Clinical trial NCT01723839
Conditions: Chronic Lymphocytic Leukemia (CLL)
Keywords: CLL FCR Rituximab Lenalidomide Cyclophosphamide
Sponsor: Hackensack Meridian Health
Start date: 2012-02-22; Completion date: 2021-06-08
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In previously-untreated subjects with CLL, fludarabine and rituximab with or without cyclophosphamide (FR or FCR) produces complete responses (CR) of 40-80%. The major complication of FCR has been grade 3/4 neutropenia which was reduced using a lower dose of fludarabine and cyclophosphamide (FCR-Lite) The objective of this study is to evaluate the minimal residual disease (MRD) complete response rate (using the 2008 IWCLL guidelines) after 4 cycles of FCR-Lite plus lenalidomide in subjects with previously untreated CLL. Lenalidomide is active in frontline treatment of CLL as well as in patients with refractory disease. MRD has been demonstrated to be a sensitive surrogate marker for progression-free survival. If patients are MRD negative complete responders (CR) they will stop at 4 cycles of FCR-Lite followed by the lenalidomide consolidation/maintenance arm of the study. If they have a MRD positive CR or partial response (PR) they will continue with 2 additional cycles of FCR-Lite plus lenalidomide followed by lenalidomide consolidation/maintenance. They will be re-tested for MRD after the 6th cycle of FCR-Lite and after 6 and 12 months of lenalidomide monotherapy If they have no response (NR) or progressive disease (PD) following 4 cycles of FCR-Lite plus lenalidomide they will be removed from the study.

Detailed description:
STUDY OBJECTIVES:

Primary:

The primary objective is to evaluate the complete response rate following 4 cycles of FCR-Lite plus lenalidomide in previously untreated patients with CLL.

Secondary:

The first secondary objective is to evaluate the toxicity of patients with previously untreated CLL treated with FCR-Lite plus lenalidomide, followed by lenalidomide. The second is to evaluate the overall response rate and overall survival of patients with previously untreated CLL treated with FCR-Lite plus lenalidomide followed by lenalidomide. The third is to determine whether adding lenalidomide as a consolidation/maintenance therapy will eliminate bone marrow minimal residual disease in CR patients and whether patients who have a PR after 6 cycles of FCR-Lite plus lenalidomide will respond to 12 months of lenalidomide. The final secondary objective is to determine whether the expression of ZAP-70, CD38, and chromosomes correlate with response rate, duration of response, and survival for previously untreated patients with CLL.

STUDY DESIGN:

2-stage phase 2 study-design. 19 subjects are treated in stage-1 with FCR-Lite plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs the study will accrue an additional 35 subjects (see statistical section). A secondary objective of this study will be to determine if MRD positive patients will become MRD negative with lenalidomide consolidation/maintenance and whether PR patients will convert to CRs Lenalidomide will begin 2 months after the last dose of FCR-Lite in all subjects with CR. It may begin as soon as 1 month after FCR-Lite plus lenalidomide in subjects with PR. Lenalidomide is given in 28 d cycles increasing the dose from 5 mg/d to 10 mg/d in cycle 2 and to 15mg in cycles 3-6 if well- tolerated (no grade-3 or -4 toxicity). Patients with creatinine clearance ≥30ml/min and \<60ml/min will start at 2.5mg daily increasing to 5 and 10mg in subsequent cycles . Reduction to the prior dose is allowed for grade-3/-4 toxicity. MRD will be studied by flow cytometry from bone marrow and peripheral blood samples following 4 and 6 cycles of FCR-Lite and after 6 and 12 months of lenalidomide in CR patients.

Arms: arm 1: Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide - 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs after 4 cycles of FCR plus lenalidomide the study will accrue an additional 35 subjects.
Interventions: intervention 1: Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide
Intervention descriptions: intervention 1: 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity.

Protocol documents:
Prot_SAP_000.pdf: 
March 14, 2014 
Hackensack University Medical Center 
John Theurer Cancer Center 
 
  
Trial Title 
 
PHASE II CLINICAL PROTOCOL FOR THE TREATMENT OF PATIENTS WITH PREVIOUSLY UNTREATED CHRONIC 
LYMPHOCYTIC LEUKEMIA WITH FOUR OR SIX CYCLES OF   FLUDARABINE AND CYCLOSPHOSPHAMIDE WITH 
RITUXIMAB PLUS LENALIDOMIDE FOLLOWED BY LENALIDOMIDE CONSOLIDATION/MAINTENANCE 
 
 
Trial  ID Numbers 
Celgene Reference No.: RV_CLL_PI_0530 
 
 
Trial Drug 
Lenalidomide (Revlimid®) 
 
 
IND #: 112004 
 
 
Support Provided By 
Celgene Corp. 
 
 
Sponsor Investigator 
Andre Goy, MD 
John Theurer Cancer Center 
Hackensack University Medical Center  
92 Second Street  
Hackensack NJ 07601 
 
Medical Monitor & Sponsor Contact: 
Andre Goy, MD Phone # 551-996-3033 
 
Primary Research Nurse Coordinator: Marisa Valentinetti, RN 
Contact Phone # 551-996-8073 
 
Regulatory Contact: 
William Marrero BS, CCRP wmarrero@hackensackUMC.org 
 
Data Management contact: 
Mary Morin marymorin@hackensackUMC.org  
 
Final Protocol Versions/ Dates: 
May 11, 2011 Original 
September 14, 2011 Amendment 1 
December 18, 2011 Amendment 2 
March 2, 2012 Amendment 3 
April 2, 2012 Amendment 4 
June 22, 2012 Amendment 5 
March 14, 2014 amendment 6 PI change only 
 
 
 
 


Version Date March 14, 2014 
 
 
 
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1.0 
INTRODUCTION 
8 
1.1 Disease Background 
8 
1.2 Treatment 
8 
2.0 
RATIONALE 
11 
3.0 
OBJECTIVES 
11 
4.0 
TRIAL POPULATION 
12 
4.1 Inclusion Criteria 
12 
4.2 Exclusion Criteria 
13 
5.0 
REGISTRATION  
14 
6.0 
TRIAL DESIGN 
14 
6.1 Treatment Plan 
14 
6.2 Lenalidomide renal dosing 
15 
6.3 
Supportive Care 
15 
6.4 
Schema 
16 
7.0 
STUDY DRUG 
16 
7.1 Rituximab 
16 
7.2 Fludarabine Phosphate 
19 
7.3 Cyclophosphamide 
20 
7.4 Lenalidomide 
22 
8.0 
PATIENT CONSENT & PEER JUDGEMENT 
24 
9.0 
DATA FORMS & SUBMISSION SCHEDULE 
24 
10.0 
RECORD RETENTION 
24 
11.0 
STUDY PARAMETERS AND CALENDAR 
24 
12.0 
DOSE MODIFICATION & TOXICITY MANAGEMENT 
27 
13.0 
CRITERIA FOR TREATMENT DISCONTINUATION 
33 
14.0 
EVALUATION OF RESPONSE 
34 
15.0 
REPORTING OF ADVERSE EVENTS  
35 
16.0 
STATISTICAL CONSIDERATIONS 
40 
16.1 Overview 
40 
16.2 Statistical Considerations for the Clinical Trial 
40 
16.3 Data Safety Plan 
41 
16.4 Correlative Analysis 
42 
17.0 
REFERENCES 
42 
 
APPENDICIES 
 


Version Date March 14, 2014 
 
 
 
Page 3 of 57 
 
 
 
 
Appendix I: Protocol Signature Page 
 
 
Appendix II: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods  
Appendix III : ECOG Performance Status 
 
 
Appendix IV: CTCAE V. 4 
 
 
Appendix V: Cairo-Bishop Tumor Lysis Criteria  
 
 
Appendix VI: Crockcroft-Gault Formula  
 
 
Appendix VI:  Sample Consent Form 
 
 
 
 
 
Protocol Synopsis 
 
PROTOCOL TITLE: PHASE II CLINICAL PROTOCOL FOR THE TREATMENT OF PATIENTS WITH PREVIOUSLY 
UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA WITH FOUR OR SIX CYCLES OF FLUDARABINE AND 
CYCLOSPHOSPHAMIDE WITH RITUXIMAB PLUS LENALIDOMIDE FOLLOWED BY LENALIDOMIDE 
CONSOLIDATION/MAINTENANCE 
DATE PROTOCOL FINAL:  
June 22, 2012 
INDICATION: 
Untreated CLL 
STUDY PHASE: 
2 
BACKGROUND AND RATIONALE:  In previously-untreated subjects with CLL, fludarabine and rituximab with or without 
cyclophosphamide (FR or FCR) produces complete responses (CR) of 40-80%. The objective of this study is to evaluate 
the minimal residual disease (MRD) complete response rate (using the 2008 IWCLL guidelines) after 4 cycles of FCR plus 
lenalidomide in subjects with previously untreated CLL.  Lenalidomide is active in frontline treatment of CLL as well as in 
patients with refractory disease. MRD has been demonstrated to be a sensitive surrogate marker for progression-free 
survival.  If patients are MRD negative complete responders (CR) they will stop at 4 cycles of FCR followed by the 
lenalidomide consolidation/maintenance arm of the study.  If they have a MRD positive CR or partial response (PR) they 
will continue with 2 additional cycles of FCR plus lenalidomide followed by lenalidomide consolidation/maintenance.  They 
will be re-tested for MRD after the 6th cycle of FCR- and after 6 and 12 months of lenalidomide monotherapy.  If they have 
no response (NR) or progressive disease (PD) following 4 cycles of FCR- plus lenalidomide they will be removed from the 
study.     
STUDY OBJECTIVES: 
Primary:   
The primary objective is to evaluate the complete response rate following 4 cycles of FCR plus lenalidomide in previously 
untreated patients with CLL. 
Secondary:   
The first secondary objective is to evaluate the toxicity of patients with previously untreated CLL treated with FCR plus 
lenalidomide, followed by lenalidomide.  The second is to evaluate the overall response rate and overall survival of 
patients with previously untreated CLL treated with FCR plus lenalidomide followed by lenalidomide.  The third is to 
determine if two additional cycles of FCR plus lenalidomide after 4 cycles will convert patients with a PR to CR and 
patients with a CR MRD + to CR MRD -. The fourth objective is to determine whether adding lenalidomide as a 
consolidation/maintenance therapy will eliminate bone marrow minimal residual disease in CR patients and whether 


Version Date March 14, 2014 
 
 
 
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patients who have a PR after 6 cycles of FCR plus lenalidomide will respond to 12 months of lenalidomide.  The final 
objective is to determine whether the expression of ZAP-70, CD38, and chromosomes correlate with response rate, 
duration of response, and survival for previously untreated patients with CLL. 
STUDY DESIGN: 
2-stage phase 2 study-design.  19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg 
and 15mg in subsequent cycles depending on toxicity.  If there are at least 5 CRs after 4 cycles of FCR plus lenalidomide 
the study will accrue an additional 35 subjects (see statistical section).  A secondary objective of this study will be to 
determine if MRD positive patients will become MRD negative with lenalidomide consolidation/maintenance and whether 
PR patients will convert to CRs.  Lenalidomide will begin 2 months after the last dose of FCR in all subjects with CR.  It 
may begin as soon as 1 month after FCR plus lenalidomide in subjects with PR.  Lenalidomide is given in 28 d cycles 
increasing the dose from 5 mg/d to 10 mg/d in cycle 2 and to 15mg in cycles 3-6 if well- tolerated (no grade-3 or -4 
toxicity). Patients with creatinine clearance ≥30ml/min and <60ml/min will start at 5 mg every other day increasing to 5 
and 10mg daily in subsequent cycles . Reduction to the prior dose is allowed for grade-3/-4 toxicity.   MRD will be studied 
by flow cytometry from bone marrow and peripheral blood samples following 4 and 6 cycles of FCR- and after 6 and 12 
months of lenalidomide in CR patients.    
 
 
STUDY ENDPOINTS 
Primary: 
Analysis of the Primary Endpoint: The complete responses will be estimated by the number of patients with CR divided by 
the total number of evaluable patients. Ninety-five percent confidence intervals for the true CR will be calculated. 
Toxicity:   
All toxicities that were determined to be possibly, probably or definitely related to the treatment will be tabulated according 
to grade and type (according to the NCI Common Toxicity Criteria, Version 4.0). The maximum grade for each type of 
toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. 
Secondary: 
Analysis of the other Secondary Endpoints: The overall response rate will be estimated by the number of patients with 
complete and partial responses divided by the total number of evaluable patients. Ninety-five percent confidence intervals 
FCR + L 
4 Cycles 
CR MRD- 
CR MRD+ 
PR 
L 
12 Cycles 
FCR- + 
Lenalidomide 
2 Cycles 
FCR + 
Lenalidomide 
2 Cycles 
CR MRD- 
CR MRD+ 
PR or CR 
NR or PD 
NR 
PD 
OFF 
STUDY 
L 
12 Cycles 
 
L 
12 Cycles 


Version Date March 14, 2014 
 
 
 
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for the true success proportion will be calculated.  Responses will be evaluated after 4 and 6 cycles of FCR plus 
lenalidomide and after 6 and 12 cycles of lenalidomide consolidation/maintenance. The overall survival (OS) is defined as 
the time interval between the treatment starting date and the documented date of death. For a surviving patient, OS is 
censored at the last follow-up date when the patient is documented to be alive. Progression-free survival (PFS) is defined 
as the time interval between the treatment starting date and the documented date of disease progression or death, 
whichever occurs first. For an alive and progression free patient, PFS is censored at the last follow-up date when patient 
is documented to be progression free. The OS and PFS will be estimated by the Kaplan-Meier method. The median 
survival and the corresponding 95% confidence interval will also be reported. However, given the small sample size, these 
estimates will be largely exploratory in nature. The relation of these endpoints to the expression of ZAP-70, CD38, IgVH 
status and chromosomes will be explored by standard group comparison methods or proper regression methods. 
Monitoring:  
The principal investigator(s) and the study statistician will review the study periodically to identify accrual, toxicity, and any 
endpoint problems that might be developing. This study will be monitored according to the data and safety monitoring plan 
that is currently in place, and if necessary will report to the HUMC Data and Safety Monitoring Board for review.  
STUDY DURATION: 24 months 
TOTAL SAMPLE SIZE: 54 
Stage 1: 19 
Stage II: 35 
DOSING REGIMEN(S): 
Induction Phase: (28 day cycles) 
NOTE: Lenalidomide starting dose recommendations for Cycle 1 for 
calculated creatinine clearance ≥30ml/min and <60ml/min* 
Cycle 1 
Fludarabine 
20mg/m2 IV days 2-4 
 
Cyclophosphamide 
150mg/m2 IV days 2-4 
 
Rituximab 
375mg/m2 IV day 1  
 
Rituximab 
500 mg/m2 IV day 14 +/- 2 
days 
 
Pegylated G-CSF* 
6mg ≥ 24 hours after last 
dose of chemotherapy 
 
Lenalidomide 
5mg po days 8 – 28 
Cycle  2 
Fludarabine  
20mg/m2 IV da s 1-3 
Cyclophosphamide  
150mg/m2 IV days 1-3 
Rituximab  
500mg/m2 IV day 1 & 14 +/- 
2 days  
pegylated G-CSF 
6mg 24 hours after last dose 
of chemotherapy 
Lenalidomide 
10mg days 8-28 if no grade 
3 or 4 toxicity at the 5mg 
dose. Dose may be adjusted 
down for grade 3/4 toxicity 
DRUG SUPPLIES: 
For study participants, Celgene Corporation will 
provide lenalidomide at no charge through 
RevAssist Program. 


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Cycle 3-6 
Fludarabine 
20mg/m2 IV days 1-3 
Cyclophosphamide 
150mg/m2 days 1-3 
Rituximab 
500mg/m2 day 1 & 14 +/- 2 
days 
Pegylated G-CSF 
6mg 24 hours after last dose 
of chemotherapy 
Lenalidomide 
15mg days 8-28 if no grade 
3 or 4 toxicity at the 10mg 
dose. Dose may be adjusted 
down for grade 3/4 toxicity 
  
Consolidation Phase for CR only 
Begins 2 months after last dose of FCR plus lenalidomide in all CR 
patients (MRD– after 4 cycles FCR, MRD+ after 6 cycles) 
Maximum of 12 cycles 
NOTE: Lenalidomide starting dose recommendations for Cycle 1 for 
calculated creatinine clearance ≥30ml/min and <60ml/min* 
Cycle 1 
Lenalidomide 
                           
5mg PO days 1-28 of 28 
day cycle 
Cycle 2 
Lenalidomide               10mg PO days 1-28 of 28 
day cycle if no grade 3/4 
toxicity in cycle 1, Dose may 
be adjusted down for grade 
3/4 toxicity 
Cycles 3-12 
Lenalidomide 
15mg PO days 1-28 of 28 
day cycle if no grade 3/4 
toxicity in cycle 2, Dose may 
be adjusted down for grade 
3/4 toxicity 
 
 
 
 
Consolidation Phase for PR only 
Begins 1-3 months after last dose of FCR plus lenalidomide in all 
PR patients  
Maximum of 12 cycles 
NOTE: Lenalidomide starting dose recommendations for Cycle 1 for 
calculated creatinine clearance ≥30ml/min and <60ml/min* 
Cycle 1 
Lenalidomide 
                             
5mg PO days 1-28 of 28 
day cycle 


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Cycle 2 
Lenalidomide 
10mg PO days 1-28 of 
28 day cycle if no grade 
3/4 toxicity in cycle 1 
Dose may be adjusted 
down for grade 3/4 
toxicity 
Cycle 3-12 
Lenalidomide 
15mg PO days 1 – 28 of 
28 day cycle if no grade 
3/4 toxicity in cycle 2. 
Dose may be adjusted 
down 
for 
grade 
3/4  
toxicity 
 
 
 
 
* Dosing of lenalidomide will begin at 5 mg every other day, days 8-28 in cycle 1 for patients with creatinine 
clearance of ≥ 30 ml/min and ≤ 60 ml/min.  Dose increase to 5mg daily, days 8-28 in cycle 2 and 10mg daily, days 
8-28 in cycles 3-12 if no grade 3/4 toxicity.  Dose may be adjusted down for grade 3/4 toxicity.  During induction, 
lenalidomide schedule is days 8-28, and during consolidation, lenalidomide schedule is days 1-28. 
**an alternative to pegylated G-CSF is filgrastim 5 mcg/kg sc (see paragraph 6.3.1) 
 
1.0 INTRODUCTION  
 
1.1. Disease Background 
 
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. It is generally 
considered to be incurable with conventional doses of chemotherapy. Until recently there has been little enthusiasm 
for more aggressive approaches to this often indolent disease. However, with the advent of purine analogues and the 
high complete remission rates they bring, new interest has been kindled in the management of this disorder. 
 
The annual incidence of CLL in the United States is approximately 10,000 cases/year (1). CLL is considered to be a 
disease of advanced age. The median age of patients at diagnosis is 72. However, increasingly younger patients are 
being diagnosed with this disorder (2). CLL is more common in males than in females (3). With the advent of “routine” 
blood tests, many patients are now being diagnosed while still asymptomatic. The most common complaints of 
symptomatic patients are fatigue, weight loss, fevers, frequent bacterial and viral infections, and increased tendency 
to bleed. On physical examination lymphadenopathy and splenomegaly are often found. Laboratory evaluation 
reveals an excess of mature appearing lymphocytes in the peripheral blood. These leukemic cells have a 
phenotypically abnormal, but characteristic, B cell immunophenotype. The patient may also have thrombocytopenia 
and anemia. 
 
The diagnosis of CLL is made by a combination of morphologic and immunophenotypic criteria. Different diagnostic 
criteria have been set forth by several organizations. The National Cancer Institute-sponsored working group 
produced guidelines for CLL clinical protocols. Their diagnostic criteria require that leukemic cells appear mature 
(morphologically resembling small lymphocytes) and that no more than 55% be prolymphocytes. The leukemic cells 
express an abnormal phenotype characteristic of CLL: co-express B cell antigens, such as CD19 and CD20, with CD5 
the T-cell antigen and have low density CD20 and slg on the cell surface. Other criteria include a minimal absolute 
lymphocyte count of 5,000/mm3, a bone marrow aspirate demonstrating ~ 30% of all nucleated cells are lymphoid, 
and the exclusion of other lymphoproliferative disorders (4). 
 
The Rai staging criteria, as originally proposed, grouped patients on the presence or absence of lymphadenopathy 
(Stage I), splenomegaly and/or hepatomegaly (Stage II), anemia (Stage III), or thrombocytopenia (Stage IV). Patients 


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with only a lymphocytosis were classified Stage 0 (5). The original Rai system was later modified to reduce the 
number of stages from five to three, without altering its prognostic capabilities (6). 
 
Patients with a good prognosis (Rai Stage 0) have a median survival of more than 12.5 years while intermediate risk 
patients (Rai Stage I and II) have worse prognosis with a median survival of less than 8 years. High risk patients (Rai 
Stage III and IV) have an expected survival of between 1.5 and 2.5 years (5, 7). 
 
Other prognostic indicators include: absolute blood lymphocyte count, bone marrow histological patterns, 
cytogenetics, lymphocyte doubling time (LDT), lactate dehydrogenase levels, beta-2 microglobulin, lymphocyte 
morphological subtypes, age, sex, and response to treatment (8, 9).  Patients with LDT of 12 months or less have a 
significantly worse prognosis than patients with a longer LDT (10).  Somatic hypermutation of immunoglobulin heavy 
chain variable region (IgVH) genes is seen in about 50% of patients and have a more favorable prognosis compared 
to patients who have leukemic cells with unmutated IgVH genes (11-14). Expression of ZAP-70 is associated with 
IgVH mutations , with ZAP-70 expression often correlated with unmutated IgGVH, and may also be an independent 
prognostic marker (15).  Trisomy 12 and 17p (p53) chromosomal deletion also correlated with poor prognosis (16-18).  
Expression of CD38 on CLL cells has also been associated with a poor prognosis(19). 
 
While partially related to stage, the pattern of infiltration of the bone marrow reflects the total burden of disease. 
Patients with a diffuse pattern (vs. nodular or interstitial) have a less favorable prognosis (20, 21). A high absolute 
blood lymphocyte count, high LDH, older age, male gender, increased percentage of prolymphocytes, and poor 
response to treatment also portend a poor prognosis. These prognostic indicators are more useful in early stage 
disease where there appears to be a subgroup of patients who have prolonged periods without disease progression. 
Efforts have been made to define a group of patients with “smoldering CLL” who have a prognosis that approximates 
that of the general population. Criteria that have been identified include peripheral blood lymphocyte doubling time 
greater than 12 months; non-diffuse bone marrow infiltration; absolute lymphocyte count <30 x 109/mm3 and 
hemoglobin >13 g/dL (8, 22). 
 
 
 
 
1.2. Treatment  
 
As CLL remains largely an incurable disease, treatment will usually be initiated with palliative intent, and therefore, 
should not necessarily begin at the time of diagnosis. Studies to date have not demonstrated an improvement in 
survival with early intervention when compared to treating later in the course of the disease (23). In general, treatment 
should begin when the patient becomes symptomatic or there is evidence of frank progression of disease. As outlined 
above, symptoms include fever, excessive fatigue, weight loss, and symptomatic enlargement of either lymph nodes 
or spleen. These symptoms are all relative indications for treatment and the urgency for initiating therapy will depend 
on the magnitude of the symptoms. For instance, minor well-tolerated lymphadenopathy does not mandate treatment. 
Infections are common in CLL and, consequently, may not necessarily be an indication to start cytotoxic therapy. In 
fact, patients having difficulty with recurrent infections as a consequence of disease-induced hypogammaglobulinemia 
may benefit from infusional therapy with intravenous gamma globulin. However, impaired bone marrow function, as 
evidenced by anemia, thrombocytopenia, or granulocytopenia caused by marrow infiltration by malignant cells 
definitely warrants specific treatment. Other life-threatening events include lymphadenopathy that compromises vital 
organs, autoimmune destruction of either platelets or red cells, and transformation of the CLL to a more aggressive 
malignancy. Finally, if patients are considering enrollment in an investigational therapeutic trial (e.g., bone marrow 
transplantation following cytotoxic therapy), treatment might be initiated earlier. 
 
Previously, chlorambucil has been considered the standard treatment for CLL. This choice has come about after initial 
studies demonstrated improved response rates but no improvement in survival for chlorambucil and prednisone over 
single agent chlorambucil alone. Subsequent trials comparing chlorambucil and prednisone to other forms of 
combination chemotherapy (COP, CVP, CMP, CHOP) failed to demonstrate a significant improvement in survival with 
these more intensive and toxic regimens, even though they were able to demonstrate improved response rates (10, 
22, 24, 25-27). The standard treatment recommendations are again being challenged with the advent of the 
nucleoside analogues. 
 
Fludarabine appears the most promising of this new class of drugs. Fludarabine monophosphate is the 2-fluoro, 5’-
phosphate derivative of the anti-leukemic agent 9-B-D-arabinofuranosyl adenine (ara-A). Its intracellular metabolic 
product F-ara-ATP suppresses DNA synthesis by inhibiting ribonucleotide reductase and DNA polymerase alpha. 


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Grever et al. demonstrated the activity of fludarabine in previously treated CLL patients. Greater than 50% of the 
patients showed clinical improvement (28). Subsequent reports confirmed the activity of this agent in CLL (29). 
Response rates in previously untreated patients approximate 70% (29, 30). In addition, a preliminary report of a 
randomized clinical trial comparing chlorambucil with fludarabine indicates a superior complete response rate with 
fludarabine (27% vs. 3%) but was not associated with improved survival (31). 
 
There is limited experience of multidrug combination therapies involving fludarabine in CLL. While the addition of 
prednisone to chlorambucil may increase the response rates when compared to the single agent, there was no 
advantage to adding prednisone to fludarabine (32). There is also a report of an increase in atypical infections, 
predominantly listeriosis or Pneumocystis carinli pneumonia (PCP), in patients treated with fludarabine in combination 
with prednisone (32, 33). These infections have not been noted to the same extent in patients who were treated with 
fludarabine alone. 
 
There is laboratory data to suggest that fludarabine and cyclophosphamide is a worthwhile combination with 
synergistic tumor killing when leukemia cells taken from patients with CLL are exposed to this combination in vitro 
(NCI Consensus conference). In a thymidine uptake assay, these investigators have demonstrated that the DNA 
repair that normally occurs after exposure to cyclophosphamide is blocked by the fludarabine. Fludarabine is known to 
inhibit DNA polymerase which is needed for DNA repair. Studies have shown enhanced cytotoxicity of alkylating 
agents and decreased DNA repair with other nucleoside analogs (34, 35).  Clinical stuides have documented activity 
of FC (36, 37). 
 
Rituximab as a single agent has modest activity in CLL (38-42).  No dose-limiting effects were observed in Phase I/II 
studies.  Reported adverse events including fever, chills, headache, nausea, vomiting, rhinitis, and mild hypotension, 
occurred primarily during rituximab infusions and typically responded to an interruption of the infusion and resumption 
at a slower rate.  Other adverse events included neutropenia, thrombocytopenia and asthenia.   
 
Patients with preexisting cardiac conditions, including arrhythmia and angina, have had recurrences of these cardiac 
events during rituximab infusions.  Although rare, tumor lysis syndrome has been reported in postmarketing studies 
and is characterized in patients with a high number of circulating malignant cells (>25,000 ul) by rapid reduction in 
tumor volume, renal insufficiency, hyperkalemia, hypocalcemia, hyperuricemia, and hyperphosphatemia.  In rare 
cases, severe and fatal cardiopulmonary events, including hypoxia, pulmonary infiltrates, acute respiratory distress 
syndrome, myocardial infarction, and cardiogenic shock have occurred (4-7/10,000 patients or 0.04-0.07%.)  Nearly 
all fatal infusion-related events occurred in association with the first infusion.  The following immune serious adverse 
events have been reported to occur rarely (<0.1%) in patients following completion of rituximab infusions: arthritis, 
disorders of blood vessels (vasculitis, serum sickness and lupus-like syndrome), lung disorders including pleuritis and 
scarring of the lung (bronchiolitis obliterans), eye disorders (uveitis and optic neuritis), and severe bullous skin 
reactions (including toxic epidermal necrolysis and pemphigus) that may result in fatal outcomes.  Patients may have 
these symptoms alone or in combination with rash and polyarthritis. 
 
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 4 months after the 
initiation of rituximab and approximately one month after the last dose.  A direct causal relationship between rituximab 
and HBV viral reactivation has not been established. 
 
The combination of fludarabine and rituximab demonstrated excellent responses in a phase 2 randomized study of 
104 patients. There were 28% and 47% complete responses in the sequential and combined arms respectively (58).  
Combining rituximab with fludarabine and cyclophosphamide suggest that the three drug combination has ever 
greater activity in patients with CLL than the combination of fludarabine and cyclophosphamide or fludarabine and 
rituximab.  Data from the M. D. Anderson Cancer Center report complete responses of 58% and overall responses of 
94% (59).  These data were confirmed by the German CLL Study Group (GCLLSG) and FCR was approved by the 
US FDA for the treatment of CLL in the front line setting and for patients with relapsed/refractory disease (60). Recent 
data published by Foon et al, suggest that low dose fludarabine and cyclophosphamide can be combined with 
rituximab to minimize hematologic toxicity with a comparable response rate and duration of response to standard 
dose FCR (74). 
 


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Lenalidomide, a thalidomide analogue, is an immunomodulating drug with antitumor activity approved by the USFDA 
for the treatment of myelodysplastic syndrome and multiple myeloma.(43-47)  Lenalidomide downregulates tumor 
necrosis factor-ά(48), alters  tumor microenvironment(49), activates T cells(50, 51), enhances antibody-dependent 
cytotoxicity(50, 52), and upregulates select tumor suppressor genes.(53)  Forty-five relapsed/refractory CLL patients 
were treated with 25mg of daily oral lenalidomide days 1 through 21 of a 28 day cycle.(54)  The overall response rate 
was 47% with 9% complete responses.  Grade 3/4 fatigue, thrombocytopenia and neutropenia were seen in 10%, 
45% and 70% of patients, respectively.  A flare reaction consisting of pain, swelling and erythema at the sites of 
disease was seen in 58% of patients and was grade 3/4 in 8%.  Onset was typically within 24 hours of the first dose 
with a median duration of 14 days.  In another study, 44 relapsed/refractory patients were treated with lenalidomide at 
5mg daily with dose escalation up to 25mg daily.(55)  An overall response rate of 32% with 7% complete remissions.  
Myelosuppression was the most common toxicity with grade 3/4 neutropenia in 41% of courses and grade 3/4 
thrombocytopenia in 16% of courses.  Tumor flare reactions were seen in 10% of courses which responded to a 6 day 
course of steroids.  In another study four patients with relapsed CLL treated with lenalidomide at 25mg/day had 
unacceptable toxicity with severe tumor flare in 3 patients and sepsis and renal failure in the fourth.(56)  Lenalidomide 
has also been studied in previously untreated CLL patients.  Two preliminary reports initiated single agent therapy at 5 
and 5mg daily with dose escalation to 25mg daily for 21 days of a 28 day cycle.(56, 57)  Partial responses were 
reported in 65% of patients in one study (57) and 54% in the other study(56). Toxicity were manageable 
myelosuppression and tumor flare in both studies. 
 
Due to activity demonstrated in the relapsed / refractory setting as well as its proposed novel mechanisms of activity, 
lenalidomide has been studied in combination in the relapsed/refractory and front line settings with promising results. 
Lenalidomide has been studied in combination with fludarabine and rituximab in two recent studies. In one study 
toxicity was excessive when lenalidomide began on day 1 of chemo-immunotherapy (61) however in another Phase 
I/II study when the lenalidomide was initiated on day 8 of the cycle, toxicity was acceptable (62) and activity was 
notable. When lenalidomide was initiated on day 8 of therapy in combination with FR the ORR was 83% in 6 patients. 
Lenalidomide has also been studied in combination with cyclophospamide and fludarabine in the relapsed setting 
(FCL). Using the FCL regimen, lenalidomide was given on days 1-14 of each cycle with an ORR of 67% and a 
maximum tolerated dose of lenalidomide of 5mg (63) per day. 
 
Our expectations of therapy in CLL have increased because the more active regimens have shown that CR with 
eradication of MRD is possible.  MRD-negative remissions have been observed after auto-HSCT, (64) alemtuzumab 
(65) and chemotherapy (66).  In all of these series, MRD-negative patients survive longer than MRD- positive patients. 
 
Quantitative assessment of MRD in 471 patients in the CLL8 trial receiving FC or FCR has provided additional insight 
into the clinical significance of MRD (67).  Four-color flow cytometry showed that a low MRD was correlated with 
longer PFS regardless of treatment.  The FCR regimen had lower median MRD compared with FC, resulting in longer 
PFS.  Several clinical studies have also suggested that eradication of MRD may improve PFS, treatment-free survival 
and possibly OS (59,66,68), 
 
Another issue that has not been addressed is length of treatment required with the FCR regimen.  Two trials have 
addressed dose of FCR suggesting that lower doses may be better tolerated and maintain efficacy (69, 70).  
Decreasing the cycles of FCR may be possible with similar efficacy.  In this trial we will decrease the cycles of FCR 
from 6 to 4 in patients who are in CR and are MRD negative after 4 cycles. 
 
In this proposed trial to minimize the potential for hematologic toxicity, FCR will be combined with lenalidomide using 
the schedule proposed by Foon et al (74).  Cycle 1 will include rituximab given slowly on day 1 at 375 mg/m2 and 500 
and 500 mg/m2 on day 14 while fludarabine will be given at 20 mg/m2 and cyclophosphamide at 150 mg/m2 on days 
2-4.  The fludarabine and cyclophosphamide will be given at the above doses every four weeks on days 1-3, 
immediately preceded by rituximab. Additionally rituximab will be administered at 500 mg/m2 (cycle 2-6) with 
subsequent cycles. Based on previous work, lenalidomide will begin in cycle 1 days 8 – 28 at a 5mg dose to be 
escalated to 10mg in cycle 2 and a maximum of 15mg in cycles 3 - 6 if there was no grade 3 or 4 toxicity at the prior 
dose. Following FCR patients will receive 12 months of lenalidomide.  FISH panel will include the common recurrent 
CLL genetic abnormalities including 11q, 6q, trisomy 12, 13q, and 17p (p53).   All patients will have bone marrow 
aspirations and biopsies to determine bone marrow infiltration for prognosis.  Flow cytometry will be used to study 
bone marrow and peripheral blood for minimal residual disease.   


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2.0 RATIONALE 
 
We and others have used 6 cycles of chemoimmunotherapy for previously untreated CLL patients (59, 68, 69).  There 
exists no data regarding reducing the cycles of chemoimmunotherapy to reduce exposure to cytotoxic agents and 
minimum data combining lenalidomide sequentially in the induction therapy.  All of the patients who entered a CR 
responded quickly yet none of the studies to date have carefully evaluated patients for response prior to the 
completion of 6 cycles.  We believe that many patients will enter a CR after only 4 cycles of FCR plus lenalidomide, 
and we expect that many of these patients will be bone marrow MRD negative.   
 
The secondary objective of this study is the effect of lenalidomide following FCR plus lenalidomide.  For patients who 
enter a CR they will have bone marrow MRD multi-color flow cytometry after completing FCR plus lenalidomide.  If 
they are CR MRD negative after 4 cycles of FCR they will receive 12 cycles of lenalidomide.  If they are CR MRD+ 
they will have two more cycles of FCR plus lenalidomide followed by repeat bone marrow & peripheral blood MRD 
studies followed by 12 cycles of lenalidomide.   One month after the 6th and 12th cycles of lenalidomide they will be 
retested for MRD.  For patients who are PRs after 4 cycles of FCR plus lenalidomide they will receive 2 additional 
cycles of FCR plus lenalidomide.  They may begin lenalidomide as soon as 1 month post FCR and lenalidomide and 
may receive up to 12 cycles at the discretion of the investigator.  We expect lenalidomide will eradicate MRD in MRD+ 
CR patients and a proportion of the PR patients should respond to lenalidomide.  The International Workshop on CLL 
criteria for treatment initiation and evaluation of response will be used in this study (71). 
 
3.0 OBJECTIVES 
 
3.1. Primary:  
To evaluate the complete response rate after 4 cycles of FCR plus lenalidomide in patients with previously 
untreated CLL. 
 
3.2. Secondary: 
 
3.2.1. To determine whether an additional 2 cycles of FCR plus lenalidomide will eliminate bone marrow minimal 
residual disease detected by 4 color flow cytometry. 
 
3.2.2. To determine whether 12 cycles of lenalidomide consolidation/maintenance will eliminate MRD in MRD+ 
CR patients. 
 
3.2.3. To determine whether patients who have a PR following 4 cycles of FCR- plus lenalidomide improve their 
responses after 2 additional cycles of FCR plus lenalidomide. 
 
3.2.4. To determine if patients with a PR will respond to lenalidomide consolidation/maintenance after 6 cycles of 
FCR plus lenalidomide. 
 
 
3.2.5. To evaluate overall response rate, progression-free survival and overall survival of patients with previously 
untreated CLL treated with FCR and lenalidomide followed by lenalidomide. 
 
3.2.6. To evaluate the toxicity of patients with previously untreated CLL treated with FCR and lenalidomide 
followed by lenalidomide. 
 
3.2.7. To determine whether the expression of ZAP-70, CD38, and chromosomes, correlate with response rate, 
duration of response, and survival for previously untreated patients with CLL. 
 
3.2.8. To determine whether lenalidomide will enhance immune recovery following FCR plus lenalidomide.  
 
3.2.9. To determine the transfusion requirement for patients while receiving this regimen. 
 
3.2.10. To determine the frequency of second malignancies among patients receiving this regimen. 
 
4.0 TRIAL POPULATION  


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Between 19 and 54 previously untreated CLL subjects will participate in this trial.  All subjects must meet the following 
criteria for eligibility; no waivers for this protocol will be provided for eligibility  
 
4.1. Inclusion Criteria 
 
4.1.1. Patients must have diagnosis of CLL (as defined by the NCI Criteria below: 
 
Patients must have peripheral blood absolute lymphocyte count of >5,000/mm3 obtained within 2 
weeks prior to start of study.  
 
 
The lymphocytosis must consist of small, mature lymphocytes, with ≤55% (not greater than 55%) 
prolymphocytes.  
 
 
Patients must have phenotypically characterized CLL as defined as:  
 
a) The predominant population of cells share B-cell antigens with CD5 in the absence of 
other pan-T-cell markers (CD3, CD2, etc.);  
b) Surface immunoglobulin (slg) and CD20 with low-cell surface density expression.  
c) If surface immunoglobulin can be demonstrated, the leukemic cells are restricted 
to expression of either kappa or lambda. 
 
 
Splenomegaly, hepatomegaly or lymphadenopathy are not required for the diagnosis of CLL.  
 
4.1.2. Patients must require chemotherapy. Indications for chemotherapy are listed below-  
4.1.2.1. one or more of the following disease related symptoms are required :  
 
a) Weight loss >10% within the previous 6 months 
 
b) Fevers of greater than 100.0° F for 2 weeks without evidence of infection.  
 
c) Night sweats without evidence of infection. Evidence of progressive marrow failure as manifested 
by the development of or worsening of anemia (<10g/dL) and/or thrombocytopenia (< 
100,000/mm3). 
d) Massive (i.e., > 6 cm below left costal margin) or progressive splenomegaly 
e) Massive nodes or clusters (i.e., >5cm in longest diameter) or progressive adenopathy.  
Progressive lymphocytosis with an increase of >50% over 2 month period, or an anticipated 
doubling time of less than 6 months.  
 
4.1.3. Patients must not have received prior treatment cytotoxic, immunotherapy or investigational therapy.  
 
4.1.4. Patients must not have history of corticosteroid treatment for CLL, Autoimmune thrombocytopenia, or 
autoimmune hemolytic anemia. 
 
NOTE: Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of 
the above criteria for active disease are not sufficient for protocol therapy.  
 
4.1.5. Calculated creatinine clearance ≥30ml/min by Crockcroft-Gault formula (see Appendix VI) 
 
4.1.6. Bilirubin must be ≤1.5mg/dl, unless secondary to tumor, obtained within 2 weeks prior to registration.  
 
4.1.7. Platelets ≥75x109/L, unless due to CLL involvement of bone marrow (within 2 weeks of registration). 
 
4.1.8. Neutrophils ≥1.5x109/L, unless due to CLL involvement of bone marrow (within 2 weeks of registration). 
 
4.1.9. AST or ALT < 2x upper limit of normal, unless related to CLL (within 2 weeks of registration). 
 
4.1.10. Age ≥18 years.  
 
4.1.11. ECOG performance status 0-2 
 


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4.1.12  Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a 
sensitivity of at least 50 mIU/mL within 10 – 14 days and again within 24 hours prior to starting Cycle 1 of 
lenalidomide (prescriptions must be filled within 7 days as required by RevAssist) and must either commit 
to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, 
one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days 
before she starts taking lenalidomide.  FCBP must also agree to ongoing pregnancy testing.  Men must 
agree to use a latex condom during sexual contact with a FCBP even if they have had a successful 
vasectomy.  .  See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods 
4.1.13. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a 
successful vasectomy.  See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods.  
 
4.1.14. Able to take aspirin (81mg or 325mg) daily as prophylactic anticoagulation (patients intolerant to ASA may 
use warfarin or low molecular weight heparin).  
 
4.1.15. Subject must provide written informed consent.  
 
4.1.16. All study participants must be registered into the mandatory RevAssist® program, and be willing and able 
to comply with the requirements of RevAssist®. 
 
 
4.2. Exclusion Criteria 
 
4.2.1. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia are not eligible. 
 
4.2.2. No prior immunotherapy, investigational or cytotoxic chemotherapy. 
 
4.2.3. Patients with a history of steroid treatment for CLL/SLL autoimmune hemolytic anemia, or autoimmune 
thrombocytopenia are not eligible 
 
4.2.4. Patients with active infections requiring oral or intravenous (IV) antibiotics until resolution of the infection and 
completion of therapeutic antibiotics.  
 
4.2.5. Women of childbearing potential and sexually active males who both refuse to use an accepted and 
effective method of contraception or women who are breastfeeding.   
 
4.2.6. Patients with a second malignancy other than basal cell carcinoma or squamous cell carcinoma of the skin 
or in situ carcinoma of the cervix are not eligible unless the tumor was treated with curative intent at least 
two years previously. 
 
4.2.7. History of known HIV 
 
4.2.8. History or presence CNS disease (CLL) 
 
4.2.9. History or presence of any comorbidity or psychiatric condition that, in the opinion of the investigator, would 
make compliance with the protocol difficult or place the subject at undue risk.   
 
4.2.10. New York Heart Classification III or IV heart disease.  
 
4.2.11. Hepatitis BsAg or Hepatitis C positive. Patients who are seropositive because of hepatitis B virus vaccine 
are eligible.  
 
4.2.12. Known hypersensitivity to thalidomide.  
 
 
 
 


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4.2.13. Evidence of laboratory TLS by Cairo-Bishop definition of Tumor Lysis Syndrome (see Appendix V). 
Subjects may be enrolled upon correction of electrolyte abnormalities.  
 
4.2.14. Patients must not have received prior treatment cytotoxic, immunotherapy or investigational therapy.  
 
4.2.15. Patients must not have history of corticosteroid treatment for CLL, Autoimmune thrombocytopenia, or 
autoimmune hemolytic anemia. 
 
5.0 REGISTRATION  
After informed consent has been obtained patients will be registered at Hackensack University Medical Center. 
 
Once eligibility has been confirmed by site, eligibility worksheets must be completed prior to initiating therapy. 
 
 
6.0 TRIAL DESIGN  
A cycle is defined as 28 days. Patients will receive treatment as outlined in section 6.1.   
 
6.1. Treatment Plan  
 
Induction:  One cycle = 28 days 
 
Cycle 
Day 
Dosing 
Cycle 1 
Day 1 
Rituximab IV 375mg/m2  this dose may be given in divided doses; 
50mg/m2 on day 1, 100mg/m2 on day 2, and 225mg/m2 on day 3 
 
Day 14 +/- 
2 days 
Rituximab IV 500mg/m2 
 
Days 2-4 
Cyclophosphamide IV 150 mg/m2 followed by fludarabine IV 20 mg/m2  
 
 
Day 5 
Neulasta SQ 6mg 
 
Days 8 - 28  Lenalidomide 5mg PO 
Cycle 2 
Day 1 & 14 
+/- 2 days 
Rituximab  IV 500 mg/m2 
 
Day 1-3 
Cyclophosphamide IV 150 mg/m2 followed by fludarabine IV 20 mg/m2  
 
Day 4 
Neulasta SQ 6mg  
 
Days 8 - 28 
Lenalidomide 10mg PO (if no grade 3/4 toxicity is observed in cycle 1) 
Cycle 3-6 
Day 1 & 14 
+/- 2 days  
Rituximab IV 500mg/ m2 
 
Day 1 – 3 
Cyclophosphamide IV 150mg/ m2  followed by fludarabine IV 20mg/ m2 
 
Day 4 
Neulasta SQ 6 mg 
 
Day 8-28 
Lenalidomide 15mg PO (if no grade 3/4 toxicity is observed in cycle 2) 
No dose adjustments will be permitted for Rituximab. 
Note: Cycle 1 starting dose recommendations and escalations guidelines after Cycle 1 for calculated 
creatinine clearance ≥30ml/min and <60ml/min. 
 
 
 
 
COMPLETE RESPONSE (CR) 
Consolidation/Maintenance: Begins 2 months after last dose of FCR plus lenalidomide 
Cycle 
Day 
Dosing 
Cycle 1 
Day 1-28 
Lenalidomide 5mg PO  
Cycle 2 
Day 1-28 
Lenalidomide 10mg PO (if no grade 3/4 toxicity is observed in cycle 1) 
Cycles 3-12 
Day 1-28 
Lenalidomide 15mg PO (if no grade 3/4 toxicity is observed in cycle 2) 


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Note: Cycle 1 starting dose recommendations and escalations guidelines after Cycle 1 for calculated 
creatinine clearance ≥30ml/min and <60ml/min. 
 
  
PARTIAL RESPONSE (PR) 
Consolidation/Maintenance: Begins 1-3 months after last dose of FCR plus lenalidomide in PR patients for a total of 
12 cycles.  
Cycle 
Day 
Dosing 
Cycle 1 
Day 1-28 
Lenalidomide PO 5mg 
Note: Cycle 1 starting dose recommendations and escalations guidelines after Cycle 1 for calculated 
creatinine clearance ≥30ml/min and <60ml/min. 
Cycle 2 
Day 1-28 
Lenalidomide 10mg PO days (if no grade ¾  toxicity is observed in 
cycle 1) 
Cycles 3-12 
Day 1-28 
Lenalidomide 15mg PO (if no grade 3/4 toxicity is observed in cycle 2) 
Note: Lenalidomide dose may be adjusted down for grade 3 or 4 toxicity, see section 12.0 for dose 
modification guidelines. No dose adjustments will be permitted for Rituximab. If dose is not tolerable 
treatment should be discontinued. 
 
 
 
6.2. Lenalidomide Starting Dose Modifications Based on Renal Function within 28 days prior to starting 
Lenalidomide and Rituximab or Single Agent Lenalidomide 
 
Baseline Calculated Creatinine Clearance (by 
Cockcroft-Gault) 
Starting Lenalidomide Dose 
> 60 ml/min 
Follow treatment plan in Section 6.1  
> 30 and < 60 ml/min 
All treatment plans: Cycle 1 only 5mg every other 
day of a 28 day-cycle 
 
Patients started with a reduced 5mg every other day lenalidomide dose due to baseline calculated creatinine 
clearance ≥ 30ml/min but < 60ml/min within 28 days prior to starting lenalidomide may, at investigator discretion, 
have their lenalidomide dose increased at the start of subsequent treatment cycles, if they tolerated the prior 
treatment cycle without requiring dose modifications, interruptions or delays due to toxicity.  For patients who initiate 
therapy at a 5mg every other day lenalidomide dose may increase to 5mg daily in cycle 2 and 10mg daily in cycles 3-
12 if no grade 3/4 toxicities are observed in prior cycles. 
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. The maximum allowable dose is lenalidomide 
15mg daily on Days 1-28 of a 28-day cycle or 10 mg daily for patients with cc ≥ 30 ml/min and ≤ 60 ml/min. 
 
 
 
 
6.3. Supportive Care 
All supportive measures consistent with optimal patient care will be given throughout the study; modifications to 
supportive care medications outlined below are at the discretion of the treating physician and will not be considered 
protocol deviations.  
 
6.3.1. Filgrastim, SC or peg-filgrastim should be initiated at least 24 hours following the completion of 
chemotherapy.  Filgrastim should be continued until post-nadir counts are 10,000/mm3. Filgrastim must be 
stopped 48 hours prior to the next cycle of chemotherapy regardless of the ANC.  
 


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6.3.2. PCP prophylaxis: Trimethoprim/sulfamethoxazole DS, one p.o. b.i.d can be given on Monday, Wednesday, 
and Friday starting with the first dose of chemotherapy and ending 6 months after last dose of 
chemotherapy. Pentamidine 4mg/kg IV q month is a suitable alternative to trimethoprim/sulfamethoxazole. 
Dapsone 100 mg daily is a suitable alternative to trimethoprim/sulfamethoxazole. To be started cycle 1 day 
4. 
 
6.3.3. Allopurinol 300mg PO daily for 14 days should be given starting seven days prior to the first dose of 
chemotherapy during the first and second cycle of chemotherapy and lenalidomide. This may be 
administered during subsequent cycles at the discretion of the treating physician.  
 
6.3.4. Antiemetics: Prophylactic antiemetic medications such as granisetron 2 mg P0 30 minutes prior to 
fludarabine and cyclophosphamide infusions are recommended and are to be administered at the discretion 
of the treating physician. 
 
6.3.5. Zoster prophylaxis (Acyclovir 400mg BID or equivalent) can be given from the start of therapy until 6 months 
after completing chemotherapy. To be started cycle 1 day 4. 
 
6.3.6. Premedications: for Rituximab, Fludaraibine, and Cyclophosphamide should be given as per your 
institutional standard of care. 
 
6.3.7. Candidiasis prophylaxis (fluconazole 200 mg daily PO or equivalent) can be given from the start of therapy 
until 6 months after completing chemotherapy. To be started cycle 1 day 4.  
 
6.3.8. Ciprofloxacin 500mg BID for ten days or equivalent should be given for prophylactic neutropenic fever. 
 
6.3.9. Rasburicase can be given at the discretion of the investigator.  
 
6.3.10. DVT prophylaxis should be started on cycle 1 day 8 (aspirin 81mg PO daily unless contraindicated. If 
ASA is contraindicated use other DVT prophylaxis according to hospital guidelines.  
 
6.3.11. All supportive measures consistent with optimal patient care will be given throughout the study. 
 
 
 
 
6.4. Schema  
 
 
 
FCR + L 
4 Cycles 
CR MRD- 
CR MRD+ 
PR 
L 
12 Cycles 
FCR- + 
Lenalidomide 
2 Cycles 
FCR + 
Lenalidomide 
2 Cycles 
CR MRD- 
CR MRD+ 
PR or CR 
NR or PD 
NR 
PD 
OFF 
STUDY 
L 
12 Cycles 
 
L 
12 Cycles 


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7.0 STUDY DRUG 
7.1. Rituximab 
Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV) administration. 
Rituximab is supplied at a concentration of 5mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The 
product is formulated for intravenous administration in 9.0 mg/mL sodium chloride, 7.35mg/mL sodium citrate 
dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for injection. The pH is adjusted to 6.5. 
 
7.1.1. Stability & Storage: Rituximab vials are stable at 2° to 8°C (36° to 46°F).  Do not use beyond expiration date 
stamped on carton. Rituximab vials should be protected from direct sunlight.  
 
The sponsor-investigator of the trial is responsible for the maintenance of complete and accurate records of 
the receipt, dispensation, and disposal or return of all trial drug in accordance with Code of Federal 
Regulations, institutional standard operating procedures and Genentech requirements.  
 
7.1.2. Dosage & Administration:  
 
 Usual Dose: The approved and accepted dosage of rituximab is 500mg/m2 given as an IV infusion once 
weekly for four doses (days 1, 8, 15, and 22). In this study rituximab is given at 375 mg/m2 for only the day 1 
dose and thereafter will be given at 500 mg/m2. Refer to protocol section 6.0 for treatment design details.   
Rituximab may be administered in an outpatient setting. DO NOT ADMINISTER AS AN INTRAVENOUS 
PUSH OR BOLUS.  
 
Preparation for Administration: Use appropriate aseptic technique. Withdraw the necessary amount of 
rituximab and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag containing either 0.9% 
Sodium Chloride USP or 5% Dextrose in Water USP. Gently invert the bag to mix the solution. Discard any 
unused portion left in the vial. Parenteral drug products should be inspected visually for particulate matter 
and discoloration prior to administration. Rituximab solutions for infusion are stable at 2° to 8°C (36° to 
46°F) for 24 hours and at room temperature for an additional 12 hours. No incompatibilities between 
rituximab and polyvinylchloride or polyethylene bags have been observed. 
 
Administration: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. Hypersensitivity 
reactions may occur. Premedications, consisting of acetaminophen and diphenhydramine, should be 
considered before each infusion of rituximab. Premedication may attenuate infusion-related events. Since 
transient hypotension may occur during rituximab infusion, consideration should be given to withholding 
anti-hypertensive medications 12 hours prior to rituximab infusion.  
 
Administration Guidelines for Adult Patient Population 
First Infusion: The rituximab solution for infusion should be administered intravenously at an initial rate of 50 
mg/hr. Rituximab should not be mixed or diluted with other drugs. If hypersensitivity or infusion-related 
events do not occur, escalate the infusion rate in 50 mg/hr increments every 30 minutes, to a maximum of 
400 mg/hr.  
 
Rituximab infusion should be interrupted for severe reactions.  In most cases, the infusion can be resumed 
at a 50% reduction in rate (e.g., from 100mg/hr to 50mg/hr) when symptoms have completely resolved.  
Treatment of infusion-related symptoms with diphenhydramine and acetaminophen is recommended. 
Additional treatment with bronchodilators or IV saline may be indicated.  Most patients who have 
experienced non-life-threatening infusion-related reactions have been able to complete the full course of 
rituximab therapy.  Epinephrine, antihistamines and corticosteroids should be available for immediate use in 
the event of a hypersensitivity reaction to rituximab (e.g., anaphylaxis). 
 
Subsequent Infusions: Subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, 
and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated. 
 
7.1.3. Over dosage 
There has been no experience with over dosage in human clinical trials. Single doses higher than 
500mg/m2 have not been tested in controlled studies.  
 
7.1.4. Safety Profile 
 


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No dose-limiting effects were observed in the Phase I/II studies.  Reported adverse events including fever, 
chills, headache, nausea, vomiting, rhinitis, and mild hypotension, occurred primarily during rituximab 
infusions and typically responded to an interruption of the infusion and resumption at a slower rate.  Other 
adverse events included neutropenia, thrombocytopenia, asthenia, other hematologic events, cardiac and 
cardiopulmonary events, and tumor lysis syndrome.  
 
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. 
 
Mucocutaneous Reactions:  Severe bullous skin reactions, including fatal cases of toxic epidermal 
necrolysis, have been reported rarely in patients treated with rituximab.  Paraneoplastic pemphigus has 
been reported very rarely in NHL and CLL patients undergoing chemotherapy plus rituximab treatment.  The 
onset of reaction has varied from 1 to 13 weeks following rituximab exposure. 
 
Cardiac Events:  Patients with preexisting cardiac conditions, including arrhythmia and angina, have had 
recurrences of these cardiac events during rituximab infusions. 
 
Cardiopulmonary Events:  In rare cases, severe and fatal cardiopulmonary events, including hypoxia, 
pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, and cardiogenic shock, 
have occurred (4-7/10,000 patients or 0.04-0.07%.)  Nearly all fatal infusion-related events occurred in 
association with the first infusion. 
 
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/mm2) or high tumor burden who experience tumor lysis 
syndrome.   
 
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 post marketing reports of prolonged pancytopenia, marrow 
hypoplasia, and late onset neutropenia (defined as occurring 40 days after the last dose of rituximab) in 
patients with hematologic malignancies.  In reported cases of late onset neutropenia (NCI-CTC Grade 3 and 
4), the median duration of neutropenia was 10 days (range 3 to 148 days).  Documented resolution of the 
neutropenia was described in approximately one-half of the reported cases; of those with documented 
recovery, approximately half received growth factor support.  In the remaining cases, information on 
resolution was not provided.  More than half of the reported cases of delayed onset neutropenia occurred in 
patients who had undergone a prior autologous bone marrow transplantation.  In an adequately designed, 
controlled, clinical trial, the reported incidence of NCI-CTC Grade 3 and 4 neutropenia was higher in 
patients receiving rituximab in combination with fludarabine as compared to those receiving fludarabine 
alone (76% [39/51] vs. 39% [21/53]). 
 
Tumor Lysis Syndrome:   Although rare, tumor lysis syndrome has been reported in post marketing studies 
and is characterized in patients with a high number of circulating malignant cells (>25,000 ul) by rapid 
reduction in tumor volume, renal insufficiency, hyperkalemia, hypocalcemia, hyperuricemia, and 
hyperphosphatemia. 
 
Infectious Events: Rituxan 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. 
 
Immunization: Response rates may be reduced with non live vaccines. 


Version Date March 14, 2014 
 
 
 
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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 disease caused by the reactivation of 
latent JC virus in the brain.  Immunosuppression allows reactivation of the JC virus which causes 
demyelination and destruction of oligodendrocytes resulting in death or severe disability.  Rare cases of 
PML, some resulting in death, have been reported in patients with hematologic malignancies who have 
received 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 
following the use of rituximab for the treatment of autoimmune diseases. The reported cases had multiple 
risk factors for PML, including the underlying disease and long-term immunosuppressive therapy or 
chemotherapy. Most cases of PML were diagnosed 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. 
 
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. 
 
Immunogenicity: Patients may develop a human anti-chimeric antibody (HACA) response with rituximab 
treatment. The clinical significance of this is unclear. 
 
Pregnancy: B-cell lymphocytopenia generally lasting less than 6 months can occur in infants exposed to 
rituximab in utero. 
 
Additional Safety Signals:  The following immune serious adverse events have been reported to occur rarely 
(<0.1%) in patients following completion of rituximab infusions: arthritis, disorders of blood vessels 
(vasculitis, serum sickness and lupus-like syndrome), lung disorders including pleuritis and scarring of the 
lung (bronchiolitis obliterans), eye disorders (uveitis and optic neuritis), and severe bullous skin reactions 
(including toxic epidermal necrolysis and pemphgus) that may result in fatal outcomes.  Patients may have 
these symptoms alone or in combination with rash and polyarthritis. 
 
See the rituximab Investigator Brochure for additional details regarding safety experience with rituximab. 
7.2. Fludarabine Phosphate 
7.2.1. Other names 
 
Fludara®, fludarabine, 2-fluoro-adenine arabinoside-5-phosphate, 2-fluoro-ARA AMP, FAMP, NSC#312887. 
 
7.2.2. Classification 
 


Version Date March 14, 2014 
 
 
 
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Purine antimetabolite 
 
7.2.3. Mode of Action  
 
Fludarabine is rapidly phosphorylated in vivo to 2-fluoro-ARA-A, incorporated into cells and converted to the 
active triphosphate form, which inhibits DNA polymerase and ribonucleotide reductase, thus inhibiting DNA 
synthesis. Fludarabine is also incorporated into DNA. 
 
7.2.4. Storage and Stability 
 
Unreconstituted vials should be stored in the refrigerator. At a concentration of 25 mg/mL and following 
dilution in normal saline or 5% dextrose to a concentration of 1 mg/mL the drug is chemically stable for at 
least 16 days at room temperature under normal laboratory light. Solutions of 0.04 mg/mI in 5% dextrose or 
normal saline in glass bottles or PVC bags are chemically stable for at least 48 hours at room and 
refrigerated temperatures. 
 
7.2.5. Preparation  
 
Fludarabine, 50 mg/vial, is reconstituted with 2 ml of sterile water, resulting in a 25 mg/mi solution. The 
desired dose is further diluted to concentrations of 0.04 - 1 mg/mi in normal saline or 5% dextrose (100- 125 
ml). The dose on this trial is 20 mg/m2.  
 
7.2.6. Administration  
 
Administer by IV infusion over 30 minutes or longer. 
 
7.2.7. Incompatibilities 
 
No information available. 
 
7.2.8. Availability 
Fludarabine, 50 mg/vial, is commercially available. 
7.2.9. Side Effects 
7.2.9.1. Hematologic: Leukopenia, primarily lymphopenia and granulocytopenia, and thrombocytopenia, dose-
related; may be cumulative, dose-limiting; anemia. 
 
7.2.9.2. Dermatologic: Alopecia (uncommon, mild); rash (rare); dermatitis (rare) 
 
7.2.9.3. Gastrointestinal: 
Nausea and vomiting are relatively uncommon and preventable with standard 
antiemetic drugs; anorexia; stomatitis (rare with conventional doses); rare; diarrhea, constipation, 
abdominal cramps. 
 
7.2.9.4. Hepatic: Increased SGOT, mild and transient. 
 
7.2.9.5. Neurologic: Somnolence, fatigue; peripheral neuropathy (paresthesias), rare and usually transient; 
delayed demyelinating central nervous system toxicities, including mental status changes, cortical 
blindness, severe somnolence and coma have occurred, usually with high doses (e.g. 150-200 mg/m2 
x 5); seizures (rare). 
 
7.2.9.6. Pulmonary: Hypersensitivity reactions characterized by dyspnea, cough, interstitial pulmonary 
infiltrate have been reported. 
 
7.2.9.7. Cardiovascular: Edema (frequent); pericardial effusion, hypotension chest pain (rare). 
 
7.2.9.8. Other: Metabolic acidosis and lactic acidemia due to rapid tumor lysis; muscle weakness (rare); fever 
(rare). 
 


Version Date March 14, 2014 
 
 
 
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7.2.10. Nursing Implications 
It is recommended that the following precautions be taken: 
 Check CBC and platelet counts, particularly with cumulative drug doses. 
 Premedicate with antiemetics. 
 Monitor for stomatitis, refer for oral health assessment if indicated. 
 Observe patient for CNS toxicity (vision changes, confusion, etc.). 
 Anticipate tumor lysis syndrome in patients with bulky disease. 
 Monitor pulmonary function, especially in patients who have received chlorambucil. 
 
7.3. Cyclophosphamide 
 
7.3.1. Other names 
 
Cytoxan, CTX, CPM, Neosar. 
 
7.3.2. Classification  
 
Alkylating agent. 
 
7.3.3. Mode of Action  
 
Cyclophosphamide prevents cell division primarily by cross-linking DNA strands. The cell continues to 
synthesize other cell constituents (RNA and protein), an imbalance occurs and the cell dies. 
Cyclophosphamide is considered cell cycle phase non-specific. 
 
7.3.4. Storage and Stability 
 
Tablets and injectable powder are stored at room temperature. The temperature is not to exceed 90°F. 
Reconstituted parenteral solutions are stable for 24 hours at room temperature or 14 days if refrigerated. 
  
7.3.5. Preparation  
 
Dissolve the 100 mg, 200 mg, 500 mg, I gm, and 2 gm vials in 5, 10, 25, 50, and 100 ml of sterile water, 
respectively, resulting in a solution of 20 mg/mI. Shake vials vigorously and warm slightly in lukewarm water 
to facilitate dissolution. The lyophilized form is more easily solubilized. 
 
7.3.6. Administration  
 
IV infusion over 1 hour 
 
7.3.7. Compatibilities 
7.3.7.1. Barbiturates, phenytoin, and chloral hydrate may increase the rate of hepatic conversion of 
cyclophosphamide to active metabolites, although the clinical importance of these interactions has not 
been established. 
 
7.3.7.2. Corticosteroids may inhibit metabolism and reduce the effect of cyclophosphamide, although the 
clinical importance of this interaction has not been established. 
 
7.3.7.3. May prolong the neuromuscular blocking activity of succinylcholine. 
 
7.3.7.4. Imipramine and phenothiazines may reduce cyclophosphamide metabolism, increasing bone marrow 
suppression.  
 
7.3.7.5. Possible potentiation of doxorubicin and daunorubicin cardiotoxicity. 
 


Version Date March 14, 2014 
 
 
 
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7.3.7.6. Cyclophosphamide (6-8 mg/mI) and doxorubicin (0.4-0.6 mg/mI) are compatible for 7 days at room 
temperature 
 
7.3.8. Availability  
 
Commercially available. 
 
7.3.9. Side Effects 
 
Hematologic: Leukopenia, with nadirs about 8-14 days after administration and recovery in 18-25 
days; spares platelets. 
 
 
Dermatologic: Alopecia. 
 
 
Gastrointestinal: Nausea and vomiting (begins 6-10 hours after administration). 
 
 
Hepatic: Increased AST, ALT. 
 
 
Neurologic: Headache, dizziness. 
 
 
Pulmonary: Rarely Interstitial pulmonary fibrosis. 
 
Cardiovascular: Cardiac necrosis with high-dose cyclophosphamide. 
 
 
Renal: Hemorrhagic cystitis (onset of cystitis may be delayed from 24 hours to several weeks); 
SIADH, dose related, more common with single large doses greater than 2 gm/m2. 
 
 
Other: Metallic taste during injection; nasal congestion; testicular atrophy, amenorrhea, may be 
long-term; rarely, anaphylaxis; teratogenic; may cause secondary neoplasms. 
 
7.3.10. Nursing Implications 
 
It is recommended that the following precautions be taken:  
 
 
Monitor CBC, platelet counts. 
 
 
Assess hydration and fluid balance. Patients receiving larger doses should force fluids up to 2 
liters/day for 72 hours after administration. Patient should void q 2-3 hours to facilitate emptying 
of bladder. 
 
 
A baseline 12 lead ECG may be obtained prior to high-dose therapy. 
 
 Premedicate with antiemetics. 
 
 
Advise patient of potential “metallic taste.”  Hard candy with a strong flavor may alleviate this side 
effect. 
 
7.4. Lenalidomide 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti-angiogenic 
properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-2,6-dione and it has 
the following chemical structure:  
 
Chemical Structure of Lenalidomide 


Version Date March 14, 2014 
 
 
 
Page 23 of 57 
 
 
 
 
N
N
H
O
O
O
NH2
 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.  
 
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water mixtures, and 
buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low pH solutions. Solubility was 
significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric 
carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with 
a net optical rotation of zero. 
 
7.5. 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. 
 
7.6. Pharmacokinetics and Drug Metabolism:  
 
Absorption:  
 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with maximum plasma 
concentrations occurring between 0.625 and 1.5 hours post-dose. 
Co-administration with food does not alter the extent of absorption (AUC) but does reduce the maximal plasma 
concentration (Cmax) by 36%. The pharmacokinetic disposition of lenalidomide is linear. Cmax and AUC 
increase proportionately with increases in dose. Multiple dosing at the recommended dose-regimen does not 
result in drug accumulation. 
Pharmacokinetic sampling in myelodysplastic syndrome (MDS) patients was not performed. In multiple myeloma 
patients maximum plasma concentrations occurred between 0.5 and 4.0 hours post-dose both on Days 1 and 28.  
AUC and Cmax values increase proportionally with dose following single and multiple doses. Exposure (AUC) in 
multiple myeloma patients is 57% higher than in healthy male volunteers. 
 
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. 
 
7.7. Suppliers 


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Celgene Corporation will supply lenalidomide to study participants at no charge through the RevAssist® 
program. 
 
7.8. Dosage form  
 
Lenalidomide will be supplied as 5mg and 25 mg capsules for oral administration. 
 
Lenalidomide will be shipped to the pharmacy at the study site in individual bottles.  Bottles will contain a 
sufficient number of capsules to last for one cycle of dosing. Lenalidomide must be dispensed in the original 
packaging with the label clearly visible.  Only enough lenalidomide for 1 cycle of therapy may be provided 
to the patient each cycle. 
7.9  Packaging  
 
Lenalidomide will be shipped directly to patients or to the clinic site for IND studies.  Bottles will contain a 
sufficient number of capsules for one cycle of dosing. 
 
7.10  Labeling 
 
Lenalidomide investigational supplies are dispensed to the patients in individual bottles of capsules.  Each 
bottle will identify the contents as study medication.  In addition, the label will bear the name of Celgene 
Corporation, quantity contained and the standard caution statement as follows:  Caution: New drug - Limited by 
Federal law to investigational use.  The drug label must be clearly visible.  Additional labels must not cover the 
Celgene label. 
 
7.10.1 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 accordance 
with the RevAssist® program of Celgene Corporation. Per standard RevAssist® requirements all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial, and all research subjects enrolled into this 
trial, must be registered in and must comply with all requirements of the RevAssist® Program.  Prescriptions 
must be filled within 7days for females of childbearing potential and 14 days for all risk categories.  Drug will be 
shipped on a per patient basis by the contract pharmacy to the clinic site for IND studies. Only enough 
Lenalidomide for one cycle of therapy will be shipped to the patient each cycle.  
 
 
7.11  Unused lenalidomide supplies 
Any unused lenalidomide must be returned as instructed through RevAssist program. 
 
7.12 Storage 
At the study site, lenalidomide will be stored in a locked, safe area to prevent unauthorized access.  Lenalidomide 
should be stored at room temperature away from direct sunlight and protected from excessive heat and cold. 
7.13 Unused lenalidomide supplies 
7.14   
Drug dispensing requirements 
In investigational studies, lenalidomide will be dispensed through a qualified healthcare professional (including but 
not limited to, nurses, pharmacists and physicians).  These healthcare professionals will be trained by Celgene in 
requirements specific to counseling of subjects.  Once trained these healthcare staff will counsel subjects prior 
to medication being dispensed to ensure that the subject has complied with all requirements including use of birth 
control and pregnancy testing (FCBP) and that the subject understands the risks associated with lenalidomide.   


Version Date March 14, 2014 
 
 
 
Page 25 of 57 
 
 
 
Counseling includes verification with the patient that required pregnancy testing was preformed and results were 
negative. A Lenalidomide Information Sheet (see Appendix IV) will be supplied with each medication dispense. 
 
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 (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). 
 
Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to initiation of Cycle 1 of 
lenalidomide.  FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and 
then every 28 days while on lenalidomide 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 lenalidomide therapy (including breaks in 
therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see 
Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).    
7 
All patients must be counseled about pregnancy precautions, risks of fetal exposure and other risks.  The 
counseling must be done on Day 1 of each cycle (or at a minimum of every 28 days) throughout the entire 
duration of lenalidomide treatment, including dose interruptions, and at lenalidomide discontinuation.   
 
7.15 Dosing Regimen 
The dosing schedule is outlined in Section 6.1. Dosing will be in the morning at approximately the same       
time each day.  Prescriptions must be filled within 7 days. . 
 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day.  If it is missed for the 
entire day, it should not be made up. 
 
Patients who take more than the prescribed dose of lenalidomide should be instructed to seek emergency 
medical care if needed and contact study staff immediately. 
 
Subjects experiencing adverse events may need study treatment modifications 
 
7.16 Special Handling Instructions 
 
 
Females of childbearing potential should not handle or administer lenalidomide unless they are wearing gloves. 
7.17 Pregnancy Prevention Risk Management Plans 
7.16.1  Lenalidomide Pregnancy Prevention Risk Management Plan 
7.16.2  Lenalidomide Pregnancy Risk Minimisation Plan for Celgene Clinical Trials  
Appendix II, III, IV applies to all patients receiving lenalidomide therapy. The following Pregnancy Risk 
Minimisation Plan documents are included in this appendix:  
1) Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth   Control Methods 
(Appendix II);  
1. The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods document (Appendix II) provides the following information: 
• 
Potential risks to the fetus associated with lenalidomide exposure 
• 
Definition of Female of Childbearing Potential 
• 
Pregnancy testing requirements for patients receiving Lenalidomide who are females of childbearing 
potential 
• 
Acceptable birth control methods for both female of childbearing potential and male patients receiving 
Lenalidomide in the study 


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• 
Requirements for counseling of all study patients receiving Lenalidomide about pregnancy 
precautions and the potential risks of fetal exposure to lenalidomide 
 
 
8.0 PATIENT CONSENT & PEER JUDGEMENT 
The protocol and informed consent document for this study must be approved in writing by the appropriate Institutional 
Review Board (IRB) prior to any patient being registered on this study. Changes to the protocol, as well as a change of 
principal investigator, must also be approved by the Board. Any advertisements used to recruit subjects must also be 
reviewed and approved by the IRB. Records of the Institutional Review Board review and approval of all documents 
pertaining to this study must be kept on file by the investigator (housed in the Clinical Trials Office) and are subject to FDA 
inspection at any time during the study.  Periodic status reports must be submitted to the Institutional Review Board at 
least yearly, as well as notification of completion of the study and a final report within 3 months of study completion or 
termination.   
 
9.0 DATA FORMS & SUBMISSION SCHEDULE 
Study data will be collected and stored in Velos or Paper CRF’s. Velos is a web based comprehensive cancer 
clinical trial software system which uses an Oracle database to store all data.   
 
10.0 
RECORD RETENTION 
 All documentation, including source documents, supporting documentation, administrative records, study drug 
inventory and accountability, must be retained by the Investigator for a minimum of 2 years after market approval 
or at least 2 years after formal discontinuation of the study. If any investigator retires, relocates, or withdraws from 
the investigation after the conduct of the study, the responsibility of maintenance of study records may be 
transferred to another person (coordinating site or other investigator). 
 
11.0 
STUDY PARAMETERS & CALENDAR 
 
11.1. 
Screening Procedures: A complete list of baseline procedures can be found in the study calendar.  
 
11.1.1. Any scans, x-rays, and baseline bone marrow biopsies used to document measurable or evaluable 
disease should be done within 8 weeks prior to initiating therapy. 
 
11.1.2. Pre-study CBC (with differential and platelet count) should be done ≤ 2 weeks before initiating therapy.  
 
11.1.3. All required pre-study chemistries, including sodium, potassium, chloride, CO2, calcium, magnesium, phosphorus, 
BUN, creatinine, glucose, albumin, total protein, alkaline phosphatase, total bilirubin, AST/SGOT, ALT/SGPT, LDH, and 
uric acid should be done ≤4 weeks before initiating therapy, unless specifically required on day 1 as per 
protocol. 
 
11.1.4. Hepatitis B surface antigen, surface antibody, and core antibody and Hepatitis C testing will be done ≤2 
weeks before initiating therapy. 
 
11.1.5. Pregnancy testing (urine or serum) is required for all females of child bearing potential (FCBP) as defined 
by a sexually mature female who 1) has not undergone hysterectomy or bilateral oophorectomy or 2) has 
not been naturally post menopausal (absence of menses) for 24 consecutive months.  
 
11.1.5.1. For FCBP with regular or no menses:  
testing is to be done with 10-14 days of first cycle of lenalidomide, within 24 hours before prescribing 
lenalidomide, weekly for the first 28 days, and every 4 weeks while receiving lenalidomide ( including 
breaks in therapy), at discontinuation of lenalidomide and 28 days post treatment. 
 
 
11.1.5.2. 
For FCBP with irregular menses: testing is to be done with 10-14 days of first cycle of lenalidomide, 
within 24 hours before prescribing lenalidomide, weekly for the first 28 days, and every 2 weeks while 
receiving lenalidomide ( including breaks in therapy), at discontinuation of lenalidomide and days 14 
and 28 days post treatment. 
 
 
 
11.2. 
Study Calendar 


March 14, 2014 
 
INDUCTION 
CONSOLIDATION/ 
MAINTENANCE 
POST 
CONSOLIDATION/MAINTENANCE 
FOLLOW-UP 
 
 
 
 
Baseline 
 
(C1D1) 
Before 
Each 
Cycle1< 8 
(C3D1) 
After 
Second 
Cycle8 
 
After 
Fourth 
and Sixth Cycle8 
 
Entry 
for 
Consolidation
/maintenance 
 
Day 1 
All Revlimid 
Cycles 
1 month after 
consolidation 
 
3 
months 
after 
consolidation/mainten
ance 
Follow-
Up 
(Stable/ 
PD) 6 
Follow- 
Up 
(PR/CR)6 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical History & Height2 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
Vital 
signs, 
weight 
& 
Performance status 
X 
X 
 
X 
 
 
 
 
X 
 
 
Education 
and 
Counseling guidance  
 
X8 
 
 
 
 
 
 
 
 
CBC with Differential 
X1 
Weekly 
 
X 
Every 
2 
weeks 
 
X 
 
X 
Chemistry3 
X 
X 
 
X 
 
 
See 
footnote 3 X 
X 
 
 
 
X 
Beta-2 microglobulin 
X 
 
 
X 
 
 
X 
X 
 
X 
Hepatitis B and C 
X1,3 
 
 
 
 
 
 
 
 
 
Serum creatinine2 
X 
X 
 
X 
 
 
X 
X 
 
X 
CT 
of 
neck, 
chest, 
abdomen & pelvis5 
 
X 
 
 
 
X 
 
See footnote 5 
 
 
 
 
Annual 
Pregnancy test4 
X 
 
 
 
X4 
X4 
 
 
 
 
Bone marrow biopsy and 
aspirate with routine flow 
cytometry, cytogenetic and 
CLL FISH panel 
Zap-70 
and 
mutational 
status of IgVH 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flow cytometry of bone 
marrow 
for 
minimal 
residual CLL  
 
 
 
 
 
X 
 
 
X7 
X7 
 
 
 
 
Annual 
Flow 
cytometry 
of 
peripheral 
blood 
for 
minimal residual CLL 
 
 
 
X 
 
X 
X7 
X7 
X 
 
Annual 
Quantitative 
immunoglobulins 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
X 
Direct & indirect Coombs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Palpable 
tumor 
measurement 
X 
 
X 
X 
 
 
 
 
X 
 
X 
Survival Follow-up & Anti-
cancer therapy 
 
 
 
 
 
 
 
 
X 
X 


March 14, 2014 
 
 
FOOTNOTES:  
1 
Baseline Studies to be performed within 28 days of start of treatment do not need to be repeated on C1D1. Day 1 
procedures should be done within 2 days of the start of treatment cycle.   
2 
Height needed only at baseline. Obtain creatinine clearance if serum creatinine> 1.5 mg/dI. 
3 
Chemistry includes sodium, potassium, chloride, CO2, calcium, magnesium, phosphorus, BUN, creatinine, glucose, 
albumin, total protein, alkaline phosphatase, total bilirubin, AST/SGOT, ALT/SGPT, LDH, and uric acid. 
Testing for Hepatitis B includes: Hepatitis B surface antigen, surface antibody, and core antibody 
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 10 or 11 of Cycle 1 during 
induction and Day 3 or 4 during consolidation of lenalidomide-containing treatment.  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 or 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 of escalating, re-escalating or re-initiating lenalidomide therapy.  
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. See section 12.3.3 for tumor lysis prophylaxis 
guidance.  
4 
Urine/serum 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 
(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: Risks of Fetal Exposure, 
Pregnancy Testing Guidelines and Acceptable Birth Control Methods).  
5 
CTs should be performed within 8 weeks prior to initiating therapy and every 6 months during consolidation until disease 
progression 
6 
All PR or CR subjects will have follow-up exams every 3 months for year 1, every 6 months for years 2-5. Patients who 
begin subsequent anti-cancer treatments will be followed for survival only until death. After year 5, PR & CR subjects will 
be followed annually until death for survival and new anti-cancer therapy only. Stable & PD subjects will be followed every 
3 months for year one then annually until death for survival and new anti-cancer therapy.  
7 
MRD will be tested from peripheral blood and bone marrow prior to cycle 7 of consolidation and after cycle 12. 
8 
All patients must be counseled about pregnancy precautions, risks of fetal exposure and other risks.  The counseling must 
be done on Day 1 of each cycle (or at a minimum of every 28 days) and at drug discontinuation.  See The Appendix C: 
Education and Counseling Guidance Document must be completed by a trained Counselor (a consenting professional or 
designated nurse who has completed training). 
    
12.0 
DOSE MODIFICATION & TOXICITY MANAGEMENT 
 
12.1. 
Dose Modification for Fludarabine and Cyclophosphamide 
The dose modifications listed below refer to both fludarabine and cyclophosphamide. It is important to remember the 
following stipulations. 
A. Dose re-escalation after downward modification will not be permitted. 
B. The investigator should grade and report adverse events according to the Common Toxicity Criteria (version 
4.0). 
 
12.1.1. Hematologic Toxicity 
 
Dose modifications should be based on the nadir of the patient’s platelet count and/or absolute neutrophil 
count (mature polys + bands) obtained immediately prior to the next planned treatment. There will be no 
dosage reduction for decreases in hemoglobin concentration. 
 
Adjustments for changes in the platelet count. 
 
Platelet Count (/mm3 ) 
Dosage Adjustment  (% reduction is relative to 
dose delivered during the first course) 
≥75,000 (after first treatment) 
No dose modification 


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<75,000 (after first treatment) 
Delay treatment and repeat the platelet count 
weekly, If repeat counts ≥75,000 proceed with next 
treatment at 25% dose reduction 
 
If required delay in treatment is > 2 weeks, 
discontinue protocol treatment  
<75,000 (after first dose reduction) 
Delay treatment and repeat the platelet count 
weekly, If repeat counts ≥75,000 proceed with next 
treatment at 50% dose reduction. 
 
If required delay in treatment is > 2 weeks, 
discontinue protocol treatment. 
 
 
 
Absolute Neutrophil Count (mm3 ) 
Dose Adjustment (% reduction is relative to dose 
delivered during the first course) 
≥ 1500 (after first treatment) 
No dose modification 
<1500 (after first planned treatment) 
 
Delay treatment and repeat WBC weekly, if repeat 
ANC ≥ 1500, proceed with next treatment with a 
25% dose reduction 
 
 If required delay in treatment is > 2 weeks, 
discontinue protocol treatment. 
 
<1500  (after first dose reduction) 
Delay treatment and repeat the ANC weekly, If 
repeat ANC ≥1,500 proceed with next treatment at 
50% dose reduction. 
 
If required delay in treatment is > 2 weeks, 
discontinue protocol treatment. 
 
 
 
12.1.2. Gastrointestinal Toxicity 
 
Patients who develop grade 2 gastrointestinal (GI) toxicity except nausea and vomiting without sufficient 
prophylaxis should receive 75% of fludarabine and cyclophosphamide. Patients who develop grade 3 
gastrointestinal toxicity should receive 50% of fludarabine and cyclophosphamide. Patients who develop 
grade 4 GI toxicity should discontinue protocol treatment. 
 
12.1.3. Infections 
 
Patients who develop grade 4 infection will discontinue protocol treatment. 
 
12.1.4. Genitourinarv Toxicity 
 
Patients who develop grade 2 GU toxicity should receive 75% of fludarabine and cyclophosphamide. 
Patients who develop grade 3 GU toxicity should receive 50% of fludarabine and cyclophosphamide. 
Patients who develop grade 4 GU toxicity should discontinue protocol treatment. 
 
12.1.5. Pulmonary Toxicity 
 
 
 
Patients who develop grade 3 or 4 fludarabine-related pneumonitis should discontinue protocol treatment. 
 
12.1.6. Cardiac Toxicity  
 
Patients who develop irreversible grade 4 cardiac toxicity should discontinue protocol treatment.  
 
12.1.7. Autoimmune Toxicity 


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Patients who develop autoimmune hemolytic anemia, autoimmune thrombocytopenia, or other 
autoimmune disorders should discontinue protocol treatment. 
 
12.1.8. Other Toxicity  
 
Patients who develop any other grade 3 toxicities not listed above, should receive 75% of fludarabine and 
cyclophosphamide. Patients who develop any other grade 4 toxicity should discontinue study treatment. 
 
12.2. 
Dose Modification for Rituximab  
 
The dose of Rituximab generally remains constant throughout the trial.  If rapid tumor lysis occurs, 
Rituximab should be stopped.  It may be restarted after symptoms and laboratory abnormalities have 
resolved.  In the event of severe or life-threatening anaphylaxis or hypersensitivity reaction, discontinue 
the patient from the treatment phase.  Do not retreat with Rituximab. 
Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection 
and for signs of hepatitis throughout their study participation. 
Hematologic Events:  In clinical trials, Grade 3 and 4 cytopenias were reported in 48% of patients treated 
with RITUXAN; 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 RITUXAN therapy were reported. 
In addition, there have been a limited number of post marketing reports of prolonged pancytopenia, 
marrow hypoplasia, and late onset neutropenia (defined as occurring 40 days after the last dose of 
RITUXAN) in patients with hematologic malignancies.  In reported cases of late onset neutropenia (NCI-
CTC Grade 3 and 4), the median duration of neutropenia was 10 days (range 3 to 148 days).  
Documented resolution of the neutropenia was described in approximately one-half of the reported cases; 
of those with documented recovery, approximately half received growth factor support.  In the remaining 
cases, information on resolution was not provided.  More than half of the reported cases of delayed onset 
neutropenia occurred in patients who had undergone prior autologous bone marrow transplantation.  In 
an adequately designed, controlled, clinical trial, the reported incidence of NCI-CTC Grade 3 and 4 
neutropenia was higher in patients receiving RITUXAN in combination with fludarabine as compared to 
those receiving fludarabine alone (76% [39/51] vs. 39% [21/53]).43 
 
See warning section of the Package insert for language for management of first infusion reactions. 
 
12.3. 
Dose Modification for Lenalidomide 
 
Doses will escalate from 5mg daily day 8-28 of the first 28 day cycle to 10mg day 8-28 in cycle 2 and to 
15mg day 8-28 in cycles 3-6 in the induction phase or 3-12 in the consolidation phase.  Dose de-
escalation from 15mg to 10mg to 5mg will be allowed for grade 3/4 toxicity at any time during cycles 1-12. 
 
Table 1: Lenalidomide Dose Modification Steps 
Current Lenalidomide Dose 
One Level Dose Reduction 
15 mg (days 8-28 or 1-28) 
10 mg (days 8-28 or 1-28) 
10 mg (days 8-28 or 1-28) 
5 mg (days 8-28 or 1-28) 
5 mg (days 8-28 or 1-28) 
5 mg every other day (days 8-
28 or 1-28) 
5 every other day (days 8-28 or 1-
28) 
See * below 
 
*Lenalidomide 5 mg every other 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 other day may, at the discretion of their 
physician, have their dose held until toxicity resolves as described below and then restart lenalidomide 5 
mg every other day.  If the same toxicity recurs at lenalidomide 5 mg every other day, consideration 
should be given to discontinuing lenalidomide. 


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Instructions for initiation of a New Cycle in all consolidation Cycles 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
• 
The ANC is ≥ 1500/mm³;  
• 
The platelet count is ≥ 75,000/mm³;  
• 
Any drug-related rash or neuropathy that may have occurred has resolved to ≤ grade 1 severity; 
• 
No evidence of laboratory TLS by Cairo-Bishop Definition of Tumor Lysis Syndrome (see 
Appendix V).  Subjects may be started on consolidation therapy with the combination of 
lenalidomide and rituximab upon correction of electrolyte abnormalities; 
• 
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 a lenalidomide 
dose reduction was taken during the previous cycle, and the cycle was completed without requiring 
further dose modification, then the next cycle will start at the same reduced dose of lenalidomide.  If 
lenalidomide dosing was omitted for the remainder of the previous cycle due to toxicity attributed 
to lenalidomide or if the new cycle is delayed due to lenalidomide-related toxicity newly 
encountered on the scheduled Day 1, then the new cycle will be started with a one-level dose reduction 
of lenalidomide.  
 
Instructions for dose modifications or interruption  
For treatment interruptions during a cycle, the 28-day schedule of each cycle will continue to be followed.  
Missed doses of lenalidomide 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 8.3), the 
restart day of therapy becomes Day 1 of the next cycle. 
 
Table 2: Dose Modifications for Lenalidomide   
NCI 
CTC 
Toxicity 
Grade 
Dose Modification Instructions 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º 
C) 
or 
Grade 
4 
neutropenia 
• 
Hold (interrupt) lenalidomide dose.  Omitted doses are NOT 
made up. 
• 
Follow CBC weekly. 
• 
First episode: If neutropenia resolves to ≤ grade 3 without 
fever prior to the scheduled end of the current cycle, restart 
lenalidomide at the current dose level and continue through 
the scheduled end of the current cycle.   Otherwise, omit for 
remainder of cycle and restart lenalidomide at the current dose 
level at the start of the next cycle.   
• 
Second and subsequent episodes: If neutropenia resolves to ≤ 
grade 3 without fever prior to the scheduled end of the current 
cycle, restart lenalidomide at the next lower dose level* and 
continue through the scheduled end of the current cycle.  
Otherwise, omit for remainder of cycle and restart lenalidomide 
at the next lower dose level* at the start of the next cycle.    
Thrombocytopenia 
≥Grade 
4 
(platelet 
count < 25,000/mm³) 
• 
Hold (interrupt) lenalidomide dose.  Omitted doses are NOT 
made up. 
• 
Follow CBC weekly. 
• 
NOTE: Consider criteria (perhaps based on platelet count) for 
holding and then resuming prophylactic anti-coagulation, if 
applicable. 
• 
If thrombocytopenia resolves to ≤ grade 3 prior to the 
scheduled end of the current cycle, restart lenalidomide at next 
lower dose level* and continue through the scheduled end of 
the current cycle.  Otherwise, omit for remainder of cycle and 
restart lenalidomide at the next lower dose level* at the start of 
the next cycle. 


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Table 2: Dose Modifications for Lenalidomide   
NCI 
CTC 
Toxicity 
Grade 
Dose Modification Instructions 
Platelet 
count 
< 
50,000/mm³ 
• 
Hold prophylactic anti-coagulation, if applicable. 
• 
Restart prophylactic anti-coagulation when platelet count is ≥ 
50,000/mm³. 
Tumor 
Lysis 
Syndrome 
(TLS) 
≥Grade 2 
(see Section 8.3.1 and 
Appendix: 
Cairo-
Bishop 
Definition 
of 
TLS) 
• 
Hold (interrupt) lenalidomide dose.  Omitted doses are NOT 
made up. 
• 
First episode: after resolution of electrolyte abnormalities to 
Grade 0, restart lenalidomide at the current dose with 
appropriate TLS prophylaxis (Section 8.3.1).   
• 
Subsequent 
episodes: 
after 
resolution 
of 
electrolyte 
abnormalities to Grade 0, restart lenalidomide with appropriate 
TLS prophylaxis (Section 8.4.6).  At physician discretion, the 
lenalidomide dose may be restarted at the current dose or 
lenalidomide may be reduced by 1 dose level*.   
• 
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 
lenalidomide for 4 consecutive weeks and on Day 3 or 4 
following initiation of lenalidomide.  See Section 2, Schedule of 
Study Assessments, for additional specifics regarding serum 
chemistry and uric acid testing. 
Non-blistering rash 
 
Grade 3 
 
 
 
 
Grade 4 
 
• 
If Grade 3, hold (interrupt) lenalidomide dose.  Follow weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to the scheduled end 
of the current cycle, restart lenalidomide at next lower dose 
level* and continue through the scheduled end of the current 
cycle.  Otherwise, omit for remainder of cycle and reduce the 
dose of lenalidomide by 1 dose level* at the start of the next 
cycle.  Omitted doses are not made up. 
 
• 
If Grade 4, discontinue lenalidomide.  Remove patient from 
study. 
Desquamating 
(blistering) rash- any 
Grade  
• 
Discontinue lenalidomide.  Remove patient from study. 
Neuropathy 
 
Grade 3 
 
 
 
 
Grade 4 
 
• 
If Grade 3, hold (interrupt) lenalidomide dose.  Follow at least 
weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to the scheduled end 
of the current cycle, restart lenalidomide at next lower dose 
level* and continue through the scheduled end of the current 
cycle.  Otherwise, omit for remainder of cycle and reduce the 
dose of lenalidomide by 1 dose level* at the start of the next 
cycle.  Omitted doses are not made up. 
 
• 
If Grade 4, discontinue lenalidomide.  Remove patient from 
study. 
Venous 
thrombosis/embolism 
≥ Grade 3 
• 
Hold 
(interrupt) 
lenalidomide 
and 
start 
therapeutic 
anticoagulation, if appropriate 
• 
Restart lenalidomide at investigator’s discretion (maintain 
dose level).   
• 
See Anticoagulation Consideration (Section 5.6.1.2). 
Hyperthyroidism 
or 
hypothyroidism 
• 
Omit lenalidomide for remainder of cycle, evaluate etiology, 
and initiate appropriate therapy.  
• 
See Instructions for Initiation of a New Cycle and reduce the 
dose of lenalidomide by 1 dose level*. 


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Table 2: Dose Modifications for Lenalidomide   
NCI 
CTC 
Toxicity 
Grade 
Dose Modification Instructions 
other 
non-
hematologic toxicity 
≥ Grade 3 
• 
Hold (interrupt) lenalidomide dose.  Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 2 prior to the scheduled end 
of the current cycle, restart lenalidomide and continue through 
the scheduled end of the current cycle.  Otherwise, omit for 
remainder of cycle.  Omitted doses are not made up.  For 
toxicity attributed to lenalidomide, reduce the lenalidomide 
dose by 1 dose level* when restarting lenalidomide. 
 
 
 
12.3.1. 
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) 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: Cairo-Bishop Definition of Tumor 
Lysis Syndrome), lenalidomide will be continued at the same dose without interruption or dose 
reduction.  TLS prophylaxis measures outlined in Section 8.4.6 should be continued or re-
instituted. 
 
Subjects with ≥ Grade 2 TLS (see Appendix: Cairo-Bishop Definition of Tumor Lysis Syndrome) 
will be managed as follows in addition to intravenous hydration and consideration for rasburicase 
therapy (above).   
 
Hold (interrupt) treatment. 
 
First episode: restart lenalidomide at the current dose with appropriate TLS prophylaxis 
(Section 8.4.6) after resolution of electrolyte abnormalities to Grade 0.   
 
Subsequent episodes: restart lenalidomide with appropriate TLS prophylaxis (Section 
8.4.6) after resolution of electrolyte abnormalities to Grade 0.  At physician discretion, the 
lenalidomide dose may be restarted at the current dose or lenalidomide may be reduced 
by 1 dose level.   
 
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 lenalidomide for 4 consecutive weeks 
and on Day 3 or 4 following initiation of lenalidomide.  See Section 10.3 Schedule of 
Study Assessments, for additional specifics regarding serum chemistry and uric acid 
testing.  
 
12.3.2. 
Tumor Flare Reaction (TFR):  
 
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 
20mg PO daily x 7 days followed by 5mg PO daily x 7 days. 
 
Tumor flare occurring during the first 2 weeks of Cycle 1 should be recorded as an adverse event and 
not as progressive disease (PD).  For tumor flare occurring after the first 2 weeks of Cycle 1, 
differentiate tumor flare from progression. 
 
 


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12.3.3. Tumor Lysis Syndrome (TLS) 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. 
 
Allopurinol 300mg po daily beginning at least 3 days before the start of lenalidomide therapy and 
continuing through at least the end of Cycle 2 as TLS prophylaxis is required for all subjects.   
 
Within the first 3 cycles of therapy, additional allopurinol should be given concurrent with any dose 
escalation (or re-escalation, if permitted) of lenalidomide.  In these instances, allopurinol should be 
started concurrent with (or if feasible, 3 days prior to) the escalation of lenalidomide, and continued 
through at least the end of the cycle.  A similar course of allopurinol should be considered when 
lenalidomide is restarted after having been held for any reason within the first 3 cycles of therapy. 
 
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 water each day for the first 14 days of Cycle 1.  Hydration levels should be adjusted 
according to age and clinical status, and lowered if the subject’s cardiovascular status indicates the 
possibility of volume overload.  Within the first 3 cycles of therapy, additional oral hydration should be 
considered concurrent with any dose escalation (or re-escalation, if permitted) of lenalidomide, or when 
lenalidomide 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, see section 12.3.1 for guidance. 
 
12.3.4. 
Anticoagulation Consideration  
Lenalidomide increases the risk of thrombotic events in patients who are at high risk or with a history a 
thrombosis, in particular when combined with other drugs known to cause thrombosis. When 
lenalidomide is combined with other agents such as steroids (e.g. dexamethasone, prednisone), 
anthracyclines (Doxil, Adriamycin) and erythropoietin the risk of thrombosis is increased.  
 
All patients should receive prophylactic anti-coagulation.  Aspirin (81 or 325 mg) is the recommended 
agent for anti-coagulation prophylaxis.  Low molecular weight heparin may be utilized in patients that 
are intolerant to ASA.  Coumadin should be used with caution and close monitoring of INR. 
 
Prophylactic 
anti-coagulation 
should 
be 
held 
for 
platelet 
counts 
< 
50,000mm³ 
and then restarted when platelet counts are above this level.  
 
Full therapeutic anti-coagulation should be considered for patients who have a history of venous 
thromboembolism.  Whether therapeutic anti-coagulation is used or not, patients with a history of 
venous thromboembolism should be closely monitored throughout the study, especially during periods 
of fluctuating platelet counts. 
 
 
13.0 
CRITERIA FOR TREATMENT DISCONTINUATION & REMOVAL FROM STUDY 
13.1. 
Treatment Discontinuation  
 
Progressive disease 
 
Subjects who meet toxicity criteria for discontinuation  
 
Subjects who wish to discontinue therapy 
 
Physician discretion that the treatment is no longer in the best interest of the patient.  
 
Pregnancy 
 
Development of HBV infection or hepatitis during treatment.  
 
13.2. 
Study Discontinuation 
 
Withdraw of consent 
 
If the study ends or is stopped by the sponsor-investigator 
 
Non-compliance 


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 
Subjects who are lost to follow-up. Lost to follow-up is defined as three (3) consecutive failed 
attempts to contact the patient or three (3) consecutive missed protocol required follow up 
assessment appointments. Such instances should be well documented in the source documents.  
Every effort should be made to continue to follow patients according to schedule of events once 
treatment has ceased, however, patients that are unwilling or unable to comply with follow up 
schedule should, at the discretion of the investigator, be removed from the study. 
 
14.0 
EVALAUTION OF RESPONSE 
14.1. 
Assessment of Clinical Response  (2008 NCIWG Guidelines, 63) 
The major criteria for determination of the response to therapy in patients with CLL include physical 
examination and evaluation of peripheral blood and bone marrow. It is recommended that the laboratory 
and clinical studies which are abnormal pre-study be repeated to document the degree of maximal 
response.  
 
14.2. 
Complete Remission (CR) 
 
Complete remission requires ALL of the following for a period of at least 2 months:  
 
Absence of lymphadenopathy by physical examination and CT 
 
 
No hepatomegaly or splenomegaly by CT 
 
 
Absence of constitutional symptoms 
 
 
Normal CBC as exhibited by: 
o 
Polymorphonuclear leukocytes >1 500/mm3. 
o 
Platelets> 100,000/mm3. 
o 
Hemoglobin> 11.0 gm/dI (un-transfused). 
o 
Peripheral blood lymphocytes <4000/mm3 
One marrow aspirate and biopsy should be performed 2 months after clinical and 
laboratory evidence of a CR to document that a complete remission has been 
achieved. The marrow sample must be at least normocellular with < 30% of 
nucleated cells being lymphocytes. If it is hypocellular, a repeat determination should 
be made in 1- 2 months. Samples will be submitted for pathology review and the 
presence of small lymphoid nodules, without definitive phenotypic evidence of 
persistent disease, noted, although not included in the current definition of CR. A   
patient who is in CR, but has small lymphoid nodules, will be considered to have 
nodular PR & recorded separately. 
 
 
Any other laboratory assays (i.e., quantitative immunoglobulins, PCR for unique 
immunoglobulin rearrangement) will not be used currently as an index for response but will 
be recorded for clinical correlations. 
 
 
Bone marrow 3 months after last dose of FCR- showing no evidence of cells with an 
abnormal, CLL-like, phenotype.  
 
14.3. 
Partial Response (PR)  
In addition to the parameters listed below, the presence or absence of constitutional symptoms will be 
recorded. 
 
To be considered a partial response, the patient must exhibit all of the following for at least 2 months: 
 
 
≥50% decrease in peripheral blood lymphocyte count from the pretreatment baseline 
value 
 
 
≥50% reduction in lymphadenopathy 
 
 
≥50% reduction in size of liver and/or spleen (if abnormal prior to therapy) 
 
AND 
 


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One or more of the following remaining features for at least 2 months: 
 
Polymorphonuclear leukocytes >1500/mm3 or 50% improvement over baseline.      
 
 
Platelets> 100,000/mm3 or 50% improvement over baseline. 
 
 
Hemoglobin > 11.0 gm/dl or 50% improvement over baseline without transfusions. 
 
14.4. 
Progressive Disease (PD) 
PD will be characterized by at least one of the following: 
 
 
50% increase in the sum of the products of at least 2 lymph nodes on 2 consecutive 
examinations 2 weeks apart (at least 1 node must be 2 cm).Appearance of new palpable 
lymph nodes. 
 
 
50% increase in the size of liver and/or spleen as determined by measurement below the 
respective costal margin; appearance of palpable hepatomegaly or splenomegaly which 
was not previously present. 
 
 
50% increase in the absolute number of circulating lymphocytes. 
 
 
In the absence of progression as defined above, the presence of a > 2 gm/dI 
 
             
decrease in hemoglobin, or> 50% decrease in platelet count and/or absolute granulocyte 
count will not exclude a patient from continuing on study. Bone marrow aspirate and 
biopsy are strongly encouraged to better define the cause of the suppressed counts. 
 
 
Transformation to a more aggressive histology (e.g., Richter’s syndrome or 
prolymphocytic leukemia with > 55% prolymphocytes). 
 
14.5. 
Stable Disease (SD)  
Patients who have not achieved a CR or a PR, or who have not exhibited findings consistent with 
Progressive Disease will be considered as having Stable Disease. 
 
15.0 
REPORTING OF ADVERSE EVENTS 
15.1. 
Adverse Event Reporting definitions 
In the event of an adverse event, the first concern will be for the safety of the subject. Each participating 
center will report adverse events to their IRB per local guidelines.  In addition, Investigators are required 
to report to Dr. Anthony Mato, who will submit to the Hackensack University Medical Center IRB any 
serious adverse event, whether expected or unexpected, and which is assessed by the investigator to be 
reasonably or possibly related to or caused by study drugs.  All events meeting these criteria will be 
reported for the time period beginning first dose of study drug(s) through the protocol-defined follow-up 
period.  Serious criteria, definitions, and guidance for reporting follow. 
 
An adverse event (AE) is any untoward medical occurrence in a subject participating in an investigational 
trial or protocol regardless of causality assessment.  An adverse event can be an unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, syndrome or disease associated 
with or occurring during the use of an investigational product whether or not considered related to the 
investigational product. 
Serious Adverse Event (SAE) Definition  
 
Serious adverse events (SAE) are adverse events occurring at any dose which meet one or more of the 
following serious criteria and MUST BE REPORTED WITHIN 24HOURS AFTER SITE’S INITIAL RECEIPT 
OF INFORMATION: 
 
(a) Death; 
(b) A life-threatening AE/ADR (i.e., the patient/subject was, in the view of the initial reporter/investigator, 
at immediate risk of death from the AE/ADR as it occurred. It does not refer to an AE/ADR that 
hypothetically might have caused death if more severe); 


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(c) Inpatient hospitalization or prolongation of existing hospitalization (i.e., hospitalization was required to 
treat or diagnose the AE/ADR; excludes hospitalization for unrelated reasons); 
(d) A persistent or significant disability or incapacity (disability here means that there is a substantial 
disruption of a person’s ability to conduct normal life functions; 
(e) A congenital anomaly/birth defect. 
(f) An important medical event (i.e., AEs/ADRs that might not be immediately life-threatening, or result in 
death or hospitalization might be considered serious when, based upon appropriate medical and 
scientific judgment, they might jeopardize the patient/subject or might require medical or surgical 
intervention to prevent one of the other serious outcomes listed above); 
 
Sponsor-Investigator shall use his/her judgment to determine the relationship between the Serious Adverse Drug 
Experience and the Study Drug. 
 
Expected adverse events are those adverse events that are listed or characterized in the Package Insert or 
current Investigator Brochure.  
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current Investigator Brochure (I.B.) 
or not identified.  This includes adverse events for which the specificity or severity is not consistent with the 
description in the P.I. or I.B. 
 
Events meeting the definition of an AE include: 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition 
• 
New conditions detected or diagnosed after investigational product administration even though it may 
have been present prior to the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a 
concomitant medication (overdose per se will not be reported as an AE/SAE). 
“Lack of efficacy” or “failure of expected pharmacological action” will not be reported as an AE or SAE. 
However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if 
they fulfill the definition of an AE or SAE.  
 
All adverse events that meet these criteria are to be reported. 
   
Events that do not meet the definition of an AE include: 
• 
Any clinically significant abnormal laboratory finding or other abnormal safety assessments that is 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the subject’s condition.  
• 
The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the subject’s condition 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the 
procedure is an AE 
• 
Situations where an untoward medical occurrence did not occur (social and/or convenience admission to 
a hospital) 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen 
 
Laboratory and Other safety assessment abnormalities as AEs and SAEs  
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from 
baseline, and felt to be clinically significant in the medical and scientific judgment of the investigator are to be 
recorded as AEs or SAEs. 
 


Version Date March 14, 2014 
 
 
 
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ALT levels of greater than 3 times the upper limit of normal (ULN) and simultaneous bilirubin levels of greater  
than 2 times ULN (>35% direct bilirubin; bilirubin fractionation required) are to be recorded as SAEs.  
 
However, any clinically significant safety assessments that are associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the subject’s condition, are not to be reported 
as AEs or SAEs. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs 
An event which is part of the natural course of the disease under study (i.e., disease progression) does not 
need to be reported as an SAE.  However, if the progression of the underlying disease is greater than that 
which would normally be expected for the subject or if the investigator considers that there was a causal 
relationship between treatment with investigational product or protocol design/procedures and the disease 
progression, then this must be reported as an SAE.  
Time Period and Frequency of Detecting AEs and SAEs 
All SAEs regardless of relationship to investigational product will be collected from the first dose of 
investigational product to 6 months after the last dose of investigational product. 
 
From the time a subject consents to participate in and completes the study, all SAEs assessed as related to 
study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing therapy) or will 
be reported to the sponsor-investigator, and local IRB, if applicable. 
 
Any pre-existing condition or signs and symptoms present prior to investigational product will be recorded as 
medical history.   
 
Any SAE brought to the investigator’s attention after the subject has completed the study and considered by 
the investigator as possibly related to investigational product must be promptly reported. 
 
Adverse Event Reporting: 
The following adverse reactions must be reported in the manner described below. 
 
All serious adverse events (SAE) regardless of causality must be reported to the PI, and Celgene (within 24 
hours) or Co-PI and the protocol coordinator for notification of Hackensack University Medical Center’s IRB. 
See section 15.2 for specific reporting criteria for adverse events associated with rituximab. See section 15.3 
for specific reporting criteria for adverse events associated with lenalidomide.  
 
 
 
Unexpected, 
fatal 
or 
life-
threatening, and 
associated with 
study drug 
Unexpected, 
of 
moderate 
or 
greater 
severity 
(but not fatal or 
life-threatening) 
and are associated 
with the research 
intervention 
Serious, 
unexpected event 
that is associated 
with 
the 
study 
drug 
Call 
to 
HUMC 
within 24 hours  
X 
 
 
Notify IRB within 
24 hours 
X 
 
 
Notify 
Celgene 
within 24 hours 
X 
X 
X 
Notify 
DSMB 
promptly & local 
IRB 
within 
10 
days 
 
X 
 
Notify FDA within 
15 days 
X 
 
 


Version Date March 14, 2014 
 
 
 
Page 39 of 57 
 
 
 
 
• 
An adverse reaction is considered serious if it is fatal or life-threatening; requires or prolongs 
hospitalization; produces a disability; or results in a congenital anomaly/birth effect. 
• 
An adverse reaction is considered to be of moderate or greater severity if it requires medical 
evaluation (such as additional laboratory testing) and/or medical treatment; or if it is a serious 
adverse reaction. 
• 
An adverse reaction is considered to be unexpected if it is not identified in nature, severity, or 
frequency in the current IRB-approved research protocol or informed consent document. 
• 
An adverse reaction is considered to be associated with the research intervention if there is a 
reasonable possibility that the reaction may have been caused by the research intervention (i.e., a 
causal relationship between the reaction and research intervention cannot be ruled out by the 
investigator(s). 
 
HUMC requires SAEs to be reported on the MedWatch form and on the HUMC IRB adverse event form.  The 
treating investigator must sign the HUMC Adverse event form. (This only applies to the John Theurer Cancer 
Center, all other participating sites will follow their own IRB guidelines and submit all SAE’s on a MedWatch form  
to Dr. Anthony Mato at fax number 551-996-0751 or via email to Amato@hackensackUMC.org  
 
 
15.2. 
Reporting Adverse Events Associated with Lenalidomide 
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 
treatment areas should have access to a copy of the CTCAE Version 4.0.  All adverse clinical experiences, 
whether observed by the investigator or reported by the patient, must be recorded, with details about the 
duration and intensity of each 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. 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on lenalidomide, or within (insert time-
frame which must be at least 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 email within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form, or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to causality, as 
SAEs. In addition, any infant death after 28 days that the Investigator suspects is related to the in utero 
exposure to the IP should also be reported to Celgene Drug Safety 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 


Version Date March 14, 2014 
 
 
 
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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. 
 
 
Celgene Drug Safety Contact Information:  
Celgene Corporation  
Global Drug Safety and Risk Management  
Connell Corporate Park  
300 Connell Dr. Suite 6000  
Berkeley Heights, NJ 07922  
Fax: (908) 673-9115  
E-mail: drugsafety@celgene.com  
 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
 
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual report is 
provided to the FDA within 60-days of the IND anniversary date. 21 CRF 312.33 provides the data elements 
that are to be submitted in the report. The Annual Report should be filed in the study's Regulatory Binder, and 
a copy provided to Celgene Corporation as a supporter of this study as follows. 
 
IND Annual Reports 
Celgene Corporation 
Attn: Medical Affairs Operations 
Connell Corporate Park 
400 Connell Drive Suite 700 
Berkeley Heights, NJ 07922 
 
All adverse experience reports must include the patient number, age, sex, weight, severity of reaction (e.g. 
mild, moderate, severe), relationship to drug (e.g. probably related, unknown relationship, definitely not 
related), date and time of administration of test medications and all concomitant medications, and medical 
treatment provided. The investigator is responsible for evaluating all adverse events to determine whether 
criteria for “serious” and as defined above are present. The investigator is responsible for reporting adverse 
events to Celgene as described below. 
 
 
Expedited reporting by investigator to Celgene 
Serious adverse events (SAE) are defined above. The investigator must inform Celgene in writing using a 
Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of being aware of the event. The 
written report must be completed and supplied to Celgene by facsimile within 24 hours/1 business day. The 
initial report must be as complete as possible, including an assessment of the causal relationship between the 
event and the investigational product(s),. Information not available at the time of the initial report (e.g., an end 
date for the adverse event or laboratory values received after the report) must be documented on a follow-up 
report. A final report to document resolution of the SAE is required. The Celgene tracking number 
(RV_CLL_PI_0530) and the institutional protocol number should be included on SAE reports (or on the fax 
cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE report to Celgene 
should be attached to the SAE and retained with the patient records. 
 
Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a serious adverse 
event according to institutional policy. 
 
 
 Trial Coordination Center Reporting Guidelines  


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All Serious Adverse Events (SAE) will be reviewed by the principal investigator to determine if they meet the 
Hackensack University Medical Center’s Institutional Review Board guidelines for reporting. The Hackensack 
Research staff will submit any reportable SAE reports to the IRB as per their guidelines, and report to other 
sub-sites, if applicable. 
 
15.3. MedWatch 3500 Reporting Guidelines: 
 
In addition to completing appropriate patient demographic and suspect medication information, the report 
should include the following information within the Event Description (section 5) of the MedWatch 3500 form: 
 
• 
Protocol description (and number, if assigned) 
• 
Description of event, onset date, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to each investigational product and 
suspect medication 
 
Follow-up information:   
 
Additional information may be added to a previously submitted report by any of the following methods: 
 
• 
Adding to the original MedWatch 3500 report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the original MedWatch 
3500 form  
• 
Summarizing new information and faxing it with a cover letter including subject identifiers (i.e. D.O.B. 
initial, subject number), protocol description and number, if assigned, brief adverse event description, and 
notation that additional or follow-up information is being submitted  (The patient identifiers are important 
so that the new information is added to the correct initial report) 
 
15.4. 
Trial Drug Relationship 
 
The investigator will determine which events are associated with the use of trial drug.  For reporting purposes, 
an AE should be regarded as possibly related to the use of the investigational product if the investigator 
believes: 
 
• 
There is a clinically plausible time sequence between onset of the AE and trial drug administration; and/or 
• 
There is a biologically plausible mechanism for trial drug causing or contributing to the AE; and 
• 
The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or procedures. 
 
Trial drug relationship will be assessed to rituximab and lenalidomide separately and specified on SAE form. 
 
15.5. 
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 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. 
 
It is the sponsor-investigator’s responsibility to ensure safety information is disseminated to any affiliate or 
sub-sites.  
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected AE(s) or 
significant risks to subjects in accordance with their IRB policy. 
 


Version Date March 14, 2014 
 
 
 
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The Investigator must keep copies of all AE information, including correspondence with Celgene and the 
IRB/EC, on file. 
 
 
16.0 
 STATISTICAL CONSIDERATIONS 
16.1. 
Overview 
This study is designed to assess the toxicity and complete response rate of FCR- plus lenalidomide 
followed by lenalidomide in patients with previously untreated CLL. The patients will be evaluated for 
response and toxicity using a two-stage, phase II study design. 
  
16.1.1. Primary Endpoint: The primary endpoint of this trial is CR after 4 cycles of FCR- in patients with 
previously untreated CLL. 
 
16.1.2. Secondary Endpoint: Secondary endpoints are MRD measured by four-color flow cytometry and 
response to lenalidomide overall survival, toxicity, duration of response, and the expression of ZAP-70, 
CD38, IgVH status, and chromosomes. 
 
16.1.3. Sample Size and Accrual: Nineteen patients will be accrued in the first stage. If the study continues to the 
second stage, an additional 35 patients will be accrued. Accrual is expected to occur at a rate of 2-3 
patients per month. 
 
 
16.1.4. Analysis population: 
Safety population: 
All enrolled patients who received at least one dose of the combination 
drug will be included in the safety population. 
 
Evaluable population:  All enrolled patients who complete the 1 cycle of treatment and follow-up 
examination and evaluation will be included in the analysis of clinical 
response. 
 
16.2. 
Statistical Considerations for the Clinical Trial 
 
16.2.1. Decision Rule, Power and Significance:  This study is designed to evaluate the CR rate of FCR- following 
four cycles of therapy in patients with previously untreated CLL.  The patients will be evaluated using an 
optimum two stage phase 2 study design.  Patients who meet the entry criteria and have completed at least 
one cycle of FCR- will be evaluated for response.  All enrolled patients who received at least one does of 
the study therapy will be included in the safety population. 
 
In the proposal for patients with untreated CLL we are interested in excluding an unfavorable CR of 20% 
versus a 40% CR rate under the alternative hypothesis.  Assuming a significance level of 0.05 and 90% 
power, we need sample sizes in 2 stages as n1=19, and n2=35 (total maximum sample size = 54).  In the 
first stage, 19 evaluable patients will be accrued.   
If fewer than 5 patients have a CR, the study will terminate.  If at least 5 CRs are observed, the study will 
continue to accrue an additional 35 patients.  After the second stage, if the total number of CRs is at least 
16, the treatment will be deemed worthy of further study.  Conversely, if the study terminates at the first 
stage, or if the CRs total 15 or fewer, the FCR- therapy will not be recommended for further study. 
Additionally if 5 patients experience a grade 3-4 non-hematologic treatment-related events during the first 
stage, we will terminate the protocol based on unacceptable toxicity.  
The MRD elimination rate will be estimated by the number of patients whose MRD is eliminated after 
lenalidomide treatment divided by the total number of CR patients with MRD who begin lenalidomide 
treatment.  The 95% exact-binomial confidence interval for the MRD elimination rate will be estimated using 
the Clopper-Pearson method.  Assuming the FCR- CR rate is 40% and that 50% of the patients 
experiencing a CR have MRD, then we would expect the MRD elimination rate to be estimated based on 
approximately 11 patients. 
16.2.2. Analysis of Endpoint:  The complete responses will be estimated by the number of patients with CR 
divided by the total number of evaluable patients.  Ninety-five percent confidence intervals for the true CR 
will be calculated. 


Version Date March 14, 2014 
 
 
 
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Analysis of the other Secondary Endpoints:  The overall response rate will be estimated by the number of 
patients with complete and partial responses divided by the total number of evaluable patients.  Ninety-five 
percent confidence intervals for the true success proportion will be calculated.  The overall survival (OS) is 
defined as the time interval between the treatment starting date and the documented date of death.  For a 
surviving patient, OS is censored at the last follow-up date when the patient is documented to be alive.  
Progression-free survival (PFS) is defined as the time interval between the treatment starting date and the 
documented date of disease progression or death, whichever occurs first.  For an alive and progression free 
patient, PFS is censored at the last follow-up date when the patient is documented to be progression free.  
The OS and PFS will be estimated by the Kaplan-Meier method.  The median survival and the 
corresponding 95% confidence interval will also be reported.  However, given the small sample size, these 
estimates will be largely exploratory in nature.  The relation of these endpoints to the expression of ZAP-70, 
CD38, lgVH status and chromosomes will be explored by standard group comparison methods or proper 
regression methods. 
16.2.3. Toxicity: All toxicities that were determined to be possibly, probably or definitely related to the treatment 
will be tabulated according to grade and type (according to the NCI Common Toxicity Criteria, Version 4.0). 
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be 
reviewed to determine toxicity patterns.  
16.2.4. Monitoring: The principal investigator(s) and the study statistician will review the study periodically to 
identify accrual, toxicity, and any endpoint problems that might be developing. This study will be monitored 
according to the data and safety monitoring plan that is currently in place, and if necessary will report to 
HUMC Data Safety Monitoring Board for review monthly.  
 
 
 
 
16.3. 
Data Safety Plan  
 
Monitoring and Quality Assurance: 
This trial will be monitored by the same monitoring process in effect for all HUMC Investigator Initiated Trials.  It is 
the responsibility of the PI (or designee) to monitor the safety data for this study. At minimum local safety 
data should be reviewed by corresponding investigator on a monthly basis. All SAEs will be reported 
according to section 15.0, section 15.1, section 15.2 and section 15.6. Major deviations are sent to the IRB per 
their requirements. All investigators are required to submit quarterly safety meeting minutes to HUMC Data Safety 
Monitoring Board. 
 
All study safety data from all patients, irrespective of enrolling center, will be monitored by the DSMB on a 
monthly basis for accrual, patient safety, and data quality.  All study participants on study are reviewed on a 
recurring basis for any toxicity or other untoward events.  The Clinical Research Monitoring Coordinator (CRMCO) 
will track patient consent and enrollment.  The principal investigator, study statistician, and CRMCO will monitor 
safety data for all patients, including adverse events (AE’s) for all grades and attributions, serious adverse events 
(SAE’s), and study drug administration. 
 
If any literature becomes available which suggests that conducting this trial is no longer ethical, the study will be 
terminated and the IRB will be notified of the new findings.  Any modifications necessary to ensure patient safety 
are discussed and modifications will be submitted to the IRB.  Modifications to this study will not be implemented 
until approved by the IRB. The IRB will be notified of any changes in the risk/benefit ratio, which would affect 
whether the study should continue.   
 
All patients will be monitored by the CRMCO routinely for accrual, patient safety and data quality. This monitoring 
will be done by comparing source documentation to the case report forms (CRF’s). Source documents may be 
requested from sites for remote monitoring.  Any variation between the two data sets will be discussed and/or 
queried. 
 
The first level of ongoing oversight is carried out by the principal investigator, Dr. Mato, primary research nurse 
and the study data coordinator. These individuals meet at least monthly with each cycle to review recently 
acquired data, stopping rules and adverse events. The data recorded within the research charts and protocol 
database is compared with the actual data that is available from the medical record and clinical histories. All 
investigators in the protocol have received formal training in the ethical conduct of human research.  


Version Date March 14, 2014 
 
 
 
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Additionally, institutional support of trial monitoring is provided in accordance with HUMC Institutional Data and 
Safety Monitoring Plan.  Under the provisions of this plan, protocols are reviewed at least monthly by the Data 
Safety Monitoring Board. and yearly IRB.  The Data Safety Monitoring Board (DSMB) will be composed of 
medical and statistical independent reviewers and will meet to review the efficacy and safety data and determine 
a risk/benefit analysis in this subject population.  The purpose of the DSMB is to advise on serious safety 
considerations, lack of efficacy and any other considerations within the charge to the Committee.  The DSMB may 
request additional meetings or safety reports as deemed necessary. The DSMB may stop the study following 
review of results from each interim analysis.  The first interim analysis will examine only safety information; the 
second interim, conducted when the database is more mature, will examine both safety and efficacy.  Appropriate 
efficacy and safety data summaries will be provided to the DSMB after each interim analysis. 
 
 
 
16.4. 
Correlative Analysis  
Median duration of response and overall survival will be estimated and Kaplan-Meier curves will be 
presented for all subjects who begin protocol treatment. The mean, median and range of the duration of 
response and survival will be cross-tabulated against expression of ZAP-70, CD38, IgVH status and MRD 
measured by multi-color flow cytometry.  Clinical response will also be tabulated against these laboratory 
endpoints. 
 
17.0 
REFERENCES 
 
1. 
Rai KR, Patel DV. Chronic Lymphocytic Leukemia, in Hoffman R, Benz E, Shattil 5, Furie B, Cohen H, Silberstein L 
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3. 
Jaksic B, Vitale B, Hauptmann E, Planinc-Peraica A, Ostojic 5, Kusec R. The roles of age and sex in the prognosis 
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4. 
Hallek M, Cheson BD, Catovsky D, Caligaris-Capplo F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, 
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5. 
Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic 
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6. 
Rai KR, Sawitsky A. A review of the prognostic role of cytogenetic, phenotypic, morphologic, and immune function 
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7. 
Montserrrat E, Rozman C.  Bone marrow biopsy in chronic lymphocytic leukemia: a review of its prognostic 
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8. 
Montserrat E, Rozman C.  Chronic lymphocytic leukaemia: prognostic factors and natural history.  Bailliere’s Clinical 
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9. 
Han T, Bhargava A, Henderson ES, et al.  Prognostic significance of beta-2-microglobulin (-2m) in chronic 
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10. 
Montserrat E, Alcala A, Parody R, Domingo A, Garcia-Conde J, Bueno J, Ferran C, Sanz MA, Giralt M, Rubio D, 
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11. 
Fais F,Ghiotto F, Hashimoto S, et al.  Chronic lymphocytic leukemia B cells express restricted sets of mutated and 
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12. 
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13. 
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14. 
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK.  Unmutated Ig V(H) genes are associated with a more 
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15. 
Crespo M, Bosch F, Villamor N. Bellosillo B, Colomer D, Rozman M, Marcé S, López-Guillermo A, Campo E, 
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16. 
Lin K, Sherrington PD, Dennis M, Matrai Z, Cawley JC, Pettitt AR.  Relationship between p53 dysfunction, CD38 
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17. 
Gahrton G, Juliusson G.  Clinical implication of chromosomal aberrations in chronic b-lymphocytic leukaemia cells.  
Nouv Rev Fr Hematol 1988; 30:389. 
 
18. 
Bird ML, Ueshima Y, Rowley JD, Haren JM, Vardiman JW.  Chromosome abnormalities in B cell chronic 
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19. 
Kröber A, Seiler T, Benner Z, Bullinger L, Brückle E, Lichter P, Döhner H, Stilgenbauer S.  VH mutation status, CD38 
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20. 
Rozman C, Montserrat E.  Bone marrow biopsy in chronic lymphocytic leukaemia. Nouv Rev Fr Hematol 1988; 
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21. 
Pangalis GA, Boussiotis VA, Kitttas C.  B-Chronic lymphocytic leukemia.  Nouv Rev Fr Hematol, 1988; 30:373. 
 
22. 
Montserrat E, Vinolas N. Reverter JC, Rozman C.  Natural history of chronic lymphocytic leukemia: on the 
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23. 
Shustik C, Mick R, Silver R, Sawitsky A, Rai K. Shapiro L.  Treatment of early chronic lymphocytic leukemia: 
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24. 
Liepman M. Votaw ML.  The treatment of chronic lymphocytic leukemia with COP chemotherapy.  Cancer 1978; 
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25. 
Oken MM, Kaplan ME.  Combination of chemotherapy with cyclophosphamide, vincristine, and prednisone in the 
treatment of refractory chronic lymphocytic leukemia.  Cancer Treatment Reports 1979; 63:441. 
 
26. 
Hansen MM, Andersen E, Christensen BE, Christansen I, Geisler C, Kristensen D, Jensen KB, Junker P.  CHOP 
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27. 
Raphael b. Andersen JW, Silber R, Oken M, Moore D, Bennet J, Bonner H, Hahn R, Knospe WH, Mazza J, Glick J.  
Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial 
treatment for chronic lymphocytic leukemia: long-term follow-up of an eastern cooperative oncology group 
randomized clinical trial J Clin Onc 1991; 9:770. 
 
28. 
Grever MR, Kopecky KJ, Coltman CA, Files JC,Greenberg BR, Hutton JJ, Talley R, Von Hoff DD, Balcerzak SP.  
Fludarabine monophosphate: a potentially useful agent in chronic lymphocytic leukemia.  Nouv Rev Fr Hematol 
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alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) cells.  Clin Exp Immunol 130:75-84, 2002. 
 
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gene mapping to the commonly deleted region in 5q-syndrome patients.  Proc Natl Acad Sci USA 104:11406-
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1987. 
 
 
74.   Foon et al.  Chemoimmunotherapy with low dose fludarabine and cyclophosphamide and high dose 
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March 14, 2014 
Appendix I 
 
PROTOCOL SIGNATURE PAGE 
 
PHASE II CLINICAL PROTOCOL FOR THE TREATMENT OF PATIENTS WITH PREVIOUSLY 
UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA WITH FOUR OR SIX CYCLES OF A 
COMBINATON OF FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB FOLLOWED 
BY LENALIDOMIDE CONSOLIDATION/MAINTENANCE 
 
 
 
Investigator: 
 
 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/EC procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United States 
Code of Federal Regulations or local regulations governing the conduct of 
clinical studies. 
 


Version Date March 14, 2014 
 
 
 
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Appendix II:   Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods) 
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. 
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 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 (Section Error! Reference source not 
found.) 
• She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
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 is contraindicated unless all of 
the following are met (i.e., all females NOT of childbearing potential must be counseled 


Version Date March 14, 2014 
 
 
 
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concerning the following risks and requirements prior to the start of lenalidomide study 
therapy):  
• She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
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 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) 
− Tubal ligation 
− Partner’s vasectomy 
• Additional effective methods: 
− Male condom 
− Diaphragm 
− Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are 
not recommended. If a patient is currently using combined oral contraception the patient 
should switch to one of the effective method listed above. The risk of venous 
thromboembolism continues for 4 to 6 weeks after discontinuing combined oral 
contraception. The efficacy of contraceptive steroids may be reduced during co-treatment 
with dexamethasone 


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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 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. 


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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.  
• 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.  
• Use of one highly effective method and one additional method of birth control 
AT THE SAME TIME. The following are examples of highly effective and 
additional effective methods of contraception:   
− Highly effective methods: 
o Intrauterine device (IUD) 


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o Hormonal (birth control pills, injections, implants) 
o Tubal ligation 
o Partner’s vasectomy 
− Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
• Pregnancy tests before and during treatment, even if the patient agrees not to 
have reproductive heterosexual contact.  Two pregnancy tests will be 
performed prior to receiving study drug, one within 10 to 14 days and the 
second within 24 hours of the start of study drug. 
• Frequency of pregnancy tests to be done: 
− Every week during the first 28 days of this study and a pregnancy test 
every 28 days during the patient’s participation in this study if menstrual 
cycles are regular or every 14 days if cycles are irregular.   
− If the patient missed a period or has unusual menstrual bleeding.   
− When the patient is discontinued from the study and at day 28 after study 
drug discontinuation if menstrual cycles are regular.  If menstrual cycles 
are irregular, pregnancy tests will be done at discontinuation from the 
study and at days 14 and 28 after study drug discontinuation. 
• Stop taking study drug immediately in the event of becoming pregnant and to 
call their study doctor as soon as possible.  
• NEVER share study drug with anyone else. 
• Do not donate blood while taking study drug and for 28 days after stopping 
study drug. 
• Do not breastfeed a baby while participating in this study and for at least 28 
days after study drug discontinuation. 
• Do not break, chew, or open study drug capsules. 
• Return unused study drug to the study doctor. 
1. Provide Lenalidomide Information Sheet to the patient. 
FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE 
FOR AT LEAST 24 CONSECUTIVE MONTHS, A HYSTERECTOMY, OR 
BILATERAL OOPHORECTOMY): 
1. I counseled the female NOT of child bearing potential regarding the following: 
• Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP) 
• NEVER share study drug with anyone else. 
• Do not donate blood while taking study drug and for 28 days after stopping 
study drug. 


Version Date March 14, 2014 
 
 
 
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• Do not break, chew, or open study drug capsules 
• Return unused study drug capsules to the study doctor. 
2. Provide Lenalidomide Information Sheet to the patient. 
MALE: 
1. I counseled the Male patient regarding the following: 
• Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP). 
• To engage in complete abstinence or use a condom when engaging in sexual 
contact (including those who have had a vasectomy) with a pregnant female or 
a female of childbearing potential,  while taking study drug, during dose 
interruptions and for 28 days after stopping study drug. 
• Males should notify their study doctor when their female partner becomes 
pregnant and female partners of males taking study drug should be advised to 
call their healthcare provider immediately if they get pregnant. 
• NEVER share study drug with anyone else. 
• Do not donate blood, semen or sperm while taking study drug and for 28 days 
after stopping study drug. 
• Do not break, chew, or open study drug capsules. 
• Return unused study drug capsules to the study doctor. 
2. Provide Lenalidomide Information Sheet to the patient. 
 
Investigator/Counselor Name (Print): ____________________ 
 
 (circle applicable) 
 
Investigator/Counselor Signature: _______________________  
Date: 
_____/_____/_____ 
(circle applicable) 
**Maintain a copy of the Education and Counseling Guidance Document in the patient 
records.** 
Appendix III – 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. 


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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. 
 
Appendix IV – NCI CTC Version 4.0  
 
TOXICITY WILL BE SCORED USING NCI CTC 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 CTC VERSION  
 
Appendix V: Cario-Bishop Tumor Lysis Criteria  
 (Cairo MS et al. Br J Haematol 2004) 
 
Table:  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome 
(LTLS) 
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 


Version Date March 14, 2014 
 
 
 
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Grade 
LTLS 
Creatinine 
Cardiac Arrhythmia 
Seizure 
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 
 
 
Appendix VI: Cockcroft-Gault Formula for Calculated Creatinine Clearance 
 
For serum creatinine concentration in mg/dL:  
 
CrCl= [(140-age) x (wt in kg)]÷ [72 x serum creatinine (mg/dL)] (x 0.85 for females) 
 
 For serum creatinine concentration in mg/dL:  
 
CrCl= [(140-age) x (wt in kg)] [0.81 x serum creatinine (µmol/L)] (x 0.85 for females) 
 
 
Source: Cockcroft and Gault 1976 
 
 
 
 Appendix VII: Sample Consent Form