Conditions: Monoclonal B-Cell Lymphocytosis Stage 0 Chronic Lymphocytic Leukemia Stage I Chronic Lymphocytic Leukemia Stage I Small Lymphocytic Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 12
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well lenalidomide improves immune response to pneumococcal 13-valent conjugate vaccine in patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or monoclonal B cell lymphocytosis. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Lenalidomide may also improve the effectiveness of pneumococcal 13-valent conjugate vaccine that is used to prevent infection.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the ability of a 6 week course of low dose lenalidomide to improve the proportion of patients with monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL) who develop an immune response to pneumococcal vaccination as measured by the proportion of patients with \>= 4-fold rise from pre-vaccine (day 15) for \>= 2 of the 3 serotypes measured at 28 days post-vaccination by opsonophagocytic activity (OPA) of antibodies from sera.

SECONDARY OBJECTIVES:

I. Evaluate disease status by physical exam and complete blood counts in patients participating in each arm of the study at the time of the 6 week assessment of immune response.

II. Evaluate time to treatment for progressive CLL for patients on each study arm.

III. Evaluate the adverse events profile in each study arm.

TERTIARY OBJECTIVES:

I. To assess the immune response to pneumococcal vaccination as measured by fold-change from pre-vaccine (day 15) to 28 days post-vaccination in OPA geometric mean titers (GMT) of antibodies from sera.

II. To assess the immune response to pneumococcal vaccination as measured by fold-change from pre-vaccine (day 15) to 28 days post-vaccination in quantitative Streptococcus pneumoniae immunoglobulin G (IgG) GMT of antibodies from sera.

III. Evaluate the effect of 6 weeks of low dose lenalidomide on global immune function including T-cell repertoire, T-cell immune synapse, serum immunoglobulin levels, and absolute numbers of T-cell and natural killer (NK) cells.

OUTLINE: Patients are randomized 1 of 2 treatment arms.

ARM I: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-42 and pneumococcal 13-valent conjugate vaccine intramuscularly (IM) on day 15.

ARM II: Patients receive pneumococcal 13-valent conjugate vaccine IM on day 15.

After completion of study treatment, patients are followed up at day 28, and then every 6 months for up to 2 years.

Arms:
arm 1: Patients receive lenalidomide PO QD on days 1-42 and pneumococcal 13-valent conjugate vaccine IM on day 15. arm 2: Patients receive pneumococcal 13-valent conjugate vaccine IM on day 15.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Lenalidomide intervention 3: Pneumococcal 13-valent Conjugate Vaccine
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Given IM

Protocol document:
Prot_SAP_000.pdf: 


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MCCC Addendum 4 
 
 
Protocol Version Date: May  2, 2017 
 
Document History 
(Effective Date) 
Activation 
June 11, 2015 
MCCC Addendum 1 
November 12, 2015 
MCCC Addendum 2 
April 20, 2016 
 
 
  MCCC Addendum 3      April 28, 2017 
 
 
  MCCC Addendum 4      June 15, 2017 
 
 
 


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Protocol Version Date: May  2, 2017 
 
 
Index 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation   
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
Consent Form  
 
Appendix I 
NYHA Classification 
Appendix II 
Rai Classification 
Appendix III 
ECOG Performance Status Scale 
Appendix IV 
Grading Scale for Hematologic Toxicity in CLL Studies 
Appendix V 
Patient Medication Diary 
 
Appendix VI 
Kit Instructions 
 
 
 


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MCCC Addendum 4 
 
 
Protocol Version Date: May  2, 2017 
SCHEMA: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Cycle 1 = 50 Day Cycle (Days -7 to 43).   Registration on Day -7 allows time for lenalidomide to be 
ordered through the Revlimid REMS®.  Treatment with lenalidomide should begin on Day 1 for 
Arm A and Prevnar 13® should be given on Day 15 for both Arms. 
2  Cycle 2 (Observation)  = 28 days (+/- 10 days) 
 
Generic name: Pneumococcal 13-valent Conjugate 
Vaccine (Diphtheria CRM197 Protein)  
Brand name: Prevnar 13®  
Mayo abbreviation: PREVNAR13   
  
Availability:   Commercial supply 
Generic name:    Lenalidomide  
Brand name(s): Revlimid 
Mayo Abbreviation: CC5013     
Availability:  Celgene supplied through the  
Revlimid REMS® program 
 
Randomization 
(Day -7) 
Arm A1 
Waiting period Days -7 to -1 
Lenalidomide Days 1 to 42 
Prevnar 13® Day 15 
Arm B1 
Waiting period Days -7 to -1 
No treatment Days 1 to 14 
Prevnar 13® Day 15 
Observation 2 
Event Monitoring 
NOTE: As of Addendum 4, 
Event monitoring will no longer 
be required 


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Protocol Version Date: May  2, 2017 
1.0 
Background   
 
1.1 
Infection and Survival in Patients with CLL and MBL 
Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid 
malignancies, accounting for ~11% of all hematologic neoplasms.1  Over the last decade, 
the precursor state to CLL termed monoclonal B-cell lymphocytosis (MBL) has been 
defined.  MBL is characterized by the presence of a small (<5 × 109/l) population of 
clonal B cells in the peripheral blood in the absence of lymphadenopathy, cytopenias or 
autoimmune disease.  In most patients with MBL, immunophenotype of the clonal B-
cells is identical to chronic lymphocytic leukemia (CLL).2  Although screening studies 
indicate that 3–12% of adults over age 40 have MBL, only a fraction of these MBL cases 
come to clinical attention (now designated as clinical or high count MBL), which is 
typically identified when patients are found to have mild lymphocytosis identified on a 
complete blood count obtained for other reasons.2,3  The risk of progression from clinical 
MBL to CLL requiring chemotherapy treatment is ~1%/year.4,5  Accordingly, given the 
typical age when clinical MBL is identified, most individuals with clinically recognized 
MBL will never require treatment for CLL.  Despite their low risk of progressing to 
require CLL treatment, these patients are now recognized as at risk for serious infections 
(see below). 
 
In addition to having a life expectancy that is substantially shorter than that of age-
matched individuals in the general population, the 100,000 individuals in the United 
States living with CLL must also deal with an increased risk of infections.  Strikingly, 
30–50% of all deaths in patients with CLL are attributed to infections or infectious 
complications.6  The increased rates of infection observed in patients with CLL even 
prior to receiving treatment suggested to us that this immunodeficiency state may be 
present among individuals with the precursor state to the disease.  Recent evidence 
indicates that patients with clinically recognized MBL are also at increased risk of 
infection and suggest the risk of serious infection in individuals with clinical MBL is 
substantially greater than the risk they will ever progress to require treatment for CLL.7  
The increased susceptibility to infection in CLL patients results from a complex 
immunodeficiency state that includes defects in both humoral and cell mediated 
immunity that predate exposure to chemotherapy.  Thus the immunodeficiency of CLL is 
multifactorial and is likely related to hypogammaglobulinemia, B- and T-cell 
dysfunction, and defects in innate immunity. 6,8,9 The mechanisms of decreased immune 
competence in MBL are poorly elucidated but surely are important ones to overcome and 
reverse. 
 
1.2 
Efforts to Reduce Infection in CLL and MBL: 
 
CLL-The high rate of death from infection among patients with CLL has generated 
interest in strategies to reduce infection risk including vaccination strategies.  
Unfortunately, even prior to administration of chemotherapy, patients with CLL have 
decreased or suboptimal response to vaccinations. 10-12 Influenza seroconversion rates 
have ranged from 5-15% for influenza A and B,11 as opposed to the 80-90% 
seroconversion rates typically seen in healthy adults. Responses to the polysaccharide 
pneumococcal vaccine (Pneumovax) have also been remarkably low, with responses 
ranging from 10-22%.13,14 
 
Since CLL patients are truly immunocompromised even in early stage disease, it is not 
surprising that conventional vaccinations given to these patients are found to be 


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Protocol Version Date: May  2, 2017 
suboptimal. The exact etiologies are yet unclear but certainly relate to deficient 
immunoglobulin production, the impact of age, and, of course, the immunosuppressive 
effect of recent chemotherapies or chemoimmunotherapy (CIT).  Efforts to enhance 
vaccine responses have been studied including the use of H2 Blockade and GM-CSF but 
have to date been unimpressive.  Ranitidine as an adjuvant for influenza and 
pneumococcal vaccines led to no improvement for either influenza15 or pneumococcal 
responses.16  GM-CSF also demonstrated no ability to augment pneumococcal vaccine 
response.14 
 
MBL-There are no published data on vaccine responses in patients with MBL. 
However, given that we have found that patients with MBL have increased risk for 
serious infections similar to patients with CLL, 7 which is likely a result of immune 
dysfunction, we hypothesize that MBL patients will also have suboptimal responses to 
vaccination.   
 
1.3 
Lenalidomide:  Lenalidomide is a proprietary IMiD® compound of Celgene 
Corporation.  IMiD® compounds have both immunomodulatory and anti-angiogenic 
properties which could confer antitumor and anti-metastatic effects.  Lenalidomide has 
been demonstrated to possess anti-angiogenic activity through inhibition of bFGF, VEGF 
and TNF-alpha induced endothelial cell migration, due at least in part to inhibition of Akt 
phosphorylation response to bFGF.{Dredge, 2005 #663}  In addition, lenalidomide has a 
variety of immunomodulatory effects.  Lenalidomide stimulates T cell proliferation, and 
the production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates 
IL-12 production.{Corral, 1999 #664}  Upregulation of T cell derived IL-2 production is 
achieved at least in part through increased AP-1 activity.{Schafer, 2003 #665} 
 
Although the exact antitumor mechanism of action of lenalidomide is unknown, a 
number of mechanisms are postulated to be responsible for lenalidomide’s activity 
against multiple myeloma.  Lenalidomide has been shown to increase T cell proliferation, 
which leads to an increase in IL-2 and IFN-gamma secretion.  The increased level of 
these circulating cytokines augment natural killer cell number and function, and enhance 
natural killer cell activity to yield an increase in multiple myeloma cell lysis{Davies, 
2001 #666}.  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{Wu, 
2004 #675}.  
 
Current Indications and Usage of Lenalidomide: 
Revlimid® (lenalidomide) is indicated for the treatment of patients with transfusion-
dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes 
associated with a deletion 5q cytogenetic abnormality with or without additional 
cytogenetic abnormalities.  Revlimid® is also approved in combination with 
dexamethasone for the treatment of patients with multiple myeloma that have received at 
least one prior therapy.  
 
Adverse Events with Lenalidomide: 
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, 


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Protocol Version Date: May  2, 2017 
infections, sepsis, pneumonia, UTI, Upper respiratory infection, 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. 
 
According to researchers, patients with cancer have a higher risk of developing a second 
new cancer when compared to people without cancer. In clinical studies of newly 
diagnosed multiple myeloma, a higher number of second cancers were reported in 
patients treated with lenalidomide as induction therapy (treatment for several cycles to 
reduce number of cancer cells) and/or bone marrow transplant followed by lenalidomide  
for a long period of time compared to patients treated with induction therapy and/or bone 
marrow transplant then placebo (a capsule containing no lenalidomide). Patients should 
make their doctors aware of their medical history and any concerns they may have 
regarding their own increased risk of other cancers.  
 
Complete and updated adverse events are available in the Investigational Drug Brochure 
and the IND Safety Letters. 
 
1.4 
Lenalidomide and Immune Reconstitution: 
Lenalidomide is an immunomodulatory drug that is FDA approved for the treatment of 
multiple myeloma and myelodysplasia.  Lenalidomide also has clinical activity in a 
number of other hematologic malignancies, including CLL.17-20  In CLL, lenalidomide is 
thought to mediate its anti-tumor activity through modulation of the tumor 
microenvironment rather than a direct cytotoxic effect on the leukemic cells. 19,21,22  
Immunomodulatory mechanisms include disrupting pro-tumor cytokines, anti-angiogenic 
signaling and activation of adaptive humoral and T-cell immunity.19,21,22 Notably, both in 
vitro and in vivo data suggest that oral lenalidomide can repair defects in the T-cell 
immune synapse and reduce T regulatory levels in patients with CLL. In addition, there 
are reports that serum immunoglobulin levels can be enhanced with exposure to 
lenalidomide.  
 
Notably, previous studies in patients with multiple myeloma also suggest that 
lenalidomide may improve the immune response to pneumococcal vaccination.23 A 
“window of opportunity” study evaluated the immune response in patients with multiple 
myeloma receiving lenalidomide treatment.  The first cohort received an initial dose of 
the pneumococcal 7-valent conjugate vaccine (PCV) prior to the initiation of 
lenalidomide and a second vaccination while on lenalidomide. The second cohort 
received both vaccinations while on lenalidomide.  The PCV-specific humoral and 
cellular responses were greater in the second cohort suggesting lenalidomide augmented 
the vaccine response of these patients.23 
 
1.5 
Strategic Concept: 
 
Most CLL patients are >age 65 and will have already received the 23 valent 
pneumococcal vaccine (Pneumovax).  As noted, the response to pneumococcal vaccine in 
patients with CLL, however, is poor ranging from 10-22%.13,14 In 2012, the Center for 
Disease Control recommended that, in addition to the Pneumovax, immunocompromised 
patients (such as those with CLL) also received the Pneumococcal 13-valent Conjugate 


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Protocol Version Date: May  2, 2017 
Vaccine (Prevnar 13) once during their lifetime to boost immunity to pneumococcal 
infection.  This recommendation is primarily based on expert opinion with no data that it 
increases immunity in patients with CLL who typically have a poor response to vaccines 
in general. 
 
In this study, we will conduct a pilot study evaluating the ability of a brief course of low 
dose lenalidomide to augment the response to the  pneumococcal conjugate vaccination 
Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein)(Prevnar 13®)  
in patients naïve to Prevnar 13 with clinical MBL and previously untreated, early stage 
CLL.   
 
The rationale for this study is that lenalidomide has been shown to mediate much of its 
clinical activity through the immunomodulation of the microenvironment, including 
enhancement of the host immune system and evidence from patients with multiple 
myeloma that lenalidomide can augment vaccine response.23 Thus, even though MBL and 
CLL patients will only have a short duration exposure to lenalidomide in this trial, we 
hypothesize that there will be significant improvement in immune response to 
Prevnar 13® for patients receiving lenalidomide, whereby the immune response to 
PCV vaccination will be enhanced and that both T cell repertoire and T cell synapse 
levels will be improved.  
 
Sixty patients who have not previously received the Prevnar 13® (PCV13) vaccine will 
be enrolled in the study.  All enrolled patients will receive a dose of PCV13 
approximately 2 weeks after registration.  Half of the study participants will be 
randomized to receive a brief course of low dose lenalidomide (2.5 mg dose for 2 weeks 
followed by 5 mg dose for 4 weeks) while remaining patients will receive only the 
vaccinations (see Schema).   Correlative studies will evaluate immune function and 
response to Prevnar 13 vaccine immune parameter assessments at entry to the trial and 
following vaccination. 
  
2.0 
Goals    
 
2.1 
Primary  
 
 
2.11   To assess the ability of a 6 week course of low dose lenalidomide to 
improve the proportion of patients with MBL and CLL who develop an 
immune response to pneumococcal vaccination as measured by the 
proportion of patients with ≥ 4-fold rise from pre-vaccine (day 15) for ≥ 
2 of the 3 serotypes measured at 28 days post-vaccination by 
opsonophagocytic activity (OPA) of antibodies from sera. 
 
2.2 
Secondary 
 
2.21  
Evaluate disease status by physical exam and complete blood counts in patients 
participating in each arm of the study at the time of the 6 week assessment of 
immune response.   
 
2.22  
Evaluate time to treatment for progressive CLL for patients on each study arm. 
 
2.23 
Evaluate the adverse events profile in each study arm. 


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MCCC Addendum 4 
 
 
Protocol Version Date: May  2, 2017 
2.3 
Correlative Research 
 
2.31   To assess the immune response to pneumococcal vaccination as measured by 
fold-change from pre-vaccine (day 15) to 28 days post-vaccination in 
opsonophagocytic activity (OPA) GMT of antibodies from sera.  
 
2.32 
To assess the immune response to pneumococcal vaccination as measured by 
fold-change from pre-vaccine (day 15) to 28 days post-vaccination in quantitative 
Streptococcus pneumoniae immunoglobulin G (IgG) GMT of antibodies from 
sera. 
 
2.33 
Evaluate the effect of 6 weeks of low dose lenalidomide on global immune 
function including T-cell repertoire, T-cell immune synapse, serum 
immunoglobulin levels, and absolute numbers of T-cell and NK cells. 
 
3.0 
Patient Eligibility    
 
3.1 
Inclusion Criteria  
 
3.11 
Diagnosis of: 
 
a.  CLL according to the NCI criteria (Hallek 2008)24 or  
 
b. SLL according to the WHO criteria (Harris, 1999)25 or 
 
c. MBL according to the consensus criteria (Marti 2006)26 
 
This includes previous documentation of: 
 
• 
Biopsy-proven small lymphocytic lymphoma (Harris, 1999) 
 
or 
• 
Diagnosis of CLL24 or MBL26 as evidenced by all of the following:  
 
 
 Clonal B-cell population in the peripheral blood with 
immunophenotyping consistent with CLL defined as: 
o The population of lymphocytes share both  
B-cell antigens [CD19, CD20 (typically dim expression), or CD23] 
as well as CD5 in the absence of other pan-T-cell markers (CD3, 
CD2, etc.) 
o Clonality as evidenced by κ (kappa) or λ (lambda) light chain 
expression (typically dim immunoglobulin expression) or other 
genetic method (e.g. IGHV analysis) 
 
NOTE: Splenomegaly, hepatomegaly, or lymphadenopathy are not 
required for the diagnosis of CLL 
 
 Patients with a peripheral blood B-cell lymphocyte count of <5 x 109/L 
and no evidence of lymphadenopathy or organomegaly will be classified 
as MBL.  Patients with a peripheral blood B-cell lymphocyte count of <5 
x 109/L who have evidence of lymphadenopathy will be classified as 
SLL.  Patients with a peripheral blood B-cell lymphocyte count > 5 x 
109/L will be considered to have CLL.   


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Protocol Version Date: May  2, 2017 
 
 Before diagnosing MBL, CLL or SLL, mantle cell lymphoma must be 
excluded by demonstrating a negative FISH analysis for 
t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy or negative 
immunohistochemical stains for cyclin D1 on involved tissue biopsy. 
 
3.12 
CLL or SLL patients only (does not apply to MBL patients): Rai Stage 0-1 (both 
CLL and SLL patients can be staged using the Rai system). 
 
3.13 
Patients must not previously have received the Prevnar 13 pneumococcal 
vaccination.  NOTE: Previous vaccination with Pneumovax (PCV23) is 
permitted but must have been at least 365 days prior to registration. 
 
3.14    Patients must be previously untreated (see note) and must NOT have any of the 
following indications for chemotherapy: 
 
• 
Evidence of progressive marrow failure as manifested by the  
development of or worsening anemia (≤11 g/dL) and/or  
thrombocytopenia (≤ 100 x 109/L) not due to autoimmune disease 
 
• 
Symptomatic or progressive lymphadenopathy, splenomegaly or 
hepatomegaly.  
 
• 
One or more of the following disease-related symptoms: 
o Weight loss ≥ 10% within the previous 6 months 
o Extreme fatigue attributed to CLL 
o Fevers >100.4oF for 2 weeks without evidence of infection 
o Drenching night sweats without evidence of infection 
 
Note: 1.  Prior chemotherapy or monoclonal antibody based 
therapy for treatment of CLL or SLL will be 
considered prior therapy.  Nutraceutical treatments 
with no established benefit in CLL (such as 
epigallocatechin gallate or EGCG, found in green tea 
or other herbal treatments) will not be considered 
“prior treatment”. 
 
2.  Prior corticosteroid therapy for an indication other 
than CLL/SLL will not be considered “prior 
treatment”. Previous use of corticosteroids for 
treatment of autoimmune complications of CLL/SLL 
does not constitute prior therapy for CLL/SLL. 
 
3.15 
Age ≥18 years. 
 
3.16 
ECOG Performance Status (PS) 0 or 1 (Appendix III). 
 


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Protocol Version Date: May  2, 2017 
3.17 
The following laboratory values obtained ≤ 14 days prior to registration.   
• 
Absolute neutrophil count (ANC) ≥1000/mm3 
• 
Platelet count ≥ 100,000/mm3 
• 
Hemoglobin ≥11.0 g/dL 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) unless due to Gilbert’s 
disease.  If total bilirubin is >1.5 x ULN, a direct bilirubin should be 
performed and must be <1.5 mg/dL for Gilbert’s to be diagnosed. 
• 
Aspartate transaminase (AST) ≤3 x ULN 
• 
Calculated creatinine clearance must be ≥ 50 ml/min using the Cockcroft-
Gault formula below: 
 
 
3.18 
Provide informed written consent. 
 
3.19a 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
3.19b All study participants must be willing to be registered into the mandatory 
Revlimid REMS® program, and be willing and able to comply with the 
requirements of the REMS® program.  NOTE: Actual registration in the 
Revlimid REMS® program may occur after the patient is randomized since this 
requirement only applies to patients randomized to Arm A. 
 
3.19c  Females of reproductive potential must be willing to adhere to the scheduled 
pregnancy testing as required in the Revlimid REMS® program.  NOTE: This 
requirement only applies to patients randomized to Arm A. 
 
3.19d  Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation 
(patients intolerant to ASA may use warfarin or low molecular weight heparin). 
 
3.19e  Willing to provide blood samples for correlative research purposes (see Sections 
6.12 and 14.0).  
 
3.2 
Exclusion Criteria  
 
3.21 
Palpable lymph nodes >3 cm in maximal dimension. 
 
3.22     Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant women 
• 
Nursing women 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =   
(140 - age)(weight in kg) 
  
 
 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =   
(140 - age)(weight in kg)(0.85) 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 


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Protocol Version Date: May  2, 2017 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.23 
Any of the following comorbid conditions: 
• 
New York Heart Association classification III or IV cardiovascular 
disease (Appendix I). 
• 
Recent myocardial infarction (≤ 30 days) 
• 
Uncontrolled infection 
 
3.24 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy.  NOTE:  Patients known to be HIV 
positive, but without clinical evidence of an immunocompromised state, are 
eligible for this trial. 
 
3.25 
Other active primary malignancy requiring treatment or limiting survival 
to ≤2 years prior to registration. 
 
3.26 
Any radiation therapy ≤28 days prior to registration. 
 
3.27   Any major surgery ≤ 28 days prior to registration. 
 
 
 
3.28 
Current use of corticosteroids. EXCEPTION: Low doses of steroids (≤ 10 mg of 
prednisone or equivalent dose of other steroid) used for treatment of non-
hematologic medical conditions. NOTE: Previous use of corticosteroids is 
allowed. 
 
3.29a  Active hemolytic anemia requiring immunosuppressive therapy or other 
pharmacologic treatment. NOTE: Patients who have a positive Coombs test but 
no evidence of hemolysis are NOT excluded from participation. 
 
3.29b History of deep venous thromboses or pulmonary embolism ≤ 365 days prior to 
registration. 
 
3.29c  Co-existent diffuse large B-cell lymphoma (Richters Transformation) 


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MCCC Addendum 4 
 
Protocol Version Date: May 2, 2017 
4.0 
Test Schedule 
 
Active Monitoring Phase 
Tests & Procedures 
Days Prior to 
Registration 
Day 15 
(+/- 3 days) 
Day 28 
(+/- 7 days) 
Day 43  
(+/- 4 days)  
Observation:  
28 days after 
end of first 
cycle  (Day 72 
+/- 10 days) 
 
≤14 days 
 
 
 
 
Medical history 
X 
 
 
 
 
Adverse event assessment 
X 
X 
 
X 
X 
Physical exam, including PS, weight and vital signs 
X 
 
 
X 
X 
Height 
X 
 
 
 
 
Register in the REVLIMID REMS® program (Arm A only) 
X8 
 
 
 
 
Counseling for the REVLIMID REMS® program (Arm A only) 
 
 
X 
 
 
Tumor measurement by physical exam 
X1 
 
 
X1 
 
Peripheral blood immunophenotyping by flow cytometry  
X2 
 
 
 
 
CBC with differential and reticulocytes 
X 
X 
 
X 
X 
Serum pregnancy test 
X3 
X3 
X3 
X3 
 
Chemistry group (SGOT [AST], SGPT [ALT],  total bilirubin,  serum 
creatinine, calcium, alkaline phosphatase, uric acid, LDH, potassium) 
X 
X 
 
X 
 
Glucose 
X 
 
 
 
 
Direct bilirubin 
X7 
 
 
 
 
CD38 
X2 
 
 
 
 
ZAP-70 
X2 
 
 
 
 
IGHV 
X4 
 
 
 
 
CD49d 
X4 
 
 
 
 
Serum protein electrophoresis  
X 
 
 
X 
 
Beta-2-microglobulin 
X 
 
 
 
 
Peripheral blood CLL FISH panel 
X6 
 
 
 
 
Serum quantitative immunoglobulins (IgG, IgA, IgM)  
X 
 
 
X 
 
Coombs test (monospecific direct coombs IgG and C3) 
X 
 
 
 
 
ECG 
X 
 
 
 
 
Quantitative T & B cells, peripheral blood 
X 
 
 
X 
 


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MCCC Addendum 4 
Protocol Version Date: May  2, 2017 
Prevnar 13 pneumococcal vaccination 
 
X 
 
 
 
Research blood specimens (see Section 14.0) 
X5,R 
X5,R 
 
X5,R 
 
1. Physical exam should measure the spleen and liver noting the maximal distance below the respective costal margins and should record the 
bidimensional diameter of the largest palpable node in each area of involvement including the following sites:  left neck (sub-mandibular, 
cervical, supra-clavicular), right neck (sub-mandibular, cervical, supra-clavicular), left axillary, right axillary, left groin (inguinal, femoral) 
and right groin (inguinal, femoral). 
2. May be waived for patients who have previously had full flow immunophenotyping consistent with CLL performed at Mayo Clinic.  
Similarly, if the patient has previously had CD38 and/or ZAP-70 testing performed at Mayo Clinic, repeat assay is elective after discussing 
with the study chair. 
3. For women of childbearing potential only.  Must follow pregnancy testing requirements as outlined in the Revlimid REMS® program 
material. 
4. If patient has previously had done clinically at Mayo Clinic, this does not need to be repeated. 
5. Blood specimens will be collected and submitted at baseline, Day 15 and Day 43.  Kits are required. 
6. This can be waived if patient has had a clinical FISH performed at Mayo Clinic ≤ 365 days prior to registration. 
7. Only needed if total bilirubin is > 1.5 x ULN. 
8. Actual registration in the Revlimid REMS® program will occur after the patient is randomized and may fall outside of this window. 
R Research funded (see Section 19.0).  Will be charged to study and not to patient’s account. 
 
 


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MCCC Addendum 4 
 
 
Protocol Version Date: May 2, 2017 
5.0 
Stratification Factors:  
 
5.1 
Age:   <65 vs. >65 
 
5.2 
Rai stage:   MBL or 0 vs. I 
 
5.3 
Previous Pneumovax: Yes vs. no 
 
6.0  
Registration/Randomization Procedures 
 
6.1 
Registration Procedures 
 
6.11 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration/randomization application.  The   
registration/randomization application is available 24 hours a day, 7 days a week.  
Back up and/or system support contact information is available on the Web site.  
If unable to access the Web site, call the MCCC Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
 
The instructions for the registration/randomization application are available on 
the MCCC web page (http://ccswww.mayo.edu/training/) and detail the 
process for completing and confirming patient registration.  Prior to initiation of 
protocol treatment, this process must be completed in its entirety and a MCCC 
subject ID number must be available as noted in the instructions.  It is the 
responsibility of the individual registering the patient to confirm the process has 
been successfully completed prior to release of the study agent.  Patient 
registration via the registration/randomization application can be confirmed in 
any of the following ways: 
• 
Contact the MCCC Registration Office 
.  If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
 
6.12 
Correlative Research 
 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.19e and 14.0). 
 
6.13 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
(fax: 
).  If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
 
6.14 
Prior to accepting the registration, the registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.15 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research of CLL at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
 
6.16 
Treatment on this protocol must commence at Mayo Clinic Rochester, Mayo 
Clinic Arizona, or Mayo Clinic Florida institution under the supervision of a 
medical oncologist or hematologist. 
 
6.17 
Treatment cannot begin prior to registration and must begin ≤ 21 days after 
registration. 
 
6.18 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.19a 
All required baseline symptoms (see Section 10.6) must be documented and 
graded. 
 
6.19b Study drug (Prevnar 13®) is available on site.  
 
6.2 
Randomization Procedures 
 
6.21 
The factors defined in Section 5.0, together with the registering membership, will 
be used as stratification factors. 
 
6.22  
After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups using the Pocock and Simon dynamic allocation procedure 
which balances the marginal distributions of the stratification factors between the 
treatment groups (35).   
 
• 
Arm A (lenalidomide + Prevnar 13® 
• 
Arm B (Prevnar 13®) 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
 
7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule  
 
Arm 
Agent 
Dose Level 
Route 
Day 
A 
lenalidomide 
2.5 mg 
Oral 
1-14 
 
lenalidomide 
5 mg* 
Oral  
15-42 
 
Aspirin  
325 mg 
Oral 
1-42 
 
Prevnar 
13®** 
1 dose 
IM  
15 
B 
Prevnar 
13®** 
1 dose 
IM  
15 
 
* Unless dose reduced for adverse events, see Section 8.0 
** Prevnar 13® vaccination should be administered on day 15 regardless of lenalidomide 
toxicity unless treating physician determines it should be held.  If Prevnar 13® held, it 
should be administered as soon as deemed appropriate by treating physician. 
 
7.2 
For this protocol, the patient must return to the consenting institution for evaluation on 
Day 15 (+/-3 days) and Day 43 (+/-4 days) of the study.   
  
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table.  If multiple adverse events are seen, administer 
dose based on greatest reduction required for any single adverse event observed.   
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
 
8.1  
ARM A: Dose Levels (Based on Adverse Events in Tables 8.2). 
Dose 
Level 
Lenalidomide 
Days 1-14 
Lenalidomide 
Days 15-42 
 0 
 
2.5 mg p.o. once daily 
5 mg p.o once daily 
-1 
 
2.5 mg p.o. every other day 
2.5 mg p.o. once daily 
-2 
 
2.5 mg p.o. Mondays and Thursdays 
2.5 mg p.o. every other day 
* Dose level 0 refers to the starting dose. 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
 
8.2 
Lenalidomide Dose Modifications 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
Days 1-42 
Blood and lymphatic 
system disorders 
Anemia 
≥ Grade 3 
 
Transfuse red blood cells at physician 
discretion.  Continue current dose level.  
For repeat episodes of anemia related to 
lenalidomide, dose may be reduced at 
physician’s discretion.    
 
Anemia 
≤ Grade 2 
 
Transfuse red blood cells at physician 
discretion.  Continue current dose level.    
Cardiac disorders  
Sinus bradycardia or 
Ventricular arrhythmia 
Grade 2 
 
Omit lenalidomide (interrupt dose). Re-
evaluate toxicity weekly.  When 
symptoms resolve to <grade 1, decrease 
lenalidomide by 1 dose level and restart 
lenalidomide at the discretion of the 
treating physician.  If symptoms do not 
resolve to <grade 1 by Day 35, 
discontinue lenalidomide treatment. 
 
Sinus bradycardia or 
Ventricular arrhythmia 
≥Grade 3 
 
Discontinue lenalidomide treatment. 
Endocrine disorders 
Hyperthyroidism 
≥ Grade 2 
 
Omit lenalidomide (interrupt dose). 
Initiate appropriate therapy.  Reassess in 2 
weeks.  If symptoms resolve to <grade 1 
decrease lenalidomide by 1 dose level and 
resume treatment.  If symptoms do not 
resolve to <grade 1 by Day 35, 
discontinue lenalidomide. 
 
Hypothyroidism 
≥ Grade 2 
 
Omit lenalidomide (interrupt dose). 
Initiate appropriate therapy for 
hypothyroidism.  Reassess in 2 weeks.  If 
symptoms resolve to <grade 1 decrease 
lenalidomide by 1 dose level and resume 
treatment.  If symptoms do not resolve to 
<grade 1 by Day 35, discontinue 
lenalidomide. 
 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
Days 1-42 
Investigations 
Platelet count decreased 
≥ Grade 3 
 
Omit lenalidomide (interrupt dose). Omit 
anti-coagulant or Aspirin while platelet 
count <50 x 109/liter.  May re-initiate 
when platelet count >75 x 109/liter (must 
re-initiate at time lenalidomide restarted).  
Recheck CBC with platelet count weekly. 
If platelet count increases to >75 x 
109/liter, decrease lenalidomide by 1 dose 
level and restart treatment.  If platelet 
count does not increase to >75 x 109/liter 
by Day 35, discontinue lenalidomide. 
 
Neutrophil count 
decreased 
≥ Grade 3 
 
Omit lenalidomide (interrupt dose). 
Recheck neutrophil count weekly.  If 
neutrophil count > 1.0 x 109/liter, 
decrease lenalidomide by 1 dose level and 
restart treatment.  If neutrophil count does 
not increase to > 1.0 x 109/liter by Day 
35, discontinue lenalidomide. 
 
Growth factor support may be 
administered at the discretion of the 
treating physician. See Section 9.2. 
Neoplasms benign, 
malignant and 
unspecified (incl 
cysts and polyps) 
Tumor pain 
≥ Grade 3 
 
Note: Differentiate tumor flare from 
disease progression. Treat with naproxen 
500 mg p.o. BID.  Continue lenalidomide 
during flare reaction.  If patient does not 
experience adequate relief after 2 days of 
naproxen, add prednisone 20 mg p.o. 
daily.  Steroids should be tapered as 
tolerated at the discretion of the treating 
physician. 
 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
Days 1-42 
Nervous system 
disorders 
Peripheral motor 
neuropathy or Peripheral 
sensory neuropathy 
Grade 3 
 
Omit lenalidomide (interrupt dose). Re-
evaluate toxicity weekly.  When 
symptoms resolve to <grade 1, decrease 
lenalidomide by 1 dose level and resume 
treatment.  If symptoms do not resolve to 
<grade 1 by Day 35, discontinue 
lenalidomide. 
 
Peripheral motor 
neuropathy or Peripheral 
sensory neuropathy 
Grade 4 
 
Discontinue lenalidomide 
Skin and 
subcutaneous tissue 
disorders 
Rash maculo-papular 
Grade 3 
 
Omit lenalidomide (interrupt dose). 
Initiate supportive care measures as 
appropriate.  Re-evaluate toxicity weekly.  
When symptoms resolve to <grade 1, 
decrease lenalidomide by 1 dose level and 
resume treatment.  If symptoms do not 
resolve to <grade 1 by Day 35, 
discontinue lenalidomide. 
 
Stevens-Johnson 
syndrome 
≥ Grade 3 
 
Discontinue lenalidomide 
 
Erythema multiforme 
≥ Grade 3 
 
Discontinue lenalidomide. 
Vascular disorders 
Thromboembolic event 
≥ Grade 3 
 
Discontinue lenalidomide. Initiate anti-
coagulation as appropriate.   
Other non-
hematologic 
≥ Grade 3 as per NCI 
Common Terminology 
Criteria for Adverse 
Events v4.0 that does 
NOT respond to 
supportive care 
measures  
 
Omit lenalidomide (interrupt dose). Re-
evaluate toxicity weekly.  When 
symptoms resolve to <grade 1, decrease 
lenalidomide by 1 dose level and restart 
treatment at the discretion of the treating 
physician.  If symptoms do not resolve to 
<grade 1 by Day 35, discontinue 
lenalidomide treatment. 
 
 
8.3  
Prevnar 13 will be given per protocol regardless of whether or not lenalidomide dose 
reduced or omitted.


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MCCC Addendum 4 
 
 
Protocol Version Date: May 2, 2017 
 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
 
NOTE:  If the patient experiences a significant adverse event requiring a dose reduction, then the 
dose will remain lowered through day 42.   
 
NOTE:  Adverse events requiring a dose-reduction step for lenalidomide beyond the two dose-
reduction steps (levels –1 and –2) will be at the discretion of the treating physician, if the decision 
is made for the patient to be kept on study.  These dose reductions must be clearly recorded in 
reported clinical data.  
 
9.0 
Ancillary Treatment/Supportive Care 
 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors should 
follow published guidelines of the :   ASCO 2006 Update of Recommendations for the 
Use of White Blood Cell Growth Factors:  An Evidence-Based Clinical Practice 
Guideline Journal of Clinical Oncology 2006;24:3187-3205.  
 
9.3 
Patients should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, and antiemetics when appropriate.  Any blood transfusions 
administered must be irradiated blood products to reduce risk of transfusion 
mediated graft versus host disease in CLL patients receiving T-cell suppressive 
therapy.  Leukocyte reduction of all blood products for patients on protocol is 
also required. All blood products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study treatment 
administration until 30 days after the final dose will be recorded in the medical 
records. 
 
9.4 
Diarrhea:  This could be managed conservatively with loperamide.  The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
9.5 
DVT prophylaxis: As indicated in section 7.0, all patients receiving lenalidomide (Arm 
A) will be required to take aspirin 325 mg/day for DVT Prophylaxis during the study as 
long as they are on lenalidomide. Patients who are intolerant or allergic to aspirin may 
use low molecular weight heparin at prophylactic dose level. 
 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
9.6 
Treatment of Tumor Flares:  Patients experiencing a tumor flare during lenalidomide 
therapy will be treated with naproxen 500 mg p.o. BID until symptoms resolve.  Study  
medications will be continued through flare symptoms if tolerated by patient.  If patient 
does not experience adequate relief after 2 days of naproxen therapy, add prednisone 20 
mg p.o. each day.  Steroids should be tapered as tolerated at the discretion of the treating 
physician. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website:  
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm)    
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
 
10.12 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).  Grade is an essential element of the Guidelines and, in 
general, relates to severity for the purposes of regulatory reporting to NCI. 
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same 
as serious AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol and the study specific consent 
form. 
 
• 
Unexpected AEs are those not listed in the agent-specific information provided in 
Section 15.0 of the protocol and the study specific consent form. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  
 
10.31  AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME Arm 
 
NOTE:  When a commercial agent(s) is (are) used on the same 
treatment arm as the investigational agent/intervention (also, 
investigational drug, biologic, cellular product, or other 
investigational therapy under an IND), the entire combination (arm) is 
then considered an investigational intervention for reporting. 
 
Routine Reporting 
 
• Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent 
is stated in the protocol.  See Section 10.6. 
 
Expedited Reporting 
 
• An AE that occurs on a combination study must be assessed in accordance with 
the guidelines for investigational agents/interventions in Section 10.4, and where 
indicated, an expedited report must be submitted. 
 
• An AE that occurs prior to administration of the investigational 
agent/intervention must be assessed as specified in the protocol. In general, 
only Grade 4 and 5 AEs that are unexpected with at least possible 
attribution to the commercial agent require an expedited report.  Refer to 
Section 10.4 for specific AE reporting requirements or exceptions. 
 
• Commercial agent expedited reports must be submitted to the FDA via 
MedWatch or Celgene SAE form. 
 
• An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent.  Therefore, if an expected AE (for the 
commercial agent) occurs with a higher degree of severity, expedited reporting 
is required.  The clinical investigator must determine severity. 
 






MC138E 
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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
 
10.41 
Special Situations for Expedited Reporting 
 
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events 
 
An expedited report may not be required for specific Grade 1, 2, 3 and 4 Serious 
Adverse Events where the AE is EXPECTED. Any protocol specific reporting 
procedures MUST BE SPECIFIED BELOW and will supercede the standard 
Expedited Adverse Event Reporting Requirements.  Note:  These adverse events 
must still be reported through the routine reporting mechanism [i.e. 
Nadir/Adverse Events Form]; see footnote 1. 
 
CTCAE 
Category 
Adverse Event 
Grade 
Attribution 
Comments 
Blood and 
lymphatic system 
disorders 
Anemia 
3 or 4 
All 
This frequent event in patients with 
CLL will be reported through the 
routine reporting mechanism 
Investigations 
Platelet count 
decreased 
3 or 4 
All  
This frequent event in patients with 
CLL will be reported through the 
routine reporting mechanism 
Neutrophil count 
decreased 
3 or 4 
All  
This frequent event in patients with 
CLL will be reported through the 
routine reporting mechanism 
Lymphocyte 
count decreased 
3 or 4 
All  
This frequent event in patients with 
CLL will be reported through the 
routine reporting mechanism 
White blood cell 
decreased 
3 or 4 
All  
This frequent event in patients with 
CLL will be reported through the 
routine reporting mechanism 
1  These exceptions only apply if the adverse event does not result in 
hospitalization.  If the adverse event results in hospitalization, then the standard 
expedited adverse events reporting requirements must be followed. 
 
Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
10.5 
Other Required Reporting 
 
10.51 Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
abnormities or birth defects, must be reported immediately if they occur at any time 
following treatment with an agent under an IND/IDE since they are considered to be a 
serious AE and must be reported to the sponsor as specified in 21 CFR 312.64(b). 
 
10.52 Death 
 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires expedited 
reporting within 24-hours. 
 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal:  A disorder characterized by cessation of life 
during the first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be attributed to a CTCAE 
term associated with Grade 5. 
 
• 
Sudden death NOS:  A sudden (defined as instant or within one hour 
of the onset of symptoms) or an unobserved cessation of life that 
cannot be attributed to a CTCAE term associated with Grade 5. 
 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease)” under the system organ 
class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
 
10.53 Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
• 
All secondary malignancies that occur following treatment with an agent 
under an IND/IDE be reported. Three options are available to describe the 
event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
10.54 
Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior malignancy 
(and is NOT a metastasis from the initial malignancy).  Second malignancies 
require ONLY routine reporting. 
 
10.55 Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject 
is on lenalidomide, or within  28 days of the subject’s last dose of lenalidomide, 
are considered immediately reportable events. Lenalidomide  is to be 
discontinued immediately. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by 
facsimile or email using the Pregnancy Initial Report Form (see Forms Packet). 
The female subject should be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the 
pregnancy, and must notify Celgene Drug Safety immediately about the outcome 
of the pregnancy (either normal or abnormal outcome) using the Pregnancy 
Follow-up Report Form (see Forms Packet).  If the outcome of the pregnancy 
was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the 
serious criteria, it must be reported as an SAE to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the IP should also be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form.  
 




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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
10.612 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.613  Grade 5 AEs (Deaths) 
 
10.6131  
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.6132 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
10.62    Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
11.0 
Treatment Evaluation  
 
11.1 
Response to Prevnar 13® Vaccine 
 
The goal of this study is to determine response to Prevnar 13® vaccine.  The two most 
common serologic methods for quantifying and evaluating the function of antibodies 
induced by pneumococcal vaccination are quantification of Streptococcus pneumoniae 
IgG antibodies and measurement of opsonophagocytic activity (OPA) of antibodies from 
sera of vaccinated individuals.  The OPA assay is a functional antibody assay that is 
important for the evaluation of candidate vaccines and is a requirement for the licensure 
of new pneumococcal conjugate vaccine formulations. OPA reflects in vivo mechanisms 
of defense against pneumococcal infection. The measurement of functional antibodies 
has been shown to better correlate with protection in infant populations and it is 
also likely to be a better indicator for elderly populations than the measurement 
of antibodies specific to the capsular polysaccharides by ELISA assay.27  While there 
is no defined correlate of protection for pneumococcal vaccines, it is thought that OPA 
titers are associated with protection against invasive pneumococcal disease.  The primary 
endpoint for Prevnar 13® adult clinical trials that led to the FDA approval of Prevnar 
13® relied on immunogenicity endpoints of OPA geometric mean titer (GMT) and 
proportion achieving at least 4-fold increase in OPA titer.28 Nevertheless, even when 
assessing OPA titers, most vaccine trials also measure and report quantitative IgG 
antibodies specific to Streptococcus pneumoniae serotypes. 
 
Accordingly, the Primary outcome for vaccine immunogenicity in this trial will be: OPA 
titers against 3 pneumococcal serotypes (4, 9V, 23F) included PCV13 vaccine will be 
measured at pre-vaccine (day 15) and 28 days after immunization (e.g. at the day 43 
evaluation; fold change from pre-vaccination sera responses).  
 
o 
Overall Prevnar 13® response will be defined as ≥ 4-fold rise from pre-vaccine 
(day 15) for ≥ 2 of the 3 serotypes measured at 28 days post-vaccination.  
 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
11.2  
CLL/SLL Disease Status: 
 
This study does not intend to treat patients’ underlying CLL/SLL.  Accordingly, the 
protocol   does not require bone marrow biopsies or CT imaging and response assignment 
according to the IWCLL/NCI criteria is therefore not possible.  Patients “disease status” 
based on physical exam and complete blood counts, however, will be assessed at the time 
of the day 43 visit. 
 
11.21 CLL/SLL:    Disease status will be classified as one of the following using the 
criteria below which are based on the IWCLL criteria without the bone marrow 
biopsy results24: 
 
progressive disease  
 
stable disease 
 
partial response  
 
clinical complete response (or clinical complete response with incomplete 
marrow recovery) 
 
11.22 MBL:  Disease status will be classified as one of the following criteria based on 
the IWCLL criteria for progressive disease: 
 
progressive disease  
 
not progressive disease  
 
11.3 
For the purposes of this study, patient’s disease status will be evaluated at the time of the 
day 43 evaluation.  Although the patient will be periodically seen Days 1 - 42, response 
evaluations will not occur on those dates. 
 
 
 
NOTE: Information from CT scans is not considered in the standard classification of 
response. 
 
11.4 
Definitions 
 
The NCI Working Group criteria (Hallek, 2008) will be used to assess response to 
therapy.  
 
11.41 COMPLETE CLINICAL RESPONSE (CCR) requires all of the following at the Day 
43 evaluation:   
 
11.411 Absence of lymphadenopathy (e.g. lymph nodes >1.5 cm) by physical 
examination. 
 
11.412 No hepatomegaly or splenomegaly by physical examination. 
 
11.413 Absence of constitutional symptoms. 
 
11.414 CBC demonstrating: 
• 
Peripheral blood lymphocytes <4000/µL. 
• 
Neutrophils >1500/µL 
• 
Platelets >100,000/ µL (untransfused). 
• 
Hemoglobin >11.0 g/dL (untransfused). 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
 
Note: Patients who fulfill all criteria for a CCR but who have a persistent 
anemia, thrombocytopenia, or neutropenia related to drug toxicity rather 
than residual CLL will be classified as CCR with incomplete marrow 
recovery (CCRi) according to the international criteria (Hallek, 2008). 
 
11.42 PARTIAL RESPONSE (PR): PR requires the patient exhibits at least two of the 
features in Sections 11.421, 11.422, and 11.423 below (if abnormal prior to 
therapy) as well as one or more of the remaining features (Sections 11.424, 
11.425, 11.426) at the day 43 evaluation.  For patients with Rai stage 0 disease 
(e.g. no palpable nodes or organomegaly) and those with MBL a 50% reduction 
in lymphocytosis will be considered to represent a PR.  In addition to the 
parameters listed below, the presence or absence of constitutional symptoms will 
be recorded.   
 
11.421 ≥ 50% decrease in peripheral blood lymphocyte count from the 
pretreatment baseline value. 
 
11.422 ≥ 50% reduction in the sum of the products of the maximal perpendicular 
diameters of the largest measured node or nodal masses in the right and 
left cervical, axillary, and inguinal lymph node regions on physical 
examination.  
 
11.423 ≥ 50% reduction in size of liver and/or spleen as measured by physical 
exam noting the maximal distance below the respective costal margins of 
palpable hepatosplenomegaly during rest.   
 
11.424 Neutrophils >1500/ul or 50% improvement over baseline. 
 
11.425 Platelets >100,000/ul or 50% increase over baseline. 
 
11.426  Hemoglobin >11.0 gm/dl or 50% increase over baseline without transfusions. 
 
11.43 PROGRESSION (PD):  Patients will be considered to have PD according to the 
NCI criteria24 if they experience any of the following: 
 
11.431 ≥ 50% increase in the sum of the products of at least 2 lymph nodes (at 
least one node must be ≥2 cm) or the appearance of new palpable lymph 
nodes >1.5 cm not due to a tumor flare.  Enlargements or the appearance 
of new nodes due to a tumor flare do NOT qualify as progression.  If 
there is uncertainty as to whether lymph node enlargement at the Day 43 
evaluation represents tumor flare, repeat examination 2-4 weeks after the 
protocol specified discontinuation of lenalidomide can be used to help 
make this determination. 
 
11.432 ≥ 50% increase in the size of the liver and/or spleen as determined by 
measurement below the respective costal margin on 2 consecutive 
determinations 2 weeks apart and with a minimum of a ≥ 2 cm increase 
in size from baseline; or appearance of hepatomegaly or splenomegaly 
which was not previously present at baseline and not due to a tumor 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
flare. If there is uncertainty as to whether an increase in liver/spleen size 
at the Day 43 evaluation represents tumor flare, repeat examination 2-4 
weeks after the protocol specified discontinuation of lenalidomide can be 
used to help make this determination. 
 
11.433 Transformation to a more aggressive histology (e.g. Richter’s 
transformation). 
 
 
NOTE:  If a patient develops DLBCL at any time, it will be considered 
progressive disease.   If the patient develops any other hematological 
malignancy while on study, it will not be considered progressive disease. 
 
11.434 ≥ 50% increase in the absolute number of circulating lymphocytes NOT 
due to infection or tumor flare (taking as reference for progressive 
disease the smallest absolute lymphocyte count recorded since the 
treatment started).   
 
11.435 Cytopenias due to lenalidomide toxicity will not be considered to 
represent disease progression.  In the absence of progression as defined 
by 11.431, 11.432, 11.433, 11.434 above, the presence of a ≥ 2 g/dL 
decrease in HGB, or ≥ 50% decrease in platelet count, or absolute 
neutrophil count will NOT be considered progression.  Work-up of such 
decreases to exclude auto-immune hemolytic anemia, pure red cell 
aplasia, or idiopathic thrombocytopenic purpura (ITP) should be 
considered. 
 
11.44 STABLE DISEASE (SD): Patients who do not meet criteria for CCR (or CCRi), 
PR, or PD will be classified as having “stable disease”. 
 
11.45 Not progressive disease (Not PD):  The patient did not meet the criteria for 
progression per section 11.43  (MBL patients only). 
 


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MCCC Addendum 4 
 
 
Protocol Version Date: May 2, 2017 
11.5 
Summary Definition of objective response for patients with B–CLL 
 
 
CCR1 
CCRi2 
PR3 
PD4 
PHYSICAL EXAM  
Nodes5 
None 
None 
≥50%  
≥50% , new nodes 
 
Liver/spleen6 
Not palpable 
Not palpable 
≥50%  
≥50% , newly palpable 
 
Symptoms 
None 
None 
N/A 
N/A 
PERIPHERAL BLOOD 
ANC 
>1500/µL 
See footnote 2 
>1500/µL  
See footnote 4 
 
Platelets 
>100,000/µL 
See footnote 2 
>100,00/µL  
See footnote 4 
 
Hemoglobin 
>11.0 g/dL without 
transfusion 
See footnote 2 
>11.0 g/dL  
See footnote 4 
 
Lymphocytes 
<4000/µL 
<4000/µL 
≥50%  
≥50%  to at least 
5,000/µL 
BONE 
MARROW 
N/A 
N/A 
N/A 
N/A 
1. 
Clinical complete response (CCR) requires fulfillment of all physical exam and peripheral blood criteria as noted in the table above.  No bone marrow biopsy is required to call a patient a 
CCR.    
2.      Patients who fulfill all criteria for a CCR but who have a persistent anemia, thrombocytopenia, or neutropenia related to drug toxicity rather than residual CLL will be classified as CCR 
with incomplete marrow recovery (CCRi).   
3. 
Partial response (PR) requires fulfillment of at least two of the above-noted decrease in circulating lymphocytes, regression in adenopathy and regression in hepatosplenomegaly, and at 
least one other parameter listed above for a duration of >2 months after  the completion of treatment.  See Section 11.42. 
4. 
Progression:  Fulfilling the criteria as noted in section 11.43.   
5. 
Measurement of lymphadenopathy will be determined on physical exam by adding the sum of the products of the maximal perpendicular diameters of measured lesion(s).  For purposes of 
determining CCR all nodes on physical exam need to be ≤ 1.5 cm in maximal dimension or documented to be free of CLL by biopsy. NOTE: Information from CT scans scans regarding 
lymphadenopathy is not considered in the standard classification of response. 
6.  
Measurement of hepatosplenomegaly will be determined by noting the maximal distance below the respective costal margins of palpable hepatosplenomegaly during rest (e.g., not during 
deep inspiration). NOTE: Information from CT scans regarding hepatosplenomegaly is not considered in the standard classification of response. 


MC138E 
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MCCC Addendum 4 
 
 
Protocol Version Date: May 2, 2017 
 
12.0 
Descriptive Factors 
 
12.1 
CD38+ expression:  Positive (≥30%) vs. negative (<30%). 
 
12.2 
Chromosomal anomalies as detected by FISH:  13q- vs. 12+ vs. 11q- vs. 17p- vs. other 
abnormality vs. normal karyotype. 
 
12.3 
IGHV mutation status:  Mutated (≥2%) vs. unmutated (<2%) vs. indeterminate.  
 
12.4 
ZAP-70 expression:  Positive (≥20%) vs. negative (<20%).  
 
12.5 
CD49d expression:  Positive (≥45%) vs. negative (<45%). 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
NOTE:  As of Addendum 4, Event monitoring will no longer be required 
 
13.1 
After completion of the Day 43 response to vaccine evaluation, patients will discontinue 
treatment and enter one cycle of OBSERVATION (28 days after end of first cycle +/- 10 
days) and then enter EVENT MONITORING. 
 
13.2 
If Lenalidomide is discontinued due to patient refusal or noncompliance, unacceptable 
toxicity, or intercurrent illness that makes treatment assessment difficult and the patient 
received the Prevnar 13 vaccine, they will receive their Day 43 response to vaccine 
evaluation at which point they will then enter one cycle of OBSERVATION (28 days 
after end of first cycle +/- 10 days) and then enter EVENT MONITORING.   
 
13.3   If a patient on Arm A does not receive the Prevnar 13 vaccine, they will discontinue 
treatment and go directly to event monitoring per Section 18.0 of the protocol.   If a 
patient on Arm B does not receive the Prevnar 13 vaccine, they will be deemed a cancel 
and will be removed from the study per Section 13.6 of the protocol. 
 
13.4 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.   
• 
If the patient received treatment, the patient will go directly to event monitoring.  All 
data up until the point of confirmation of ineligibility must be submitted.  Event 
monitoring will be required per Section 18.0 of the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted.  No further data submission 
is necessary.  
 
Note:  Due to the nature of the disease, if the patient is diagnosed with DLBCL within the 
first cycle of treatment, it will be assumed that the DLBCL was present at registration.  
The patient will be deemed ineligible per Sec 3.29c. 
 
13.5 
A patient is deemed a major violation, if protocol requirements regarding Lenalidomide 
treatment during Days 1-42 are severely violated such that evaluability for primary end 
point is questionable.  All data up until the point of confirmation of a major violation 


MC138E 
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MCCC Addendum 4 
 
 
Protocol Version Date: May  2, 2017 
must be submitted.  The patient will go directly to the event-monitoring phase of the 
study.  Event monitoring will be required per Section 18.0 of the protocol. 
 
13.6 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any Lenalidomide (Arm A) or Prevnar (Arm B) is given .  On-study material and the End 
of Active Treatment/Cancel Notification Form must be submitted.  No further data 
submission is necessary. 
 
 
 
13.7      A patient will be deemed a flagr if they received Lenalidomide and then failed to receive 
the Prevnar 13 vaccine (Arm A).   Patients classified as a flagr will not be evaluable for 
response and will be replaced. 
 


MC138E 
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MCCC Addendum 4 
 
 
Protocol Version Date: May 2, 2017 
 
14.0 
Body Fluid Biospecimens   
 
14.1  
The collection of blood/blood products is mandatory for the translational/pharmacologic research component of this study. 
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Baseline  
Day 15 
visit  
Day 43 
visit 
Process 
at site? 
(Yes or 
No) 
Temperature 
 Conditions 
for Storage 
/Shipping  
 
T cell immune 
function 
(repertoire, 
synapse) and 
plasma cytokine 
profile (14.21) 
Mandatory 
Whole 
Blood  
Sodium 
heparin 
(green) 
10 mL 
(5) 
X 
X 
X 
No 
Refrigerate/ 
Cold pack. 
Specific immune 
response to 
Prevnar 13 
vaccination 
(Streptococcus 
pneumoniae IgG 
antibodies,, 
OPA)(14.22) 
Mandatory 
Serum 
(red top) 
10 mL 
(2) 
X 
X 
X 
No 
Refrigerate/ 
Cold pack. 


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MCCC Addendum 4 
 
 
Protocol Version Date: May 2, 2017 
 
14.2  
Background and Methodology  
 
14.21  Global immune changes in CLL T cell function.  
 
a) T cell repertoire: T lymphocytes recognize complexes of major 
histocompatibility complex gene products and bound, processed peptides 
through T cell receptors (TcRs) that are heteroduplexes of alpha and beta 
subunits.  T lymphocyte populations are characterized by diverse TcR 
repertoires that have been hypothesized to be essential for effective T 
lymphocyte responses to large numbers of pathogens. The importance of 
diversity in T lymphocyte populations for maintenance of robust immune 
responses relevant to human health has driven the development of methods to 
quantitate TcR repertoire diversity. We have developed a novel method to 
analyze diversity of murine TcR beta transcripts29 designated as the BV:BJ 
matrix method. This is based on amplification in real-time PCRs using 252 
combinations of BV (beta variable) and BJ (beta-joining)-specific primer 
pairs that derive from 21 BV and 12 BJ genes.  This method is able to 
reliably analyze TcR repertoire diversity in total populations of T 
lymphocytes.  Our studies and others in CLL patients have shown significant 
deficits in repertoire along with individual T cell populations that have major 
expansions.  
 
Processing: Peripheral blood mono-nuclear cells will be isolated by Ficoll-
hypaque separation and frozen in liquid nitrogen.  Malignant CD19+ CLL B-
cells will be positively selected while CD3+ T-cells will be negatively 
selected using MACS cell isolation kits with an autoMACSTM Pro Separator 
(Miltenyi Biotec, Auburn, CA). 
 
Total RNA will be extracted, and residual genomic DNA will be removed 
with an RNase-Free DNase Set (Qiagen) and used to assess T-cell repertoire. 
Extracted RNA levels from 106 CD3+ T-cells will typically range anywhere 
from 2-4 µg.   
 
Assessment of T-cell repertoire using a BV-BJ Matrix Method: In brief, this 
method is designed to generate a single estimate of repertoire diversity and 
increase the success of identifying and sequencing transcripts that are 
expressed by expanded T-cell clonotypes.  Since BV and BJ genes belong to 
relatively closely related families, BV- and BJ-specific primers are 
rigorously selected to ensure specificity and comparable efficiency.29,30  
 
b) T regulatory cells: In addition, a relative increase of circulating regulatory 
CD4+ T cells (T-regs) and their function has been observed in CLL, 
providing yet another explanation for increased infections and diminished 
responses to vaccinations.   
 
Processing: T-cells isolated by magnetic bead sort (outlined above), will 
undergo immunophenotyping by flow cytometry. 
 
c) T cell synapse: In CLL leukemic B cells inhibit normal T lymphocytes 
through the impairment of the formation of the immunologic synapse in a 


MC138E 
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MCCC Addendum 4 
 
 
Protocol Version Date: May  2, 2017 
contact-dependent manner. Because of the leukemic nature of CLL, these 
inhibiting cell contacts can occur ubiquitously. The resulting state of cellular 
immunodeficiency offers a plausible explanation for the frequent infections 
and secondary cancers seen in CLL. We have just reported on the 
administration of a 6 month course of lenalidomide in CLL patients 
following  chemoimmunotherapy (CIT) where we found enhanced T cell 
synapse levels for the responding patients.31 
 
Processing: T-cell: APC immune synapse bioassays: The ability of CD3+ T-
cells to interact (% conjugation) with APCs (baseline fluorescently labeled 
CLL cells pulsed with superantigen, sAg) and assemble signaling complexes 
to the immune synapse site will be visualized and quantified using combined 
multi-color high-resolution imaging flow cytometry (ImageStream) and 
confocal (Zeiss)  Imagestream/Axiovision quantitative image analysis 
software will characterize and analyze the functional organization of T-cell 
synapses including the receptor layer (CD4, CD8, co-signaling molecules), 
the signaling layer and the cytoskeletal layer as previously described.32,33 
Granzyme B+ will act as a biomarker for CTL lytic synapses. These data will 
then be exported for statistical analysis to generate mean values at each 
treatment time-point using the published approach.32,33  
 
14.22  Specific immune response to Prevnar 13® vaccination:  
 
Immunity following pneumococcal disease is directed primarily against the 
capsular polysaccharide of the bacteria serotype involved. Antibody mediated 
killing of Streptococcus pneumoniae by phagocytes is an important mechanism 
of protection. The two most common serologic methods for quantifying and 
evaluating the function of antibodies induced by pneumococcal vaccination are 
IgG quantification by enzyme-linked immunosorbent assay (ELISA) and 
measurement of opsonophagocytic activity (OPA) of antibodies from sera of 
vaccinated individuals.  The OPA assay is a functional antibody assay that is 
important for the evaluation of candidate vaccines and is a requirement for the 
licensure of new pneumococcal conjugate vaccine formulations. OPA reflects in 
vivo mechanisms of defense against pneumococcal infection. The measurement 
of functional antibodies has been shown to better correlate with protection 
in infant populations and it is also likely to be a better indicator for elderly 
populations than the measurement of antibodies specific to the capsular 
polysaccharides by ELISA assay.27  While there is no defined correlate of 
protection for pneumococcal vaccines, it is thought that OPA titers are associated 
with protection against invasive pneumococcal disease.  The primary endpoint 
for Prevnar 13® adult clinical trials that led to the FDA approval of Prevnar 13® 
relied on immunogenicity endpoints of OPA geometric mean ratio (GMT) and 
proportion achieving at least 4-fold increase in OPA titer.28 Nevertheless, even 
when assessing OPA titers, most vaccine trials also measure and report 
quantitative IgG antibodies specific to Streptococcus pneumoniae serotypes. 
 
• 
We will report pre-vaccination (baseline) and Day 28 post-vaccination 
OPA GMTs for each serotype (4, 9V, 23F) in vaccine group and vaccine 
group + lenalidomide.  






MC138E 
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MCCC Addendum 4 
 
 
Protocol Version Date: May  2, 2017 
15.13 Preparation and storage: Lenalidomide should be stored at room 
temperature, between 59 and 86ºF (15-30ºC).  Store drug away from direct 
sunlight.   
 
15.14 Administration:  Capsules are administered by mouth daily with water. Patients 
should not break, chew or open the capsules.  
 
 
15.15 Pharmacokinetic information: 
a)  Absorption – Lenalidomide is rapidly absorbed following oral administration 
to subjects with multiple myeloma or MDS, with maximum plasma 
concentrations occurring between 0.5 and  1.5 hours post-dose. 
Co-administration with a high-fat and high-calorie meal in healthy subjects 
reduced the extent of absorption, resulting in an approximately 20% decrease in 
AUC and 50% decrease in Cmax in plasma.   
 
In the pivotal MM and MDS registration trials where the efficacy and safety were 
established for lenalidomide, the drug was administered without regard to food 
intake. Thus, lenalidomide can be administered with or without food. 
 
Multiple dosing (up to 100 mg BID) did not cause marked drug accumulation.   
 
 
b)  Distribution – In vitro (14C)-lenalidomide binding to plasma proteins is 
approximately 30%. 
 
c)  Metabolism – Lenalidomide undergoes limited metabolism. Unchanged 
lenalidomide is the predominant circulating component in humans. Two 
identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each 
constitutes less than 5% of parent levels in circulation. 
 
d)  Excretion – Elimination is primarily renal.  Approximately 65% to 85% of 
lenalidomide is eliminated unchanged through urinary excretion in subjects with 
normal renal function. The half-life of elimination is approximately 3 to 4 hours 
(2 to 3 hours in patients 5 to 21 years) at the clinically relevant doses (5 to 50 
mg/day). Steady-state levels are achieved within 4 days. 
 
15.16 Potential Drug Interactions:  In vitro studies demonstrate that lenalidomide is 
not a substrate of CYP enzymes. In addition, lenalidomide shows little inhibitory 
or induction potential towards the CYP enzymes in vitro. Hence, 
coadministration of CYP substrates, inhibitors, or inducers with lenalidomide is 
not likely to result in clinically relevant drug-drug interactions in humans.  
 
In vitro, lenalidomide is not a substrate of BCRP, MRP1, MRP2, MRP3, OAT1, 
OAT3, OATP1B1, OCT1, OCT2, MATE1, OCTN1, or OCTN2. Thus, it is 
unlikely that substrates or inhibitors of these transporters would affect 
lenalidomide disposition in humans. 
 
Lenalidomide is not an inhibitor of BSEP, BCRP, MRP2, OAT1, OAT3, 
OATP1B1, OATP1B3, or OCT2. Thus, lenalidomide is not anticipated to cause 
any significant drug-drug interactions due to inhibition of these transporters. 
 


MC138E 
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MCCC Addendum 4 
 
 
Protocol Version Date: May  2, 2017 
Lenalidomide is not an inhibitor of UGT1A1 and is not anticipated to cause any 
significant drug-drug interactions due to UGT1A1 inhibition. 
 
In vitro, lenalidomide is a weak substrate, but not an inhibitor of P-glycoprotein 
(P-gp). 
 
Erythropoietic agents or other agents that may increase the risk of thrombosis, 
such as hormone replacement therapy and oral contraceptives, should be used 
with caution in patients with multiple myeloma receiving lenalidomide with 
dexamethasone. 
 
 
Periodic monitoring of digoxin plasma levels is recommended due to increased 
Cmax and AUC with concomitant lenalidomide therapy.  Close monitoring of PT 
and INR is recommended in multiple myeloma patients taking concomitant 
warfarin. 
 
15.17 Known potential toxicities:   
 
Pregnancy Warning: 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, a teratogenic 
effect of lenolidomide in humans cannot be ruled out. Pregnancy must be 
excluded before start of treatment. Prevent pregnancy during treatment by the use 
of two reliable methods of contraception. 
 
Very Common AEs (≥ 10%): anemia, leukopenia, neutropenia, 
thrombocytopenia, cataracts, blurred vision, abdominal pain, constipation, 
diarrhea, dyspepsia, nausea, vomiting, asthenia, chills, edema including 
peripheral, fatigue, pyrexia, abnormal liver function tests, bronchitis, 
nasopharyngitis, pneumonia, rhinitis, upper respiratory tract infection, urinary 
tract infection weight decreased, decreased appetite, hyperglycemia, 
hypocalcemia, hypokalemia, arthralgia, back pain, bone pain, muscle spasms, 
musculoskeletal pain, myalgia, pain in extremity, dizziness, dysgeusia, headache, 
hypoesthesia, neuropathy peripheral, neuropathy, tremor, depression, insomnia, 
cough, dyspnea, epistaxis, pharyngitis, pulmonary embolism, dry skin, pruritus, 
rash, and deep vein thrombosis. 
 
Common (≥ 1% and < 10%): febrile neutropenia, granulocytopenia, hemolytic 
anemia, lymphopenia, pancytopenia, acute myocardial infarction, atrial 
fibrillation, cardiac failure, congestive heart failure, myocardial ischemia, 
tachycardia, vertigo, upper abdominal pain, dry mouth, , toothache, chest pain, 
fall, , cholestasis, bacteremia, erysipelas, gastroenteritis, herpes simplex, herpes 
zoster, influenza, lower respiratory infection, respiratory infection, sinusitis, 
sepsis, contusion, alanine aminotransferase increased, c-reactive protein 
increased, gamma-glutamyltransferase increased, dehydration, diabetes mellitus, 
gout, hyperuricemia, hypophosphatemia, hypomagnesemia, hyponatremia, iron 
overload, muscular weakness, acute myeloid leukemia, basal cell carcinoma, 
Myelodysplastic syndrome, squamous cell carcinoma of skin, tumor flare, tumor 
lysis syndrome, cerebrovascular accident, lethargy, paresthesia, peripheral 
sensory neuropathy, syncope, mood altered, renal failure, respiratory distress, 


MC138E 
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MCCC Addendum 4 
 
 
Protocol Version Date: May  2, 2017 
erythema, hyperhidrosis, night sweats, hematoma, hypertension, hypotension, 
peripheral ischemia, thrombosis, and vasculitis. 
 
Uncommon, limited to important or life-threatening (< 1%): hypersensitivity, 
Graft vs. Host Disease 
 
The following additional adverse reactions have been reported in Celgene-
sponsored clinical studies and are considered by the company to be at least 
possibly related to the administration of lenalidomide: pneumonitis, transient 
abnormal liver laboratory tests, hyperthyroidism, , TLS, TFR, rhabdomyolysis, 
and allergic conditions, including angioedema, SJS, and toxic epidermal 
necrolysis.  These reactions are reported voluntarily from a population of 
uncertain size, so it is not possible to reliably estimate their frequency. 
  
Lenalidomide may have minor or moderate influence on the ability to drive and 
use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have 
been reported with the use of lenalidomide. Therefore, caution is recommended 
when driving or operating machines. 
 
Please refer to the Investigator’s Brochure for a more comprehensive list of 
treatment-emergent adverse events. 
 
15.18 Drug procurement:  Lenalidomide (Revlimid®) will be provided directly to 
research subjects for the duration of their participation in this trial at no charge to 
them or their insurance providers in accordance with the REVLIMID REMS™  
program.  Per standard requirements all physicians who prescribe lenalidomide 
for research subjects enrolled into this trial, and all research subjects enrolled into 
this trial, must be registered in and must comply with all requirements of the 
Celgene  REVLIMID REMS™  program.  Prescriptions must be filled within 7 
days.  Only enough lenalidomide for one cycle of therapy will be supplied to 
the patient each cycle. 
 
 
Any unused lenalidomide should be returned for disposition in accordance with 
the REVLIMID REMS™   program. 
 
 
15.19 Nursing Guidelines:  
 
15.191 Myelosuppression is dose-dependent and reversible with treatment 
interruption and/or dose reduction. Monitor CBC w/diff regularly. 
Instruct patient to report any unusual bruising or bleeding 
(thrombocytopenia); signs and symptoms of infection (neutropenia); and 
energy conserving lifestyle (anemia). 
 
15.192 Lenalidomide can have thrombotic adverse events (i.e DVT and PE). 
Instruct patient to report any limb swelling or pain, and to seek medical 
attention for shortness of breath or chest pain. 
 
15.193 Because of the potential for birth defects patients should be instructed in 
effective methods of birth control. Female patients should use 2 forms of 
birth control during treatment and for 4 weeks after discontinuing 


MC138E 
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MCCC Addendum 4 
 
 
Protocol Version Date: May  2, 2017 
therapy. Males must be instructed to use a latex condom during any 
sexual contact with a woman of child bearing potential (even if they have 
had a vasectomy), because it is unknown if lenalidomide is present in 
semen. 
 
15.194 Patents may experience pruritus, rash and dry skin. Because of the rare 
risk of Steven’s Johnson Syndrome, patients should immediately report 
any rash to their provider. 
 
15.195 Drug may cause hyperglycemia. Patients with diabetes or impaired 
fasting glucose may need to have their glucose levels monitored more 
closely. 
 
15.196 Gastrointestinal side effects (diarrhea, constipation, nausea, dyspepsia, 
anorexia, etc) are commonly seen. Manage patient symptomatically and 
monitor for effectiveness. 
 
15.197 Patients may experience myalgias, arthralgias, and other generalized 
pain. Administer analgesics as ordered and monitor for their 
effectiveness. 
 
15.198 Upper respiratory symptoms (nasopharyngitis, cough, epistaxis, etc.) can 
be seen. Manage symptomatically and monitor for effectiveness. 
 
15.199 Agent may cause fatigue, dizziness, vertigo, or blurred vision.  Instruct 
patients to use caution when driving or operating machines. 
 
15.2 
Pneumococcal 13-valent Conjugate Vaccine (Prevnar 13) 
 
15.21 Background: Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 
Protein), is a sterile solution 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. 
 
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. 
 
15.22 Formulation: Supplied as ready-to-use prefilled syringes (10 x 0.5-mL prefilled 
syringes per package).  Pneumococcal 13-valent Conjugate Vaccine is 
manufactured as a liquid preparation for intramuscular injection. 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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Protocol Version Date: May  2, 2017 
15.23 Preparation and storage: Pneumococcal 13-valent Conjugate Vaccine is 
stored at refrigerated temperatures of 2ºC to 8ºC (36ºF to 46ºF) away from 
freezer compartment. DO NOT FREEZE. Discard if frozen. 
 
15.24 Administration:  Shake vigorously immediately prior to use to obtain a uniform 
suspension in the vaccine container. The vaccine should not be used if it cannot 
be resuspended.  After shaking, the vaccine is a homogeneous, white suspension.  
Do not mix the vaccine with other products in the same syringe.   
 
The dose is 0.5 mL to be given intramuscularly.  Do not inject intravenously, 
intradermally or subcutaneously.  The vaccine should not be injected in the 
gluteal area or areas where there may be a major nerve trunk and/or blood vessel. 
Before injection, the skin at the injection site should be cleansed and prepared 
with a suitable germicide. After insertion of the needle, aspirate and wait to see if 
any blood appears in the syringe, which will help avoid inadvertent injection into 
a blood vessel. If blood appears, withdraw the needle and prepare for a new 
injection at another site. 
 
 
15.25 Potential Drug Interactions:  Patients receiving therapy with 
immunosuppressive agents (large amounts of corticosteroids, antimetabolites, 
alkylating agents, cytotoxic agents) may not respond optimally to active 
immunization. 
 
As with other intramuscular injections, Pneumococcal 13-valent Conjugate 
Vaccine should be given with caution to patients on anticoagulant therapy. 
 
See complete prescribing information for information regarding co-
administration of Pneumococcal 13-valent Conjugate Vaccine with other 
vaccines. 
 
15.26 Known potential toxicities:  There is no safety data available in the adult 
patient population.  Please see Prevnar 13 prescribing information for 
comprehensive toxicity data.   
 
The following systemic events were noted within 2-3 days of the 
Pneumococcal 13-valent Conjugate Vaccine injection in pediatric patients: 
fever, irritability, drowsiness, restless sleep, decreased appetite, vomiting, 
diarrhea, and urticaria-like rash. The following local reactions occurred 
within 3 days of immunization pediatric patients: erythema, induration, 
tenderness and interference with limb movement. 
 
15.27 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
 
15.28 Nursing Guidelines:  
 
15.281 Monitor for injection site reaction. Local reaction is usually seen within 3 
days of vaccination, including erythema, induration and tenderness. Treat 
symptomatically and monitor for signs on infection. 
 


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Protocol Version Date: May  2, 2017 
15.282 Patients may experience mild fever. Acetaminophen can be used 
symptomatically. Monitor for effectiveness. 
 
15.283 Patients may experience “flu-like” symptoms (fever, irritability, 
decreased appetite, vomiting and diarrhea). Treat symptomatically. 
 
16.0  
Statistical Considerations and Methodology  
 
16.1  
Overview:  
 
This is a randomized Phase II study designed to compare the response rate of the control 
arm (Prevnar 13 alone) to the experimental arm (Prevnar 13 plus lenalidomide).   
 
16.11  Primary Endpoint:  
 
The primary endpoint of this trial is the rate of response to the Prevnar 13 
vaccine, which will be compared between the two arms. A response will be 
defined as a four-fold rise from pre-vaccine (day 15) to 28 days after 
immunization (day 43) for ≥ 2 of the 3 serotypes studied by opsonophagocytic 
activity (OPA) of antibodies from sera.  Throughout Section 16.0, response will 
be considered synonymous with “success”, unless specified otherwise.  All 
patients meeting the eligibility criteria who have signed a consent form and, 
received the Prevnar 13 vaccine will be evaluable for response, with the 
exception of patients who are determined to be a major treatment violation or 
flagr. 
 
16.2  
Statistical Design: 
 
16.21 Decision Rule:  
 
It has been shown that CLL patients have poor response to vaccines.  In previous 
studies, responses to the polysaccharide pneumococcal vaccine (Pneumovax) 
have been remarkably low, with responses ranging from 10-22%.13,14  Similar 
responses are expected with the Prevnar 13 vaccine.  The addition of 
lenalidomide is expected to increase response rates to Prevnar 13 vaccine. 
 
A randomized trial comparing the experimental arm (Prevnar 13 plus 
lenalidomide) against the control arm (Prevnar 13 alone) will be conducted as 
described by Rubinstein34.  We will enter 26 evaluable patients on each arm of 
the study using a 1:1 randomization scheme utilizing the Pocock and Simon 
dynamic allocation procedure35, where patients are stratified based on age (<65 
vs. ≥65), Rai stage (MBL or 0 vs. I), and previous Pneumovax (yes vs. no).  A 
sample size of 26 patients per arm provides 80% power to detect an improvement 
in response rate from 10% to 30%, using a one-sided test at a significance level 
of 0.16 (EAST 6.2).   
 
The z-score will be calculated for testing the null hypothesis that the difference 
of response rates between the two arms is equal to zero, based on the normal 
approximation with pooled variance of standardized test statistics.  
 
16.211 Final Decision Rule: The final analysis will take place after all 52 
evaluable patients have completed the response evaluation at 43 days.  


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Protocol Version Date: May  2, 2017 
The response rates will be compared between the two arms using 
EAST6.  If the response rate is higher in the experimental arm, where the 
z-score is greater than 0.988 (p-value  < 0.162), this will be considered 
sufficient evidence that the experimental arm may be recommended for 
further testing in subsequent studies.  Otherwise, we will conclude that 
there is not statistical evidence of superiority of the experimental 
regimen. 
 
16.212 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.33. 
 
 
16.22  Sample Size:  
 
The randomized phase II study design to be used is fully described in section 
16.21.  A maximum of 52 evaluable patients (26 in each arm) will be accrued 
onto this phase II study unless undue toxicity is encountered.  We anticipate 
accruing an additional 6 patients (3 in each arm) to account for ineligibility, 
cancellation, major treatment violation, or failure to receive the Prevnar 
13vaccine.  Maximum projected accrual is 58 patients. 
 
16.23  Accrual Rate and Study Duration:  
 
The anticipated accrual rate is approximately 3-4 patients per month.  Therefore, 
the accrual period for this phase II study is expected to be about 1.5 years.  The 
final analysis can begin approximately 1.75 years after the trial begins, i.e. as 
soon as the final patient accrued to this trial has completed the response 
evaluation at 43 days and data entry has been completed.  
 
16.24 Power and Significance Level: Assuming that the responses are binomially 
distributed in each arm, the operating characteristics of the current design can be 
tabulated according to various true differences of the proportions, including the 
probabilities that the experimental regimen is superior to the control regimen. 
 
If the true difference is proportions is 
0 
0.10 
0.20 
0.30 
Then the probability of declaring that the 
experimental regimen warrants further studies 
is…. 
0.16 
0.51 
0.80 
0.95 
 
 
16.25 Other Considerations: Toxicity, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
16.3 
Analysis Plan:  The analysis for this trial will commence at planned time points (see 16.2) 
and at the time the patients have become evaluable for the primary endpoint. Such a 
decision will be made by the Statistician and Study Chair, in accord with CCS Standard 
Operating Procedures, availability of data for secondary endpoints (eg, laboratory 
correlates), and the level of data maturity. It is anticipated that the earliest date in which 


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Protocol Version Date: May  2, 2017 
the results will be made available via manuscript, abstract, or presentation format is when 
last patient has been followed for at least 2 months. 
 
16.31 Primary Endpoint:   
 
16.311  Definition: The primary endpoint of this trial is the rate of response to the 
Prevnar 13 vaccine, which will be compared between the two arms. A 
response will be defined as a four-fold rise from pre-vaccine (day 15) to 
28 days after immunization (day 43) for ≥ 2 of the 3 serotypes studied by 
opsonophagocytic activity (OPA) of antibodies from sera.  Patients who 
are not evaluated for the OPA titers at both pre-vaccine (day 15) and day 
43 due to a missed blood draw or other reasons will be considered a non-
responder.  All patients meeting the eligibility criteria who have signed a 
consent form and  received the Prevnar 13 vaccine will be evaluable for 
response, with the exception of patients who are determined to be a 
major treatment violation or flagr. 
 
16.312  Estimation:  The proportion of successes will be estimated in each arm 
by the number of successes divided by the total number of evaluable 
patients. Ninety-five percent confidence intervals for the true success 
proportion will be calculated in each arm based on the normal 
approximation.  Comparison of response rates between the two treatment 
groups will be performed using a one-sided z-test (based on normal 
approximation with pooled variance of standardized test statistics) at 
significance level 0.16.   
 
16.32 Secondary Endpoints: 
 
16.321 Disease status by physical exam and complete blood counts will be 
evaluated in each patient.  For CLL, each patient will be classified as 
CCR, CCRi, PR, SD, or PD per Section 11.2 at the time of the 6 week 
assessment of immune response.   The distribution of disease status will 
be evaluated in each arm and will be summarized descriptively.  Patients 
will be classified as responders (CCR, CCRi, PR) vs. non-responders 
(SD, PD).  For MBL, patients will be classified as Not PD vs. PD.  
Differences in disease status response will be compared between the two 
arms using Fisher’s exact test.   
 
16.322 Time to treatment for progressive CLL will be defined as the time from 
the date of registration to the date of initiation of treatment for 
progressive CLL.  The distribution of time to treatment will be estimated 
in each arm using the method of Kaplan-Meier.  Time to treatment will 
be compared between the two arms using log-rank statistics. 
 
16.323 Adverse Events: All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s). Platelets and 
hemoglobin will be graded according to the Grading Scale for 
Hematologic Adverse Events in CLL Studies in Appendix IV. The 
maximum grade for each type of adverse event will be recorded for each 
patient, and frequency tables will be reviewed for each arm to determine 


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Protocol Version Date: May  2, 2017 
patterns. Additionally, the relationship of the adverse event(s) to the 
study treatment will be taken into consideration. 
 
16.33 Correlative Analyses: 
 
16.331  Pre-vaccination (day 15) and day 28 post-vaccination OPA GMTs 
for each serotype (4, 9V, 23F) will be reported in the vaccine and 
vaccine + lenalidomide groups.  The fold-change in OPA GMT from 
baseline to 28 days post-vaccination will be evaluated for each 
serotype, where two-sample t-tests will be used to compare GMTs 
between the vaccine and vaccine + lenalidomide groups. 
 
16.332 Pre-vaccination (day 15) and day 28 post-vaccination Streptococcus 
pneumoniae serotype specific IgG GMTs for each serotype (1, 3, 4, 5, 
6B, 7F, 9V, 14, 18C, 19F, 19A, and 23) will be reported in the 
vaccine and vaccine + lenalidomide groups.  The fold-change in 
quantitative IgG GMT from pre-vaccine (day 15) to 28 days post-
vaccination will be evaluated for each serotype, where two-sample t-
tests will be used to compare GMTs between the vaccine and vaccine 
+ lenalidomide groups. 
 
 
 
16.333 Measures of global immune function including T-cell repertoire, T-
cell immune synapse, serum immunoglobulin levels, and absolute 
numbers of T-cell and NK cells will be evaluated at both baseline and 
after 6 weeks of low dose lenalidomide.  Values over time will be 
summarized graphically and descriptively.  Changes from baseline to 
6 weeks will be evaluated using paired t-tests.  Two sample t-tests 
will be used to compare each measure between the vaccine and 
vaccine + lenalidomide groups. 
 
16.34   Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final point 
estimates and confidence intervals. 
 
16.35 Data & Safety Monitoring 
 
16.351 The principal investigator(s) and the study statistician will review the 
study at least every quarter to identify accrual, adverse event, and any 
endpoint problems that might be developing. The Mayo Clinic Cancer 
Center (MCCC) Data Safety Monitoring Board (DSMB) is responsible 
for reviewing accrual and safety data for this trial at least twice a year, 
based on reports provided by the MCCC Statistical Office. 
 
16.352 Adverse Event Stopping (applies to each arm independently): The 
stopping rule specified below is based on the knowledge available at 
study development.  We note that the rule may be adjusted in the event 
of either (1) the study re-opening to accrual or (2) at any time during the 
conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatments under investigation.  


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MCCC Addendum 4 
 
 
Protocol Version Date: May  2, 2017 
The study team may choose to suspend accrual because of unexpected 
adverse event profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to both arms if at any time we 
observe events considered at least possibly related to study treatment (i.e. 
an adverse event with attribute specified as “possible,” “probable,” or 
“definite”) that satisfy either of the following: 
 
• 
if 4 or more patients in the first 15 treated patients in either arm 
experience a grade 4 or higher non-hematologic adverse event at 
least possibly related to treatment. 
 
• 
if after the first 15 patients have been treated, 25% of all patients in 
either arm experience a grade 4 or higher non-hematologic adverse 
event at least possibly related to treatment. 
 
• 
Any grade 5 event related to treatment 
 
We note that we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
 
16.353   Enhanced Safety Monitoring Rule:  If at any time after the first 12 
patients have been treated on the experimental arm, the rate of grade 3 
or 4 non-hematologic adverse events in the experimental arm is ≥ 
25%higher than the rate in the control arm, the study team will review 
the adverse events profile in each arm.  Accrual may be temporarily 
suspended to evaluate the types of adverse events and the relation to 
study treatment. 
 
16.4   Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
along with other required information for this study will be reported on 
ClinicalTrials.gov. For purposes of timing of the Results Reporting, the initial estimated 
completion date for the Primary Endpoint of this study is 1.75 years after the study opens 
to accrual. The definition of “Primary Endpoint Completion Date” (PECD) for this study 
is at the time the last patient registered has completed the response evaluation at 43 days. 
 
16.5 
Inclusion of Women and Minorities 
 
16.51 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.52 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race or gender, and there is no reason to expect 
such differences to exist.  Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 


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Protocol Version Date: May  2, 2017 
 
16.53 The geographical region served by Mayo, has a population which includes 
approximately 3% minorities. Based on prior Mayo studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 30% of patients will be women.  Expected sizes of racial by 
gender subsets are shown in the following table: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 0 
 1 
 1 
Not Hispanic or Latino 
 17 
 40 
 57 
Ethnic Category: Total of all subjects 
 17 
 40 
 58 
Racial Category 
American Indian or Alaskan Native 
 0 
 0  
 0 
Asian 
 0 
 0 
 0 
Black or African American 
 0 
 1 
 1 
Native Hawaiian or other Pacific Islander 
 0 
 0 
 0 
White 
 17 
 40 
 57 
Racial Category: Total of all subjects 
 17 
 41 
 58 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South 
or Central American, or other Spanish culture or origin, regardless of 
race. The term “Spanish origin” can also be used in addition to “Hispanic 
or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of 
the original peoples of North, Central, or South America, and who 
maintains tribal affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far 
East, Southeast Asia, or the Indian subcontinent including, for example, 
Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine 
Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine 
Islands have been recorded as Pacific Islanders in previous data collection 
strategies.)  
Black or African American – a person having origins in any of the black 
racial groups of Africa. Terms such as “Haitian” or “Negro” can be used 
in addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in 
any of the original peoples of Hawaii, Guam, Samoa, or other Pacific 
Islands. 
White – a person having origins in any of the original peoples of Europe, 
the Middle East, or North Africa. 
 
17.0  
Pathology Considerations/Tissue Biospecimens: None.  
 


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Protocol Version Date: May  2, 2017 
18.0 
Records and Data Collection Procedures   
 
 
18.1   Submission Timetable 
  
Initial Material(s)  
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
On-Study  
≤2 weeks after registration 
Adverse Event - Baseline 
Measurement - Baseline 
Research Blood Submission (see Section 
14.0) 
Other Laboratory Results  
OPA Titers  
Quantitative IgG Levels  
FISH Results - Baseline 
Quantitative Flow Cytometry  
Immunophenotyping Reports including 
CD38, CD49d, and ZAP-701, 2 
IgVH Mutation Analysis Report1 
CLL FISH Report1 
End of Active Treatment/Cancel Notification  
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
1. Submit copy of the report, Attention: 
. 
2. For patients who previously had full flow immunophenotyping performed and at pre-study workup 
had limited repeat flow immunophenotyping, submit a copy of both reports. 
 


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MCCC Addendum 4 
 
 
 
Protocol Version Date: May  2, 2017 
  
Test Schedule Material(s)  
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
At each evaluation 
during treatment 
At end of treatment 
Observation 
Evaluation/Treatment 2  
 
X 
 
Evaluation/Observation 1 
 
 
X 
Nadir/Adverse Event  
 
X 
X 
Measurement  
 
X 
X 
Research Blood Submission  
 
X (see Section 14.0) 
 
Other Laboratory Results  
 
X 
 
Interval Laboratory  
 
X 
 
OPA Titers  
 
X 
 
Quantitative IgG Levels  
 
X 
 
Quantitative Flow Cytometry  
 
X 
 
End of Active Treatment/Cancel 
Notification  
 
X 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
 
1. Complete at each evaluation during Observation (see Section 4.0). 
2. Complete at each evaluation during Active Treatment (see Section 4.0). 
 
Follow-up Material(s) 
 
CRF 
Event Monitoring Phase1 
 
q. 6 months until 
PD or subsequent 
treatment for 
CLL2 
 
 
 
At PD or 
subsequent 
treatment 
for CLL2 
q. 12 mos. 
after PD or 
subsequent 
treatment 
for CLL 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring  
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 2 years after registration, no further follow-up is required. 
NOTE:  As of Addendum 4, Event monitoring will no longer be required 
2. Submit copy of documentation of response or progression, Attention: 
 
. 
 
19.0  
Budget 
 
 
19.1 
Costs charged to patient:  routine clinical care and Prevnar 13® vaccine. 
 
19.2 
Tests to be research funded: Research bloods and associated correlative studies (see 
Section 14), and lenalidomide will be research funded. 


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Protocol Version Date: May  2, 2017 
 
20.0 
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26. Marti GE, Rawstron AC, Ghia P, et al. Diagnostic criteria for monoclonal B-cell 
lymphocytosis. Br J Haematol. 2005;130(3):325-332. 
27. Jackson LA, Janoff EN. Pneumococcal vaccination of elderly adults: new paradigms for 
protection. Clinical infectious diseases : an official publication of the Infectious Diseases 
Society of America. 2008;47(10):1328-1338. Prepublished on 2008/10/11 as DOI 
10.1086/592691. 


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28. Licensure of 13-valent pneumococcal conjugate vaccine for adults aged 50 years and older. 
MMWR Morbidity and mortality weekly report. 2012;61(21):394-395. Prepublished on 
2012/06/01 as DOI. 
29. Wettstein P, Strausbauch M, Therneau T, Borson N. The application of real-time PCR to the 
analysis of T cell repertoires. Nucleic Acids Res. 2008;36(21):e140. 
30. Riera-Fernandez P, Munteanu CR, Escobar M, et al. New Markov-Shannon Entropy models 
to assess connectivity quality in complex networks: from molecular to cellular pathway, 
Parasite-Host, Neural, Industry, and Legal-Social networks. Journal of theoretical biology. 
2012;293:174-188. Prepublished on 2011/11/01 as DOI 10.1016/j.jtbi.2011.10.016. 
31. Shanafelt TD, Ramsay AG, Zent CS, et al. Long-term repair of T-cell synapse activity in a 
phase II trial of chemoimmunotherapy followed by lenalidomide consolidation in previously 
untreated chronic lymphocytic leukemia (CLL). Blood. 2013;121(20):4137-4141. 
Prepublished on 2013/03/16 as DOI 10.1182/blood-2012-12-470005. 
32. Ramsay AG, Johnson AJ, Lee AM, et al. Chronic lymphocytic leukemia T cells show 
impaired immunological synapse formation that can be reversed with an immunomodulating 
drug. J Clin Invest. 2008;118(7):2427-2437. 
33. Ramsay AG, Clear AJ, Fatah R, Gribben JG. Multiple inhibitory ligands induce impaired T-
cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with 
lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood. 
2012;120(7):1412-1421. Prepublished on 2012/05/02 as DOI 10.1182/blood-2012-02-
411678. 
34. Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design issues of 
randomized phase II trials and a proposal for phase II screening trials. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2005;23(28):7199-
7206. Prepublished on 2005/09/30 as DOI 10.1200/JCO.2005.01.149. 
35. Pocock S, Simon J. Sequential treatment assignment with balancing for prognostic factors in 
the controlled clinical trial. . Biometrics 1975;31:103-115. 
 
 
 


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Appendix I 
NYHA Classification 
 
Class I:  
NO Symptoms with ordinary activity  
Class II:  
Symptoms with ordinary activity  
Class III:  Symptoms with minimal activity 
Class IV:  Symptoms at rest 
 


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Appendix II 
Rai Classification 
 
 
 
0 
lymphocytosis (> 5 x 109/L) 
I  
 
lymphocytosis and lymphadenopathy  
II   
lymphocytosis and splenomegaly +/- lymphadenopathy  
III  
anemia (Hgb < 11 g/dL) 
IV  
thrombocytopenia (platelets < 100 x 109/L) 
 


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Appendix III 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 
 
 
 


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Appendix IV 
Grading Scale for Hematologic Toxicity in CLL Studies1 
 
Decrease from 
Grade2 
Pretreatment value (%) 
Platelets3, 5 
Hemoglobin4, 5 
No change - 10% 
0 
0 
11-24% 
1 
1 
25-49% 
2 
2 
50-74% 
3 
3 
≥ 75% 
4 
4 
 
1. A decrease in circulating granulocytes is not being considered since it is not a reliable 
index in CLL. 
2. Grades:  1–mild; 2–moderate; 3–severe; 4–life–threatening.  Grade 5 (fatal) toxicity 
can potentially occur at any level of decrease from pretreatment values and will be 
recorded as such. 
3. If, at any level of decrease the platelet count is <20,000/µL, this will be considered 
grade 4, unless the initial platelet count was ≤ 20,000 µL in which case the patient is 
inevaluable for toxicity referable to platelet counts. 
4. Baseline and subsequent hemoglobin determinations must be immediately prior to 
any given transfusions. 
5. If, at any level of decrease from the baseline value the platelet and/or hemoglobin 
counts are within normal limits, this will be considered a grade 0. 
 
* Hallek BD, et al.:  Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a 
report from the International Workshop on Chronic Lymphocytic Leukemia updating the National 
Cancer-Institute- Working Group 1996 guidelines:  Blood 111:54465456, 2008. 
 
 


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Appendix V 
PATIENT MEDICATION DIARY 
 
Patient Instructions 
 
• 
Take at the same time each day with or without food. 
• 
Please indicate on the calendar below every day that you take your study medication by placing the dose taken 
on the line under the date.  
• 
If you miss a dose, place a check “0” under the date, but remember to take your prescribed dose at the next 
regularly scheduled time. 
• 
Bring all bottles and any unused study medication along with this diary when you return for your next 
appointment. 
• 
Lenalidomide capsules should be swallowed whole, and should not be broken, chewed or opened. 
 
Medication(s) 
Dose 
Lenalidomide 
Days 1-14: 2.5 mg  
Days 15-42: 5 mg (unless dose is reduced 
due to adverse events) 
 
 
 
 
 
 
 
 
 
 
Date:__________________                 Participant’s Signature___________________________________ 
 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
Lenalidomide 
 
 
 
 
 
 
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date 
 
 
 
 
 
 
 
Lenalidomide 
 
 
 
 
 
 
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date 
 
 
 
 
 
 
 
Lenalidomide 
 
 
 
 
 
 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Date 
 
 
 
 
 
 
 
Lenalidomide 
 
 
 
 
 
 
 
Study Drug 
Day 29 
Day 30 
Day 31 
Day 32 
Day 33 
Day 34 
Day 35 
Date 
 
 
 
 
 
 
 
Lenalidomide 
 
 
 
 
 
 
 
Study Drug 
Day 36 
Day 37 
Day 38 
Day 39 
Day 40 
Day 41 
Day 42 
Date 
 
 
 
 
 
 
 
Lenalidomide