Phase II Study of Lenalidomide to Repair Immune Synapse Response and Humoral Immunity in Early-Stage, Asymptomatic Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) With High-Risk Genomic Features
Phase: PHASE2
Conditions: Ann Arbor Stage I Small Lymphocytic Lymphoma, Ann Arbor Stage II Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia With Unmutated Immunoglobulin Heavy Chain Variable-Region Gene, Small Lymphocytic Lymphoma, Small Lymphocytic Lymphoma With Unmutated Immunoglobulin Heavy Chain Variable-Region Gene, Stage 0 Chronic Lymphocytic Leukemia, Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 8834 
Version Date: March 15, 2024   
 
 
 
 
 
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SUMMARY OF CHANGES 
NCI Protocol #: 8834 
Local Protocol #: OSU 10156 
 
NCI Version Date: March 15, 2024 
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3.  
6.3.1 
28 
Adverse events 
of White Blood 
Cell Decreased 
and 
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added as 
exception for 
dose 
modifications. 
These events 
are an expected 
therapeutic 
outcome of 
treatment with 
Lenalidomide.  
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collection to be 
discontinued 
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NCI Protocol #: 8834 
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NCI PROTOCOL #: 8834 
 
Local Protocol #: 
OSU 10156 
 
Phase II study of lenalidomide to repair immune synapse response and humoral immunity 
in early-stage, asymptomatic chronic lymphocytic leukemia/small lymphocytic lymphoma 
(CLL/SLL) with high-risk genomic features 
 
 
Coordinating Center: 
 
 
The Ohio State University 
 
*Principal Investigator: 
Kerry Rogers 
458 Wiseman Hall 
400 W. 12th Ave. 
Columbus, OH 43210 
(614) 293-3196 
Kerry.Rogers@osumc.edu 
 
 
 
 
 
 
Laboratory Co-Investigators: Natarajan Muthusamy PhD, DVM 
Amy Johnson, PhD 
 
 
 
Mitch Phelps, PhD 
 
Statistician: 
 
Qiuhong Zhao  
 
320 West 10th Avenue 
Columbus, OH 43210  
(614)-366-7523 
 
 
Qiuhong.Zhao@osumc.edu 
 
NCI Supplied Agent:  Lenalidomide (CC-5013, Revlimid, NSC# 703813, Celgene Corporation) 
 
Protocol Type / Version # / Version Date:  
Original / Version #2 / November 22, 2010 
                                                                        Amendment 1 / Version 3 / April 12, 2011 
                                                                        Amendment 2 / Version 4 / May 25, 2011 
                                                                        Amendment 3 / Version 5 / June 15, 2011 
Amendment 4 / Version 6 / September 9, 2011 
Amendment 5 / Version 7 / January 30, 2012       
Amendment 6 / Version 8 / October 23, 2012  
Amendment 6 / Version 9 / November 8, 2012             
 
 
 
 
Amendment 7 / Version 10 / January 2, 2013 
Amendment 8/ Version 11 / August 27, 2013 
 
 
 
 
Amendment 9 / Version 12 / December 16, 2013 
 
 
 
 
Amendment 10 / Version 13 / January 14, 2014 
 
 
 
 
Amendment 11 / Version 14 / April 25, 2014 

NCI Protocol #: 8834 
Version Date: March 15, 2024 
 
4 
 
 
 
 
Amendment 12 / Version 15 / May 14, 2014 
 
 
 
 
Amendment 13 / Version 16 / July 16, 2014 
 
 
 
 
Amendment 14 / Version 17 / June 20, 2016 
 
 
 
 
Amendment 15 / Version 1 / September 28, 2016
 
                                                      Amendment 16 / Version 1 / July 14, 2017  
Amendment 17 / Version 1 / January 25, 2018 
Amendment 18 / Version 1 / February 9, 2018 
Amendment 19 / Version 1 / May 14, 2018 
Amendment 20 / Version 1 / August 20, 2018 
Amendment 21 / Version 1 / September 5, 2018 
Amendment 22 / Version 1 / August 23, 2019 
Amendment 23 / Version 1 / June 9, 2021 
Amendment 24 / Version 1 / March 15, 2024 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 8834 
Version Date: March 15, 2024 
 
5 
 
 
 
SCHEMA 
 
Patient Eligibility 
 
 
 
Required Laboratory Values 
Histologically confirmed, asymptomatic CLL/SLL 
ANC ≥ 1500/μL 
with at least one high-risk genomic feature  
Platelets ≥ 100,000/μL 
Age ≥18 years and < 80 years 
 
 
 
Bilirubin ≤ 1.5 x ULN 
ECOG performance status ≤ 2 
 
 
AST/ALT ≤ 2.5 x ULN 
Non-pregnant and/or using adequate birth control 
Creatinine clearance ≥60 mL/min 
No previous treatment for CLL/SLL 
No history of AIHA/ITP 
No VTE events within 6 months 
Estimated life expectancy ≥24 months 
 
Treatment Plan 
 
 
 
Arm A: Concurrent 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
Month 8+ 
 
 
V 
 
V 
 
 
 
L 
L 
L 
L 
L 
L 
L 
L 
 
Arm B: Sequential 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
Month 8+ 
V 
 
V 
 
 
 
 
 
 
 
 
L 
L 
L 
L 
L 
 
 
 
V = PCV13 pneumococcal vaccine administration; L = lenalidomide 
Patients will be randomized to receive concurrent lenalidomide and pneumococcal vaccine (Arm 
A) or sequential pneumococcal vaccine alone followed by lenalidomide (Arm B).  Since the 
primary endpoint is to determine the change in anti-pneumococcal antibody titer levels, this 
endpoint will be evaluated in each arm about one month after the booster (2nd) vaccination is 
administered.  In Arm A, this will be evaluated at the beginning of cycle 6.  In Arm B, this 
corresponds to the beginning of cycle 4.  Secondary aims will include response, progression free 
survival, and immunologic response to primary tumor cells. 
Lenalidomide treatment will be administered on a continuous basis.  For the sake of convenience 
of dose-modification and response and toxicity monitoring, one cycle will be defined as 28 days.  
Treatment will be administered at 2.5 mg/day during the first cycle to minimize risk for tumor 
flare and/or tumor lysis.  If tolerated, the dose will be increased to 5 mg/day beginning in the 
second cycle.  Treatment will continue for at least 24 cycles (approximately 2 years) in the absence 
of disease progression or irreversible Grade ≥ 3 hematologic or non-hematologic toxicities. 
Patients will receive 2 doses of 13-valent protein-conjugated pneumococcal vaccine (Prevnar 13, 
PCV13) administered 2 months apart.  In Arm A, the vaccine will be administered at the beginning 
of Cycles 3 and 5.  In Arm B, the vaccine will be administered at the beginning of Cycles 1 and 3.   
 

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6 
TABLE OF CONTENTS 
 
SUMMARY OF CHANGES ......................................................... Error! Bookmark not defined. 
SCHEMA .........................................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................9 
1.1 
Primary Objectives...................................................................................................9 
1.2 
Secondary Objectives...............................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Chronic Lymphocytic Leukemia (CLL/SLL) ..........................................................9 
2.2 
Lenalidomide .........................................................................................................11 
2.3 
Protein-conjugated Pneumococcal Vaccines .........................................................13 
2.4 
Rationale for Study Drug and Population ..............................................................15 
2.5 
Correlative Studies Background ............................................................................16 
3. 
PATIENT SELECTION ....................................................................................................18 
3.1 
Eligibility Criteria ..................................................................................................18 
3.2 
Exclusion Criteria ..................................................................................................19 
3.3 
Inclusion of Women and Minorities ......................................................................20 
3.4 
Accrual Targets ......................................................................................................21 
4. 
REGISTRATION PROCEDURES ...................................................................................21 
5. 
TREATMENT PLAN ........................................................................................................21 
5.1 
Agent Administration.............................................................................................21 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................24 
5.3 
Duration of Therapy ...............................................................................................26 
5.4 
Duration of Follow Up ...........................................................................................27 
5.5 
Criteria for Removal from Study ...........................................................................27 
5.6 
Criteria for Halting the Study ................................................................................28 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................28 
6.1 
Dose Modifications due to Toxicity ......................................................................28 
6.2 
Criteria for Starting a New Cycle ..........................................................................28 
6.3 
Critieria for Dose Reductions ................................................................................28 
6.4 
Intrasubject Escalation ...........................................................................................32 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................33 
7.1 
CAEPR for Lenalidomide ......................................................................................33 
7.2 
Adverse Event Characteristics ...............................................................................40 
7.3 
Expedited Adverse Event Reporting ......................................................................40 
7.4 
Routine Adverse Event Reporting .........................................................................42 
7.5 
OSU Institutional Safety Monitoring and Reporting Requirements ......................42 
7.6 
Celgene Drug Safety Contact Information ............................................................44 

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7 
7.7 
Pregnancy ...............................................................................................................44 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................45 
8.1 
Lenalidomide (Revlimid, CC-5013 NSC#703813) ...............................................46 
8.2 
13-valent Protein-Conjugated Pneumococcal Vaccine (Prevnar 13, 
PCV13) ..................................................................................................................50 
9. 
CORRELATIVE/SPECIAL STUDIES .............................................................................51 
9.1 
Anti-pneumococcal Antibody Levels ....................................................................52 
9.2 
Pharmacodynamic Studies: Immunoglobulins and Anti-Tumor Antibodies .........53 
9.3 
Lenalidomide Pharmacokinetics ............................................................................54 
9.4 
Pharmacodynamics: Cytokines ..............................................................................55 
9.4.1 Collection of Samples: ...........................................................................................55 
9.5 
Flow Cytometry B-, T-, and NK-cell subsets and activation status.......................55 
9.6 
Pharmacodynamic Studies: T-cell Function and Epigenetic Changes in 
CLL Cells ...............................................................................................................56 
9.7 
Correlative Studies Prioritization ...........................................................................57 
10. 
Study Calendar ...................................................................................................................57 
11. 
MEASUREMENT OF EFFECT........................................................................................62 
11.1 
Response Criteria. ..................................................................................................62 
11.2 
Complete Response ................................................................................................62 
11.3 
Partial Response .....................................................................................................62 
11.4 
Stable Disease ........................................................................................................63 
11.5 
Progressive Disease ...............................................................................................63 
11.6 
Duration of response ..............................................................................................63 
11.7 
Progression Free Survival (PFS) ............................................................................64 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................64 
12.1 
Data Reporting .......................................................................................................64 
12.2 
CTEP Multicenter Guidelines ................................................................................64 
12.3 
Collaborative Agreements Language .....................................................................64 
13. 
STATISTICAL CONSIDERATIONS...............................................................................66 
13.1 
Study Overview .....................................................................................................66 
13.2 
Primary Endpoint: ..................................................................................................67 
13.3 
Study Design ..........................................................................................................67 
13.4 
Sample Size/Accrual Rate ......................................................................................68 
13.5 
Analysis of Secondary Endpoints ..........................................................................68 
13.6 
Reporting and Exclusions ......................................................................................69 
REFERENCES ..............................................................................................................................71 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................76 
APPENDIX B 
Medication Calendar ..................................................................................77 

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APPENDIX C 
Risks of fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods .......................................................................................................80 
APPENDIX D 
Lenalidomide Education and Counseling Guidance Document ................84 
APPENDIX E: Lenalidomide Information Sheet ...........................................................................89 
 
 
 

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9 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To determine the proportion of early-stage, high-risk CLL patients achieving a response 
(≥ 4-fold increase from baseline and/or antibody concentrations ≥0.35 μg/mL in 6 of 7 
type-specific anti-pneumococcal antibody levels) after 2 doses of pneumococcal 13-
valent conjugated vaccine (Prevnar 13, PCV13) administered concurrent with versus 
sequential to low-dose lenalidomide 
 
1.2 
Secondary Objectives 
 
1.2.1 To determine the complete response (CR) rate after 2 years of lenalidomide therapy 
 
1.2.2 To determine the time to first treatment (TFT), defined as the time from diagnosis to first 
non-lenalidomide therapy for progressive CLL as described by IWCLL 2008 criteria1. 
 
1.2.3 To determine the incidence of infection and invasive pneumococcal infections following 
treatment with the PCV13 vaccine and either concurrent or sequential lenalidomide. 
 
1.2.4 To determine the frequency of humoral and cellular immune response to CLL  tumor 
antigens following treatment with the PCV13 vaccine and either concurrent or sequential 
lenalidomide. 
 
1.2.5 To determine the safety and toxicity associated with long-term lenalidomide exposure 
 
1.2.6 To perform correlative pharmacodynamic and pharmacokinetic studies and correlate 
these with vaccine/tumor immunologic and disease response. 
 
 
2. BACKGROUND 
 
2.1 
Chronic Lymphocytic Leukemia (CLL/SLL) 
 
2.1.1 CLL and infection risk 
 
Chronic lymphocytic leukemia (CLL) is the most frequently diagnosed form of leukemia 
in the western world.  It was initially defined as a generalized, self-perpetuating neoplastic 
proliferation of lymphoid tissue, particularly of small lymphocytes.[1.a.i.2]  It is now 
recognized as a clinically heterogeneous disease originating from B lymphocytes that may 
differ in activation, maturation state, or cellular subgroup.[1.a.i.3]  Accordingly, CLL 
displays a marked survival heterogeneity, ranging from months to over 20 years (SEER 
data).  One of its clinically defining features is the predisposition to infectious 
complications. That predisposition continue to be one of the principal causes of morbidity 
and mortality in patients with this disease, accounting for 30 to 50% of deaths.[1.a.i.4] The 
immune defect in CLL is characterized by both humoral and cellular deficits.  

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10 
Hypogammaglobulinemia is often present at diagnosis and typically increases in incidence 
as disease progresses such that 75% of patients are ultimately affected.[5]  Impaired 
immunoglobulin production significantly increases the risk for bacterial infection, 
particularly those caused by encapsulated organisms such as Streptococcus pneumoniae.  
Cellular immune defects are characterized by alterations in the number and function of T 
cell subsets.[6-8]  Studies in both murine models of human CLL and in patients 
demonstrate the CLL cells are very immunosuppressive[7,9,10].  Defects in both cellular 
and humoral immunity likely account for the poor response to vaccination in CLL patients, 
and developing strategies to enhance vaccine response represents an important area in CLL 
research.   
 
 
2.1.2 Vaccination in patients with CLL 
 
CLL patients typically respond poorly to vaccines, particularly pneumococcal 
polysaccharide and influenza vaccines.  This is especially true in patients with advanced 
disease stage. In 1960, a series of 42 previously untreated CLL patients was challenged 
with antigens to mumps, diphtheria, influenza, and typhoid.  While there was some 
correlation between the level of gamma-globulin deficiency and response to antigenic 
stimulation, this response did not reach that of normal controls, even in patients with 
normal gamma-globulin levels.  In observing these patients over the next year, the patients 
with the best response to vaccines had the fewest number of bacterial infections.[11]  A 
subsequent study evaluated the responses of patients with hematologic malignancies to 
influenza vaccines.  Eight of the thirteen patients with lymphoproliferative disorders failed 
to have a four-fold increase in antibody titer with vaccination.  Stiver and colleagues 
demonstrated a 4-fold increase in antibody titer in 36% of patients to influenza A and 32% 
of those to influenza B.  Four patients included in this study had received chemotherapy, 
and none of these patients had a 4-fold rise in antibody titer in response to vaccination.[12]  
A correlation between immunologic response to vaccine and absolute numbers of 
CD4+/CD45RA+ naïve T cells has been identified, which may suggest a role of this subset 
of cells in antibody response.[13]  With a booster, response rates increased from 5% to 
15% for influenza A and from 15% to 30% for influenza B, but this did not have a 
significant impact on protection rates.[14]  This poor response was confirmed in an open, 
randomized study, where the response rates in two doses compared to one was 18% vs 22% 
for H1N1, 26% vs 14% for H3N2, and 25% vs 22% for influenza B.  The results in patients 
with previous versus current chemotherapy were not statistically different, and patients 
who had received monoclonal antibody therapy were uniformly poor responders.  Of seven 
patients, there was only one who had a response to influenza B, and no patients responded 
to H1N1 or H3N2.[15] 
 
Purified polysaccharide antigens result in T cell-independent type-2 antibody formation.  
In conjugated vaccines, the polysaccharide antigen is conjugated to a toxoid as a carrier 
protein, resulting in antibody responses to the polysaccharide antigens in a T cell-
dependent way.  T cell-dependent antigens induce immunological memory, resulting in the 
possibility of booster vaccinations.  Recent studies have indicated that conjugation of 
polysaccharides may render the antigen more immunogenic in the CLL population, and 
there is evidence that patients with CLL have a more significant immune response to 

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11 
Haemophilus influenzae b conjugate than to plain polysaccharide antigen.  A statistically 
significant response to H. influenza has been described, where 6 of 28 patients developed 
a protective antibody level, but no patients in this series had a response to the 
polysaccharide pneumococcal vaccine.  This same study demonstrated a much more robust 
response to immunizations in control populations than in CLL patients.  However, age, 
disease stage, and IgG levels all play a role in the degree of response to immunization, as 
illustrated in the study by Hartkamp et al.16  This study showed poor responses to 
immunization with both the polysaccharide pneumococcal vaccine, as well as the protein-
conjugated H. influenza vaccine overall. However, a significant correlation was 
demonstrated with less advanced disease stage and absence of hypogammaglobulinemia, 
as well as higher levels of total IgG, IgG2, and IgG4 subclasses and lower levels of soluble 
CD23 (sCD23).  Sinsalo et al have since reported that 39% of patients achieved a 
significant response to administration of a 7-valent conjugated pneumococcal vaccine. 
Responding patients had Binet stage A and had not yet received chemotherapy or 
developed hypogammaglobulinemia.  Responses in more advanced stage of disease were 
only 5%.[17] 
 
2.1.3 Agents used to augment vaccine response 
 
Histamine acts as a mediator of immune and inflammatory reactions, has a direct inhibitory 
effect on immunoglobulin production by B-cells in vitro through histamine H2 receptors, 
and acts as an immune regulatory factor, which can be modulated by histamine type-2 
receptor antagonists.[18] Histamine is seen in higher levels in patients with CLL.[19]   The 
theory that responses to vaccines may be further enhanced by adjuvant treatment with H2-
blocker, however, is not well-supported by clinical evidence.  In a study by Jurlander and 
colleagues, antibody to Hib conjugated with a tetanus-toxioid increased to protective levels 
in 90% of patients vaccinated with adjuvant ranitidine.  On the other hand, the use of 
ranitidine to help mount antibody responses resulted in no significant difference in the 
response to vaccination against influenza types A and B.[19]  Patients in this study tended 
to be younger, lower stage, and minimally treated, though.  A more recent study by Van 
der Velden et al confirmed that administration of ranitidine increases levels of anti-Hib 
antibody and anti-tetanus toxoid antibody when compared with case-controls, but no 
significant improvements were noted with pneumococcal antibody responses.[20]   
 
Co-administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) is 
another method that has been tried to augment immune response.  GM-CSF has been 
demonstrated to expand the myeloid subset of dendritic cells, inducing high levels of Th2 
cytokines.  Mice studies showed a significant increase in titers to ovaalbumin vaccine 
antibodies when those antibodies were coadministered with GM-CSF, specifically in IgG1 
titers.[21]  Administration of GM-CSF with the 23-valent polysaccharide vaccine did not 
improve response. A 4-fold rise in IgG was seen in less than 10% of patients given multiple 
dose levels of GM-CSF.[22]   
 
 
2.2 
Lenalidomide 
 

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12 
2.2.1 Lenalidomide activity in relapsed and treatment-naïve CLL 
 
Lenalidomide is a potent immunomodulatory analogue of thalidomide and has been 
demonstrated to possess  anti-angiogenic  activity  through  inhibition  of  bFGF, VEGF 
and TNF-alpha induced endothelial cell migration, due at least in part to inhibition of 
Akt phosphorylation response to bFGF.[23]  In addition, lenalidomide has  a  variety  of  
immunomodulatory effects including stimulation of T cell proliferation and the 
production of IL-2, IL-10 and IFN-γ, as well as inhibition of IL-1 beta and IL-6 
production, and modulation of  IL-12  production.[24]  Upregulation of T cell derived 
IL-2 production is achieved, at least in part, through increased AP-1 activity.[25]  
Although the exact mechanism of lenalidomide anti-tumor activity is unknown, a 
number of mechanisms are postulated for this agent’s activity against multiple myeloma.  
Lenalidomide increases T cell proliferation, which leads to an increase in IL-2 and IFN-
γ secretion.  The increased level of these circulating cytokines augment natural killer 
cell number and  function,  and  enhance  natural  killer  cell  activity  to  yield  an  increase  
in multiple myeloma cell lysis.[26] In addition, lenalidomide has direct activity against 
multiple myeloma and induces apoptosis or G1 growth arrest in multiple myeloma cell  
lines  and  in  multiple  myeloma  cells  of  patients  resistant  to  melphalan, doxorubicin 
and dexamethasone.[27] 
 
Lenalidomide 
has 
demonstrated 
promising 
activity 
in 
both 
untreated 
and 
relapsed/refractory CLL, including patients with high-risk genomic features such as 
del(17p) and del(11q).[28-32]  In refractory disease, overall and complete response rates 
of 37% and 7%, respectively have been reported.  At the doses employed in those studies 
(10-25mg/day), however, higher than expected rates of tumor flare response were 
observed.[28,29]  Ferrajoli and colleagues have recently updated their experience treating 
60 previously untreated CLL patients over the age of 65 with single-agent lenalidomide.  
Lenalidomide was initiated at 5mg/day on a continuous schedule with dose-escalation to 
25 mg allowed, although the average tolerated dose was 10mg.  At median follow-up of 
15.5 months, 3 patients had achieved CR, 7 patients nPR (12%), and 22 patients PR (36%) 
for an ORR of 53%.[32]  Importantly, most CR and nPR responses were achieved between 
9 and 15 cycles of treatment and have thus far proved durable with continuation of therapy.  
While the optimal dose has yet to be established, lenalidomide appears to be highly active 
at even lower doses. Chen reported an overall response rate of 65% among 25 previously 
untreated patients.  Safety and tolerability were improved with an initial dose of 2.5 
mg/day slowly escalated to no more than 10mg/day.[31]  In our institution’s own phase I 
study, MTD was established at 2.5 mg/day escalated to 5 mg/day continuously 
administered, at which dose both biological and clinical activity were noted.[30] 
 
2.2.2 Low-dose lenalidomide can potentially reverse the immune deficiency of CLL 
 
Our group has reported the case of a relapsed CLL patient with high-risk disease 
(unmutated IgVH, complex karyotype including del17p) treated with low-dose 
lenalidomide (5mg/day continuously) who demonstrated gradual reduction of lymph node 
volume and peripheral blood lymphocytosis over 5 months of therapy.  A polyclonal 
hypergammoglobulinemia (IgM, IgG, and IgA expansion) was observed concomitant with 

NCI Protocol #: 8834 
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13 
disease response.[33]  Badoux and colleagues have since reported an increase in 
immunoglobulin levels in elderly patients treated with lenalidomide.  They found that IgG 
levels increased by a median 140 g/dL, most typically observed between 3 and 9 cycles of 
therapy.[34]  Further, that group noted an early kinetic T-cell response with increases in 
the absolute number and proportion of CD3+, CD4+, and CD8+ T-cells concurrent with 
decreases in the peripheral blood absolute lymphocyte count.  Over time this promoted 
normalization of CD4+/CD8+ T-cell ratios in both peripheral blood and bone marrow. 
 
2.2.3 Lenalidomide can break humoral tumor tolerance in CLL 
 
The exact mechanism by which lenalidomide induces these effects remains uncertain, but 
the drug has been reported to promote both cellular and innate immune activation and 
interference with the tumor cell microenvironment.  Co-culture of CLL cells and 
autologous T-cells with lenalidomide can reverse the T cell immune synapse defect present 
in this disease, and lenalidomide effectively increases the co-stimulatory molecules CD40, 
CD80, and CD86 on CLL cells.[7]  Previously, it has been shown that transduction of 
human CD154 (the surface ligand of CD40) into primary CLL cells likewise promotes 
expression of co-stimulatory molecules on bystander CLL cells.[35,36]  In those 
experiments, 
residual 
normal 
B 
cells 
demonstrated 
improvement 
in 
both 
hypogammaglobulinemia and development of antibodies to the CLL-specific antigen 
ROR1. Our group has now shown that extended duration lenalidomide treatment promotes 
a similar CD154 gene therapy phenotype through PI3-kinase dependent activation of NF-
κB mediated transcriptional activation and post-transcriptional mRNA stabilization of 
CD154.[33]  Increases in CD154 mRNA were observed in serial samples from 
lenalidomide treated patients (at 2.5-5 mg/day).  Further, in a subject who had not received 
prior therapy with the B-cell depleting agent rituximab prior to lenalidomide, there was 
evidence of increased titers of ROR1 antibody following lenalidomide treatment as well as 
increases in polyclonal IgG production.  These findings suggest the potential benefit of 
administering lenalidomide much earlier in the disease course, when both humoral and 
cellular immune mechanisms are more likely to remain intact.   
 
2.3 
Protein-conjugated Pneumococcal Vaccines 
 
2.3.1 Prevnar (Pneumococcal 7-valent conjugate vaccine, PCV7) in Immunocompromised 
Patients 
 
Pneumococcal 7-valent conjugate vaccine, or Prevnar, is a solution of saccharides of the 
capsular antigens of S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F individually 
conjugated to diphtheria CRM197 protein.  It is typically administered in childhood as a 3-
dose primary series with a booster given in the second year of life.  It has been studied in 
several immunocompromised patient populations, such as transplant recipients, in an 
attempt to improve rates of invasive pneumococcal disease over the polysaccharide 23-
valent vaccine.  Many anti-rejection medications are designed to impair T cell function. 
However, many of the current immunosuppressive regimens affect both T and B cell 
function.  The American Academy of Pediatrics recommends immunization with 
sequential pneumococcal vaccines for pediatric solid organ recipients based on data from 

NCI Protocol #: 8834 
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14 
the sickle cell population with two doses of the 7-valent conjugate pneumococcal vaccine 
(PCV7) and a single dose of 23V given at two months apart.  This has been found to be 
safe, but the efficacy of the second dose of PCV7 or the dose of 23V was unknown.  
Significant increases in antibody titer were seen by Lin et al in response to the first dose of 
PCV7, but only moderate, and not significant, increases were seen after the second 
dose.[37]   There has been evidence since published that the administration of 23V 
following immunization with PCV7 results in a rapid rise in IgG, consistent with a booster 
effect, followed by a rapid decline, suggesting the induction of suppressor cells or 
tolerance.[38]  Vaccination with PCV7 has been demonstrated to be safe and efficacious 
in several immunocompromised adult populations, including the elderly, patients with 
COPD, stem cell transplant recipients, those with specific antibody deficiency, and patients 
with HIV, although an optimal dosing strength or schedule has not been clearly 
identified.[39-44]  A recently published study evaluating PCV7 to prevent recurrent 
invasive pneumococcal infections in patients with HIV demonstrated a statistically 
significant reduction in the episodes of infection caused by the serotypes included in the 
vaccine with an efficacy of 74% when two doses of PCV7 were administered within a 28 
to 56 day window.[45] 
 
The widespread use of PCV7 in children has changed the epidemiology of invasive 
pneumococcal disease among adults over the past decade.  The incidence of invasive 
pneumococcal disease declined overall from 40.8 cases/100,000 among adults over the age 
of 50 in 1998-1999 to 29.4 cases/100,000 in 2002-2003, with a decline of 55% in disease 
caused by the 7 serotypes included in PCV7.  In contrast, disease caused by the 16 serotypes 
included only in the polysaccharide vaccine did not change, and disease not caused by 
serotypes included in either vaccine increased.[46]  The proportion of adults who are 
colonized with PCV7-type pneumococci has decreased, as well; however, the proportion 
of isolates with intermediate susceptibility to penicillin has increased.47  A recent study of 
175 HIV-positive patients, all but one of whom had received vaccination with the 
polysaccharide vaccine, revealed colonization with pneumococci in a total of 6 (3.4%) 
patients, reflecting a relatively low incidence of colonization.  Five of the isolates were 
serotypes not included in PCV7.[48]  Due to herd immunity and serotype replacement 
effects in the general population, this suggests that there may be a need for a more 
expansive vaccination strategy in immunocompromised adults. 
 
2.3.2 Prevnar 13 (Pneumococcal 13-valent conjugate vaccine, PCV13) 
 
Prevnar 13 (PCV13) is a 13-valent pneumococcal conjugate vaccine that was recently 
licensed by the Food and Drug Administration (FDA) for prevention of invasive 
pneumococcal disease (IPD) caused by the 13 pneumococcal serotypes covered by the 
vaccine and for prevention of otitis media caused by the serotypes in PCV7.  Dosing 
recommendations and safety profile are identical to those for PCV7.  PCV13 contains 
polysaccharides of the capsular antigens of S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 
9V, 14, 18C, 19A, 19F, and 23F, individually conjugated to a nontoxic diphtheria CRM197 
(CRM, cross-reactive material) carrier protein.  A 0.5 ml PCV13 dose contains 
approximately 2 μg of polysaccharide from each of 12 serotypes and approximately 4 μg 
of polysaccharide from serotype 6B.[49]    For the 7 common serotypes, PCV13 and PCV7 

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elicited comparable responses, with a similar percent of previously unimmunized infants 
achieving the 0.35 μg/ml IgG threshold required for response; while the IgG level was 
lower among patients receiving PCV13, functional response as measured by serotype-
specific opsonophagocytic assays (OPAs) were comparable.[50]  It is estimated that adding 
these 6 serotypes will increase coverage for prevention of IPD to 80-92% globally.  The 
addition of 6A and 19A, in particular, is an important advance, as these serotypes mediate 
a substantial proportion of IPD worldwide, and 19A has emerged as a serotype that is 
resistant to penicillin.[51]  While the Advisory Committee on Immunization Practices 
(ACIP) has not made recommendations for vaccination with PCV13 in patients over the 
age of 6 years, the recommended dosing schedule for children over the age of 12 months 
with an immunocompromising condition who have not been previously vaccinated against 
S. pneumoniae is 2 doses with a minimum interval of 8 weeks between doses. 
 
2.3.3 Lenalidomide as an adjuvant to Prevnar in Multiple Myeloma 
 
A study by Noonan et al in patients with multiple myeloma administered Prevnar before 
or concurrently with lenalidomide [52]. Response to vaccine included pneumococcal 
serotype titres as well as CRM-197 T cell responses quantified the B and T cell responses 
to Prevnar vaccination. All patients had measurable T cell and antibody responses to 
Prevnar. T cell responses to CRM-197 were significantly higher in the concurrent 
arm.  Vaccination primed serotype humoral responses were noted in both treatment arms 
but an enhanced response to the booster vaccine was only noted in the patients receiving 
concurrent lenalidomide suggesting augmentation of a T-cell dependent response.  DTH 
responses to Candida were examined to determine systemic immunity where concurrent 
lenalidomide demonstrated up to a 78-fold increase in induration compared to no change 
with sequentially administered prevnar followed by lenalidomide. An increase in T cell 
activation was also noted in the concurrent arm of prevnar and lenalidomide. 
Unexpectadly, the overall response rate was also higher in the concurrent arm (57%) as 
compared to sequential treatment (10%).  Collectively, the preliminary findings of this 
study suggest synergy between the immunomodulatory effects of lenalidomide and 
vaccines.  Although preliminary, the authors hypothesized that the increased anti-tumor 
effect observed in the concurrent arm might support the hypothesis of lenalidomide-
induced vaccine-mediated epitope spreading.  However, no direct anti-tumor immunologic 
response was observed in this study.    
 
 
2.4 
Rationale for Study Drug and Population 
 
Notwithstanding the potential benefits accruing to lenalidomide treatment early in the 
natural history of disease, routine treatment for patients with early-stage CLL at diagnosis 
has previously not been considered beneficial.  The standard of care remains to treat only 
patients progressing to symptomatic disease, sparing patients with early stage disease from 
toxicity.[1.a.i.1,53]  Accumulating data, however, suggests that there exists an identifiable 
high-risk subgroup for whom the likelihood of early progression and subsequent death 
from their disease is great.  Genomic and molecular features of the CLL clone explain 
much of the variation in prognosis and can identify higher-risk subpopulations meriting 

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16 
consideration for risk-adapted intervention.[54,55]  Patients with CLL demonstrating 
unmutated immunoglobulin heavy chain genes (IgVH), complex karytotype (≥3 
abnormalities), and FISH-detected deletions of chromosomes 11q22.3 and 17p13.1 
demonstrate a shorter treatment-free interval and impaired survival.[56-60]  
 
While initially described in a heterogeneous (early-/late-stage) population, more recent 
prospective studies have validated the independent prognostic value of these markers in 
early-stage (Rai 0/1, Binet A) disease.[61-63]  Preliminary evidence suggests that these 
markers may also characterize a group among monoclonal B-cell lymphocytosis patients 
more likely to require treatment.[64]  Recent studies assessing the benefit of treatment in 
early-stage disease, including the recently closed U.S. intergroup “early intervention” 
study (CALGB 10501), have targeted a similarly defined high-risk population.[65] 
  
The preliminary data summarized above support the contention that treatment with the 
immunomodulatory agent lenalidomide, when initiated early in the disease course, can 
potentially change the natural history of not only the disease itself but also the 
immunological derangements responsible for its chief morbidities.  We hypothesize that 
low-dose lenalidomide can enhance the efficacy of vaccination for infectious diseases as 
measured by antibody response to pneumonia vaccination with conjugated 13-valent 
pneumococcal vaccine.  Correlative studies will evaluate parameters of immune 
reconstitution (quantitative immunoglobulins, T-cell subsets) and explore postulated 
mechanisms of lenalidomide activity. We further hypothesize that initiation of low-dose 
lenalidomide in asymptomatic patients with high genomic risk CLL can induce complete 
remissions with continued exposure to the drug. 
 
2.5 
Correlative Studies Background 
 
2.5.1 Serum immunoglobulin levels: Quantitative serum immunoglobulin levels (IgG, IgA, 
IgM) will be obtained at baseline and every 2 months thereafter.  Improvement in 
immunoglobulin levels over time will be correlated with the ability of lenalidomide to 
up-regulate CD154 on CLL cells and pharmacokinetics of lenalidomide.  We have 
observed that CD154 up-regulation occurs in approximately 75% of CLL patients treated 
with lenalidomide [66]. 
 
2.5.2 B-, T-, and NK-cell subsets and activation status: Changes in subsets and activation 
status of B-, T-, and NK lymphocytes in peripheral blood following lenalidomide therapy 
will be evaluated using multiparametric flow cytometry.  Lymphocyte CD4, CD8, T-
regulatory, and NK cell subsets will be enumerated and markers of activation status will 
be characterized for each.  Recent un-published data from our laboratory has 
demonstrated that lenalidomide can increase CD4 expression of IL21 which will be 
assessed by real time PCR from RNA isolated from these cells and serial plasma cytokine 
measurement.  Activation of T- and NK-cells will be correlated with both up-regulation 
of CD154 on CLL cells and pharmacokinetics of lenalidomide. 
 

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2.5.3 CLL cell activation: B-cell activation will be further characterized by upregulation of 
CD154 as the primary measure (based upon our data), along with CD40, CD80, CD86.  
CD154, CD40, CD80, CD86 expression will be analyzed by flow cytometry on gated 
CLL cells.  Additionally, we will measure serial changes in different cytokine receptor 
expression on CLL cells that could contribute to cytoxicity and immunogeneticity.  
Concurrent with such receptor measurement we will also assess serum cytokines and 
cellular cytokine production by accessory immune cells. Change in CD154 expression 
will be correlated with pharmacokinetics and immune response. 
 
2.5.4 Anti-ROR1 antibody levels: Tumor-specific anti-ROR1 antibody titers will be 
determined by ELISA in plasma at baseline and every 6 months thereafter. Development 
of ROR1 antibodies will be correlated with the ability to up-regulate CD154 on CLL cells 
and pharmacokinetics of lenalidomide. 
 
2.5.5 Anti-CLL tumor antibody levels: Tumor-specific antibody titers will be determined by 
an adapted flow cytometry assay from plasma at baseline and every 6 months thereafter.  
Development of anti-CLL antibodies will be correlated with the ability to up-regulate 
CD154 on CLL cells and pharmacokinetics of lenalidomide In patients developing such 
antibodies, normal B-cells derived from these patients will be isolated for identification 
of relevant target antigens.  This work will be performed in collaboration with Christoph 
Rader at the intramural program of the NCI. 
 
2.5.6 Anti-pneumococcal antibody levels: Serum antibody levels to specific pneumococcal 
antigens will be assessed at baseline, 2 months following initiation of lenalidomide 
therapy (cycle 3 day 1), 2 months after initial vaccination (cycle 5 day 1) and 1 month 
after second vaccination (cycle 6 day 1) and every 6 months thereafter for patients 
remaining in follow-up for patients in Arm A.  For those in Arm B, titers will be assessed 
at baseline, 2 months after initial vaccination (cycle 3 day 1), 1 month after second 
vaccination (cycle 4 day 1), and every 6 months thereafter starting with cycle 7 day 1.  
ELISA will be used to quantitate anti-capsular polysaccharide antibodies against 
serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F.   Development of increasing pneumococcal 
titers will be correlated with the ability to up-regulate CD154 on CLL cells, T-cell 
activation, and pharmacokinetics of lenalidomide.   
 
2.5.7 Epigentic changes in CLL cells: Histone modifications have been reported following 
treatment with lenalidomide.  We will assess for modification of histone proteins by 
liquid chromatography and mass spectrometry.  These histone changes will be correlated 
with response and pharmacokinetics of lenalidomide in an exploratory fashion. 
 
2.5.8 Expression of MDR1 on CLL and immune cells: Our group has recently demonstrated 
that lenalidomide is an MDR1 substrate.  Given that CLL cells express this transporter to 
varying degrees, we will assess baseline expression of this and correlate it with CLL cell 
activation. 
 

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2.5.9 Pharmacokinetic studies: Pharmacokinetic studies will be performed to correlate Pk 
features with measures of B-cell activation and other pharmacodynamic studies.  
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically identified chronic lymphocytic leukemia (CLL) or small 
lymphocytic lymphoma (SLL) as defined by the WHO classification of hematopoietic 
neoplasms. 
 
3.1.2 CLL/SLL cells must demonstrate one or more of the following high-risk genomic 
features: 
 Del(17p13.1) as detected by fluorescence in-situ hybridization (FISH) in >20% 
of cells 
 Del(11q22.3) as detected by FISH in >20% of cells 
 Complex karyotype (≥3 cytogenetic abnormalities on stimulated karyotype) 
 Unmutated IgVH (≥98% sequence homology compared with germline 
sequence) 
 
3.1.3 Patients cannot meet any of the following consensus criteria for initiating treatment: 
 Progressive splenomegaly and/or lymphadenopathy identified by physical 
examination or radiographic studies 
 Progressive lymphocytosis with total WBC ≥ 300,000/µL 
 Anemia (<11 g/dL) or thrombocytopenia (<100,000/μL) due to bone marrow 
involvement 
 Presence of unintentional weight loss > 10% over the preceding 6 months 
 NCI CTCAE grade 2 or 3 fatigue 
 Fevers > 100.5° or night sweats for > 2 weeks without evidence of infection 
 Progressive lymphocytosis with an increase of > 50% over a 2 month period or 
an anticipated doubling time of < 6 months 
 
3.1.4 No prior therapy for CLL/SLL, including chemotherapy, radiotherapy, and/or 
immunotherapy will be allowed. 
 
3.1.5 Age ≥ 18 years and < 80 years (or with justification if older than 80 years due to the 
higher risk of toxicity in patients older than 80 years). CLL is rare in children and likely 
represents a different disease process. As a result, children are excluded from this study 
but may be eligible for future pediatric phase 2 combination trials. 
 
3.1.6 Estimated life expectancy of greater than 24 months. 
 
3.1.7 ECOG performance status ≤ 2 (Karnofsky ≥ 60%; see Appendix A). 
 

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3.1.8 Patients must have normal organ and marrow function as defined below: 
 
 Total bilirubin 
 ≤ 1.5 x ULN unless secondary to Gilbert’s  
 
 
disease 
 AST(SGOT)/ALT(SGPT) 
≤ 2.5 X institutional upper limit of normal 
 Creatinine clearance 
≥ 60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
according to the Cockcraft-Gault formula 
 Absolute neutrophil count 
≥ 1,500/μL 
 Platelet count 
≥ 100,000/μL 
 
3.1.9 Able to swallow capsules without difficulty and no history of malabsorption syndrome, 
disease significantly affecting gastrointestinal function, or resection of the stomach or 
small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or 
complete bowel obstruction. 
 
3.1.10 Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy 
test with a sensitivity of at least 25 mIU/mL within 10 – 14 days prior to and again within 
24 hours of starting lenalidomide. Further, they 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 starting 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.  A FCBP is a sexually 
mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months).  All patients must be 
counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal 
exposure.  (See Appendix C: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods, and also Appendix D: Education and Counseling 
Guidance Document). 
 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had any treatment for their CLL/SLL, including but not limited to 
chemotherapy, radiotherapy, or immunotherapy, prior to entering the study.  
 
3.2.2 No corticosteroid use will be permitted within two weeks prior to study, except for 
maintenance therapy for a non-malignant disease.  Maintenance therapy dose may not 
exceed 20 mg/day prednisone or equivalent. 
 
3.2.3 Patients who meet consensus criteria for the treatment of CLL/SLL as defined in 3.1.3 
above. 
 

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3.2.4 Patients may not be receiving any other investigational agents. 
 
3.2.5 Patients with a recent history (within 6 months of study entry) of DVT/PE are not 
eligible.  Patients with a distant history (greater than 6 months before study entry) of 
venous thromboembolic disease are eligible, but should receive prophylactic aspirin or 
low molecular weight heparin. (See 5.2.3 below) 
 
3.2.6 History of allergic reactions attributable to compounds of similar chemical or biologic 
composition to thalidomide, lenalidomide or any component of PCV7 or PCV13, 
including the diphtheria toxoid. 
 
3.2.7 Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, 
in situ cervical cancer, or other cancer from which the subject is considered by his or her 
physician to have a 2 year survival expectation. 
 
3.2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.. 
 
3.2.9 Pregnant women are excluded from this study because lenalidomide is an 
immunomodulatory agent (IMID) with the potential for teratogenic or abortifacient 
effects.  Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with lenalidomide, breastfeeding should be 
discontinued if the mother is treated with lenalidomide. 
 
3.2.10 HIV-positive patients on combination antiretroviral therapy will be eligible if they 
otherwise meet required hematologic parameters and are not receiving an antiviral agent 
with known or potential interaction with lenalidomide. Because the primary aim of this 
study is to measure the immune response to pneumococcal vaccination, only patients 
with CD4 cell counts ≥ 200 and viral load < 50 will be eligible. 
 
3.2.11 Patients who have been treated for autoimmune hemolytic anemia or autoimmune 
thrombocytopenia within the last 6 months or are direct antiglobulin test/Coomb’s test or 
indirect antiglobulin test positive at the time of screening. 
 
3.2.12 Patients who have developed erythema nodosum characterized by a desquamating rash 
while taking thalidomide or similar drugs in the past are excluded. 
 
3.2.13 Because of the potential for H2-blockers to modulate antibody response to pneumococcal 
vaccine, patients must discontinue treatment with H2-blockers (cimetidine, ranitidine, 
etc.) prior to beginning protocol therapy. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  

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21 
 
3.4 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 
2 
= 
4 
Not Hispanic or Latino 
22 
+ 
22 
= 
44 
Ethnic Category: Total of all subjects 
24 (A1) 
+ 
24 (B1) 
= 
          48 (C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
1 
+ 
1 
= 
2 
Black or African American 
2 
+ 
2 
= 
4 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
21 
+ 
21 
= 
42 
Racial Category: Total of all subjects 
24 (A2) 
+ 
24 (B2) 
= 
48 (C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
Accrual Rate: 
3 
pts/month 
Total Expected 
Accrual: 
44 
Min 
48 
Max 
Projected Start Date of 
Study: 
01/01/2011 
 
 
 
 
 
 
 
4. REGISTRATION PROCEDURES 
 
Each site must have two trained counselors available for counseling all patients receiving 
lenalidomide supplied by the Division of Cancer Treatment and Diagnosis.  Trained counselors 
must complete training using the online program provided free by Celgene, the Celgene 
Pregnancy Prevention Counseling Program (CPPCP). Registration for CPPCP is done by 
completing the form found in Appendix C and following the directions provided in the email 
notification. After the training is complete, the counselors must generate a training certificate 
and provide it to PMB (fax number 240-276-7893; Attention CPPCP) for documentation. Sites 
may not order lenalidomide until documentation for two trained counselors is provided to the 
appropriate office. 
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Patients will be randomized to one of the following two treatment arms: Arm A 
(Concurrent PCV13 + lenalidomide) or Arm B (Sequential PCV13 + lenalidomide).  (See 
Table 1). No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy.  Treatment 
will be administered on an outpatient basis.  
 

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Table 1: Treatment Overview 
 
 
 
 
Arm A: Concurrent 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
Month 8+ 
 
 
V 
 
V 
 
 
 
L 
L 
L 
L 
L 
L 
L 
L 
 
Arm B: Sequential 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
Month 8+ 
V 
 
V 
 
 
 
 
 
 
 
 
L 
L 
L 
L 
L 
 
 
V = PCV13 pneumococcal vaccine administration; L = lenalidomide 
 
All patients will be instructed on how to use a medication diary documenting each dose 
of medication (Appendix B).  At monthly visits the patient will bring the medication 
calendar to the clinic.  All bottles of study medication should be brought to each clinic 
visit for comparison with the medication calendar.  The medication calendar for the 
previous month will be reviewed, and a new medication calendar will be given to the 
patient with each new lenalidomide supply. 
 
5.1.1 Lenalidomide 
 
Lenalidomide treatment will be administered on a continuous basis.  However, for 
convenience of dose-modification, response, and toxicity monitoring, the treatment 
period will be divided into cycles of 28-day length.  Lenalidomide will be dispensed in no 
more than one 28-day supply.  Before each supply is released, each patient’s medication 
calendar from the previous cycle will be reviewed to assess compliance.  Patients will 
also be required to review the Lenalidomide Information Sheet (Appendix E) and the 
Education and Counseling Guidance Documents (Appendix D) prior to receiving each 
monthly supply of lenalidomide.   
 
 
 
 
Table 2: Lenalidomide Dosing and Administration 
Treatment 
Arm 
Cycle 
Dose 
Ancillary Medications 
Schedule 
Cycle 
Length 
A 
Concurrent 
1 
2.5 mg/day 
 
Allopurinol 300 mg/day 
beginning 3 days prior to 
lenalidomide and continuing 
through at least the end of 
Cycle 1 
 
Dexamethasone may be 
given for up to 7 days during 
Cycles 1 and 2 for 
symptomatic tumor flare 
 
Days 1-28 
continuous 
28 days 
2+ 
5 mg/day 

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B 
Sequential 
1-3 
No 
lenalidomide 
 
Allopurinol 300 mg/day 
beginning 3 days prior to 
lenalidomide and continuing 
through at least the end of 
Cycle 4 
 
Dexamethasone may be 
given for up to 7 days during 
Cycles 4 and 5 for 
symptomatic tumor flare 
 
Days 1-28 
continuous 
4 
2.5 mg/day 
5+ 
5 mg/day 
 
Lenalidomide dosing and administration are summarized in Table 2.  Lenalidomide 
treatment will be administered at 2.5 mg/day during the first cycle of treatment (Arm A: 
Cycle 1; Arm B: Cycle 4) to minimize risks for tumor flare and/or tumor lysis. The dose 
of lenalidomide will be increased to 5 mg/day beginning as early as the second cycle of 
therapy (Arm A: Cycle 2; Arm B: Cycle 5) if all of the following criteria are met on Day 
1: 
• No clinically significant Grade 3 or greater non-hematologic toxicities 
attributable to lenalidomide during the preceding cycle. 
• Any hematologic toxicity is resolved to ≤ Grade 1. 
• Maintained platelet count >50K at all times during the previous cycle. 
• Maintained ANC >1K at all times during the preceding cycle. 
• Any other drug-related adverse events have resolved to Grade ≤ 1 severity. 
 
During the first cycle of lenalidomide exposure, and any cycle in which the dose is 
subsequently escalated, patients are seen on Days 1 and 8 for laboratory evaluation 
(CBC, chemistries), history, and physical examination to evaluate for tumor lysis and/or 
tumor flare, respectively.  Management of tumor flare response is detailed in 5.2.1 below. 
 
Patients not meeting criteria for dose escalation upon beginning the second cycle of 
lenalidomide can be re-evaluated for dose escalation at the start of subsequent cycles, at 
which time the same criteria will apply.  However, dose escalation beyond 5 mg/day will 
not be permitted so as to limit the risk in this patient population who would not otherwise 
be receiving therapy.  Criteria for removal from study (Section 5.5), dose modifications 
for toxicity (Section 6.1), and guidelines for intrasubject dose escalation (Section 6.4) 
are further discussed below.  Management of biochemical and clinical tumor lysis is 
described in 6.3.9 and 6.3.10 below. 
 
Lenalidomide can be taken without regard to meals.  If a patient misses a dose of 
lenalidomide, the patient should take it as soon as he or she remembers that day.  If the 
patient does not remember until the next day, the patient should skip the missed dose.  
Patients should NOT take two doses the same day.  Missed doses will not be made-up, 
and the resulting remainder of study drug should be returned with the bottle at the next 
follow-up visit. 
 

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24 
5.1.2 Protein-conjugate 13-valent pneumococcal vaccine 
 
PCV13 administration is summarized in Table 3 below. Patients will receive 2 doses of 
PCV13 administered 8 weeks apart.  In Arm A (Concurrent), vaccine will be administered 
on Day 1 of cycles 3 and 5.  In Arm B (Sequential), patients will be vaccinated on Day 1 
of cycles 1 and 3.  Each 0.5 mL dose of vaccine will be given intramuscularly in the deltoid 
muscle of the upper arm.  PCV13 should not be administered intravenously, intradermally, 
or subcutaneously. 
 
 
 
    Table 3: Dosing and Administration of PCV13 
 
Treatment 
Arm 
Cycle 
Dose 
Schedule 
Cycle 
Length 
A 
Concurrent 
3 
0.5 mL IM 
Cycle 3 
Day 1 
28 days 
5 
0.5 mL IM 
Cycle  5 
Day 1 
B 
Sequential 
1 
0.5 mL IM 
Cycle 1 
Day 1 
3 
0.5 mL IM 
Cycle 3 
Day 1 
 
 
5.1.3 Other modality(ies) or procedures 
 
N/A 
 
 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, and antiemetics when appropriate.  All concomitant medications, 
including the reason(s) for treatment, dosage, and the dates of treatment, should be 
recorded on the flow sheets. 
 

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5.2.1 Corticosteroids for tumor flare: Swelling, erythema, and tenderness of lymph nodes 
(especially pathologically involved lymph nodes), with/without fever and rash, are 
expected effects of treatment with lenalidomide.  First line treatment is analgesics  (e.g. 
NSAIDs, acetaminophen, oral narcotics) or corticosteroids at the discretion of the treating 
physician. If the treating physician believes steroids are indicated, administration of 
dexamethasone (recommended dose = 4mg/day x 7 days) during the first two cycles of 
lenalidomide treatment is permitted. Steroid administration beyond 7 days can be 
considered after consultation with the principal  investigator. 
 
5.2.2 Allopurinol: All patients, unless allergic, should receive allopurinol 300 mg orally 
daily starting 3 days prior to initiating lenalidomide therapy and continuing through at 
least the end of the first cycle of treatment as tumor  lysis  syndrome prophylaxis. This 
coincides with Cycle 1 in Arm A and Cycle 4 in Arm B.  Allopurinol may be continued 
through the second cycle of lenalidomide treatment and beyond at the discretion of the 
treating physician. If the patient is allergic to allopurinol, this drug will be omitted.   
 
5.2.3 Thromboprophylaxis: Lenalidomide increases the risk of thrombotic events in patients 
who are at high risk or with a history of thrombosis, in particular when combined with 
other drugs known to cause thrombosis.  When lenalidomide is combined with other 
agents such as corticosteroids, anthracyclines and erythropoeitic stimulating agents, the 
risk of thrombosis is increased.  Consequently, concurrent use of ESAs will not be 
permitted. Prophylactic aspirin (recommended dose = 81 mg/day) or low molecular 
weight heparin (e.g enoxaparin 40 mg/day SQ) are to be given to patients with a high risk 
of developing DVT/PE or arterial thromboses unless otherwise contraindicated.  High 
risk will be defined as a history of DVT/PE, significant family history, performance 
status ≥ 2, smoking history, or use of oral contraceptives. Patients with diabetes mellitus 
or coronary artery disease are considered to be at high risk for arterial thromboembolic 
events. All patients will be counseled to discontinue smoking and to seek appropriate 
cardiovascular risk reduction consistent with good medical practice. Patients requiring 
anticoagulation for something other than a history of thrombosis (i.e. prophylaxis for 
atrial fibrillation or mechanical heart valve) will not be excluded from the study.  If 
warfarin is used, close monitoring of the INR is recommended.  If anticoagulation 
becomes necessary for any reason other than a thrombotic event during the study period, 
patients may continue on the study provided that they are appropriately monitored.  In the 
unexpected event that a patient develops severe thrombocytopenia (platelet count <50K), 
thromboprophylaxis should be held, irrespective of the indication, unless the treating 
physician, in consultation with the principal investigator, believes the benefit to the 
patient otherwise outweighs the risks. 
 
5.2.4 Transfusion: Cytopenias requiring transfusion are not an expected complication of 
treatment on this study.  If necessary, however, all blood products should be irradiated 
and leukoreduced to prevent transfusion-associated graft versus host disease. 
 

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5.2.5 Antibiotics:  Routine antimicrobial prophylaxis will not be permitted.  Antibiotics given 
for other indications should be carefully documented. 
 
5.2.6 Colony stimulating factor use: Myeloid growth factors will not be permitted except for 
the treatment of febrile neutropenia as outlined in 6.3.2. below. Erythropoetic stimulating 
agents (ESAs) will not be permitted for any indication. 
 
5.2.7 CYP inhibitors: Lenalidomide has not been demonstrated to be a substrate, inhibitor, or 
inducer of the CYP group of enzymes and clinically relevant pharmacokinetic drug-drug 
interactions are unlikely to occur between lenalidomide and co-administered CYP 
substrates or inhibitors 
 
5.2.8 Potential drug interactions: Periodic monitoring of digoxin levels is recommended during 
coadministration with lenalidomide.  Digoxin levels were slightly higher when digoxin was 
administered with lenalidomide in a clinical study.  There was no effect on lenalidomide 
pharmacokinetics. Warfarin and lenalidomide may be co-administered without additional 
monitoring.  No pharmacokinetic or pharmacodynamic interactions were observed between 
lenalidomide and warfarin.  
 
5.2.9 Concomitant medications:  Study flow sheets and/or case report forms must capture the 
concurrent use of all other drugs, over-the-counter medications, supplements, or 
alternative therapies on a monthly basis.  
 
 
5.3 
Duration of Therapy 
 
Patients demonstrating clinical benefit, defined as achievement of an objective response 
(CR, CRi, or PR) or stable disease (SD), may continue therapy for up to 24 cycles 
(approximately 2 years) of treatment with lenalidomide.  Therapy beyond 24 cycles may 
be considered after discussion with the principal investigator and consultation with the 
study sponsor.   
 
Investigators are encouraged to keep patients experiencing clinical benefit on study unless 
significant toxicity puts the subject at risk or routine noncompliance puts the study 
outcomes at risk.  If the subject meets any 1 of the following criteria, withdrawal from 
treatment is mandatory: 
 Disease progression meeting 2008 IWCLL consensus criteria for treatment. 
 Intercurrent illness that prevents further lenalidomide administration. 
 Any treatment-related Grade 4 non-hematologic toxicity. 
 Unacceptable and/or unmanageable Grade ≥ 3 toxicity attributable to lenalidomide. 
 Any treatment-related hematologic or non-hematologic toxicity delaying treatment 
more than 14 days. 

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 Development of autoimmune hemolytic anemia (AIHA) or immune-mediated 
thrombocytopenia (ITP) 
 Subject elects to withdraw from study or becomes pregnant. 
 General or specific changes in the patient’s condition rendering the patient 
unacceptable for further treatment in the judgment of the investigator. 
 Subject is noncompliant with study procedures and/or scheduled evaluations. 
 Investigator considers withdrawal to be in the best interest of the subject. 
 Diagnosis of new or secondary malignancies after initiating treatment 
 
Subjects with inadequate study drug compliance (i.e. ≤ 80% of planned doses 
administered) may be replaced. 
 
5.4 
Duration of Follow Up 
 
Each subject should be followed for at least 30 (±7) days after his or her last dose of 
lenalidomide (i.e. the “safety follow-up period”) to monitor for resolution or progression 
of AEs and to document the occurrence of new events unless the subject receives a new 
CLL therapy within this time frame.   
 
Subjects who withdraw consent should still be encouraged to complete the safety follow-
up assessments, but these assessments cannot be mandated once consent is withdrawn.  
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.   
 
Beyond the safety follow-up period, patients no longer receiving protocol therapy will 
continue to be evaluated at 3 month intervals for the first year and every 6 months thereafter 
until they receive a new CLL therapy, withdraw consent, or expire. Patients may remain in 
follow-up if disease progression occurs. Required historical, laboratory, and physical 
examination procedures at each follow-up visit are detailed in the Study Table (Section 
10). 
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from treatment when any of the criteria listed in Section 5.3 
applies.  Irreversible or unacceptable treatment-related toxicities that are Grade ≥ 3 as listed 
in Section 5.3 necessitate discontinuation from study treatment.  A patient with a treatment-
related Grade ≥ 3 adverse event that resolves to Grade ≤ 1 within 14 days may continue 
treatment with appropriate dose reductions as outlined in Section 6.  Any Grade 4 toxicity 
attributable to lenalidomide will require discontinuation from study treatment.  The reason 
for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 

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5.6 
Criteria for Halting the Study 
 
If there are ≥ 2 treatment-related Grade 4 non-hematologic events in the first 10 patients or 
any grade 5 events, enrollment in the study will be temporarily halted pending review by 
the PI and the study sponsors regarding the need for modifications to the protocol or 
consent. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Modifications due to Toxicity 
 
Because this study assesses the benefits of treating early-stage, asymptomatic CLL/SLL 
patients who would not otherwise be receiving therapy, the definition of “unacceptable” 
toxicity will be defined as any treatment-related Grade 4 non-hematologic toxicity or any 
treatment-related Grade ≥ 3 toxicity deemed unmanageable or unacceptable by the patient, 
his or her treating physician, or the study chair. As described, in Section 5.3 and Section 
5.5, unacceptable toxicity will require discontinuation of protocol therapy. 
 
Subjects will be evaluated for adverse events at each visit with the NCI CTEP CTCAE 
version 5 used as a guide for grading of severity for both hematologic and non-hematologic 
toxicity. 
 
6.2 
Criteria for Starting a New Cycle 
 
A new course of treatment may begin on the scheduled day 1 of a new cycle if: 
 
 
All lenalidomide-related hematologic toxicity has resolved to Grade ≤ 1 severity. 
 
 
Any lenalidomide-related rash or neuropathy that may have occurred has resolved 
to Grade ≤ 1 severity. 
 
 
Any other drug-related adverse events that may have occurred have resolved to 
Grade ≤ 1 severity. 
 
6.3 
Criteria for Dose Reductions 
 
Dose modifications of lenalidomide may be made at any time during treatment if 
lenalidomide is held for toxicity or at the start of a new cycle if the previous dose was not 
well-tolerated. Lenalidomide dose levels are displayed in Table 4.  No dose reductions 
below dose level -1 (2.5 mg every other day) will be permitted. Specific criteria for holding 
and/or modifying the dose of lenalidomide are further detailed in this section. 
 
 
 
 

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Table 4. Lenalidomide Dose Levels 
 
Dose Level 
Lenalidomide Dose 
1 
5 mg daily 
0 
2.5 mg daily 
-1 
2.5 mg every other day 
 
If a toxicity requiring dose reduction is experienced, appropriate measures will be taken as 
described below (6.3.1), and when therapy with the study drug resumes it will be 
considered the next day of the patient’s current cycle.  For example, if drug is held prior to 
the daily dose on day 8 for a toxicity, and the toxicity resolves to allow lenalidomide 
resumption after 7 days, it would then be considered day 8 of the current cycle. 
 
6.3.1 Hematologic Toxicity 
 
 In the instance of Grade ≥ 3 lenalidomide-related hematologic toxicity on day 1 of 
a cycle, delay lenalidomide therapy and monitor CBC at least weekly.  If toxicity 
resolves to Grade ≤1 within 2 weeks, then resume lenalidomide at the next lower 
dose level. 
 
 If Grade ≥ 3 lenalidomide-related hematologic toxicity occurs during a cycle, delay 
lenalidomide therapy and monitor CBC at least weekly.  If toxicity resolves to 
Grade ≤1 within 2 weeks, then resume lenalidomide at the next lower dose level. 
 
 If treatment is delayed for more than 2 weeks, discontinue protocol therapy. 
 
 WBC colony stimulating factors may not be used to avoid dose reductions but can 
be used in the treatment of febrile neutropenia as outlined in 6.3.2 below. 
 
 Because of the potential to increase the risk for venous thromboembolic disease, 
the use of erythropoetic stimulating agents (ESAs) will not be permitted. 
 
 Because a decrease in absolute lymphocyte count (and thus WBC count) is an 
expected therapeutic outcome of treatment with Lenalidomide, no dose 
modification is required for the AEs of White Blood Cell Decreased or Lymphocyte 
Count Decreased. 
 
6.3.2 Febrile Neutropenia 
 
 In the event of febrile neutropenia occurring at any time during a cycle, hold 
lenalidomide therapy and administer G-CSF until recovery (ANC ≥1500/μL + 
absence of fever). If the patient recovers within 2 weeks, then resume lenalidomide 
at the next lower dose level. 
 
 If treatment is delayed for more than 2 weeks, discontinue protocol therapy 
 

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6.3.3 Allergic Reaction 
 
 Patients experiencing an IgE-mediated allergic reaction (including anaphylaxis, 
hives, or asthma) attributable to lenalidomide should discontinue treatment 
immediately and be removed from further protocol therapy. 
 
 In the instance of any other Grade 2 allergic reaction attributable to lenalidomide, 
hold lenalidomide therapy and monitor toxicity at least weekly.  If toxicity resolves 
to Grade ≤ 1 within 2 weeks, then resume lenalidomide at the next lower dose level. 
 
 In the instance of any Grade ≥ 3 allergic reaction to lenalidomide, remove patient 
from protocol therapy. 
 
 For any Grade ≥ 3 allergic reaction to Prevnar 13 vaccine, further vaccination must 
be discontinued.  Further treatment with lenalidomide, however, can be continued. 
 
6.3.4 Dermatologic and Skin Toxicity 
 
 For any grade bullous, hemorrhagic, or desquamating rash (i.e. TEN), remove 
patient from protocol therapy. 
 
 For any grade erythema multiforme, remove patient from protocol therapy. 
 
 For other Grade ≥ 3 non-desquamating rash, hold lenalidomide therapy and monitor 
toxicity at least weekly.  If toxicity resolves to Grade ≤ 1 within 2 weeks, then 
resume lenalidomide at the next lower dose level. 
 
6.3.5 Autoimmune Hemolytic Anemia or Thrombocytopenic Purpura 
 
Lenalidomide will be discontinued in patients developing autoimmune hemolytic anemia 
or autoimmune thrombocytopenia. 
 
6.3.6 Cardiac Toxicity 
 
 For lenalidomide-related grade 2 toxicity, hold lenalidomide and follow at least 
weekly. If toxicity resolves to Grade ≤ 1 within 2 weeks, then resume lenalidomide 
at the next lower dose level. 
 
 For lenalidomide-related Grade ≥ 3 toxicity, discontinue lenalidomide. 
 
6.3.7 Venous Thromboembolic Disease 
 
For any grade deep venous thrombosis, arterial thrombosis, or embolism, discontinue 
lenalidomide. 
 

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31 
6.3.8 Tumor Flare 
 
 Swelling, erythema, and tenderness of lymph nodes (especially pathologically 
involved lymph nodes) are expected effects of treatment with lenalidomide.  First 
line treatment is analgesics (e.g. NSAIDs, acetaminophen, oral narcotics) or 
corticosteroid therapy at the discretion of the treating physician.  Suggested 
corticosteroid dosing is detailed in 5.2.1 above. 
 
 Symptomatic tumor flare alone will not require that lenalidomide be held unless:  
 Symptomatic tumor flare persists beyond 3 days of corticosteroid treatment 
 Treating physician believes it is in the patient’s best interest. 
 
 If lenalidomide is held, therapy should be resumed when tumor flare resolves, or at 
the principal investigator’s discretion. 
 
 
6.3.9 Tumor Lysis Syndrome (NCI CTCAE Grade  > 2) 
 
 Hold (interrupt) lenalidomide dose.  
 
 First episode: When attributable electrolyte abnormalities resolve to Grade ≤ 1, 
restart lenalidomide at the current dose with appropriate TLS prophylaxis.  . 
 
 Subsequent episodes at the same dose level: When attributable electrolyte 
abnormalities resolve to Grade≤ 1, restart lenalidomide at the next lowest dose 
level with appropriate TLS prophylaxis. 
 
 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 on 
Day 3 or Day 4 following re-initiation of lenalidomide and at least every week 
following re-initiation of lenalidomide for 4 consecutive weeks. 
 
6.3.10 Infection 
 
It is imperative that accurate reporting of infectious events occur not only as a secondary 
endpoint of the study, but also so prophylactic therapies (if needed) can be included for 
future patients enrolled.  Infectious toxicity (particularly Grade ≥2 severity) needs to be 
recorded and graded in a standard fashion both during treatment and at least every three 
months following completion of protocol therapy for patients remaining on study.  The 
following information related to all infections must be documented: site of infection (lungs, 
sinus, skin, blood, urine, fever of unknown origin, etc.), causative agent (type of bacteria, 
fungus, virus, etc.) if any identified, specific therapeutic interventions.  All herpes simplex 
and varicella zoster cases should be reported and noted as infectious (not skin) toxicities.   
 

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 Because infections are an expected complication of CLL, infections occurring in 
the absence of hematologic toxicity (i.e those not meeting criteria for neutropenic 
fever) will not require dose reductions. 
 
 For Grade ≥ 3 infection, hold lenalidomide and administer medically appropriate 
therapy.  If toxicity resolves to Grade ≤ 2 within 2 weeks, then resume lenalidomide 
at the same dose level. 
 
 Lenalidomide therapy can continue during an episode of Grade ≤ 2 infection, so 
long as infection is adequately controlled. 
 
6.3.11 Abnormal Menstruation or Pregnancy Test 
 
If a female study patient misses a period, or for abnormal menstrual bleeding or abnormal 
pregnancy test, obtain a serum pregnancy test.  Hold lenalidomide therapy until pregnancy 
is excluded.  Discontinue protocol therapy if pregnancy test is positive. See Section 7.7 for 
further information regarding management and reporting requirements pertaining to 
pregnancy occurring during lenalidomide treatment. 
 
6.3.12 Other Non-Hematologic Toxicity 
 
 In the instance of Grade ≥ 2 lenalidomide-related non-hematologic toxicity on day 
1 of a cycle, delay lenalidomide therapy and monitor at least weekly.  If toxicity 
resolves to Grade ≤ 1 within 2 weeks, then resume lenalidomide at the next lower 
dose level. 
 
 If Grade ≥ 2 lenalidomide-related non-hematologic toxicity occurs during a cycle, 
delay lenalidomide therapy and monitor at least weekly.  If toxicity resolves to 
Grade ≤ 1 within 2 weeks, then resume lenalidomide at the next lower dose level. 
 
 If treatment is delayed for more than 2 weeks, discontinue protocol therapy 
 
6.4 
Intrasubject Escalation 
 
As described previously in 5.1.1, the dose of lenalidomide may be increased to 5 mg/day 
beginning as early as the second treatment cycle if all of the following criteria are met: 
 
• No clinically significant Grade 3 or greater non-hematologic toxicities attributable 
to lenalidomide during the preceding cycle. 
• Any lenalidomide-associated hematologic toxicity has resolved to Grade ≤ 1 
severity. 
• Maintained platelet count >50K at all times during the previous cycle. 
• Maintained ANC >1K at all times during the preceding cycle. 
• Any other drug-related adverse events have resolved to Grade ≤ 1 severity. 
 
Patients not meeting criteria for dose escalation upon beginning the second cycle of 

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33 
lenalidomide can be re-evaluated for dose escalation at the start of subsequent cycles, at 
which time the same criteria will apply.  Dose escalation beyond 5 mg/day will not be 
permitted so as to limit the risk in this patient population who would not otherwise be 
receiving therapy. 
 
If the lenalidomide dose has been reduced for toxicity, dose re-escalation is permitted if 
the patient has tolerated the reduced dose for greater than one cycle.  The patient will 
then be re-evaluated for dose escalation at the beginning of each subsequent cycle of 
therapy according to the parameters detailed above.  If the patient subsequently develops 
toxicity requiring dose reduction, no further attempts at dose escalation will be permitted. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (07.1.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited (via CTEP-AERS) reporting in addition 
to routine reporting. 
 
7.1 
CAEPR for Lenalidomide 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Lenalidomide (CC-5013, NSC 703813) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  
for further clarification. Frequency is provided based on 4081 patients. Below is the CAEPR for 
Lenalidomide (CC-5013). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
                                                                                                                                   Version 2.8, June 27, 20191 
 
 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 

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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Blood and lymphatic system 
disorders - Other 
(pancytopenia) 
 
  
 
Febrile neutropenia 
 
  
 
Hemolysis 
 
  
CARDIAC DISORDERS 
  
 
 
Atrial fibrillation 
  
 
 
Heart failure 
  
 
 
Myocardial infarction2 
  
EAR AND LABYRINTH DISORDERS 
  
 
Vertigo 
 
  
ENDOCRINE DISORDERS 
  
 
 
Hyperthyroidism 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 3) 
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Cataract 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
Constipation 
 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
  
 
Dyspepsia 
 
  
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 3) 
 
Generalized edema 
 
  
 
Non-cardiac chest pain 
 
  
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
 
 
Hepatobiliary disorders - Other 
(cholestasis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
 
 
Anaphylaxis 
  
 
 
Immune system disorders - Other 
(angioedema) 
  
 
 
Immune system disorders - Other 
(graft vs. host disease)3 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
 Infection4 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  

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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Bruising 
 
  
 
Fall 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
 
Blood bilirubin increased 
 
  
 
GGT increased 
 
  
 
Investigations - Other (C-
Reactive protein increased) 
 
  
 
 
Lipase increased 
  
 
Lymphocyte count decreased  
 Lymphocyte count decreased (Gr 4) 
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased  
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hyperglycemia 
 
  
 
Hyperuricemia 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hyponatremia 
 
  
 
Hypophosphatemia 
 
  
 
Iron overload 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
 
Bone pain 
 
  
 
Generalized muscle 
weakness 
 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
 
 
Rhabdomyolysis5 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
 
Leukemia secondary to oncology 
chemotherapy6 
  
 
 
Myelodysplastic syndrome6 
  

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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Neoplasms benign, malignant 
and unspecified (incl cysts and 
polyps) - Other (tumor flare)7 
  
 
 
Neoplasms benign, malignant 
and unspecified (incl cysts and 
polyps) - Other (second primary 
malignancies) 
  
 
 
Treatment related secondary 
malignancy6 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Depressed level of 
consciousness 
 
  
 
Dysesthesia 
 
  
 
Dysgeusia 
 
  
 
Headache 
 
  
 
Paresthesia 
 
  
 
Peripheral motor neuropathy  
  
 
Peripheral sensory 
neuropathy 
 
  
 
 
Stroke2 
  
 
Syncope 
 
  
 
Tremor 
 
  
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
 
Psychiatric disorders - Other 
(mood altered) 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
  
 
 
Erythema multiforme 
  
 
Hyperhidrosis 
 
 Hyperhidrosis (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
 
 
Skin and subcutaneous tissue 
disorders - Other (drug reaction 
with eosinophilia and systemic 
symptoms [DRESS]) 
  
 
Skin and subcutaneous tissue 
disorders - Other (pyoderma 
gangrenosum) 
 
  
 
 
Stevens-Johnson syndrome 
  

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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Toxic epidermal necrolysis 
  
SURGICAL AND MEDICAL PROCEDURES 
  
 
 
Surgical and medical procedures 
- Other (impaired stem cell 
mobilization)8 
  
VASCULAR DISORDERS 
  
 
Hematoma 
 
  
 
Hypertension 
 
  
 
Hypotension 
 
  
 
Peripheral ischemia 
 
  
 
Thromboembolic event9 
 
 Thromboembolic event9 (Gr 3) 
 
Vasculitis 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Myocardial infarction and cerebrovascular accident (stroke) have been observed in multiple myeloma 
patients treated with lenalidomde and dexamethasone. 
 
3Graft vs. host disease has been observed in subjects who have received lenalidomide in the setting of 
allo-transplantation. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5The rare adverse event of rhabdomyolysis has been observed with lenalidomide. The reports of 
rhabdomyolysis were confounded by concurrent use of statins and dexamethasone, concurrent viral and 
bacterial infections, trauma, and serotonin syndrome. Statins, infections, trauma, and serotonin syndrome 
are known risk factors for rhabdomyolysis. 
 
6There has been an increased frequency of secondary malignancies (SPM) including ALL, AML, and 
MDS, and certain other types of cancers of the skin and other organs in multiple myeloma (MM) patients 
being treated with melphalan, prednisone,  and lenalidomide post bone marrow transplant.  The use of 
lenalidomide in cancers other than MM, shows that invasive SPMs occurred in a small number of 
patients.  Patients treated with lenalidomide should be closely followed for the occurance of SPMs. 
 
7Serious tumor flare reactions have been observed in patients with chronic lymphocytic leukemia (CLL) 
and lymphoma. 
 
8A decrease in the number of stem cells (CD34+ cells) collected from patients treated with >4 cycles of 
lenalidomide has been reported. 
 
9Significantly increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), and arterial 
thrombosis has been observed in patients with multiple myeloma receiving lenalidomide with 
dexamethasone. 
 
10Gastrointestinal hemorrhage includes: Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 

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Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
11Gastrointestinal obstruction includes:  Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small 
intestinal obstruction under the GASTROINTESTINAL DISORDERS SOC. 
 
12Osteonecrosis of the jaw has been seen with increased frequency when lenalidomide is used in 
combination with bevacizumab, docetaxel (Taxotere®), prednisone, and zolendronic acid (Zometa®). 
 
NOTE:  While not observed in human subjects, lenalidomide, a thalidomide analogue, caused limb 
abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. 
If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. Pregnancy 
must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable 
methods of contraception. 
 
NOTE: In a trial of first line treatment of patients with chronic lymphocytic leukemia (CLL), single agent 
lenalidomide (CC-5013) increased the risk of death as compared to control arm (chlorambucil). 
 
NOTE: In two randomized trials of patients with multiple myeloma (MM), the addition of MK-3475 
(pembrolizumab) to a thalidomide analog plus dexamethasone, resulted in increased mortality.  
Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody, such as MK-3475 
(pembrolizumab), in combination with a thalidomide analog, such as lenalidomide, is not recommended 
outside of controlled clinical trials. 
 
NOTE:  In a clinical trial in patients with Mantle cell lymphoma (MCL), there was an increase in early 
deaths (within 20 weeks); 12.9% in the lenalidomide (CC-5013) arm vs. 7.1% in the control arm. 
 
 
Adverse events reported on lenalidomide (CC-5013) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that lenalidomide (CC-5013) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(monocytosis); Disseminated intravascular coagulation; Eosinophilia 
CARDIAC DISORDERS - Atrial flutter; Atrioventricular block first degree; Cardiac arrest; Cardiac 
disorders - Other (cardiovascular edema); Cardiac disorders - Other (ECG abnormalities); Chest pain - 
cardiac; Left ventricular systolic dysfunction; Palpitations; Pericarditis; Sinus bradycardia; Sinus 
tachycardia; Supraventricular tachycardia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Cushingoid 
EYE DISORDERS - Dry eye; Flashing lights; Retinopathy 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal mucositis; Ascites; Colonic perforation; 
Dysphagia; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (Crohn's 
disease aggravated); Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other 
(pale feces); Gastrointestinal hemorrhage10; Gastrointestinal obstruction11; Ileus; Mucositis oral; 
Pancreatitis; Rectal mucositis; Small intestinal mucositis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Multi-organ failure 
HEPATOBILIARY DISORDERS - Cholecystitis 
INFECTIONS AND INFESTATIONS - Conjunctivitis; Infections and infestations - Other (opportunistic 
infection associated with >=Grade 2 Lymphopenia); Myelitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Hip fracture; Vascular access 
complication 

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39 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Cholesterol high; Creatinine 
increased; Electrocardiogram QT corrected interval prolonged; INR increased; Investigations - Other 
(hemochromatosis) 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; Hypoglycemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall pain; Joint 
effusion; Muscle weakness lower limb; Neck pain; Osteonecrosis of jaw12 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dysphasia; Edema cerebral; 
Encephalopathy; Intracranial hemorrhage; Ischemia cerebrovascular; Leukoencephalopathy; Memory 
impairment; Nervous system disorders - Other (hyporeflexia); Spinal cord compression; Seizure; 
Somnolence; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Psychosis 
RENAL AND URINARY DISORDERS - Urinary frequency; Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - 
Other (hypogonadism); Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Atelectasis; Bronchopulmonary hemorrhage; Hypoxia; Laryngeal mucositis; Pharyngeal 
mucositis; Pleural effusion; Pulmonary hypertension; Respiratory failure; Tracheal mucositis; Voice 
alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Nail loss; Photosensitivity; Rash 
acneiform; Skin and subcutaneous tissue disorders - Other (Sweet’s Syndrome); Urticaria 
VASCULAR DISORDERS - Hot flashes; Phlebitis; Vascular disorders - Other (hemorrhage NOS) 
 
 
Note: Lenalidomide (CC-5013) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
 

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40 
7.1.1 Adverse event list for PCV13 
 
• Administration site conditions: injection site dermatitis, injection site urticaria, 
injection site pruritus, redness, inflammation or skin discoloration, mass, or local 
hypersensitivity reactions 
 
• Blood and lymphatic system disorders: lymphadenopathy localized to the region of 
the injection site 
 
• Immune system disorders: hypersensitivity reaction including fevers, face edema, 
dyspnea, generalized urticaria, bronchospasm; anaphylactic/anaphylactoid reaction 
including shock  
 
• Skin and subcutaneous tissue disorders: angioneurotic edema, erythema multiforme 
 
• Respiratory: apnea 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized until March 31, 2018 for AE reporting. CTCAE 
version 5.0 will be utilized for AE reporting beginning April 1, 2018. All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the 
CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
•  ‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for 
expedited reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold and 
italicized in the CAEPR (07.1.1). 
 
• Attribution of the AE: 
− 
Definite – The AE is clearly related to the study treatment. 
− 
Probable – The AE is likely related to the study treatment. 
− 
Possible – The AE may be related to the study treatment. 
− 
Unlikely – The AE is doubtfully related to the study treatment. 
− 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
Expedited AE reporting for this study must use CTEP-AERS (Adverse Event Expedited 
Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements” which can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).  These requirements are briefly outlined in the table below (7.3.1). 
 

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41 
A 24-hour notification is to be made to CTEP by telephone at 301-897-7497, only when 
internet connectivity is disrupted.  Once internet connectivity is restored, an AE report 
submitted by phone in must be entered electronically into CTEP-AERS by the original 
submitter at the site. 
 
7.3.1 Expedited reporting guidelines – CTEP-AERS Reporting Requirements for Adverse 
Events that occur within 30 Days1 of the Last Dose of the Investigational Agent on Phase 
2 and 3 Trials 
 
Phase 2 and 3 Trials 
 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
Unex-
pected 
Expected 
Unexpected 
Expected 
Unex- 
pected 
Expected 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
with 
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 
Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
• 
Pregnancy of a female subject or the female partner of a male subject occurring while the subject is on 
lenalidomide or within 4 weeks after the subject’s last dose of lenalidomide are considered expedited 
reportable events.  If the subject is on lenalidomide, it is to be discontinued immediately and the subject is to 
be instructed to return any unused portion of lenalidomide to the Investigator.  The pregnancy must be 
reported via CTEP-AERS within 24 hours of the Investigator’s knowledge of the pregnancy. 
 
The Investigator will follow the pregnant female until completion of the pregnancy, and must report via CTEP-
AERS the outcome as specified below.  The Investigator will provide this information as a follow-up to the initial 
SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., spontaneous 
abortion [any congenital anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal death, 
or congenital anomaly), the Investigator should follow the procedures for reporting the event via CTEP-AERS 
within 24 hours of the Investigator’s knowledge of the event). 
 
Any suspected fetal exposure to lenalidomide must be reported via CTEP-AERS within 24 hours of being 
made aware of the event.  The pregnant female should be referred to an obstetrician/gynecologist experienced 
in reproductive toxicity for further evaluation and counseling. 
 
All neonatal deaths that occur within 30 days of birth should be expeditiously as Grade 4, “Death neonatal” 
under the General disorders and administration SOC.  In addition, any infant death after 30 days that the 
Investigator suspects is related to the in utero exposure to lenalidomide should also be reported. 
 
In the case of a live “normal” birth, the outcome should be reported via CTEP-AERS as soon as the 
information is available. 
 
CTEP-AERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 
Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report 
is required as outlined in the table. 
 
 
 
 
 
 
December 15, 2004 
 

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42 
Note:  All deaths on study require both routine and expedited reporting 
regardless of causality.  Attribution to treatment or other cause must be 
provided. 
 
• Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the 
AE via CTEP-AERS within 24 hours of learning of the event followed 
by a complete CTEP-AERS report within 5 calendar days of the initial 
24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must 
be submitted within 10 calendar days of the investigator learning of the 
event.  
 
• Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be 
reported regardless of attribution and designation as expected or unexpected 
with the exception of any events identified as protocol-specific expedited 
adverse event reporting exclusions.   
 
• Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS if 
the event occurs following treatment with an agent under a CTEP IND. 
 
• All new or secondary malignancies including solid tumors (this includes 
non-melanoma 
skin 
malignancies), 
hematologic 
malignancies, 
Myelodysplastic Syndrome (MDS)/Acute Myelogenous Leukemia (AML) 
and in situ tumors that occur during study treatment and/or during protocol 
specified follow-up periods must be reported via CTEP-AERS regardless 
of attribution. 
 
• Use the NCI protocol number and the protocol-specific patient ID assigned 
during trial registration on all reports. 
 
7.3.2 Protocol-specific expedited adverse event reporting exclusions 
 
None 
 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
through CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 
OSU Institutional Safety Monitoring and Reporting Requirements 
 

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7.5.1 OSU Comprehensive Cancer Center Data and Safety Monitoring Plan 
 
The data and safety monitoring plan will involve the continuous evaluation of safety, data 
quality and data timeliness. Investigators will conduct continuous review of data and 
patient safety at their regular Disease Group meetings (at least monthly) and the discussion 
will be documented in the minutes. The PI of the trial will review toxicities and responses 
of the trial where applicable at these disease center meetings and determine if the 
risk/benefit ratio of the trial changes. Frequency and severity of adverse events will be 
reviewed by the PI and compared to what is known about the agent/device from other 
sources; including published literature, scientific meetings and discussions with the 
sponsors, to determine if the trial should be terminated before completion. Serious adverse 
events and responses will also be reviewed by the OSUCCC Data and Safety Monitoring 
Committee (DSMC). The PI will also submit a progress report biannually for Phase II and 
quarterly for Phase I) that will be reviewed by the committee per the DSMC plan. All 
reportable Serious Adverse Events (SAE) will also be reported to the IRB of record as per 
the policies of the IRB. 
 
7.5.2 OSU Cancer IRB reporting requirements 
 
7.5.2.1 
Reporting procedures 
 
All adverse events will be noted in the study forms. Any unexpected adverse events 
or adverse events Grade ≥2 will be reported immediately to the principal investigator. 
All adverse events will be reported on Form FDA 3500 A (i.e. Med Watch Form). 
 
7.5.2.2 
Reporting to the OSU Cancer IRB 
 
Reporting of adverse events to the OSU Cancer IRB will be performed in accordance 
with FDA regulations. Details are described below. The OSU Event Reporting Form 
should be used to report untoward events that may affect participants in research 
approved by an OSU IRB. Events requiring prompt reporting include adverse events, 
protocol deviations, and other unforeseen problems or findings that suggest 
participants, research staff, or others are placed at greater risk by the research than 
previously expected. These events, classified broadly as unanticipated problems 
involving risks to the subjects or others, must be reported promptly to the IRB. 
Unanticipated problems can occur in any type of research and may involve physical, 
psychological, social, legal, or economic harms. 
 
7.5.2.3 
Events requiring prompt reporting 
 
Events that may represent unanticipated problems involving risks to subjects 
or others and therefore require prompt reporting include the following: 
 
• Adverse events or injuries that are serious, unexpected, and related 
• Events requiring prompt reporting according to the protocol or sponsor 

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44 
• Data and Safety Monitoring Board (DSMB) reports, interim analyses, or other 
oversight committee/monitoring reports altering the risk/benefit profile 
• These events should be promptly reported (see below), regardless of whether 
they occur during the study, after study completion, or to a participant who has 
withdrawn from or completed study participation 
 
7.5.2.4 
Time frame for reporting 
 
All internal events (those occurring in research at OSU or at a site under an OSU IRB’s 
jurisdiction) as described above should be reported within 10 days of the Investigator’s 
or research staff member’s learning of the event. Events resulting in temporary or 
permanent interruption of study activities by the Investigator or sponsor to avoid 
potential harm to participants should be reported immediately (within 48 hours) 
whenever possible. 
 
7.5.2.5 
Additional information 
 
Related adverse events and other problems involving risk that do not meet the 
reporting requirements and do not represent potential unanticipated problems 
involving risks to subjects or others should be reported in summary form at the time 
of continuing IRB review. However, any problem or adverse event that an 
investigator believes could influence the safe conduct of the research should be 
reported promptly. 
 
7.6 
Celgene Drug Safety Contact Information 
 
Celgene Corporation 
Worldwide Drug Safety Surveillance (WWDSS) 
86 Morris Avenue 
Summit, N.J. 07901 
 
Toll Free: 
(800)-640-7854 
Phone: 
(908) 673-9667 
Fax: 
(908) 673-9115 
e-mail: 
drugsafety@celgene.com 
 
7.7 
Pregnancy 
 
• Pregnancy Reporting:  
 
Females of Childbearing Potential: 
• 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject or the partner of a male 
subject occurring while the subject is on lenalidomide or within 28 days after 
the subject’s last dose, are considered immediately reportable events. 
Lenalidomide is to be discontinued immediately. The pregnancy, suspected 

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45 
pregnancy, or positive pregnancy test must be reported via CTEP-AERS as a 
grade 4 event under: SOC pregnancy, puerperium and perinatal conditions; 
adverse event: pregnancy, puerperium and perinatal conditions-other, 
fetal exposure. 
o 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 make an amendment to the initial pregnancy report 
immediately regarding the outcome of the pregnancy and neonatal status 
(either normal or abnormal outcome). 
• 
If the outcome of the pregnancy was abnormal (including spontaneous or 
therapeutic abortion, fetal demise and congenital abnormalities), the 
Investigator should report the abnormal outcome as an amendment to the 
initial pregnancy report as soon as the as the Investigator has knowledge of 
the outcome.  
• 
All neonatal deaths and neonatal complications that occur within 28 days of 
birth should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC., as an amendment to the initial 
pregnancy report. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the lenalidomide 
should also be reported as an amendment within 24 hours of the Investigator’s 
knowledge of the event. 
 
 
Male Subjects 
• 
If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taking lenalidomide should notify the Investigator, 
and the pregnant female partner should be advised to call her healthcare 
provider immediately. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 7.1. 
 
NOTE: 
Before lenalidomide is dispensed, patients must have 1) a negative pregnancy test (if applicable) 
and 2) be counseled by a trained counselor. Pharmacists may be trained counselors (see 
Lenalidomide Counselor Program Site Counselor Identification Form in the protocol). The 
counseling requirements for investigational-use lenalidomide are separate from the RevAssist 
program. Only a 28-day supply may be dispensed to a patient at one time. 
 
 

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46 
8.1 
Lenalidomide (Revlimid, CC-5013 NSC#703813) 
 
Lenalidomide, 3-(4’aminoisoindoline-1’-one)-1-piperidine-2, 6-dione, is an 
immunomodulatory agent.  The Chemical Abstract Service (CAS) registry number for 
lenalidomide is 191732-72-6.  Lenalidomide is also known by the earlier clinical code 
names CC-5013 and CDC-501.  Lenalidomide has an empirical formula of C13H13N3O3 
and a molecular weight of 259.25.  It is an off-white to pale-yellow solid. 
 
8.1.1 Mode of Action:  Lenalidomide, a thalidomide analog, is an immunomodulatory agent 
with a spectrum of activity that is not fully characterized.  In vitro, it inhibits secretion of 
the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 and increases secretion of the 
anti-inflammatory cytokine IL-10.  It also induces T-cell proliferation, IL-2 and IFN-γ 
production in vitro.  
 
8.1.2 How Supplied:    Celgene supplies and CTEP, NCI, DCTD distributes lenalidomide 2.5 
mg (size 4) and 5 mg (size 2) hard gelatin capsules in tamper-evident, child-resistant, 
opaque, high density polyethylene (HDPE) bottles with HDPE caps. Bottles contain 100 
capsules per container.  
 
 The capsules also contain anhydrous lactose, microcrystalline cellulose, 
croscarmellose sodium, and magnesium stearate.  
 
 
8.1.3 Storage:  The capsules should be stored at room temperature (15-30°C) away from 
moisture and direct sunlight.  At the study site, all investigational study drugs will be 
stored in a locked, safe area to prevent unauthorized access. 
 
8.1.4 Stability:  Refer to the package labeling for expiration date. Lenalidomide stability is 
adequate for at least 28 days after transferring to a pharmacy vial. 
 
  
8.1.5 Route of Administration: Take lenalidomide by mouth with or without food. Do not 
crush, chew or open capsules. 
 
 
8.1.6 Dispensing: Only a 28-day supply may be dispensed at one time. Sites may not mail 
lenalidomide to patients. 
 
Patient Care Implications and Counseling: 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. 

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47 
Definition of female 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). 
 
Before starting study drug:   
Female Subjects:   
• FCBP must have two negative pregnancy tests (minimum sensitivity of 25 
mIU/mL) prior to starting study drug.  The first pregnancy test must be 
performed within 10-14 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 subject may not receive study drug until the Investigator has 
verified that the results of these pregnancy tests are negative. 
 
 
Male Subjects:   
• Must agree to use a latex condom during sexual contact with females of 
childbearing potential while participating in the study and for at least 28 days 
following discontinuation from the study even if he has undergone a 
successful vasectomy.  
 
All Subjects: 
• Only enough lenalidomide for one cycle of therapy may be dispensed with 
each cycle of therapy.  
 
• If pregnancy or a positive pregnancy test does occur in a study subject or 
the partner of a male study subject during study participation, lenalidomide 
must be immediately discontinued. 
 
Counseling 
• In investigational studies where lenalidomide is supplied by the 
NCI, patients will be counseled by a qualified healthcare professional 
(including but not limited to, nurses, pharmacists and physicians).  Two 
healthcare professionals at each site will be trained by Celgene in 
requirements specific to counseling of subjects (investigators cannot counsel 
patients as part of this requirement). Refer to specific protocol sections for 
more information about training requirements. 
 
• 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.  This step 

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48 
will be documented with a completed Lenalidomide Education and 
Counseling Guidance Document (Appendix D) and no drug will be dispensed 
until this step occurs. Counseling includes verification with the female patient 
that required pregnancy testing was performed and results were negative. 
A Lenalidomide Information Sheet (Appendix E) will be supplied with each 
medication dispense. 
 
 
 
8.1.7 Females of childbearing potential should not handle the clinical dosage forms unless 
they are wearing gloves. 
 
 
8.1.8 Drug dispensing requirements 
 
In investigational studies, lenalidomide will be dispensed by a healthcare professional. 
The healthcare professional will counsel subjects prior to medication being dispensed to 
ensure that the subject had complied with all requirements including use of birth control 
and pregnancy testing.  This step will be documented with a completed Education and 
Counseling Guidance Document (Appendix D), and no drug will be dispensed until this 
step occurs. Counseling includes verification with the patient that required pregnancy 
testing was preformed and results were negative.  A Lenalidomide Information Sheet 
(Appendix E) will be supplied with each medication dispense. 
 
8.1.9 Potential Drug Interactions:  Periodic monitoring of digoxin levels is recommended 
during coadministration with lenalidomide.  Digoxin levels were slightly higher when 
digoxin was administered with lenalidomide in a clinical study.  There was no effect on 
lenalidomide pharmacokinetics.  
Warfarin and lenalidomide may be co-administered without additional monitoring.  No 
pharmacokinetic or pharmacodynamic interactions were observed between lenalidomide 
and warfarin.  
 
8.1.10 Eligibility and screening 
The Investigator is responsible for keeping a record of all subjects who sign an Informed 
Consent Form for entry into the study.  All subjects will be screened for eligibility.  
Screening procedures are outlined in Section 2, Schedule of Study Assessments and 
unless otherwise specified, must take place within 14 days prior to initiation of therapy. 
Screening pregnancy tests (sensitivity of at least 25 mIU/mL) for women of child-bearing 
potential must occur 10 to 14 days prior and again ≤  24  hours  from  initiation  of  
therapy. 
 
8.1.11 Agent ordering 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The eligible 
participating investigators at each participating institution must be registered with CTEP, 

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49 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), 
NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are 
several participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead participating 
investigator at that institution. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status. For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any 
time. Refer to the PMB’s website for specific policies and guidelines related to 
agent management. 
8.1.12 Agent accountability 
 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
8.1.13  Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application. Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status, 
a “current” password and active person registration status. Questions about IB access 
may be directed to the PMB IB Coordinator via email. 
 
8.1.14 Adverse events with lenalidomide 
The most frequently reported adverse events reported during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of presumed 
relationship to study medication include: anemia, neutropenia, thrombocytopenia and 
pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, rash, 
itching,  infections,  sepsis, pneumonia,  UTI,  Upper  respiratory  infection, cellulitis, 
atrial fibrillation,  congestive heart failure, myocardial infarction, chest pain, 
weakness, hypotension,  hypercalcemia, hyperglycemia, back pain, bone pain, 
generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, 
pleural effusion, pulmonary embolism, deep  vein thrombosis, CVA, convulsions, 
dizziness, spinal cord compression, syncope, disease progression, death not specified 
and fractures. 
 
 
Complete and updated adverse events are available in the Investigational Drug Brochure 
and the IND Safety Letters. 
 

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50 
8.1.15 Useful Links and Contacts 
 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
 
8.2 
13-valent Protein-Conjugated Pneumococcal Vaccine (Prevnar 13, PCV13) 
 
8.2.1 Supplier(s) 
 
PCV13 is manufactured by Wyeth Pharmaceuticals and is commercially available. 
 
8.2.2 Description 
 
PCV13 is a sterile suspension of saccharides of the capsular antigens of Streptococcus 
pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, individually 
linked to non-toxic diphtheria CRM197 protein.  Each serotype is grown in soy peptone 
broth.  The individual polysaccharides are purified through centrifugation, precipitation, 
ultrafiltration, and column chromatography.  The polysaccharides are chemically activated 
to make saccharides, which are directly conjugated by reductive amination to the protein 
carrier CRM197, to form the glycoconjugate.  CRM197 is a nontoxic variant of diphtheria 
toxin isolated from cultures of Corynebacterium diphtheriae strain C7 (β197) grown in a 
casamino acids and yeast extract-based medium.  CRM197 is purified through ultrafiltration, 
ammonium sulfate precipitation, and ion-exchange chromatography.  The individual 
glycoconjugates are purified by ultrafiltration and column chromatography and analyzed 
for saccharide to protein ratios, molecular size, free saccharide, and free protein. 
 
The individual glycoconjugates are compounded to formulate PCV13.  Potency of the 
formulated vaccine is determined by quantification of each of the saccharide antigens and 
by the saccharide to protein ratios in the individual glycoconjugates.  Each 0.5 mL dose of 
the vaccine is formulated to contain approximately 2.2 μg of each of Streptococcus 
pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F saccharides, 4.4 μg 
of 6B saccharides, 34 μg CRM197 carrier protein, 100 μg polysorbate 80, 295 μg succinate 
buffer, and 125 μg aluminum as aluminum phosphate adjuvant. 
 

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51 
8.2.3 Packaging 
 
PCV13 is supplied as 0.5 mL single-dose pre-filled syringes for intramuscular injection, 
with 10 doses per package (NDC 0005-1971-02).  The vial stopper and the tip cap and 
rubber plunger of the pre-filled syringe do not contain latex. 
 
8.2.4 Storage and stability 
 
The product is a suspension containing an adjuvant and should be vigorously shaken prior 
to use.  Unopened containers should be stored at 2-8oC and unused portions discarded.  
PCV13 should not be frozen and should be discarded if frozen. 
 
8.2.5 Contraindications 
 
Known hypersensitivity to PCV7, PCV13, or to any of the components of the conjugate 
vaccine. 
 
8.2.6 Adverse effects 
 
Local reactions include erythema, induration, and tenderness.  Other adverse reactions 
include fever, irritability, drowsiness, restless sleep, decreased appetite, vomiting, diarrhea, 
urticaria-like rash, lymphadenopathy localized to the region of the injection site, 
hypersensitivity reactions including face edema, dyspnea, bronchospasm, and 
anaphylactoid reactions, angioneurotic edema, and erythema multiforme. 
 
8.2.7 Administration guidelines 
 
Since this product is a suspension containing an adjuvant, it should be vigorously shaken 
immediately prior to use to obtain a homogenous, white suspension in the vaccine 
container.  If it cannot be resuspended, the product should not be used.  It should not be 
used if particulate matter or discoloration is found on visual inspection. It should not be 
mixed with any other vaccines/products in the same syringe. A 0.5 ml dose is given 
intramuscularly in the deltoid muscle of the upper arm.  It should not be administered 
intravenously, intradermally, or subcutaneously. Patients will receive 2 doses of PCV13 
administered 8 weeks apart.  In Arm A (Concurrent), vaccine will be administered on Day 
1 of cycles 3 and 5.  In Arm B (Sequential), patients will be vaccinated on Day 1 of cycles 
1 and 3.   
 
 
9. CORRELATIVE/SPECIAL STUDIES 
 
The rich biology associated with lenalidomide administration in CLL offers the 
opportunity to perform detailed correlative studies.  These studies are outlined below.  
Outside of studies outlined in Section 9.1 which are related to the study primary endpoint, 
collection times or samples may be deleted or altered (with no excess draws or collection 
from this baseline) if deemed to be impractical.  If this occurs, an amendment will be 

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52 
submitted related to this but accrual to the study will not be interrupted while this is under 
review. 
 
Study end points have been met, therefore all research sample collection will cease upon 
approval of protocol version 24.  Given the low number of patients continuing to receive 
treatment additional research samples will not be of scientific interest. 
 
9.1 
Anti-pneumococcal Antibody Levels 
 
Specimens collected for anti-pneumococcal antibody levels will be processed in the OSU 
CLL Experimental Therapeutics Laboratory prior to shipment to a contract laboratory 
(Mayo Medical Laboratories, Rochester, MN) where type-specific antibody levels will be 
measured. 
 
9.1.1 Collection of Specimens 
In Arm A (Concurrent), serum antibody levels specific to each of 7 pneumococcal 
antigens contained in the PCV13 vaccine will be assessed at Cycle 1 Day 1 (baseline), 2 
months following initiation of lenalidomide therapy (Cycle 3 Day 1), 2 months after 
initial vaccination (Cycle 5 Day 1) and 1 month after second vaccination (Cycle 6 Day 1) 
and every 6 months thereafter for patients remaining in follow-up.  For those in Arm B, 
titers will be assessed at Cycle 1 Day 1(baseline), 2 months after initial vaccination 
(Cycle 3 Day 1), 1 month after second vaccination (Cycle 4 Day 1), and every 6 months 
thereafter. 
 
9.1.2 Handling of Specimens 
One 5 mL of blood will be collected in plain red top tubes, mixed 5 times and allowed to 
clot 30 minutes.  Samples will then be spun at 1,200 x g for 10 minutes to isolate serum.  
Serum in three separate vials will be stored in -80°C freezer. Each sample will be labeled 
with the protocol number, patient number, reference time point relative to the protocol, 
date and time the sample was obtained, and date and time the sample was placed in the -
80°C freezer until further analysis. 0.5 mL of refrigerated serum sent to the Mayo 
Medical Laboratories, Rochester, MN, as outlined in the laboratory manual. Additional 
serum remaining may be used for other tests related to understanding mechanism of 
action/response of lenalidomide or biology of CLL. 
 
9.1.3 Sample and Data Analysis. 
IgG antibodies to Streptococcus pneumoniae serotypes are measured by microsphere 
photometry. Purified pneumococcal polysaccharides coupled covalently to polystyrene 
microspheres bind IgG antibodies in patients' sera during the first incubation. After 
incubation, the microspheres are washed and incubated with phycoerythrin conjugated 
antihuman IgG antibody. The concentration of IgG antibodies to each polysaccharide is 
determined by comparison to dose-response curves calculated from serial dilutions of a 
serum pool from immunized adults with known concentrations of antibodies to each 
polysaccharide (secondary standard). The secondary standard is traceable to a standard 
reference preparation (FDA 89-SF) that contains known concentrations of IgG antibodies 
to 23 different Streptococcus pneumoniae serotypes. Dose-response curves prepared from 

NCI Protocol #: 8834 
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53 
serial dilutions of the secondary standard parallel the dose-response curves of the primary 
reference preparation for all polysaccharides. (Jacob GL, Homburger HA:  Simultaneous 
Quantitative Measurement of IgG Antibodies to Streptococcus Pneumoniae Serotypes by 
Microsphere Photometry. Poster Presentation; AAAAI 60th Annual Meeting, March 19-
23, 2004. San Francisco, CA. J Allergy Clin Immunol, Vol. 113, No 2,  [Abstract 1049, 
pS288] 2004; Plikaytis BD, Holder PF, Pais LB, et al: Determination of parallelism and 
nonparallelism in bioassay dilution curves. J Clin Microbiol 1994;2441-2447; Plikaytis 
BD, Goldblatt D, Frasch CE, et al:  An analytical model applied to a multicenter 
pneumococcal enzyme-linked immunosorbent assay study. J Clin Microbiol 
2000;38:2043-2050) 
 
9.2 
Pharmacodynamic Studies: Immunoglobulins and Anti-Tumor Antibodies 
 
Pharmacodynamic studies concerning serum immunoglobulin and anti-tumor antibody 
levels will be performed at the OSU CLL Experimental Therapeutics Laboratory in 
collaboration with Dr. Christoph Rader of the NCI intramural research program. 
 
9.2.1 Collection of Specimens 
For patients treated on Arm A (patients who receive lenalidomide beginning Cycle 1, 
collection of blood samples will occur on Days 1 (baseline), and Day 1 of 3, 5, 7 and 
every 6 months subsequently. For patients treated on Arm B (patients who receive 
lenalidomide beginning with Cycle 4), samples will be collected at Day 1 of Cycle 1 
(baseline), Day 1 of Cycles 4, 5, 7, and every 6 months subsequently. 
 
9.2.2 Handling of Specimens 
Two x 5 mL of blood will be collected in plain Red top tubes, mixed 5 times and allowed 
to clot 30 minutes.  Samples will then be spun at 1,200 x g for 10 minutes to isolate 
serum.  Serum in three separate vials will be stored in -80°C freezer. Each sample will be 
labeled with the protocol number, patient number, reference time point relative to the 
protocol, date and time the sample was obtained, and date and time the sample was 
placed in the -80°C freezer until further analysis.  
 
9.2.3 Sample and Data Analysis. 
The samples will be analyzed in batches to assess quantitative total and vaccine specific 
immunoglobulin levels as outlined below. Levels of immunoglobulin levels over time will 
be correlated with the ability of lenalidomide to up-regulate CD154 on CLL cells and 
pharmacokinetics of lenalidomide. 
 Anti-IgG1, IgG2, IgG3, IgG4, IgM, and IgA will be determined from serum at 
baseline and every 6 months thereafter on select patients for whom reversal of 
hypogammaglobulinemia occurs.     
 Anti-ROR1 antibody levels: Tumor-specific anti-ROR1 antibody titers will be 
determined by ELISA in serum at baseline and every 6 months thereafter. 
Development of ROR1 antibodies will be correlated with the ability to up-regulate 
CD154 on CLL cells and pharmacokinetics of lenalidomide 
 Anti-CLL tumor antibody levels: Tumor-specific antibody titers will be determined 

NCI Protocol #: 8834 
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54 
by an adapted flow cytometry assay from serum at baseline and every 6 months 
thereafter.  Development of anti-CLL antibodies will be correlated with the ability to 
up-regulate CD154 on CLL cells and pharmacokinetics of lenalidomide In patients 
developing such antibodies, normal B-cells derived from these patients will be 
isolated for identification of relevant target antigens. This will be done in 
collaboration with Dr. Christoph Radar. 
 
9.3 
Lenalidomide Pharmacokinetics  
 
Pharmacokinetic evaluations for lenalidomide will be conducted in collaboration with the 
Pharmacoanalytical Shared Resource at OSU. 
 
9.3.1 Collection of Specimens.  
 
Arm A: For patients treated on Arm A (patients who will receive lenalidomide during 
cycles 1 and 2), pharmacokinetic assessments of lenalidomide will occur during days 1 
and 2 of cycle 2. Samples will be collected at the following time points: prior to dosing 
(time 0), 0.5, 1, 2, 3, 4.5, and 6 hours after dose administration on day 1 of cycle 2. An 
additional sample will be obtained prior to lenalidomide ingestion on day 2 of cycle 2 
(i.e. 24 hours after the dose is ingested on day 1).   
 
Arm B: For patients in Arm B (patients who receive lenalidomide beginning in cycle 4) 
PK sampling will occur during days 1 and 2 of cycle 5. The sampling times will be 
consistent with those in Arm A and comprise the following time points: prior to dosing 
(time 0), 0.5, 1, 2, 3, 4.5, and 6 hours after dose administration on day 1 of cycle 5. An 
additional sample will be obtained prior to lenalidomide ingestion on day 2 of cycle 5 
(i.e. 24 hours after the dose is ingested on day 1).   
 
9.3.2 Handling of Specimens.   
 
Four mL of blood will be collected in EDTA (purple top) tubes, placed on ice and 
immediately centrifuged at 1,200 x g for 10 minutes to isolate plasma. Plasma will be 
frozen in two separate vials and stored in a -20°C freezer. Each sample will be labeled with 
the protocol number, patient number, reference time point relative to the protocol, date and 
time the sample was obtained, and date and time the sample was placed in the -20°C 
freezer.  
 
 
9.3.3 Sample and Data Analysis. 
 
The samples will be analyzed in batches to assess plasma drug concentrations, the plasma 
drug concentration-time profile (AUC), volume of distribution (Vss), clearance (CL), and 
half-life using liquid chromatographic/mass spectrometry (LC/MS) according to 
previously described methods.67 Comparisons of PK data from patients treated on Arm A 

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55 
vs. Arm B will be made to assess possible PK alterations due to PCV13 administration. 
Additional comparisons will be made between patients who received dexamethasone 
treatment on cycles 1 (Arm A) or 5 (Arm B) to identify potential interactions between 
lenalidomide and dexamethasone due to steroid-induced induction of MDR1 or other 
lenalidomide clearance mechanisms. 
 
9.4 
Pharmacodynamics: Cytokines  
9.4.1 Collection of Samples: For patients treated on Arm A (patients who receive 
lenalidomide beginning Cycle 1), collection of blood samples will occur on Days 1 
(baseline), 3 and 8 of the Cycle 1 and Day 1 of Cycles 2, 3, 5, 7 and every 6 months 
subsequently. For patients treated on Arm B (patients who receive lenalidomide 
beginning with Cycle 4) samples will be collected at Day 1 of Cycle 1 (baseline), Day 1 
of Cycles 4, 5, 7 and every 6 months subsequently. 
 
9.4.2 Handling of Samples:  
Venous whole blood (approximately 10 mL) should be drawn into two 5-mL potassium 
EDTA (lavender-top) vacutainers.  Samples will then be spun at 1,200 x g for 10 minutes 
to isolate plasma.  Plasma in three separate vials will be stored in -80°C freezer. Each 
sample will be labeled with the protocol number, patient number, reference time point 
relative to the protocol, date and time the sample was obtained, and date and time the 
sample was placed in the -80°C freezer until further analysis.  
 
9.4.3 Sample and Data Analysis:  
The samples will be analyzed in batches to assess cytokine (such as IL-6, TNF-α, VEGF, 
bFGF) and soluble chemokines will be examined by a multiplex flow cytometry assay or 
ELISA.  Other cytokines, chemokines, or soluble factors may be assessed on residual 
material not used for these studies.   These studies will be done in the CLL experimental 
Therapeutics Laboratory 
 
9.5 
Flow Cytometry B-, T-, and NK-cell subsets and activation status 
 
These studies will be performed at the OSU CLL Experimental Therapeutics Laboratory.  

NCI Protocol #: 8834 
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56 
9.5.1 Collection of Specimens  
For patients treated on Arm A (patients who receive lenalidomide beginning Cycle 1), 
collection of blood samples will occur on Days 1 (baseline), 3 and 8 of the Cycle 1 and 
Day 1 of Cycles 3, 5, 7 and every 6 months subsequently. For patients treated on Arm B 
(patients who receive lenalidomide beginning with Cycle 4) samples will be collected at 
Day 1 of Cycle 1 (baseline), Day 1, 3, and 8 of Cycle 4, Day 1 of Cycle 5, 7, and every 6 
months subsequently. 
 
9.5.2 Handling of Specimens  
One x 5mL of blood will be collected in sodium heparin containing green top tube (Flow 
cytometry).   Each sample will be labeled with the protocol number, patient number, 
reference time point relative to the protocol, date and time the sample was obtained.  The 
heparin green top tube will be transported at room temperature to the flow cytometry 
laboratory.   
 
9.5.3 Sample and Data Analysis.  
Changes in subsets and activation status of B-, T-,and NK lymphocytes in peripheral 
blood following lenalidomide therapy will be evaluated using multiparametric flow 
cytometry immune modulation panel at OSU.  Lymphocyte CD4, CD8, T-regulatory, and 
NK cell subsets will be enumerated and markers of activation status will be characterized 
for each.   
 
CLL cell activation studies: B-cell activation will be further characterized by 
upregulation of CD154 as the primary measure (based upon our data), along with CD40, 
CD80, CD69, and CD86 by flow cytometry.  Additionally, we will measure serial 
changes in IL-21 receptor expression on CLL cells which we recently have shown is up-
regulated by lenalidomide.  Change in CD154 expression will be correlated with 
pharmacokinetics, immune, and clinical response.  
 
9.6 
Pharmacodynamic Studies: T-cell Function and Epigenetic Changes in CLL Cells  
 
9.6.1 Collection of Specimens  
 
For patients treated on Arm A (patients who receive lenalidomide beginning Cycle 1), 
collection of blood samples will occur on Days 1 (baseline), 3 and 8 of the Cycle 1 and 
Day 1 of Cycles 2, 3, 5, 7 and every 6 months subsequently. For patients treated on Arm B 
(patients who receive lenalidomide beginning with Cycle 4) samples will be collected at 
Day 1 of cycle 1 (baseline), Day 1, 3, and 8 of cycle 4, Day 1 of cycle 5, 6, 7, and every 6 
months subsequently. 
 
9.6.2 Handling of Specimens  
 
Two x 10mL of blood will be collected in sodium heparin containing green top tube (Flow 
cytometry).   Each sample will be labeled with the protocol number, patient number, 
reference time point relative to the protocol, date and time the sample was obtained.   
 

NCI Protocol #: 8834 
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57 
9.6.3 Sample and Data Analysis.  
 
T-cell Functional activation studies: CRM197 specific T cells numbers and frequency 
will be evaluated by flow cytometry.  CD4 cell production of specific cytokines will be 
assessed.  Other T-cell dependent activation studies toward primary tumor cells will be 
performed including ELISPOT and T-cell synapse studies as previously reported.7  These 
will be done in the CLL experimental Therapeutics Laboratory.   
 
Activation and Epigenetic Changes in CLL Cells: Activation and epigenetic studies will 
be performed in the OSU CLL Experimental Therapeutics Laboratory.   Tumor cells will 
be isolated from peripheral blood by ficoll density gradient centrifugation using Rosette-
Sep reagent (Stem Cell Technologies, Vancouver BC). Cells will be washed and counted, 
and histones acid-extracted from 5x107 cells as we described previously.[68]  Histones will 
be analyzed by mass spectrometry according to our published procedures [69]  Activation 
studies will be performed using methods previously published by our group.[70] Other 
studies related to understanding mechanism of action of lenalidomide, CLL biology, or 
predicting response to lenalidomide may be performed on remaining material. 
 
9.7 
Correlative Studies Prioritization 
 
Studies 9.1-9.4 rely upon serum or plasma for their analyses.  Adequate sample volume 
has been requested to perform the studies outlined.  Studies 9.5 and 9.6 rely upon adequate 
tumor and immune cell subsets.  Priority will be given to the immune subset analysis by 
flow cytometry; next activation studies, then T cell function, and epigenetics changes based 
upon the number of CLL cells available at each sample time point. 
 
 
10. STUDY CALENDAR 
 
Screening evaluations including history and physical examination and all laboratory 
studies are to be conducted within 14 days prior to the start of protocol therapy. CT 
scans of the chest, abdomen and pelvis will be completed within 6 weeks and bone 
marrow biopsy and aspirate (optional) are to be completed within 12 weeks prior to the 
start of therapy and should include evaluation for myelodysplasia. Visits Cycle 7+ have 
a +/- 7 day visit window. Follow-Up visits have a +/- 14 day visit window. Additional 
required data are summarized in the study calendar.

NCI Protocol #: 8834 
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58 
Schedule of Study Assessments: Arm A (Concurrent) 
 
 
Procedure 
Screening 
Cycle 1 & 2 
 
Cycle 
 3 
Cycle  
4 
Cycle 
 5 
Cycle 
6 
Cycle 7+ 
End of 
Therapyo 
Follow-
Upp 
W1 
W2 
W3 
W4 
Clinical Assessment 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Statusb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Interval infection historyc 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Perform Drug Accountabilityd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Education and Counseling e 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
Response assessmentn 
 
 
 
 
 
X 
 
X 
 
Xn 
X 
X 
Laboaratory Studies and Procedures 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete blood countm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistriesf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
Quantitative serum immunoglobulins 
X 
 
 
 
 
X 
 
X 
 
Every 6 mo 
Xq 
X 
Direct and indirect antiglobulin test 
X 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testingg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bone marrow biopsyh 
Optional 
 
 
 
 
 
 
 
 
 
X 
 
Risk stratification studiesi 
X 
 
 
 
 
 
 
 
 
 
 
 
CT scans r 
X 
 
 
 
 
 
 
 
 
 
 
 
Anti-pneumococcal antibody titers 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
Treatment 
Allopurinolj 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Thromboprophylaxisk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense Lenalidomidel 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
Lenalidomide 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PCV13 administration 
 
 
 
 
 
X 
 
X 
 
 
 
 
Correlative Studies 
Pharmacokinetic Studiess 
 
C2 D1,2 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic Studiest 
X 
C1 D1,3 
C2 D1 
C1 D8 
 
 
X 
 
X 
 
 
 
 

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Version Date: March 15, 2024 
 
59 
Schedule of Study Assessments: Arm B (Sequential) 
 
Procedure 
Screening 
Cycle 
1  
Cycle 
2 
Cycle 
3 
Cycle 4 & 5 
Cycle 
6 
Cycle 7+ 
End of 
Therapyo 
Follow-
Upp 
W1 
W2 
W3 
W4 
Clinical Assessment 
Informed Consent 
X 
 
 
 
 
 
  
 
 
 
 
 
Physical Examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Statusb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Interval infection historyc 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Perform Drug Accountabilityd 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Education and Counseling e 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Response assessmentn 
 
 
 
 
C5 
 
 
 
 
Xn 
X 
X 
Laboaratory Studies and Procedures 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete blood countm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistriesf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
Quantitative immunoglobulins 
X 
X 
 
X 
X 
 
 
 
 
Every 6 mo 
Xq 
X 
Direct and indirect antiglobulin 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testingg 
X 
 
 
 
Xg 
X 
X 
X 
X 
X 
X 
 
Bone marrow biopsyh 
Optional 
 
 
 
 
 
 
 
 
 
X 
 
Risk stratification studiesi 
X 
 
 
 
 
 
 
 
 
 
 
 
CT scansr 
X 
 
 
 
 
 
 
 
 
 
X 
 
Anti-pneumococcal antibody titers 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Treatment 
Allopurinolj 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Thromboprophylaxisk 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Dispense Lenalidomidel 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Lenalidomide 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
PCV13 administration 
 
X 
 
X 
 
 
 
 
 
 
 
 
Correlative Studies 
Pharmacokinetic Studiess 
 
 
 
 
C5 D1,2 
 
 
 
 
 
 
 
Pharmacodynamic Studiest 
X 
X 
 
 
C4 D1,3 
C5 D1 
C4 D8 
 
 
X 
 
 
 

NCI Protocol #: 8834 
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60 
 
 
a.  
Physical examination should include vitals signs, weight, general physical examination (including neurologic examination), measurement of liver and spleen   
span in centimeters below the costal margin in the anterior axillary line, and bi-dirmensional measurement of cervical, supraclavicular, axillary, and inguinal 
nodes. 
b.  
See Appendix A. 
c.  
See 6.3.10 for required information to be documented for each episode of infection. 
d.  
Patient medication diary is reviewed to assess patient compliance on the first day of each cycle in which lenalidomide is administered. 
e.   
The Lenalidomide Education and Counseling Guidance Document (Appendix D) must be completed and signed by a trained counselor at the participating 
site prior to each dispensing of lenalidomide treatment.   A copy of this document must be maintained in the patient records. The Lenalidomide Information 
Sheet (Appendix E) will be given to each patient receiving lenalidomide treatment. The patient must read this document prior to starting lenalidomide study 
treatment and each time they receive a new supply of study drug. 
f.  
Serum chemistries should include: comprehensive metabolic panel, phosphate, uric acid, and LDH. 
g.  
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 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 study treatment (including breaks in treatment); 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 study 
treatment (including breaks in treatment), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix C: 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods). 
h.  
Unilateral bone marrow biopsy and aspirate will be obtained at end of treatment.  In addition to routine pathology, aspirate samples should be studied for, 
interphase cytogenetics, standard CLL FISH panel, CpG stimulated karyotype, and flow cytometry.  If patients decline bone marrow biopsy at end of study , 
these same studies should be done on peripheral blood.  If patients demonstrate anti-ROR1 antibody response, a research bone marrow aspirate may be 
done every 6 months to isolate normal B-cells for correlative studies.  
i. 
 Risk stratification studies will include serum β2-microglobulin in addition to tests performed on the screening bone marrow biopsy specimen: IgVH 
mutational analysis (unless already known), interphase cytogenetics, stimulated karyotype and standard CLL FISH panel. 
j.  
Allopurinol should be administered beginning 3 days before first lenalidomide administration and continued through the first cycle of lenalidomide treatment 
in its entirety.  Allopurinol can be continued during subsequent cycles at the treating physician’s discretion. 
k. 
 Thromboprophylaxis should begin with lenalidomide in patients at high-risk for venous or arterial thromboembolism (see 5.2.3). 
l.  
Only enough lenalidomide for 28 days or one cycle of study treatment (whichever is shorter) may be provided to the patient each cycle. 
m. 
 CBC is checked on D1 and D8 during the first cycle of lenalidomide exposure and during the second cycle and/or any subsequent cycle in which the dose 
of lenalidomide has been escalated. CBC should be checked weekly during any subsequent cycle in which the dose of lenalidomide has been reduced for 
hematologic toxicity. 
n.  
Response is assessed clinically (CBC, physical examination) after every 2 cycles of lenalidomide treatment beginning with Cycle 3 (Arm A) or Cycle 5 (Arm 
B), respectively.  For patients meeting clinical criteria for CR for ≥ 2 months, bone marrow biopsy and CT scans should be performed to confirm response.  
o.  
The End of Therapy visit is defined as that occurring after 24 cycles.  Patients discontinuing treatment at other times secondary to toxicity, progression, or 
preference only need the clinical assessment (except informed consent and education and counseling) and a complete blood count.  Patients discontinuing 
for any reason are followed for at least 30 days to ensure resolution of any adverse events; however, these patients will still be followed for outcome until 
meeting criteria outlined in footnote “p” below. 
p.  
Patients no longer receiving active treatment are followed every 3 months during the first year and every 6 months thereafter until the patient receives a  
new CLL therapy, withdrawal of consent, or death. 
q.  
Unless completed within the last month. 
r.   
CT scans of the chest, abdomen, and pelvis. 

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s.  
For patients treated on Arm A (patients who will receive lenalidomide during cycles 1 and 2), pharmacokinetic assessments of lenalidomide will occur during 
days 1 and 2 of cycle 2. Samples will be collected at the following time points: prior to dosing (time 0), 0.5, 1, 2, 3, 4.5, and 6 hours after dose administration 
on day 1 of cycle 2. An additional sample will be obtained prior to lenalidomide ingestion on day 2 of cycle 2 (i.e. 24 hours after the dose is ingested on day 
1).  For patients in Arm B (patients who receive lenalidomide beginning in cycle 4) PK sampling will occur during days 1 and 2 of cycle 5. The sampling times 
will be consistent with those in Arm A and comprise the following time points: prior to dosing (time 0), 0.5, 1, 2, 3, 4.5, and 6 hours after dose administration 
on day 1 of cycle 5. An additional sample will be obtained prior to lenalidomide ingestion on day 2 of cycle 5 (i.e. 24 hours after the dose is ingested on day 
1).  
 t.  
Blood for pharmacodynamic studies is obtained on the first day of each cycle indicated unless stated otherwise.  Details regarding specimen collection and 
handling are found in Sections 9.1-9.6 above. 

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62 
11. MEASUREMENT OF EFFECT 
 
11.1 
Response Criteria. 
 
All patients will be evaluated for response. Response will be characterized according to 
the 2008 International Workshop on CLL (IWCLL) guidelines for the diagnosis and 
treatment of CLL7, which include clinical, hematologic, and bone marrow features as 
outlined below. 
 
11.2 
Complete Response 
 
Requires all of the following for a period of at least two months from completion 
of therapy: 
 
• Absence of adenopathy on physical exam. 
 
• No hepatomegaly or splenomegaly on physical exam. 
 
• Absence of constitutional symptoms. 
 
• Normal CBC as exhibited by polymorphonuclear leukocytes ≥ 1500/µL, 
platelets > 100,000/µL, hemoglobin > 11.0 g/dL (untransfused), and 
lymphocyte count < 5,000/ µL. 
 
• Bone marrow aspirate and biopsy must be normocellular for age with < 30% of 
nucleated cells being lymphocytes.  Lymphoid nodules must be absent.  If the 
marrow is hypocellular, a repeat determination should be performed in one month. 
 
• Patients who otherwise fulfill the criteria for CR after induction, with the 
exception of a persistent cytopenia that is believed to be treatment related, will 
be considered a partial response.  Additionally, patients who fulfill the criteria 
for CR with exception of having bone marrow lymphoid nodules will be 
considered a partial response. 
 
• Flow cytometry will be used to further characterize patients who achieve a CR 
by the above criteria.  Those without evidence of marrow disease by this 
technique will be identified as such in analysis of treatment-free survival. 
 
11.3 
Partial Response 
 
Requires > 50% decrease in peripheral lymphocyte count from pre-treatment value, > 
50% reduction in lymphadenopathy, and/or > 50% reduction in Splenomegaly or 
hepatomegaly for a period of at least two months from completion of therapy.  All lymph 
nodes will be measured bi-dimensionally and the sums of these added to determine if 
50% or greater reduction has occurred.  Patients may have bone marrow lymphoid 
nodules and persistent cytopenias.  Additionally, these patients must have one of the 
following: 

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• Polymorphonuclear leukocytes ≥ 1500/µL or 50% improvement from pre- 
treatment value. 
 
• Platelets  > 100,000/µL or 50% improvement from pre-treatment value. 
 
• Hemoglobin > 11.0 g/dL (untransfused) or 50% improvement from pre- 
treatment value. 
 
11.4 
Stable Disease 
 
Patients who do not fulfill the criteria for complete or partial response as defined 
above but do not exhibit progressive disease will be considered as having stable 
disease. 
 
11.5 
Progressive Disease 
 
Characterized by any one of the following events: 
 
• ≥ 50% increase in the products of at least two lymph nodes on two 
consecutive determinations two weeks apart (at least one lymph node must 
be ≥2 cm); appearance of new palpable lymph nodes. 
 
• ≥ 50% increase in the size of the 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 to at least 
5,000/µL. 
 
• Transformation to a more aggressive histology (i.e. Richter’s syndrome or 
prolymphocytic leukemia with > 55% prolymphocytes). 
 
• Patients not fulfilling the above criteria for progressive disease but 
demonstrating a decrease in hemoglobin > 2 g/dl or a decrease ≥ 50% in platelet 
or granulocyte count, will not be rated as progressive disease because these 
may occur as both a consequence of therapy and of underlying CLL.  A bone 
marrow biopsy in such settings is strongly encouraged. 
 
11.6 
Duration of response 
 
11.6.1 Duration of overall response 
 
The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease that smallest measurements recorded since treatment started). 

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64 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
 
11.6.2 Duration of stable disease 
 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since 
treatment started. 
 
11.7 
Progression Free Survival (PFS) 
 
PFS is defined as the duration of time from start of treatment to time of disease 
progression or death secondary to any cause. 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in 
Section 7.0 (Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  
Reports are due January 31, April 30, July 31, and October 31.  Instructions for submitting 
data 
using 
the 
CDUS 
can 
be 
found 
on 
the 
CTEP 
Web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/cdus.htm).  Note:  
All adverse events that have occurred on the study, including those reported through 
CTEP-AERS, must be reported via CDUS. 
 
12.1.2 Responsibility for Data Submission 
 
N/A 
12.2 
CTEP Multicenter Guidelines 
 
N/A 
 
 
12.3 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, Agent-CRADA, CTA, CSA) between 
the Pharmaceutical Company(ies) (hereinafter referred to as “Collaborator(s)”) and the 
NCI Division of Cancer Treatment and Diagnosis.  Therefore, the following 

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65 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option 
to Collaborator” (http:// ctep.cancer.gov/industry) contained within the terms of award, 
apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators.  The protocol documents for 
studies utilizing investigational Agents contain confidential information and should 
not be shared or distributed without the permission of the NCI.  If a copy of this 
protocol is requested by a patient or patient’s family member participating on the 
study, the individual should sign a confidentiality agreement.  A suitable model 
agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”. ): 
 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court order 
as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used, and 
disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 CFR Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 

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66 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for 
advisory review and comment prior to submission for publication.  Collaborator(s) 
will have 30 days from the date of receipt for review.  Collaborator shall have the 
right to request that publication be delayed for up to an additional 30 days in order to 
ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must 
be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon 
as possible and preferably at least three (3) days prior to submission, but in any case, 
prior to presentation at the meeting or publication in the proceedings.  Press releases 
and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be 
sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Overview 
 
This is a randomized phase II trial designed to evaluate the impact of lenalidomide given 
concurrently with the conjugated 13-valent pneumococcal vaccine (PCV13) versus when 
PCV13 is administered first and then followed by lenalidomide. We will evaluate 
serotype-specific antibody responses along with PK and PD markers in each of the 
treatment arms.  
In addition, we will evaluate the clinical efficacy of lenalidomide when given with 
PCV13 in terms of whether or not a complete response (CR) is achieved in the first two 
years along with progression-free survival (PFS), incidence of infection, and general 
toxicity and tolerability of this regimen in this patient population.  
 

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13.2 
Primary Endpoint:  
 
The primary endpoint for evaluation and comparison in this study is the proportion of 
patients who achieve an antibody response. Following the definitions used by the WHO 
for serotype-based response as well as recent definitions of antibody response in the 
literature for multi-valent pneumococcal conjugate vaccine, we will define an antibody 
response in the context of this trial as achieving at least a four-fold increase in post-
vaccination serotype-specific IgG titers or serotype-specific IgG concentrations of ≥ 
0.35 µg/mL for 6 of 7 serotypes measured by a standard ELISA assay. These will be 
measured as changes from baseline compared to repeat assessment 1 month after the 
second (booster) dose of PCV13.  
 
13.3 
Study Design 
 
In this trial, patients will be randomized in a 1:1 allocation to receive lenalidomide with 
PCV13 up front concurrently (Arm A) vs. PCV13 up front and then subsequent 
administration of lenalidomide (Arm B). In this study we will compare the proportion of 
patients in each arm who achieve a significant antibody response as defined above. While 
it is not typical to employ a direct comparison of primary endpoints in the phase II setting, 
we believe that a randomized phase II design will better control for cohort and sampling 
variability necessary to assess the primary endpoint. In addition, in a secondary manner, 
we will also evaluate the clinical efficacy of treatment with lenalidomide in these patients 
vaccinated with PCV13, where clinical efficacy will be primarily determined through the 
proportion of patients who achieve a CR within two years (see Analysis Plan for more 
details).  
 
Randomization will be stratified on exposure to pneumococcal vaccination in the 
previous 5 years.  Those patients who have previously received a polysaccharide 
pneumococcal vaccine will not be excluded.  If a patient drops out of the study prior to 
administration of a 2nd (booster) pneumococcal vaccination, they will not be considered 
evaluable for the primary endpoint and will be replaced on the study.  However, the 
patient will be included in analyses of efficacy and tolerability as appropriate. 
 
Assuming that vaccine success in each arm is binomially distributed, we will use a two-
sided chi-square test to compare the difference in proportions.  We will constrain the 
Type I error rate in the comparison of vaccine response rates to 0.10. Using a two-sided 
test, we will have at least 90% power to detect a difference of 0.40 between the two rates 
(0.20 vs. 0.60) with a total of 44 evaluable patients (22 in each arm).  Comparing these 
two vaccine success rates, if pA≠pB and the resulting p-value < 0.10, we will consider the 
arm with the higher antibody response rate to have a significantly higher rate of vaccine 
success than the other arm. This design also allows for an interim analysis to be conducted 
after 11 patients have been accrued to each treatment arm (i.e. 50% of total planned 
accrual). Under a Lan-DeMets alpha spending function to constrain the Type I error rate, 
we will consider it sufficient evidence that one arm has a significantly higher antibody 
response rate than the other arm if the observed p-value <0.0056 (design generated using 
East version 5.3). 
 
Independent of the comparison of vaccine-related efficacy, we will also formally evaluate 

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68 
clinical efficacy using the two-year CR rate.  Previous experience with lenalidomide 
suggests that late responses may be observed.  Therefore, to effectively capture evidence 
of regimen efficacy (beyond the primary endpoint analysis) we will assess the CR rate in 
a pooled analysis across both arms since the main component of the regimen is 
lenalidomide therapy. If we find that one arm has shown to be superior to another in terms 
of antibody response rate as described above, then we will also compare the CR rates 
between these two arms in an exploratory manner. For the purposes of this trial, if a 
patient has a documented CR on at least two consecutive evaluations during the first two 
years, they will deemed a clinical success.  Given the extended time required to observe 
this clinical endpoint in these patients, we will use a one-stage design. With 44 patients, 
we will have at least 90% power and a Type I error of 0.10 to be able to detect a 25% or 
greater true CR rate versus the null hypothesis that the true CR rate is at most 10%.  If 8 
or more patients are deemed a clinical success as defined above, then we will consider 
this evidence of efficacy and worth pursuing further.  Otherwise, if at most 7 of these 44 
evaluable subjects have a CR at the end of two years of follow-up, then we will consider 
this insufficient clinical activity and may look to modify the treatment regimen to build 
on observed vaccine response. 
 
13.4 
Sample Size/Accrual Rate 
 
We expect that at most 10% will potentially drop out prior to administration of the 2nd 
vaccination, which translates to a total maximum sample size of 22+2=24 in each arm for 
a total of 48 patients.  With an anticipated accrual rate of about 3 patients per month, we 
expect that this trial will be fully accrued in at most 16 months.   
 
 
13.5 
Analysis of Secondary Endpoints 
 
In addition to evaluating the proportion of patients who have a vaccine-related antibody 
response to PCV13, we will also evaluate the seroconversion rates and antibody titre 
levels for each of the serotypes of the 13-valent pneumococcal vaccine. These markers 
will be summarized using descriptive statistics by treatment arm. We will graphically 
evaluate changes in these serotype-specific markers between the two arms, and we will 
also use the nonparametric Mann-Whitney rank sum test to compare the geometric mean 
concentrations.  
 
Secondary endpoints will also include the CR rate following 2 years of lenalidomide 
treatment. Assuming that the number of CRs is binomially distributed, then we will also 
generate corresponding 95% confidence intervals for the CR rate estimate. If there is also 
a significant difference between the arms in terms of the vaccine response to PCV13, then 
we will also compare the CR rates between the two arms in an exploratory manner, 
although we will only be able to detect a large differential in CR rates (10% vs. 40%) 
with at least 80% power and a Type I error rate of 10%. In addition, we will evaluate time 
to event outcomes such as time to first treatment (TFT) and overall survival (OS). TFT 
will be defined as the time from study entry to first therapy for progressive CLL as 
defined by IWCLL 2008 criteria.1 To evaluate this endpoint, patients will be followed 
even after discontinue therapy, where we will document date of subsequent treatment 
and/or progressive disease. Survival will also be evaluated, although we do not expect 

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69 
many events in this early stage, asymptomatic group of patients. Time to event outcomes 
will be summarized and explored between treatment arms using Kaplan-Meier methods. 
Formal comparison of these endpoints between the two arms will not be done due to lack 
of statistical power to do so. In a very exploratory manner, we will also assess time to 
treatment in relation to the results reported by Shanafelt et al (2009); in an exploratory 
manner, we will utilize their prognostic scoring to identify an expected versus observed 
time to treatment.[64,65] 
 
In each arm, we will evaluate the overall and complete response rates after two years, the 
proportion of patients in each arm who are progression-free at 2 years, and safety and 
tolerability of each regimen.  Adverse events will be summarized by and across treatment 
arms, where we will summarize the type, severity, and perceived attribution to study 
treatment according to NCI’s CTCAE (version 5). The rates of severe (grade 3+) toxicity 
(at least possibly related to treatment) and non-hematologic toxicity will be summarized; 
assuming the incidence of severe toxicity is binomially distributed, 95% confidence 
intervals will be calculated.  The maximum grade for each type of toxicity will be 
recorded for each patient, and frequency tables will be reviewed to determine the toxicity 
patterns. In addition, we will assess time to treatment failure, defined as the time from 
study entry to discontinuation of treatment; we will also summarize reasons patients 
discontinue study treatment.  
 
Descriptive statistics (i.e. means, standard deviations, 95% confidence intervals for 
continuous variables and frequencies for discrete data) will be computed for all 
correlative laboratory parameters.  Given the small sample size in this phase II trial, a 
total of 44 patients may limit our ability to perform inferential tests. Still, we will 
graphically evaluate these PK and PD markers within and across arms to assess potential 
patterns and relationships. Where model assumptions are met, we will also utilize 
repeated measures models (linear or nonlinear mixed models, generalized estimating 
equation models) to explore relationships with the various markers and clinical outcomes 
of interest.  
 
13.6 
Reporting and Exclusions 
 
13.6.1 Evaluation of toxicity  
 
All patients will be evaluable for toxicity from the time of their first treatment with 
lenalidomide. 
 
13.6.2 Evaluation of response    
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 

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70 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
 
 
 
 

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71 
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expression on CLL cells and enhances production of antibodies by normal B cells through a 
PI3-kinase-dependent pathway. Blood;115:2619-2629. 
34. Badoux XC, Reuben J, Lee B, et al. Lenalidomide Therapy is Associated with Normalization 
of Lymphocyte Populations and Increase in Immunoglobulin Levels in Elderly Patients with 

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Version Date: March 15, 2024 
 
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Chronic Lymphocytic Leukemia. Haematologica. 2009;94:S1-98. 
35. Wierda WG, Cantwell MJ, Woods SJ, Rassenti LZ, Prussak CE, Kipps TJ. CD40-ligand 
(CD154) gene therapy for chronic lymphocytic leukemia. Blood. 2000;96:2917-2924. 
36. Dicker F, Kater AP, Prada CE, et al. CD154 induces p73 to overcome the resistance to 
apoptosis of chronic lymphocytic leukemia cells lacking functional p53. Blood. 
2006;108:3450-3457. 
37. Lin PL, Michaels MG, Green M, et al. Safety and immunogenicity of the American Academy 
of Pediatrics--recommended sequential pneumococcal conjugate and polysaccharide vaccine 
schedule in pediatric solid organ transplant recipients. Pediatrics. 2005;116:160-167. 
38. Musher DM, Rueda AM, Nahm MH, Graviss EA, Rodriguez-Barradas MC. Initial and 
subsequent response to pneumococcal polysaccharide and protein-conjugate vaccines 
administered sequentially to adults who have recovered from pneumococcal pneumonia. J 
Infect Dis. 2008;198:1019-1027. 
39. Cordonnier C, Labopin M, Chesnel V, et al. Randomized study of early versus late 
immunization with pneumococcal conjugate vaccine after allogeneic stem cell 
transplantation. Clin Infect Dis. 2009;48:1392-1401. 
40. Shrimpton A, Duddridge M, Ziegler-Heitbrock L. Vaccination with polysaccharide-
conjugate-vaccines in adult patients with specific antibody deficiency. Vaccine. 
2006;24:3574-3580. 
41. Dransfield MT, Nahm MH, Han MK, et al. Superior immune response to protein-conjugate 
versus free pneumococcal polysaccharide vaccine in chronic obstructive pulmonary disease. 
Am J Respir Crit Care Med. 2009;180:499-505. 
42. Goldblatt D, Southern J, Andrews N, et al. The immunogenicity of 7-valent pneumococcal 
conjugate vaccine versus 23-valent polysaccharide vaccine in adults aged 50-80 years. Clin 
Infect Dis. 2009;49:1318-1325. 
43. Jackson LA, Neuzil KM, Nahm MH, et al. Immunogenicity of varying dosages of 7-valent 
pneumococcal polysaccharide-protein conjugate vaccine in seniors previously vaccinated 
with 23-valent pneumococcal polysaccharide vaccine. Vaccine. 2007;25:4029-4037. 
44. Musher DM, Ceasar H, Kojic EM, et al. Administration of protein-conjugate pneumococcal 
vaccine to patients who have invasive disease after splenectomy despite their having received 
23-valent pneumococcal polysaccharide vaccine. J Infect Dis. 2005;191:1063-1067. 
45. French N, Gordon SB, Mwalukomo T, et al. A trial of a 7-valent pneumococcal conjugate 
vaccine in HIV-infected adults. N Engl J Med;362:812-822. 
46. Lexau CA, Lynfield R, Danila R, et al. Changing epidemiology of invasive pneumococcal 
disease among older adults in the era of pediatric pneumococcal conjugate vaccine. JAMA. 
2005;294:2043-2051. 
47. Hammitt LL, Bruden DL, Butler JC, et al. Indirect effect of conjugate vaccine on adult 
carriage of Streptococcus pneumoniae: an explanation of trends in invasive pneumococcal 
disease. J Infect Dis. 2006;193:1487-1494. 
48. Onwubiko C, Swiatlo E, McDaniel LS. Cross-sectional study of nasopharyngeal carriage of 
Streptococcus pneumoniae in human immunodeficiency virus-infected adults in the 
conjugate vaccine era. J Clin Microbiol. 2008;46:3621-3625. 
49. Stamatopoulos K. CLL: promiscuity leads to risks. Blood. 2009;114:3508-3509. 
50. Kieninger DM, Kueper K, Steul K, et al. Safety, tolerability, and immunologic noninferiority 
of a 13-valent pneumococcal conjugate vaccine compared to a 7-valent pneumococcal 
conjugate vaccine given with routine pediatric vaccinations in Germany. Vaccine. 
51. Emergence of antimicrobial-resistant serotype 19A Streptococcus pneumoniae--
Massachusetts, 2001-2006. MMWR Morb Mortal Wkly Rep. 2007;56:1077-1080. 

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74 
52. Noonan KA, Ferguson A, Emerling A, et al. Lenalidomide Augments Immune Responses to 
Prevnar Vaccination in Relapsed Myeloma Patients: Implications for Cancer and Infectious 
Vaccines. Vol. 114; 2009:1864-. 
53. Byrd JC, Stilgenbauer S, Flinn IW. Chronic lymphocytic leukemia. Hematology Am Soc 
Hematol Educ Program. 2004:163-183. 
54. Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: 
clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are 
independent prognostic factors. Blood. 2002;100:1177-1184. 
55. Zenz T, Dohner H, Stilgenbauer S. Genetics and risk-stratified approach to therapy in chronic 
lymphocytic leukemia. Best Pract Res Clin Haematol. 2007;20:439-453. 
56. Juliusson G, Oscier DG, Fitchett M, et al. Prognostic subgroups in B-cell chronic 
lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med. 
1990;323:720-724. 
57. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic 
lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916. 
58. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel 
prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94:1840-1847. 
59. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are 
associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 
1999;94:1848-1854. 
60. Krober A, Seiler T, Benner A, et al. V(H) mutation status, CD38 expression level, genomic 
aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100:1410-1416. 
61. Shanafelt TD. Predicting clinical outcome in CLL: how and why. Hematology Am Soc 
Hematol Educ Program. 2009:421-429. 
62. Stilgenbauer S, Bullinger L, Lichter P, Dohner H. Genetics of chronic lymphocytic leukemia: 
genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. 
Leukemia. 2002;16:993-1007. 
63. Bergmann MA, Eichhorst BF, Busch R, et al. Prospective Evaluation of Prognostic 
Parameters in Early Stage Chronic Lymphocytic Leukemia (CLL): Results of the CLL1-
Protocol of the German CLL Study Group (GCLLSG). ASH Annual Meeting Abstracts. 
2007;110:625-. 
64. Rossi D, Sozzi E, Puma A, et al. The prognosis of clinical monoclonal B cell lymphocytosis 
differs from prognosis of Rai 0 chronic lymphocytic leukaemia and is recapitulated by 
biological risk factors. Br J Haematol. 2009;146:64-75. 
65. Zent CS, Call TG, Shanafelt TD, et al. Early treatment of high-risk chronic lymphocytic 
leukemia with alemtuzumab and rituximab. Cancer. 2008;113:2110-2118. 
66. Lapalombella R, Andritsos L, Liu Q, et al. Lenalidomide treatment promotes CD154 
expression on CLL cells and enhances production of antibodies by normal B Cells through a 
PI3-kinase dependent pathway. Blood. 2009. 
67. Liu Q, Farley KL, Johnson AJ, et al. Development and Validation of a Highly Sensitive 
Liquid Chromatography/Mass Spectrometry Method for Simultaneous Quantification of 
Lenalidomide and Flavopiridol in Human Plasma. Ther Drug Monit. 2008;30:620-627. 
68. Zhang L, Freitas MA, Wickham J, et al. Differential expression of histone post-translational 
modifications in acute myeloid and chronic lymphocytic leukemia determined by high-
pressure liquid chromatography and mass spectrometry. J Am Soc Mass Spectrom. 
2004;15:77-86. 
69. Su X, Lucas DM, Zhang L, et al. Validation of an LC-MS based approach for profiling 
histones in chronic lymphocytic leukemia. Proteomics. 2009;9:1197-1206. 

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70. Lapalombella R, Yu B, Triantafillou G, et al. Lenalidomide down-regulates the CD20 antigen 
and antagonizes direct and antibody-dependent cellular cytotoxicity of rituximab on primary 
chronic lymphocytic leukemia cells. Blood. 2008;112:5180-5189. 
 
 

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76 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 

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77 
APPENDIX B 
MEDICATION CALENDAR 
 
 
SUBJECT DIARY 
 
Site # 
8834 
PI Name: 
Dr. Kerry Rogers Subject #: 
 
 
Instructions:  The study drug is stored at room temperature. Please do not freeze or 
refrigerate the study drug.  The study drug must be taken by mouth once a day with 8 
ounces (approximately 240 mL) of water.  The capsules should be swallowed intact.  Do 
not open capsules or dissolve them in water. 
 
Each dose should be taken at approximately the same time each day with or without food. If 
a dose is missed, it can be taken up to 6 hours after the scheduled time with a return to the 
normal schedule the following day.  If it has been more than 6 hours, the dose should be 
skipped and you must take the next dose at the scheduled time the next day.  The missed 
dose will not be made up and all the capsules from the missed dose must be returned to the 
clinic or hospital at the next visit. 
Please complete the form below EVERY DAY to keep track of your doses.  The purpose 
of this form is to help you remember to take the study drug once a day.  For each day, 
complete the date and time (including circling “am” or “pm”) for when you took the 
study drug, and the number of capsules you took.  If you experienced any symptoms that 
you feel might have been related to the study drug, write those down as well.  Always take 
this form with you when you attend your visits with the clinic or hospital. 
 
 
 

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78 
 
 
 
 
 
CYCLE  
(fill in cycle #) 
 
DAY 
DATE 
TIME 
# CAPSULES 
SYMPTOMS 
1 
am 
pm 
2 
am 
pm 
3 
am 
pm 
4 
am 
pm 
5 
am 
pm 
6 
am 
pm 
7 
am 
pm 
8 
am 
pm 
9 
am 
pm 
10 
am 
pm 
11 
am 
pm 
12 
am 
pm 
13 
am 
pm 
14 
am 
pm 
15 
am 
pm 
16 
am 
pm 
17 
am 
pm 
18 
am 
pm 

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79 
19 
am 
pm 
20 
am 
pm 
21 
am 
pm 
22 
am 
pm 
23 
am 
pm 
24 
am 
pm 
25 
am 
pm 
26 
am 
pm 
27 
am 
pm 
28 
am 
pm 
 
28 DAYS IS THE END OF THE CYCLE.  YOUR STUDY DOCTOR WILL LET YOU 
KNOW IF YOU CAN CONTINUE WITH THE NEXT CYCLE. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX C 
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):  
• 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 
• 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 

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81 
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 concerning 
the following risks and requirements prior to the start of lenalidomide):  
• 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): 
• 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) during 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 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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82 
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 (minimum sensitivity of 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 treatment 
must be discontinued during this evaluation. 

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83 
• Females must agree to abstain from breastfeeding during study participation and 
for at least 28 days after study drug discontinuation. 
Male Patients: 
• Counseling about the requirement for complete abstinence or condom use during 
sexual contact with a pregnant female or a female of childbearing potential and 
the potential risks of fetal exposure to lenalidomide must be conducted at a 
minimum of every 28 days.   
• If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 
Additional precautions 
• Patients should be instructed never to give this medicinal product to another 
person and to return any unused capsules to the study doctor at the end of 
treatment. 
• Female patients should not donate blood during treatment and for at least 28 days 
following discontinuation of lenalidomide. 
• Male patients should not donate blood, semen or sperm during treatment or for at 
least 28 days following discontinuation of lenalidomide. 
• Only enough study drug for 28 days or one cycle of therapy (whichever is shorter) 
may be dispensed with each cycle of therapy.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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84 
APPENDIX D 
LENALIDOMIDE EDUCATION AND COUNSELING GUIDANCE 
DOCUMENT 
 
Protocol Number: ____________________________________________ 
Patient Name (Print): __________________ DOB: _____/_____/_____ (mm/dd/yyyy) 
(Check the appropriate box to indicate risk category) 
Female:  □ 
If female, check one: 
□ FCBP (Female of childbearing potential): sexually mature female who: 1) has not 
undergone a hysterectomy (the surgical removal of the uterus) or bilateral 
oophorectomy (the surgical removal of both ovaries) 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 during the preceding 24 consecutive months) 
□ NOT FCBP 
Male: 
□ 
⁯ 
Do Not Dispense study drug  if: 
• The patient is pregnant. 
• No pregnancy tests were conducted for a FCBP. 
• The patient states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence of heterosexual intercourse) [at least 28 days prior to 
treatment, during treatment, and during dose interruption]. 
 
1. I verified that the required pregnancy tests performed are negative. 
2. I counseled FCBP regarding the following: 
• Potential risk of fetal exposure to lenalidomide:  If lenalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby.  Females are 
advised to avoid pregnancy while taking lenalidomide. The teratogenic potential of 
lenalidomide in humans cannot be ruled out.  FCBP must agree not to become 
pregnant while taking lenalidomide.  
• Using TWO reliable methods of birth control at the same time or complete abstinence 
from heterosexual contact [at least 28 days prior to treatment, during treatment, 
during dose interruption and 28 days after discontinuation of lenalidomide]. 
• That even if she has amenorrhea she must comply with advice on contraception   

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85 
• 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) 
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, during, and after 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. 
3. Provide Lenalidomide Information Sheet to the patient. 

NCI Protocol #: 8834 
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86 
FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR AT 
LEAST 24 CONSECUTIVE MONTHS, A HYSTERECTOMY, OR BILATERAL 
OOPHORECTOMY): 
4. 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. 
− Do not break, chew, or open study drug capsules 
− Return unused study drug capsules to the study doctor. 
5. Provide Lenalidomide Information Sheet to the patient. 
MALE: 
6. 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. 
7. Provide Lenalidomide Information Sheet to the patient. 
 
Counselor Name (Print): ____________________ 
 
 
Counselor Signature: _______________________  
Date: _____/_____/_____ 
 
**Maintain a copy of the Lenalidomide Education and Counseling Guidance Document in the patient 
records.** 
 

NCI Protocol #: 8834 
Version Date: March 15, 2024 
 
87 
 
 
 
 
• 
Please identify at least two (2) counselors and fax back to 888-314-2392 
• 
Use one form per counselor. 
• 
Identified counselors must be licensed healthcare professionals (e.g. RN, PA, RPh, PhD, LPN, CNP, or 
MD) and must not be the principal investigator. 
• 
If you have any questions, please email (coop_ma@celgene.com) 
 
Celgene 
Corporation 
Celgene Pregnancy Prevention & Counseling Program 
Site Counselor Identification Form 
for NCI Studies 
NCI Protocol #: _______________________________ 
Principal Investigator: _______________________ Institution Name: ___________________ 

NCI Protocol #: 8834 
Version Date: March 15, 2024 
 
88 
 
Counselor Information  
 
CTEPpersonID:  _______________________________    CTEPsiteID:  _______________________________________ 
 
 
First Name: __________________________    Middle Initial:______    Last Name: ______________________________ 
 
 
License Type: (circle one)    MD        PhD        PA        CNP        RN        LPN       RPh      Other:_____________________ 
 
 
Email Address: _____________________________________________________________________________________ 
 
 
Phone: _________________________________________   Fax: _____________________________________________ 
 
 
Institution Street Address: ____________________________________________________________________________ 
 
 
City: __________________________________________ State/Region: _______________________________________ 
 
 
Zip/Post Code: ___________________________ Country: _________________________________________________ 
 
Previously approved as a Counselor? □ No □ Yes 
 
If no, please list all the protocols #(s), corresponding CTEPsiteID(s) and institution names(s) that you plan to provide 
counseling for: 
 
If yes, please list the protocols #(s), corresponding CTEPsiteID(s) and institution names(s) for protocols Celgene has 
already associated you with: 
 
Protocol#: 
CTEPsiteID  
Institution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Version Date: March 15, 2024 
 
89 
APPENDIX E: LENALIDOMIDE INFORMATION SHEET 
 
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES 
Please  read   this   Lenalidomide  Information  Sheet  before  you  start  taking 
study drug and each time you get a new supply. This Lenalidomide Information 
Sheet does not take the place of an informed  consent  to  participate  in  clinical  
research  or  talking  to  your  study doctor or healthcare provider about your medical 
condition or your treatment. 
 
What  is  the  most  important  information  I  should  know  about 
lenalidomide? 
 
Lenalidomide may cause birth defects (deformed babies) or death of an unborn 
baby. Lenalidomide is similar to the medicine thalidomide. It is known thalidomide 
causes life-threatening birth defects. Lenalidomide has not been tested in pregnant 
women but may also cause birth defects. Findings from a monkey study indicate 
that lenalidomide caused birth defects in the babies of female monkeys who 
received the drug during pregnancy. 
 
If you are a woman who is able to become pregnant: 
 
• Do  not  take  lenalidomide  if  you  are  pregnant  or  plan  to 
become pregnant 
 
• 
for 28 days before starting lenalidomide 
 
• 
while taking lenalidomide 
 
• 
during dose interruptions of lenalidomide 
 
• 
for 28 days after stopping lenalidomide 
 
 
 
• You must have pregnancy testing done at the following times: 
 
• 
within 10 – 14 days and again 24 hours prior to the 
first dose of lenalidomide 
 
• 
weekly for the first 28 days 
 
• 
every 28 days after the first month or every 14 days if 
you have irregular menstrual periods 
 
• 
if you miss your period or have unusual menstrual 
bleeding 
 
• 
28 days after the last dose of lenalidomide (14 and 
28 days after the last dose if menstrual periods are 
irregular) 
• Stop taking study drug if you become pregnant during treatment 

NCI Protocol #: 8834 
Version Date: March 15, 2024 
 
90 
− If you suspect you are pregnant at any time during the study, you must stop 
lenalidomide immediately and immediately inform your study doctor. Your study 
doctor will report all cases of pregnancy to the National Cancer Institute and the 
pharmaceutical collaborator, Celgene Corporation.  
• Do not breastfeed while taking study drug 
• The study doctor will be able to advise you where to get additional advice on 
contraception. 
If you are a female not of childbearing potential: 
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor 
will confirm that you are not able to become pregnant. 
If you are a man: 
Lenalidomide is detected in trace quantities in human semen. The risk to the fetus in 
females of child bearing potential whose male partner is receiving lenalidomide is 
unknown at this time.   
• Men (including those who have had a vasectomy) must either abstain from sexual 
intercourse or use a condom during sexual contact with a pregnant female or a female 
that can become pregnant: 
− While you are taking lenalidomide 
− During dose interruptions of lenalidomide 
− For 28 days after you stop taking lenalidomide 
• Men should not donate sperm or semen while taking study drug and for 28 days 
after stopping lenalidomide.  
• If you suspect that your partner is pregnant any time during the study, you must 
immediately inform your study doctor. The study doctor will report all cases of 
pregnancy to the National Cancer Institute and the pharmaceutical collaborator, 
Celgene Corporation. Your partner should call their healthcare provider 
immediately if she gets pregnant. 
Restrictions in sharing lenalidomide and donating blood: 
• Do not share lenalidomide with other people. It must be kept out of the reach of 
children and should never be given to any other person. 
• Do not donate blood while you take lenalidomide and for 28 days after stopping 
study drug.  
• Do not break, chew, or open study drug capsules. 
• You will get no more than a 28-day supply of lenalidomide at one time. 
• Return unused study drug capsules to your study doctor. 
Additional information is provided in the informed consent form and you can ask your study 
doctor for more information.