cancer Center pharmacy or participating site’s pharmacy and 
billed to the patient or a third party payer. 
5.3.2.4 
Dosage form 
Rituximab is supplied as a sterile, colorless, preservative-free liquid concentrate for 
intravenous (IV) administration. Rituximab is supplied at a concentration of 10 mg/ml in either 
100 mg (10 mL) or 500 mg (50 mL) single-use vials. The product is formulated for IV 
administration in 9 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dehydrate, 0.7 mg/mL 
polysorbate 80, and sterile water for injection. The pH is adjusted to 6.5. 
5.3.2.5 
Storage 
Unopened vials may be stored refrigerated.  When diluted for infusion, the solutions are stable 
at 2-8 degrees C (36-46 degrees F) for 24 hours and at room temperature for an additional 12 
hours. 
5.4 Screening and Eligibility 
The Investigator is responsible for keeping a record of all subjects who sign an Informed 
Consent Form for entry into the study.  All subjects will be screened for eligibility.  Screening 
procedures are outlined in Section 2, Schedule of Study Assessments and unless otherwise 
specified, must take place within 28 days prior to initiation of therapy. Screening pregnancy 
tests for women of child-bearing potential must occur 10-14 days and again ≤ 24 hours from 
initiation of therapy.   
Approximately 30 subjects with previously untreated indolent Non-Hodgkin’s Lymphoma will 
be screened for enrollment and must meet the eligibility criteria below. 
5.4.1 Inclusion Criteria 
Subjects must meet the following inclusion criteria to be eligible for the study. (All responses 
to inclusion criteria should be YES) 
1. All patients must be informed of the investigative nature of the clinical trial and give 
written informed consent in accordance with institutional and federal guidelines. 
2. Age ≥18 years at the time of signing the informed consent form. 
3. Able to adhere to the study visit schedule and other protocol requirements. 
4. Previously untreated, histologically confirmed indolent lymphoma including follicle 
cell lymphoma, WHO classification, grade I or II, and marginal zone lymphoma. Bone 

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marrow biopsies as the sole means of diagnosis are not acceptable, but they may be 
submitted in conjunction with nodal biopsies. Fine needle aspirates are not acceptable. 
5.  At least one measurable lesion according to the International Working Group Response 
criteria for lymphomas.  There must be measurable lymphadenopathy to follow with 
serial exam and/or imaging. 
6. Submission of original biopsy for review by hematopathologist at local institution. 
7. ECOG performance status of 0 -2 at study entry. (see appendix II) 
8. No major organ dysfunction with laboratory test results within these ranges: 
• Absolute neutrophil count ≥ 1000 /uL 
• Platelet count ≥ 75 x 109/L 
• Total bilirubin ≤ 2.0 mg/dL. 
• HIV negative 
• Subjects must have calculated creatinine clearance ≥ 30ml/min by Cockcroft-Gault 
formula.  See section below, “Dosing Regimen”, regarding lenalidomide dose 
adjustment for calculated creatinine clearance ≥ 30ml/min and < 60ml/min. 
 
9. Life expectancy of greater than 3 months. 
10. 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™ 
11. Females of reproductive potential must adhere to the scheduled pregnancy testing as 
required in the Revlimid REMS® program. 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 and again within 24 hours prior to prescribing 
lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by 
Revlimid REMS™) 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. 
                                               
 
† 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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12. Disease free of prior malignancies for ≥ 4 years with exception of currently treated 
basal cell, squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix or 
breast. 
13. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation. (Patient’s 
intolerant to ASA may use low molecular weight heparin). 
14. Must be able to swallow lenalidomide capsules.  
 
Inclusion Criteria for Radiotherapy Cohort 
• Enrolled on UCDCC#224 and progress through protocol therapy 
• At least two measurable sites of disease according to the International Working 
Group Response criteria for lymphomas.  There must be measurable 
lymphadenopathy to follow with serial exam and/or imaging, and one lesion must 
be suitable for local radiotherapy, with an additional lesion(s) to follow for response 
assessment. 
5.4.2 Exclusion criteria   
1. Any prior treatment for Non-Hodgkin’s Lymphoma. 
2. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from signing the informed consent form. 
3. Pregnant or breast-feeding females. (Lactating females must agree not to breast feed 
while taking lenalidomide). 
4. 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. 
5. Use of any other experimental drug or therapy within 28 days of baseline. 
6. Known hypersensitivity to thalidomide or rituximab. 
7. The development of erythema nodosum if characterized by a desquamating rash while 
taking thalidomide or similar drugs. 
8. Any prior use of lenalidomide. 
9. Concurrent use of other anti-cancer agents or treatments. 
10. Known positive for HIV  
11. Known active hepatitis, type A, B or C. Patients who are seropositive because of 
hepatitis B virus vaccine are eligible.  
12. Evidence for CNS metastatic disease 
13. Subjects with ≥ Grade 2 neuropathy 

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14. For Radiotherapy cohort, prior radiotherapy to the planned target lesion (prior 
radiotherapy to other sites of disease is permitted at investigator discretion) 
15. For the radiotherapy cohort, CNS disease at the time of progression 
5.5 Visit schedule and assessments 
Screening Assessments and all on study scheduled visits and assessments are outlined in 
Section 2 Table of Study Assessments.  
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. 
At treatment discontinuation, subjects will undergo off study evaluations per the Schedule of 
Assessments, Section 2.   In addition, a safety assessment will be done approximately 30 days 
post the last dose of study drug.  Follow-Up contact with the subjects should occur at a 
minimum of 4 weeks. 
If the subject is in remission for more than 1 year then follow-up will be every four months 
unless there are clinical indications. 
 
Treatment assignments 
6
All patients will receive the treatment regimen outlined below. 
6.1 Treatment Schedule 
Lenalidomide capsules will be taken orally in the morning each day on days 1 - 21, followed 
by 7 days of no therapy of each 28-day cycle. Rituximab will be given by intravenous infusion 
weekly for 4 weeks beginning on day 15 of treatment start, thus on days 15, 22 of cycle 1 and 
days 1 and 8 of cycle 2. 
Following cycle one, therapy with lenalidomide will continue in 28-day cycles, until there is 
disease progression, unacceptable toxicity or the patient chooses to withdraw from therapy. 
Lenalidomide may be discontinued after twelve cycles if complete response demonstrated, per 
physician and patient discretion. Additional course of rituximab will be administered if CR not 
attained after cycle 4, to be administered during cycle 5 on days 1, 8, 15 and 22. The patient 
must see the study physician before the next cycle may begin.  There will be a +/-3 day 
window for study visits and procedures after completion of cycle one.   
Dosing regimen 
The planned maximum dose of lenalidomide for investigation is 20 mg daily, days 1- 21 of a 
28 day cycle.  Dosing will be in the morning at approximately the same time each day.  
Lenalidomide may be taken orally either with a full or an empty stomach. 
 
Due to the uncertain amount of re-absorption of lenalidomide, there will be no re-dose for 
lenalidomide if the patient vomits the pills. 

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Lenalidomide capsules should be swallowed whole, and should not be broken, chewed or 
opened.    
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.   
Prophylactic anti-coagulation is required during lenalidomide treatment.  See Section 6.5.1.2. 
Rituximab 375 mg/m2/week will be administered by IV infusion starting on day 15 from start 
of treatment and will continue weekly for 4 weeks (a total of four doses). The course of 
rituximab will be repeated if CR not attained after cycle 4. It will be administered at 375 
mg/m2 weekly during cycle 5 on days 1, 8, 15 and 22. 
For patients with peripheral blood involvement (leukemic presentation) as defined for this 
purpose as >20,000 lymphocytes per mm3 as determined by flow cytometry studies, the 
initiation of rituximab should be delayed until the lymphocyte count drops to <20,000/mm3 in 
the peripheral blood.  For such patients, or for those with high tumor burden, despite 
lymphocyte count <20,000 cells/mm3 (as determined by the principal investigator), the infusion 
of rituximab may be divided as outlined below: 
• Day 1 – Rituximab 50 mg/m2 
• Day 2 – If no cytokine release phenomenon is noted on Day 1 of rituximab and the 
peripheral blood white cell counts have decreased to < 20,000 cells/mm3 or <25% of 
baseline WBC counts, then the dose of rituximab can be increased to 325 mg/m2 on 
Day 2 at the PI discretion. 
A similar 2-day split dose approach may be taken for rituximab infusion on subsequent dose of  
rituximab in patients with high tumor burden or high peripheral blood WBC counts as 
determined by the PI prior to each infusion of rituximab. 
Pre-medication consisting of acetaminophen and diphendydramine should be considered before 
each infusion of rituximab to attenuate potential infusion reactions.  Since transient 
hypotension may occur during rituximab infusion, consideration should be given to 
withholding antihypertensive medications 12 hours prior to rituximab infusion. 
Rituximab First Infusion: The rituximab solution for infusion should be administered 
intravenously at an initial rate of 50 mg/hr. Rituximab should not be mixed or diluted with 
other drugs.  If hypersensitivity or infusion related events do not occur, the infusion can be 
escalated to 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.  If 
hypersensitivity or an infusion-related event develops, the infusion should be temporarily 
slowed or interrupted.  The infusion can continue at one-half the previous rate upon 
improvement of patient symptoms. 
Subsequent Rituximab Infusions: Subsequent rituximab infusions can be administered at an 
initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 minute intervals, to a 
maximum of 400 mg/hr as tolerated. 
 

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Route of Administration 
Rituximab is administered intravenously.  To prevent infusion related or hypersensitivity 
events, rituximab is not to be administered as an intravenous push or bolus. 
Please refer to rituximab package insert for details concerning drug storage, preparation and 
administration guidelines. 
Subjects experiencing adverse events may need study treatment modifications (See section 6.4). 
6.2 
Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless they 
are wearing gloves. 
6.3 
Record of administration 
Accurate records will be kept of all study drug administration (including dispensing and 
dosing) will be made in the source documents.  
 
To monitor treatment compliance, reconciliation of lenalidomide capsules will be done at each 
visit.  Subject diaries will be provided to assist in the collection of dosing information to 
monitor compliance. 
6.4 Dose Continuation, Modification and Interruption    
Subjects will be evaluated for AEs at each visit with the NCI CTCAE v4.0 (Appendix III: NCI 
CTCAE v4.0) used as a guide for the grading of severity.  Refer to Sections 6.5.1, 6.5.2 and 
6.5.3 for full instruction on initiation of a new cycle of therapy and dose modifications during a 
cycle of therapy.    
6.4.1 Lenalidomide Dose Reduction Steps 
Lenalidomide will be initiated at a dose of 20 mg daily for 21 days on a 28 day cycle, except 
patients with renal insufficiency, who will start at a lower dose, as above. 
Rituximab: There will be no dose reduction for rituximab.  The rate of administration may be 
slowed or divided as needed based on tolerability.  Patients with unacceptable hypersensitivity 
to rituximab will not receive further rituximab therapy. 
6.4.2 Instruction 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 ≥ 800/μL; 
• The platelet count is ≥ 50,000/μL; 
• Any lenalidomide or rituximab-related rash, allergic reaction/hypersensitivity or sinus 
bradycardia/ other cardiac arrhythmia adverse event that may have occurred has 
resolved to ≤ grade 1 severity; 
• Any other lenalidomide-related adverse event that may have occurred has resolved to ≤ 
grade 2 severity. 

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If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly 
and a new cycle of lenalidomide 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. 
 
Dose Reduction Steps 
 
Dose level 
Lenalidomide 
Rituximab 
0 
20 mg (days 1-21/28 day cycle) 
375 mg/m2 weekly x4  
-1 
15 mg (days 1-21/28 day cycle) 
-- 
-2 
10 mg (days 1-21/28 day cycle) 
-- 
-3 
5 mg (days 1-21/28 day cycle) 
-- 

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6.4.3 Instructions for dose modifications or interruption of lenalidomide during a cycle. 
Table 2: Dose Modification for Lenalidomide 
NCI CTC Toxicity 
Grade 
Day 2-14 of Cycle 
≥Day 15 of Cycle 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia 
• Hold (interrupt dose). 
• Follow CBC weekly. 
• If neutropenia has resolved to ≤ grade 2 
prior to Day 21, restart at next lower dose 
level and continue the cycle until Day 21. 
• Omit lenalidomide for remainder of 
cycle 
. 
NOTE: If neutropenia is the only toxicity for which a dose reduction is required. G-
CSF may be used and the dose maintained for the next cycle at the investigators 
discretion 
Thrombocytopenia 
≥Grade 4 (platelet 
count < 25,000/mm³) 
• Hold (interrupt dose). 
• Follow CBC weekly. 
• If thrombocytopenia resolves to ≤ grade 2 
prior to Day 21, restart at next lower dose 
level and continue the cycle until Day 21. 
• Omit lenalidomide for remainder of 
cycle 
• Hold ASA or other anticoagulant 
Thrombocytopenia, 
Grade 3 (platelet count  
25,000 to 50,000/mm³) 
• Hold ASA or other anticoagulant 
• Hold ASA or other anticoagulant 
Non-blistering rash 
Grade 3 
 
 
 
             Grade 4 
• If Grade 3 hold (interrupt) dose.  Follow 
weekly. 
• If the toxicity resolves to ≤ grade 1 prior 
to Day 21 restart at next lower dose level 
and continue the cycle until Day 21. 
 
• Discontinue lenalidomide study drug. 
• Omit lenalidomide for remainder of 
cycle. 
 
 
 
 
• Discontinue lenalidomide study drug. 
Desquamating 
(blistering) rash- any 
Grade  
• Discontinue lenalidomide study drug. 
• Discontinue lenalidomide study drug. 
Erythema multiforme ≥  
Grade 3 
• Discontinue lenalidomide study drug. 
• Discontinue lenalidomide study drug. 
Sinus bradycardia/ 
other cardiac 
arrhythmia 
Grade 2 
 
 
            ≥ Grade 3 
 
• Hold (interrupt) dose.  Follow at least 
weekly. 
• If the toxicity resolves to ≤ grade 1 prior 
to Day 21 restart at next lower dose level 
and continue the cycle until Day 21. 
 
• Discontinue lenalidomide study drug. 
• Omit lenalidomide for the remainder of 
the cycle. 
 
 
 
• Discontinue lenalidomide study drug. 

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Table 2: Dose Modification for Lenalidomide 
NCI CTC Toxicity 
Grade 
Day 2-14 of Cycle 
≥Day 15 of Cycle 
Allergic reaction or 
hypersensitivity 
Grade 2-3 
 
 
 
Grade 4 
 
• Hold (interrupt) dose.  Follow at least 
weekly. 
• If the toxicity resolves to ≤ grade 1 prior 
to Day 21 restart at next lower dose level 
and continue the cycle until Day 21. 
 
• Discontinue lenalidomide study drug. 
• Omit lenalidomide for the remainder of 
the cycle. 
 
 
 
 
• Discontinue lenalidomide study drug 
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. See Anticoagulation 
Consideration (Section 6.5.1.2) 
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 
• 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 21. 
• Omit lenalidomide for remainder of 
cycle.  
• See Instructions for Initiation of a New 
Cycle and reduce the dose of 
lenalidomide by 1 dose level. 
 
 
6.4.4 Treatment compliance 
At all times, when dispensing study drug, research center personnel will review the 
instructions, printed on the packaging, with subjects. Subjects will be asked to maintain a diary 
to record the drug administration.  
6.5 Radiation Therapy 
6.5.1 Selection of a target lesion 
All patients should have at least 2 measurable sites of disease (one target lesion and one 
or more lesions for response assessment). The target lesion for radiation should 
measure a minimum of 1 cm and a maximum of 8 cm in greatest diameter. The lesion 
least likely to result in normal tissue toxicity should generally be selected for treatment 
at investigator discretion. Suitable targets include lymph nodes and extranodal tumor 
deposits. CNS disease is NOT a suitable target and patients with CNS involvement are 
not eligible for enrollment. 
 
6.5.2 Treatment planning/target volumes 
GTV: Will include visible target lesion as identified by diagnostic and/or treatment 
planning CT or PET and clinical exam  

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PTV: An additional margin of 5-10 mm will be added to account for setup error at 
treating physician discretion.   
 
If clinical setup is used, a 1.5 cm block margin on clinically apparent disease should be 
applied  
 
6.5.3 Dose specifications  
All patients will receive a dose of 20 Gy delivered in 5 daily fractions of 4 Gy each. At 
least 95% of the GTV should receive the full prescription dose of 20 Gy.  Coverage 
may be estimated in the case of clinical set-up. 
 
6.5.4 Technical parameters 
Radiation will be delivered with megavoltage equipment at photon energies ≥ 6 MV or 
with electron fields ≥4 MeV.  Cobalt-60 and proton beams are not permitted.  Any 
beam arrangement that allows for optimal coverage of the target lesion and minimizes 
dose to surrounding structures is permitted.  
 
6.5.5  Immobilization and simulation 
Patients will be positioned reproducibly with a customized thermoplastic 
immobilization cast or a molded foam cradle as needed or stabilization.  CT simulation 
is encouraged, but clinical set-up is permitted for superficial lesions that can be easily 
demarcated without CT simulation.   
 
6.5.6 Normal critical structures and dose constraints 
Normal critical structures located within 5 cm of the PTV should be delineated and 
dose should be tracked, including but not limited to: Spinal cord, lungs (right and left), 
heart, esophagus, liver, small bowel, large bowel, bladder, rectum, brain, orbits (right 
and left), brainstem. As the prescription dose is such that normal tissue tolerance is 
generally not expected  
 
 
6.5.7 Treatment Verification and Image Guidance 
At the start of treatment, electronic portal imaging should be used to verify treatment 
fields. More frequent imaging is permitted but not required. 
 
6.5.8 Radiation Adverse Events 
Adverse Events will be categorized and graded based on the Common Toxicity Criteria 
for adverse events Version 4.0 (CTCAE version 4.0). 
 
Radiotherapy should be discontinued for Grade 4 in-field toxicity  
 
6.6 Concomitant therapy   
All medications (prescription and non-prescription), treatments, and therapies taken from the 
first day of study drug through the end of the study, must be recorded on the source documents. 

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6.6.1 Recommended concomitant therapy   
The use of filgrastim (G-CSF) for subjects in this study is permitted when used to treat 
neutropenia. Subjects should receive full supportive care, including transfusions of blood and 
blood products, antibiotics, and antiemetics when appropriate.  
Use of steroids is allowed in emergencies including the management of infusion reactions to 
rituximab. 
6.6.1.2 Anticoagulation Consideration 
Lenalidomide likely 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. Based on data with thalidomide it has been hypothesized that when lenalidomide is 
combined with other agents such as steroids (e.g. dexamethasone, prednisone), anthracyclines 
(Doxil, adriamycin) and erythropoeitin the risk of thrombosis may be increased.  
The use of aspirin (81 or 325 mg) or some other form of prophylaxis as deemed appropriate is 
required. 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 at the discretion of the PI.  
Hold anticoagulation for platelet count < 50,000 mm3. 
6.6.1.3 Prohibited concomitant therapy 
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.  Concomitant use of other anti-lymphoma 
therapy, including steroids (except for the treatment of hypersensitivity reactions), while the 
subject is on study drug is prohibited. 
6.7 Discontinuation of Study Treatment  
Treatment will continue until evidence of disease progression or the occurrence of any of the 
following events.   
Treatment with study drug is to be discontinued when any of the following occurs: 
• Lack of therapeutic effect/progressive disease as defined in section 8.0 
• Adverse event(s) that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of study drug. 
• Major violation of the study protocol. 
• Withdrawal of consent 
• Lost to follow up 
• Death 
• Suspected pregnancy 
• Treatment may also be discontinued after a total of twelve cycles of treatment if a 
patient achieves and maintains a complete response. This will be decided by the 
treating physician. 
 

U C D C C # 2 2 4 
C o nfi de nti al  
P a ge 4 4  of 8 0  
Cel ge ne # R V -N H L -PI -0 4 8 8  
Versi o n D ate: 0 9/ 1 0 / 18 
6. 8  
F oll o w- U p 
S u bjects w h o disc o nti n ue treat me nt f or a n y reas o n will be f oll o we d f or disease pr o gressi o n a n d 
o verall s ur vi val. At treat me nt disc o nti n uati o n, s u bjects will u n der g o a safet y assess me nt 
a p pr o xi matel y 3 0 da ys p ost t he last d ose of st u d y dr u g.  I n a d diti o n of f st u d y e v al uati o ns per 
t he Sc he d ule of Ass ess me nts, Secti o n 2 will be d o ne.  If t he s u bject is i n re missi o n f or m ore 
t ha n 1 year t he n f oll o w- u p will be e ver y f o ur m o nt hs u nless t here are cli nical i n dicati o ns. 
Patie nts will be f oll o we d f or s ur vi val e v er y t hree m o nt hs.  
6. 9 O n St u d y E v al u ati o ns  
All st u d y e val u ati o ns o utli ne d i n sc he d ule 2 of Assess me nts will be c o m plete d d uri n g st u d y f or 
assess me nts of res p o ns e a n d t o xicit y.   
St u d y  visits  a n d  pr oce d ures  ma y  be  sc he d ul e d  +/ - 3  d a ys  wi n d o w  e x ce pt  f or  s cree ni n g  a n d 
c ycle o ne.   
C T sca ns s h o ul d i ncl u de nec k if necessar y 
If  i n  C R  b y  ra di ol o gic  e val uati o n,  b o ne  marr o w  bi o ps y  a n d  P E T  sca n,  c ol o n osc o p y  or 
e n d osc o p y wit h ra n d o m bi o ps y m a y be n ecess ar y t o c o nfir m C R.  
After C R has b ee n c o nfir me d b y a re peat sca n, t h e resta gi n g s ca ns will be o btai ne d e v er y f o ur 
c ycles, u nless dee me d cli nicall y n ecess ar y b y treati n g p h ysicia n.  
 
A d v er s e e v e nt s  
7
7. 0  
Seri o us A d verse E ve nt ( S A E) Defi niti o n 
A seri o us a d verse e v e nt is o ne t hat at a n y d ose (i n cl u di n g o ver d ose): 
 
Res ults i n deat h
 
Is life-t hreate ni n g1
 
Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n
 
Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y 2
 
Is a c o n ge nital a n o mal y or birt h defect
  
Is a n i m p orta nt me dical e ve nt3
 1 “Life -t hreate ni n g”  mea ns  t hat  t he  s u bject  was  at  i m me diate  ris k  of  deat h  at t he  ti me  of  t he 
seri o us a d verse e ve nt; it d oes n ot refer t o a seri o us a d verse e ve nt t hat h y p ot heticall y mi g ht ha ve 
ca use d deat h if it were m ore se vere.  
2 “ Persiste nt or si g nifica nt disa bilit y or i nca pacit y” mea ns t hat t here is a s u bsta ntial disr u pti o n 
of a pers o n’s a bilit y t o carr y o ut n or mal life f u ncti o ns. 
3 Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her e x pe dite d re p orti n g 
is  a p pr o priate  i n  sit uati o ns  w here  n o ne  of  t he  o utc o mes  liste d  a b o ve  occ urre d.    I m p orta nt 
me dical e ve nts t hat ma y n ot be i m me diatel y life -t hreate ni n g or res ult i n deat h or h os pitalizati o n 
b ut ma y j e o par dize t he patie nt or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes 
liste d  i n  t he  defi niti o n  a b o ve  s h o ul d  als o  us uall y  be  c o nsi dere d  seri o us.    E xa m ples  of  s uc h 
e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at 

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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.  
 
7.1 
Adverse Event Reporting 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting.  A 
copy of the CTCAE Version 4.0 can be downloaded from the CTEP homepage 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html).  All appropriate treatment areas have access to a 
copy of the CTCAE Version 4.0.  All adverse clinical experiences, whether observed by the 
investigator or reported by the patient, must be recorded, with details about the duration and 
intensity of each 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. 
Second primary malignancies are considered events of interest and should be included as part 
of the assessment of adverse events throughout the course of the study. Investigators are to 
report any second primary malignancies as serious adverse events regardless of causal 
relationship to lenalidomide, occurring at any time for the duration of the study For all subjects 
who develop second primary malignancies, sites will be required to submit all diagnostic 
reports (eg pathology, cytogenetics, flow cytometry results) from the indication diagnostic 
confirmation samples submitted at screening and all reports for the tumor samples from the 
SPM diagnosis. For SPMs diagnosed at another institution (outside the investigational site), 
sites are to make every effort to obtain these reports for the SPM confirmation. 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age 
or disease state) of a female subject occurring while the subject is on lenalidomide, or within 
28 days of the subject’s last dose of lenalidomide, are considered immediately reportable 
events.  Lenalidomide is to be discontinued immediately. The pregnancy, suspected pregnancy, 
or positive pregnancy test must be reported to Celgene Drug Safety immediately by facsimile 
or email using the Pregnancy Initial Report Form. The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for further 
evaluation and counseling.  
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form. If the outcome of the 
pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, or 

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other appropriate method, within 24 hours of the Investigator’s knowledge of the event using 
the SAE Report Form,  
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the study drug should also be reported to Celgene Drug 
Safety immediately by facsimile, or other appropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form. 
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking lenalidomide should notify the Investigator, and the pregnant female partner 
should be advised to call their healthcare provider immediately. 
7.1.1 Celgene Drug Safety Contact Information 
Celgene Corporation 
Global Drug Safety and Risk Management 
86 Morris Avenue 
Summit, NJ 07901 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
7.2 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 312.33 
provides the data elements that are to be submitted in the report.  The Annual Report should be 
filed in the study's Regulatory Binder, and a copy provided to Celgene Corporation as a 
supporter of this study as follows. 
 
Celgene Corporation 
Attn: Medical Affairs Operations 
86 Morris Avenue 
Summit, NJ 07901 
All adverse experience reports must include the patient number, age, sex, weight, severity of 
reaction (mild, moderate, severe), relationship to study drug (probably related, unknown 
relationship, definitely not related), date and time of administration of test medications and all 
concomitant medications, and medical treatment provided.   The investigator is responsible for 
evaluating all adverse events to determine whether criteria for “serious” and as defined above 
are present.  The investigator is responsible for reporting adverse events to Celgene as 
described below. 

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7.2.1 Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator should inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours 
of being aware of the event. The written report must be completed and supplied to Celgene by 
facsimile within 24 hours/1 business day   The initial report must be as complete as possible, 
including an assessment of the causal relationship between the event and the investigational 
product(s).  Information not available at the time of the initial report (e.g., an end date for the 
adverse event or laboratory values received after the report) must be documented on a follow-
up report.   A final report to document resolution of the SAE is required.  The Celgene tracking 
number (RV-NHL-PI-0488) and the institutional protocol number should be included on SAE 
reports (or on the fax cover letter) sent to Celgene.  A copy of the fax transmission 
confirmation of the SAE report to Celgene should be attached to the SAE and retained with the 
patient records. 
 
Participating study sites must report SAEs to Celgene as described and within 24 hours of 
awareness.  Participating sites should also report SAEs to the primary study site. 
7.2.2 Report of Adverse Events to the Institutional Review Board 
The Principal Investigator is required to notify his/her Institutional Review Board (IRB) of a 
serious adverse event according to institutional policy.   
7.2.3 Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly associated 
to the drug, and that have not previously been reported in the Investigators brochure, or 
reference safety information document should be reported promptly to the Food and Drug 
Administration (FDA) by telephone or fax. Fatal or life threatening SAEs that meet the criteria 
for reporting to the FDA must be reported to the FDA within 7 calendar days after awareness 
of the event. All other SAEs that meet the criteria for reporting to the FDA must be reported to 
the FDA within 15 calendar days after awareness of the event. A clear description of the 
suspected reaction should be provided along with an assessment as to whether the event is drug 
or disease related.  
Participating study sites should NOT report SAEs to the FDA.  Rather, participating sites should report 
SAEs to Celgene and the primary study site, and the primary site will be responsible for reporting to 
FDA. 
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. 
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected 
AE(s) or significant risks to subjects. 

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The Investigator must keep copies of all AE information, including correspondence with 
Celgene and the IRB/EC, on file (see Section 12.4 for records retention information). 

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Response Criteria 
8
Responses will be assessed by Revised Working Group Response Criteria for Malignant 
Lymphoma (Cheson et al, JCO Vol 25, No 5 (February 10), 2007: pp. 579-586), as follows: 
 
8.1 Complete Response (CR):   
1. Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy. 
 
2a. Typically FDG-avid lymphoma: in patients with no pretreatment PET scan or when the 
PET scan was positive before therapy, a post-treatment residual mass of any size is 
permitted as long as it is PET negative. 
 
2b. Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, all lymph nodes and 
nodal masses must have regressed on CT to normal size ( ≤ 1.5 cm in their greatest 
transverse diameter for nodes > 1.5 cm before therapy). Previously involved nodes that 
were 1.1 to 1.5 cm in their long axis and more than 1.0 cm in their short axis before 
treatment must have decreased to ≤ 1.0cmin their short axis after treatment. 
 
2. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear. However, determination of splenic involvement is not always reliable 
because a spleen considered normal in size may still contain lymphoma, whereas an 
enlarged spleen may reflect variations in anatomy, blood volume, the use of 
hematopoietic growth factors, or causes other than lymphoma. 
 
3. If the bone marrow was involved by lymphoma before treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy. The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core). If the 
sample 
is 
indeterminate 
by 
morphology, 
it 
should 
be 
negative 
by 
immunohistochemistry. A sample that is negative by immunohistochemistry but that 
demonstrates a small population of clonal lymphocytes by flow cytometry will be 
considered a CR until data become available demonstrating a clear difference in patient 
outcome. 
8.2 Complete Response Unconfirmed (CRu): 
 
The use of the above definition for CR and that below for PR eliminates the category of 
CRu. 
 
 
 
 

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8.3 Partial Response (PR) 
 
1.  At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of 
the largest dominant nodes or nodal masses. These nodes or masses should be selected 
according to all of the following: they should be clearly measurable in at least 2 
perpendicular dimensions; if possible they should be from disparate regions of the 
body; and they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved. 
 
 
 
2.   No increase should be observed in the size of other nodes, liver, or spleen. 
 
 
 
3.  Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, 
in the greatest transverse diameter. 
 
 
 
4.  With the exception of splenic and hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present. 
 
 
5.  Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment. However, if positive, the cell type should be specified (eg, 
large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR by the 
above criteria, but who have persistent morphologic bone marrow involvement will be 
considered partial responders. When the bone marrow was involved before therapy and 
a clinical CR was achieved, but with no bone marrow assessment after treatment, 
patients should be considered partial responders. 
 
 
6.  No new sites of disease should be observed. 
 
 
 
7.  Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the 
PET scan was positive before therapy, the post-treatment PET should be positive in at 
least one previously involved site. 
 
 
8.  Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, CT criteria should 
be used. In patients with follicular lymphomaor mantle-cell lymphoma, a PET scan is 
only indicated with one or at most two residual masses that have regressed by more 
than 50% on CT; those with more than two residual lesions are unlikely to be PET 
negative and should be considered partial responders. 
8.4 Stable disease (SD):   
 
1. A patient is considered to have SD when he or she fails to attain the criteria needed for 
a CR or PR, but does not fulfill those for progressive disease (see Relapsed Disease 
[after CR]/Progressive Disease [after PR, SD]). 
 
 
 
2.  Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease 
with no new areas of involvement on the post treatment CT or PET. 

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3.  Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan or if the pretreatment PET was negative, there must be no 
change in the size of the previous lesions on the post-treatment CT scan. 
 
 
8.5 Relapsed Disease (after CR)/Progressive Disease (after PR, SD) 
 
 
 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm 
regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should 
only be considered abnormal if its short axis is more than 1.0. Lymph nodes ≤1.0 
≤1.0cm will not be considered as abnormal for relapse or progressive disease. 
 
 
 
1.  Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease 
after confirmation with other modalities. In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign. Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation. 
 
 
2.  At least a 50%increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be 
considered progressive disease, a lymph node with a diameter of the short axis of less 
than 1.0cm must increase by ≥ 50% and to a size of 1.5x1.5 cm or more than 1.5 cm in 
the long axis. 
 
 
3.  At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis. 
 
 
4.  Lesions should be PET positive if observed in a typical FDG avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected 
with current PET systems (<1.5 cm in its long axis by CT). 
 
 
 
Measurable extranodal disease should be assessed in a manner similar to that for nodal 
disease. For these recommendations, the spleen is considered nodal disease. Disease that is 
only assessable (eg, pleural effusions, bone lesions) will be recorded as present or absent 
only, unless, while an abnormality is still noted by imaging studies or physical 
examination, it is found to be histologically negative. 
 
 
8.6 Progressive disease (PD) in PR patients or nonresponders 
• ≥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. 
 

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Summary of response criteria: 
Response 
Category 
Definition 
Nodal Mass 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of all 
evidence of disease 
(a) FDG-avid or 
PET positive 
prior to therapy; 
mass of any size 
permitted if PET 
negative 
 
(b) Variably 
FDG-avid or 
PET negative; 
regression to 
normal size on 
CT 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared 
on repeat 
biopsy; if 
indeterminate 
by morphology, 
immuno- 
histochemistry 
should be 
negative 
PR 
Regression of measurable 
disease and no new sites 
≥ 50% decrease 
in SPD of up to 6 
largest dominant 
masses; no 
increase in size 
of other nodes 
 
(a) FDG-avid or 
PET positive 
prior to therapy; 
one or 
more PET 
positive at 
previously 
involved site 
 
(b) Variably 
FDG-avid or 
PET negative; 
regression on 
CT 
≥50% decrease 
in SPD of 
nodules (for 
single nodule in 
greates 
transverse 
diameter); no 
increase in size 
of liver or spleen 
Irrelevant 
SD 
Failure to attain CR/PR or 
PD 
(a) FDG-avid or 
PET positive 
prior to therapy; 
PET positive at 
prior sites of 
disease and no 
new sites on CT 
or PET 
 
 

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Response 
Category 
Definition 
Nodal Mass 
Spleen, Liver 
Bone Marrow 
 
(b) Variably 
FDG-avid or 
PET negative; no 
change in size of 
previous lesions 
on CT 
Relapse/PD 
Any new lesion or increase 
by _≥ 50% of previously 
involved sites from nadir 
Appearance of a 
new lesion(s) 
>1.5 cm in any 
axis, ≥ 50% 
increase in SPD 
of more than 
one node, 
 
Or 
 
≥ 50% increase 
in longest 
diameter of a 
previously 
identified node 
>1 cm in short 
axis 
 
Lesions PET 
positive if FDG-
avid lymphoma 
or PET positive 
prior to therapy 
> 50 increase 
from nadir in 
the SPD of 
any previous 
lesions 
New or recurrent 
involvement 
 
8.7 Duration of Overall Response: 
The duration of overall response is measured from the time measurement criteria are met for 
CR/PR (whichever status is recorded first) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
 

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8.7.1 Duration of Stable Disease:  
Stable disease is measured from the start of the treatment until the criteria for disease 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started. 
The clinical relevance of the duration of SD varies for different tumor types and grades.  
Therefore, it is highly recommended that the protocol specify the minimal time interval 
required between two measurements for determination of SD.  This time interval should take 
into account the expected clinical benefit that such a status may bring to the population under 
study. 
8.7.2 Time to Progression:  
Time to progression will be measured as the time from when the patient started treatment to the 
time the patient is first recorded as having disease progression, or the date of death if the 
patient dies due to causes other than disease progression. 
8.7.3 Time to Treatment Failure:  
Time to treatment failure will be measured as the time from when the patient started treatment 
to the time the patient is withdrawn due to: adverse events, progressive disease/insufficient 
therapeutic response, death, failure to return, and refused treatment/did not cooperate/withdrew 
consent.  The date of last dose of treatment will be used as the date of event in the case that PD 
was not recorded earlier. 
8.7.4 Survival:  
Survival will be measured as the time from start of treatment to the date of death or the last 
date the patient was known to be alive. 
 
Data Management 
9
9.1 Analyses and Reporting 
Data will be analyzed and reported after all 30 patients have enrolled in the clinical trial and 
have received 2 cycles of treatment.  All subsequent data collected will be analyzed and 
reported in a follow-up clinical report.  
9.2 Data and Safety Monitoring  
In addition to the requirements for adverse event reporting as outlined in section 7.2, this 
protocol is also subject to the UC Davis Cancer Center’s (UCDCC) Data and Safety 
Monitoring Plan. The UCDCC is committed to pursuing high-quality patient-oriented clinical 
research and has established mechanisms to ensure both scientific rigor and patient safety in 
the conduct of clinical research studies. The UCDCC relies on a multi-tiered committee system 
that reviews and monitors all cancer clinical trials and ensures the safety of its participants, in 
compliance with institutional and federal requirements on adverse event (AE) reporting, 
verification of data accuracy, and adherence to protocol eligibility requirements, treatment 
guidelines, and related matters. The Scientific Review Committee (SRC) assumes overall 

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oversight of cancer studies, with assistance and input from two independent, but interacting, 
committees: the Quality Assurance Committee and the Data Safety Monitoring Committee. A 
multi-level review system strengthens the ability of the UCDCC to fulfill its mission in 
conducting high quality clinical cancer research. 
 
As per University of California Davis Cancer Center (UCDCC) Clinical Trials Support Unit 
(CTSU) SOP AM 506: Protocol Specific Meetings, the principal investigator (PI) and clinical 
research coordinator (CRC) meet at least monthly for ongoing study information, to discuss 
patient data and adverse events and to determine if dose escalation is warranted, when 
applicable.  Representatives from all participating centers will be included via conference call, 
as well as representatives from the drug provider or financial sponsor if necessary. The call 
will update participants on the current status of the trial, any serious adverse events 
encountered will be discussed, and appropriate action taken. In between these regularly 
scheduled conference calls, investigators will be informed of any serious adverse events via 
email. 
 
According to the UCDCC Data and Safety Monitoring Plan (DSMP), any new serious adverse 
events related to the drugs being used on this trial are reviewed monthly by the UCDCC Data 
and Safety Monitoring Committee (DSMC) and any applicable changes to the study are 
recommended to the PI, if necessary. 
 
The UCDCC Scientific Review Committee (SRC) determines if a UCDCC Data and Safety 
Monitoring Board (DSMB) is required.  If required, the DSMC will appoint a DSMB. The 
DSMB is responsible for reviewing study accrual logs, adverse event information and dose 
escalation meeting minutes (where applicable) to ensure subject safety and compliance with 
protocol defined guidelines. 
 Study monitoring and auditing 
10
10.1 
Investigator responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) 
and in the US Code of Federal Regulations. 
Investigators must enter study data onto CRFs or other data collection system.  The 
Investigator will permit study-related monitoring visits and audits by Celgene or its 
representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), 
providing direct access to the facilities where the study took place, to source documents, to 
CRFs, and to all other study documents  
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during monitoring visits 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. 

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 Biostatistical Analysis 
11
11.1 
Overview 
This is a Phase II trial designed to assess the efficacy and toxicity of the combination of  
lenalidomide with rituximab in patients  previously untreated follicular NHL. 
11.2 
Datasets to be analyzed 
The primary study endpoint is response to therapy (defined as a CR, nCR, or PR of 4 months).  
The secondary end points (time to progression, tolerability, duration of response and overall 
survival will be measured from the time of entry into the clinical trial.   
 
Toxicity information recorded will include the type, severity, time of onset, time of resolution, 
and the probable association with the study regimen.  Tables will be constructed to summarize 
the observed incidence by severity and type of toxicity.   
11.3 
Statistical Methodology 
30 patients will be treated with rituximab and lenalidomide at indicated dose levels. Objective 
response (CR +PR) will be monitored using Simon’s optimal 2-stage design. This study design 
is optimal in that sense that it minimizes the expected sample size among competing designs. 
The OR rate of rituximab naïve follicular lymphoma patients treated with rituximab alone is 
approximately 60%. A 20% increase in the objective response rate with the addition of 
lenalidomide to 80% in this treatment naïve patient population would justify evaluation of this 
regimen in larger, more definitive trials. We assume a one-sided type I error rate of 5% and 
desire at least 80% power to conclude that this regimen elicits and objective response rate 
significantly greater than  60% if the true response rate of this regimen is 60% or higher. Under 
these assumptions, if 11 or fewer OR’s are observed in the first 26 patients, the principal 
investigator may conclude that regimen is insufficiently active to warrant further study. 
Otherwise, accrual will continue to a total of 30 patients. If 15 or more OR’s are observed in 30 
patients, this regimen will be deemed sufficiently active to warrant further study. Given the 
relatively small sample size the additional study in patients receiving radiation therapy would 
be considered exploratory.  Any  documented response would be considered “significant” and 
warrant further study. 
 
Analysis Plan: 
Continuous variables (e.g., age, hematology values) will be summarized using the mean (s.d.) 
or median (range). Frequency tables will be used to summarize categorical variables. Logistic 
regression will be used to assess the impact of patient characteristics (e.g., low/high LDH) on 
the objective response rate. The distribution of time-to-event endpoints (e.g., CR duration, 
overall survival) will be estimated using the method of Kaplan and Meier. Comparison of time-
to-event endpoints by important subgroups of patients will be made using the logrank test. Cox 
(proportional hazards) regression will be used to evaluate multivariable predictive models of 
time-to-event outcomes. 

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11.4 
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 drugs and had this confirmed, 
will not be evaluated for safety. 
The severity of the toxicities will be graded according to the NCI CTCAE v4.0 whenever 
possible.  
11.5 
Sample Procurement for Immunologic Assessment 
If a patient has consented and agreed to allow their blood to be used for research studies, 7-10 
mL of whole blood in one purple top tube, 8mL in one BD vacutaner CPT cell preparation 
tube, and 7-10 mL in a serum separator tube will be acquired at the following timepoints: prior 
to treatment, and at day 15, 30, 60, and 120 and at the completion of treatment. Samples will be 
held on ice, centrifuged at 2500 RPM for 10 min, separated as soon as possible, and aliquoted 
into one (Preferably two) vials containing 0.1 – 0.5 mL serum each and two vials with the 
cellular contents. The cellular material obtained from the CPT tubes by removing the top layer 
(according to the manufacturers recommendations) and will be mixed with an equal part of 
freezing solution (30% DMSO + 70% fetal calf serum). The tubes will be labeled with a non-
patient identifying ID number with the date of collection, protocol number, and source and 
intended use of the material (i.e., plasma sample for cytokine assays). Sample volumes 
between 0.05 and 0.1 mL are acceptable, but the laboratory will not be able to repeat the 
analysis or further dilute the sample, if necessary. Samples will be frozen at -70°C batched and 
archived. Immune assessment will be done as described below. If there are any questions with 
sample procurement please page the study PI (Joseph Tuscano) 
 
 
11.6 CORRELATIVE STUDIES.  
 
In this Phase II clinical trial the immunological affects of the combination of Lenalidomide and 
Rituximab in patients with previously untreated indolent NHL will be explored.   
 
Rationale:  
This clinical study will be a unique opportunity to measure and characterize the baseline 
immune parameters and immune modulating effects of lenalidomide with or without rituximab 
in patients with previously untreated indolent NHL. This will allow for a better understanding 
of the mechanism of action, better prediction of who will respond to treatment, and allow for 
rational design of future clinical trials with these and/or other biologics. 
 
Objectives: 
Comprehensive assessment of immune parameters prior to therapy, after treatment with 
lenalidomide alone, and after treatment with the combination of lenalidomide and rituximab 
 
Assay timeline: 
Baseline, day + 15, +30, +60, and +120, completion of study, progression or withdrawal. 
Additional blood draws for immunologic profiling for patients taking part in the additional 
radiation therapy cohort will be done at day 15, 30 after starting radiation therapy and at the 

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time of progression. If the patient progresses within 8 weeks, the blood draw at progression 
will not be done. 
 
Given that the protocol requires 2 weeks of lenalidomide alone followed by rituximab, this will 
allow for assessment of immune parameters at baseline, after treatment with lenalidomide 
alone, and after combination therapy with lenalidomide and rituximab. Because there have 
been dramatic responses to lenalidomide alone in the first cohort of patients on the relapsed 
protocol immune profiling patients before and after rituximab is added is justified. 
 
Methods: 
 
Distribution, phenotype, and frequency of mononuclear cell subsets: To examine the 
overall pattern of mononuclear cell subsets, blood will be collected from patients (see Study 
Calendar) prior to, during and after therapy. After preparation via standard procedures, the 
cells will be analyzed using a multi-parameter, Hi-D FACS to determine the frequency and 
phenotype of mononuclear subsets including: helper T cells, cytotoxic T cells, regulatory T 
cells, naive T cells, memory T cells, NKT cells, NK cells, dendritic cell subsets and B-cell 
subsets, Table 1. 
 
Assay of T Cell Proliferation, Cytokine Production and Cytotoxic Lymphocyte (CTL) 
Activity: CD4 and CD8 T cells will be purified from blood using EasySep (Stem cell 
Technologies; Vancouver, BC, Canada). Cells (1x105/well in 200 µL culture media) will be 
cultured in quadruplicate 96-well U-bottom plates for each condition: culture medium alone or 
medium supplemented with CD3/CD28 mAb (0.5 µg/ml), or PHA (5 µg/ml). Cells will be 
incubated for 3-5 days at 37°C, 5% CO2. Sixteen hours before the end of the incubation, 1 µCi 
of [3H] thymidine will be added per well. Following harvest of cells, [3H] thymidine 
incorporation will be measured with a beta counter following dissolution in scintillation fluid.  
 
The culture supernatants will be collected prior to addition of [3H] thymidine and stored at -
70°C.  The supernatants will be assayed for several cytokines/chemokines (e.g. IL-2, IFN-γ, 
IL-17, IL-10, IL-4, TNF-α, TGF-β) using the Multiplex Bead-based Luminex® Technology, 
Cytokine Human 10-Plex Panel (or if batched with other samples, the Cytokine Human 25-
Plex Panel) (Invitrogen, Carlsbad, CA), see below.  
 
CTL activity will be assessed by using the ELISpot Assay Kit (R&D Systems, Minneapolis, 
MN) by measuring IFN-gamma producing CD8+T cells, per the manufacturer’s 
recommendations. 
    
 
 
 
 
 
 
 
 

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Table 1:  Phenotypic markers for analysis of various immune cells 
Cell subset 
 
Phenotype marker 
T cell 
CD4+ helper T cell 
CD3+CD4+ 
CD8+ cytotoxic T cell 
CD3+CD8+ 
Regulatory T cells 
CD3+CD4+ CD25+ Foxp3+  
Naïve T cell 
CD4+/CD8+ CD45RA+ CD11a+ 
Memory T cell 
CD4+/CD8+ CD45RO+ CD11a+ 
NK T cell 
CD3+ CD56+ CD16+ 
iNKT cell 
CD3+ CD56+ CD16+ 6B11+ CD1d+ 
NK cell 
 
CD3- CD56+ CD16+ 
B cell 
B2 cell 
CD19+ IgD+ CD11b- CD5- 
B1a cell 
CD19+ IgM+ CD11b+ CD5+  
B1b cell 
CD19+ IgM+ CD11b+ CD5- 
Dendritic cell 
 
 
 
Myeloid DC 
CD11c+ HLADR+ lymphomononuclear cell 
lineage negative  
Plasmacytoid DC (pDC) 
CD123+ BCDA2/BCDA4+ HLADR+ 
lymphomononuclear cell lineage negative 
  
T-reg Cells Function: CD4+CD25+ FoxP3+T cells will be isolated using magnetic separation 
with the MACS CD4+CD25+ isolation kit (Miltenyi Biotec, Auburn, CA) and then cultured 
with CD4+CD25- T cells in plates coated with anti-CD3/CD28 antibodies (5 µg/ml each) in the 
presence of Lenalidomide, or saline (control) for 3 days. The supernatant will be collected 
before the addition of [3H] thymidine for measurement IL-10, IL-4, TGF-β, IL-2, TNF-α, and 
IFN-γ by multi-parameter Hi-D FACS analyses or Multiplex Bead-based Luminex® 
Technology.  Proliferation will be measured after 72h in culture, with [3H] thymidine labeling 
for the last 16 hours. 
 
Multiplex Bead-based Luminex® Technology: The microbead multiplex detection system 
developed by Invitrogen) enables detection of numerous cytokines simultaneously in a single 
reaction container [39].  In this technology, molecular reactions take place on the surface of 
microscopic plastic beads (2 um).  For each reaction, capture molecules (i.e., mono-specific 
antibodies) are covalently attached to the surface of internally color-coded microbeads.  The 
assigned color-code identifies the reaction in a specific microbead population throughout the 
test.  Multiplex capability involves mixing several populations of microbeads, each with a 
specific capture molecule, into one reaction vessel at the start of the test.  The magnitude of the 
biomolecular reaction is measured using a reporter molecule which signals the extent of the 
reaction by attaching to the test molecules captured on the microbeads. To perform a test, the 
color-coded microbeads, reporter molecules, and sample (e.g., tumor cell lysate) are mixed and 
then injected into the Luminex flow cytometer where lasers illuminate the colors inside and on 
the surface of each microbead. This method is rapid, sensitive, and quantitative, and lends itself 
to high-throughput in an economical fashion [40].   
 
Serum Cytokines: The Luminex assay for immunologic analytes will include 37 different 
cytokines and growth factors (including IL-1, 2, 4, 5, 6, 7, 10,12, 17, TNF, INF-γ, TGF-beta, 
GM-CSF, PDGF, and VEGF) (Invitrogen). This test will allow for the ultrasensitive 

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determination of cytokines in the serum of patients before and during Lenalidomide alone and 
Lenalidomide in combination with Rituximab. 
 
B-cell Phenotype and Functional Analysis: The B-cell phenotype will also be assessed. 
Blood mononuclear cells will be prepared with EasySep and stained with antibodies (Zymed, 
San Francisco, CA) against each set of markers listed in Table 1. Clearly B-cells in these 
patients are going to be radically different at different stages of the protocol, because the 
patients will have been on rituximab, which depletes B-cells. This will give us an opportunity 
to assess Lenalidomide’s function before and after rituximab in the same patients. The 
phenotype of B-cell subsets (Table 1) will be analyzed by FACS.  
A B cell functional assay will be performed by measuring IgM production using B cells 
isolated from blood. CD19+ B cells will be isolated by positive selection using magnetic beads 
(2).  B cell subsets will be sorted by FACS.  B cell will be stimulated by LPS or CpG for 3 
days, then IgM production will be measured by ELISA [41].  
 
Immunoglobulin Levels: Serum samples will be obtained at various time points to assess for 
the serum levels of IgM, IgA, and IgG. Immunoglobulin levels will be measured by the clinical 
lab at UCDMC using standard techniques. 
 
NK, NKT and iNKT cell phenotype and functional assay: Human iNKT cells will be 
identified using CD1d tetramer and a novel monoclonal antibody (clone 6B11) specific for the 
CDR3 loop of the human Vα24Jα18 TCR alpha chain which specifically identify iNKT cells. 
Other antibodies comprise CD3-APC, CD4-PerCP and CD8α-FITC (BD Biosciences, San 
Jose, CA). For surface staining, cells will be washed with staining buffer (PBS with 2% FCS), 
and incubated for 30 minutes, on ice in the dark with the relevant antibody combinations. Cells 
will then be washed twice with staining buffer and analyzed by flow cytometry (BD Coulter). 
Data will be collected using a FACS ARIA (BD Biosciences) and analyzed by "Flowjo" flow 
cytometry data analysis software (Tree Star Inc, Ashland, OR). 
 
NK (CD3-CD56+CD16+), NKT (CD3+CD56+CD16+) and iNKT cells will be sorted from 
blood. The sorted NK/NKT cells will be stimulated with poly IC for 12 and 24 h. iNKT cells 
will be stimulated with iNKT cell-specific ligand, α-GalCer. Supernatants will be collected to 
analyze the levels of IFN-gamma, IL-6 and IL-8 using the BD cytometric bead array kit per the 
manufacturer’s recommendations. IFN-gamma and IL-4 will be measured by CBA kit or 
intracellular staining. Sera cytokine will be measured by CBA kit.  
 
NK Cell Killing Activity:  NK cells bind to, and kill K562 cells (a human myelogenous cell 
line, ATCC) thus forming the basis of this functional killing assay [42]; this flow cytometric 
assay can detect binding and killing. K562 cells will be grown in RPMI 1640 with 10% fetal 
calf serum and checked for viability by trypan blue exclusion before use. Sorted NK cells that 
are obtained before and after treatment initiation will be combined with K562 cells at an 
effector-target-cell ratio of 20:1. Incubation will proceed for up to 3 hours at 37oC in 5% CO2. 
NK cells will be tested for their killing activity with or without stimulation by IL-2 (1 ng/ml of 
human rIL-2; Genzyme, Cambridge MA). Spontaneous lysis will be tested at each time point 
using equivalently cultured K562 cells in the absence of effectors. If we encounter any 
problems with this assay, a standard 51Cr-release assay will be done, testing groups equivalent 

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to those described above. NK cells will also be assessed for Rituximab-mediated ADCC by 
using the human NHL cell line Raji (ATCC) as the target cell. The assay will be done as 
described above with and without 50ug/ml of Rituximab added. 
 
Response of PBMC to Stimulation with Tetanus Toxoid and Tetanus Specific Antibody 
Production: The response to tetanus toxoid or PPD will be used to assess the immune response 
of patients on the study. As in the general population, the patients in this study will have been 
vaccinated against tetanus at some point in their lives. The response to tetanus toxoid does vary 
between people with a number of factors such as age, steroid use and other random factors [43, 
44], however that is not a problem in this study since pre-study values will act as an internal 
control. As similar to the other assays assessment will be at baseline and after the first and 
fourth cycle.  
 
Cellular Proliferation Response to Tetanus Toxoid: The in vitro cellular proliferative 
response will be measured as previously described [43, 44]. Using standard isolation 
techniques, PBMC (1x 105) in 100 µL RPMI 1640 (10% human AB+ sera)  will be cultured in 
96-well round bottom microtiter plates, in triplicate with either tetanus toxoid (10 µg/ml, 
Massachusetts Public Health Biological Laboratories; Cambridge, MA) or PPD (10 µg/ml 
Statens Serum Institute). Phytohemagglutinin (PHA) will be the positive control, and 
unstimulated cells will be the negative control.  Cultures will proceed for 5 days at 37oC and 
5% CO2, then pulsed with 1 µCi/well of 3H-thymidine for 18 hours. Cells will then be 
harvested; tritiated thymidine uptake determined and reported as the proliferation index. 
 
Antibody Response to Tetanus Toxoid: Tetanus toxoid-specific antibodies will be 
determined using ELISA as previously described [44]. PBMC from patients will be cultured 
with tetanus toxoid for 7 days as described above, and then the supernatant from the wells will 
be harvested.  Microtiter plates (96-well) will be coated with tetanus toxoid (2 µg/ml) 
overnight at 4oC, then washed and blocked with 1% human serum albumin in 0.05 M carbonate 
buffer. Then serum samples obtained from patients (100 µl) will be added to the wells and 
incubated for 120 minutes, then washed. Biotinylated goat anti-human IgG or IgM (Zymed) 
will be diluted and added to the wells. Subsequently, streptavidin-conjugated alkaline 
phosphatase (Zymed) will be added along with the color substrate (Bio-Rad, Hercules, CA). 
Optical density will be read at 405 nm in an automatic plate reader.  
 
Monocyte Activation: Monocytes play a critical role in immunity, antigen presentation and 
regulation. CD80 (B7.1), HLA-DR and TNF-α secretion are markers of monocyte activation. 
Their activation status will be tested. Monocytes will be obtained and cultured as described 
previously [45], with or without LPS (1 µg/ml E. coli 055:B5, Sigma, St. Louis, Mo). Cells 
will be incubated with fluorescein isothiocyanate-conjugated anti-CD80 or anti-HLA-DR 
(Pharmingen, San Diego, CA) and subjected to FACS for analysis. The secretion of TNF-α 
will be done by using with the Multiplex Bead-based Luminex system, see above. Samples for 
TNF-α may be frozen and stored for batch analysis. 
 
RNA sequence analysis: When available, protocol required biopsy material (formalin fixed 
paraffin embedded or fresh frozen) either at the time of diagnosis, study enrollment, or at 
relapse will be labeled with a non-patient indemnifying ID number with the date of collection, 

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review.  Written verification of IRB/EC approval will be obtained before any amendment is 
implemented.  The Investigator is also responsible for notifying the IRB/EC of any serious 
deviations from the protocol, or anything else that may involve added risk to subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved by 
the IRB/EC prior to use. 
 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and 
functions. 
 
The Investigator should maintain a list of Sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study-related duties. 
 
12.2 
Informed consent 
The Investigator must obtain informed consent of a subject or his/her designee prior to any 
study related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study and 
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. 
12.3 
Subject confidentiality 
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. 
12.4 
Study records requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the study drug, that is copies of CRFs and source documents 
(original documents, data, and records [e.g., hospital records; clinical and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; pharmacy dispensing 
records; recorded data from automated instruments; copies or transcriptions certified after 
verification as being accurate copies; 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 study; documents regarding subject 
treatment and study drug accountability; original signed informed consents, etc.]) be retained 
by the Investigator for as long as needed to comply with national and international regulations 
(generally 2 years after discontinuing clinical development or after the last marketing 

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 RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE 
14
 
14.1 
Confidentiality of Records 
 
The original data collection forms will be stored at the originating institution.  The forms will 
be stored in a secure location. 
 
14.2 
Patient Consent Form  
 
An original signed and dated participant Informed Consent document will reside in a secured 
location within the UCD CTSU or participating site. Copies of the signed and dated Informed 
Consent document will be provided to the study participant and UCD Health System 
Information Management for inclusion in the participant’s UCD Health System Medical 
Record or per participating site’s institutional policies.  
 
 
14.3 
Quality Assurance and Control 
 
Quality assurance audits of select patients and source documents may be conducted by the UC 
Davis Cancer Center Quality Assurance Committee as outlined in the UC Davis Cancer Center 
Data and Safety Monitoring plan. 
 
Quality control will be maintained by the CTSU Quality Assurance team according to CTSU 
policy. 
 
Quality assurance audits may be accomplished in one of two ways: (1) source documents and 
research records for selected patients are mailed/sent by from participating sites to the 
Coordinating Center for audit, or (2) selected patient records may be audited on-site at 
participating sites. If the sponsor/PI chooses to have an audit at the Coordinating Center, then 
the Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, Drug Accountability Record forms, patient registration lists, 
response assessment scans, x-rays, etc. available for the audit.  
 MINORITIES AND GENDER STATEMENT 
15
 
Recruitment is open to all minorities and both genders.  Although distributions may vary by 
disease type, our recruitment procedures have been developed to enroll patients who are 
representative of the respective target population.    
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16
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Appendix I Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods  
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has 
the effect of the lenalidomide on human eggs and sperm.  Lenalidomide is structurally related 
to thalidomide.  Thalidomide is a known human teratogenic 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™. Females of 
reproductive potential must adhere to the scheduled pregnancy testing as required in the 
Revlimid REMS® program. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female who: 1) 
has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing 
potential) 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 or pregnant 
female, 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 or 
pregnant female.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods related to this study: 1) for at least 

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28 days before starting lenalidomide; 2) throughout the entire duration of lenalidomide 
treatment; 3) during dose interruptions; and 4) for at least 28 days after lenalidomide 
discontinuation.  
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception:   
o Highly effective methods: 
 Intrauterine device (IUD) 
 Hormonal (birth control pills, injections, implants) 
 Tubal ligation 
 Partner’s vasectomy 
o Additional effective methods: 
 Male condom 
 Diaphragm 
 Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple myeloma 
taking lenalidomide and dexamethasone, combined oral contraceptive pills are not 
recommended.  If a patient is currently 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 lenalidomide 
Female Patients: 

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FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
prescribing lenalidomide.  The first pregnancy test must be performed within 10-14 days prior 
to prescribing lenalidomide and the second pregnancy test must be performed within 24 hours 
prior to prescribing lenalidomide.  The patient may not receive lenalidomide until the 
Investigator has verified that the results of these pregnancy tests are negative. 
Male Patients: 
Must agree to practice complete abstinence or agree to use a condom during sexual contact 
with pregnant females or females of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 28 days following 
lenalidomide discontinuation, even if he has undergone a successful vasectomy.   
During study participation and for 28 days following lenalidomide discontinuation  
Female Patients: 
• FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly 
for the first 28 days of lenalidomide treatment, including dose interruptions, and then 
every 28 days throughout the remaining duration of lenalidomide treatment, including 
dose interruptions, at lenalidomide discontinuation, and at Day 28 following 
lenalidomide discontinuation.  If menstrual cycles are irregular, the pregnancy testing 
must occur weekly for the first 28 days of lenalidomide treatment, including dose 
interruptions, and then every 14 days throughout the remaining duration of 
lenalidomide treatment, including dose interruptions, at lenalidomide discontinuation, 
and at Day 14 and Day 28 following lenalidomide discontinuation.   
• At each visit, the Investigator must confirm with the FCBP that she is continuing to use 
two reliable methods of birth control at each visit during the time that birth control is 
required.   
• If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide 
must be immediately discontinued. 
• Pregnancy testing and counseling must be performed if a patient misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment 
must be temporarily discontinued during this evaluation. 
• Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after lenalidomide discontinuation. 
Male Patients: 
• Must practice complete abstinence or use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire duration of 

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lenalidomide treatment, during dose interruptions and for at least 28 days following 
lenalidomide discontinuation, even if he has undergone a successful vasectomy.   
• If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 
• Male patients should not donate blood, semen or sperm during therapy or for at least 28 
days following discontinuation of lenalidomide. 
 
Additional precautions 
• Patients should be instructed never to give lenalidomide to another person. 
• Patients should not donate blood during therapy and for at least 28 days following 
discontinuation of lenalidomide. 
• Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle 
of therapy.  
• Any unused lenalidomide must be returned as instructed through Revlimid REMS™ 
program. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix II  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 III  
 
Cockcroft-Gault estimation of CrCl: 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl):  
(Cockcroft, 1976; Luke 1990) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)__           
   (Males) 
 
72 x (serum creatinine, mg/dL) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)_    x 0.85         
   (Females) 
 
72 x (serum creatinine, mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix IV 
NCI CTC Version 4.0 
 
TOXICITY WILL BE SCORED USING NCI  CTCAE VERSION 4.0 FOR TOXICITY 
AND ADVERSE EVENT REPORTING.  A COPY OF THE NCI CTC VERSION 4.0 
CAN BE DOWNLOADED FROM THE CTEP HOMEPAGE: 
(HTTP://CTEP.INFO.NIH.GOV OR HTTP://EVS.NCI.NIH.GOV/FTP1/CTCAE/ABOUT.HTML).  
ALL APPROPRIATE TREATMENT AREAS HAVE ACCESS TO A COPY OF THE 
CTCAE VERSION 4.0 
 

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Appendix V  
Rituxan® (Rituximab) Package Insert 
This can be obtained at: 
http://www.gene.com/gene/products/information/pdf/rituxan-prescribing.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix VI 
Revlimid® (Lenalidomide) Package Insert 
This can be obtained at: 
http://www.revlimid.com/pdf/REVLIMID_PI.pdf 
 
 
 
 
 

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Appendix VIII 
 
Data Collection Forms and Submission Schedule 
 
All data will be collected using the UCD Database System (eVELOS) forms.  All data forms 
will be completed, submitted and processed in accordance with UCD CTSU policies.  Any and 
all source documentation should be maintained. 
 
 
 SUBMIT WITHIN 24 HOURS OF REGISTRATION:  
Patient Registration Form  
 
 SUBMIT WITHIN 14 DAYS OF REGISTRATION:  
In‐House Pre‐Study Evaluation Form (IH‐102)  
 
 SUBMIT WITHIN 7 DAYS OF SCREENING FAILURE:  
Patient Screen Failure Form  
 
 SUBMIT WITH 14 DAYS OF CYCLE COMPLETION:  
Adverse Event/Drug Relationship Form  
 
 
 SUBMIT WITHIN 14 DAYS OF END OF EACH TREATMENT CYCLE:  
In‐House Treatment Cycle Form (IH‐201)  
 
 SUBMIT WITHIN 14 DAYS OF EACH RESPONSE ASSESSMENT:  
Tumor Measurement Log  
 
 SUBMIT WITHIN 14 DAYS OF OFF TREATMENT:  
Off Treatment/In Follow-up/Off Study/Expiration Form (IH‐301)  
 
 SUBMIT WITHIN 14 DAYS OF KNOWLEDGE OF DEATH IF PATIENT IS STILL 
ON STUDY OR 30–DAYS IF OFF STUDY:  
Off Treatment/In Follow-up/Off Study/Expiration Form (IH‐301)  
 
 SUBMIT WITHIN 2 DAYS OF KNOWLEDGE OF PROTOCOL DEVIATION:  
Clinical Trials Support Unit: Notice of Protocol Deviation  
 
 SUBMIT WITHIN 14 DAYS OF EACH REQUIRED FOLLOW‐UP ENCOUNTER:  
Follow‐Up Form (IH‐302)  
 
 ALL SERIOUS ADVERSE EVENTS MUST BE REPORTED AS OUTLINED IN 
THE PROTOCOL.  
 
 

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Appendix IX    
Correlative Studies (Instructions for Sutter Pacific Medical Foundation):   
 
1. Three tubes of EDTA blood (10-ml each) and One serum tube, collected at the time-
points per protocol. 
2. Ship to UC Davis overnight, in ambient shipper with cool packs inside (not frozen 
packs)