Conditions: Hematologic Disorder
Keywords: Hematologic Disorder Chronic Lymphocytic Leukemia CLL Hypogammaglobulinemia Impaired Response to Vaccinations Immunoglobulins Immune system's function Lenalidomide CC-5013 Revlimid Flu vaccine TIV Pneumonia vaccine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if lenalidomide can increase the level of immunoglobulins (parts of the blood that may help to improve the immune system's function) and/or will improve the protective effect of the flu and pneumonia vaccines in patients with CLL.

Detailed description:
Study Drug Administration:

If you are found to be eligible to take part in this study, you will take lenalidomide by mouth on Monday, Wednesday and Friday for 3 months.

In order to participate in this study you must register into and follow the requirements of the Revlimid REMS™ program of Celgene Corporation. This program provides education and counseling on the risks of fetal exposure, blood clots and reduced blood counts. You will be required to receive counseling every 28 days during treatment with lenalidomide, follow the pregnancy testing and birth control requirements of the program that are appropriate for you and take telephone surveys regarding your compliance with the program.

Depending on how you respond to the drug, after 3 months, you will either:

°Take lenalidomide every Monday, Wednesday and Friday on a 3 months on/3 months off schedule. You will then repeat this process for up to 2 years.

or

°Take lenalidomide every day for an extra 3 months. If you respond well, you will take lenalidomide every day for 3 months, then for the next 3 months stop the drug. You will then repeat this process for up to 2 years.

You should swallow the lenalidomide capsules whole with water. Do not open, crush, or break the lenalidomide capsules. If you touch a broken lenalidomide capsule, wash the area of your body with soap and water.

If you miss a dose of lenalidomide, and it has been less than 12 hours since your regular dose time, take it as soon as you remember. If it has been more than 12 hours, just skip your missed dose. Do not take 2 doses at the same time. If you take too much lenalidomide or overdose, call your healthcare provider right away. If you vomit after any dose, do not take another dose.

You will also receive a vaccine for the flu (Trivalent or Fluzone) 1 time a year. If you have not received one in the last 5 years, you will receive a vaccine for pneumonia (Pneumovax) between months 6 and 21. You will receive these vaccines as an injection under the skin.

Study Visits:

Before the first dose of study drug:

°Blood (about 2 teaspoons) will be drawn to test cytokines (proteins that may affect the immune system) and to test your immune system.

If you are able to become pregnant, 1 time a week for the first 4 weeks and then every 28 days while on treatment, you will have a blood (about 1 teaspoon) or urine pregnancy test.

While you are taking lenalidomide, blood (about 1 teaspoon) will be drawn for routine tests every 2-4 weeks.

At 3 months (+/- 3 weeks):

* You will have a physical exam.
* Blood (about 1 teaspoon) will be drawn for routine tests.

Before the flu vaccine, blood (about 1 teaspoons) will be drawn for antibody testing. Antibodies are created by the immune system and may attack foreign cells or substances, such as the study drug.

At 4 weeks (+/- 2 weeks) and 3 months (+/- 3 weeks) after the vaccine, blood (about 2 teaspoons) will be drawn for antibody testing, cytokine testing, and to test your immune system.

Length of Study:

You will take the study drug for up to 2 years. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

End of Study:

°Blood (about 2 teaspoons) will be drawn for antibody testing and cytokine testing.

This is an investigational study. Lenalidomide is FDA approved and commercially available for the treatment of multiple myeloma, myelodysplastic syndrome and mantle cell lymphoma. The use of this to help prevent infections by improving immunoglobulin levels and its use in combination with the flu and pneumonia vaccine is investigational.

Up to 35 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Lenalidomide administered at the dose of 5 mg/day on Monday, Wednesday and Friday for 3 months. If Immunoglobulin G (IgG) levels improve by at least 25% of baseline, lenalidomide administration continued for 3 months on, and 3 months off for 2 years. If IgG levels do not improve, frequency of lenalidomide increased to 5 mg/day for additional 3 months and if response is achieved, lenalidomide continued at 5mg/day 3 month on/3 month off for a total of 2 years. Seasonal influenza vaccination (Trivalent Influenza Vaccine, Fluzone High Dose) administered yearly, during the fall/winter season and pneumococcal immunization (Pneumococcal Polysaccharide Vaccine, Pneumovax) administered once between month 6 and month 21.

Interventions: intervention 1: Lenalidomide intervention 2: Influenza Vaccine intervention 3: Pneumovax Vaccine
Intervention descriptions: intervention 1: 5 mg/day by mouth on Monday, Wednesday and Friday for 3 months. Process repeated for up to 2 years.

If IgG levels do not improve, frequency of lenalidomide increased to 5 mg/day by mouth for additional 3 months and if response is achieved, lenalidomide continued at 5mg/day 3 month on/3 month off for a total of 2 years. intervention 2: Administered as injection yearly, during the fall/winter season. intervention 3: Administered by injection once between month 6 and month 21. Patients, who have received the Pneumovax vaccine within last 5 years, will not receive Pneumovax vaccination.

Protocol document:
Prot_000.pdf: 
 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
1 
 
 
A Study of Immune-adjuvant Effect of Lenalidomide in Patients with Chronic 
Lymphocytic Leukemia and Hypogammaglobulinemia and Impaired Response to 
Vaccinations – RV-CL-CLL-PI-002544 
 
Table of Contents 
 
 
 
 
 
 
 
 
 
 
 
Page 
1.0  Objectives 
 
 
 
 
 
 
 
1 
2.0  Background 
 
 
 
 
 
 
 
1 – 3 
3.0  Treatment Plan 
 
 
 
 
 
 
3 – 6 
4.0  Patient Eligibility 
 
 
 
 
 
 
7 – 9 
5.0  Pretreatment Evaluation 
 
 
 
 
 
9 – 10 
6.0  Evaluation During Study 
 
 
 
 
 
10 – 11 
7.0  Evaluation of Toxicity 
 
 
 
 
 
11 – 14 
8.0  Criteria for Response 
 
 
 
 
 
14 – 16 
9.0  Statistical Design/Exploratory Endpoints 
 
 
16 – 21 
10.0 References 
 
 
 
 
 
 
 
22 - 23 
 
 
 
 
 
 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
2 
 
1.0 Objectives 
 To evaluate the ability of lenalidomide to improve the Hypogammaglobulinemia 
(achieve target IgG response) in patients with CLL. 
 To evaluate the ability of lenalidomide to improve the protective antibody titers 
and serological responses specific to influenza and pneumococcal vaccination 
(seroconversion response). 
 To evaluate the ability of lenalidomide to improve non IgG immune dysfunction 
such as T cells, cytokines and immunoglobulin subclasses. 
2.0 Background 
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. It arises from 
clonal and functionally incompetent B cells. Patients with CLL suffer from 
immunosuppression, predominantly due to hypogammaglobulinemia (IgG3 and IgG4), 
and infections are a common cause of morbidity and mortality among these patients [1]. 
Immunodeficiency in patients with CLL is complex and multifactorial involving defects in 
immunoglobulin secretion, T cell functions, complement cascade and neutrophil 
functions. Very few clinical studies have focused on strategies to overcome the humoral 
immunodeficiency associated with CLL [2]. Prophylactic antimicrobial therapy and/or 
intravenous immunoglobulins are often administered to patients with CLL who develop 
repeated infections. In patients requiring treatment, chemoimmunotherapy further 
compromises the immune system by decreasing T cell counts and worsening 
hypogammaglobulinemia. Thus there is a need for strategies which could correct the 
hypogammaglobulinemia and improve immune reconstitution in patients with CLL.  


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
3 
 
Streptococcus pneumoniae, Haemophilus influenza type b (Hib) and influenza viruses 
are common causes of infections in patients with CLL [3]. Vaccinations for influenza 
and pneumococcus are recommended, but their effectiveness due to decreased 
antibody response to immunizations is questionable [4]. A prior study from our center 
[5] has shown that a 23-valent polysaccharide vaccine against pneumococcus does not 
mount an effective antibody response in 75% of patients with CLL even when multiple 
doses of GM-CSF are used concomitantly. Hypogammaglobulinemia is likely to further 
contribute to impaired vaccination responses in these patients [6]. Conjugation with 
immune adjuvants (like ranitidine) and conjugate vaccines with high valency were found 
helpful in mounting an effective antibody response to Haemophilus influenza type B, but 
did not have an effect in the response to Influenza immunization [7],[8].  Thus immune 
strategies which could circumvent these issues are needed. 
Lenalidomide is an immunomodulatory agent related to thalidomide. This oral agent 
induces clinical responses in patients with CLL. Its mode of action is pleiotropic, 
affecting the bone marrow and tumor microenvironments, angiogenesis, T cell immune 
synapse dysfunction, antibody production, regulatory T cells numbers and function and 
other unknown mechanisms. When patients with CLL received lenalidomide as initial 
treatment of their disease, improvement in serum levels of immunoglobulins (IgG, IgA 
and IgM) was observed in a subset of patients [9]. We demonstrated that out of 16 
patients who had low IgG level (<700 mg/dL) before therapy, 8 patients (50%) showed a 
normalization of IgG after 15 cycles and another 3 (19%) showed a rise in IgG of >50% 
from that of baseline. [9]. In a parallel study from the same patient cohort, we showed 
that treatment with lenalidomide was also followed by normalization of T cell number 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
4 
 
and function [10]. Lapalombella and colleagues have also shown that lenalidomide can 
enhance CD154 expression on CLL cells and enhance antibody producing ability of B 
cells in vitro and ex vivo further supporting our hypothesis that lenalidomide could have 
a positive immunomodulatory effect in patients with CLL [11].  
Therefore, we propose to conduct a single arm prospective clinical trial to assess the 
efficacy of lenalidomide in improving immunoglobulin levels and to potentiate antibody 
responses to immunizations with influenza and pneumococcal vaccination in patients 
with CLL. 
A low dose of lenalidomide, 5 mg, will be administered three times a week with the plan 
to escalate to daily dosing in the case of no response. The rationale for the low dose is 
the potential to obtain an immunoresponse while avoiding the risk for mylosuppression. 
In our previous experience increase in immunoglobulin levels were seen in patients 
receiving lenalidomide, 5 mg every-other-day. 
3.0 Treatment Plan 
We will administer lenalidomide at the dose of 5 mg/day on Monday, Wednesday and 
Friday for 3 months. If IgG levels improve by at least 25% of baseline, we will continue 
lenalidomide administration 3 months on and 3 months off for 2 years. If IgG levels do 
not improve we will increase the frequency of lenalidomide to 5 mg/day for additional 3 
months and if response is achieved, lenalidomide will be continued at 5mg/day 3 month 
on/3 month off for a total of 2 years. Seasonal influenza vaccination (Trivalent Influenza 
Vaccine, Fluarix, quadrivalent) will be administered yearly, during the fall/winter season 
and pneumococcal immunization (Pneumococcal Polysaccharide Vaccine, Pneumovax) 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
5 
 
will be administered once between month 6 and month 21. Patients, who have received 
the Pneumovax vaccine within last 5 years, will not receive Pneumovax vaccination.  
Serum levels of all the immunoglobulin subclasses will be measured at baseline and 
every 3 months (+/- 3 weeks) during therapy. Serum levels of antipneumococcal 
capsular polysaccharide antibodies will be measured before, 4 weeks (+/- 2 week) and 
3 months (+/- 3 weeks) after pneumococcal vaccination and at end of the study (to 
assess sustainable antibody responses) by ELISA. Haemagglutination inhibition 
antibody titres (HAI) will be assessed by WHO influenza reagent kit, before vaccination, 
4 weeks (+/- 2 week) and 3 months (+/- 3 weeks) after influenza vaccination [12]. 
Influenza specific quantitative and qualitative CD8+ and CD4+ T cell responses will be 
determined by multiparameter flow cytometry technique from stored PBMC’s from the 
patients before vaccination,  4 weeks (+/- 2 week) and 3 months (+/- 3 weeks) after 
influenza vaccination and at the end of the study [13, 14]. 
Dosage form 
Lenalidomide will be supplied by Celgene Corporation as 2.5mg and 5mg capsules for 
oral administration. 
Prescribing Information 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide 
will be provided in accordance with the  Celgene Corporation’s Revlimid REMS® 
program.  Per standard Revlimid REMS® program requirements,  all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial, and all research 
subjects enrolled into this trial, must be registered in, and must comply with, all 
requirements of the Revlimid REMS® program.   
 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
6 
 
Only enough lenalidomide for one cycle of therapy will be supplied to the patient each 
cycle. 
Pregnancy Testing    
Must follow pregnancy testing requirements as outlined in the Revlimid REMS® prDose 
modification for lenalidomide: 
               Table 1: Dose Modification Guidelines for Lenalidomide 
 
NCI CTC Toxicity Grade 
 
Action 
Grade 3 neutropenia associated with fever 
(temperature >38.5o C) 
or Grade 4 neutropenia (ANC <500/mm3, or 
≤75% of baseline)*. 
 
1) Hold (interrupt dose). 
2) Follow CBC weekly until resolution or stabilization 
3) If neutropenia has resolved to ≤ grade 2, implement 
dose reduction and continue therapy. 
 
Thrombocytopenia Grade 4 (platelet count 
≤ 25,000/mm3) or ≤ 75% of baseline.* 
 
1) Hold (interrupt dose). 
2) Follow CBC weekly until resolution or stabilization 
3) If thrombocytopenia resolves to ≤ grade 2, implement 
dose reduction and continue therapy. 
 
Non-blistering rash 
Grade 3 
 
 
 
 
Grade 4 
 
1) If grade 3, hold (interrupt) dose. Follow weekly until 
resolution or stabilization. 
2) If the toxicity resolves to ≤ grade 1, implement dose 
reduction and continue therapy. 
 
1) Discontinue lenalidomide study drug. 
 
Desquamating (blistering) rash-any Grade 
 
Discontinue lenalidomide study drug. 
 
Erythema multiforme - Grade 3 
 
Discontinue lenalidomide study drug. 
 
Neuropathy 
Grade 3 
 
 
 
 
Grade 4 
 
1) If grade 3, hold (interrupt) dose. Follow weekly until 
resolution or stabilization. 
2) If the toxicity resolves to ≤ grade 2, implement dose 
reduction and continue therapy. 
 
Discontinue lenalidomide study drug. 
 
Sinus bradycardia/other cardiac arrhythmia 
Grade 2 
 
 
 
 
≥ Grade 3 
 
1) Hold (interrupt dose). Follow at least weekly until 
resolution or stabilization. 
2) If the toxicity resolves to <grade 1, implement dose 
reduction and continue therapy. 
 
Discontinue lenalidomide study drug. 
 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
7 
 
Allergic reaction or hypersensitivity 
Grade 3 
 
 
 
Grade 4 
 
1) Hold (interrupt dose). Follow at least weekly until 
resolution or stabilization 
2) If the toxicity resolves to <grade 1, implement dose 
reduction and continue therapy. 
 
Discontinue lenalidomide study drug. 
 
Venous thrombosis/embolism ≥Grade 3 
 
Hold (interrupt) dose and start anticoagulation; restart at 
investigator's discretion (maintain dose level). 
 
Hepatic or other non-hematologic toxicity 
assessed as lenalidomide-related 
≥ Grade 3 
 
1) Hold (interrupt) dose. Follow at least weekly until 
resolution or stabilization. 
2) If the toxicity resolves to <grade 2, implement dose 
reduction and continue therapy. 
 
Tumor flare refractory to oral pain meds 
Hold dose and differentiate tumor flare from progression. 
Restart therapy at the investigator's discretion. 
 
 
*The use of cytokine support and/or transfusions to maintain adequate blood neutrophil and platelet 
counts may be considered at the investigator's discretion. 
 
Dose reduction consists of 2.5 mg/daily.  
 
Anticoagulation Consideration 
Lenalidomide increases the risk of thrombotic events in patients who are at high risk or 
who have a history of thrombosis in particular when combined with other drugs known 
to cause thrombosis. When lenalidomide is combined with other agents such as 
steroids, e.g. dexamethasone and prednisone, and Adriamycin or daunorubicin the risk 
of thrombosis is increased. Treating physicians may consider the use of aspirin or low 
molecular weight heparin in patients at high risk for thrombotic events. 
 
Recommended Concomitant Therapy 
Subjects should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, and antiemetics when appropriate. Use of filgrastim (G-CSF), to 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
8 
 
treat for neutropenia is permitted while on study. Use of erythropoiesis stimulating agent 
is strongly discouraged. 
4.0 Patient Eligibility 
Inclusion criteria: 
1. Chronic lymphocytic leukemia (CLL) patients with IgG less than 500 mg/dl 
with/without symptoms who are either untreated or previously treated, regardless 
of response, at least 6 months from prior therapy (including mAb). 
2. ECOG/WHO performance status of 0-2. 
3. Adequate renal functions as indicated by serum creatinine ≤2 mg/dl. 
4. Adequate hepatic function indicated as total bilirubin ≤ 2 mg/dl and ALT ≤ two 
times the upper limit of normal. 
5. Disease free of prior malignancies for 3 years with exception of currently treated 
basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the 
cervix or breast. Patients with malignancies with indolent behavior such as 
prostate cancer treated with radiation or surgery can be enrolled in the study as 
long as they have a reasonable expectation to have been cured with the 
treatment modality received. 
6. Females of childbearing potential (FCBP). A female of childbearing potential is a 
sexually mature woman who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has not had menses at any time in the preceding 24 
consecutive months). 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
9 
 
7. FCBP must have a negative serum or urine pregnancy test with a sensitivity of at 
least 50 mIU/mL within 10 – 14 days prior to and again within 24 hours of starting 
lenalidomide and must either commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth control, one highly 
effective method and one additional effective method AT THE SAME TIME, at 
least 28 days before she starts taking lenalidomide. 
8. FCBP must also agree to ongoing pregnancy testing (weekly for the first four 
weeks and then every 28 days while on therapy and at discontinuation of 
treatment). 
9. Men must agree to use a latex condom during sexual contact with a FCBP even 
if they have had a successful vasectomy. All patients must be counseled at a 
minimum of every 28 days about pregnancy precautions and risks of fetal 
exposure.  
10. Patients must be 18 years of age or older. 
11. All study participants must be registered into the mandatory Revlimid®.program, 
and be willing and able to comply with the requirements of Revlimid®. 
12. Females of reproductive potential must adhere to the scheduled pregnancy 
testing as required in the Revlimid REMS® program. Able to take aspirin (81 or 
325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use 
warfarin or low molecular weight heparin). 
13.  
 
Exclusion criteria 
1. Known sensitivity to lenalidomide or other thalidomide derivatives. 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
10 
 
2. History of Guillain-Barre within 6 weeks of previous influenza vaccination  
3. Patient on steroids therapy. 
4. Documented prolymphocytic leukemia (prolymphocytes more than 55% in the 
blood) or Richter’s transformation. 
5. Known positivity for HIV or active hepatitis (B or C). 
6. Pregnant or breast feeding females. 
7. History of tuberculosis treated within the last five years or recent exposure to 
tuberculosis. 
8. Any serious medical condition, laboratory abnormality, or psychiatric illness that 
places the subject at unacceptable risk if he/she were to participate in the study. 
9. Patients with a recent history of deep vein thrombosis (DVT) or pulmonary 
embolus (PE), in six months prior to enrollment are not eligible for this study. 
10.  Subjects who have currently active hepatic or biliary disease (with exception of 
patients with Gilbert's syndrome).  
11. Patients with severe allergic reaction (e.g., anaphylaxis) after previous dose of 
any influenza vaccine or to a vaccine component, including egg protein.  
12. Moderate or severe acute illness with or without fever.  
13.  Use of any other experimental drug or therapy within 28 days of baseline. 
14.  Concurrent use of other anti-cancer agents or treatments. 
5.0 Pretreatment evaluation 
Within 7 days (+/- 4 days)  prior to start of treatment, patients should have a history and 
physical examination. Electrocardiogram (ECG), CBC with differential and serum 
chemistry tests (sodium, potassium, calcium, magnesium, phosphorus, BUN, creatinine, 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
11 
 
glucose, and albumin, total proteins, alkaline phosphatase, total bilirubin, ALT, uric 
acid).  Serum beta-2-microglobulin and IgA, IgG, IgM levels. Serum levels of all the 
immunoglobulin subclasses will be measured at the baseline (+/- 4 days). T-cell 
lymphocyte number and T-cell subsets, CD4+, CD8+ will be measured baseline. Serum 
samples for cytokine levels (properdin, IFN-γ, IL-10, TNF-α, BAFF, IL-8, CCL3, and 
CCL4) will be stored at baseline. Pregnancy tests for females of childbearing potential 
and Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods will be discussed..  . 
6.0 Evaluation during the Study 
Complete blood counts (white blood cell, hemoglobin, platelets and differential), serum 
chemistry, basic metabolic profile, (sodium, potassium, chloride, CO2, BUN, creatinine 
and glucose) will be monitored once every two-four weeks (+/- 4 days) while on 
lenalidomide.  
At 3 months (+/- 3 weeks), patients will have a physical examination, CBC with 
differential and chemical survey, serum beta-2-microglobulin and IgA, IgG, IgM levels, 
flow cytometry (CD4+, CD8+). Pregnancy tests for females of childbearing potential and 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods, will be discussed with the patients.  
Pneumococcal vaccination: Serum levels of antipneumococcal capsular polysaccharide 
antibodies will be measured before, 4 weeks (+/- 2 week) and 3 months (+/- 3 weeks) 
after vaccination and at the end of the study (to assess sustainable antibody responses) 
by ELISA.  Influenza vaccination: Haemagglutination inhibition antibody titres (HAI) will 
be assessed by WHO influenza reagent kit before, 4 weeks (+/- 2 week) and 3 months 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
12 
 
(+/- 3 weeks) after vaccination and at end of the study (to assess sustainable antibody 
responses) [12]. Influenza specific quantitative and qualitative CD8+ and CD4+ T cell 
responses will be determined by multiparameter flow cytometry techniques from stored 
PBMC’s from the patients before vaccination, 4 weeks (+/- 2 week) and 3 months (+/- 3 
weeks) after vaccination [13, 14].Serum samples for cytokine levels (properdin, IFN-γ, 
IL-10, TNF-α, BAFF, IL-8, CCL3, and CCL4) will be stored before influenza vaccination 
at 4 weeks (+/- 2 week), 3 months (+/- 3 weeks) and at the end of the study). PBMC’s 
will be stored at baseline, 4 weeks (+/- 2 week) and 3 months (+/- 3 weeks) after 
influenza vaccination to determine by multiparameter flow cytometry technique changes 
in influenza specific quantitative (using HLA-A2 restricted FluMP pentamer) and 
qualitative (using CD107a, IFN-gamma, IL-2 and TNF-alpha by intracellular staining) 
CD8+ and CD4+ T cell responses, as described [15]. 
Criteria for study discontinuation: 
Treatment with study drug is discontinued and the patient will be removed from study 
when any of the following occurs: 
1. Lack of response 
2. Adverse event(s) that in the judgment of the investigator or the patient may cause   
severe or permanent harm or which rule out continuation of the study drug 
3. Withdrawal of consent 
4. Lost to follow-up 
5. Suspected pregnancy 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
13 
 
7.0 Evaluation of Toxicity 
 
Adverse events are reported as per UTMDACC and Leukemia Phase 2-3 studies 
(Appendix I and Appendix D). Please refer to lenalidomide package insert for a 
complete list of side effects.  
Myelosuppression and associated complications are expected events during 
leukemia therapy and are part of the treatment success (marrow emptying of 
leukemic cells). Therefore, myelosuppression and associated complications such as 
fever, infections, bleeding and related hospitalizations will not be reported as 
individual ADRs, but will be summarized in the updated and final reports.  Only 
prolonged myelosuppression, as defined by the new NCI criteria specific for 
leukemia, i.e., marrow cellularity <5% on day 42 or later (6 weeks) from start of 
therapy without evidence of leukemia, will be reported as an ADR and considered in 
defining the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of 
particular agents or regimens.  
M. D. Anderson (Sponsor) Reporting Requirements for Serious Adverse 
Events (SAE) and Dose Limiting Toxicities: 
Serious Adverse Event (SAE) Definition  
A serious adverse event is one that at any dose (including overdose): 
 Results in death 
 Is life-threatening1 
 Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization 
 Results in persistent or significant disability or incapacity2 
 Is a congenital anomaly or birth defect 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
14 
 
 Is an important medical event3 
 Suspected positive Pregnancy 
 
 1 “Life-threatening” means that the subject was at immediate risk of death at 
the time of the serious adverse event; it does not refer to a serious adverse 
event that hypothetically might have caused death if it were more severe. 
2 “Persistent or significant disability or incapacity” means that there is a 
substantial disruption of a person’s ability to carry out normal life functions. 
3 Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in situations where none of the outcomes 
listed above occurred.  Important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed 
in the definition above should also usually be considered serious.  Examples 
of such events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.  A new diagnosis of cancer during the course of a treatment 
should be considered as medically important.  
Adverse Drug Reaction Reporting 
As Per UTMDACC and Leukemia Phase II-III Studies (Appendix I and D), toxicity will be 
scored using CTC Version 4.0 for toxicity and adverse event reporting according to the 
M.D. Anderson guidelines. Hematologic toxicity will be assessed, graded, and 
summarized according to the 2008 IWCLL Guidelines (See Table IWCLL Guidelines). 
Adverse events will be documented in the medical record and entered into the case 
report form according to the Leukemia-Specific Adverse Event Recording and Reporting 
Guidelines (Appendix D). The Investigator or physician designee is responsible for 
verifying and providing source documentation for all adverse events and assigning the 
attribution for each event for all subjects enrolled on the trial.  
 
 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
15 
 
 
 
2008 IWCLL Grading 
for Hematological 
Toxicity Grade 
 
Decrease in PLT* or 
HGB** (nadir) from 
pretreatment value, % 
 
Absolute neutrophil 
count (ANC)/l*** 
(nadir) 
0 
10% 
2000 
1 
11 – 24% 
1500 – < 2000 
2 
25 – 49% 
1000 – < 1500 
3 
50 – 74% 
500 – < 1000 
4 
75% 
< 500 
 
Death occurring as a result of toxicity at any level of decrease from pretreatment will be 
recorded as grade 5. 
* 
PLT counts must be below normal levels for grades 1-4.  If, at any level of decrease, the 
PLT count is < 20K/l, this will be considered grade 4 toxicity, unless there was severe or life-
threatening low initial PLT count (< 20K/l) pretreatment, in which case the patient is not 
evaluable for toxicity referable to PLT count. 
** HGB levels must be below normal levels for grades 1-4.  Baseline and subsequent HGB 
determinations must be performed before any given transfusions. 
*** If the ANC reaches <1000/l, it should be judged to be grade 3 toxicity.  If the ANC was   
<1000/l before therapy, the patient is not evaluable for toxicity referable to the ANC. 
 
If any abnormal laboratory result is considered clinically significant, the investigator 
must provide details about the action taken with respect to the test drug and about the 
patient’s outcome. 
 
Serious Adverse Events Reporting:  The principal investigator has the obligation to 
report all serious adverse events to the University of Texas M. D. Anderson Cancer 
Center (MDACC) IRB via the Office of Protocol Research within 24 hours.  
 
All deaths during treatment or within 30 days following completion of active protocol 
therapy must be reported within 24 hours of knowledge regardless of the attribution. 
SAEs beyond 4 weeks after the end of study drug administration will be reported if 
thought to be drug related. 
 
 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
16 
 
Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform 
Celgene in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE 
within 24 hours of being aware of the event.  The written report must be completed and 
supplied to Celgene by facsimile within 24 hours/1 business day.  The initial report must 
be as complete as possible, including an assessment of the causal relationship between 
the event and the investigational product(s),.  Information not available at the time of the 
initial report (e.g., an end date for the adverse event or laboratory values received after 
the report) must be documented on a follow-up report.  A final report to document 
resolution of the SAE is required.  The Celgene tracking number (RV-XX-PI-###) and 
the institutional protocol number should be included on SAE reports (or on the fax cover 
letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE report to 
Celgene should be attached to the SAE and retained with the patient records. 
 
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. The female subject should be referred to an obstetrician-
gynecologist, preferably one experienced in reproductive toxicity for further evaluation 
and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and 
must notify Celgene Drug Safety immediately about the outcome of the pregnancy 
(either normal or abnormal outcome) using the Pregnancy Follow-up Report Form.  If 
the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE. If the 
abnormal outcome meets any of the serious criteria, it must be reported as an SAE to 
Celgene Drug Safety immediately by facsimile, or other appropriate method, within 24 
hours of the Investigator’s knowledge of the event using the SAE Report Form. 
 
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 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
17 
 
suspects is related to the in utero exposure to the IP should also be reported to Celgene 
Drug Safety immediately by facsimile, or other appropriate method, within 24 hours of 
the Investigator’s knowledge of the event using the SAE Report Form.  
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, 
the male subject taking lenalidomide  should notify the Investigator, and the pregnant 
female partner should be advised to call their healthcare provider immediately. 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax:  
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
 
Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above. The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 
hours of being aware of the event.  The written report must be completed and supplied 
to Celgene by facsimile within 24 hours/1 business day. The initial report must be as 
complete as possible, including an assessment of the causal relationship between the 
event and the investigational product(s), if available.  Information not available at the 
time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number RV-CL-CLL-
PI-002544 ) and the institutional protocol number should be included on SAE reports (or 
on the fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of 
the SAE report to Celgene should be attached to the SAE and retained with the patient 
records. 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
18 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: (908) 673-9115 
E-mail:  drugsafety@celgene.com 
 
8.0 Criteria for Response 
Response criteria - 
Ig response – Only IgG levels will be considered for response. IgG levels will be 
measured as mg/dL by nephelometry (normal range 700-1,600 mg/dL).Response will 
consist of normalization or improvement by 25% of baseline levels at 6 months during 
therapy. 
Response criteria for the immunization –  
Quadrivalent Influenza Vaccine (Fluvarix). HI assay was performed as previously 
described. Samples were assayed at baseline, 4 weeks (+/- 2 week) and 3 months (+/- 
3 weeks) post-vaccination. Response or protection to influenza vaccination was defined 
as > 40 HU or a fourfold increase in HI titer at 4 weeks (+/- 2 week) and 3 months (+/- 3 
weeks) post vaccination, against any of the three strains.  
Assessment of the functionality of antigen-specific CD8+ and CD4+ T cells will be 
performed by intracellular cytokine staining for interferon (INF)-g and tumor necrosis 
factor (TNF)-a and evaluation of CD154 expression and CD107a cytotoxicity. In brief, 
PBMCs will be thawed and stimulated for 24 hours with or without the seasonal 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
19 
 
influenza vaccine [A/Brisbane/59/2007(H1N1)-, A/Brisbane/10/2007 (H3N2)- and 
B/Florida/30/2008-like strain; CSL Biotherapies, Hattersheim, Germany]. A response will 
be considered positive if the % of antigen-specific IFN-g–, TNF-a–, or CD107a-
expressing T cells is ≥2-fold higher than background (unstimulated PBMCs) and if there 
is a minimum of 0.05% antigen-specific T cells (after subtracting the background or 
FMO fluorescence minus one). 
Pneumococcal Polysaccharide Vaccine - Seroconversion will be defined as at least a 
two fold increase in levels of antipneumococcal capsular polysaccharide (PCP) IgG 
antibody or achievement of concentration of >0.5µg/ml in anti-pneumococcal capsular 
polysaccharide antibody titer (against 6 serotypes). They will be measured before, 4 
weeks (+/- 2 week) and 3 months (+/- 3 weeks) post vaccination using ELISA and at the 
end of the study.  
Exploratory Endpoints: 
1. Infection rates of influenza or Pneumococcal pneumonia will be recorded during 
the study. 
2. Sustained immunoglobulin responses will be recorded along with serological 
responses to both the vaccines. 
3. Sera will be analysed for cytokine levels and properdin levels. 
Correlative studies – 
Cytokine levels from stored serum samples (before, 4 weeks (+/- 2 week) and 3 
months (+/- 3 weeks) and at the end of the study) – properdin, IFN-γ, IL-10, TNF-α, 
BAFF, IL-8, CCL3, and CCL4. Influenza specific quantitative (using HLA-A2 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
20 
 
restricted FluMP pentamer) and qualitative (using CD107a, IFN-gamma, IL-2 and 
TNF-alpha by intracellular staining) CD8+ and CD4+ T cell responses will be 
determined by multiparameter flow cytometry technique from stored PBMC’s before, 
4 weeks (+/- 2 week) and 3 months (+/- 3 weeks) after influenza vaccination as 
described [15].  
 
9.0 Statistical design with exploratory endpoints –  
The primary efficacy endpoint is IgG response, defined as having improvement in IgG 
level by at least 25% at 6 months, compared to baseline. We are targeting an IgG 
response rate of 50% and we would not be interested in pursuing further if the IgG 
response rate is 20% or lower.  Using Simon’s optimal two-stage design, we will enroll 
12 patients in the first stage and the trial will be stopped if there are 3 or less IgG 
responders among the first 12 patients. If there are 4 or more responders, we will 
continue the enrollment until 31 patients are reached.  The effect of lenalidomide is 
demonstrated and worth pursuing further if among the total 31 patients, at least 10 
patients achieve IgG response. This design is based on a type I error rate of 0.025 and 
a 90% power. Under the null hypothesis, the probability of early termination is 79% and 
the expected sample size is 16 patients. Patient enrollment will be suspended if there 
are not at least 3 IgG responders in the first 12 patients and not all 12 patients have 
been evaluated at 6 months. To account for a potential 10% early drop-out rate, we will 
enroll 35 patients so as to have 31 patients with both baseline and 6-month evaluations 
on IgG. Potential reasons for early dropouts are patients' choice, inability to return to our 
center or changes in CLL status that may require a different intervention. Sensitivity 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
21 
 
analysis will be performed to assess the impact of early dropouts. For example, we will 
analyze the data counting early dropouts either as "failures" (the most conservative 
approach) or as "missing" (thus, excluded from the analysis) and evaluate the response 
rate in both scenarios. Also, since the treatment requires at least 3 months of therapy 
before seeing an effect on immunoglobulin levels, we will also perform a secondary 
analysis by including only those patients who have been treated for at least 3 months, 
while counting those early dropouts between 3 and 6 months as "failures".  
Lenalidomide-related toxicity (defined as any grade 3 or greater non-hematological 
toxicity) will be monitored using the method of Thall, Simon and Estey [16] and the 
study will be terminated early if toxicity occurs in more than 40% of patients. 
Specifically, denoting the probability of toxicity by p, the study will be stopped early if 
Prob (p>0.40 data) > .95. The above decision criterion will be applied in cohort size of 5. 
Assuming a beta (.4, .6) priori for p, the above decision criterion implies that we will stop 
the trial according to the table below. For example, the trial will be terminated if 4 or 
more patients experienced toxicities among the first 5 patients.  
Number of patients 
Number of patients with 
toxicities is at least 
5 
4 
10 
7 
15 
10 
20 
12 
25 
15 
30 
17 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
22 
 
The operating characteristics of this study design based on 10,000 simulations are illustrated in 
Table 2.  
                   
              Table 2.  Operating Characteristics for Toxicity Monitoring Rule.  
True toxicity rate 
Prob (stop early) 
Sample Size 
25th, 50th and 75th 
percentiles 
0.20 
0.006 
35, 35, 35 
0.30 
0.039 
35, 35, 35 
0.40 
0.152 
35, 35, 35 
0.50 
0.447 
10, 35, 35 
0.60 
0.808 
5, 15, 30 
 
For the primary analysis, we will estimate the rate of IgG response along with the 95% 
confidence interval. As secondary analyses, we will also estimate the rates of 
Pneumococcus and Influenza seroconversion response, as defined in the response 
criteria section, and the corresponding 95% confidence intervals. The study will be 
considered positive in regard to the secondary endpoints if seroconversion is observed 
in 60% or more of the subjects for at least one of the vaccinations given. Similar method 
will be used to estimate the rate of influenza or Pneumococcal pneumonia. The duration 
of IgG response will be estimated using the Kaplan-Meier method. The cytokine levels 
and serum properdin levels will be summarized using descriptive statistics and will be 
compared between IgG responders and non-responders using two-sample t-test or 
Wilcoxon rank-sum test, as appropriate.  
 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
23 
 
Amendments, Deviations, Regulatory 
Protocol Amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and 
reviewed by Celgene.  Amendments should only be submitted to IRB after consideration 
of Celgene review.  Written verification of IRB approval will be obtained before any 
amendment is implemented.   
 
Protocol Deviations 
When an emergency occurs that requires a deviation from the protocol for a subject, a 
deviation will be made only for that subject.  A decision will be made as soon as 
possible to determine whether or not the subject (for whom the deviation from protocol 
was effected) is to continue in the study.  The subject’s medical records will completely 
describe the deviation from the protocol and state the reasons for such deviation.  In 
addition, the Investigator will notify the IRB in writing of such deviation from protocol. 
Investigator Responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice 
(GCP) and in the US Code of Federal Regulations. 
The Investigator will permit study-related monitoring visits and audits by MDACC, 
Celgene or its representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, 
EMEA, and TPP), providing direct access to the facilities where the study took place, to 
source documents, to CRFs, and to all other study documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available 
at some time during monitoring visits to review data and resolve any queries and to 
allow direct access to the subject’s records (e.g., medical records, office charts, hospital 
charts, and study related charts) for source data verification.  The data collection must 
be completed prior to each visit and be made available to MDACC and the Celgene 
representative so that the accuracy and completeness may be checked. 
Institutional Review Board/Ethics Committee Approval 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
24 
 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki. The review of this protocol by the IRB 
and the performance of all aspects of the study, including the methods used for 
obtaining informed consent, must also be in accordance with principles enunciated in 
the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations 
(CFR), Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards. 
 
The Investigator will be responsible for preparing documents for submission to the 
relevant IRB and obtaining written approval for this study.  The approval will be obtained 
prior to the initiation of the study. The approval for both the protocol and informed 
consent must specify the date of approval, protocol number and version, or amendment 
number.  
 
Any amendments to the protocol after receipt of IRB approval must be submitted by the 
Investigator to the IRB for approval.  The Investigator is also responsible for notifying 
the IRB of any serious deviations from the protocol, or anything else that may involve 
added risk to subjects. 
 
Any advertisements used to recruit subjects for the study must be reviewed and 
approved by the IRB prior to use. 
 
Informed consent 
 
The Investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
 
Documentation that informed consent occurred prior to the subject’s entry into the study 
and the informed consent process should be recorded in the subject’s source 
documents.   
 
Study records requirements 
 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
25 
 
The Investigator must ensure that the records and documents pertaining to the conduct 
of the study  and the distribution of the study drug, that is copies of CRFs and source 
documents (original documents, data, and records [e.g., hospital records; clinical and 
office charts; laboratory notes; memoranda; subject’s diaries or evaluation checklists; 
pharmacy dispensing records; recorded data from automated instruments; copies or 
transcriptions certified after verification as being accurate copies; microfiches; 
photographic negatives, microfilm, or magnetic media; x-rays; subject files; and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical study; documents regarding subject treatment and study drug 
accountability; original signed informed consents, etc.]) be retained by the Investigator 
for as long as needed to comply with national and international regulations (generally 2 
years after discontinuing clinical development or after the last marketing approval).  The 
Investigator agrees to adhere to the document/records retention procedures by signing 
the protocol. 
Premature Discontinuation of Study 
Single Center 
The responsible local clinical Investigator as well as Celgene has the right to 
discontinue this study at any time for reasonable medical or administrative reasons in 
any single center.  Possible reasons for termination of the study could be but are not 
limited to: 
1.  Unsatisfactory enrollment with respect to quantity or quality. 
2.  Inaccurate or incomplete data collection. 
3.  Falsification of records. 
4.  Failure to adhere to the study protocol. 
 
 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
26 
 
 
10.0 References  
1. 
Morrison, V.A., Infectious complications of chronic lymphocytic leukaemia: pathogenesis, 
spectrum of infection, preventive approaches. Best Pract Res Clin Haematol, 2010. 23(1): p. 145-53. 
2. 
Hamblin, A.D. and T.J. Hamblin, The immunodeficiency of chronic lymphocytic leukaemia. Br 
Med Bull, 2008. 87: p. 49-62. 
3. 
Wadhwa, P.D. and V.A. Morrison, Infectious complications of chronic lymphocytic leukemia. 
Semin Oncol, 2006. 33(2): p. 240-9. 
4. 
Hartkamp, A., et al., Antibody responses to pneumococcal and haemophilus vaccinations in 
patients with B-cell chronic lymphocytic leukaemia. Vaccine, 2001. 19(13-14): p. 1671-7. 
5. 
Safdar, A., et al., Multiple-dose granulocyte-macrophage-colony-stimulating factor plus 23-
valent polysaccharide pneumococcal vaccine in patients with chronic lymphocytic leukemia: a 
prospective, randomized trial of safety and immunogenicity. Cancer, 2008. 113(2): p. 383-7. 
6. 
Sinisalo, M., et al., Vaccination against infections in chronic lymphocytic leukemia. Leuk 
Lymphoma, 2003. 44(4): p. 649-52. 
7. 
Jurlander, J., et al., Improved vaccination response during ranitidine treatment, and increased 
plasma histamine concentrations, in patients with B cell chronic lymphocytic leukemia. Leukemia, 1995. 
9(11): p. 1902-9. 
8. 
Sinisalo, M., et al., Antibody response to 7-valent conjugated pneumococcal vaccine in patients 
with chronic lymphocytic leukaemia. Vaccine, 2007. 26(1): p. 82-7. 
9. 
Badoux, X.C., et al., Lenalidomide as initial therapy of elderly patients with chronic lymphocytic 
leukemia. Blood, 2011. 118(13): p. 3489-98. 
10. 
Lee, B.N., et al., Treatment with lenalidomide modulates T-cell immunophenotype and cytokine 
production in patients with chronic lymphocytic leukemia. Cancer, 2011. 117(17): p. 3999-4008. 
11. 
Lapalombella, R., et al., Lenalidomide treatment promotes CD154 expression on CLL cells and 
enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway. Blood, 
2010. 115(13): p. 2619-29. 
12. 
W.H.O., Identification of isolates by hemagglutination inhibition. In: WHO. WHO animal manual: 
diagnosis and surveillance. Geneva: Department of Communicable Disease Surveillance and Response. 
WHO Global Programme. WHO, 2002: p. 5. 
13. 
Mao, Z.R., et al., [Clonality analysis and mutational status of IgVH gene in Hodgkin variant of 
Richter syndrome]. Zhonghua Bing Li Xue Za Zhi, 2008. 37(8): p. 523-8. 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
27 
 
14. 
Medlicott, S.A., et al., Multiple lymphomatous diverticulosis and comorbid chronic lymphocytic 
leukemia: novel manifestations of ileocolic mantle cell lymphoma. Int J Surg Pathol, 2007. 15(4): p. 408-
13. 
15. 
Garland, P., et al., Humoral and cellular immunity to primary H1N1 infection in patients with 
hematologic malignancies following stem cell transplantation. Biol Blood Marrow Transplant, 2011. 
17(5): p. 632-9. 
16. 
Thall, P.F. and H.G. Sung, Some extensions and applications of a Bayesian strategy for 
monitoring multiple outcomes in clinical trials. Stat Med, 1998. 17(14): p. 1563-80. 
 
 
 

SAP_001.pdf: 
Protocol 2013-0371 
20 
July 30, 2013 
9.0 Statistical design with exploratory endpoints –
The primary efficacy endpoint is IgG response, defined as having improvement in IgG 
level by at least 25% at 6 months, compared to baseline. We are targeting an IgG 
response rate of 50% and we would not be interested in pursuing further if the IgG 
response rate is 20% or lower.  Using Simon’s optimal two-stage design, we will enroll 
12 patients in the first stage and the trial will be stopped if there are 3 or less IgG 
responders among the first 12 patients. If there are 4 or more responders, we will 
continue the enrollment until 31 patients are reached.  The effect of lenalidomide is 
demonstrated and worth pursuing further if among the total 31 patients, at least 10 
patients achieve IgG response. This design is based on a type I error rate of 0.025 and 
a 90% power. Under the null hypothesis, the probability of early termination is 79% and 
the expected sample size is 16 patients. Patient enrollment will be suspended if there 
are not at least 3 IgG responders in the first 12 patients and not all 12 patients have 
been evaluated at 6 months. To account for a potential 10% early drop-out rate, we will 
enroll 35 patients so as to have 31 patients with both baseline and 6-month evaluations 
on IgG. Potential reasons for early dropouts are patients' choice, inability to return to our 
center or changes in CLL status that may require a different intervention. Sensitivity 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
21 
 
analysis will be performed to assess the impact of early dropouts. For example, we will 
analyze the data counting early dropouts either as "failures" (the most conservative 
approach) or as "missing" (thus, excluded from the analysis) and evaluate the response 
rate in both scenarios. Also, since the treatment requires at least 3 months of therapy 
before seeing an effect on immunoglobulin levels, we will also perform a secondary 
analysis by including only those patients who have been treated for at least 3 months, 
while counting those early dropouts between 3 and 6 months as "failures".  
Lenalidomide-related toxicity (defined as any grade 3 or greater non-hematological 
toxicity) will be monitored using the method of Thall, Simon and Estey [16] and the 
study will be terminated early if toxicity occurs in more than 40% of patients. 
Specifically, denoting the probability of toxicity by p, the study will be stopped early if 
Prob (p>0.40 data) > .95. The above decision criterion will be applied in cohort size of 5. 
Assuming a beta (.4, .6) priori for p, the above decision criterion implies that we will stop 
the trial according to the table below. For example, the trial will be terminated if 4 or 
more patients experienced toxicities among the first 5 patients.  
Number of patients 
Number of patients with 
toxicities is at least 
5 
4 
10 
7 
15 
10 
20 
12 
25 
15 
30 
17 


 
 
Protocol 2013-0371 
 
 
July 30, 2013 
 
22 
 
The operating characteristics of this study design based on 10,000 simulations are illustrated in 
Table 2.  
                   
              Table 2.  Operating Characteristics for Toxicity Monitoring Rule.  
True toxicity rate 
Prob (stop early) 
Sample Size 
25th, 50th and 75th 
percentiles 
0.20 
0.006 
35, 35, 35 
0.30 
0.039 
35, 35, 35 
0.40 
0.152 
35, 35, 35 
0.50 
0.447 
10, 35, 35 
0.60 
0.808 
5, 15, 30 
 
For the primary analysis, we will estimate the rate of IgG response along with the 95% 
confidence interval. As secondary analyses, we will also estimate the rates of 
Pneumococcus and Influenza seroconversion response, as defined in the response 
criteria section, and the corresponding 95% confidence intervals. The study will be 
considered positive in regard to the secondary endpoints if seroconversion is observed 
in 60% or more of the subjects for at least one of the vaccinations given. Similar method 
will be used to estimate the rate of influenza or Pneumococcal pneumonia. The duration 
of IgG response will be estimated using the Kaplan-Meier method. The cytokine levels 
and serum properdin levels will be summarized using descriptive statistics and will be 
compared between IgG responders and non-responders using two-sample t-test or 
Wilcoxon rank-sum test, as appropriate.