Clinical trial NCT01125176
Conditions: Chronic Lymphocytic Leukemia
Keywords: CLL
Sponsor: Weill Medical College of Cornell University
Start date: 2012-03-30; Completion date: 2020-12-29
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The investigators' hypothesis is that treatment of CLL with an alternating daily dosing schedule of thalidomide and lenalidomide may result in better tolerability by decreasing each agent's individual toxicities, while preserving efficacy, and therefore lead to a longer duration of therapy and improved responses. Additionally, the combination of the 2 agents may have additive or synergistic effects therapeutically.

In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. Starting with cycle 1, patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.)

Detailed description:
This is an open label, phase II, single arm, and single institution study investigating daily alternating therapy with IMiD™ compounds, thalidomide and lenalidomide, plus rituximab in untreated CLL patients requiring treatment. In order to obtain correlative samples, patients will receive a two week course of single agent thalidomide or lenalidomide before beginning treatment with the combination regimen. Half of the patients (odd numbered subjects) will start with a two week course of single agent thalidomide and the other half of the patients (even numbered subjects) will start with a two week course of single agent lenalidomide. This will allow the study of correlative samples of monotherapy with either IMiD™ agent. In Cycle -1 half of the patients (odd numbered subjects) will receive thalidomide 50mg PO daily on days 1-14, followed by no treatment days 15-28 and the other half of the patients (even numbered subjects) will receive lenalidomide PO daily on days 1-14, followed by no treatment days 15-28. Starting cycle 1: Patients will receive thalidomide 50 mg every other day (every odd day on days 1-28: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 \& 27 of a 28 day cycle) alternating with lenalidomide on alternate every other day, dosed based upon current level with stepwise incremental dosing (every even day on days 1-28: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 \& 28 of a 28 day cycle). The starting dose of lenalidomide will be based on calculated creatinine clearance and the dose of lenalidomide may be escalated as tolerated to maximal dose of 25 mg (see Section 5 for details). Rituximab 375 mg/m2 will be administered on days 1, 8, 15 and 22 starting with Cycle 1 and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycles 7, 13, 19, etc).

Arms: arm 1: In Cycle -1, even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Starting with cycle 1, all patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.)
Interventions: intervention 1: thalidomide intervention 2: lenalidomide intervention 3: rituximab
Intervention descriptions: intervention 1: 50 mg oral dosing every other day intervention 2: varying oral doses every other day (max 25 mg/day) intervention 3: 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.)

Protocol documents:
Prot_SAP_000.pdf: 




SCHEMA 
PROTOCOL TITLE: A phase II study of daily alternating Thalidomide and Lenalidomide therapy plus rituximab 
(THRiL) as initial treatment for patients with CLL. 
 
 
STUDY DRUGS: 
Revlimid®, lenalidomide 
Thalomid®, thalidomide 
Rituxan®, rituximab 
INDICATION: 
Untreated CLL patients 
STUDY PHASE: 
Phase II 
BACKGROUND AND RATIONALE:  
While CLL lymphocytes demonstrate impaired apoptosis in vivo, they undergo spontaneous apoptosis ex vivo, even 
when cultured with cytokines that maintain normal and other malignant B lymphocytes.  These data are often taken as 
evidence of CLL lymphocyte dependency upon cell surface derived signals (either cytokine or cell to cell mediated 
interactions) for survival. Thalidomide and lenalidomide are proprietary IMiD™ compounds of Celgene Corporation. 
These immunomodulatory agents are thought to work, in part, through similar mechanisms involving the inhibition of 
cytokine networks and alteration of adhesion molecules [1-2].  Both thalidomide and lenalidomide have shown activity 
as single agents and in combination with chemotherapy for the treatment of patients with CLL [3-6].  Treatment with 
thalidomide, studied first given its earlier development, was limited by its toxicities of neuropathy, sedation, and 
constipation.  While lenalidomide demonstrates increased potency and tolerability compared with thalidomide, its use is 
complicated by neutropenia, thrombocytopenia, tumor flare, and tumor lysis syndrome [4, 6] and there are ongoing 
studies addressing these issues. 
Our hypothesis is that treatment of CLL with an alternating daily dosing schedule of thalidomide and lenalidomide may 
result in better tolerability by decreasing each agent’s toxicities, while preserving efficacy, and therefore lead to longer 
duration of therapy and improved responses than has been accomplished with either agent alone.  Additionally, the 
combination of thalidomide and lenalidomide may have additive or synergistic effects therapeutically. 
STUDY OBJECTIVES: 
Primary:   

To assess the response rate (overall, complete, and partial) in patients with CLL receiving initial treatment
with thalidomide, lenalidomide, and rituximab.
Secondary:   

To determine the safety, tolerability, and feasibility of combining thalidomide, lenalidomide, and rituximab as 
initial treatment for patients with CLL requiring therapy.

To evaluate duration of response, time to response, progression free survival, and overall survival

To perform correlative studies to determine the potential mechanism of action of how thalidomide and
lenalidomide are affecting CLL lymphocytes.


STUDY DESIGN: 
This is an open label, phase II, single arm, and single institution study investigating daily alternating therapy with the 
IMiD™ compounds, thalidomide and lenalidomide, plus rituximab in untreated CLL patients requiring treatment.  In 
order to obtain correlative samples, patients will receive a two week course of single agent thalidomide or lenalidomide 
before beginning treatment with the combination regimen.  Half of the patients (odd numbered subjects) will start with a 
two week course of single agent thalidomide and the other half of the patients (even numbered subjects) will start with a 
two week course of single agent lenalidomide.  This will allow the study of correlative samples of monotherapy with 
either IMiD™ agent.  In Cycle -1, half of the patients (odd numbered subjects) will receive thalidomide 50mg PO daily 
on days 1-14, followed by no treatment days 15-28.  The other half of the patients (even numbered subjects) will receive 
lenalidomide PO daily on days 1-14, followed by no treatment days 15-28.  Starting cycle 1, patients will receive 
thalidomide 50 mg every other day (every odd day on days 1-28: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27 
of a 28 day cycle) alternating with lenalidomide on alternate every other day, dosed based upon current level with 
stepwise incremental dosing (every even day on days 1-28: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28 of a 
28 day cycle).  The starting dose of lenalidomide will be based on calculated creatinine clearance and the dose of 
lenalidomide may be escalated as tolerated to maximal dose of 25 mg (see Section 5 for details).  Rituximab 375 mg/m2 
will be administered on days  1, 8, 15 and 22 starting with Cycle 1 and then again on the same weekly x 4 schedule 
every 6th cycle through Cycle 19 (Cycles 7, 13, and 19). 
STUDY ENDPOINTS 
Primary: 

Overall response rate (CR + PR) measured at time of best response
Secondary: 

Progression free survival

Duration of response

Time to response

Overall survival

Toxicity profile

Correlative studies
STUDY DURATION: 3 years 
TOTAL SAMPLE SIZE: 24 patients 
DOSING REGIMEN(S): 
Cycle -1:  thalidomide 50 mg PO daily on days 1-14 or 
lenalidomide PO daily on days 1-14 of a 28 day cycle (odd 
numbered subjects will receive thalidomide and even 
numbered subjects will receive lenalidomide).  Days 15-28 
no drug treatment. 
Starting on Cycle 1: Alternating every other day 
thalidomide 50 mg (every ODD day on days 1-28: Days- 
1,3,5,7,9,11,13,15,17,19,21,23,25 & 27 of a 28 day cycle) 
with lenalidomide (every EVEN day on days 1-28: Days- 
STUDY DRUG SUPPLIES: 
Celgene Corporation will supply lenalidomide and 
thalidomide as capsules for oral administration through 
the RevAssist® and S.T.E.P.S. programs. 


2,4,6,8,10,12,14,16,18,20,22,24,26 & 28 of a 28 day 
cycle). The starting dose of lenalidomide will be based on 
calculated creatinine clearance and the dose of 
lenalidomide may be escalated at the start of any 
subsequent 28 day cycle beginning with the start of Cycle 
2 as tolerated to a maximal dose of 25 mg (see Section 5 
for details).  Rituximab 375 mg/m2 will be administered on 
days 1, 8, 15 and 22) starting with Cycle 1 and then again 
on the same weekly x 4 schedule every 6th cycle through 
Cycle 19 (Cycles 7, 13, and 19). 


TABLE OF CONTENTS 
Page 
SCHEMA ........................................................................................................................................ i 
1. OBJECTIVES ..........................................................................................................................1
1.1 
Primary Objectives ......................................................................................................1 
1.2 
Secondary Objectives ..................................................................................................1 
2. BACKGROUND ......................................................................................................................1
2.1 
Introduction .................................................................................................................1 
2.2 
Indications and Usage .................................................................................................2 
2.3 
Adverse Events .............................................................................................................2 
2.4 
Overview of CLL .........................................................................................................3 
2.5 
Rational for Treatment in this Setting.......................................................................4 
3. PATIENT SELECTION ..........................................................................................................5 
3.1 
Inclusion Criteria  ........................................................................................................5 
3.2 
Exclusion Criteria ........................................................................................................7 
4. REGISTRATION PROCEDURES ........................................................................................8 
4.1  
Central Patient Registration .......................................................................................8 
5. TREATMENT PLAN ..............................................................................................................8 
5.1 
Overall Design ..............................................................................................................8 
5.2 
Investigational Study Drug Combination (THRiL) ...............................................10 
5.3 
Visit Schedule and Assessments ...............................................................................11 
5.4 
Drug Administration .................................................................................................11 
5.5 
General Concomitant Medication and Supportive Care Guidelines ....................12 
5.6 
Duration of Therapy and Criteria for Removal From Study ................................15 
5.7 
Duration of Follow Up ...............................................................................................16 
6. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................16 
6.1        Dose Reduction Steps ................................................................................................16 
6.2        Instructions for Initiation of a New Cycle ..............................................................17 
6.3        Instructions for Dose Modifications or Interruption During a Cycle ..................18 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................20
7.1  
Adverse Event Characteristics .................................................................................20 
7.2  
Recording of Adverse Events ....................................................................................21 
7.3  
Serious Adverse Event (SAE) Reporting .................................................................21 
7.4  
Celgene Drug Safety Contact Information ..............................................................23 
7.5 
Investigator Reporting Responsibilities ...................................................................23 
7.6 
Expedited Reporting by Investigator to Celgene ....................................................23 
7.7 
Report of Adverse Events to the IRB .......................................................................24 


7.8 
Adverse Event Updates/IND Safety Reports ...........................................................24 
8. PHARMACEUTICAL INFORMATION ............................................................................25 
8.1 
Revlimid (lenalidomide) ............................................................................................25 
8.2 
Thalomid (thalidomide) .............................................................................................28 
8.3 
Rituximab ...................................................................................................................34 
9. CORRELATIVE/SPECIAL STUDIES ...............................................................................37
10. STUDY CALENDAR ............................................................................................................41
11. MEASUREMENT OF EFFECT ..........................................................................................46
11.1 
Complete Response ....................................................................................................46 
11.2 
Partial Response ........................................................................................................47 
11.3 
Progressive Disease ....................................................................................................47 
11.4 
Stable Disease .............................................................................................................48 
11.5 
Relapse ........................................................................................................................48 
11.6 
Refractory Disease .....................................................................................................48 
11.7 
Duration of Response Definitions .............................................................................48 
12. DATA REPORTING / REGULATORY CONSIDERATIONS ........................................48 
12.1 
Protocol Amendments ...............................................................................................48 
 
12.2 
Protocol Deviations ....................................................................................................48 
 
12.3 
Data Monitoring Committee .....................................................................................49 
 
12.4 
Data Collection ...........................................................................................................49 
 
12.5 
Regulatory Considerations ........................................................................................49 
 
12.6 
Investigator Responsibilities .....................................................................................49 
 
12.7 
Institutional Review Board/Ethics Committee Approval ......................................50 
 
12.8 
Informed Consent ......................................................................................................50 
 
12.9 
Subject Confidentiality ..............................................................................................50 
 
12.10 Study Records Requirements ...................................................................................51 
 
12.11 Premature Discontinuation of Study ........................................................................51 
13. STATISTICAL CONSIDERATIONS .................................................................................51
13.1     Overview  ....................................................................................................................51 
13.2     Datasets to be Analyzed .............................................................................................52 
13.3     Statistical Methodology .............................................................................................52 
13.4     Safety Evaluation .......................................................................................................53 
13.5     Interim Analyses ........................................................................................................53 
14. REFERENCES .......................................................................................................................54 


 
 
 
APPENDICES 
 
APPENDIX A 
Lenalidomide and Thalidomide:  Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods .............................................................................62 
 
APPENDIX B 
ECOG Performance Status Scale   .....................................................................................66 
 
APPENDIX C 
NCI CTC Version 4.0 ........................................................................................................67 
 
APPENDIX D 
 
 
Cairo-Bishop Definition of Tumor Lysis Syndrome…………………………………… 68 
 
APPENDIX E 
Cockcroft-Gault Estimation of Creatinine Clearance (CrCl) .............................................69 
 
APPENDIX F 
 
Instructions for Enrolling in P-TAP Program. ...................................................................70 
 
APPENDIX G 
 
Instructions for Enrolling in RASP Program. ....................................................................73 
 
APPENDIX H 
 
Summary of Changes from Previous Protocol Version. ....................................................76 
 
 
 


 
1 
 
1. OBJECTIVES 
 
1.1. 
Primary Objectives  
 
 To assess the response rate (overall, complete, and partial) in patients with CLL 
receiving initial treatment with thalidomide, lenalidomide, and rituximab 
 
1.2. 
Secondary Objectives 
 
 To determine the safety, tolerability, and feasibility of combining thalidomide, 
lenalidomide, and rituximab as initial treatment for patients with CLL requiring therapy. 
 To evaluate duration of response, time to response, progression free survival and overall 
survival 
 To perform correlative studies to determine the potential mechanism of action of how 
thalidomide and lenalidomide are affecting CLL lymphocytes. 
 
1.3. 
Primary Endpoint 
 Overall response rate (CR + PR) measured at time of best response 
 
1.4. 
Secondary Endpoints 
 Progression free survival 
 Duration of response 
 Time to response 
 Overall survival 
 Toxicity profile 
 Correlative studies 
 
2. BACKGROUND 
 
2.1  
Introduction 
 
Lenalidomide and thalidomide are proprietary IMiD™ compounds 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 [7].  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 


 
2 
 
production [8].  Up regulation of T cell derived IL-2 production is achieved at least in part through 
increased AP-1 activity [9]. 
 
Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of 
mechanisms are postulated to be responsible for the activity of lenalidomide seen 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 [10].  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 [11]. 
 
2.2  
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.  
 
Thalomid® (thalidomide) is indicated for the treatment of patients with newly diagnosed multiple 
myeloma in combination with dexamethasone.  
 
Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-
grade or follicular, CD20-positive, B-cell NHL as a single agent,  Previously untreated follicular, 
CD20-positive, B-cell NHL in combination with CVP chemotherapy,  Non-progressing (including 
stable disease), low-grade, CD20-positive B-cell NHL, as a single agent, after first-line CVP 
chemotherapy and  Previously untreated diffuse large B-cell, CD20-positive NHL in combination 
with CHOP or other anthracycline-based chemotherapy regimens.  
 
 
2.3  
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. 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 


 
3 
 
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. 
 
2.4  
Overview of CLL 
 
Chronic lymphocytic leukemia (CLL) is the most common leukemia in North America, with an 
estimated 15,000 new cases diagnosed in the United States in 2007 [12].  CLL is typically a disease of 
advanced age, with a median age at diagnosis of approximately 65 years, and a male-to-female ratio 
of 2:1 [13].  CLL is characterized by the clonal expansion of long-lived, mature B lymphocytes that 
co-express the CD5, CD19, and CD23 surface antigens [14-15].  The malignant cells of CLL are 
frozen in the G0 stage of the cell cycle, increasing in numbers due more to a lack of apoptosis than 
augmented proliferation [16-21].  The morbidity and mortality associated with CLL results primarily 
from the progressive accumulation of lymphocytes in secondary lymphoid tissues and bone marrow.  
Patients might remain asymptomatic for prolonged periods of time, but most develop disease 
progression, with 70% of CLL patients dying from causes related to their disease [22]. 
 
Overall, patients with CLL have a median life expectancy of almost nine years, but great variability 
exists depending upon several well described prognostic markers [23].  Traditional prognostic 
markers include stage [24-25], age [26], gender [26], pattern of bone marrow involvement [27-28], 
lymphocyte doubling time [29-30], number of circulating prolymphocytes [31-32], and beta-2-
microglobulin level [33-34].  More recently, prognostic markers have been identified that are based 
more on the biological features of the malignant lymphocytes themselves.  These novel prognostic 
markers include: IgVH mutational status [35-36], CD38 expression [36], zap-70 expression [37], and 
interphase FISH (iFISH) abnormalities [38]. 
 
Criteria initially described by the National Cancer Institute Working Group (NCI-WG) on CLL [14], 
and updated by the International Workshop on CLL (IWCLL) [15], describe the indications for 
initiation of therapy for patients with CLL as: evidence of progressive marrow failure as evidence by 
anemia or thrombocytopenia (Rai stage III or IV), massive or symptomatic splenomegaly, massive or 
symptomatic lymphadenopathy, progressive lymphocytosis with an increase of more than 50% over a 
2-month period or a lymphocyte doubling time of less than 6 months, autoimmune cytopenias poorly 
responsive to corticosteroids, or the presence of B symptoms (fevers greater than 38.0, unintentional 
weight loss >10% in six months, significant fatigue, or night sweats) [15]. 
 
The first chemotherapy treatments proven to be of benefit for patients with CLL were alkylator based 
regimens, with or without steroids.  For untreated patients, response rates range from 50-80%, but 
these include few complete remissions and a 5-year survival of approximately 50% [39-40] [41] [42-
43].  In the late 1980s, the nucleoside analogs, fludarabine [44-49], 2-chlorodeoxyadenosine [50-51], 
and pentostatin [52-53], emerged as effective therapies for CLL.  Based upon the very high response 
rates apparent in early clinical trials, fludarabine has received the most interest.  Fludarabine produces 
response rates of approximately 70-80% in previously untreated patients, including a complete 
response rate of up to 30%.  In previously treated patients, response rates to fludarabine of 50-70% 
are seen, including a 67% response rate in patients who received fludarabine as their initial therapy 
[44-49].  By combining fludarabine with rituximab [54-55] or cyclophosphamide plus rituximab [56-


 
4 
 
57], response rates as high as 90-95% can be achieved.  Two additionally approved agents for 
treatment of CLL include alemtuzumab and bendamustine.  Alemtuzumab, originally approved for 
fludarabine refractory CLL with overall response rates of 33% [58], has also received FDA approval 
in untreated CLL patients with an overall response rate of 83%, including a CR rate of 24% [59].  
Bendamustine, approved in 2008 for all lines of treatment of CLL, can generate an overall response 
rate of 68% and a CR rate of 30% in untreated patients with CLL [60]. 
 
Once a patient has progressed on fludarabine, few therapeutic options remain.  Fludarabine 
retreatment offers a possible option for some patients, with overall response rates of 67%, but a CR 
rate of only 20% [45].  Once a patient becomes refractory to fludarabine, the median overall survival 
is only nine to ten months [61-62].  Alemtuzumab, initially approved for patients whose disease is 
refractory to fludarabine, demonstrated 33% response rates, but an overall survival of only 16 months 
[58].  Ofatumumab, a novel antibody directed against CD20, is currently undergoing testing in these 
patients, with preliminary overall response rates of 51% in fludarabine-refractory patients that 
progress after alemtuzumab and 44% in fludarabine-refractory patients with bulky lymphadenopathy 
that are unlikely to respond to alemtuzumab [63].  Unfortunately, the overall survival for the two 
groups was 14 and 15 months, respectively. 
 
2.5  
Rational for Treatment in this Setting 
 
While CLL lymphocytes demonstrate impaired apoptosis in vivo, they undergo spontaneous apoptosis 
ex vivo, even when cultured with cytokines that maintain normal and other malignant B lymphocytes. 
 These data are often taken as evidence of CLL lymphocyte dependency upon cell surface derived 
signals (either cytokine or cell to cell mediated interactions) for survival.  Numerous cognate and non-
cognate pathways that may play vital roles in CLL cell survival have been identified, including 
CD40-CD154, VEGF, bFGF, BAFF/BLyS, APRIL, TNF-alpha, IL-4, and IL-10 [64-83].  Agents that 
alter or inhibit these cytokine networks may be able to play an important role in CLL therapy. 
 
Thalidomide and lenalidomide are immunomodulatory agents that are thought to work, in part, 
through the inhibition of cytokine networks and alteration of adhesion molecules, including multiple 
TNF family members [1-2].  One of the early rationales for testing thalidomide as a therapy for CLL 
were data suggesting a role for TNF-alpha in CLL cell survival [79-81] and the ability of thalidomide 
to inhibit TNF-alpha production [84].  Subsequent work has demonstrated additional mechanisms of 
action for thalidomide [85-87].  Clinical studies involving thalidomide, alone and in combination with 
chemotherapy, confirmed its activity as a therapy for CLL [3, 5].  Unfortunately, treatment with 
thalidomide was limited by its toxicities of neuropathy, sedation, and constipation.  
 
Lenalidomide, developed by chemically modifying thalidomide, demonstrates improved efficacy and 
tolerability compared with thalidomide, although its use is still limited by its toxicities of neutropenia, 
thrombocytopenia, tumor flare, and tumor lysis syndrome [4, 6, 88].  
 
Given the likely similar mechanisms of action for thalidomide and lenalidomide and that the toxicities 
of both agents are dose related, alternate daily dosing of these agents would provide continuous anti-
tumor effect, while utilizing a lower dose of each of the agents.  The alternating daily dosing of 
thalidomide and lenalidomide may result in better tolerability by potentially decreasing each agent’s 
toxicities, lead to longer duration of therapy and result in improved responses than has been 
accomplished with either agent alone.  Additionally, the combination of thalidomide and lenalidomide 


 
5 
 
may have additive or synergistic effects therapeutically.  The tolerability of thalidomide and 
lenalidomide used in combination has been demonstrated in studies of patients with multiple 
myeloma [89-90]. 
 
The potential tolerability and response rate of a regimen combining thalidomide, lenalidomide, and 
rituximab make it an ideal treatment for patients with CLL early in the course of their disease.  
Positioning such a regimen early in the treatment algorithm enables agents with greater toxicities to 
be delayed until required, helping preserve the patient’s quality of life for as long as possible. 
 
This phase II study would investigate the combination of thalidomide, lenalidomide and rituximab in 
patients with untreated CLL.  Patients will remain on the treatment regimen as long as they do 
demonstrate disease progression or toxicity. 
 
3. PATIENT SELECTION 
 
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 10, Schedule of Study Assessments and unless otherwise specified, must take 
place within 28 days prior to initiation of therapy.  Approximately 24 subjects with untreated CLL 
will be screened for enrollment and must meet the eligibility criteria below. 
 
Subjects must meet the following inclusion/exclusion criteria to be eligible for the study. 
3.1  
Inclusion Criteria 
1. Confirmed diagnosis of CLL or SLL based upon standard criteria as outlined in the 
IWCLL Update of the 1996 NCI-Working Group criteria for CLL [15]: 
a) Presence of one of the following: 
1. more than or equal to 5 x 109 B lymphocytes/L in the peripheral blood for 
a duration of at least 3 months.  Patients with a B lymphocytosis will be 
characterized as CLL, while those without will be characterized as SLL 
2. the presence of lymphadenopathy resulting from infiltration with 
lymphocytes with the phenotype of CLL 
3. bone marrow infiltration with lymphocytes with the phenotype of CLL 
b) Lymphocytes with the morphologic appearance of small, mature appearing 
lymphocytes, with < 55% prolymphocytes (blood or bone marrow) 
c) Cellular phenotype characterized by the: 
1. co-expression of the CD5, CD20, and CD23 surface antigens 
2. clonal kappa or lambda light chain expression 


 
6 
 
3. dim surface immunoglobulin expression 
2. No prior therapy for CLL, including treatment for autoimmune conditions that have 
developed since the initial diagnosis of CLL. 
3. Active disease requiring therapy as defined by the IWCLL Update of the 1996 NCI-
WG guidelines [15]: 
a) Evidence of progressive marrow failure as manifested by the development of 
worsening of anemia and / or thrombocytopenia 
b) Massive, progressive, or symptomatic splenomegaly 
c) Massive, progressive, or symptomatic lymphadenopathy 
d) Progressive lymphocytosis with an increase of more than 50% over a 2-month 
period or a lymphocyte doubling time of less than 6 months. 
e) Autoimmune 
anemia 
and/or 
thrombocytopenia 
poorly 
responsive 
to 
corticosteroids or other standard therapy 
f) Presence of disease related symptoms: unintentional weight loss of more than 10% 
within previous six months, significant fatigue, fevers greater than 100.5 F or 38.0 
C for 2 or more weeks without evidence of infection, night sweats for more than 1 
month without evidence of infection. 
4. Understand and voluntarily sign an informed consent form. 
5. Age 18 years at the time of signing the informed consent form. 
6. Able to adhere to the study visit schedule and other protocol requirements. 
7. ECOG performance status of  2 at study entry (see Appendix B). 
8. Laboratory test results within these ranges: 
 Absolute neutrophil count  1000/mm³ 
 Platelet count  50,000/mm³ 
 Creatinine clearance of ≥ 30 mL/min by Cockroft-Gault formula (see Appendix 
E).   Patients with a baseline creatinine clearance of >30 and < 60 mL/min will 
have a starting dose of lenalidomide 5 mg PO every other day per the defined 
schedule.  Patients with a baseline creatinine clearance of ≥ 60 mL/min will have a 
starting dose of lenalidomide 5 mg PO daily per the defined schedule (see Section 
5 for details). 
 Total bilirubin  1.5 times the ULN, unless abnormality is the result of Gilbert’s 
disease or the result of the CLL 


 
7 
 
 AST (SGOT) and ALT (SGPT)  3 x ULN (or  5 x ULN if due to the CLL) 
9. Disease free of prior malignancies for  2 years with exception of curatively treated 
basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma “in situ” of 
the cervix or breast.  
10. All study participants must be registered into the mandatory Revlimid REMS®    and 
S.T.E.P.S.® ( P-TAP: Protocol Therapy Assistance Program) program(s), and be 
willing and able to comply with the requirements of Revlimid REMS®  and 
S.T.E.P.S®. 
11. Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 – 14 days prior to 
and again within 24 hours of starting treatment and again within 24 hours before the 
first dose of lenalidomide AND thalidomide.  FCBP must either commit to continued 
abstinence from heterosexual intercourse or begin TWO acceptable methods of birth 
control, one highly effective method and one additional effective method AT THE 
SAME TIME, at least 28 days before she starts taking lenalidomide and/or 
thalidomide. Females of reproductive potential must adhere to the scheduled 
pregnancy testing as required in the Revlimid REMS® program .  Men must agree to 
use a latex condom during sexual contact with a FCBP even if they have had a 
successful vasectomy.  All patients must be counseled at a minimum of every 28 days 
about pregnancy precautions and risks of fetal exposure.  See Appendix A: Risks of 
Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Method.. 
12. Able to take aspirin 81 or 325 mg daily as prophylactic anticoagulation, unless already 
on therapeutic anticoagulation.  Patients intolerant to ASA may use coumadin or low 
molecular weight heparin. 
 
3.2  
Exclusion Criteria  
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from providing informed consent. 
2. 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.   
3. Evidence of laboratory TLS by Cairo-Bishop Definition of Tumor Lysis Syndrome 
(see Appendix D).  Subjects may be enrolled upon correction of electrolyte 
abnormalities.  
4. Concurrent use of other anti-cancer agents or treatments. 
                                                 
 
† 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). 




 
9 
 
mechanisms of action of thalidomide and lenalidomide.  Daily alternating IMiD™ agent therapy will 
begin with cycle 2 as follows: 
 Cycle -1: half of the patients (odd numbered subjects) will receive thalidomide 50 mg 
PO daily on days 1-14, followed by no treatment days 15-28 and the other half of the 
patients (even numbered subjects) will receive lenalidomide PO daily on days 1-14, 
followed by no treatment days 15-28.  The lenalidomide dose will be based on 
baseline calculated creatinine clearance*. 
 Cycles 1 and all escalation cycles: Patients will receive thalidomide 50 mg (every 
ODD day on Days 1-28 of a 28 day cycle: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 
25 & 27) with lenalidomide (every EVEN day on Days 1-28 of a 28 day cycle: Days 
2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28). Each cycle will be 28 days in 
length.  Patients who received lenalidomide during Cycle -1 will receive the same 
dose of lenalidomide starting with Cycle 1.  For patients who did not receive 
lenalidomide during Cycle -1, lenalidomide will be initiated at a starting dose based 
on baseline calculated creatinine clearance*.   
 Cycle 1: Patients will also receive rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 
(+/- 2 days) and then again on the same weekly x 4 schedule every 6th cycle through 
Cycle 19 (Cycle 7, 13, and 19).   
 
**** Rituximab can be given +/- 2days.   
****All correlative work must be drawn prior to Rituximab administration regardless of the day 
Rituximab is given. 
 
 
*The lenalidomide starting dose will be based on baseline calculated creatinine clearance as 
follows: 
 
Lenalidomide Starting Dose Based on Renal Function at Study Entry 
Baseline Calculated Creatinine 
Clearance (by Cockcroft-Gault) 
Starting Lenalidomide Dose 
 60 ml/min 
5 mg every EVEN day during Days 1 – 28 of each 28-
day cycle** 
 30 and < 60 ml/min 
5 mg every 2nd EVEN day during Days 1 - 28 of each 
28-day cycle** 
**For patients who receive lenalidomide during Cycle -1, the lenalidomide dose during Cycle -1 
will be at the dose indicated above (5 mg every other day or 5 mg  every 2nd EVEN day depending 
on baseline calculated creatinine clearance) taken daily on Days 1 – 14 of the 28-day cycle. 


 
10 
 
At investigator discretion, the lenalidomide dose may be gradually increased in a step-wise 
manner (in 5 mg increments) at the start of any subsequent 28-day treatment cycle beginning with 
the start of Cycle 2, if the patient tolerated the prior treatment cycle without requiring dose 
modifications, interruptions or delays due to toxicity.  For patients who initiate therapy at a 
lenalidomide 5 mg every 2nd EVEN day starting dose, the first dose titration would be to 
lenalidomide 5 mg every EVEN day, and subsequent dose titrations would be permitted in 5 mg 
increments.  The lenalidomide dose may only be increased at the start of a new cycle of therapy, 
may only be increased once every 28 days (or less frequently), and may only be increased if the 
prior treatment cycle was completed without requiring dose modifications, interruptions or delays 
due to toxicity.  For patients who initiate treatment at lenalidomide 5 mg based on baseline 
calculated creatinine clearance ≥ 60ml/min, the maximum allowable dose is lenalidomide 25 mg 
every EVEN day during Days 1-28 of a 28-day cycle.  For patients who initiate treatment at 
lenalidomide 5 mg every 2nd EVEN day due to baseline calculated creatinine clearance ≥ 
30ml/min but < 60ml/min, the maximum allowable dose is lenalidomide 15 mg every EVEN day 
during Days 1-28 of a 28-day cycle. 
 
5.2  
Investigational Study Drug Combination (THRIL) 
Starting with Cycle 1:   
A cycle is 28 days:  
Thalidomide 50 mg every ODD day, days 1-28 every 28 days 
Lenalidomide every EVEN day, days 1-28 every 28 days at the dose indicated above and with 
possible dose escalation as described in 5.1.    
Rituximab 375 mg/m2 IV on days 1, 8, 15 and 22 (+/- 2 days) starting with Cycle 1 and then again on 
the same weekly x 4 schedule every 6th cycle through Cycle 19 (Cycles 7, 13, and 19).   
Responses will be assessed at monthly intervals using the response criteria outlined by the IWCLL 
update of the 1996 NCI-Working Group criteria.  Patients will remain on treatment until they 
demonstrate disease progression or unacceptable toxicity.  It will be important for the investigator to 
differentiate disease progression from tumor flare.  While no strict criteria can be established for this 
distinction, rapid changes in clinical status that occur within four weeks of a dose escalation are likely 
to be tumor flares and should be treated as such. 
Tumor flare has been described with both thalidomide and lenalidomide treatment.  Therefore, 
patients should be monitor closely for signs and symptoms of tumor flare for four weeks after each 
increase in dose.  Prophylaxis for (TFR) is not recommended.  Grade 1 TFR may be treated with 
NSAIDs (i.e. ibuprofen 400-600 mg orally every 4-6 hours as needed).  TFR ≥ Grade 2 may be 
treated with corticosteroids.  Narcotic analgesics may be added as needed for pain control in subjects 
experiencing ≥ Grade 2 tumor flare.  If corticosteroids are used, the following dosage schedule is 


 
11 
 
recommended: prednisone 20 mg PO QD x 7 days followed by 10 mg PO QD x 7 days. (See 
Appendix D: Cairo Bishop Tumor Lysis Definition and Grading Criteria.) 
 
5.3 
Visit schedule and assessments 
Screening Assessments and all on study scheduled visits and assessments are outlined in Section 10 
Table of Study Assessments. 
At treatment discontinuation, subjects will undergo off study evaluations per the Schedule of 
Assessments, Section 10.   In addition, a safety assessment will be done approximately 28 days post 
the last dose of study drug.  Follow-Up contact with the subjects should occur at a minimum of sixth 
months. 
 
5.4 
Drug Administration 
 
5.4.1 Dosing regimen 
 Cycle -1: patients will receive thalidomide 50 mg PO daily on days 1-14 or lenalidomide 
PO on days 1-14, followed by no treatment days 15-28, as described previously in 5.1.   
 Cycle 1 and subsequent cycles: Patients will receive thalidomide 50 mg (every ODD day 
on days 1-28 of a 28 day cycle) with lenalidomide (every EVEN day on days 1-28 of a 28 
day cycle), as described previously. Each cycle will be 28 days in length.     
 Cycle 1: Patients will also receive rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22  and 
then again on the same weekly x 4 schedule every 6th cycle through Cycle 19 (Cycle 7, 13, 
and 19), as described previously.   
Patients unable to tolerate either thalidomide or lenalidomide will be removed from protocol.  Patients 
unable to tolerate rituximab can continue on with protocol treatment without additional rituximab 
being administrated.  
Dosing of thalidomide and lenalidomide should be at bedtime in order to allow for the sedative effects 
of thalidomide to not cause daytime somnolence and to maintain regular dosing intervals.  Only 
enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle. At the 
start of any non-clinic visit treatment cycles subsequent to Cycle 24, one cycle of study drug will be 
shipped to the subject. 
See Section 5.5 for allopurinol and oral hydration requirements as prophylaxis against tumor lysis 
syndrome (TLS). 
Thalidomide and lenalidomide capsules should be swallowed whole, and should not be broken, 
chewed or opened.    
If a dose of thalidomide or 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. 


 
12 
 
Patients who take more than the prescribed dose of thalidomide or 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 5.6). 
 
5.4.2 Record of administration 
Accurate records will be kept of all study drug administration (including dispensing 
and dosing) will be made in the source documents. At all times, when dispensing 
study drug, research center personnel will review the instructions, printed on the 
packaging, with subjects. Subjects will be asked to maintain a diary to record the drug 
administration. 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 visit and 
reconcile with the patient diary. At the start of any non-clinic visit treatment cycles 
subsequent to Cycle 24, the packaging instructions will be reviewed with subjects by 
telephone call, and study drug and medication log will be shipped to the subject. 
 
5.5  
General Concomitant Medication and Supportive Care Guidelines 
 
 
5.5.1 Recommended Concomitant Therapy   
Subjects should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, and antiemetics when appropriate.  Starting with  Cycle   -1 and 
while on study, subjects will receive prophylaxis against Pneumocystis pneumonia 
(with Bactrim DS thrice weekly or equivalent), varicella zoster (with valacyclovir 500 
mg daily or equivalent), tumor lysis syndrome (with allopurinol and 8-10 eight ounce 
glasses of  fluid daily), and thrombosis (with aspirin 81 mg daily). 
Patients intolerant to or unable to take allopurinol beyond the first 2 cycles and can 
maintain adequate oral hydration are still eligible to continue to receive treatment on 
study.  Patients who cannot take allopurinol for at least the first 2 cycles are to be 
removed from study. 
Treating physicians must watch for signs of tumor lysis syndrome.  It is recommended 
that all patients with signs of significant tumor lysis syndrome be hospitalized for 
monitoring, aggressive fluid management, and possible rasburicase. 
 
Hematopoietic Growth Factors 
Myeloid growth factors (G-CSF and pegfilgrastim only) may be used.  GM-CSF may 
not be used given the theoretical impact it might have on CLL disease activity.  
Erythropoietic Stimulating Agents (ESAs; Aranesp, Procrit) may be used at the 
discretion of the treating physician and need to be recorded in the medication list. 


 
13 
 
 
 
Anticoagulation Considerations 
Patients already on aspirin or other anticoagulation should remain on the current 
anticoagulation dosing regimen they are on.  If they are not on anticoagulation, then 
they should initiate prophylaxis with aspirin 81 mg or 325 mg daily on Day 1 of Cycle 
-1.  Dose is at the discretion of the Investigator.  Coumadin or low molecular weight 
heparin may be utilized in patients that are intolerant to ASA. 
If prophylactic anti-coagulation is used, it should be held for platelet counts < 
50,000/mm3 and then restarted when platelet counts are above this level. 
 
 
 
Tumor Lysis Syndrome Prophylaxis (allopurinol and hydration) 
Tumor lysis syndrome (TLS), characterized by hyperkalemia, hyperuricemia, and 
hyperphosphatemia resulting from the rapid release of potassium, uric acid, and 
phosphate, has been reported in CLL patients treated with lenalidomide necessitating 
TLS prophylaxis including allopurinol and oral hydration.  The risk of TLS is highest 
during the first cycle of therapy and may be elevated when lenalidomide is re-started 
after treatment interruptions or when the lenalidomide dose is escalated. 
If patients are intolerant or unable to take allopurinol beyond the first 2 cycles AND 
can maintain adequate hydration, it will be up to the discretion of the Investigator if 
patient can continue the treatment plan.  Patients who cannot take allopurinol for at 
least the first 2 cycles are to be removed from study. 
Allopurinol 300 mg daily beginning at least 3 days before the start of Cycle -1,  
continuing through any cycle of lenalidomide escalation and continuing, at least for 
one additional cycle post escalation as TLS prophylaxis is required for all subjects.   
Subjects should be instructed to maintain adequate hydration and maintain urinary 
output as an additional measure to prevent TLS.  To maintain fluid intake, subjects 
should be instructed to drink 8 to 10 eight ounce glasses of fluid each day for the first 
14 days of Cycle -1 and Cycle 1 and any subsequent cycle of lenalidomide escalation. 
 Hydration levels should be adjusted according to age and clinical status, and lowered 
if the subject’s cardiovascular status indicates the possibility of volume overload.  
Within the first 3 cycles of therapy, additional oral hydration should be considered 
concurrent with any dose escalation (or re-escalation, if permitted) of treatment, or 
when treatment is restarted after having been held for any reason. 
Based on a patient’s reaction and laboratory parameters, TLS prophylaxis may be 
continued or restarted as needed at the Investigator’s discretion. 
 


 
14 
 
 
 
 
Treatment and Dose Modification for Tumor Lysis Syndrome 
All subjects meeting criteria of laboratory TLS or ≥ Grade 1 TLS according to the 
Cairo-Bishop Definition of Tumor Lysis Syndrome (see Appendix D) should receive 
vigorous intravenous hydration and should be considered for rasburicase therapy as 
needed to reduce hyperuricemia, until correction of electrolyte abnormalities.   
 In cases of laboratory TLS and Grade 1 TLS (see Appendix D: Cairo-Bishop 
Definition of Tumor Lysis Syndrome), lenalidomide and thalidomide will be 
continued at the same dose without interruption or dose reduction.  TLS 
prophylaxis measures outlined in Section 5.5.1 should be continued or re-
instituted. 
 Subjects with ≥ Grade 2 TLS (see Appendix D: Cairo-Bishop Definition of Tumor 
Lysis Syndrome) will be managed as follows in addition to intravenous hydration 
and consideration for rasburicase therapy (above).   
o Hold (interrupt) treatment. 
o First episode: restart lenalidomide and thalidomide at the current dose with 
appropriate TLS prophylaxis (Section 5.5.1) after resolution of electrolyte 
abnormalities to Grade 0.   
o Subsequent episodes: restart lenalidomide and thalidomide with 
appropriate TLS prophylaxis (Section 5.5.1) after resolution of electrolyte 
abnormalities to Grade 0.  At physician discretion, the doses of 
lenalidomide and thalidomide may be restarted at the current dose or the 
dose of lenalidomide and/or thalidomide may be reduced by 1 dose level.  
o First or subsequent episodes: subjects should be closely monitored for 
signs of TLS after resuming treatment.  To monitor for TLS, serum 
chemistry and uric acid tests should be performed at least every week 
following initiation of treatment for 4 consecutive weeks and on Day 3 or 
4 following initiation of treatment.  See Section 10, Schedule of Study 
Assessments, for additional specifics regarding serum chemistry and uric 
acid testing.  
 
 
 
 
Tumor Flare Reaction 
Prophylaxis for (TFR) is not recommended.  Grade 1 TFR may be treated with 
NSAIDs (i.e. ibuprofen 400-600 mg orally every 4-6 hours as needed).  TFR ≥ Grade 
2 may be treated with corticosteroids.  Narcotic analgesics may be added as needed for 
pain control in subjects experiencing ≥ Grade 2 tumor flare.  If corticosteroids are 
used, the following dosage schedule is recommended; prednisone 20 mg PO QD x 7 


 
15 
 
days followed by 10 mg PO QD x 7 days. Given the potential for tumor flares to occur 
at each escalation of lenalidomide dose, prednisone treatment may be repeated at each 
occurrence of tumor flare.  Patients experiencing tumor flares should not have their 
dose of lenalidomide escalated the subsequent cycle. 
Tumor flare occurring during a cycle when the dose of lenalidomide or thalidomide 
was escalated should be recorded as an adverse event and not as progressive disease 
(PD).  For tumor flare occurring after the first 2 weeks of any cycle of lenalidomide 
escalation, it is up to the discretion of the physician to differentiate tumor flare from 
progression.  It is expected that some degree of tumor flare reaction is likely until the 
patient is on the maximum dose of lenalidomide for more than four weeks.  Because 
of this and the typically indolent nature of CLL, investigators are encouraged to 
continue escalating a subject’s lenalidomide dose if safe and not to determine a patient 
as having progressive disease until after they have been on the maximum dose of 
lenalidomide for more than four weeks. 
 
 
 
5.5.2 Prohibited concomitant therapy 
Concomitant use other anti-cancer therapies, including radiation, or other 
investigational agents is not permitted while subjects are receiving study drug during 
the treatment phase of the study.  Corticosteroids may be administered for treatment of 
a tumor flare reaction as detailed above.   
 
5.6  
Duration of Therapy and Criteria for Removal From Study 
 
 Treatment will continue until the occurrence of any of the following events.   
 Disease progression (excluding tumor flare) 
 Adverse event(s) that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of the treatment regimen. 
 Discontinuation of thalidomide or lenalidomide for any reason.  (Note, patients 
who are unable to tolerate rituximab infusions may still continue on the protocol.) 
 Major violation of the study protocol. 
 Withdrawal of consent 
 Lost to follow up 
 Death 
 Suspected pregnancy or positive pregnancy 
 
5.7 
Duration of Follow Up 
Subjects who discontinue treatment for any reason will be followed for 30 days. At 28 days post 
treatment, subjects will undergo a safety assessment.  In addition, off study evaluations per the 
Schedule of Assessments, Section 10 will be done. 
 


 
16 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Reduction and Escalation Steps 
Doses of the agent believed to be the cause of the AE should be held until resolution of the AE (see 
Section 6.3 for detailed dose modification instructions). 
Table 1 below is used for step-wise dose titration of lenalidomide and for dose reductions of 
lenalidomide or thalidomide.  In all cases, dose modifications should be applied one Dose Level at a 
time.  Please see Section 5.1 for dose escalation criteria and other details. 
 
 
Table 1: Dose Levels 
Lenalidomide 
Dose Level -2* 
5 mg every 3rd EVEN day on Days 1-28 of a 28 day cycle* 
Dose Level -1*** 
5 mg every 2nd EVEN day on Days 1-28 of a 28 day cycle  
Dose Level 1** 
5 mg every EVEN  day on Days 1-28 of a 28 day cycle 
Dose Level 2 
10 mg every EVEN  day on Days 1-28 of a 28 day cycle  
Dose Level 3 
15 mg every EVEN other day on Days 1-28 of a 28 day cycle   
Dose Level 4 
20 mg every EVEN other day on Days 1-28 of a 28 day cycle   
Dose Level 5 
25 mg every EVEN other day on Days 1-28 of a 28 day cycle   
Thalidomide 
Dose Level -1 
50 mg every 2nd ODD day on Days 1-28 of a 28 day cycle  
Dose Level 1 
50 mg every ODD day on Days 1-28 of a 28 day cycle  
 
Lenalidomide 5 mg every 3rd even day is the minimum lenalidomide dose.  Lenalidomide will be discontinued in patients 
who cannot tolerate this dose.  However, patients who experience toxicity requiring dose reduction while receiving 
lenalidomide 5 mg every 3rd even day may, at the discretion of their physician, have their dose held until toxicity resolves 
as described in Sections 6.2 and 6.3, and then restart lenalidomide at 5 mg every 3rd even day.  If the same toxicity recurs 
at lenalidomide 2.5 mg every second even day, consideration should be given to discontinuing lenalidomide. 
 
** For lenalidomide, Dose Level 1 is the starting dose for patients that have a baseline creatinine clearance ≥ 60ml/min 
(along with thalidomide Dose Level 1). 
*** For lenalidomide, Dose Level -1 is the starting dose for patients that have a baseline creatinine clearance ≥ 30ml/min 
and < 60ml/min (along with thalidomide Dose Level 1). 
 
Lenalidomide dose escalation is permitted in a step-wise manner per Table 1.  Please see Section 
5.1 for dose escalation criteria and other details. 
 
6.2  
Instructions for Initiation of a New Cycle  
A new course of treatment may begin on the scheduled day 1 of a new cycle utilizing the same criteria 
as outlined for dose modifications in sections 6.3, table 2. 


 
17 
 
 The ANC is ≥ 1000/mm³; if ANC is between 500-1000/mm3 and not associated with 
fever > 38.5°C, the new cycle should start as planned and G-CSF or pegfilgrastim may 
be used to support neutrophil count.   
 The platelet count is ≥ 25,000/mm³;  
 Any drug-related rash that may have occurred has resolved to ≤ grade 1 severity; 
 Any drug-related neuropathy that may have occurred has resolved to < grade 2 in 
severity; 
 Tumor lysis syndrome (TLS) has not exceeded grade 1 severity during previous cycle 
(see Appendix D: Cairo-Bishop Definition of Tumor Lysis Syndrome); 
 If TLS ≥ grade 2 during previous cycle (see Appendix D: Cairo-Bishop Definition of 
Tumor Lysis Syndrome), electrolyte abnormalities have resolved to ≤ grade 0 severity; 
 Any other drug-related adverse events that may have occurred have resolved to ≤ 
grade 2 severity.  
 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly and a 
new cycle of treatment will not be initiated until the toxicity has resolved as described above.  If the 
dose of lenalidomide or thalidomide was reduced during the previous cycle, and the cycle was 
completed without requiring further dose modification, then the next cycle will start at the same doses 
of lenalidomide and thalidomide as given at the end of the previous cycle.  If lenalidomide or 
thalidomide dosing was omitted for the remainder of the previous cycle due to toxicity 
attributed to lenalidomide or thalidomide or if the new cycle is delayed due to lenalidomide-
related or thalidomide-related toxicity newly encountered on the scheduled Day 1, then the   new 
cycle will be started with a one-level dose reduction of lenalidomide or thalidomide based on 
attribution. 
Instructions for dose modifications or interruption  
Dose delay and dose reduction rules are as follows and in the table below. 
 Lenalidomide and thalidomide dose reduction steps are outlined in Section 6.1.   
 For treatment interruptions during a cycle, the 28-day schedule of each cycle will continue to 
be followed.  Missed doses of lenalidomide or thalidomide are not made up.   
 For treatment interruptions that delay the scheduled start of a new cycle, when toxicity has 
resolved as required to allow the start of a new cycle (Section 6.2), the restart day of therapy 
becomes Day 1 of the next cycle. 
 


 
18 
 
Dose re-escalation of lenalidomide following dose reductions due to neutropenia, thrombocytopenia, 
tumor lysis syndrome, tumor flare, rash, neuropathy, hypothyroidism or hyperthyroidism: 
 If the dose of lenalidomide has been reduced for neutropenia, thrombocytopenia, rash, 
neuropathy, lenalidomide dose re-escalation is permitted if the subject completes one full 
cycle without experiencing any toxicity that requires dose interruption or reduction.  The 
lenalidomide dose may be increased by one dose level at the initiation of a new cycle of 
therapy.   
 If the dose of lenalidomide has been dose reduced for tumor lysis syndrome, lenalidomide 
dose re-escalation is permitted if the subject completes one full cycle without experiencing a 
laboratory TLS or ≥ Grade 1 TLS (see Appendix D: Cairo-Bishop Definition of Tumor Lysis 
Syndrome), unless the subject requires a dose interruption/reduction for other toxicity.   
 If the dose of lenalidomide has been dose reduced for tumor flare, lenalidomide dose re-
escalation is permitted if the subject completes one full cycle without experiencing ≥ Grade 1 
tumor flare, unless the subject requires a dose interruption/reduction for other toxicity.   
 The dose of lenalidomide will be reduced for hypothyroidism or hyperthyroidism as outlined 
in Table 2.    
 Serum chemistry and uric acid should be closely monitored for signs of laboratory or clinical 
TLS (see Appendix D: Cairo-Bishop Definition of Tumor Lysis Syndrome) following 
lenalidomide dose re-escalation (see Section 2, Schedule of Study Assessments, for details 
regarding serum chemistry and uric acid monitoring).   
 TLS prophylaxis with allopurinol and hydration as described in Section 5.5.1 should be 
considered with each dose re-escalation. 


 
19 
 
 
6.3  
Instructions for dose modifications or interruption during a cycle 
 
 
Table 2: Dose Modifications 
NCI CTC Toxicity Grade 
Action 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) or 
Grade 4 neutropenia 
 Hold lenalidomide, thalidomide and, if applicable, rituximab dosing.   
Omitted doses are not made up. 
 Follow CBC weekly. 
 Once neutropenia has resolved to ≤ grade 3, restart treatment as scheduled. 
Restart lenalidomide at next lower dose level.*  If neutropenia is the only 
toxicity for which a dose reduction is required, G-CSF or pegfilgrastim may 
be used in order to allow maintaining the dose of lenalidomide. 
 
Thrombocytopenia ≥ 
Grade 4 (platelet count < 
25,000/mm³) 
 Hold lenalidomide, thalidomide and, if applicable, rituximab dosing.  Omitted 
doses are not made up. 
 Hold prophylactic anti-thrombotic agents 
 Follow CBC weekly. 
 Once thrombocytopenia resolves to ≤ grade 3, restart treatment as scheduled. 
Restart lenalidomide at next lower dose level.*   
 
Platelet count < 
50,000/mm³ 
 Hold prophylactic anti-coagulation, if applicable. 
 Restart prophylactic anti-coagulation when platelet count is ≥ 50,000/mm³. 


 
20 
 
Table 2: Dose Modifications 
NCI CTC Toxicity Grade 
Action 
 
Non-blistering rash 
Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
             Grade 4 
 If Grade 3, hold lenalidomide, thalidomide, and, if applicable, rituximab 
dosing.  Omitted doses are not made up.. 
 Follow weekly. 
 If rash development is related to a rituximab infusion, restart treatment as 
scheduled at the previous doses once toxicity resolves to ≤ grade 1. 
 If the development of the rash is not related to a rituximab infusion, and the 
rash is purpuric, vasculitic, or bullous, or possibly the result of Stevens-
Johnson Syndrome or toxic epidermal necrolysis, the patient will be 
discontinued from the study. 
 If the development of the rash is not related to a rituximab infusion and 
inconsistent with Stevens - Johnson syndrome, the clinician may re-institute 
therapy once the toxicity resolves to ≤ grade 1.  Re-institute lenalidomide 
monotherapy at a one dose level reduction.   If no recurrence of the rash 
occurs after one week, then restart thalidomide monotherapy at 50 mg every 
other day.   Further dose escalation of the lenalidomide will be at the 
discretion of the treating physician per guidelines in Section 6.2. 
 
 Discontinue treatment and remove patient from study. 
Desquamating (blistering) 
rash- any Grade  
 Discontinue treatment and remove patient from study. 
Neuropathy 
Grade 3 
 
 
 
 
Grade 4 
 Hold lenalidomide and, if applicable, rituximab, and discontinue thalidomide 
doses.  Follow weekly.  Omitted doses are not made up.. 
 When toxicity improves to ≤ grade 2, restart treatment as scheduled.  Restart 
lenalidomide one dose level lower.  Thalidomide will not be re-introduced 
given its strong association with neuropathy. 
 
 Discontinue lenalidomide.  Remove patient from study. 
Venous 
thrombosis/embolism 
≥ Grade 3 
 Hold lenalidomide, thalidomide, and, if applicable, rituximab, doses and start 
anticoagulation; restart lenalidomide and thalidomide dosing at investigator’s 
discretion (maintain dose level).   
 Omitted doses are not made up.. 
Hyperthyroidism or 
hypothyroidism 
 
Grade 3 
 Hold thalidomide, lenalidomide and, if applicable, rituximab.   Omitted doses 
are not made up.. 
 Evaluate etiology and initiate appropriate therapy.  When toxicity improves to 
≤ grade 2, restart treatment as scheduled.  Restart lenalidomide at one dose 
level lower and thalidomide at the same dose.   
other non-hematologic 
toxicity ≥ Grade 3 
 Hold lenalidomide, thalidomide, and, if applicable, rituximab doses.  Follow 
weekly.  Omitted doses are not made up.. 
 Restart lenalidomide, thalidomide, and / or rituximab therapy at discretion of 
investigator, if the toxicity resolves to ≤ grade 2 and consider dose reduction of 
most likely causative agent. 
* Lenalidomide 5 mg every 3rd even day is the minimum lenalidomide dose.  Lenalidomide will be discontinued 
in patients who cannot tolerate this dose.  However, patients who experience toxicity requiring dose reduction 
while receiving lenalidomide 5 mg every 3rd even day may, at the discretion of their physician, have their dose 
held until toxicity resolves as described in Sections 6.2 and 6.3, and then restart lenalidomide 5 mg every 3rd even 
day.  If the same toxicity recurs at lenalidomide 5 mg every 3rd even day, consideration should be given to 
discontinuing lenalidomide. 


 
21 
 
Treatment Compliance 
At all times, when dispensing protocol therapy, research center personnel will review the instructions, 
printed on the packaging, with subjects. Subjects will be asked to maintain a medication log to record 
the drug administration. Subjects will be asked to bring any unused drug and empty drug containers to 
the research center at their next visit.  Research personnel will count and record the number of used 
and unused drug at each visit and reconcile with the patient medication log.  Any unused Thalomid® 
(thalidomide) or Revlimid® (lenalidomide) should be returned to the patient for disposition in 
accordance with the STEPS® and RevAssist® programs. At the start of any non-clinic visit treatment 
cycles subsequent to Cycle 24, the packaging instructions will be reviewed with subjects by telephone 
call, and study drug and medication log will be shipped to the subject. 
 
 
7. ADVERSE EVENT REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The investigator 
will be required to provide appropriate information concerning any findings that suggest significant 
hazards, contraindications, side effects, or precautions pertinent to the safe use of the drug under 
investigation.  Safety will be monitored by evaluation of adverse events reported by patients or 
observed by investigators or research staff, as well as by other investigations such as clinical 
laboratory tests, x-rays, electrocardiographs, etc. 
 
7.1  
Adverse Event Characteristics  
 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  A copy of the CTCAE version 
4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
7.2 
Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific adverse event log.  The AE log 
will be maintained by the research staff and kept in the patient’s research chart.    
 
 
7.3 
Serious Adverse Event (SAE) Reporting 
 
 
7.3.1  Definition of SAE 
 
 
Serious Adverse Event (SAE) Definition  
A serious adverse event is one that at any dose (including overdose): 


 
22 
 
 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 
 Positively identified 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 result in inpatient hospitalization, or the development of drug dependency or drug abuse.  A new 
diagnosis of cancer during the course of a treatment should be considered as medically important.  
 
7.3.2  Adverse Event Reporting 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE Version 4.0 can be downloaded from the CTEP 
homepage (HTTP://CTEP.INFO.NIH.GOV).  All appropriate areas should have 
access to a copy of the CTCAE Version 4.0.  All adverse clinical experiences, whether 
observed by the investigator or reported by the patient, must be recorded, with details 
about the duration and intensity of each 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. 
 
 
7.3.3 Pregnancies 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless 
of age or disease state) of a female subject occurring while the subject is on IP 
(Investigational Product), or within (insert time-frame which must be at least 28 days 






 
25 
 
 If the event is unexpected AND definitely or probably related to the study, 
complete the IRB Unexpected, Study-related Adverse Events, Incidents, and 
Information Reporting Form.  This form should be submitted within 24 hours of 
investigator notification of the event. 
 If the event is expected OR possibly or unrelated to the study, only the SAE Cover 
Sheet must be completed.  These events will be reported to the IRB at the time of 
continuing renewal on the Adverse Event & IND Safety Reporting Cumulative 
Table. 
 
Forms may also be downloaded from the IRB website at: 
http://www.med.cornell.edu/research/for_pol/ins_rev_boa.html 
 
 
7.8 
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. 
 
The Investigator must keep copies of all AE information, including correspondence with 
Celgene and the IRB/EC, on file (see Section 12.1 for records retention information). 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1  
Lenalidomide 
8.1.1   Chemistry 
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
 


 
26 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight 
is 259.3.  
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble 
in organic solvents and low pH solutions. Solubility was significantly lower in less 
acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric 
carbon atom and can exist as the optically active forms S(-) and R(+), and is produced 
as a racemic mixture with a net optical rotation of zero. 
REVLIMID® (lenalidomide) is available in 5 mg and 25 mg capsules for oral 
administration.  
 
 
8.1.2 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 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.   
 
 
8.1.3 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 


 
27 
 
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.  
 
 
8.1.4 Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no 
charge through the RASP program (RevAssist® for Study Participants).  See 
Appendix G.   
 
 
8.1.5 Dosage form 
 
Lenalidomide will be supplied as 5 mg and 25 mg capsules for oral administration.   
 
 
8.1.6 Packaging 
Lenalidomide will be shipped on a per subject basis by the contract pharmacy to the 
clinic site.   Bottles will contain a sufficient number of capsules for one cycle of 
dosing.    
 
 
 
 
8.1.7 Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold.     
 
 
 
8.1.8 Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless 
they are wearing gloves. 
 
 
 
8.1.9 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 Celgene Corporation’s 
Revlimid REMS® program.  Per standard Revlimid REMS® program requirements,  


 
28 
 
all physicians who prescribe lenalidomide for research subjects enrolled into this trial, 
and all research subjects enrolled into this trial, must be registered in, and must 
comply with, all requirements of the Revlimid REMS® program.   
Only enough lenalidomide for one cycle of therapy will be supplied to the patient each 
cycle. 
 
8.1.10 Pregnancy Testing    
Pregnancy tests for females of childbearing potential.  A female of childbearing 
potential (FCBP) is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal 
for at least 24 consecutive months (i.e., has had menses at any time in the preceding 
24 consecutive months). 
 
Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to 
prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days).  
FCBP with regular or no menstruation must have a pregnancy test weekly for the first 
28 days and then every 28 days while on therapy (including breaks in therapy); at 
discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide.  
Females with irregular menstruation must have a pregnancy test weekly for the first 28 
days and then every 14 days while on therapy (including breaks in therapy), at 
discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of 
lenalidomide (see Appendix A: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods).    
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject is 
on lenalidomide, or within  28 days of the subject’s last dose of lenalidomide, are 
considered immediately reportable events. Lenalidomide  is to be discontinued 
immediately. The pregnancy, suspected pregnancy, or positive pregnancy test must 
be reported to Celgene Drug Safety immediately by facsimile or email using the 
Pregnancy Initial Report Form. The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for 
further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, 
and must notify Celgene Drug Safety immediately about the outcome of the 
pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up 
Report Form.  If the outcome of the pregnancy was abnormal (e.g., spontaneous or 
therapeutic abortion), the Investigator should report the abnormal outcome as an 
AE. If the abnormal outcome meets any of the serious criteria, it must be reported 
as an SAE to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form. 


 
29 
 
 
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the IP should also be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form.  
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taking lenalidomide should notify the Investigator, and 
the pregnant female partner should be advised to call their healthcare provider 
immediately. 
 
8.2  
THALOMID (thalidomide) 
 
 
8.2.1 Chemistry 
THALOMID(thalidomide), α-(N-phthalimido) glutarimide, is an immunomodulatory 
agent.  The empirical formula for thalidomide C₁₃H₁₀N₂O₄ and the gram molecular 
weight is 258.2.  The CAS number of thalidomide is 50-35-1.  Thalidomide is off-
white to white, nearly odorless, crystalline powder that is soluble at 25°C in dimethyl 
sulfoxide and sparingly soluble in water and ethanol.  The glutarimide moiety contains 
a single asymmetric center and, therefore, may exist in either of two optically active 
forms designated S (-) or R (+).  THALOMID (thalidomide) is an equal mixture of 
the S (-) and R (+) forms and, therefore, has net optical rotation of zero. 
Active ingredient: thalidomide.  Inactive ingredients: anhydrous lactose, 
microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous 
silica, and gelatin.  
 
8.2.2 Pharmacology and Pharmacokinetics 
Clinical pharmacokinetics studies have shown that thalidomide when administered as 
a single 200 mg dose, the mean peak plasma concentration is 1.9 g/ml  0.5, 
occurring 3.3 hours  1.7 after dosing.  Mean half-life of elimination is 5.9 hours  
2.1. Single dose, dose proportionality was evaluated over the clinical dose range, i.e., 
from 50 to 400 mg. The extent of absorption is proportional to dose, however, as the 
dose increases beyond 200 mg, a flattening of the peak concentration is seen with a 
delay in the time to the peak concentration. The mean peak plasma concentration 
following a single 400 mg dose administration was 2.82 g/ml  0.80 occurring by 4.3 
 1.6 hours after the dose; mean half-life of elimination was 7.29 hours  2.62. The 
rate of absorption was also slower at the highest dose as evidenced by a rate constant 


 
30 
 
of absorption that was approximately one-half that observed at the lower doses. 
 
8.2.3 Human Toxicology 
Available data from three clinical pharmacology studies sponsored by Celgene 
Corporation showed that 38 subjects have been exposed to single doses of thalidomide 
given either on one occasion or three occasions with one to two week washouts 
between doses. Two studies were conducted in healthy volunteers and the third study 
was conducted in patients with Hansen’s disease. Thalidomide was administered in a 
50 to 400 mg single dose range. 
Based on the results of the studies, the most frequently reported adverse experiences 
were dizziness (31 subjects or 82 %), somnolence (29 subjects or 76%), headache (15 
subjects or 39%), and asthenia (12 subjects or 32%).  Somnolence and dizziness were 
reported to occur more frequently at doses of 200 mg and 400 mg than they did at a 
dose of 50 mg. There was no dose relationship evident for the remaining adverse 
experiences. 
There was no reported severity in intensity of all adverse experiences. All events were 
mild with the exception of moderate somnolence in 13 subjects, moderate dizziness in 
6 subjects, moderate headache in 4 subjects, moderate hypotension in 2 subjects and 
moderate constipation and moderate pallor in 2 subjects, and a single report of 
moderate asthenia, diarrhea, leg cramps, nausea and rhinitis.  There have been reports 
of a slowing of the heart rate. 
Thalidomide is known to cause nerve damage that may be permanent. Peripheral 
neuropathy is a common, potentially severe, side effect of treatment with thalidomide 
that may be irreversible. Peripheral neuropathy generally occurs following chronic use 
over a period of months, however, reports following short-term use also exist. The 
correlation with cumulative dose is unclear. Patients should be examined at monthly 
intervals for the first three months of thalidomide therapy to enable the clinician to 
detect early signs of neuropathy, which include numbness, tingling or pain in the 
hands and feet. Patients should be evaluated periodically thereafter during treatment. 
If symptoms of drug-induced neuropathy develop, thalidomide should be discontinued 
immediately to limit further damage, if clinically appropriate. Usually treatment with 
thalidomide should only be reinitiated if the neuropathy returns to baseline status.  
Serious dermatologic reactions including toxic epidermal necrolysis and Stevens-
Johnson syndrome, which may be fatal, have been reported in association with 
thalidomide therapy.  THALOMID should be discontinued, if a skin rash occurs and 
only resumed following appropriate clinical evaluation.  If the rash is purpuric, 
vasculitic, exfoliative, or bullous or if Stevens-Johnson syndrome or toxic epidermal 
necrolysis is suspected, use of THALOMID should not be resumed. 


 
31 
 
The use in Thalidomide in Multiple Myeloma results in an increased risk of venous 
thromboembolic events, such as deep vein thrombosis and pulmonary embolus. The 
risk increases significantly when thalidomide is used in combination with standard 
chemotherapeutic agents including dexamethasone. In one controlled trial the rate of 
venous thromboembolic events was 22.5% in patients receiving thalidomide in 
combination with dexamethasone compared to 4.9% receiving dexamethasone alone. 
Patients and physicians are advised to be observant for signs of thromboembolism. 
Patients should seek medical attention should they develop symptoms such as 
shortness of breath, chest pain or leg or arm swelling. Preliminary reports suggest that 
patients who are appropriate candidates may benefit from concurrent prophylactic 
anticoagulation or aspirin treatment. 
Although not reported from pre-marketing controlled clinical trials, seizures, including 
grand mal convulsions, have been reported during post-approval use of THALOMID® 
(thalidomide) in clinical practice.  Because these events are reported voluntarily from 
a population of unknown size, estimates of frequency cannot be made.  Most patients 
had disorders that may have predisposed them to seizure activity, and it is not 
currently known whether thalidomide has any epileptogenic influence.  During 
therapy with thalidomide, patients with a history of seizures or with other risk factors 
for the development of seizures should be monitored closely for clinical changes that 
could precipitate acute seizure activity. 
THALOMID(thalidomide) can cause severe birth defects in humans.   Women 
and men taking thalidomide must take special precautions and be willing and 
able to comply with all aspects of the FDA-mandated S.T.E.P.S.® program. (see 
Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods).   
This medicine is for subject use ONLY. IT SHOULD NOT BE SHARED WITH 
ANYONE. It should be safely stored.  It must be kept out of the reach of children and 
should never be given to women who are able to have children, and used only as 
directed by the physician. 
Subjects should not drink alcohol or take any other medicine that has not been 
prescribed by the doctor, especially nonprescription drugs that makes the subject 
sleepy. 
 
8.2.4 Formulation 
 
THALOMID(thalidomide) is available in 50 mg capsules for oral administration. 
 
8.2.5 Storage and Stability 
Thalidomide has been shown to be stable for up to 36 months when stored under 


 
32 
 
ambient   conditions. Over this time period, the capsules show no significant loss in 
potency and no increase in degradation products. Thalidomide has been shown also to 
be stable when stored under accelerated conditions (40°C/75% Relative humidity, 3 
months). Clinical supplies should be retained in a secure, cool dry place. 
 
 
8.2.6 Supplier(s) 
Celgene Corporation will supply Thalomid® (thalidomide) to study participants at no 
charge through the P-TAP (S.T.E.P.S®) program (see Appendix F).  
 
 
8.2.7 Dosage form 
Thalidomide will be supplied as capsules for oral administration.   
 
  
 
8.2.8 Packaging 
Thalidomide will be shipped on a per subject basis by the contract pharmacy to the 
clinic site.   Bottles will contain a sufficient number of capsules for one cycle of 
dosing.    
 
 
8.2.9 Special Handling Instructions 
 
Females of childbearing potential should not handle or administer lenalidomide unless 
they are wearing gloves. 
            8.2.10 Prescribing Information 
Patients enrolled into this trial are eligible to participate in Celgene’s Protocol 
Therapy Assistance Program (PTAP). Celgene will provide Thalidomide to study 
patients free of charge through PTAP.  Thalidomide (Thalomid®) will be provided in 
accordance with the S.T.E.P.S.® program of Celgene Corporation.  Per standard 
S.T.E.P.S.® requirements all physicians who prescribe thalidomide 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 S.T.E.P.S.® program.  
Prescriptions must be filled within 7 days.  Authorization numbers are only valid for 7 
days.  Only enough thalidomide for one cycle of therapy will be supplied to the 
patient each cycle, but no more than a 28 day supply.  
 
Thalidomide must be prescribed through and in compliance with the S.T.E.P.S® 
program of Celgene Corporation.  Prescriptions must be filled within 7 days.  
Authorization numbers are only valid for 7 days.  Consideration should be given to 
prescribing thalidomide 5 to 7 days in advance of Day 1 of each cycle to allow time 
for required patient and prescriber surveys, and drug shipment to patient.  Any unused 
Thalomid® (thalidomide) should be returned to the patient for disposition in 


 
33 
 
accordance with the S.T.E.P.S ® program. 
Only enough drug for one 28 day cycle will be supplied at a time. 
        8.2.11 
Pregnancy Risk  
 
Thalidomide is a powerful human teratogen, inducing a high frequency (about 30%) 
of severe and live-threatening birth defects such as: ectromelia (amelia, phocomelia, 
hemimelia) of the upper and/or lower extremities, microtia with abnormality of the 
external acoustic meatus (blind or absent), middle and internal ear lesions (less 
frequent), ocular lesions (anophthalmia, microphthalmia), congenital heart disease, 
renal abnormalities. Other less frequent abnormalities have also been described. 
Females of childbearing potential (FCBP) must agree to use two reliable forms of 
contraception simultaneously or to practice complete abstinence from heterosexual 
contact during the following time periods related to this study: 1) for at least 4 weeks 
before starting study drug; 2) while taking study drug; 3) during dose interruptions and 
4) for at least 4 weeks after discontinuation of the study drug. The two methods of 
reliable contraception must include one highly effective method (i.e. intrauterine 
device (IUD), hormonal [birth control pills, injections, patch or vaginal implants], 
tubal ligation, partner’s vasectomy) and one additional effective (barrier) method (i.e. 
male condom, diaphragm, cervical cap).  The FCBP must be referred to a qualified 
provider of contraceptive methods if needed.  
Combined hormonal contraceptives are not recommended due to the increased risk of 
venous thrombo-embolic disease. The choice of contraceptive methods should 
necessitate a risk/benefit discussion between the patient and a qualified physician 
experienced in the use of contraceptive methods. Effective measures to avoid 
pregnancy must be taken.  
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding. 
Prophylactic antibiotics should be considered particularly in patients with neutropenia.  
Copper-releasing intrauterine devices are generally not recommended due to the 
potential risks of infection at the time of insertion and menstrual blood loss which may 
compromise patients with neutropenia or thrombocytopenia 
Criteria for females of childbearing potential (FCBP) 
Two categories: 
1 – Females not of childbearing potential include females who have had a natural 
menopause 
for at least 24 consecutive months, a hysterectomy, and/or bilateral oophorectomy 


 
34 
 
2 – Females of childbearing potential are all other females who are menstruating, 
amenorrheic from previous medical treatments, under 50 years of age, and/or 
perimenopausal 
           8.2.12 Pregnancy Testing    
Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to 
prescribing Thalidomide for Cycle 1 (prescriptions must be filled within 7 days).  
FCBP with regular or no menstruation must have a pregnancy test weekly for the first 
28 days and then every 28 days while on therapy (including breaks in therapy); at 
discontinuation of thalidomide and at Day 28 post the last dose of thalidomide.  
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 thalidomide and at Day 14 and Day 28 post the last dose of 
thalidomide (see Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods).    
 
8.3 
Rituximab  
 
8.3.1   Chemistry 
Rituximab is a genetically engineered chimeric murine/human monoclonal antibody 
directed against the CD20 antigen found on the surface of normal and malignant B-
lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine 
light- and heavy-chain variable region sequences and human constant region 
sequences.  The Fab domain of rituximab binds to the CD20 antigen on B 
lymphocytes, and the Fc domain recruits immune effector functions to mediate B-
lymphocyte lysis in vitro.  Possible mechanisms of cell lysis include complement-
dependent cytotoxicity (CDC) and antibody dependent cell mediated cytotoxicity 
(ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-
cell lymphoma line. 
 
8.3.2   Pharmacology and Pharmacokinetics 
In prior studies patients treated at the 375 mg/m2 dose levels exhibited detectable 
antibody concentrations throughout the treatment period. Most patients exhibited 
increasing pre-infusion antibody concentrations with each subsequent infusion. In nine 
patients, the T1/2 following the first antibody infusion was 59.8 hours (11.1-104.6 hr) 
with a Cmax of 271 μg/ml. Following the fourth antibody infusion when circulating B 
cells had been depleted and antigenic sites coated, the T 1/2 was 174 hr (26.4-442.3 
hr) and Cmax 496.7 μg/ml. 
 
8.3.3 Human Toxicology 


 
35 
 
No dose-limiting effects were observed in the Phase I/II studies.  Reported adverse 
events including fever, chills, headache, nausea, vomiting, rhinitis, asthenia, and 
hypotension, occurred primarily during rituximab infusions and typically responded to 
an interruption of the infusion and resumption at a slower rate.  
Fatal Infusion Reactions:  Severe and fatal cardiopulmonary events, including 
angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, 
myocardial infarction, and cardiogenic shock, have been reported.  These severe 
reactions typically occurred during the first infusion with time to onset of 30-120 
minutes. 
Cardiac Events:  Patients with preexisting cardiac conditions, including arrhythmia 
and angina, have had recurrences of these cardiac events during rituximab infusions. 
Tumor Lysis Syndrome:  Tumor lysis syndrome has been reported and is 
characterized in patients with a high number of circulating malignant cells 
(≥25,000/mm3) by rapid reduction in tumor volume, renal insufficiency, hyperkalemia, 
hypocalcemia, hyperuricemia, and hyperphosphatemia. 
Renal Events:  Rituximab has been associated with severe renal toxicity including 
acute renal failure requiring dialysis, and in some cases has lead to death.  Renal 
toxicity has occurred in patients with high numbers of circulating malignant cells 
(≥25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in 
patients administered concomitant cisplatin. 
Mucocutaneous Reactions:  Severe bullous skin reactions, including fatal cases of 
toxic epidermal necrolysis and paraneoplastic pemphigus, have been reported in 
patients treated with rituximab.  The onset of reaction has varied from 1 to 13 weeks 
following rituximab exposure. 
Hematologic Events:  In clinical trials, Grade 3 and 4 cytopenias were reported in 
48% of patients treated with rituximab; these include: lymphopenia (40%), 
neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%).  The 
median duration of lymphopenia was 14 days (range, 1 to 588 days) and of 
neutropenia was 13 days (range, 2 to 116 days).  A single occurrence of transient 
aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia 
following Rituximab therapy were reported. 
In addition, there have been a limited number of postmarketing reports of prolonged 
pancytopenia, marrow hypoplasia, and late onset neutropenia. 


 
36 
 
Infectious Events:  Rituximab induced B-cell depletion in 70% to 80% of patients 
with NHL and was associated with decreased serum immunoglobulins in a minority of 
patients; the lymphopenia lasted a median of 14 days (range, 1-588 days).  Infectious 
events occurred in 31% of patients: 19% of patients had bacterial infections, 10% had 
viral infections, 1% had fungal infections, and 6% were unknown infections.  Serious 
infectious events (Grade 3 or 4), including sepsis, occurred in 2% of patients. 
Hepatitis B Reactivation:  Hepatitis B virus (HBV) reactivation with fulminant 
hepatitis, hepatic failure, and death has been reported in some patients with 
hematologic malignancies treated with rituximab.  The majority of patients received 
rituximab in combination with chemotherapy.  The median time to the diagnosis of 
hepatitis was approximately four months after the initiation of rituximab and 
approximately one month after the last dose. 
Other Serious Viral Infections:  The following additional serious viral infections, 
either new, reactivated or exacerbated, have been identified in clinical studies or 
postmarketing reports. The majority of patients received Rituxan in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections 
included JC virus (progressive multifocal leukoencephalopathy [PML]), 
cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West 
Nile virus, and hepatitis C. In some cases, the viral infections occurred up to one year 
following discontinuation of Rituxan and have resulted in death. 
Progressive multifocal leukoencephalopathy (PML): PML is a rare and 
demyelinating disease of the brain caused by infection with the JC virus that usually 
leads to death or severe disability.  JC virus infection resulting in PML and death has 
been reported rarely in patients with hematologic malignancies receiving rituximab. 
The majority of these patients had received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant.  Cases of PML 
resulting in death have also been reported in patients with systemic lupus 
erythematosus (SLE) treated with rituximab.  These patients with SLE had 
longstanding disease, history of prior immunosuppressant therapy, and were 
diagnosed with PML within 12 months of their last infusion of rituximab. 
Physicians should consider PML in any patient presenting with new onset neurologic 
manifestations. Consultation with a neurologist, brain MRI, and lumbar puncture 
should be considered as clinically indicated.  In patients who develop PML, rituximab 
should be discontinued and reductions or discontinuation of any concomitant 
chemotherapy or immunosuppressive therapy should be considered. 


 
37 
 
Bowel Obstruction and Perforation:  Abdominal pain, bowel obstruction and 
perforation, in some cases leading to death, were observed in patients receiving 
Rituxan in combination with chemotherapy for DLBCL. In post-marketing reports, 
which include both patients with low-grade or follicular NHL and DLBCL, the mean 
time to onset of symptoms was 6 days (range 1−77) in patients with documented 
gastro-intestinal perforation. Complaints of abdominal pain, especially early in the 
course of treatment, should prompt a thorough diagnostic evaluation and appropriate 
treatment. 
Additional Safety Signals:  The following serious adverse events have been reported 
to occur in patients following completion of rituximab infusions: arthritis, disorders of 
blood vessels (vasculitis, serum sickness and lupus-like syndrome), eye disorders 
(uveitis and optic neuritis), lung disorders including pleuritis and scarring of the lung 
(bronchiolitis obliterans), that may result in fatal outcomes, and fatal cardiac failure. 
 
8.3.4   Formulation 
Rituximab is commercially available in 10 mL and 50 mL single-use vials containing 
100 mg or 500 mg rituximab solution, respectively, at a concentration of 10 mg/mL. 
 
8.3.5   Storage and Stability 
Intact vials should be stored under refrigeration (2°-8°C). Dilute solutions for infusion 
(1-4 mg/mL) are stable for 24 hours under refrigeration, and for an additional 24 hours 
at room temperature. The desired dose of rituximab should be diluted in 0.9% NaCl or 
D5W to a final concentration of 1-4 mg/mL. The solution should be mixed by gently 
inverting the bag. 
 
8.3.6   How Supplied 
Rituximab will be obtained from commercial stock from the non-investigational 
pharmacy and, along with its administration costs, will be billable to the patient. 
 
8.3.7   Rituximab Administration 
Rituximab will be administered on days  1, 8, 15 and 22 starting with Cycle 1 and then 
again on the same weekly x 4 schedule every 6th cycle through Cycle 19 (Cycles 7, 
13, and 19). All patients should be premedicated with acetaminophen 650 mg and 
diphenhydramine 25-50 mg (or equivalent) 30 minutes prior to the rituximab.  
Rituximab 375 mg/m2 will be administered by IV infusion starting at a rate of 50 
mg/hour.  If no infusion related reactions occur, the infusion rate should be escalated 
in 50 mg/hour increments every 30 minutes to a maximum of 400 mg/hour until the 
infusion is completed.  Vital signs will be monitored every 15 minutes while infusion 
rate is being escalated. 


 
38 
 
 
9. CORRELATIVE/SPECIAL STUDIES 
See Section 5.1 for specific dosing instructions 
Cycle -1: Half of the patients will receive 14 days of thalidomide 50 mg PO daily, followed 
by 14 days off and the other half of the patients will receive 14 days of lenalidomide 5 mg PO 
daily, followed by 14 days off 
Cycle 1 and beyond: Alternating thalidomide and lenalidomide continuously 
Samples will be collected for correlative studies to be performed in association with the trial.  The 
following samples will be collected: 
1. CLL Prognostic Profiles*: 
Samples will be analyzed as described in the Schedule of Assessments (Section 10) and 
will include:  
1) IgVH Mutation Analysis 
2) Zap-70 expression by immunohistochemistry 
3) CD38, CD 5, CD19/CD20, CD 23, sIg 
4) Interphase FISH for trisomy 12, deletion 17p, deletion 13q14, deletion 11q23 (blood 
and bone marrow) 
5) Purified CLL cell interphase FISH  (not called Purified on calendar)  
6) beta-2-microglobulin 
 
2. BLyS/BAFF Analysis* 
1) Measurement of serum levels of BLyS and APRIL 
a. day 1 and 15 of cycle -1 (prior to administration of study agents). 
b. immediately prior to rituximab at cycles  1, 7, 13, and 19,  and then prior to the 
last dose of rituximab (day 22) for that cycle. 
2) BLyS expression on monocytes:  
a. day 1 and 15  of cycles -1 (prior to administration of study drug) 
b. day 1 and 15 of cycle 1  (immediately prior to Rituximab administration) 
3) BLyS receptor expression on CLL cells:  
a.  Prior to administration of study drug on days 1 and 15 of cycles -1  
b.  Immediately prior to administration of Rituximab on days 1 and 15 of Cycle 1 
4) BLyS gene polymorphisms: baseline 
5) MMP-9 activity: baseline 
 
3. Impact of IMID therapy on TNF Family and cox Family mRNA stability*: 
1) Impact on p38 MAPK activity: day 1, 15  of cycles -1 and 1 prior to administration of 
study drugs 


 
39 
 
2) TNF-alpha / cox-2 / BAFF mRNA levels: day 1, 15  of cycles -1 and 1 prior to 
administration of study drugs  
3) Level of HuR binding to TNF-alpha / cox-2 mRNA / BAFF mRNA: day 1, 15  of 
cycles -1 and 1 prior to administration of study drugs  
  
4. RNA Expression Arrays* 
Changes in RNA expression resulting from the IMID therapy will be assessed using RNA 
expression arrays.  Samples to be assessed: 
1) CLL cells: day 1, 2, and 15 of cycles -1 and 1 prior to administration of study drug 
2) T cells: day 1, 2, and 15 of cycles -1 and 1 prior to administration of study drug  
3) Monocytes: day 1, 2, and 15 of cycles -1 and 1 prior to administration of study drug  
 
5. Methylation Arrays* 
Changes in gene methylation patterns resulting from IMID therapy will be assessed using 
methylation oligomicroarrays (MOMA) at: 
Day 1 and 15 of cycles -1 and 1 prior to administration of study drug  
 
6. Metabolomics*: day 1, 15 of cycles -1 and 1 prior to administration of study drug  
 
7. Peripheral Blood Activation Markers* 
Changes in cell surface markers will be assessed by flow cytometry and will include: 
CD38, HLA-DR, CD25: Prior to administration of study drug in Cycle -1, 1 and 2 on 
Days 1 and 15. 
 
8.  Peripheral Blood Cell Subset Analysis* 
Changes in peripheral blood mononuclear cell subsets: baseline; Cycle 1 prior to 
administration of study drug on days 1 and 15 ; Cycles 2 and 3 prior to administration of 
study drug on Day 1; every three cycles for Cycle 6 through Cycle 24; followed by every 
six cycles thereafter. 
Panel to include: 
CD3/CD4/CD8: T cell subsets 
CD16/CD56: NK cells 
CD14: monocytes 
CD3/CD25/FoxP3: regulatory T cells 
Circulating Endothelial cell precursors 
 
9. VEGF Analysis* prior to administration of study drug in Cycles -1, 1 and 2 on Days 1 and 8.  
1) VEGF, bFGF serum levels 
2) Changes in VEGF Receptor expression profile 
 


 
40 
 
10. Genetic polymorphisms predictive of response* prior to administration of study drug in 
Cycles -1, 1 and 2 on Days 1 and 15.  
1) TNF-alpha 
2) BAFF 
 
11. T-cell Repertoire Studies: samples will be collected prior to treatment on cycle -1 and prior to 
cycles 6, 12, and 24 and evaluated for T-cell Repertoire 
 
12. PI 3-Kinase Assessment:  samples will be assessed for PI 3-Kinase activity levels prior to 
cycle -1, day 15 of cycle -1, and day 15 of cycle #1. 
 
**** Rituximab can be given +/- 2days.   
****All correlative work must be drawn prior to Rituximab administration regardless of the day 
Rituximab is given. 
 
* See Section 10 for further details 
 


 
41 
 
10. STUDY CALENDAR 
 
 
Schedule of Study Assessments 
 
 
 
Procedure 
Screening1 
Cycles -1, 1 and  2 
24hrs 
before 
study 
drug 
Day 1 
 
Day 2 
 
Day 4 
(+/- 1) 
Day 8 
Day 11 
(+/- 1) 
Day 15 
Day 22 
Medical history assessment 
X 
 
 
 
 
 
 
 
 
Interim history 
 
 
X 
 
X 
X 
X 
X 
X 
Physical examination, vital signs 
X 
 
X 
 
X 
X 
X 
X 
X 
ECOG performance status, weight 
X 
 
X 
 
 
X 
 
X 
X 
Lymph node, spleen and liver assessment by 
physical exam 15 
X 
 
X 
 
 
X 
 
X 
X 
CLL Flow Cytometry16 
X 
 
 
 
 
 
 
 
 
interphase FISH (CLL Panel) 2 
X 
 
 
 
 
 
 
 
 
Purified CLL cell interface FISH 
X 
 
 
 
 
 
 
 
 
IgVH Mutation Analysis 
X 
 
 
 
 
 
 
 
 
BLyS/BAFF Analysis3  
 
 
X3 
 
 
 
 
X3 
X3 
IMiD™ compound studies and Methylation 
Arrays4 
 
 
X4 
 
 
 
 
X4 
 
RNA Expression Arrays5 
 
 
X 
 
X5  
Day 2 
 
 
X 
 
Metabolomics 
 
 
X18 
 
 
 
 
X18 
 
T-cell Repertoire Studies19 
 
 
X19 
 
 
 
 
 
 
PI 3-Kinase Assessment20 
 
 
X20 
 
 
 
 
X20 
 
Peripheral Blood Activation Markers:  CD38, 
HLA-DR, CD25 
 
 
X 
 
 
 
 
X 
 
Peripheral Blood Cell Subset Analyisis6 
X 
 
X6 
 
 
 
 
X6 
 
VEGF Analysis 
 
 
X 
 
 
X 
 
 
 
Genetic polymorphisms  
X 
 
 
 
 
 
 
 
 
Bone marrow assessment12  
X 
 
 
 
 
 
 
 
 
CT of the chest / abdomen / pelvis12 
X 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
Hematology7 
X 
 
X 
 
X 
X 
X 
X 
X 
Serum chemistries8    
X 
 
X 
 
X 
X 
X 
X 
X 
IFE, beta-2-microglobulin, DAT 
X 
 
 
 
 
 
 
 
 
Pregnancy testing 9,10 
X 
X 
X10 
 
 
X10 
 
X10 
X10 
Register and comply with RevAssist® and 
S.T.E.P.S.® program 
X 
X 
 
 
 
 
 
 
 
Rituximab administration 
 
 
X17 
 
 
X17 
 
X17 
X17 
Response assessment 12 
 
 
 
 
 
 
 
 
 
Record adverse events 13 
 
 
 
 
 
X 
 
 
X 
Perform drug accountability 
 
 
X 
 
 
 
 
 
 
Prescribe and dispense study drugs for next cycle 
14 
 
 
X 
 
 
 
 
 
 


 
42 
 
 
 
 
Procedure 
Cycles 
3, 4, 5, 6 
Cycles 3, 4 and any Cycle where lenalidomide dose is 
escalated 
Day 1 
 
Day 4 
(or) 
Day  3 
Day 8 
Day 11 
(or) 
Day 10 
Day 15 
Day 22 
Medical history assessment 
 
 
 
 
 
 
Interim history 
X 
X 
X 
X 
X 
X 
Physical examination, vital signs, weight 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
 
X 
 
X 
X 
Lymph node, spleen and liver assessment by physical exam 15 
X 
 
X 
 
X 
X 
Bone marrow assessment12 
 
 
 
 
 
 
Peripheral Blood Cell Subset Analyisis6 
X6 
 
 
 
 
 
CT of the chest / abdomen / pelvis12 
 
 
 
 
 
 
Hematology7 
X 
X 
X 
X 
X 
X 
Serum chemistries8    
X 
X 
X 
X 
X 
X 
Pregnancy testing 9,10 
X10 
 
 
 
X10 
 
T-cell Repertoire Studies19 
X19 
 
 
 
 
 
Comply with RevAssist® and S.T.E.P.S.® program 
X 
 
 
 
 
 
Response assessment 12 
X 
 
 
 
 
 
Record adverse events 13 
X 
 
X 
 
 
X 
Perform drug accountability 
X 
 
 
 
 
 
Prescribe and dispense study drugs for next cycle 14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
An unscheduled visit can occur at any time during the study.  Source must be maintained for these unscheduled visits. 
The date for the visit and any data generated must be recorded on the appropriate CRF.  Source documents for these 
unscheduled visits must also be maintained. 
 
 
 
 
 
 
 


 
43 
 
 
Procedure 
Rituximab administration 
Cycles 7, 13, and 19 
 
For all other 
cycles 8 and 
beyond11   
Discontinuation 
From Protocol 
therapy  
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Medical history assessment 
X 
 
 
 
X 
 
Interim history 
X 
X 
X 
X 
X 
 
Physical examination, vital signs, weight 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
Lymph node, spleen and liver assessment by physical 
exam15 
X 
X 
X 
X 
X 
 
Bone marrow assessment12 
 
 
 
 
 
 
BlyS/BAFF Analysis3  
X 
 
 
 
X3 
 
Peripheral Blood Cell Subset Analyisis6 
 
 
 
 
X6 
 
CD4/CD8/CD56 cell count 
 
 
 
 
 
X 
CT of the chest / abdomen / pelvis12 
X 
 
 
 
X12 
X 
Hematology7 
X 
X 
X 
X 
X 
X 
Serum chemistries8 
X 
X 
X 
X 
X 
X 
Pregnancy testing 9,10 
X10 
 
X10 
 
X10 
X10 
Comply with RevAssist® and S.T.E.P.S.® program 
X 
 
 
 
X 
 
T-cell Repertoire Studies19 
 
 
 
 
X19 
 
IFE, beta-2-microglobulin, DAT 
X 
 
 
 
X21 
 
Response assessment 12 
X 
 
 
 
X12 
X 
Record adverse events 13 
X 
X 
X 
X 
X 
X13 
Perform drug accountability 
X 
 
 
 
X 
 
Prescribe and dispense study drugs for next cycle 14 
X 
 
 
 
X11 
 
Rituximab administration 
X17 
X17 
X17 
X17 
 
 
MRD status – peripheral blood assessment  
X 
 
 
 
X12 
 
Obtain Follow-Up anti-cancer treatments 
 
 
 
 
 
F/u phase : Q 3 
months 
Obtain Follow-Up survival information 
 
 
 
 
 
F/u phase : Q 3 
months 
 
1  28 days from baseline (First day study drug administration) 
2 To include iFISH for trisomy 12, deletion 17p, deletion 13q14, deletion 11q23; should be performed on peripheral blood 
and bone marrow 
3 BLyS/BAFF Analysis: 
 
Baseline: BLyS gene polymorphisms, MMP-9 activity 
 
 
Cycle -1 and 1;  Days 1 & 15 prior to administration of study drug: serum levels of BLyS & APRIL, BLyS 
expression on monocytes, BLyS receptor expression on CLL cells 
 
Cycle 1, 7, 13, and 19 –immediately prior to Rituximab: serum levels of BLyS & APRIL 
4 IMiD™ compound Studies and Methylation Arrays: 
 
Cycle -1 and 1:  Days 1 & 15 prior to administration of study drug:  p38Mark activity, TNF-alpha/cox-
2/BAFF mRNA levels, level of HuR binding to TNF-alpha/cox-2 mRNA/BAFF mRNA 
 
Cycle -1 and 1:  Days 1 & 15 prior to administration of study drug:  Changes in gene methylation patterns 
resulting from IMID therapy by MOMA 
5 RNA Expression Arrays: 
 
Cycle -1 and 1:  Days 1, 2 & 15 prior to administration of study drug:  CLL cells, T cells, Monocytes 
6  Peripheral Mononuclear cell subsets 
 
Prior to administration of study drug Days: 1 and 15 of Cycle 1; Day 1 of Cycles 2 and 3;q 3 cycles 
through Cycle 24(cycle 6, 9, 12, etc.); then q 6 cycles thereafter:  CD3/CD4/CD8-T cell subsets;  


 
44 
 
CD16/CD56- NK cells;  CD14- monocytes; CD3/CD25/FoxP3-regulatory T cells;  Circulating Endothelial 
cell precursors 
7 To include WBC, differential, hemoglobin, hematocrit, platelets. Hematology profiles are required weekly during Cycle 
-1 of lenalidomide-containing therapy, and during any cycle in which the dose of lenalidomide is escalated or re-
escalated.  For subjects who are on a stable lenalidomide dose (without escalation or interruption) for ≥ 1 cycle of 
treatment, hematology profiles are required on Days 1 and 15 of the cycle. 
8 To include Na, K, Cl, CO2, BUN, Cr, glu, Ca, phos, uric acid, LDH, alkaline phosphatase, total bilirubin, ALT, AST, 
albumin, total protein.  At a minimum, for tumor lysis syndrome (TLS) monitoring purposes, subjects will have 
chemistry assessments weekly during at least the first 2 cycles of lenalidomide-containing treatment as well as on Day 3 
or 4 of Cycle -1.  In addition, because the risk for TLS may be elevated when lenalidomide is re-started after treatment 
interruptions or when the lenalidomide dose is escalated, in any cycle in which the lenalidomide dose is escalated, re-
escalated, or treatment is interrupted for more than 1 week, subjects will have weekly chemistry assessments performed 
for at least 4 consecutive weeks, as well as an additional chemistry assessment on day 3 or 4 during the first week.  For 
subjects who do not experience any abnormalities in serum chemistry assessments for 2 consecutive cycles while on a 
stable lenalidomide dose (without escalation or interruption) throughout these 2 cycles, the timing of chemistry 
assessments may be reduced to Day 1 and Day 15 in subsequent cycles. 
9 Pregnancy tests required 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). 
10 Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to initiation of lenalidomide and 
thalidomide.  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/thalidomide and at day 
28 post the last dose of lenalidomide/thalidomide.  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/thalidomide and at day 14 and day 28 post the last dose of lenalidomide/thalidomide (see Appendix A: 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods). 
11 After cycle 24, clinic visits (and the corresponding assessments) are only required every 3rd cycle (e.g. Cycle 24, 27, 30, 
etc.). For any non-clinic visit treatment cycles (e.g. Cycle 25, 26, 28, 29, etc.), subjects must still meet all requirements 
for the initiation of a new treatment cycle, including compliance with the RevAssist® and S.T.E.P.S.® programs, and all 
pregnancy testing and pregnancy risk counseling requirements. Hematology assessment (see number 7) will be done 
locally as required for the initiation of a new treatment cycle. 
12 CT scans should be done every six months for three years, and every twelve months thereafter. Response assessment and 
MRD assessment should be performed every six months subsequent to Cycle 24. Patients whose blood counts meet 
criteria of a CR should undergo a CT scan within 4 weeks.  If CT scan supports a response of CR, then bone marrow 
examination and peripheral blood MRD assessment should be performed within 4 weeks. 
13 An additional safety assessment will be done 28 days (+/- 2 days) following the last dose of study drug. 
14 Only enough thalidomide and lenalidomide for 1 cycle of therapy may be provided to the patient each cycle. For non-
clinic visit treatment cycles subsequent to Cycle 24 (e.g. Cycle 25, 26, 28, 29, etc.), study drug will be shipped to the 
subject at the start of each cycle. 
15 Physical examination of lymphadenopathy, spleen and liver will be performed on Days 1, 8, 15, and 22 of Cycles -1, 1, 
2, 3,4 and 5 to access for tumor flare reaction, and on Day 1 of subsequent cycles starting with cycle 5 to assess 
response.   
16 CLL Flow Cytometry should include markers for diagnosis and prognosis: CD5, CD19/CD20, CD23, CD38, sIg, and 
zap-70, by immunohistochemistry. Also IgVH Mutation Analaysis, Purified CLL cell interphase FISH, beta 2 
microglobulin  
17 Rituximab administration starting with Cycle 1 and then every 6th cycle through Cycle 19 (i.e. 7, 13, and 19)  on Days 1, 
8, 15 and  22.  
18 Metabolimics on Days 1 and 15 prior to study drug administration for Cycles -1 and 1.   
19 T-cell Repertoire Studies: samples will be collected prior to treatment on cycle -1 and prior to cycles 6, 12, and 24 and evaluated for 
T-cell Repertoire 
20 PI 3-Kinase Assessment:  samples will be assessed for PI 3-Kinase activity levels prior to cycle -1, day 15 of cycle -1, and day 15 of 
cycle #1. 
21 After Cycle 19, IFE, beta-2-microglobulin, DAT assessment will be done every 6 cycles starting with Cycle 24. 
 


 
45 
 
**** Rituximab can be given +/- 2days.   
****All correlative work must be drawn prior to Rituximab administration regardless of the day 
Rituximab is given. 


 
46 
 
11. MEASUREMENT OF EFFECT 
Baseline lesion assessments must occur within  28 days of study drug administration or as indicated 
in Section 10, Schedule of Study Assessments. 
Efficacy assessments are scheduled to occur every four weeks.  It should be noted that signs and 
symptoms of a tumor flare may appear similar to disease progression.  Investigators should decide 
whether apparent increases in disease are indicative of a tumor flare or disease progression.  If the 
increases in lymphadenopathy, tenderness, leukocytosis, or cytopenias occur within four weeks of a 
dose escalation, then it is possible the changes are indicative of a disease flare.  If these changes begin 
more than four weeks after a dose increase, then the changes are likely disease progression.  These are 
guidelines to help investigator in making their decision, but the decision regarding classifying their 
disease as progression or flare remains ultimately with the investigator. 
Response and progression will be evaluated in this study using the International Workshop on CLL 
(IWCLL) update of the 1996 NCI-Working Group criteria for CLL [15]. 
11.1 
Complete response: requires all of the following conditions to be met: 
1. Absence of clonal lymphocytes in the peripheral blood by flow cytometry. 
2. Blood counts above the following values: 
a) neutrophil count > 1500/ mm3, without the use of growth factors 
b) hemoglobin > 11 gm/dL, untransfused (men and women) 
c) platelet count > 100,000/ mm3, untransfused 
3. Absence of lymphadenopathy on CT examination of the neck, chest, abdomen, and pelvis 
(lymph nodes < 1.5 cm in diameter). 
4. Absence of hepatomegaly or splenomegaly by CT examination 
5. Absence of constitutional symptoms. 
6. Bone marrow biopsy and aspirate demonstrating normal cellularity for the age of the 
patient and free of clonal CLL cells by conventional (not 4-color) flow cytometry and / or 
immunohistochemistry.  If lymphoid nodules are present (formerly nPR), they should be 
assessed by immunohistochemistry to determine whether they are composed of CLL cells. 
 If the lymphoid nodules are not CLL cells, then the patient will be considered a CR.  If the 
lymphoid nodules are composed of CLL cells, then the patient will be categorized as a PR. 
 If the bone marrow is found to be hypocellular, a repeat marrow biopsy should be 
performed after 4-6 weeks. 
7. Patients who fulfill all of the criteria for CR, including marrow examination, but who have 
persistent anemia or thrombocytopenia, or neutropenia unrelated to CLL but related to 
drug toxicity will be characterized as CR with incomplete marrow recovery (CRi).  These 
patients will be followed in order to determine whether their prognosis differs from 


 
47 
 
patients in CRs or PRs. 
11.2  
Partial response: any response less than a complete response but still meeting the following 
criteria: 
1. 50% decrease in peripheral blood lymphocytes from the pre-treatment value. 
2. 50% reduction in lymph node size by CT examination as measured by the sum of the 
products of up to 6 lymph nodes, or in one lymph node diameter if only a single lymph 
node is present. 
3. No increase in the size of any lymph node, and no new enlarged lymph nodes, by CT 
examination. 
4. 50% reduction in the size of the liver and / or spleen by CT examination 
5. Blood counts must show one of the following: 
a) neutrophil count > 1500/mm3 or 50% improvement over baseline without the use 
of growth factors. 
b) hemoglobin > 11.0 gm/dL or 50% improvement over baseline without transfusions 
or erythropoietin support. 
c) platelet count > 100,000/mm3 or 50% improvement over baseline without 
transfusions. 
11.3 
Progressive disease: any of the following characteristics: 
1. Progressive lymphadenopathy, as defined by: 
a) Appearance of any newly enlarged lymph nodes to > 1.5 cm. 
b) An increase by 50% or more in greatest diameter of any previous site of disease.  
For a lymph node of 1 to 1.5 cm must increase by at least 50% to a size greater 
than 1.5 cm.  A lymph node greater than 1.5 cm in diameter must increase to more 
than 2.0 cm in diameter. 
c) An increase of 50% or more in the sum of the products of diameters of multiple 
lymph nodes. 
2. An increase in liver or spleen size by 50% or more or the appearance of new hepatomegaly 
or splenomegaly. 
3. An increase in the number of blood lymphocytes by 50% or more with at least 5000 B 
lymphocytes /mm3. 
4. Transformation to a more aggressive histology. 
5. Occurrence of cytopenias attributable to CLL, excluding those related to therapy or 
autoimmune phenomenon.  The progression of any cytopenia is defined by: 


 
48 
 
a) decrease in Hb by more than 2 g/dL or to less than 10 g/dL. 
b) decrease in platelet counts by more than 50% or to less than 100,000/ mm3. 
11.4 
Stable disease: patients who have not achieved a CR or a PR, and who have not exhibited 
progressive disease, will be considered to have stable disease. 
11.5 
Relapse: patients who has previously achieved a CR or PR, but after a period of 6 or more months, 
demonstrate evidence of disease progression. 
11.6 
Refractory disease: disease progression within 6 months of the last treatment. 
11.7 
Duration of response definitions: 
1. Duration of response: from the end of the last treatment until evidence of progressive 
disease. 
2. Time to response: interval from the first treatment day to the date response first identified. 
2. Progression-free survival: interval between the first treatment day and the first sign of 
disease progression. 
3. Event-free survival: interval between the first treatment day to the first sign of disease 
progression, treatment for relapse, or death, whichever occurs first. 
4. Survival duration: interval between the first day of treatment and death 
 
 
12. DATA REPORTING / REGULATORY CONSIDERATIONS 
 
12.1  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.   
 
12.2  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.  


 
49 
 
 
 
12.3 
Data Safety Monitoring Board  
The role of the Data Safety Monitoring Board (DSMB) will be fulfilled by the Weill Cornell Medical 
College DSMB. The purpose of the Data Safety Monitoring Board (DSMB) is to advise on serious 
safety considerations, lack of efficacy and any other considerations within the charge to the 
Committee. Data will be analyzed and submitted to the DSMB annually in order to allow for 
assessments of response and toxicities. 
 The DSMB may request additional meetings or safety reports as deemed necessary upon discussion 
with Celgene and its representatives.  The DSMB may stop the study following review of results from 
each interim analysis.  Appropriate efficacy and safety data summaries will be provided to the DMC 
after each interim analysis. 
 
12.4 
Data Collection 
 
The data collection plan for this study is to utilize the HemOnc database to capture all treatment, 
toxicity, and efficacy data for all enrolled patients. 
 
12.5   Regulatory Considerations 
 
All protocol amendments and consent form modifications will be made by the Principal 
Investigator. Celgene Corporation will have the opportunity to review and approve the changes 
prior to submission of these changes to the local IRB and distribution to participating sites. 
 
12.6   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 inspec-
tion(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 audits to review data and resolve any queries and to allow direct access to the subject’s records 
(e.g., medical records, office charts, hospital charts, and study related charts) for source data 
verification.  The data collection must be completed prior to each visit and be made available to the 
Celgene representative so that the accuracy and completeness may be checked. 
 
12.7  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 


 
50 
 
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 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. 
 
12.8  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. 
 
12.9  Subject confidentiality 
Celgene affirms the subject’s right to protection against invasion of privacy.  In compliance with 
United States federal regulations, Celgene requires the Investigator to permit Celgene’s 
representatives and, when necessary, representatives of the FDA or other regulatory authorities to 
review and/or copy any medical records relevant to the study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from the subject’s 
statement of informed consent, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual. 


 
51 
 
 
12.10   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 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. 
 
12.11  Premature discontinuation of study 
 
 
 
12.11.1 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. 
 
12.11.2 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.). 
 
 
13. STATISTICAL CONSIDERATIONS 
 


 
52 
 
13.1 
 Overview 
Sample size recommendations for the phase II design are determined according to Simon’s two-stage 
Minimax design [91].  We project an overall response proportion (CR + PR) of 60%, below which the 
response will be unacceptable, and an overall response proportion of 80% above which the regimen 
will be considered worthy of further exploration.  The null hypothesis that the overall response 
proportion is less than or equal to 60% will be tested against the alternative hypothesis that the overall 
response proportion is greater than or equal to 80%.  For the purpose of these statistical analyses, 
responses will be assessed starting after cycle #6 of treatment and then every cycle thereafter. 
The sample size computations were performed assuming a 10% level of significance and 80% power. 
 In the first stage, 11 patients will enter the study.  If 6 or fewer patients respond, the study will be 
terminated early and declared to have a negative result.  If 7 or more patients respond, enrollment will 
be extended to 24 patients.  At Stage 2, the treatment will be declared effective and worthy of further 
testing if 18 or more patients respond among the 24 patients entered.  This two-stage design yields a ≥ 
0.80 probability of a positive result if the true percentage of overall responders is ≥ 80%.  It yields a ≥ 
0.90 probability of a negative result if the true percentage of overall responders is ≤ 60%. 
 
Table A. Numbers of observed overall responders required to accept or reject H0 at each stage. 
Under this design, H0 will not be rejected at Stage 1 
 
 
N 
Accept H0 
Reject H0 
Stage 1 
11 
≤ 6 
--- 
Stage 2 
24 
 17 
 18 
 
13.2  Datasets to be analyzed   
Primary Endpoint: 
 Overall response rate (CR + PR) 
Secondary Clinical Endpoints: 
 Progression Free Survival 
 Duration of response 
 Time to response 
 Overall survival 
 Toxicity profile 
 
 
13.3  Statistical Methodology 
Primary Endpoint: 


 
53 
 
 The primary endpoint of response rate (overall, CR, PR) will be estimated and a 95% 
confidence interval will be estimated via binomial proportions 
 
Secondary Endpoints: 
 With adequate follow-up time, progression-free survival (PFS) will be assessed by 
Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using 
Greenwood’s formulae.  PFS will be defined as the time from the first treatment day 
until objective or symptomatic progression (or until date of last follow-up if no 
progression).  
 Duration of Response: from the end of the last treatment until evidence of progressive 
disease. 
 Time to Response 
 Overall Survival 
 The frequency of subjects experiencing toxicities will be tabulated.  Toxicities will be 
assessed and graded according to CTCAE v4.0 terminology.  Exact 95% confidence 
intervals around the toxicity proportions will be calculated to assess the precision of 
the obtained estimates. 
13.4  Safety evaluation 
Data from all subjects who receive any drug while on study will be included in the safety 
analyses. Subjects enrolled on to the study but who did not take any study drugs, will not be 
evaluated for safety. 
The severity of the toxicities will be graded according to the NCI CTCAE v4.0 whenever 
possible (Appendix C).  
13.5  Interim analyses 
 
 
13.5.1  Interim analysis strategy 
Accrual will not be put on hold during the study in order to perform an interim 
analysis given the preliminary clinical data already generated demonstrating activity 
for lenalidomide in CLL.  Efficacy and safety data will be analyzed after the first 
eleven patients reach cycle four.  Data will be analyzed subsequently every four 
months in order to allow for assessments of response and toxicities.  For the purpose 
of performing the interim analysis, responses will be assessed starting after cycle #6 of 
treatment and then every cycle thereafter. 
In the first stage, 11 patients will enter the study.  If 6 or fewer patients respond, the 
study will be terminated early and declared to have a negative result.  If 7 or more 
patients respond, enrollment will be extended to 24 patients. 
 


 
54 
 
14.0 
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Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods 


 
62 
 
 
Risks Associated with Pregnancy 
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic 
active substance that causes severe life-threatening birth defects.  An embryofetal development 
study in animals indicates that lenalidomide produced malformations in the offspring of female 
monkeys who received the drug during pregnancy.  The teratogenic effect of lenalidomide in 
humans cannot be ruled out.  Therefore, a risk minimization plan to prevent pregnancy must be 
observed. 
All study participants must be registered into the mandatory RevAssist® and S.T.E.P.S programs, and 
be willing and able to comply with the requirements of RevAssist® and S.T.E.P.S. 
 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman who: 1) has 
not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) 
for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 
consecutive months). 
Counseling 
For a female of childbearing potential, lenalidomide and thalidomide is contraindicated unless all 
of the following are met (i.e., all females of childbearing potential must be counseled concerning 
the following risks and requirements prior to the start of lenalidomide study therapy):  
 She understands the potential teratogenic risk to the unborn child 
 She understands the need for effective contraception, without interruption, 4 weeks 
before starting study treatment, throughout the entire duration of study treatment, dose 
interruption and 28 days after the end of study treatment 
 She should be capable of complying with effective contraceptive measures 
 She is informed and understands the potential consequences of pregnancy and the need 
to notify her study doctor immediately if there is a risk of pregnancy 
 She understands the need to commence the study treatment as soon as study drug is 
dispensed following a negative pregnancy test 
 She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol  


 
63 
 
 She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide and thalidomide 
The investigator must ensure that for females of childbearing potential: 
 Complies with the conditions for pregnancy risk minimization, including confirmation 
that she has an adequate level of understanding 
 Acknowledge the aforementioned requirements 
For a female NOT of childbearing potential, lenalidomide and/or thalidomide is contraindicated 
unless all of the following are met (i.e., all females NOT of childbearing potential must be 
counseled concerning the following risks and requirements prior to the start of lenalidomide 
and/or thalidomide study therapy):  
 She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide and/or thalidomide 
Traces of lenalidomide have been found in semen.  Male patients taking lenalidomide must meet 
the following conditions (i.e., all males must be counseled concerning the following risks and 
requirements prior to the start of lenalidomide and/or thalidomide study therapy): 
 Understand the potential teratogenic risk if engaged in sexual activity with a pregnant 
female or a female of childbearing potential 
 Understand the need for the use of a condom even if he has had a vasectomy, if 
engaged in sexual activity with a pregnant female or a female of childbearing potential. 
  
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence from heterosexual 
contact during the following time periods related to this study: 1) for at least 28 days before 
starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 28 
days after study treatment discontinuation.  
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception:   
 Highly effective methods: 
 Intrauterine device (IUD) 
 Hormonal (birth control pills, injections, implants) 


 
64 
 
 Tubal ligation 
 Partner’s vasectomy 
 Additional effective methods: 
 Male condom 
 Diaphragm 
 Cervical Cap 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of 
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be 
considered particularly in patients with neutropenia.  
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below. 
Before starting study drug 
Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting 
study drug.  The first pregnancy test must be performed within 10 to 14 days prior to the start of 
study drug and the second pregnancy test must be performed within 24 hours prior to the start of 
study drug.  The patient may not receive study drug until the study doctor has verified that the 
results of these pregnancy tests are negative. 
Male Patients: 
Must practice complete abstinence or  agree to use a condom during sexual contact with a 
pregnant female or a female of childbearing potential while participating in the study, during dose 
interruptions and for at least 28 days following study drug discontinuation, even if he has 
undergone a successful vasectomy.   
During study participation and for 28 days following study drug discontinuation  
Female Patients: 
 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 study drug discontinuation. If menstrual 
cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and 


 
65 
 
then every 14 days while on study, at study discontinuation, and at days 14 and 28 
following study drug discontinuation.   
 At each visit, the Investigator must confirm with the FCBP that she is continuing to 
use two reliable methods of birth control.   
 Counseling about pregnancy precautions and the potential risks of fetal exposure must 
be conducted at a minimum of every 28 days.  
 If pregnancy or a positive pregnancy test does occur in a study patient, study drug must 
be immediately discontinued. 
 Pregnancy testing and counseling must be performed if a patient misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Study drug treatment must 
be discontinued during this evaluation. 
 Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after study drug discontinuation. 
Male Patients: 
 Counseling about the requirement for complete abstinence or condom use during 
sexual contact with a pregnant female or a female of childbearing potential and the 
potential risks of fetal exposure to lenalidomide must be conducted at a minimum of 
every 28 days.   
 If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 
Additional precautions 
 Patients should be instructed never to give this medicinal product to another person 
and to return any unused capsules to the study doctor at the end of treatment. 
 Female patients should not donate blood during therapy and for at least 28 days 
following discontinuation of study drug. 
 Male patients should not donate blood, semen or sperm during therapy or for at least 
28 days following discontinuation of study drug. 
 Only enough study drug for one cycle of therapy may be dispensed with each cycle of 
therapy.  


 
66 
 
Appendix B: ECOG Performance Status Scale 
 
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours. 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 


 
67 
 
Appendix C: NCI CTCAE Version 4.0 
 
Toxicity will be scored using NCI CTCAE Version 4.0 for toxicity and adverse event reporting.  
A copy of the NCI CTC Version 4.0 can be downloaded from the CTEP homepage: 
(http://ctep.info.nih.gov).  All appropriate treatment areas have access to a copy of the CTCAE 
Version 4.0. 
 
 


 
68 
 
Appendix D: Cairo-Bishop Definition of Tumor Lysis Syndrome [92] 
Table:  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome 
Uric Acid 
≥ 476 μmol/l (≥ 8.0 mg/dl) or 25% increase from baseline 
Potassium 
≥ 6.0 mmol/l (≥ 6.0 mEq/l) or 25% increase from baseline 
Phosphorous 
≥1.45 mmol/l  (≥ 4.5 mg/dl) or 25 % increase from baseline 
Calcium 
≤ 1.75 mmol/l (≤ 7.0 mg/dl) or 25% decrease from baseline 
Laboratory tumor lysis syndrome (LTLS) is defined as either a 25% change or level above or below normal, as 
defined above, for any two or more serum values of uric acid, potassium, phosphate, and calcium within 3 days 
before or 7 days after the initiation of chemotherapy.  This assessment assumes that a patient has or will receive 
adequate hydration (± alkalinization) and a hypouricaemic agent(s). 
Table:  Cairo-Bishop Definition of Clinical TLS 
The presence of laboratory TLS and one or more of the following criteria: 
1. Creatinine:  ≥ 1.5 ULN (age > 12 years or age adjusted) 
2. Cardiac arrhythmia / sudden death 
3. Seizure* 
ULN, Upper limit of normal 
*Not directly attributable to a therapeutic agent 
Table:  Cairo-Bishop Grading System for TLS 
Grade 
LTLS 
Creatinine 
Cardiac Arrhythmia 
Seizure 
0 
- 
≤ 1.5 x ULN 
None 
None 
1 
+ 
1.5 x ULN 
Intervention not 
indicated 
None 
2 
+ 
> 1.5 – 3.0 x ULN 
Non-urgent medical 
intervention indicated 
One brief generalized seizure; seizure(s) 
well controlled or infrequent; focal motor 
seizures not interfering with ADL 
3 
+ 
> 3.0 – 6.0 x ULN 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device 
Seizure in which consciousness is altered; 
poorly controlled seizure disorder; 
breakthrough generalized seizures despite 
medical intervention 
4 
+ 
> 6.0 x ULN 
Life-Threatening 
Seizures of any kind that are prolonged, 
repetitive, or difficult to control 
5 
+ 
Death* 
Death* 
Death* 
LTLS, laboratory tumor lysis syndrome; ULN, upper limit of normal; ADL, activities of daily living 
*Probably or definitely attributable to clinical TLS 


 
69 
 
Appendix E:  Cockcroft-Gault estimation of CrCl 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl):  
(Cockcroft, 1976; Luke 1990) 
 
(Males) 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)
           
    
 
 
72 x (serum creatinine, mg/dL) 
(Females) 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)_    x 0.85         
    
 
 
72 x (serum creatinine, mg/dL) 
 
 
 
 














 
76 
 
Appendix H: Summary of Changes from Protocol Version 2 dated September 23, 2013 
The protocol has been amended to discontinue rituximab after Cycle 19 and reduce the frequency 
of subject visits to every three cycles subsequent to Cycle 24. 
List of substantive changes [relevant sections]: 
‐ 
Treatment with rituximab will be discontinued after Cycle 19.  
[Schema, Sections 5.1, Section 5.2, Section 5.4.1, Section 8.3.7, Section 10] 
‐ 
Subsequent to Cycle 24, clinic visits are required every three cycles. At the start of non-clinic 
visit treatment cycles, subjects must still meet all the requirements for the initiation of a new 
treatment cycle, including compliance with the RevAssist® and S.T.E.P.S.® programs, and all 
pregnancy testing and pregnancy risk counseling requirements. Hematology assessment will 
be done locally as required for the initiation of a new treatment cycle. Study drug will be 
shipped to subjects at the start of non-clinic visit cycles.  
[Section 5.4.1, Section 5.4.2, Section 6.3, Section 10] 
‐ 
The provision of Lenalidomide and Thalidomide has been corrected to state that both drugs 
are shipped on a per subject basis by the contract pharmacy to the clinic site, rather than 
direct-to-patient.  
[Section 8.1.6, Section 8.2.8] 
‐ 
BLyS/BAFF Analysis will be discontinued after the last cycle of Rituximab treatment.  
[Section 9, Section 10] 
‐ 
Peripheral Blood Cell Subset Analysis will now be done every six cycles subsequent to Cycle 
24. 
[Section 9, Section 10] 
‐ 
CT scans will be done every six months for three years, and every twelve months thereafter.  
Response assessment and MRD assessment should be performed every six months subsequent 
to Cycle 24. 
[Section 10] 
‐ 
IFE, beta-2-microglobulin, DAT assessment will be done every 6 cycles starting with Cycle 
24. 
[Section 10] 
‐ 
The DSMB concluded at the 8/11/2016 meeting that the data and safety review schedule be 
changed from quarterly to annual. 
[Section 12.3]