Clinical trial NCT01178814
Conditions: Myelodysplastic Syndrome
Sponsor: Columbia University
Start date: 2009-06-01; Completion date: 2022-12-07
Enrollment: 57 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective trial of Revlimid for subjects who have a blood cell cancer called myelodysplastic syndrome (MDS). Cells in their marrow make proteins through messages that are carried from the genes. The amount of the message tells researchers if the protein it is going to make is high or low. This is known as expression of genes. The purpose of this study is to conduct a prospective trial testing the idea that expression of specific genes can help to predict which patients will respond to study drug administration with Revlimid (lenalidomide).

Detailed description:
The first Revlimid® study reported by List et al included all transfusion dependent MDS patients, but given the early experience which showed a better response in del(5q) patients and those with lower risk disease, more patients belonging to this category were entered on the trial. The subsequent multi-center studies were focused entirely on the low/Int-1 patients who were transfusion dependent. In the present study, we would like to recapitulate the initial study by only treating the transfusion dependent, low and intermediate-1 risk MDS patients without deletion (5q). Since the predictive assay is most applicable for the non-del(5q) patients, and to avoid confusion resulting from an admixture of patients with del(5q) for whom the drug is already FDA approved, we have elected to restrict this clinical trial to only the non-del(5q) patients.

In the present study, only the non-del(5q) transfusion dependent, low and intermediate-1 risk MDS patients will be treated with single agent Revlimid®. All patients will have their pre-therapy bone marrows studied by gene expression microarray, Luminex bead assay, and real-time PCR.

Arms: arm 1: Revlimid (Lenalidomide) capsule taken orally once a day
Interventions: intervention 1: Revlimid (Lenalidomide)
Intervention descriptions: intervention 1: The starting dose will be 10 mg days 1-28 with the first dose reduction going to 5 mg days 1-28 of a 28 day cycle. Therapy will cease if there is no response after 12 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
Version Date:  29 Oct 2013 
NCT01178814 
 
Protocol Title: 
A prospective trial of Revlimid® in transfusion dependent patients with non-
del(5q) low/Intermediate-1 risk Myelodysplastic Syndrome  
 
 
  
 
Celgene Tracking #: 
 
RV-MDS-PI-388 
 
DATE FINAL: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4:  
 
10-October-2008 
29-April-2009 
13-November-2009 
8-May-2010 
26-October-2010 
Amendment 5: 
Amendment 6: 
23-April-2013 
29-October-2013 
  
 
 
 
 
 
 
 
 
CONFIDENTIAL 


 
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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. 
 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Principal Investigator: 
 
Mark Heaney, M.D., Ph.D. 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
Printed Name of Investigator 
 
 
 
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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STUDY PERSONNEL 
 
Supporter: 
Celgene Corporation 
86 Morris Ave. 
Summit, NJ  07901 
1-800-742-3107 
 
Study Location: 
Columbia University Medical Center 
 
New York, NY  10011 
 
Principal Investigator: 
Mark Heaney, M.D., Ph.D. 
Columbia University Medical Center 
mlh2192@columbia.edu   
Scientific Principal Investigator: 
Naomi Galili, Ph.D. 
Columbia University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table of Contents 
Protocol Synopsis………………………………………………………………..   5 
 
 
Schedule of Study Assessments……………………………………………….   7 
Schema……………………………………………………………………………   9 
Background and Rational……………………………………………………….   9 
Study Objectives and End Points……………………………………………… 17 
Investigational Plan……………………………………………………………… 18 
Adverse Events………………………………………………………………….. 32 
 
Response Criteria……………………………………………………………….. 37 
Protocol Amendments and Deviations………………………………………… 39 
Data Management………………………………………………………………. 39 
Biostatistical Analysis…………………………………………………………… 41 
Regulatory Considerations……………………………………………………… 43 
References……………………………………………………………………….. 46 
Appendices 
I 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and  
Acceptable Birth Control Methods……………………………… 50 
II   
ECOG Performance Status Scale….………………………….. 52 
III   
NCI CTC Version 3.0……………………………………………. 53 


 
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1  Protocol Synopsis 
PROTOCOL TITLE: A prospective trial of Revlimid® in transfusion dependent 
patients with non-del(5q) low/Intermediate-1 risk Myelodysplastic Syndrome  
DATE PROTOCOL FINAL: 
26-OCT-2010 
INDICATION: 
MDS 
STUDY PHASE: 
 
BACKGROUND AND RATIONALE:  The myelodysplastic syndromes (MDS) are 
clonal hematopoietic disorders characterized by the presence of variable 
cytopenias in the presence of a hypercellular bone marrow (BM) (1).  These 
disorders are comprised of several distinct syndromes (2), with varying incidence 
of transformation to acute myeloid leukemia (AML). No etiologic agent has been 
identified so far, and the disease appears to predominate in the elderly.  Most of 
the clinical problems in the low risk group of patients are related to the 
consequences of cytopenias, while transformation to acute leukemia is the most 
serious threat in higher risk patients.  A number of therapeutic strategies have 
been tried with limited and essentially palliative success. Treatment options 
range from supportive care to stem cell transplantation (SCT), with supportive 
care being the most commonly used therapy at this time (3-6).  SCT is the only 
potentially curative therapy for this disease; unfortunately it is an option for <5% 
patients due to the advanced age of the majority of cases.   
STUDY OBJECTIVES:   
 
Primary: 
To conduct a prospective trial testing the Revlimid® (lenalidomide) response 
signature in patients who have transfusion dependent, non-del(5q), low and 
intermediate-1 risk Myelodysplastic syndromes (MDS) in order to confirm the 
predictive value of the signature and to establish the boundaries of the z-score 
which can be used to pre-select patients in future clinical studies. 
 
Secondary:   
 The primary clinical efficacy parameter will be transfusion independence 
 The secondary efficacy parameters will be the remaining criteria as defined 
by the IWG 
 
Time to disease progression 
 
Overall and progression-free survival 


 
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STUDY DESIGN: 
In the present study, only the non-del(5q) transfusion dependent, low and intermediate-1 
risk MDS patients will be treated with single agent Revlimid®. All patients will have their 
pre-therapy bone marrows studied by gene expression microarray, Luminex bead 
assay, and real-time PCR. 
 
STUDY ENDPOINTS 
Primary: 
 
To conduct a prospective trial testing the Revlimid® (lenalidomide) response 
signature in patients who have transfusion dependent, non-del(5q), low and 
intermediate-1 risk myelodysplastic syndromes (MDS) in order to confirm the 
predictive value of the signature and to establish the boundaries of the z-score which 
can be used to pre-select patients in future clinical studies. 
 
Assessment 
of 
pre-therapy 
expression 
profile 
associated 
with 
Revlimid® 
responsiveness 
 
 
Secondary: 
 
Response will be evaluated every 4 weeks during the first 12 weeks of therapy for 
each of the 56 transfusion-dependent, non-del(5q) low/Int-1 risk MDS patients. 
Treatment will be stopped and the patient will be taken off the protocol in case of no 
response or stable disease by 12 weeks. International Working Group (IWG 2006) 
criteria will be used for response evaluation. The proportion of TI will be calculated 
and an exact 95% confidence interval of TI proportion will be estimated.  
 
The percent of major and minor responses in erythroid, platelets, neutrophils  will 
also be calculated as the secondary endpoints.  
 
STUDY DURATION: 12 weeks.  Patients 
responding to treatment will continue on 
Revlimid® 
until 
disease 
progression 
or 
unmanageable toxicities. 
TOTAL SAMPLE SIZE: 56 
DOSING REGIMEN(S): The starting dose of 
REVLIMID® will be 10 mg days 1-28 with the 
first dose reduction going to 5 mg days 1-28 of 
a 28 day cycle. Therapy will cease if there is no 
response after 12 weeks 
 
STUDY DRUG SUPPLIES: 
For study participants, Celgene Corporation will 
provide lenalidomide at no charge through the 
RevAssist® program.   
 


 
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2 Schedule of Study Assessments*  
 
 
Procedure 
Screening 
 28days from 
Baseline (First 
day study drug 
administration) 
Cycle 1  
 
Cycle 
2  
 
Cycle 
39 
 
Cycle 4 
and 
higher12 
Disco
ntinua
tion 
From 
Study 
Drug 
30 Days 
(+/- 7 
days) 
following 
last dose 
of study 
drug6 
Follow-
Up Phase 
Day  
114 
 
Day  
814 
Day  
1514 
Day  
2214 
Day  
115 
Day  
115 
Day  
1 
Every 3 
months 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Reconfirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
Medical history  
(including signs/symptoms/diagnoses) 
X 
 
 
 
 
 
 
 
 
 
 
Record prior medications, treatments 
X 
 
 
 
 
 
 
 
 
 
 
Record prior anti-cancer therapies 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs, weight 
X 
 
 
 
 
X 
X 
X11,  
X 
X 
 
Transfusion  History 
X 
X7 
 
 
 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
 
 
 
 
X 
X 
X11 
X 
X 
 
Bone marrow biopsy and aspirate1  
X1 
 
 
 
 
 
 
 
X10 
 
 
ECG 
X 
 
 
 
 
 
 
 
X 
 
 
Hematology2 
X 
X 
X 
X 
X 
X2 
X2 
X2 
X2 
X2 
 
Serum chemistry3   
X 
X 
 
X 
 
X3 
X3 
X13 
X3 
X3 
 
MDS-specific tests (Serum B12,  erythropoietin) 
X 
 
 
 
 
 
 
 
 
 
 
TSH3 
X 
 
 
 
 
 
 
X3 
X3 
 
 
Pregnancy testing4 
X5 
X 
X 
X 
X 
X5 
X5 
X5 
X5 
X5 
 
Register patient into RevAssist® program 
X 
 
 
 
 
 
 
 
 
 
 
Prescribe lenalidomide via RevAssist® 8 
 
X8 
 
 
 
 
X8 
X8 
X8 
 
 
Record adverse events 
X 
X7 
X 
 
X 
X 
X 
X11 
X 
X 
 
Record concomitant therapies/procedures 
 
X7 
X 
 
X 
X 
X 
X11 
X 
X 
 
Obtain Follow-Up anti-cancer treatments 
 
 
 
 
 
 
 
 
 
 
X 
Obtain Follow-Up survival information 
 
 
 
 
 
 
 
 
 
 
X 
 
*Variations of ± 3 days of the scheduled visit are permitted during Cycles 1 to 3, and ± 7 days of scheduled visits are permitted thereafter.   
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.   
 
1Include testing for expression assays. Within 6 weeks of starting therapy.  
2Hgb, Hct, RBC indices: RBC count, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, WBC w/diff, platelet count, at screening and then 
weekly during Cycles 1 to 3, and then monthly (i.e., at Day 1 of each cycle) thereafter. 


 
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3 To include creatinine, BUN, total bilirubin, alkaline phosphatase, ALT, AST, LDH, total protein at screening, on Days 1 and 15 during Cycle 1 and on Day 1 of  Cycles 2 
and 3, and then every other cycle on Day 1(Cycles 4, 6, 8, 10, etc.), study drug discontinuation visit, and 30 days post-study drug discontinuation visit.  Thyroid Stimulating 
Hormone (TSH) at screening, Cycle 4, and then every 16 weeks (Cycle 8, 12, 16, etc.), and at treatment discontinuation.  T3 and T4 levels may be assessed as clinically 
indicated.  
4Pregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive 
months). 
5Pregnancy tests must occur within 10-14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled within 7 days).  FCBP with regular or 
no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on therapy (including breaks in therapy); at discontinuation of 
lenalidomide and at Day 28 post the last dose of lenalidomide.  Females with irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 
14 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix I: 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).    
6This safety assessment will be done 30 days (+/- 7 days) following the last dose of study drug. 
7If screening assessments were done within 7 days of Day 1, they do not need to be repeated at Study Day 1. 
8Lenalidomide must be prescribed through and in compliance with Celgene’s RevAssist® program.  Prescriptions must be filled within 7 days.  Any unused Revlimid® 
(lenalidomide) should be returned to the patient for disposition in accordance with the RevAssist® program. 
9Subject will follow this schedule if determined to have a response after the first 12 weeks of treatment for subsequent visits. 
10To document complete response, as needed. 
11Performed every other cycle starting at Cycle 4 (i.e., Cycles 4, 6, 8, 10, etc.) 
12After cycle 4, subjects may have Day 1 evaluations of odd number cycles performed by their local oncologist. Day 1 of even numbered cycles must be performed at 
Columbia University Medical Center.   
13After cycle 4, perform only as clinically indicated 
14 Subjects who do not reside locally, may have this visit performed by their local oncologist 
15Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1 visits must be performed at Columbia University Medical Center.  Other visits during Cycles 2 and 3 may be performed 
by subject’s local oncologist. 
 
 
 


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3 Schema: 
 
All transfusion dependent non-del(5q) low/Int-1 risk MDS patients  
 
 
 
 Perform gene expression studies on pre-treatment bone marrow aspirate specimens  
 
 
 
Start Revlimid® therapy in cycles of 10mg po day 1-28 
 
 
Evaluate for response every 4 weeks X 12 weeks. Clinical decision made at week 12. 
 
 
 
 
      Response     
 
     Stable Disease      
 
Progressive Disease 
 
 
 
Continue Revlimid®                
 Off Study                 
 Off Study     
 
All responders should continue therapy until disease progression 
4 Background and Rationale 
4.1  
The myelodysplastic syndromes (MDS) are clonal hematopoietic disorders 
characterized by the presence of variable cytopenias in the presence of a 
hypercellular bone marrow (BM) (1).  These disorders are comprised of several 
distinct syndromes (2), with varying incidence of transformation to acute myeloid 
leukemia (AML). No etiologic agent has been identified so far, and the disease 
appears to predominate in the elderly.  Most of the clinical problems in the low 
risk group of patients are related to the consequences of cytopenias, while 
transformation to acute leukemia is the most serious threat in higher risk patients.  
A number of therapeutic strategies have been tried with limited and essentially 
palliative success. Treatment options range from supportive care to stem cell 
transplantation (SCT), with supportive care being the most commonly used 
therapy at this time (3-6).  SCT is the only potentially curative therapy for this 


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disease; unfortunately it is an option for <5% patients due to the advanced age of 
the majority of cases.   
4.2 
Recent biological insights show that cytopenias in MDS are most probably the 
result of excessive apoptosis of hematopoietic cells in the BM (7-10).  This 
apoptosis appears to be both cytokine mediated as well as the result of an 
increased propensity of CD34+ BM stem cells to undergo premature 
programmed cell death (11).  Biochemical pathways of apoptosis appear to 
involve both Fas/FasL and caspases (12-14). Our group was the first to 
demonstrate that an excessive apoptosis of hematopoietic cells in the bone 
marrow accounts for the quintessential variable cytopenias in MDS and that a 
suppression of apoptosis by anti-cytokine therapies can produce clinical 
improvement (15-18).  We also showed that there are at least three major 
biochemical pathways leading to this excessive cell death.  First, there appears 
to be a sequential activation of caspases 1 and 3 (19).  Second, there is 
upregulation of the Fas/FasL system (20).  Finally, there is an attenuation of Fap-
1 pathway, which is normally responsible for initiating an anti-apoptosis effect 
(21).  In addition to the increase in apoptosis of maturing hematopoietic cells, we 
have also demonstrated the propensity of early CD34+ progenitor cells to die 
prematurely (22).  
4.3 
The bone marrows of MDS patients also demonstrate markedly increased neo-
angiogenesis and higher than normal levels of vascular endothelial growth factor 
(VEGF) (19). In MDS/AML myeloblasts and myelo-monocytic cells, production of 
VEGF along with co-expression of one or more cognate receptor tyrosine 
kinases has been demonstrated (23). In addition, increased microvessel density 
correlates with blast percentage. VEGF activity through promotion of adhesion 
via beta-1 and beta-2 integrins could actually explain the central clustering of 
ALIPs (abnormally localized immature precursors) in more advanced cases of 
MDS (24). Matrix metalloproteinases (MMP) produced by the malignant clone as 
well as the stroma appear to liberate membrane bound TNF and fas ligand which 
have been associated with the excessive intramedullary apoptosis of 
hematopoietic cells (25).  In other words, both autocrine and paracrine 
angiogenic molecules potentiate self-renewal and promote neo-vascularity, 
inflammatory cytokine generation and ineffective hematopoiesis. Agents which 
antagonize the elaboration of angiogenic molecules thus potentially have 
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4.4 
Finally, a more intrinsic immune defect may also exist in some MDS patients and 
suppression of T-cell function by using anti-thymocyte globulin (ATG) and 
cyclosporin is associated with improvement in the cytopenias (26, 27). 
Thalidomide was considered a potentially useful drug for MDS patients. It is both 
an immune-modulatory agent with anti-cytokine activities (28-32), and anti-
angiogenic effects (33-35). Based on this rationale, a pilot study was conducted 
to test the efficacy of thalidomide in improving the ineffective hematopoiesis seen 
in patients with myelodysplastic syndromes. Thalidomide was administered to 83 
patients with myelodysplastic syndrome (MDS) starting at 100mg po daily and 
increasing to 400mg as tolerated.  Thirty-two patients stopped therapy before 12 
weeks (minimum period for response evaluation), and 51 have completed 12 
weeks of therapy. International Working Group (IWG) response criteria for MDS 
were used to evaluate responses. Intent-to-treat (ITT) analysis classified all off 
study patients as non-responders. Off-study patients belonged to a higher risk 
category (p=0.002) and had a higher percentage of blasts in their pre-therapy 
bone marrows (BM) than patients who completed 12 weeks of therapy (p=0.003). 
No cytogenetic or complete responses were seen, but 16 showed hematologic 
improvement, 
ten 
previously 
transfusion 
dependent 
patients 
becoming 
transfusion independent. Responders had lower pre-therapy blasts (p=0.016), 
lower duration of pre-therapy platelet transfusions (p=0.013) and higher pre-
therapy platelets (p=0.003). Among responders, 9 had refractory anemia (RA), 5 
had RA with ringed sideroblasts, and 2 had RA with excess blasts. By ITT 
analysis, 19% patients responded (16/83), and by analyzing only evaluable 
patients, 31% (16/51) responded.  We concluded from this pilot study that 
thalidomide, as a single agent, is effective in improving cytopenias of some MDS 
patients, especially those who present without excess blasts 
4.5 
Celgene has now synthesized several analogs of thalidomide that appear to be 
more potent and less toxic than the parent drug. Two of these (Revlimid® and 
CC-1088) have been undergoing clinical trials in hematologic malignancies, and 
the background for one of these (Revlimid®) will now be provided in detail. During 
the development of thalidomide analogs such as Revlimid®, chemical 
modifications of the thalidomide template were made in an effort to specifically 
optimize the anti-TNF- activity.  Two discrete sub-structures of the thalidomide 
molecule were altered, namely the phthaloyl and glutarimide portions of the 
molecule.  Both families of compounds were tested for TNF- inhibition and 
further structural modifications were made to optimize this activity. The primary 
hydrolysis products of thalidomide were also used as subsidiary templates even 


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though they showed poor potency as TNF- modulators in their unmodified form.  
This strategy led to the development of two primary families of compounds 
showing enhanced TNF- inhibition properties: substituted phthaloyl analogs with 
intact glutarimide functionality and molecules which retain the basic phthaloyl 
moiety, but have substituted -amino acid functionality in place of the glutarimide 
ring of thalidomide, such as Revlimid®.  The finding that these varied structural 
modifications could yield the same enhanced potency in TNF- inhibition 
suggests the presence of two different pharmacophores that most likely have 
different pharmacological targets, but are both capable of TNF- downregulation.  
Revlimid® is a thalidomide analog.  In vitro studies have shown that REVLIMID® 
is more potent than thalidomide in inhibiting TNF- production and multiple 
myeloma cell proliferation.  Furthermore, in preliminary non-clinical and clinical 
studies conducted to-date, Revlimid® appears to lack the sedative and 
teratogenic activity of thalidomide.  
The structures of Revlimid® and thalidomide are illustrated below. 
 
 
 
           REVLIMID®                      Thalidomide 
 
 
N
N
H
O
O
O
NH2
    
N
O
O
H
N
O
O
 
 
 
 
MW=259.26 
 
 
 
MW=258.2 
 
4.6 
 Lenalidomide is a proprietary IMiD™ compound of Celgene Corporation.   
IMiD™ compounds 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).  In addition, lenalidomide 
has a variety of immunomodulatory effects.  Lenalidomide stimulates T cell 
proliferation, and the production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta 
and IL-6 and modulates IL-12 production.(37)  Upregulation of T cell derived IL-2 
production is achieved at least in part through increased AP-1 activity. (38) 
  


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Although the exact antitumor mechanism of action of lenalidomide is unknown, a 
number of mechanisms are postulated to be responsible for lenalidomide’s 
activity against multiple myeloma.  Lenalidomide has been shown to increase T 
cell proliferation, which leads to an increase in IL-2 and IFN-gamma secretion.  
The increased level of these circulating cytokines augment natural killer cell 
number and function, and enhance natural killer cell activity to yield an increase 
in multiple myeloma cell lysis (39).  In addition, lenalidomide has direct activity 
against multiple myeloma and induces apoptosis or G1growth arrest in multiple 
myeloma cell lines and in multiple myeloma cells of patients resistant to 
melphalan, doxorubicin and dexamethasone (40).   
 
4.7 
Clinical experience in myelodysplastic syndromes (MDS) with lenalidomide 
Phase I/II study of REVLIMID® in transfusion dependent MDS patients: At 
the University of Arizona Cancer Center, a pilot study was conducted in 
transfusion dependent MDS patients by List et al (41) to show that the most 
tolerable dose/schedule was 10mg po q day X 3 weeks on and 1 week off in 
repeated cycles (syncopated schedule). Among 36 evaluable patients treated 
with Revlimid® in a safety and efficacy trial, 24 (67%) experienced an erythroid 
response according to International Working Group (IWG) criteria, with 21 
patients experiencing sustained transfusion independence. Response rate varied 
by cytogenetic pattern and was highest among patients with a chromosome 
5q(31.1) deletion (91%) compared to a normal karyotype (68%) or other 
chromosome abnormality (17%) [P = 0.009]. Similarly, patients with lower risk 
International Prognostic Scoring System (IPSS) categories experienced a higher 
frequency of erythroid response compared to patients with higher risk disease 
(72% vs 25%). Unlike cytokine therapy, cytogenetic remissions were common, 
with 65% of informative patients experiencing 50% or greater reduction in 
abnormal metaphases, including 10 (57%) complete cytogenetic remissions. 
Major cytogenetic response occurred most commonly in patients with a 
chromosome 5(q31.1) interstitial deletion (9 of 11 patients). Perhaps of greater 
importance, responses appear durable. After a median follow-up of 81 weeks, 
median duration of transfusion-independence had not been reached (48+; range, 
13+ to > 101 weeks) with median sustained hemoglobin of 13.2 g/dL (range, 
11.5–15.8 g/dL).     
Multi-institutional experience (MDS 002 and 003 trials): 
 
Revlimid® in del(5q) patients: The List experience described above was 
followed by a multicenter Phase II study (42) evaluating the efficacy of 
REVLIMID® in transfusion dependent (TD)-MDS pts with del5q31. A multicenter 
Phase II trial (MDS 003) for transfusion dependent low to Int-1 del(5q) patients 


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showed remarkable results.  Among 148 pts with del(5q31), 111 had this as an 
isolated cytogenetic abnormality, and 37 patients had additional chromosomal 
changes. The median age was 71 years (range, 37-95) with 66% females and 
146 patients had a confirmed transfusion dependence. In an intent-to-treat 
analysis, transfusion independence was achieved in 99 patients (67%) with a 
median 5.3/dl hemoglobin increase (range: 1.1-11.4/dl). The median time to 
response was 4 weeks (range: 3.6-5.3 weeks). The transfusion independence 
rate was greater in patients with isolated del(5q) abnormality (69% versus 49%; 
p=0.003). Cytogenetic response (>50 decrease in abnormal metaphases) was 
achieved in 70% of transfusion independent patients with 44% achieving a 
complete cytogenetic remission. Pathologic complete remission was documented 
in 32/110 (29%) evaluable patients. After a median follow-up of 9.3 months 
(range: 4.2 to 14.8+ months), the median response duration is not reached with 
only 10 responders (9%) failing.  
 
Revlimid® in non-del(5q) patients: The results of Revlimid® treatment of 
transfusion dependant low to Int-1 patients without the del(5q) has also shown 
that Revlimid® is an effective treatment option (43). A total of 214 patients were 
treated with Revlimid® (MDS 002). Overall, 56 (26%) of 214 enrolled patients 
achieved transfusion independence. Median time to response was 5 weeks, 
median duration of response was 41.0 weeks (range, 8.0-136.4), and median 
Hgb increase achieved was 3.2 g/dL (range, 1.0-9.8). An additional 36 patients 
experienced a 50% reduction in RBC transfusions (hematological improvement 
in 92 [43%] patients). Of 47 (22%) patients who had an abnormal karyotype at 
baseline, 9 (19%) patients achieved a cytogenetic response (4 complete). These 
early findings indicate that Revlimid® has significant erythroid activity in patients 
with low- to int-1-risk MDS.  
 
4.8 
Results of the expression analysis suggesting a signature profile 
associated with Revlimid® responsiveness (44):  
Clinical response to a specific agent is one way of unifying seemingly unrelated 
subsets of MDS patients who carry a common therapeutic target. The most 
important observation from the Revlimid® trials is that the majority of del(5q) 
patients as well as a small but definite subset of non-del(5q) patients experience 
equally good hematologic responses. The precise mechanism of response 
remains unknown. Thalidomide is thought to be effective because of its anti-TNF, 
anti-angiogenic and immune-modulatory effects. Revlimid® shares these 
signature thalidomide activities, except with greater potency (and less toxicity). 
This would suggest that MDS patients are responding to Revlimid® because of its 
broad spectrum of activity both on the clone of cells as well as the bone marrow 
microenvironment. The exceptionally high response rate in the del(5q) patients 
on the other hand suggests a more specific target. Supporting this specificity is 


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the observation that some of the non-del(5q) patients have equally striking 
responses as the del(5q) patients. We used these clinical observations as a 
means 
of 
defining 
an 
expression 
profile 
associated 
with 
Revlimid® 
responsiveness. Our hypothesis was that the responders share a common 
genetic abnormality/molecular signature.  
 
Microarray technology offers a chance to explore disease pathology in greater 
detail, yet only a limited number of these studies have been reported so far in 
MDS, mainly due to the marrow cellular heterogeneity. An inherent problem in 
MDS is that a single cell type is not rapidly proliferating and becoming the 
dominant cell population in the marrow. Several strategies have been tried to 
overcome this challenge, yet no approach appears to be perfectly suited for 
expression profiling in MDS. While some investigators based their work on 
selecting cell types (CD34+, AC133+, neutrophils), IPSS (high versus low risk) or 
cytogenetics (monosomy 7 versus trisomy 8), our hypothesis is that differences 
between individual marrow samples may be minimized by using clinical response 
as a means of identifying uniform groups of patients. For example, responders to 
Revlimid® whether they have the del(5q) abnormality or not, may share some 
common genetic and/or expression profiles which makes them sensitive to the 
drug. We propose that a bedside to bench approach as evidenced by response 
to a given drug can serve as the initial guideline in defining patient subgroups 
with relatively similar biology and natural history of the disease. A total of 51 
patients were enrolled by our group, with 28 participating in the multi-center 
MDS-002 and 23 in MDS-003 trials. Under an independent IRB protocol for 
Tissue Repository, we collected and stored BM aspirates from the patients 
enrolled in these two studies. These samples have been used for the following 
expression studies (35). Both DNA and RNA were isolated from the pre-therapy 
bone marrow cells of 33 MDS patients that were enrolled in the Revlimid® 
protocols. The RNA was amplified and used to generate biotin labeled anti-sense 
DNA that was fragmented and hybridized to Affymetrix chips.  
 
Initial microarray data was available on 8 responders and 8 non-responders 
who did not have the del(5q). (the “training” set). There was a very distinct 
pattern of gene expression that separated the responders from non-responders. 
Equally exciting was the observation that among the 100 ranked genes of 
interest in the heat-map were groups of genes that have previously been shown 
to be associated with MDS pathology. It seems that a number of genes involved 
in erythropoiesis are clearly under-expressed in patients, including all of the 
responders. For example HBA1 (alpha1 globin), ankyrin1 erythrocytic, dematin or 
EPB 49 (erythrocyte membrane protein band 49), EPB3 (red cell anion 
exchanger), ferrochelatase, hemoglobin alpha 2/DEF (human alpha globin gene 
with flanks), human sickle cell beta globin, Kidd blood group (SLC14A1) are 
genes that are under-expressed in the cells of the responders. This expression 
signature can be used for predicting which patients have a chance to respond 
versus those who definitely will not benefit. However, the DNA microarray 
technology cannot be easily adapted for prospective clinical testing in a timely 
fashion. Two simpler assays to measure gene expression currently used by 


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clinical labs are quantitative real time PCR and the Luminex bead hybridization 
assay. The relative ease of use and cost of these assays will allow them to be 
easily implemented in a clinical setting in the future. This bead based technology 
is being rapidly developed for clinical, research and diagnostic purposes. It is 
less complex than microarray analysis, and can analyze the expression of up to a 
hundred genes in a single well, making it easier to use in the clinical diagnostic 
setting. The results with the Luminex assay gave essentially the same results as 
the Affymetrix chips, and better results than the TaqMan. Identical methodology 
for analysis of Affymetrix, TaqMan qPCR and Luminex data were used. Thus 
Luminex may be adaptable to the broader clinical setting. 
  
Validation of the Microarray Profiles (the “test set”): An independent set of 
26 Revlimid® treated patients enrolled in the national trials patients was 
used to validate the microarray data (35). A predictive analysis of the “test” set 
that including patients with del(5q) and those without del(5q) with known clinical 
outcomes, showed that the expression profile on pre-treatment marrow aspirates 
may be a useful tool in the clinical management of MDS patients. The ability to 
avoid potentially toxic side effects in patients unlikely to respond to Revlimid® 
would be of great benefit to the patients. 
 
4.8.1 INDICATIONS AND USAGE: 
Revlimid® (lenalidomide) is indicated for the treatment of patients with 
transfusion-dependent 
anemia 
due 
to 
Low- 
or 
Intermediate-1-risk 
myelodysplastic syndromes associated with a deletion 5q cytogenetic 
abnormality with or without additional cytogenetic abnormalities.  Revlimid® is 
also approved in combination with dexamethasone for the treatment of patients 
with multiple myeloma that have received at least one prior therapy.  
4.9 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, 
cellulites, 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, 
death not specified and fractures. 


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Tumor flare reaction (TFR) has been reported frequently in CLL patients treated 
with lenalidomide.  Tumor lysis syndrome (TLS) has been reported in CLL 
patients treated with lenalidomide.  Precautions must be taken to prevent TLS 
including proper selection of patients with regard to renal function, correction of 
electrolyte abnormalities, and TLS prophylaxis and monitoring. Lenalidomide has 
been shown to increase the level of digoxin in the blood in some patients. 
Complete and updated adverse events are available in the Investigational Drug 
Brochure and the IND Safety Letters. 
4.10 Rational for Treatment in this Setting 
Selection of patients: The first Revlimid® study reported by List et al included all 
transfusion dependent MDS patients, but given the early experience which 
showed a better response in del(5q) patients and those with lower risk disease, 
more patients belonging to this category were entered on the trial. The 
subsequent multi-center studies were focused entirely on the low/Int-1 patients 
who were transfusion dependent. In the present study, we would like to 
recapitulate the initial study by only treating the transfusion dependent, low and 
intermediate-1 risk MDS patients without deletion (5q). Since the predictive assay 
is most applicable for the non-del(5q) patients, and to avoid confusion resulting 
from an admixture of patients with del(5q) for whom the drug is already FDA 
approved, we have elected to restrict this clinical trial to only the non-del(5q) 
patients. 
 
Current Protocol: In the present study, only the non-del(5q) transfusion 
dependent, low and intermediate-1 risk MDS patients will be treated with single 
agent Revlimid®. All patients will have their pre-therapy bone marrows studied by 
gene expression microarray, Luminex bead assay, and real-time PCR. 
 
5 Study Objectives and Endpoints 
5.1 Objectives 
 
5.1.1 Primary Objective 
To conduct a prospective trial testing the Revlimid® (lenalidomide) response 
signature in patients who have transfusion dependent, non-del(5q), low and 
intermediate-1 risk myelodysplastic syndromes (MDS) in order to confirm the 
predictive value of the signature and to establish the boundaries of the z-score 
which can be used to pre-select patients in future clinical studies. 
 
 


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5.1.2 Secondary Objectives 
 The primary clinical efficacy parameter for these patients will be transfusion 
independence. 
 The secondary efficacy parameters for the study will be the remaining criteria 
as defined by the IWG.  The following parameters also will be assessed: 
 Time to disease progression 
 
Overall and progression-free survival 
5.2 Endpoints 
5.2.1 Primary Endpoint 
 Assessment of pre-therapy gene expression profile associated with Revlimid® 
responsiveness. 
 
 
 
5.2.2 Secondary Endpoints 
 Response will be evaluated every 4 weeks during the first 12 weeks of 
therapy for each of the 56 transfusion-dependent, non-del(5q) low/Int-1 risk 
MDS patients. Treatment will be stopped and the patient will be taken off the 
protocol in case of no response or stable disease by 12 weeks. International 
Working Group (IWG 2006) criteria will be used for response evaluation. The 
proportion of TI will be calculated and an exact 95% confidence interval of TI 
proportion will be estimated.  
 The percent of major and minor responses in erythroid, platelets, neutrophils 
will also be calculated as the secondary endpoints. 
 
6 Investigational Plan 
6.1 Overall design 
6.1.1     PRE, INTRA, and POST-THERAPY STUDIES: 
 
 Bone marrow (BM) aspirate and biopsy 
 All patients must have a BM aspirate and biopsy 
examination performed within 6 weeks before starting 
therapy.  Routine diagnostic studies include morphology, 
histochemistry, 
flow 
cytometry, 
immuno-phenotyping, 
karyotyping, fluorescence in situ hybridization (FISH), 
cytogenetics.  A marrow sample will be saved for the gene 


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expression microarray, Luminex bead assay, and real-time 
PCR.   
 A repeat bone marrow aspirate and biopsy will be done at 
discontinuation from study drug to document complete 
response, if needed. 
 
 Medical/Medication History: Obtained at screening.  Medical 
history to include diagnoses and any signs/symptoms within prior 
28 days.   Medication history within prior 28 days and all prior 
treatment for MDS. 
 
 Physical Exam: Screening, monthly at Day 1 of Cycles 2, 3, and 4 
and at Day 1 of every other cycle thereafter, and at discontinuation 
from study drug, and 30 days (+/- 7 days) following the last dose of 
study drug. 
 
 ECOG Status:  At screening, Day 1 of Cycles 2, 3, and 4, and 
every other cycle thereafter. 
 
 Transfusion History:  Screening, monthly at Day 1 of Cycles 1, 2, 
3, each Day 1 study visit thereafter, at discontinuation from study 
drug, and 30 days (+/- 7 days) following the last dose of study drug. 
 
 
 Hematology (hemoglobin, hematocrit, RBC indices: RBC count, 
mean cell volume, mean cell hemoglobin, mean cell hemoglobin 
concentration; WBC count with differential; and platelet count) at 
screening, weekly during cycles 1 to 3, and then monthly (i.e., at 
Day 1 of each cycle) thereafter, at discontinuation from study drug, 
and 30 days (+/- 7 days) following the last dose of study drug. 
 Clinical Chemistry (creatinine, BUN, total bilirubin, alkaline 
phosphatase, ALT, AST, LDH, total protein) at screening, on Cycle 
1 Day 1 and Cycle 1 Day 15 and on Day 1 of Cycles 2, 3, 4 and 
then as clinically indicated after cycle 4, at discontinuation from 
study drug, and 30 days (+/- 7 days) following the last dose of study 
drug.  Thyroid stimulating hormone (TSH) will be done at screening  
Cycle 4 and then every 16 weeks (i.e., Cycles 8, 11, 16, etc.), and 
at discontinuation from study drug.  T3 and T4 levels may be 
assessed as clinically indicated. 
 All study participants must be registered into the mandatory 
RevAssist® program, and be willing and able to comply with the 
requirements of RevAssist®. 
 


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 Pregnancy test for women: Females of childbearing potential 
(FCBP)† must have a negative serum or urine pregnancy test with a 
sensitivity of at least 50 mIU/mL within 10 – 14 days prior to and 
again within 24 hours of prescribing lenalidomide.  FCBP with 
regular or no menstruation must have a pregnancy test weekly for 
the first 28 days and then every 28 days while on therapy (including 
breaks in therapy), at discontinuation of lenalidomide and at Day 28 
post the last dose of lenalidomide.  Females with irregular 
menstruation must have a pregnancy test weekly for the first 28 
days and then every 14 days while on therapy (including breaks in 
therapy), at discontinuation of lenalidomide and at Day 14 and Day 
28 post the last dose of lenalidomide (see Appendix I: Risks of 
Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods). 
 12-Lead EKG will be performed prior to therapy.  
 MDS-Specific Tests: at baseline and as clinically appropriate 
thereafter (serum B12 and erythropoietin). Optional depending on 
clinical situation: serum iron, total iron-binding capacity (TIBC), 
ferritin; flow cytometry for CD34. 
 Adverse Events, Toxicity, Concomitant 
Medications/Procedures: at each study visits per Schedule of 
Study Assessments (Section 2), assessed by NCI Common 
Terminology Criteria for Adverse Events, Ver.3   Note: After Cycle 
4, these assessments will be obtained every 8 weeks. 
 Patient blood counts, chemistries, transfusion requirements will be 
reviewed at 4-week intervals with decision for continued therapy at 
week 12.  At the discretion of the Principal Investigator, therapy will 
be discontinued in the event of a serious adverse event. 
 
 Transfusion criteria: Packed red blood cells (PRBC) will be 
transfused in case hemoglobin falls below 8.0 Gm/dL or at a higher 
level in a symptomatic patient.  Platelet transfusions will be given 
only if the patient is showing evidence of bleeding or if at risk of 
bleeding. 
 
6.1.1.2  Patient Entry Procedure 
                                               
†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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o Once an eligible candidate has been identified for the study, the 
Research Study Specialist should be called to bring the IRB 
approved informed consent form and HIPAA Authorization to the 
Investigator and potential participant. 
 
o The Investigator will consent the participant and verify the eligibility 
criteria of the candidate.  No study related procedures will be 
performed prior to the participant signing the consent form. 
 
o Anticoagulated bone marrow and peripheral blood specimens and 
bone marrow biopsies will be placed on ice and sent to Dr. Naomi 
Galili’s lab for gene expression assays required for this study. 
 
6.1.1.3   
The starting dose of REVLIMID® will be 10 mg days 1-28 with the first dose 
reduction going to 5 mg days 1-28 of a 28 day cycle. Therapy will cease if there 
is no response after 12 weeks.  Patients responding to treatment will continue on 
Revlimid® until disease progression or unmanageable toxicities. 
 Based on previous trials in del 5q MDS patient one hundred 
percent of patients reported at least one adverse event; 89% 
(131/148) experienced at least one grade 3/4 adverse event.  
Eighty percent required a dose delay and/or reduction for toxicity 
during the study.  Thirty-four percent required a second dose 
delay/reduction.  
Dose 
adjustment 
recommendations 
for 
neutropenia and thrombocytopenia are provided in product 
labeling.  Patients should have complete blood counts monitored 
weekly for the initial 12 weeks and at least monthly thereafter.  
Thromboembolic events were rare in the Revlimid® studies in MDS 
patients with deletion 5q cytogenetic abnormalities.  However, in 
recently reported trials conducted in multiple myeloma, a 
significantly increased risk of deep venous thrombosis and 
pulmonary embolism was observed in patients treated with 
Revlimid® combination therapy.  An elevated risk of thrombosis has 
also been reported when erythropoietin is used during Revlimid® 
treatment.  The role of prophylactic anticoagulation and/or 
antiplatelet therapy with Revlimid® has not been adequately 
assessed.  Any prophylactic measures should be prescribed after a 
careful assessment of individual risk factors. 
 Patients with serum creatinine above 2.5 mg/dl were excluded from 
the studies.  Because Revlimid® is predominately excreted by the 
kidney, renal function should be carefully monitored. 
 Females should be advised to avoid pregnancy while taking 
Revlimid®. Revlimid is an analogue of thalidomide, a known human 
teratogen that causes severe human birth defects.  Additional 


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reproductive toxicity studies will be performed to assess any 
potential 
Revlimid® 
teratogenicity.  
Only 
prescribers 
and 
pharmacists registered under the RevAssist® program can 
prescribe or dispense Revlimid®.  Patients must agree to comply 
with the RevAssist® program requirements.   
 
Clinical toxicity has been infrequent with administration of 
REVLIMID® (see section 4.9). Cases of neutropenia and 
thrombocytopenia have been reported in the phase I/II experience 
in the majority of patients and appear to be dose and/or duration 
dependent. MDS patients with existing neutropenia and/or 
thrombocytopenia should be monitored closely during treatment for 
potential exacerbation that may merit a treatment hiatus and dose 
reduction as described below.  
6.1.2 Study Drug  
6.1.2.1   Lenalidomide Description 
REVLIMID®  (lenalidomide), a thalidomide analogue, is an immunomodulatory 
agent with anti-angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 
1,3-dihydro -2H-isoindol-2-yl) piperidine-2,6-dione and it has the following 
chemical structure:  
Chemical Structure of Lenalidomide 
 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular 
weight is 259.3.  
Lenalidomide is 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. 
6.1.2.2   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 


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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.   
6.1.2.3   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: 
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.  
6.1.2.4   Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at 
no charge through the RevAssist® program.  All physicians who prescribe 
lenalidomide for research subjects enrolled into this trial and all research subjects 
enrolled into this trial must be registered in and must comply with all 
requirements of the RevAssist® program. 


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6.1.2.5   Dosage form 
Lenalidomide will be supplied as capsules for oral administration.   
6.1.2.6   Packaging 
Lenalidomide will be shipped directly to patients.   Bottles will contain a sufficient 
number of capsules for one cycle of dosing.    
6.1.2.7   Storage 
Lenalidomide should be stored at room temperature away from direct sunlight 
and protected from excessive heat and cold.     
6.1.2.8   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 RevAssist® program.  Per 
standard RevAssist® 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 
RevAssist® program.  Prescriptions must be filled within 7 days.  Only enough 
lenalidomide for one cycle of therapy will be supplied to the patient each 
cycle. 
     
6.2 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.  
Approximately 
56 
of 
subjects 
with 
transfusion-dependent, 
non-del(5q) 
low/Intermediate-1 risk Myelodysplastic Syndrome will be screened for 
enrollment and must meet the eligibility criteria below. 
6.2.1 Inclusion Criteria 
Subjects must meet the following inclusion/exclusion criteria to be eligible for the 
study. 
Inclusion criteria  
1. Understand and voluntarily sign an informed consent form. 


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2. Age  21 years at the time of signing the informed consent form. 
3. Able to adhere to the study visit schedule and other protocol requirements. 
4. A confirmed diagnosis (using standard FAB criteria) of a myelodysplastic 
syndrome with low/Int-1 risk and with a non-del(5q) karyotype must be 
established.  
5. Patients must have transfusion dependence (at least 2 units within 8 
weeks prior to starting therapy).  
6. All transfusion dependent non-del(5q) low/Int-1 risk patients will be eligible 
for treatment with Revlimid® 
7. Newly diagnosed as well as previously treated patients will be eligible 
8. Patients with primary de novo or secondary MDS will be eligible  
9. All previous cancer therapy, including radiation, hormonal therapy and 
surgery, must have been discontinued at least 4 weeks prior to treatment 
in this study.  
10. ECOG performance status of 0-2 at study entry (see Appendix II). 
11. Laboratory test results within these ranges: 
 Absolute neutrophil count > 250/uL  
 Platelet count > 30,000/uL  
 Serum creatinine  2.0 mg/dL 
 Total bilirubin  1.5 mg/dL 
 AST (SGOT) and ALT (SGPT)  3 x ULN  
 BUN  2 x ULN 
12. Disease free of prior malignancies for  2 years with exception of currently 
treated basal cell, squamous cell carcinoma of the skin, or carcinoma “in 
situ” of the cervix or breast.  
13. All study participants must be registered into the mandatory RevAssist® 
program, and be willing and able to comply with the requirements of 
RevAssist®. 


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14. Females of childbearing potential (FCBP)† must have a negative serum or 
urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 
days prior to and again within 24 hours of prescribing lenalidomide 
(prescriptions must be filled within 7 days) and must either commit to 
continued abstinence from heterosexual intercourse or begin TWO 
acceptable methods of birth control, one highly effective method and one 
additional effective method AT THE SAME TIME, at least 28 days before 
she starts taking lenalidomide.  FCBP must also agree to ongoing 
pregnancy testing.  Men must agree to use a latex condom during sexual 
contact with a FCBP even if they have had a successful vasectomy.  See 
Appendix I:   Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods. 
6.2.2 Exclusion criteria   
1. Any serious medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from signing the informed consent 
form. 
2. Pregnant or breast feeding females. (Lactating females must agree not to 
breast feed while taking lenalidomide). 
3. 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. 
4. Any clinically significant cardiac disease, including congestive heart failure 
5. Liver function studies including SGOT/SGPT > 3 x ULN 
6. Clinically significant renal disease.   
7. Any previous chemotherapy, hematopoietic growth factors, erythropoietin, 
or cytokines within 4 weeks of starting treatment.  Note: prior therapy with 
G-CSF within 4 weeks is allowed. 
8. Use of any other experimental drug or therapy within 28 days of baseline. 
9. Known hypersensitivity to thalidomide. 
10. The development of erythema nodosum if characterized by a 
desquamating rash while taking thalidomide or similar drugs. 
                                               
 
† 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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11. Any prior use of lenalidomide.  (Patients with prior therapy with 
thalidomide will be eligible as long as at least 4 weeks have elapsed 
between end of the drug and accrual on the present trial) 
12. Concurrent use of other anti-cancer agents or treatments. 
13. Known positive for HIV or infectious hepatitis, type B or C. 
14. Life expectancy < 3 months 
6.3 Visit schedule and assessments 
Screening Assessments and all on study scheduled visits and assessments are 
outlined in Section 2 Table of Study Assessments, and Section 6.1.1.  
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 (±7 days) post the last dose of study drug.   
6.4 Drug Administration 
6.4.1 Treatment assignments 
Transfusion-dependent, non-del(5q) low/intermediate-1 risk myelodysplastic 
syndrome patients will be eligible for this study. 
6.4.2 Dosing regimen 
The planned dose of lenalidomide for investigation is 10 mg/day, orally on days 
1-28 for a 28 day cycle.  Dosing will be in the morning at approximately the same 
time each day.  Prescriptions must be filled within 7 days. 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the 
same day.  If it is missed for the entire day, it should not be made up. 
Patients who take more than the prescribed dose of lenalidomide should be 
instructed to seek emergency medical care if needed and contact study staff 
immediately. 
Subjects experiencing adverse events may need study treatment modifications 
(See section 6.5). 
6.4.3 Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide 
unless they are wearing gloves. 


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6.4.4 Record of administration 
Accurate records will be kept of all study drug administration (including 
prescribing and dosing) will be made in the source documents.   
6.5     Dose Continuation, Modification and Interruption    
Patients will be evaluated for adverse events at each visit with the National 
Cancer Institute (NCI) Common Toxicity Criteria (CTC) used as a guide to the 
grading of severity (See Appendix III).  Dosing should be modified per the dose 
reduction steps in Section 6.5.1 for toxicities as outlined Section 6.5.2 and in the 
dose modification table in Section 6.5.3 (Table 2). 
   6.5.1     Dose Reduction Steps 
 
Table 1: LENALIDOMIDE Dose Reduction Steps 
 
Starting Dose 
10 mg daily on Days 1-28 every 28 days 
 
Dose Level – 1 
5 mg daily on Days 1-28 every 28 days 
Dose Level – 2 
5 mg every other day on Days 1-28 every 28 days 
Dose Level – 3 
5 mg q 3 days on Days 1-28 every 28 days 
 
6.5.2 Instructions for initiation of a New Cycle  
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
 The ANC is ≥ 250/ul or at least half of baseline 
 The platelet count is ≥ 30,000/ul or at least half of baseline 
 Any drug-related rash or neuropathy that may have occurred has resolved 
to ≤ grade 1 severity; 
 Any other drug-related adverse events that may have occurred have 
resolved to ≤ grade 2 severity.  
If these conditions are not met on Day 1 of a new cycle, the subject will be 
evaluated weekly and a new cycle of treatment will not be initiated until the 
toxicity has resolved as described above.  Resolution of the toxicity must occur 
within 4 weeks or the patient will be removed from study.  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 


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scheduled Day 1, then the new cycle will be started with a one-level dose 
reduction of lenalidomide. 
 
 
 
 
 
 
 
 
 
 6.5.3   Instructions for dose modifications or interruption during a cycle. 
 
Table 2: Dose Modifications  
NCI CTC Toxicity Grade 
(unless otherwise 
noted) 
Dose Modification Instructions 
If baseline ANC  
≥ 1000/ mm³: 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia 
 
 
 
Hold (interrupt) lenalidomide dose. 
 
Follow CBC weekly. 
 
If neutropenia has resolved to ≤ grade 2 prior to Day 21, restart 
lenalidomide at next lower dose level and continue through the 
scheduled end of the cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at the start of the 
next cycle.  Omitted doses are not made up.  If neutropenia is the 
only toxicity for which a dose reduction is required, G-CSF may be 
used and the lenalidomide dose maintained 
If baseline ANC  
< 1000/ mm³: 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or ANC < 50% of 
baseline 
 
Hold (interrupt) lenalidomide dose. 
 
Follow CBC weekly. 
 
If ANC has recovered to ≥50% of baseline and fever has resolved 
prior to Day 21, restart lenalidomide at next lower dose level and 
continue through the scheduled end of the cycle.  Otherwise, omit for 
remainder of cycle and reduce the dose of lenalidomide by 1 dose 
level at the start of the next cycle.  Omitted doses are not made up.  If 
neutropenia is the only toxicity for which a dose reduction is required, 
G-CSF may be used and the lenalidomide dose maintained 
If baseline platelet 
count ≥ 50,000/mm³: 
Thrombocytopenia 
≥Grade 3 (platelet count 
< 50,000/mm³) 
 
Hold (interrupt) lenalidomide dose. 
 
Follow CBC weekly. 
 
If thrombocytopenia has recovered to ≤ grade 2 prior to Day 21, 
restart lenalidomide at next lower dose level and continue through the 
scheduled end of the cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at the start of the 
next cycle.  Omitted doses are not made up. 
If baseline platelet 
count < 50,000/mm³: 
Platelet count < 50% of 
baseline 
 
Hold (interrupt) lenalidomide dose. 
 
Follow CBC weekly. 
 
If platelet count resolves to ≥ 50% of baseline prior to Day 21, restart 
lenalidomide at next lower dose level and continue through the 
scheduled end of the cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at the start of the 
next cycle.  Omitted doses are not made up. 


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Table 2: Dose Modifications  
NCI CTC Toxicity Grade 
(unless otherwise 
noted) 
Dose Modification Instructions 
Non-blistering rash 
 
Grade 3 
 
 
 
             Grade 4 
 
 
If Grade 3, hold (interrupt) lenalidomide dose.  Follow weekly. 
 
If the toxicity resolves to ≤ grade 1 prior to Day 21, restart 
lenalidomide at next lower dose level and continue through the 
scheduled end of the cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at the start of the 
next cycle.  Omitted doses are not made up. 
 
 
If Grade 4, discontinue lenalidomide.  Remove patient from study. 
 
 
Desquamating 
(blistering) rash- any 
Grade  
 
Discontinue lenalidomide.  Remove patient from study. 
Neuropathy 
 
Grade 3 
 
 
 
Grade 4 
 
 
If Grade 3, hold (interrupt) lenalidomide dose.  Follow at least weekly. 
 
If the toxicity resolves to ≤ grade 1 prior to Day 21, restart 
lenalidomide at next lower dose level and continue through the 
scheduled end of the cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at the start of the 
next cycle.  Omitted doses are not made up. 
 
 
If Grade 4, discontinue lenalidomide.  Remove patient from study. 
Venous 
thrombosis/embolism 
≥ Grade 3 
 
Hold (interrupt) lenalidomide and start anticoagulation; restart 
lenalidomide at investigator’s discretion (maintain dose level). 
 
Omit lenalidomide for remainder of cycle. See Anticoagulation 
Consideration (Section 6.6.1.2) 
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. 
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 and continue through the scheduled end of the cycle.  
Otherwise, omit for remainder of cycle.  Omitted doses are not made 
up.  For toxicity attributed to lenalidomide, reduce the lenalidomide 
dose by 1 dose level when restarting lenalidomide. 
 
  
6.5.4   Treatment compliance 
Research center personnel will review the dosing instructions with subjects. 
Subjects will be asked to maintain a diary to record the drug administration. 
Subjects will be asked to bring any unused study drug and empty study drug 
containers to the research center at their next visit.  Research personnel will 
count and record the number of used and unused study drug capsules at each 
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Any unused Revlimid® (lenalidomide) should be returned to the patient for 
disposition in accordance with the RevAssist® program. 
6.6    Concomitant therapy   
6.6.1   Recommended concomitant therapy   
Subjects should receive full supportive care, including transfusions of blood and 
blood products, antibiotics, and antiemetics when appropriate.  
6.6.1.2   Anticoagulation Consideration   
Lenalidomide increases the risk of thrombotic events in patients who are at high 
risk or with a history a thrombosis, in particular when combined with other drugs 
known to cause thrombosis. When lenalidomide is combined with other agents 
such as steroids (e.g. dexamethasone, prednisone), anthracyclines (Doxil, 
Adriamycin) and erythropoietin the risk of thrombosis is increased.  
Consideration should be given to the requirement or optional use of aspirin (81 or 
325 mg) or some other form of prophylaxis as deemed appropriate. Low 
molecular weight heparin may be utilized in patients that are intolerant to ASA. 
Coumadin should be used with caution and close monitoring of INR. 
6.6.2    Prohibited concomitant therapy 
G-CSF is permitted for neutropenic fever and/or when clinically indicated.  
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. 
6.7   Discontinuation of Study Treatment  
Treatment will continue  for 12 weeks of treatment or the occurrence of any of the 
following events.   
 Disease progression as defined by IWG 
 Adverse event(s) that, in the judgment of the Investigator, may cause 
severe or permanent harm or which rule out continuation of the treatment 
regimen. 
 Toxicity that delays the start of the next cycle by more than 4 weeks. 
 Discontinuation of lenalidomide for any reason. 
 Major violation of the study protocol. 
 Withdrawal of consent 


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 Lost to follow up 
 Death 
 Suspected pregnancy 
 
 
6.8 
Follow-Up   
Subjects who discontinue treatment for any reason will have a discontinuation 
from study drug visit and a 30 days (± 7 days) post-drug discontinuation visit 
evaluations per the Schedule of Assessments, Section 2.  In addition, off study 
follow-up evaluations for anti-cancer treatments and survival will be obtained 
every 3 months per the Schedule of Assessments, Section 2. 
7 Adverse events 
7.1 Serious Adverse Event (SAE) Definition  
A serious adverse event is one that at any dose (including overdose): 
 Results in death 
 Is life-threatening1 
 Requires inpatient hospitalization or prolongation of existing 
hospitalization 
 Results in persistent or significant disability or incapacity2 
 Is a congenital anomaly or birth defect 
 Is an important medical event3 
 Suspected positive Pregnancy 
 
1“Life-threatening” means that the subject was at immediate risk of death at the time of 
the serious adverse event; it does not refer to a serious adverse event that hypothetically 
might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred.  
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above should also usually be considered 
serious.  Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
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A new diagnosis of cancer during the course of a treatment should be considered as 
medically important.  
7.2 Adverse Drug Reaction Reporting 
Toxicity will be scored using CTCAE Version 3.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE Version 3.0 can be downloaded from the CTEP 
homepage (HTTP://CTEP.INFO.NIH.GOV).  All appropriate treatment areas should 
have access to a copy of the CTCAE Version 3.0.  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. 
 
Severity Ratings: 
 
The investigator will evaluate the severity of each adverse experience using the 
following definitions: 
 
 
 
Mild: event may be noticeable to the patient, does not influence daily activities, 
usually does not require intervention. 
 
Moderate: event may be of sufficient severity to make subject uncomfortable;                       
performance of daily activities may be influenced; intervention may be needed. 
 
Severe: event may cause severe discomfort; usually interferes with daily 
activities; subject may not be able to continue in the study; treatment or other 
intervention usually needed. 
 
Relationship to Study Drug: 
 
 
Probably Related 
An adverse event which might be due to the use of the drug. The 
relationship in time is suggestive. An alternative explanation is less 
likely, e.g. concomitant drug(s), concurrent diseases(s). 
 
Possibly Related 
An adverse event which might be due to the use of the drug. The 
relationship in time is reasonable; therefore, a casual relationship 
cannot be excluded. An alternative explanation is inconclusive, e.g. 
concomitant drug(s), concurrent disease(s). 
 
Not Related 


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An adverse event which is judged to be clearly due only to 
extraneous causes (disease, environment, etc.). The cause must 
be noted on the AE CRF. 
 
7.2.1 Pregnancies 
Pregnancies occurring while the subject is on lenalidomide or within 4 weeks 
after the subject’s last dose of lenalidomide are considered expedited reportable 
events.  If the subject is on lenalidomide, it is to be discontinued immediately and 
the subject is to be instructed to return any unused portion of lenalidomide to the 
Investigator.  The pregnancy must be reported to Celgene Drug Safety within 24 
hours of the Investigator’s knowledge of the pregnancy by phone and facsimile 
using the SAE Form. 
 
The Investigator will follow the subject until completion of the pregnancy, and 
must notify Celgene Drug Safety of the outcome as specified below.  The 
Investigator will provide this information as a follow-up to the initial SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as 
a SAE (i.e., spontaneous abortion [any congenital anomaly detected in an 
aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for Expedited Reporting 
of SAEs to Celgene (i.e., report the event to Celgene Drug Safety by facsimile 
within 24 hours of the Investigator’s knowledge of the event). 
 
Any suspected fetal exposure to lenalidomide must be reported to Celgene within 
24 hours of being made aware of the event.  The patient should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without 
regard to causality, as SAEs.  In addition, any infant death after 30 days that the 
Investigator suspects is related to the in utero exposure to lenalidomide should 
also be reported. 
 
In the case of a live “normal” birth, Celgene Drug Safety should be advised as 
soon as the information is available. 
 
7.2.2 Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Drug Safety 
86 Morris Avenue 


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Summit, N.J. 07901 
 
Toll Free:   (800)-640-7854 
Phone:  
(908) 673-9667 
Fax:  
(908) 673-9115 
e-mail:  
drugsafety@celgene.com 
 
 
7.3 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 Development 
 
86 Morris Avenue 
 
Summit, NJ  07901 
 
Tel: (908) 673-9000 
 
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. 
7.3.1 Expedited reporting by investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform 
Celgene in writing with a Celgene SAE form or MEDWATCH 3500A of any SAE 
within 24 hours of being aware of the event.  The date of awareness should be 
noted on the report.  This written report must be completed and supplied to 
Celgene by facsimile within 24 hours/1 business day at the latest on the following 
working day.  The initial report must be as complete as possible, including details 
of the current illness and (serious) adverse event, and 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 


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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-MDS-PI-388) and the 
institutional protocol number should be included on SAE reports (or on the fax 
cover letter) 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. 
7.3.2 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.   
7.3.3 Investigator Reporting to the FDA 
Adverse drug reactions that are Serious, Unlisted/unexpected, and at least 
possibly associated to the drug, and that have not previously been reported in 
the Investigators brochure, or reference safety information document should be 
reported promptly to the Food and Drug Administration (FDA) in writing by each 
investigator/physician engaged in clinical research.  A clear description of the 
suspected reaction should be provided along with an assessment as to whether 
the event is drug or disease related.   
 
The investigator/physician shall notify the FDA by telephone or by fax of any 
unexpected fatal or life threatening experience associated with the use of the 
drug. As soon as possible, but no later than 7 calendar days after the sponsors 
initial receipt of the information.    Each phone call or fax shall be transmitted to 
the FDA new drug review division in the Center for Drug Evaluation and 
Research or the product review division in the Center for Biologics Evaluation 
and Research that has responsibility for review of the IND if applicable. 
. 
7.4 Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following 
information: 
 
 Any AE associated with the use of study drug in this study or in other 
studies that is both serious and unexpected. 
 Any finding from tests in laboratory animals that suggests a significant risk 
for human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
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 11.4 for 
records retention information). 
8 Response Criteria 
8.1 The International Working Group (IWG 2006) Response Criteria 
for Myelodysplastic Syndromes will be used for efficacy 
assessments. 
 
The primary efficacy parameter for these patients will be transfusion 
independence. 
 
8.2 The secondary efficacy parameters for the study will be the 
remaining criteria as defined by the IWG.  For each cohort, the 
parameters that were primary in one cohort will be secondary in 
the other; the following parameters also will be assessed: 
 Time to disease progression; 
 Overall and progression-free survival 
 
8.3 Complete remission (CR): 
 
Bone marrow evaluation: Repeat BM showing less than 5% myeloblasts with 
normal maturation of all cell lines, with no evidence of dysplasia (8 weeks 
duration).  When erythroid precursors constitute less than 50% of BM nucleated 
cells, the % blasts is based on all nucleated cells; when there are 50% or more 
erythroid cells, the % blasts should be based on the non-erythroid cells. 
 
Peripheral blood evaluation:  (absolute values must last at least 
2 months). 
 
 
Hemoglobin:  greater than 11gm/dL (untransfused patient not on   
erythropoietin). 
 
Neutrophils: 1000/ul or more (not on a myeloid growth factor). 
 
Platelets: 100,000 ul or more (not on a thrombopoietic agent) 
 
Blasts: 0%. 
 
No dysplasia. 
 


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8.4 Partial remission (PR): (absolute values must last at least 2 months). 
 
All the CR criteria (if abnormal before treatment), except: 
Bone marrow evaluation-blasts decrease by 50% or more over pretreatment but still 
>5%.  Cellularity or morphology is not relevant. 
 
Marrow CR 
Bone marrow blasts < or = 5% myeloblasts and decreased by 50% or more over 
pretreatment 
 
Stable disease: 
Failure to achieve at least a PR, but with no evidence of progression for at least 8 
weeks 
 
8.5  
Failure: 
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in the % BM blasts, or progression to an MDS FAB sub-type 
more advanced than pre-treatment. 
 
8.6 
Disease transformation: 
Transformation to AML, 20% or more blasts. 
 
8.7 
Cytogenetic response: Requires 20 analyzable metaphases using 
conventional cytogenetic techniques. 
 
Complete: No detectable cytogenetic abnormality, if pre-existing abnormality 
was present. 
Partial: 50% or more reduction in abnormal metaphases. 
 
8.8 
Pre-therapy assessments: Baseline complete blood count (CBC) to 
which improvements will be compared was standardized using a mean value of 
the 4 weeks prior to the start of therapy for all patients. 
 
8.9     During therapy: Responses will be assessed at 12 weeks of therapy. With regard 
to packed red blood cell transfusions (PRBC) and transfusion independence, the same 4 
week time period was used prior to treatment to determine transfusion dependence and 
to obtain a baseline monthly requirement. Subsequent transfusions will be reviewed at 
16 weeks, and 1-year time points.  
 
8.10      Hematologic Improvement or HI: 
All improvements must last at least 8 weeks.  For a designated response (CR, 
PR HI) all relevant response criteria must be noted on at least two successive 
determinations at least one week apart after appropriate period following therapy. 
8.11     Erythroid response (HI-E): 


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 Response: For patients with pre-treatment Hb less than 11 Gm/dL, greater 
than1.5Gm/dL increase in Hb; relevant reductions in units of RBC transfusion by 
an absolute number of at least 4 RBC transfusions/8wks compared with pre-
treatment. Only RBC transfusions given for Hgb of < or = to 9.0g/dL pre-
treatment will be count for transfusion response evaluation 
 
8.12 Platelet response (HI-P): 
Response: For patients with a pretreatment platelet count more than 200,000/ul, 
an absolute increase of 30,000/ul or more; for patients with a pretreatment 
platelet count less than 200,000/ul, a 100% or more increase in platelet count to 
more than 200,000/ul 
8.12    Absolute neutrophil response (HI-ANC): 
  Response: For ANC less than 1000/ul before therapy at least a 100% increase 
or an absolute increase of 500/ul, whichever is greater. 
9 Protocol Amendments/Deviations 
9.1 Protocol amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator 
and reviewed by Celgene.  Amendments should only be submitted to IRB/EC 
after consideration of Celgene review.  Written verification of IRB/EC approval 
will be obtained before any amendment is implemented.   
9.2 Protocol deviations 
When an emergency occurs that requires a deviation from the protocol for a 
subject, a deviation will be made only for that subject.  A decision will be made as 
soon as possible to determine whether or not the subject (for whom the deviation 
from protocol was effected) is to continue in the study.  The subject’s medical 
records will completely describe the deviation from the protocol and state the 
reasons for such deviation.  In addition, the Investigator will notify the IRB/EC in 
writing of such deviation from protocol. 
Non-emergency minor deviations from the protocol will be permitted with 
approval of the Principal Investigator.  
10 Data Management 
 
10.1 Data Collection: 


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Study-specific case report forms will be created to capture protocol 
information.  
10.2    Analyses and Reporting 
Data will be analyzed and reported after accrual is completed. All subsequent 
data collected will be analyzed and reported in a follow-up clinical report.  
10.3   Data Monitoring Committee 
The Data Monitoring Committee (DMC) will be composed of medical and 
statistical independent reviewers and will meet to review the efficacy and safety 
data and determine a risk/benefit analysis in this subject population.  The 
purpose of the DMC is to advise on serious safety considerations, lack of efficacy 
and any other considerations within the charge to the Committee.  The DMC may 
request additional meetings or safety reports as deemed necessary upon 
discussion with Celgene and its representatives.  The DMC may stop the study 
following review of results from each interim analysis.  The first interim analysis 
will examine only safety information; the second interim, conducted when the 
database is more mature, will examine both safety and efficacy.  Appropriate 
efficacy and safety data summaries will be provided to the DMC after each 
interim analysis. 
10.4   Study monitoring and auditing 
10.4.1   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 
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 audit 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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11   Biostatistical Analysis 
11.1 Overview 
The aim of the study is to compare the diagnostic ability of the gold standard 
microarray assay to the Luminex Bead assay and to quantitative real-time PCR 
assay in order to detect Revlimid®-response in patients with MDS. Earlier studies 
have shown microarray assay to identify responders with a sensitivity of 94% and 
a specificity of 86%(44)  It is hypothesized that the less expensive and more 
clinically useful Luminex Bead assay will predict MDS Revlimid® responders with 
a sensitivity of 75% and a specificity of 70% compared to criterion gold standard 
microarray assay.  However, it may be possible that real-time PCR will also be 
equally useful clinically and an easier assay to perform in the clinical lab setting 
as many pathology laboratories are now equipped with the  necessary 
instrumentation.  We will thus compare both the Luminex and real-time PCR 
assays, assuming the same level of sensitivity and specificity for each, to the 
gold standard microarray assay.  These levels would be 80% of the sensitivity 
and specificity of the gold standard. 
 
To test this hypothesis, a paired design will be used with each subject being 
tested with both diagnostic tests [microarray versus either Luminex or PCR; 
(written “Luminex” in the formula)].   The null hypothesis is that the difference in 
sensitivity rates will be more than 0.80, and the alternative hypothesis will be that 
the difference in rates will be less or equal to 0.80.  Using the sample size: 
formula: 
 
Where 1-β is the power (0.80) and α is the Type I error rate (0.95), δ is the 
percentage difference between the microarray assay true positive rate (TPR) and 
the luminex TPR.  The concordance probability is the estimated percentage of 
both tests having concordant true positives.  Using the estimated concordance of 
50%, an estimated 100 subjects will be required.  With concordance set at 60%, 
an estimated 59 subjects will be required. (Alonzo, T Sample size calculations for 
comparative studies of medical tests for detecting presence of disease.  Stats in 
medicine 2002: 21:835-852) 
11.2  Analysis of Clinical Response  
 Response will be evaluated every 4 weeks during the first 12 weeks of 
therapy for each of the 56 transfusion-dependent low/Int-1 risk MDS patients. 
Treatment will be stopped and the patient will be taken off the protocol in case 
of no response or stable disease by 12 weeks. International Working Group 
(IWG 2006) criteria will be used for response evaluation. The proportion of TI 
will be calculated and an exact 95% confidence interval of TI proportion will 
be estimated. The percent of major and minor responses in erythroid, 


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platelets, neutrophils, bone marrow and cytogenetic will also be calculated as 
the secondary endpoints.  
 
11.3 Assessment of pre-therapy expression profile associated with 
Revlimid® responsiveness 
 
Bone marrow samples will be collected and stored in the laboratory of Dr. Naomi 
Galili for gene expression analysis. 
11.4 Microarray analysis 
Microarray analysis will be performed on RNA purified from mononuclear cells 
using Trizol (Invitrogen).  Linear amplification of 20 ng of total RNA will be 
performed using the Ovation Biotin RNA Amplification and Labeling System 
(Nugen, Inc.).  Fragmented, labeled cDNA will be hybridized to Affymetrix 
HG_U133 Plus 2.0 oligonucleotide microarrays as described by the 
manufacturer.  Raw expression values will be normalized using Robust 
Multiarray Averaging (RMA) (41).  The genes to be analyzed in this trial are the 
same genes that were identified in Plos Medicine (44). 
 
Ligation-mediated amplification and Luminex detection: All MDS patients 
enrolled in the Revlimid® protocol described below will have their pre-therapy 
bone marrow mononuclear cells stored in Dr. Naomi Galili’s laboratory at 
Columbia University Medical Center. Total RNA from bone marrow mononuclear 
cells preserved in Trizol will be used for the Luminex assay the expression of 32 
genes, which includes the 24 genes of interest and controls will be evaluated 
using multiplexed ligation mediated amplification (LMA).   
 
For each transcript, two LMA probes have been designed.  The upstream probe 
contains a T7 universal primer sequenced, one of 32 different barcodes (Tm 
Bioscience, www.universalarray.com), and a 20 nucleotide gene specific 
sequence.  The downstream probes are 5’ phosphorylated, and contain a 20 
nucleotide sequence contiguous with the gene-specific fragment of the upstream 
probe and a T3 universal primer site.  Gene specific probe sequences are unique 
to the target gene when compared to the Human RefSeq database, have similar 
base composition, and target the 3’ end of the target genes. 
 
Prior to LMA, 100 ng/well of total RNA will be applied to oligo-dT coated plates 
(GenePlateHT, RNAture) in Lysis Buffer (RNAture).  Bound, poly(A) RNA will be 
reverse transcribed using Superscript II (Invitrogen).  LMA probes will be 
annealed to their target cDNAs and ligated by Taq DNA ligase (New England 
Biolabs).  Ligation products, all 104 nucleotides in length, will be amplified by 34 
cycles of PCR using T3 and 5'-biotinylated T7 primers.  Amplicons will be 
detected using fluorescent microspheres of 32 different colors (xMAP Multi-
Analyte COOH Microspheres, Luminex).  Microspheres of each color are 
covalently coupled to a unique capture probe complementary to one of the 32 
gene-specific barcodes.  Following labeling of the biotinylated amplicons with 


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streptavidin-coated phycoerythrin, the labeled amplicons will be annealed to 
capture probe-linked fluorescent microspheres.  Microspheres are detected by 
flow cytometry and captured labeled amplicons are quantified (Luminex) by 
subtracting background from the mean fluorescent intensity of each bead. 
 
Real-time PCR: Total RNA from bone marrow mononuclear cells preserved in 
Trizol will be used for the Real-time PCR assay for the expression of 32 genes, 
which includes the 24 genes of interest and controls. Primers for each gene will 
be designed (Roche Biosystems) such that only the RNA transcript and no 
genomic DNA will be measured by the Roche Light Cycler quantitative PCR 
assay . The Sybergreen kit (Roche) which measures relative amount of gene 
specific transcript will be used. Results will be analyzed with the Roche Light 
Cycler analysis package.  
 
11.5 Safety evaluation 
Data from all subjects who receive any study drug will be included in the safety 
analyses. Subjects who entered the study and did not take any of the study 
drug(s) and had this confirmed, will not be evaluated for safety. 
The severity of the toxicities will be graded according to the NCI CTCAE v3.0 
whenever possible.  
12 
Regulatory Considerations 
12.1 Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general 
ethical principles outlined in the Declaration of Helsinki.  The review of this 
protocol by the IRB/EC and the performance of all aspects of the study, including 
the methods used for obtaining informed consent, must also be in accordance 
with principles enunciated in the declaration, as well as ICH Guidelines, Title 21 
of the Code of Federal Regulations (CFR), Part 50 Protection of Human Subjects 
and Part 56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to 
the relevant IRB/EC and obtaining written approval for this study.  The approval 
will be obtained prior to the initiation of the study. 
The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be 
submitted by the Investigator to the IRB/EC for approval.  The Investigator is also 


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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. 
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 representatives of Celgene Corporation 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; SAE reports, 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 


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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 approval).  The Investigator agrees to adhere to the 
document/records retention procedures by signing the protocol. 
12.5 Premature discontinuation of study 
12.5.1 Single center 
The responsible local clinical Investigator as well as Celgene have the right to 
discontinue this study at any time for reasonable medical or administrative 
reasons in any single center.  Possible reasons for termination of the study could 
be but are not limited to: 
 Unsatisfactory enrollment with respect to quantity or quality. 
 Inaccurate or incomplete data collection. 
 Falsification of records. 
 Failure to adhere to the study protocol. 
12.5.2    Study as a whole 
Celgene reserves the right to terminate this clinical study at any time for 
reasonable medical or administrative reasons. 
Any possible premature discontinuation would be documented adequately with 
reasons being stated, and information would have to be issued according to local 
requirements (e.g., IRB/EC, regulatory authorities, etc.). 


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13 
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Appendices 
 
Appendix I: Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been 
studied nor has the effect of the lenalidomide on human eggs and sperm.  The 
risks to a fetus are not known.  However, because lenalidomide is related to 
thalidomide, and thalidomide is known to cause severe birth defects, the 
following requirements must be observed. 
All study participants must be registered into the mandatory RevAssist® 
program, and be willing and able to comply with the requirements of RevAssist®. 
Females of childbearing potential (FCBP)† must agree to use two reliable forms 
of contraception simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods related to this study: 1) 
for at least 28 days before starting lenalidomide 2) while participating in the 
study; and 3) for at least 28 days after discontinuation from the study. The two 
methods of reliable contraception must include one highly effective method (i.e. 
intrauterine device (IUD), hormonal [birth control pills, injections, or implants], 
tubal ligation, partner’s vasectomy) and one additional effective (barrier) method 
(i.e. latex condom, diaphragm, cervical cap).  FCBP must be referred to a 
qualified provider of contraceptive methods if needed.   
Before starting lenalidomide:   
Female Subjects:   
 FCBP must have two negative pregnancy tests (sensitivity of at least 50 
mIU/mL) prior to prescribing lenalidomide.  The first pregnancy test must 
be performed within 10-14 days prior to prescribing lenalidomide and the 
second pregnancy test must be performed within 24 hours prior to 
prescribing lenalidomide (prescriptions must be filled within 7 days).  The 
subject may not receive lenalidomide until the Investigator has verified that 
the results of these pregnancy tests are negative. 
                                               
 
† 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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Male Subjects:   
 Must agree to use a latex condom during sexual contact with females of 
childbearing potential while participating in the study and for at least 28 
days following discontinuation from the study even if he has undergone a 
successful vasectomy.  
During study participation and for 28 days following discontinuation from 
the study: 
All Subjects: 
 If pregnancy or a positive pregnancy test does occur in a study subject or 
the partner of a male study subject during study participation, lenalidomide 
must be immediately discontinued. 
Female Subjects:   
 FCBP with regular or no menstrual cycles must agree to have pregnancy 
tests weekly for the first 28 days of study participation and then every 28 
days while on study, at study discontinuation, and at day 28 following 
discontinuation from the study. If menstrual cycles are irregular, the 
pregnancy testing must occur weekly for the first 28 days and then every 
14 days while on study, at study discontinuation, and at days 14 and 28 
following discontinuation from the study.   
 In addition to the required pregnancy testing, the Investigator must confirm 
with FCBP that she is continuing to use two reliable methods of birth 
control at each visit.   
 
Pregnancy testing and counseling must be performed if a subject misses 
her period or if her pregnancy test or her menstrual bleeding is abnormal.  
Lenalidomide treatment must be discontinued during this evaluation. 
Male Subjects: 
 Must agree to use a latex condom during sexual contact with females of 
childbearing potential while participating in the study and for at least 28 
days following discontinuation from the study even if he has undergone a 
successful vasectomy. 
 


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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 NCI CTC Version 3.0 
 
TOXICITY WILL BE SCORED USING NCI  CTC VERSION 3.0 FOR 
TOXICITY AND ADVERSE EVENT REPORTING.  A COPY OF THE NCI CTC 
VERSION 3.0 CAN BE DOWNLOADED FROM THE CTEP HOMEPAGE: 
(HTTP://CTEP.INFO.NIH.GOV).  ALL APPROPRIATE TREATMENT AREAS 
HAVE ACCESS TO A COPY OF THE CTC VERSION