Clinical trial NCT01002755
Conditions: Chronic Lymphocytic Leukemia Fatigue Fever Hypogammaglobulinemia Lymphadenopathy Lymphocytosis Night Sweats Paraproteinemia Small Lymphocytic Lymphoma Thrombocytopenia
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-01-19; Completion date: 2018-01-31
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well lenalidomide and ofatumumab work in treating participants with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as ofatumumab, may interfere with the ability of tumor cells to grow and spread. Giving lenalidomide and ofatumumab may work better in treating participants with chronic lymphocytic leukemia or small lymphocytic lymphoma

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate efficacy and tolerability of the combination of ofatumumab and lenalidomide in patients with recurrent chronic lymphocytic leukemia (CLL).

OUTLINE:

Participants receive ofatumumab intravenously (IV) over 4 hours on days 1, 8, 15, and 22 of course 1, day 1 of courses 2-6, and day 1 of every even course beginning course 8. Beginning day 9 of course 1, participants also receive lenalidomide orally (PO) daily. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 6 months, then every 3 months thereafter.

Arms: arm 1: Participants receive ofatumumab IV over 4 hours on days 1, 8, 15, and 22 of course 1, day 1 of courses 2-6, and day 1 of every even course beginning course 8. Beginning day 9 of course 1, participants also receive lenalidomide PO daily. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Lenalidomide intervention 2: Ofatumumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
2009-0283
August 17, 2010
Page 1
Protocol Page
Combination of Lenalidomide and Ofatumumab in Patients with Previously Treated 
Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (CLL/SLL)
2009-0283
Core Protocol Information
Short Title 
Lenalidomide and Ofatumumab in Previously Treated CLL/SLL
Study Chair: 
Alessandra Ferrajoli
Additional Contact:
Diane R. Lee
Tawana Heiskell
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-2063
Unit:
428
Full Title: 
Combination of Lenalidomide and Ofatumumab in Patients with Previously Treated Chronic 
Lymphocytic Leukemia and Small Lymphocytic Lymphoma (CLL/SLL)
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 01/31/2018
Version:
13
Submitted by:
Tawana Heiskell--2/5/2014 11:31:04 AM
OPR Action:
Accepted by:  Matthew D. Geidel -- 2/14/2014 12:45:50 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2009-0283
August 17, 2010
Page 2
Protocol Body
 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
1  
 
 
 
 
Table of Contents 
 
 
 
 
 
 
 
 
 
 
 
Page 
 
1.0 
Objectives  
 
 
 
 
 
1 
2.0 
Background  
 
 
 
 
 
2 - 3 
3.0 
Study Design 
 
 
 
 
 
4 
4.0 
Treatment Plan 
 
 
 
 
 
4 - 11 
5.0 
Patient Eligibility  
 
 
 
 
11 - 13 
6.0 
Pretreatment Evaluation  
 
 
 
13 - 14 
7.0 
Evaluation During Study  
 
 
 
15 - 16 
8.0 
Criteria For Response 
 
 
 
 
16 
9.0 
Evaluation of Toxicity 
 
 
 
 
16 - 22 
10.0 
Statistical Design  
 
 
 
 
23 - 24 
11.0 
Amendments, Deviations, Regulatory  
 
24 - 26 
12.0 
Optional Correlative Studies 
 
 
 
26 - 27 
13.0 
References  
 
 
 
 
 
27 - 28 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
2  
 
 
1.0 Objectives 
 
The objective of this study is to evaluate efficacy and tolerability of the 
combination of ofatumumab and lenalidomide in patients with recurrent CLL. 
 
The primary end-point will be efficacy and an overall response rate of 40% or 
higher will be the target for this combination. The secondary endpoint is tolerance 
of the combination. Excessive toxicity will consist in a rate of grade 3-4 non-
hematological toxicity in more than 50% of the patients.  
 
2.0 Background 
 
CLL is the most common form of adult leukemia in the United States. It has been 
estimated that there are approximately 150,000 individuals living with CLL in the 
United States. The use of combination of chemoimmunotherapy as initial therapy 
is associated with a high response rates.  Unfortunately, once disease relapse 
has been observed second line treatment is less effective and responses 
obtained tend to be shorter(1). A treatment for second line consists in the use of 
the monoclonal antibody (mAb) alemtuzumab. Alemtuzumab is able to induce a 
response in up to 30% of the patients, but is associated with significant 
immunosuppression. Also, it lacks activity in patients that have developed bulk 
lymphadenopathies (larger than 5 centimeters)(2). Combination of purine-
analogue based regimens have limited activity: the combination of fludarabine, 
cyclophosphamide, rituximab, alemtuzumab (CFAR) is associated with an overall 
response rate of 65% in patients that have received prior therapy and once 
patients are fludarabine refractory their median survival is less than twelve 
months based on our published experience (3,4).   
 
Lenalidomide is a thalidomide derivative with immunomodulatory and anti-
angiogenic properties. Lenalidomide has been studied in patients with previously 
treated CLL as a single-agent and has shown encouraging activity with an overall 
response rate of 30-50% (5,6 ). The mechanism of action of lenalidomide in CLL 
is not completely known at this point: there is indication that its activity could be 
mediated through the stimulation of the immune system. An increased number of 
circulating T-cells has been observed in patients with CLL treated with this agent. 
Lenalidomide has also the ability to affect the interaction between the leukemic 
cells and the bone marrow stromal cells and T-cells (supported by pre-clinical 
data) and is able to suppress TNF-alpha and alter the cytokines milieu that is 
potentially important for CLL proliferation (7,8). 
   
Ofatumumab is a novel anti-CD20 mAb, and has potential advantages over 
rituximab in the specific setting of CLL. Ofatumumab is a fully human monoclonal 
antibody (IgG1) produced via a transgenic mouse technology and binds 
specifically to a unique epitope on the human CD20 molecule expressed on B-


 
 
2009-0283 
 
 
August 17, 2010 
 
 
3  
 
cells. Ofatumumab has shown clinical activity in a phase II study of patients with 
refractory CLL, the overall response rate was 58% in patients refractory to 
fludarabine and alemtuzumab and 47% in patients with bulky lympho-nodes and 
refractory to fludarabine (9, 10). The toxicity profile was favorable with mainly 
infusion-related reactions. 
 
On human tissue sections ofatumumab demonstrated tissue reactivity that is 
consistent with its target antigen specificity. Following the binding of ofatumumab 
to tumor B-cells clustering of CD20 into lipid rafts, as seen with rituximab, was 
observed. Strong differences in antibody cell-surface off-rates were detected 
between ofatumumab and rituximab. Ofatumumab dissociated much more slowly 
from surface CD20 than rituximab, corresponding to a half life of 180 minutes for 
ofatumumab and 90 minutes for rituximab. In this respect, both efficient 
clustering into rafts and a lower off-rate value for ofatumumab are important 
characteristics for an effective activation of the complement and may explain the 
superiority of ofatumumab over rituximab in CDC of B-cells. Ofatumumab-CD20 
was able to induce complement-mediated lysis of freshly isolated human B-CLL 
tumor cells, and rituximab-resistant cells lines expressing low levels of CD20 and 
high levels of CD55/CD59, which is known to diminish the lytic effect of 
complement. Ofatumumab -CD20- and rituximab-mediated Antibody Dependent 
Cell-mediated Cytotoxicity (ADCC) were equivalent. In an in vivo study 
employing a SCID mouse tumor model, HuMax-CD20-treated animals showed a 
dose-dependent prolongation of survival that was superior to rituximab. A pilot 
pharmacokinetic study in cynomolgus monkeys demonstrated that depletion of 
CD20 expressing B lymphocytes occurred rapidly after antibody administration. 
Depletion of B cells with ofatumumab lasted four times longer than depletion 
observed after administration of a similar dose of rituximab (11,12)         
 
The rationale for combining lenalidomide and ofatumumab is to potentiate the 
clinical efficacy of these agents without increasing their toxicity. This is based on 
different mechanisms of action and non-overlapping toxicity profile. The toxicity 
of ofatumumab consists mainly in infusion reactions and lenalidomide toxicity 
consisting mainly of early myelosuppression, fatigue, skin rash, diarrhea, and 
tumor flare. There is also the possibility that the combination will ameliorate the 
tumor flare reaction seen with lenalidomide because of the rapid reduction in 
tumor burden seen with anti-CD20 mAb therapy. Because of the debulking 
properties of ofatumumab, lenalidomide will be started on day 9, after two doses 
of ofatumumab have been administered.  
 
Current experience with the combination of lenalidomide and the anti-CD20 mAb 
rituximab (MDACC study 2007-0208) shows favorable activity with 7 of the first 
12 patients responding and 8 non-hematological grade >3 adverse events during 
the 39 treatment cycles administered (data on file). 
 
 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
4  
 
 
3.0 Study Design 
 
This is a single center open label phase II study to evaluate the efficacy and 
safety of the combination of lenalidomide and ofatumumab in patients with CLL 
who have received prior treatment. Celgene Corporation will supply lenalidomide 
as capsules via the RevAssist® program and GlaxoSmithKline (GSK) will supply 
ofatumumab for this study.  
 
4.0 Treatment Plan 
 
The administration of ofatumumab will be four weekly IV infusions at the dose of 
300mg week 1, 1,000 mg week 2, 3 and 4, then monthly during months 2-6 and 
once every two months during months 7-24 (even months: 8,10,12 etc.). 
Lenalidomide will be given at the dose of 10mg daily. Lenalidomide will be 
started on day 9 – the day after the second infusion of ofatumumab and will be 
continued daily. Treatment duration will be 24 cycles and it will be possible to 
continue lenalidomide beyond 24 cycles if there is a significant benefit such as an 
ongoing PR or CR. Response will be evaluated after three, six, twelve, eighteen 
and twenty-four cycles. Only enough lenalidomide for 28 days of therapy will be 
supplied to the patient each cycle. Each cycle consists of 28 days. Patients with 
baseline creatinine clearance or calculated GFR ≥ 30ml/min but < 50ml/min will 
begin treatment at Dose Level – 1 (lenalidomide 5mg daily).  These patients may 
be escalated to lenalidomide 10mg daily on Day 29 or later at physician 
discretion based on tolerability.  Dose reduction steps will follow in accordance 
with Table 4 taken from their current dose. 
 
Drug Dispensing Requirements 
 
Lenalidomide: 
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 RevAssist® program of 
Celgene Corporation.  Per standard RevAssist® requirements all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial, and all 
research subjects enrolled into this trial, must be registered in and must comply 
with all requirements of the RevAssist® program.  Prescriptions must be filled 
within 7 days.  Only enough lenalidomide for one cycle of therapy will be supplied 
to the patient each cycle. 
 
Lenalidomide capsules should be swallowed whole, and should not be broken, 
chewed or opened.    


 
 
2009-0283 
 
 
August 17, 2010 
 
 
5  
 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the 
same day.  If it is missed for the entire day, it should not be made up. 
Patients who take more than the prescribed dose of lenalidomide should be 
instructed to seek emergency medical care if needed and contact study staff 
immediately.   
Labeling and Lenalidomide Distribution 
 
Lenalidomide will be shipped directly to patients via a specialty, Registered 
Pharmacy.   Bottles will contain a sufficient number of capsules for one cycle of 
dosing.    
Unused Lenalidomide supplies 
All unused lenalidomide shall be returned via procedures outlined in the 
RevAssist® program. 
Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide 
unless they are wearing gloves. 
 
Ofatumumab 
 
The investigational medicinal product (IMP) is a clear colorless liquid concentrate 
intended for intravenous infusion after dilution in sterile, pyrogen free 0.9% 
sodium chloride. During infusion the IMP will be filtered using a 0.2 mm in-line 
filter. 
 
Ofatumumab is supplied as a 100 mg (5 mL) vial or as a 1000 mg (50 mL) vial. 
 
Packaging and Labeling of Ofatumumab IMP 
 
The Ofatumomab IMP will be supplied to the site/pharmacy in cartons, each 
containing 10 vials. Labeling will be according to local legal requirements. 
 
Storage of Ofatumomab IMP 
 
The IMP will be stored refrigerated (2-8°C) in a safe and secure place. The IMP 
will not be frozen. A temperature log with daily readings will be kept. 
After dilution in 0.9% sodium chloride the IMP can be kept at room temperature 
and will be administered to the patient within 24 hours. Exact time of dilution will 
be written on the infusion bag label. 
 
The IMP will not be utilized after the expiry date printed on the label, unless 
extended in writing by the sponsor (MDACC) based on ongoing stability studies. 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
6  
 
Drug supplies will be kept in an appropriate restricted area, accessible only to the 
investigator,pharmacist or duly designated person. Returned, unused or expired 
ofatumumab will be destroyed according to MDACC guidelines. 
 
Ofatumumab Drug Accountability and Compliance Check. 
The investigator will ensure that a designated person receives IMP deliveries 
from GlaxoSmithKline (GSK). 
 
Ofatumumab administration: 
 
Pre-medication before each ofatumumab infusion must be given within 30 
minutes to 2 hours prior to the treatment: 
Table 1 
   Pre-medication Requirements prior to Ofatumumab Infusions 
Infusion # 
Acetaminophen 
(po) 
or equivalent 
Antihistamine (iv or po) 
diphenhydramine  
or equivalent 
Glucocorticoid (iv) 
 prednisolone  
or equivalent  
1st  
1000 mg 
50 mg 
50 mg 
2nd  
1000 mg  
50 mg 
50 mg 
3rd -Nth  
1000 mg 
50 mg 
0 – 50 mg1  
1.If the 2nd infusion has been completed without the subject experiencing any 
grade = 3 adverse events (AEs), pre-medication with glucocorticoid may be 
reduced or omitted before the 3rd to Nth infusion at the discretion of the 
investigator.  
Ofatumumab dosing recommendation for combination therapy in CLL: the first 
cycle of ofatumumab in combination with chemotherapy should consist of an 
infusion of 300 mg on Day 1 and an infusion of 1000 of Day 8 of Cycle 1.  For 
subsequent cycles, a dose of 1000 mg should be infused on Day 1 of each cycle.  
 
 
First Infusion of 300mg Ofatumumab 
The first dose administered of ofatumumab should be 300 mg to minimize 
infusion reactions. The initial rate of the first infusion of 300mg ofatumumab 
(0.3mg/ml) should be 12ml/h. If no infusion reactions occur the infusion rate 
should be increased every 30 minutes, to a maximum of 400 ml/h, according to 
Table 2. If this schedule is followed, the infusion duration will be approximately 
4.5 hours. 
 
 
 
 
Table 2 
Infusion rate at 1st Ofatumumab infusion 
Time 
mL/hour 
0 – 30 minutes 
12 
31 – 60 minutes 
25 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
7  
 
61 – 90 minutes 
50 
91 – 120 minutes 
100 
121 - 150 minutes 
200 
151 - 180 minutes 
300 
181+ minutes 
400 
 
If an infusion reaction develops, the infusion should be temporarily slowed or 
interrupted. Upon restart, the infusion rate should be half of the infusion rate at 
the time the infusion was paused. If, however, the infusion rate was 12 mL/hour 
before the pause, the infusion should be restarted at 12 mL/hour. Hereafter, the 
infusion rate may be increased according to the judgment of the investigator, in 
the manner described in this section. 
 
Subsequent infusion of full dose Ofatumumab 
 
If the previous infusion has been completed without grade ≥ 3 infusion-
associated AEs, the subsequent infusion of the first full dose of ofatumumab can 
start at a rate of 25 mL/hour and should be doubled every 30 minutes up to  
a maximum of 400 ml/h, according to Table 3. Duration of the infusion will be 
approximately 4 hours if this schedule is followed. If the previous infusion has 
been completed with grade ≥ 3 infusion associated AEs, the subsequent infusion 
should start at a rate of 12 mL/hour according to Table 2. 
 
Table 3 
Infusion rate at subsequent Ofatumumab infusion 
Time 
mL/hour  
0 – 30 minutes 
25 
31 – 60 minutes 
50 
61 – 90 minutes 
100 
91 – 120 minutes 
200 
121+ minutes 
400 
 
During infusion the patient should be monitored closely and appropriate 
measurements should be performed whenever judged necessary. 
 
Dose Reduction: DOSE REDUCTION GUIDELINES FOR OFATUMUMAB. 
No dose reduction is planned for ofatumumab, its administration will be held for 
grade 3 or higher hepatic toxicity and can be omitted if clinically indicated. 
 
 
Dose Reduction: DOSE REDUCTION GUIDELINES FOR LENALIDOMIDE. 
 
 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
8  
 
Table 4: LENALIDOMIDE Dose Reduction Steps 
Starting Dose                                                      10 mg daily  
 
Dose Level – 1  5 mg daily  
Dose Level – 2   5 mg daily, day 1-21 of a 28 days cycle - or 5 mg 
every other day for 28 days. 
Dose Level  – 3  5 mg every third day 
 
 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
9  
 
Table 4: Dose Modification Guidelines for Lenalidomide 
NCI CTC Toxicity Grade 
Action 
Sustained (>7 days) Grade 3 neutropenia, or 
Grade 3 neutropenia associated with fever 
(temperature >38.5o C) 
or Grade 4 neutropenia (ANC <500/mm3, or 
<25% of baseline ANC)*. 
1)  Hold (interrupt dose). 
2)  Follow CBC weekly until resolution or 
stabilization 
3)  If neutropenia has resolved to <grade 
2, or 50% of baseline ANC, implement one 
dose reduction step and continue 
therapy***.  
Thrombocytopenia Grade 4 (platelet count 
<25,000/mm3) or <25% of baseline platelet 
count.* 
1)  Hold (interrupt dose). 
2)  Follow CBC weekly until resolution or 
stabilization 
3)  If thrombocytopenia resolves to < grade 
2, or 50% of baseline thrombocytopenia 
implement one dose reduction step 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 one dose reduction step and 
continue therapy***.  
 
 
 
1) Discontinue lenalidomide. 
Desquamating (blistering) rash-any Grade 
Discontinue lenalidomide. 
Erythema multiforme 
Grade 3 
Discontinue lenalidomide. 
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 one dose reduction step and 
continue therapy***.  
 
 
 
Discontinue lenalidomide. 
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 one dose reduction step and 
continue therapy***. 
 
 
Discontinue lenalidomide. 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
10  
 
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 one dose reduction step and 
continue therapy***.  
 
 
Discontinue lenalidomide. 
Constipation 
Grade 1-2 
 
> Grade 3 
1) Initiate bowel regimen and maintain 
dose level 
 
If the toxicity resolves to <grade 2, 
implement one dose reduction step and 
continue therapy***.  
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 one dose reduction step 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 
and as clinically indicated. 
**Further dose reduction will be allowed at the discretion of the investigator in 
case of persistent non hematological toxicity of Grade 3 or less and in case of a 
change in laboratory evaluation such as platelet count, absolute neutrophil count, 
or hemoglobin count that indicates upcoming myelosuppression or as clinically 
indicated. 
***Once toxicity has resolved, lenalidomide dose can be increased to 10 mg/daily 
at the discretion of the investigator or to the dose that is clinically indicated. 
 
 
Concomitant Medication:  
 
Tumor Lysis: 
Tumor lysis syndrome (TLS) has been reported in CLL patients treated with 
lenalidomide and ofatumumab.  Precautions must be taken to prevent TLS 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
11  
 
including proper selection of patients with regard to renal function, correction of 
electrolyte abnormalities, and TLS prophylaxis and monitoring. 
Allopurinol at the dose of 300mg daily will be given during the first two weeks of 
treatment as standard tumor lysis prophylaxis, it can then be continued at the 
discretion of the treating physician as clinically indicated.  
Subjects should be instructed to maintain adequate hydration and maintain 
urinary output as an additional measure to prevent TLS.  To maintain fluid intake, 
subjects should be instructed to drink 8 to 10 eight ounce glasses of water each 
day for the first 14 days of Cycle 1.  Hydration levels should be adjusted 
according to age and clinical status, and lowered if the subject’s cardiovascular 
status indicates the possibility of volume overload.  Within the first 3 cycles of 
therapy, additional oral hydration should be considered concurrent with any dose 
escalation (or re-escalation, if permitted) of lenalidomide, when lenalidomide is 
restarted after having been held for any reason or in concomitance with 
ofatumumab administration. 
Based on a patient’s reaction and laboratory parameters, TLS prophylaxis may 
be continued or restarted as needed as clinically indicated. 
Prophylactic hepatitis treatment will be initiated if clinically indicated. 
 
 
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, prednisone, erythropoietin, 
Adriamycin and daunorubicin), anthracyclines (Doxil, Adriamycin), the risk of 
thrombosis is increased. Treating physicians may consider the use of aspirin 
(81mg or 325mg) or low molecular weight heparin in patients at high risk for 
thrombotic events. 
 
5.0  Patient Eligibility 
 
Inclusion Criteria: 
 
Patients will be eligible for inclusion in the study if they meet all of the following 
criteria: 
 
1.  Patients age > 18 years at the time of signing informed consent. Understand 
and voluntarily sign an informed consent. 
 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
12  
 
2.  Patients with CLL or SLL with active disease. 
 
3.  Prior treatment with purine analog based chemotherapy or 
chemoimmunotherapy. 
 
4.  Platelet count > 30,000 mm3 
 
5.  ECOG/WHO performance status of 0-2  
 
6.  Adequate renal function indicated by creatinine clearance > 30ml/min 
(calculated by 24 hours urine collection) or a GFR > 30 ml/min estimated using 
the Cockcroft-Gault equation.  Adequate hepatic function indicated as total 
bilirubin less or equal to 2 mg/dl and ALT less or equal to two times the upper 
limit of normal. 
 
7. 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. 
 
8. Females of childbearing potential (FCBP)† must have a negative serum or 
urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days 
prior to starting lenalidomide and again within 24 hours prior to prescribing 
lenalidomide (prescriptions must be filled within 7 days) and prior to first  
administration of ofatumumab 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 and continue it for 6 
months after therapy has been completed.  FCBP must also agree to ongoing 
pregnancy testing.  Men must agree to use a latex condom during sexual contact 
with a FCBP even if they have had a successful vasectomy.  All study 
participants must be registered into the mandatory RevAssist® program, and be 
willing and able to comply with the requirements of RevAssist®. See Appendix: 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods. 
 
 
Exclusion Criteria: 
 
                                                 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
 
 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
13  
 
1. Known sensitivity to lenalidomide, other thalidomide derivatives or 
ofatumumab. 
 
2. Documented prolymphocytic leukemia (prolymphocytes more than 55% in the 
blood). 
 
3. Known positivity for HIV or active hepatitis B or C.   
 
Known positivity for HIV or active hepatitis B or C. Positive serology for hepatitis 
B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but 
HBcAb positive regardless of HbsAb status, a HB DNA test will be performed and 
if positive the subject will be excluded.  
 
4. Pregnant or breast feeding females. Women of childbearing potential must 
have a negative pregnancy test at screening. Male subjects unable or unwilling to 
use adequate contraception methods from study start to one year after the last 
dose of protocol therapy. 
 
5. Chronic or current infectious disease requiring systemic antibiotics, antifungal, 
or antiviral treatment such as, but not limited to, chronic renal infection, chronic 
chest infection with bronchiectasis and tuberculosis. History of tuberculosis 
treated within the last five years or recent exposure to tuberculosis.  
6. 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. 
 
7. Patients with a recent history of deep vein thrombosis (DVT) or pulmonary 
embolus (PE), in the six months prior to enrollment are not eligible for this study.. 
 8.Treatment with any known non-marketed drug substance or experimental 
therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is 
longer, or currently participating in any other interventional clinical study 
9. Prior treatment with other monoclonal antibodies within 4 weeks prior to 
enrollment. 
10. Subjects meeting any of the following criteria must not be enrolled on study: 
Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In 
addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), 
a HB DNA test will be performed and if positive, the subject will be excluded. 
 
6.0 Pretreatment Evaluation 
 
Pretreatment evaluation will include a physical examination including vital signs 
ECOG/WHO performance status and query for concomitant medications, height 
and weight and recording of concurrent medications (within 7 days of Day 1).  


 
 
2009-0283 
 
 
August 17, 2010 
 
 
14  
 
Clinical laboratory evaluation will include serum chemistry. This will include 
sodium, potassium, calcium, magnesium, phosphorus, BUN, creatinine, glucose, 
albumin, total protein, alkaline phosphatase, total bilirubin, ALT, AST, uric acid, 
and TSH and Beta-2-microglobulin (within 7 days of Day 1). 
 
Hematology: Complete CBC (white blood cell, hemoglobin, platelets and 
differential) and differential and peripheral blood lymphocyte subset and 
immunoglobulin levels (within 7 days of registration). 
 
Bone marrow aspiration and biopsy within one month from registration. Bone 
marrow will be evaluated by flow cytometry for clonality and for IgVH mutation 
studies (unless known) ZAP-70 expression (unless known), cytogenetic and 
genomic abnormalities by FISH (unless known). 
 
Electrocardiogram monitoring will be conducted at baseline (within 7 days of Day 
1). 
Pregnancy Testing and Counseling per the RevAssist® program, assess patient 
child bearing potential according to the RevAssist® program guidelines outlined 
below.   
 
Pregnancy tests for females of childbearing potential.  A female of childbearing 
potential (FCBP) is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months).  Pregnancy tests must occur 
within 10 – 14 days prior to starting lenalidomide, and  again within 24 hours prior 
to prescribing lenalidomide (prescriptions must be filled within 7 days) and prior 
to first administration of ofatumumab.  FCBP with regular or no menstruation 
must have a pregnancy test weekly for the first 28 days and then every 28 days 
while on therapy (including breaks in therapy); at discontinuation of lenalidomide 
and at Day 28 post the last dose of lenalidomide.  Females with irregular 
menstruation must have a pregnancy test weekly for the first 28 days and then 
every 14 days while on therapy (including breaks in therapy), at discontinuation 
of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see 
Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods).    
 
Lenalidomide must be prescribed through and in compliance with the RevAssist® 
program of Celgene Corporation.  Prescriptions must be filled within 7 days.  
Consideration should be given to prescribing lenalidomide 5 to 7 days in advance 
of lenalidomide administration of each cycle to allow time for required patient and 
prescriber surveys, and drug shipment to patient.  Any unused Revlimid® 
(lenalidomide) should be returned to the patient for disposition in accordance with 
the RevAssist® program.  
 
 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
15  
 
7.0 Evaluation during Study 
 
Clinic visits (this will include vital signs and physical exam) at The University of 
Texas, M.D. Anderson Cancer Center are required at the end of cycles 3, 
7,13,19, 23, and every 6 cycles (+ 14 days) after that. Hematology complete 
blood counts (white blood cell, hemoglobin, platelets and differential) will be 
monitored once weekly (+ 3 days) for the first five weeks and once every two 
weeks (+ 5 days) in case of dose increase until a stable dose of lenalidomide has 
been established for the specific patient (the once every two weeks laboratory 
monitoring will not apply if the dose is decreased for non-hematological or 
laboratory measurable toxicity), and then every four weeks (once per cycle) 
thereafter. Pregnancy testing and counseling per the RevAssist® program.   
Serum chemistry basic metabolic profile, (sodium, potassium, chloride, CO2, 
BUN, creatinine, uric acid, calcium and phosphorus, ALT, AST, alkaline 
phosphatase, (bilirubin and glucose) will be monitored once weekly (+ 3 days) for 
the first five weeks and then once every two weeks (+5 days) until a stable dose 
of lenalidomide has been established for the specific patient and then every four 
weeks (once per cycle) thereafter. Additional laboratory evaluations may be 
obtained after the first dose of lenalidomide, in week 2 of cycle 1 and at any time 
during the study if clinically indicated.  TSH, beta-2-microglobulin, lymphocyte 
subset, immunoglobulin levels, bone marrow biopsy and aspiration will be 
performed at the end of cycles  3,7,13,19,23, and every 6 cycles after that (+ 14 
days). If patients continue on the study past 24 cycles a bone marrow biopsy and 
aspirate (with flow cytometry and molecular studies if indicated) to check the 
status of the disease will be obtained once every 6-12 cycles (+ 28 days) as 
clinically indicated and blood will also be drawn for routine tests. 
Electrocardiogram will be conducted as clinically indicated during and after 
treatment.  
 
In subjects that are HBsAg negative, HBcAb positive and have a negative HBV 
DNA testing at study entry monitoring for hepatitis B reactivation by HBV DNA 
PCR testing is required during the on treatment periods at least every 2 months 
and during follow up at a minimum of every 2-3 months up to 6 months after the 
last dose of ofatumumab. 
 
Once treatment has been completed or discontinued, liver function test (ALT, 
AST, alkaline phosphatase and bilirubin) will be performed 6 months (+ 28 days) 
after the last dose of ofatumumab has been administered unless patients have 
received subsequent treatment for their CLL. Correlative laboratory studies and 
Quality of Life questionnaire (Appendix E) are optional and if the patient agrees 
they will be collected at baseline, at the end of cycles 3, 7, 13,19, 23 and every 6 
cycles after that (+ 14 days).  
You will be required to use TWO reliable forms of birth control, one highly 
effective method and one additional effective method at the same time or 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
16  
 
practice complete abstinence from heterosexual intercourse during the following 
time periods related to this study: 1) for at least 28 days before starting 
lenalidomide; 2) while participating in this study; and 3) for at least 28 days after 
discontinuation from the study.   The following are the acceptable birth control 
methods:  
Highly Effective Methods 
Additional Effective 
Methods 
Intrauterine device (IUD)  
Latex condom 
Hormonal (birth control pills, injections, implants) 
Diaphragm 
Tubal ligation   
Cervical Cap 
Partner’s vasectomy 
Females must not breastfeed a baby while participating in this study and for at 
least 28 days after you have been discontinued from the study. 
 
Females of childbearing potential with regular or no menstrual cycles must agree 
to have pregnancy tests weekly for the first 28 days of study participation and 
then every 28 days while on study, at study discontinuation, and at day 28 
following discontinuation from the study.  If menstrual cycles are irregular, the 
pregnancy testing must occur weekly for the first 28 days and then every 14 days 
while on study, at study discontinuation, and at days 14 and 28 following 
discontinuation from the study.   
 
8.0 Criteria for Response 
 
The 1996 NCI Working Group criteria will be used. (See Appendix F).  
Responses will be assessed after 3, 7, 13, 19 and 23 cycles and every 6-12 
months as clinically indicated. 
 
9.0 Evaluation of Toxicity 
 
Adverse events are reported as per UTMDACC and Leukemia Phase 2-3 studies 
(Appendix H and Appendix I). 
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, infections, sepsis, pneumonia, UTI, upper respiratory infection, 
cellulitis, atrial fibrillation, congestive heart failure, myocardial infarction, chest 
pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone 
pain, generalized pain, dizziness, mental status changes, syncope, renal failure, 
dyspnea, pleural effusion, pulmonary embolism, deep vein thrombosis, CVA, 


 
 
2 0 0 9- 0 2 8 3 
 
 
A u g ust 1 7, 2 0 1 0 
 
 
17   
 
c o n v ul si o n s, di z zi n e s s, s pi n al c or d c o m pr e s si o n, s y n c o p e, di s e a s e pr o gr e s si o n, 
d e at h n ot s p e cifi e d a n d fr a ct ur e s.  
Pl e a s e r ef er t o l e n ali d o mi d e p a c k a g e i n s ert or I n v e sti g at or Br o c h ur e f or a 
c o m pl et e li st.  
A d v er s e E v e nt s wit h Of at u m u m a b 
T h e f oll o wi n g r e a cti o n s s h o ul d b e r e g ar d e d a s e x p e ct e d i nf u si o n -r el at e d a d v er s e 
r e a cti o n s i n c o n n e cti o n wit h t h e u s e of of at u m u m a b a s a c o n s e q u e n c e of B-
l y m p h o c yt e d e pl eti o n: pr urit u s, d y s p n e a, br o n c h o s p a s m, t hr o at irrit ati o n, c o u g h, 
p h ar y n g ol ar y n g e al p ai n, fl u s hi n g, h y p er hi dr o si s, n a u s e a a n d v o m iti n g, a b d o mi n al 
p ai n, h y p ot e n si o n, r a s h/ urti c ari a, i nfl u e n z a-li k e-ill n e s s, f ati g u e, f e v er, c hill s, 
h e a d a c h e, di z zi n e s s, m y al gi a a n d  artr al gi a. Pr of o u n d a n d l o n g-la sti n g d e pl eti o n 
of C D 2 0 + B l y m p h o c yt e s h a s b e e n s e e n d uri n g tr e at m e nt wit h of at u m u m a b a s 
e x p e ct e d wit h a n a nti- C D 2 0 a nti b o d y, b ut s o f ar wit h o ut a n y si g n s of a n 
i n cr e a s e d ri s k of i nf e cti o u s c o m pli c ati o n s. I n all cli ni c al st udi e s a d v er s e e v e nt s 
w er e r e p ort e d wit h s u b st a nti a ll y hi g h er fr e q u e n c y o n t h e fir st i nf u si o n d a y, 
c o m p ar e d t o t h e s u b s e q u e nt i nf u si o n s. 
F urt h er i nf or m ati o n c a n b e f o u n d i n t h e Of at u m u m a b I n v e sti g at or’ s Br o c h ur e. 
M y el o s u p pr e s si o n a n d a s s o ci at e d c o m pli c ati o n s ar e e x p e ct e d e v e n t s d uri n g 
l e u k e mi a t h er a p y a n d ar e p art of t h e tr e at m e nt s u c c e s s ( m arr o w e m pt yi n g of 
l e u k e mi c c ell s). T h er ef or e, m y el o s u p pr e s si o n a n d a s s o ci at e d c o m pli c ati o n s s u c h 
a s f e v er, i nf e cti o n s, bl e e di n g a n d r el at e d h o s pi t ali z ati o n s will n ot b e r e p ort e d a s 
i n di vi d u al a d v er s e dr u g r e a cti o n s ( A D R s), b ut will b e s u m m ari z ed i n t h e u p d at e d 
a n d fi n al r e p ort s.  O nl y pr ol o n g e d m y el o s u p pr e s si o n, a s d efi n e d  b y t h e n e w N CI 
crit eri a s p e cifi c f or l e u k e mi a, i . e., m arr o w c ell ul arit y < 5 % on d a y 4 2 or l at er ( 6 
w e e k s) fr o m st art of t h er a p y wit h o ut e vi d e n c e of l e u k e mi a, will  b e r e p ort e d.  
M D A n d er s o n ( S p o n s or) R e p orti n g R e q uir e m e nt s f or S eri o u s A d v er s e E v e nt s 
a n d D o s e Li miti n g T o xi citi e s:  
 
S eri o u s A d v er s e E v e nt ( S A E) D efi niti o n  
A s eri o u s a d v er s e e v e nt i s o n e t h at at a n y d o s e (i n cl u di n g o v er d o s e): 
  
R e s ult s i n d e at h 
  
I s lif e-t hr e at e ni n g1 
    
R e q uir e s i n p ati e nt h o s pit ali z ati o n or pr ol o n g ati o n of e xi sti n g 
h o s pit ali z ati o n 
  
R e s ult s i n p er si st e nt or si g nifi c a nt di s a bilit y or i n c a p a cit y2 
  
I s a c o n g e nit al a n o m al y or birt h d ef e ct 
  
I s a n i m p ort a nt m e di c al e v e nt3 
 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
18  
 
1“Life-threatening” means that the subject was at immediate risk of death at the 
time of the serious adverse event; it does not refer to a serious adverse event 
that hypothetically might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a 
substantial disruption of a person’s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in situations where none of the outcomes listed 
above occurred.  Important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other outcomes listed in the 
definition above should also usually be considered serious.  Examples of such 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug 
abuse.  A new diagnosis of cancer during the course of a treatment should be 
considered as medically important.  
Adverse Drug Reaction Reporting 
AS PER UTMDACC AND LEUKEMIA PHASE II-III STUDIES (APPENDIX H 
AND APPENDIX I), Toxicity will be scored using CTCAE Version 3.0 for toxicity 
and adverse event reporting and myelosuppression will be reported according to 
the recommended guidelines for CLL (Appendix J).  A copy of the CTCAE 
Version 3.0 can be downloaded from the CTEP homepage 
(http://ctep.info.nih.gov).  All appropriate treatment areas should have access to 
a copy of the CTCAE Version 3.0.  All adverse clinical experiences (according to 
Appendix H), whether observed by the investigator or reported by the patient, 
must be recorded, with details about the duration and intensity of each episode, 
the action taken with respect to the test drug, and the patient’s outcome.  The 
investigator must evaluate each adverse experience for its relationship to the test 
drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical 
significance.  If any abnormal laboratory result is considered clinically significant, 
the investigator must provide details about the action taken with respect to the 
test drug and about the patient’s outcome. Abnormal lab values are only 
significant if they require intervention or treatment. 
 
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 in accordance 
with the timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy on Reporting Serious 
Adverse Events and to Celgene and GSK within 24 hours.  
 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
19  
 
All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy on Reporting Serious Adverse Events”. Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be 
reported to ORERM, regardless of attribution (within 5 working days of 
knowledge of the event). 
 
All life-threatening or fatal events, expected or unexpected, and regardless of 
attribution to the study drug, must have a written report submitted within 24 
hours (next working day) of knowledge of the event to the Safety Project 
Manager in ORERM. 
 
The MDACC “Internal SAE Report Form for Prompt Reporting” will be used 
for reporting to ORERM. 
 
Serious adverse events will be captured from the time the patient signs 
consent until 30 days after the last dose of lenalidomide and  for a 
minimum of 5 half lives (6 months) after the last dose of ofatumumab If a 
subject does start other therapy, then SAEs will no longer be required to be 
reported.  
 
 Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the 
event has stabilized, or there has been acceptable resolution of the event. 
 
Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to ORERM. 
This may include the development of a secondary malignancy. 
 
Reporting to FDA: 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager ORERM) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, 
and Institutional Review Board policy. 
 
NOTE:  Instructions concerning procedures and reporting for pregnancies below. 
Pregnancies 
Pregnancy of a female subject or the female partner of a male subject occurring 
while the subject is on lenalidomide and ofatumumab or within 4 weeks after the 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
20  
 
subject’s last dose of lenalidomide or ofatumumab are considered expedited 
reportable events.  If the subject is on lenalidomide, it is to be discontinued 
immediately and the subject is to be instructed to return any unused portion of 
lenalidomide to the Investigator.  The pregnancy must be reported by the 
investigator to MDACC IRB and ORERM AND to Celgene Corporation 
Worldwide Drug Safety Surveillance (WWDSS) and to GSK within 24 hours of 
the Investigator’s knowledge of the pregnancy by phone and facsimile using the 
SAE Form. 
 
The Investigator will follow the subject until completion of the pregnancy, and 
must notify Celgene Corporation Worldwide Drug Safety Surveillance (WWDSS) 
of the outcome as specified below.  The Investigator will provide this information 
as a follow-up to the initial SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as 
a SAE (i.e., spontaneous abortion [any congenital anomaly detected in an 
aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for reporting SAEs (i.e., 
report the event to Celgene Corporation Worldwide Drug Safety Surveillance 
(WWDSS)  by facsimile within 24 hours of the Investigator’s knowledge of the 
event) and report the event to MDACC IRB and ORERM. 
 
Any suspected fetal exposure to lenalidomide must be reported to Celgene, 
GSK, MDACC IRB AND ORERM within 24 hours of being made aware of the 
event.  The patient should be referred to an obstetrician/gynecologist 
experienced in reproductive toxicity for further evaluation and counseling. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without 
regard to causality, as SAEs.  In addition, any infant death after 30 days that the 
Investigator suspects is related to the in utero exposure to lenalidomide should 
also be reported. 
In the case of a live “normal” birth, Celgene Corporation Worldwide Drug Safety 
Surveillance (WWDSS), GSK, MDACC IRB AND ORERM should be advised as 
soon as the information is available. 
 
Drug Safety Contact Information: 
 
Celgene Corporation 
Worldwide Drug Safety Surveillance (WWDSS) 
86 Morris Avenue 
Summit, N.J. 07901 
 
Toll Free:   
(800)-640-7854 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
21  
 
Phone:  
(908) 673-9667 
Fax:  
(908) 673-9115 
e-mail:  
drugsafety@celgene.com 
 
 
 
GlaxoSmithKline 
1250 South Collegeville Road 
Collegeville, PA  19426, USA 
Fax:  610-917-6715 
E-mail:  Robert.a.friedman@gsk.com 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
Serious Adverse Events Reporting:  The principle 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 in accordance 
with the timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy and also to Celgene 
and GSK within 24 hours.  
 
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, 
that an annual report is provided to the FDA within 60-days of the IND 
anniversary date.  21 CRF 312.33 provides the data elements that are to be 
submitted in the report.  The Annual Report should be filed with MD Anderson’s 
ORERM, who will then forward to FDA.  An additional copy should be placed in 
the study's Regulatory Binder and a copy must be sent by the PI/research team 
to Celgene and GSK as supporters of this study as follows. 
 
 
Celgene Corporation 
 
Attn: Medical Development 
 
86 Morris Avenue 
 
Summit, NJ  07901 
 
Tel: (908) 673-9000 
 
 
GlaxoSmithKline 
 
1250 South Collegeville Road 
 
Collegeville, PA 19426, USA 
 
Phone: 610-917-7000 
 
 
All adverse experience reports must include the patient number, age, sex, 
severity of reaction (mild, moderate, severe), relationship to study drug (probably 
related, unknown relationship, definitely not related), date and time of 
administration of test medications and all concomitant medications, and medical 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
22  
 
treatment provided.  The investigator is responsible for evaluating all adverse 
events to determine whether criteria for “serious” and as defined above are 
present.  The investigator is responsible for reporting adverse events to Celgene 
and GSK as described below. 
Expedited reporting by Principal Investigator to Celgene and GSK 
Serious adverse events (SAE) are defined above.  The investigator should inform 
Celgene and GSK of any SAE within 24 hours of being aware of the event.  The 
date of awareness should be noted on the report.  This must be documented on 
an MD Anderson SAE form. This form must be completed and supplied to  
Celgene and GSK within 24 hours/1 business day at the latest on the following 
working day.  The initial report must be as complete as possible, including details 
of the current illness and (serious) adverse event, and 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 MD Anderson SAE form.  A final report to document 
resolution of the SAE is required.  The Celgene protocol number (RV-CLL-PI-
0468) should be included on SAE reports to Celgene.  A copy of the fax 
transmission confirmation of the SAE report to Celgene and GSK should be 
attached to the SAE and retained with the patient records. 
Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board 
(IRB) of a serious adverse event according to institutional policy.   
Sponsor Reporting to the FDA 
Adverse drug reactions that are Serious, Unlisted/unexpected, and at least 
possibly associated to the drug, and that have not previously been reported in 
the Investigators brochure, or reference safety information document should be 
reported promptly to the Food and Drug Administration (FDA) in writing by each 
investigator/physician engaged in clinical research.  A clear description of the 
suspected reaction should be provided along with an assessment as to whether 
the event is drug or disease related.   
 
The sponsor shall notify the FDA by telephone or by fax of any unexpected fatal 
or life threatening experience associated with the use of the drug. As soon as 
possible, but no later than 7 calendar days after the sponsors initial receipt of the 
information. Each phone call or fax shall be transmitted to the FDA new drug 
review division in the Center for Drug Evaluation and Research or the product 
review division in the Center for Biologics Evaluation and Research that has 
responsibility for review of the IND if applicable. 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
23  
 
Adverse event updates/IND safety reports 
Celgene and GSK shall notify the Investigator via an IND Safety Report of the 
following information: 
 
1.  Any AE associated with the use of study drug in this study or in other studies 
that is both serious and unexpected. 
 
2.  Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. 
 
The Investigator must keep copies of all AE information, including 
correspondence with Celgene and the IRB/EC, on file. 
 
 
10.0 Statistical Design 
 
This is a single-arm, phase II study of combination of lenalidomide and 
ofatumumab. The study population consists of patients with previously treated 
CLL/SLL and patients will have to have received at least one purine analog-
based regimen. The primary outcome is overall response. A Simon’s two-stage 
minmax design will be used for this study. A sample size of 36 is chosen to 
differentiate between a good response rate of 40% and a poor response rate of 
20% with 90% power at a significance level of 0.1. In particular, 19 patients will 
be enrolled at the first stage. If there are 3 or fewer responses in the first 19 
patients, accrual will be suspended until we have 4 responders among the first 
19 patients. The trial will be terminated if all 19 patients have been evaluated for 
6 cycles and there are 3 or fewer responses; otherwise another 17 patients will 
be treated for a total of 36 patients. If there are 10 or fewer responses among 36 
patients, the treatment will be concluded ineffective. The probability of early 
termination due to futility is 0.46. Overall response includes complete remission 
(CR) and partial remission (PR). Patients are considered non-responders if there 
is progression of disease. CR, PR and SD allow continuation of treatment.  
 
The probability of toxicity (grade 3 and 4 non-hematological) will be monitored 
based on the Bayesian model (beta-binomial) by assuming a priori probability of 
toxicity following Beta (1,1).  The trial will be terminated if Prob(toxicity > 0.33 | 
data) > .85. Following this rule, the trial will be terminated if [# toxicities]/[# 
patients evaluated] >/= 3/5, 5/10, 7/15, 9/20, 11/25, 13/30, and 15/35. A 
simulation study was performed to show the operating characteristics for the 
stopping rule based on 10,000 repetitions. The results are summarized in the 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
24  
 
following table. For example, the trial will be terminated early 90.8% of times if 
the true toxicity rate is 50%.  
 
True Prob(tox)  
Pr(stop)  Median 
#Pts (25%, 75%)  
0.10  
0.011 
36 (36, 36)  
0.20  
0.084 
36 (36, 36)  
0.30  
0.305  
36 (15, 36)  
0.40  
0.646  
15 (5, 36)  
0.50  
0.908  
10 (5, 15) 
0.60  
0.991  
5 (5, 10) 
 
 
The first time point to evaluate efficacy and toxicity will be at completion of cycle 
6 of treatment. Toxicity will be monitored closely during the entire treatment, but 
toxicities occurring after cycle 6 will not be applied to the stopping boundaries. 
The descriptive statistical analysis can be used to explore the data, including 
histograms or box-plots, proportions, mean, standard deviations. The Fisher’s 
exact test will be used for the univariate analysis on categorical variables 
(response variable with Yes versus No, for example). The t-test or Wilcoxon test 
will be used for continuous variables (Age and WBC, for example). Descriptive 
statistical analysis will also be used to report correlative studies and the quality of 
life questionnaire. 
 
11.0 Amendments, Deviations, Regulatory 
Protocol Amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator 
and by M. D. Anderson Cancer Center and by Celgene and GSK.  Amendments 
should only be submitted to IRB after consideration of M. D. Anderson Cancer 
Center, Celgene and GSK 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. 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
25  
 
Investigators must enter study data into MDACC’s PDMS.  The Investigator will 
permit study-related monitoring visits and audits by MDACC’s ORERM, Celgene 
or its representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, 
EMEA, TPP), providing direct access to the facilities where the study took place, 
to source documents, to CRFs, and to all other study documents. 
The Investigator, or a designated member of the Investigator’s staff, must be 
available at some time during 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 ORERM and the Celgene representative so that the 
accuracy and completeness may be checked. 
Institutional Review Board/Ethics Committee Approval 
The protocol for this study has been designed in accordance with the general 
ethical principles outlined in the Declaration of Helsinki. The review of this 
protocol by the IRB/EC and the performance of all aspects of the study, including 
the methods used for obtaining informed consent, must also be in accordance 
with principles enunciated in the declaration, as well as ICH Guidelines, Title 21 
of the Code of Federal Regulations (CFR), Part 50 Protection of Human Subjects 
and Part 56 Institutional Review Boards. 
 
The Investigator will be responsible for preparing documents for submission 
to the relevant IRB/EC and obtaining written approval for this study.  The 
approval will be obtained prior to the initiation of the study. 
 
The approval for both the protocol and informed consent must specify the 
date of approval, protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be 
submitted by the Investigator to the IRB/EC for approval.  The Investigator is 
also responsible for notifying the IRB/EC of any serious deviations from the 
protocol, or anything else that may involve added risk to subjects. 
 
Any advertisements used to recruit subjects for the study must be reviewed 
and approved by the IRB/EC prior to use. 
 
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 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
26  
 
subject’s source documents.  A copy of the original consent form signed and 
dated by the subject and by the person consenting the subject prior to the 
subject’s entry into the study, must be maintained in the Investigator’s study 
files. 
 
Study records requirements 
 
The Investigator must ensure that the records and documents pertaining to 
the conduct of the study  and the distribution of the study drug, that is copies 
of CRFs and source documents (original documents, data, and records [e.g., 
hospital records; clinical and office charts; laboratory notes; memoranda; 
subject’s diaries or evaluation checklists; 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 and GSK have the 
right to discontinue this study at any time for reasonable medical or 
administrative reasons in any single center.  Possible reasons for termination of 
the study could be but are not limited to: 
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. 
 
12.0 Optional Correlative Studies 
 
Quality of life questionnaire. The M.D. Anderson symptom inventory (MDASI) will 
be collected at baseline, at the end of cycles  3, 6,12, and every 6 cycles after 
that. (Appendix E). 
At baseline, at the end of cycles 3, 6, 12,18, and every 6 cycles after that, 
PBMNC will be collected to measure the number of CLL B-cells that express 
constitutively active, pSTAT3,  the percentage of Annexin-V+ leukemic cell, the 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
27  
 
number of Treg cells and the function of T cells measured by the ability of anti-
CD3 activated T cells to synthesis of IL-2, IFN-gamma, and IL-10; and NK cell 
cytotoxicity of K562 targets. At baseline, at the end of cycles 3, 6, 12,18, and 
every 6 cycles after that, plasma will be collected to measure VEGF, bFGF, TSP-
1, and IFN-gamma using Luminex Multiplex assay system. At baseline, at the 
end of cycles 3, 6, 12,18, and every 6 cycles after that, the ability of neoplastic 
unstimulated and CD40L-activated B cells to act as APC for T-cell activation will 
be assessed by the production of IL-2 and IL-10, and T-cell proliferation in mixed 
lymphocyte cultures. 
 
13.0 References 
 
1.Wierda W, O’Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, 
cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic 
leukemia. J Clin Oncol. 2005;18:1–9. 
 
2.Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-
1H) in patients who have failed fludarabine: results of a large international study. 
Blood. 2002;99:3554–3561. 
 
3.Wierda W, O’Brien S, Faderl S, et al. Combined cyclophosphamide, 
fludarabine, alemtuzumab, and rituximab (CFAR) an active regimen for heavily 
treated patients with CLL. Blood. 2006;108:31a 
 
4. Tam CS, O’Brien S, Lerner S, et al. The natural history of fludarabine-
refractory chronic lymphocytic leukemia patients who fail alemtuzumab or have 
bulky lymphadenopathy. Leuk Lymphoma.  2007;48:1931–1939. 
 
5.  Ferrajoli A, O'Brien S, Faderl SH, Wierda WG, Davis D, Lee B-L, Reuben JM, 
Schlette E, Kantarjian HM, Keating MJ. Lenalidomide induces complete and 
partial responses in patients with relapsed and treatment-refractory chronic 
lymphocytic leukemia (CLL). Blood 2008 (epub).  
 
6. Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita 
K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne 
C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical 
efficacy of lenalidomide in patients with relapsed or refractory chronic 
lymphocytic leukemia: results of a phase II study. J Clin Oncol 24(34):5343-5349, 
2006. 
7. Immunomodulatory drugs Revlimid (lenalidomide) and CC-4047 induce 
apoptosis of both hematological and solid tumor cells through NK cell activation. 
Zhu D, Corral LG, Fleming YW, Stein B. 
Cancer Immunol Immunother. 2008 Dec;57(12):1849-59. Epub 2008 Apr 8 
 


 
 
2009-0283 
 
 
August 17, 2010 
 
 
28  
 
8. 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;118:2427-24373.  
 
9. Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, Van Oers 
MH, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-
CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic 
leukemia: a phase 1-2 study. Blood 2008 Feb 1;111(3):1094-100. 
 
10. Osteborg A, Kipps TJ, Mayer J, et al. Ofatumumab (HuMax-CD20), a novel 
CD20 monoclonal antibody, is an active treatment for patients with CLL refractory 
to both fludarabine and alemtuzumab or bulky fludarabine-refractory disease: 
results from the planned interim analysis of an international pivotal trial. Blood. 
2008;112:36. (Abstract) 
 
11. Mous R, Savage P, Eldering E, Teeling P, van Oers MH, van Lier RA. 
Adequate synapse formation between leukemic B cells and effector T cells 
following stimulation with artificial TCR ligands. Leuk Lymphoma. 2008 
Aug;49(8):1592-602. 
 
12. Teeling JL, Mackus WJ, Wiegman LJ, van den Brakel JH, Beers SA, French 
RR, van Meerten T, Ebeling S, Vink T, Slootstra JW, Parren PW, Glennie MJ, 
van de Winkel JG. The biological activity of human CD20 monoclonal antibodies 
is linked to unique epitopes on CD20. J Immunol. 2006 Jul 1;177(1):362-71.