Phase II Study of Ofatumumab as Front-Line Treatment in Elderly, Unfit Patients With Chronic Lymphocytic Leukemia (CLL)
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
Sponsor: M.D. Anderson Cancer Center

Protocol Page
Phase II Study of Ofatumumab as Front-line Treatment in Elderly, Unfit Patients 
with Chronic Lymphocytic Leukemia (CLL)
2011-0520
Core Protocol Information
Short Title 
Phase II Study of Ofatumumab in Elderly Patients with CLL
Study Chair: 
Alessandra Ferrajoli
Additional Contact:
Diane R. Lee
Tawana Heiskell
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
None
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-792-2063
Unit:
428
Full Title: 
Phase II Study of Ofatumumab as Front-line Treatment in 
Elderly, Unfit Patients with Chronic Lymphocytic Leukemia 
(CLL)
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 12/10/2015
Version:
16
Document Status:
Saved as "Final"
Submitted by:
Tawana Heiskell--4/1/2015 12:15:31 PM
OPR Action:
Accepted by:  Virginia M Gonzales -- 4/13/2015 5:59:08 
PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

Protocol Body
 
  

 
 
Protocol 2011-0520 
 
 
February 27, 2013 
 
1 
 
 
 
Phase II Study of Ofatumumab as Front-line Treatment in Elderly, Unfit 
Patients with Chronic Lymphocytic Leukemia 
 
 
Table of Contents 
 
 
1.0 
Background  
 
 
 
 
 
 
2 – 3 
 
2.0 
Objectives  
 
 
 
 
 
 
3  
 
3.0 
Study Design 
 
 
 
 
 
 
4 – 7 
 
4.0 
Patient Eligibility  
 
 
 
 
 
8  
 
5.0 
Criteria For Removal From Study 
 
 
 
9  
 
6.0 
Visit Schedule & Assessments  
 
 
 
9 – 10 
 
7.0 
Criteria For Response 
 
 
 
 
 
10 
 
8.0 
Evaluation Of Toxicity 
 
 
 
 
 
10 – 14 
 
9.0 
Optional Correlative Studies 
 
 
 
 
14 
 
10.0 Statistical Design  
 
 
 
 
 
15 
 
11.0 Study Monitoring & Auditing 
 
 
 
 
15 – 16 
 
12.0 Regulatory Considerations 
 
 
 
 
16 – 17 
 
13.0 Data Confidentiality Plan  
 
 
 
 
18 
 
14.0 References  
 
 
 
 
 
 
18 - 20 
 
 
 
 
 
 
 
 
 
 

 
 
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1.0 Background  
 
Ofatumumab 
 
Ofatumumab, a novel anti-CD20 antibody, has been tested in various 
hematologic malignancies, and is currently FDA approved for treatment of 
patients with CLL that is relapsed/refractory to prior treatments with fludarabine 
and alemtuzumab. 
 
Ofatumumab is a human immunoglobulin (Ig) G1k antibody which 
binds to a different epitope of CD20 than rituximab, a site which includes the 
small extracellular loop (residues 74 to 80) and the N-terminal region of the 
second large extracellular loop, that includes amino acids 163 and 166 (Cheson, 
J Clin Oncol, July 20, 2010) (Teeling JL, et al. J Immunol, 177:362-371, 2006).  
 
Ofatumumab has been demonstrated to have greater binding avidity than 
rituximab and can bind closer to the cell membrane than rituximab, which may 
lead to be more effective complement-dependent cytotoxicity (CDC) and 
therefore has a potential advantage over other anti-CD20 antibodies in the 
setting of CLL (Teeling, 2006 and Teeling JL, et al. Blood 104:1793-1800, 2004). 
 
Chronic lymphocytic leukemia (CLL) 
 
CLL is the most common form of adult leukemia in the United States. It affects 
males more frequently than females and affects elderly individuals with more 
than 50% of the patients being 70 years of age or older at the time of diagnosis. 
It has been estimated that there are approximately 150,000 individuals living with 
CLL in the United States (SEER database). The course of the disease is diverse 
with patients that may not require therapy for many years and eventually die of 
unrelated causes and patients with high risk features that survive only a few 
months despite treatment.  
 
Treatment options for patients with newly diagnosed CLL in the United States 
consist of treatment with fludarabine as single-agent or in association with 
chemoimmunotherapy. In our center, frontline treatment consists of the 
combination of fludarabine, cyclophosphamide and rituximab (FCR) (Keating MJ, 
et al., J Clin Oncol, 2005, 23: 4079-4088). This combination 
chemoimmunotherapy has resulted in a high percentage of responses. When we 
reviewed our experience in elderly patients (defined as age 70 or older) treated 
with this combination, response rate observed in 54 patients showed an overall 
response rate of 80% indicating that this treatment is active. We also noted that 
75% of the patients treated with this approach developed myelosuppression and 
were able to receive only a median of 4 out of the 6 cycles of planned 
chemotherapy, indicating that the FCR is poorly tolerated by older patients 
(Ferrajoli A, et al. Leuk and Lymph, 46 (Suppl.1):S86, 2005). Furthermore, the 
positive results with FCR have been reported in patients that are fit, have a low 

 
 
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number of co-morbidities and, most importantly, have a normal renal function 
(Hallek M, et al. Lancet 2010;376(9747):1164-1174).  
 
Rationale for Use of Ofatumumab in CLL 
 
The rationale for evaluating the activity of ofatumumab in elderly patients with 
CLL is based on the experience with rituximab. Two clinical studies have been 
conducted at our center evaluating the activity of monotherapy with 
rituximab as initial treatment of patients with CLL. One study focused on the 
activity of rituximab in patients without indications for treatment, but with high-risk 
for progression based on beta2 microglobulin level. In this subset of patients the 
overall response (OR) rate was 82% and the duration of response was 23 
months (Ferrajoli et al., Cancer 2011). In a subsequent study, we treated 32 
patients age 70 or older with rituximab in association with GM-CSF. All patients 
had indication for treatment and patients with poor performance status were 
allowed to participate. In this group the OR rate was 69% and the median 
duration of response was 18 months (Ferrajoli, et al. Leuk and Lymph, 2009). 
This elderly group tolerated the treatment well, with toxicity limited to infusion 
reactions. 
 
Ofatumumab therefore, with its favorable toxicity profile, its clinical activity in the 
relapsed/refractory setting, and in vitro studies suggest that ofatumumab has 
greater complement-dependent cytotoxicity and antibody-dependent cellular 
cytotoxicty compared to rituximab, is an attractive therapeutic option for elderly 
patients with CLL requiring initial therapy. 
 
2.0 Objectives  
 
Primary Objective: 
 
1.1 To evaluate the overall response rate of ofatumumab in the upfront setting in 
elderly, unfit patients with CLL. [Unfit patients in this trial are: patients with and 
ECOG/WHO performance status of 2-3 (usually defined as “slow-go or no-go”) or 
patients with an ECOG/WHO performance status of 0-1 and a CIRS or Charlson 
(Charlson, 1987 J Chronic Dis 40(5): 373-83) co-morbidity score of 2 or higher.] 
 
Secondary Objectives: 
 
1.2. To determine the overall survival with ofatumumab in the upfront setting in 
elderly, unfit CLL patients. 
1.3. To evaluate the complete response rate and time to progression after 
repeated doses of ofatumumab in elderly, unfit patients with CLL. 
1.4. To determine the plasma levels of ofatumumab in elderly, unfit patients. 
1.5. To evaluate predictive capability of miRNAs detection in plasma samples. 
 
 

 
 
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3.0 Study Design  
 
This is a single center open label phase II study to evaluate the efficacy and 
safety of ofatumumab as initial treatment of elderly, unfit patients with CLL and 
indications for treatment according to NCI-WG guidelines.  
 
Treatment Plan: 
 
The administration of ofatumumab will be four weekly IV infusions at the dose of 
300 mg during week 1, then 2000 mg in weeks 2, 3 and 4, then monthly during 
months 2-12. 
 
Pre-medication before each ofatumumab infusion must be given within 30 
minutes to 2 hours prior to each treatment: 
• Acetaminophen (PO) 1000 mg or equivalent 
• Diphenhydramine (IV) 50 mg 
• Glucocorticoid (IV) equivalent to 50 mg prednisolone. The dose of 
glucocorticoid can be decreased at the time of subsequent doses if grade 3 or 
greater infusion reaction did not occur with the preceding dose. 
  
First Infusion of 300 mg Ofatumumab: 
 
The initial rate of the first infusion of 300 mg ofatumumab (0.3 mg/ml) should be 
12 ml/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 1. If this schedule is 
followed, the infusion duration will be approximately 4.5 hours. 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 infusions of 2000 mg ofatumumab: 
 
If the previous infusion has been completed without grade ≥ 3 infusion-
associated AEs, the subsequent infusion of 2000 mg (2 mg/ml) 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 2.  
 
Duration of the infusion will be approximately 4 hours if this schedule is followed. 
If a Grade ≥3 AE related to the infusion occurs, the infusion must be interrupted. 
When the AE decreases to grade <3, the investigator may restart the infusion. 
 

 
 
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During infusion the patient should be monitored closely and appropriate 
measurements should be performed whenever judged necessary. Allopurinol 300 
mg/day will be given during the first 14 days of treatment for tumor lysis 
prophylaxis.  
 
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. 

 
 
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Precautions with Ofatumumab Treatment:  
 
Chronic obstructive pulmonary disease, moderate to severe (unapproved use); 
risk of grade 3 bronchospasm during infusion. Cytopenias, including prolonged 
severe neutropenia and thrombocytopenia may occur; monitoring recommended.  
 
Hepatitis B infection, carriers or at risk of infection; risk of hepatitis B reactivation 
with fulminant hepatitis, hepatic failure, and death; evaluate for evidence of 
infection before beginning treatment and closely monitor for reactivation for 6 to 
12 months following therapy; discontinue therapy if viral hepatitis occurs.  
 
Infusion reactions, some serious (e.g. bronchospasm, dyspnea, laryngeal 
edema, pulmonary edema, angioedema, cardiac ischemia/infarction) have been 
reported; especially during first 2 infusions; premedication is recommended; 
depending on the severity of the reaction, adjustment in infusion rate, 
interruption, and/or discontinuation of therapy is recommended. Obstruction of 
small intestinal may occur. Progressive multifocal leukoencephalopathy (PML) 
including fatalities, may occur; new onset or changes in preexisting neurological 
signs and symptoms may be indicative of PML; discontinue therapy if PML 
occurs.  
 
Viral live vaccination; do not use in patients who recently received ofatumumab 
therapy.  
 
Potential Side Effects of Ofatumumab:  
 
Common  
Dermatologic: rash (all grades, 14% to 17%; grade 3 or greater, less than 1% to 
2%). Gastrointestinal: diarrhea (18% to 19%), nausea (11% to 12%). Hematologic: 
anemia (all grades, 16% to 17%; grade 3 or greater, 5% to 8%).  
Respiratory: bronchitis (all grades, 11% to 19%; grade 3 or greater, less than 1% 
to 2%), cough (19%), dyspnea (all grades, 14% to 19%; grade 3 or greater, 2% to 
5%), pneumonia (all grades, 23% to 25%; grade 3 or greater, 14% to 15%), upper 
respiratory infection (3% to 11%).  
Other: fatigue (15%), Fever (all grades, 20% to 25%; grade 3 or greater, 3% to 
5%)  
 
Serious  
Gastrointestinal: bowel obstruction.  
Hematologic: neutropenia, Grade 3 or greater (42%).  
Hepatic: relapsing type B viral hepatitis.  
Immunologic: infectious disease (all grades, 70%; grade 3 or greater, 29%), sepsis 
(all grades, 8% to 10%; grade 3 or greater, 8% to 10%).  
Neurologic: progressive multifocal leukoencephalopathy.  

 
 
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Other: complication of infusion (first infusion, 44%; second infusion, 29%).  
 
Further information can be found in the Ofatumumab Investigator’s Brochure. 
Supplier 
GlaxoSmithKline (GSK) will supply commercial ofatumumab for this study. 
 
 
Receipt of Study Drug 
The Investigator or designee is responsible for taking an inventory of each 
shipment of study drug received, and comparing it with the accompanying study 
drug accountability form. The Investigator or designee will verify the accuracy of 
the information on the form, sign and date it, retain a copy in the study file, and 
return a copy to GSK or its representative.  
 
Storage 
The study drug will be stored refrigerated (2-8oC) in a safe and secure place. The 
study drug will not be frozen. A temperature log with daily readings will be kept. 
 
Recommended Concomitant Therapy  
Allopurinol 300 mg/day will be given during the first 14 days of treatment for 
tumor lysis prophylaxis. Subjects should receive full supportive care, including 
transfusions of blood and blood products, antibiotics, and anti-emetics when/if 
appropriate. Use of filgrastim (G-CSF), erythropoietin to treat for neutropenia and 
anemia respectively is permitted while on study.  
 
4.0 Patient Eligibility  
 
Inclusion Criteria: Patients will be eligible for inclusion in the study if they meet 
all of the following criteria: 
 
1) Patients with chronic lymphocytic leukemia requiring treatment >65 at the time 
of signing informed consent. 
 
2) ECOG/WHO performance status of 2-3 or patients with chronic lymphocytic 
leukemia requiring treatment age >65 years at the time of signing informed 
consent and ECOG/WHO performance status of 0-1 and a CIRS or Charlson co-
morbidity score of 2 or higher. 
 
3) Adequate renal and hepatic function (creatinine <2mg/dL and eGFR more than 
30cc/minute, bilirubin <2mg/dL). Patients with renal or liver dysfunction due to 
organ infiltration by lymphocytes may be eligible after discussion with the study 
chairman. Patients with Gilbert’s syndrome are eligible. 

 
 
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Exclusion Criteria:  
 
1. Patients with documented prolymphocytic leukemia (prolymphocytes more 
than 55% in the blood).  
 
2. Known positivity for HIV.  
 
3. 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. Prior treatment for CLL. 
 
5. Concurrent chemotherapy, radiotherapy, or immunotherapy, including other 
monoclonal antibodies.  Localized radiotherapy to an area not compromising bone 
marrow function does not apply.  
 
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. 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. Any known hypersensitivity to ofatumumab or its components. 
 
 
5.0 Criteria for Removal from Study: 
 
Treatment with study drug is discontinued and the patient will be removed from 
study when any of the following occurs: 
 
1. Lack of therapeutic effect. 
 
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. 
 

 
 
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6.0 Visit Schedule and Assessments: 
 
Pretreatment evaluation  
 
Pretreatment evaluation will include a physical examination, height and weight 
and recording of concurrent medications (within 7 days of registration).  
 
Chemistry: 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, uric 
acid, and TSH. Beta-2-microglobulin (within 7 days of registration). 
 
Hematology: Complete CBC 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 (unless known). 
 
HIV, Hepatitis B and C screening (if not performed within 3 months from 
registration). 
 
Evaluation During Study  
 
Monitoring will consist of biweekly (every other week ±3 days) blood counts and 
SMA12 during treatment, then every 3 months (±2 weeks) during follow-up until 
alternative treatment for CLL or death, whichever occurs first. For patients who 
are HBsAg-, HBcAb+, HBsAb+/-, and HBV DNA- on enrollment and proceeded 
with treatment, HBV DNA PCR testing will be done every 2 months while on 
treatment and maintenance, then every 3 months during follow-up for 6 months.  
 
A physician will see patients at least monthly (±5 days) during treatment, then 
every 6 months (±2 weeks) during follow-up.  All patients will be followed for 
survival.  
 
CD4+, CD8+ and peripheral blood lymphocyte subset, beta-2-microglobulin will 
be analyzed after month 6 and every six months thereafter. Bone marrow biopsy 
and aspiration will be performed as clinically indicated after month 6 and every 
six months thereafter. 
 
7.0 Criteria for Response  
 
The 2008 NCI Working Group criteria for response will be used. Response will be 
assessed after month 3, month 6 and every 6 months thereafter.  
 

 
 
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8.0 Evaluation of Toxicity  
 
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 3). 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). PDMS/CORe will be 
used as the electronic case report form for this protocol. 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.  
 
Table 3. 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  
 
 
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. 
 
M.D. Anderson (Sponsor) Reporting Requirements for Serious Adverse 
Events and Dose Limiting Toxicities: 
 
As per MDACC and Leukemia phase II-III studies.  
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.  

 
 
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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. 
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.  
 
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, GSK and NCCN within 24 hours. 
Email Krulewicz@gsk.com or  
 
Fax SAEs to:  1.610.917.6715 
 
 
 
AND 
 
Email: ORPReports@nccn.org or fax 215-358-7699 
All serious adverse events not requiring expedited reporting should be reported 
to MDACC IRB within 5 business days. 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, in 
compliance with MDACC IRB, GSK and NCCN required SAE reporting 
requirements. 
 
Investigator Reporting Responsibilities  
The conduct of the study will comply with all FDA safety reporting requirements. 
Serious Adverse Events Reporting: The principal investigator has the obligation 

 
 
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to report all serious adverse events to MDACC IRB, GSK and NCCN within 24 
hours. 
 
Annual Reports 
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 
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 MDACC 
IRB, GSK and NCCN as described below.  
Expedited reporting by Principal Investigator to GSK  
Serious adverse events (SAE) are defined above. The investigator should inform 
GSK and NCCN 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 M. D. Anderson SAE form. This form must be completed and supplied to 
MDACC IRB, NCCN 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 study drug. 
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 M. D. Anderson SAE form. A final report to document 
resolution of the SAE is required. The GSK protocol number (115857) should be 
included on SAE reports to GSK and NCCN. A copy of the fax transmission 
confirmation of the SAE report to GSK and NCCN 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). A clear description 
of the suspected reaction should be provided along with an assessment as to 
whether the event is drug or disease related.  
 

 
 
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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.  
Adverse event updates and safety reports  
1.GSK shall notify the Investigator via a Safety Report of the following 
information: 
 
2.Any AE associated with the use of study drug in this study or in other studies 
that is both serious and unexpected. 
3.Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
4.The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. 
5.The Investigator must keep copies of all AE information, including 
correspondence with GSK and the IRB/EC, on file.  
Protocol amendments  
Any amendment to this protocol must be agreed to by the Principal Investigator 
and reviewed by NCCN and GSK. Amendments should only be submitted to 
IRB/EC after consideration of NCCN and GSK review. Written verification of 
IRB/EC 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/EC in 
writing of such deviation from protocol.  
9.0 Optional Correlative Studies  
 
Ofatumumab serum levels 

 
 
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Ofatumumab serum levels will be measured at baseline, 1 week, and month 3, 6, 
9 and 12. Samples will be collected and shipped to GSK for analysis as 
ofatumumab assays are proprietary to GSK and must be used through them.  
 
miRNA plasma levels and profiling 
 
Selected miRNA plasma levels in CLL patients will be determined. 
 
Genome-wide profiling study on plasma samples collected from all the patients 
before the start of the treatment and we will further perform follow-up studies at 
specific time points (month 3, 6, 9 and 12) will be conducted by quantitative RT-
PCR (Rossi et al., Blood 116, 945-952 2010). 
 
10.0 Statistical design  
 
This is a phase II trial to assess the activity and tolerability of ofatumumab in 
elderly (age 65 or greater), unfit patients with previously untreated CLL.  
Response will be assessed after month 3, month 6 and every 6 months 
thereafter using the 2008 NCI-WG criteria. Toxicity will be score using CTCAE 
v4.0. The first time point to evaluate efficacy and toxicity will be at completion of 
month 6 of treatment. Toxicity will be monitored during the entire treatment. 
 
The primary endpoint of this study is OR (CR + PR) and a Simon’s two-stage 
optimum design will be used for this study. A sample size of 34 is chosen to 
differentiate between a good response rate of 70% and a poor response rate of 
40% with 95% power at a significance level of 0.05. The trial will stop early due to 
lack of efficacy if there are 6 or fewer patients with OR in the first 14 patients. 
Lack of efficacy will also occur if there are 18 or fewer responses in 34 patients. 
Secondary endpoints are progression-free survival (PFS) and CR rate. PFS is 
defined as time from start of therapy to death or progression of disease and it will 
be calculated using Kaplan Meier estimates. Responses will be assessed by 
Fisher’s exact test with intention to treatment analysis by pre-treatment 
characteristics. Potential relationships between ofatumumab plasma 
concentrations and clinical outcomes (e.g. OR) will be explored using regression 
analyses. 
 
For the correlative studies, we will assess the association between survival data 
and miRNA marker expression using proportional hazards models and estimate 
the distributions of time-to-event outcomes using the Kaplan and Meier method. 
We will then compare these distributions among treatment or cohort groups using 
the log-rank test. We will compare the proportions of complete responses 
between positively and negatively expressed miRNAs that are therapeutic 
markers in various trials. Fifty-eight samples (2-3 sequential samples from each 
patient) will be required to achieve 80% power at a 2-sided significance level of 
0.05 and Bonferroni adjustment for testing 10 markers, assuming that 50% 

 
 
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patients are marker positive and that the response rates in the positively and 
negatively expressed markers are 75% and 25%, respectively. 
 
11.0 Study Monitoring and Auditing  
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 NCCN, 
GSK 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 made 
available to NCCN and GSK representatives so that the accuracy and 
completeness may be checked. 
12.0 Regulatory Considerations  
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.  

 
 
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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 subject’s 
source documents. 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 NCCN 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: 
ꞏ Unsatisfactory enrollment with respect to quantity or quality. 
ꞏ Inaccurate or incomplete data collection. 
ꞏ Falsification of records. 
ꞏ Failure to adhere to the study protocol.  

 
 
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Study as a whole  
NCCN and GSK reserves the right to terminate this clinical study at any time for 
reasonable medical or administrative reasons.  
Any possible premature discontinuation would be documented adequately with 
reasons being stated, and information would have to be issued according to local 
requirements (e.g., IRB/EC, regulatory authorities, etc.).  
 
13.0 Data Confidentiality Plan  
 
All laboratory and clinical data gathered in this protocol will be stored in a 
password-protected database. All patient information will be handled using 
anonymous identifiers. Linkage to patient identity is only possible after accessing 
a password-protected database. Access to the database is only available to 
individuals directly involved in the study.  
Information gathered for this study will not be reused or disclosed to any other 
person or entity, or for other research. Once the research has been completed, 
identifiers will be retained for as long as is required by law and by institutional 
regulations, and at that point will be destroyed. 
14.0 References 
  
Calin GA and Croce CM. MicroRNA signatures in human cancers. Nature 
Reviews Cancer 6, 857-866, 2006. 
 
Calin GA and Croce CM. Chronic lymphocytic leukemia: interplay between 
noncoding RNAs and protein coding genes. Blood 114(23):4761-4770. Epub 
2009 Sep 10, 2009. 
 
Chanan-Khan et al. Blood 106(11): Abstract 447, 2005. 
 
Cheson, BD: Ofatumumab, a novel anti-CD20 monoclonal antibody for the 
treatment of B-cell malignancies. J Clin Oncol 28:3525-3530, 2010. 
 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying 
prognostic co-morbidity in longitudinal studies: development and validation. J 
Chronic Dis 40(5):373-383, 1987. 
 
Ferrajoli A, Keating MJ, O'Brien S, Cortes J, Thomas DA. Experience with 
rituximab immunotherapy as an early intervention in patients with Rai stage 0 to 
II chronic lymphocytic leukemia. Cancer, e-Pub 1/2011. 
 

 
 
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Ferracin M, Zagatti B, Rizzotto L, Cavazzini F, Veronese A, Ciccone M, Saccenti 
E, Lupini L, Grilli A, De Angeli C, Negrini M, Cuneo A. MicroRNAs involvement in 
fludarabine refractory chronic lymphocytic leukemia. Mol Cancer, 9:123, 2010. 
 
Ferrajoli A, O’Brien S., Wierda W, Lerner S, Faderl S, Kantarjian H, Keating MJ. 
Treatment of patients with CLL 70 years old and older: A single center 
experience of 142 patients. Leuk & Lymph 46 (Suppl.1):S86, 2005. 
 
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to 
fludarabine and cyclophosphamide in patients with chronic lymphocytic 
leukaemia: a randomised, open-label, phase 3 trial. Lancet. 376(9747):1164-
1174, 2010. 
 
Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmunotherapy 
regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for 
chronic lymphocytic leukemia. J Clin Oncol 23:4079-4088, 2005. 
 
Liu CG, Calin GA, Volinia S and Croce CM. MicroRNA expression profiling using 
microarrays. Nature Protocols 3:563-578, 2008. 
 
Liu CG, Calin GA, Meloon B, Gamliel N, Sevignani C, Ferracin M, Dumitru 
CD,Shimizu M, Zupo S, Dono M, et al. An oligonucleotide microchip for genome-
wide microRNA profiling in human and mouse tissues. Proc Natl Acad Sci U.S.A. 
101, 9740-9744, 2004. 
 
Moussay E, Wang K, Cho JH, van Moer K, Pierson S, Paggetti J, Nazrov PV, 
Palissot V, Hood LE, Berchem G, Galas DJ. MicroRNA as biomarkers and 
regulators in B-cell chronic lymphocytic leukemia. Proc Natl Acad Sci U.S.A. 
108(16): 6573-6578, 2011.  
 
Rossi S, Shimizu M, Barbarotto E, Nicoloso MS, Dimitri F, Sampath D, Fabbri M, 
Lerner S, et al. A microRNA fingerprinting of CLL patients with chromosome 17p 
deletion identify a miR-21 score that stratifies early survival. Blood 116:945-952, 
2010. 
 
Teeling JL, Mackus WJM, Wiegman LJJM, van den Brakel JHN, Beers SA, 
French RR, van Meerten T, Ebeling S, Vink T, Slootstra JW, Parren PWHI, 
Glennie MJ, van de Winkel JGJ. The biological activity of human CD20 
monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 177:362-
371, 2006. 
 
Teeling JL, French RR, Cragg MS, van den Brakel J, Pluyter M, Huang H, Chan 
C, Parren P, Hack CE, Dechant M, Valerius T, van de Winkel JJ and Glennie MJ. 
Characterization of new human CD20 monoclonal antibodies with potent cytolytic 
activity against non-Hodgkin lymphomas. Blood 104(6):1793-1800, 2004 
 

 
 
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Vasilescu C, Rossi S, Shimizu M, Tudor S, Veronese A, Ferracin M, Nicoloso 
MS, Barbarotto, E, Popa M, et al. MicroRNA fingerprints identify miR-150 as a 
plasmaprognostic marker in patients with sepsis. PLoS ONE 4, e7405, 2009. 
 
Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Lorio M, 
Roldo C, Ferracin M, et al. A microRNA expression signature of human solid 
tumors defines cancer gene targets. Proc Natl Acad Sci U.S.A. 103:2257-2261, 
2006. 
 
Yanaihara N, Caplen N, Bowman E, Kumamoto K, Okamoto A, Yokota J, Tanaka 
T, Calin GA, Liu CG, Croce CM, et al.  A microRNA signature in lung cancer 
diagnosis and prognosis. Cancer Cell 9:189-198, 2006. 
 
Flinn IW, Harwin WN, Ward P, Doss HH, Papish SW, Hainsworth JD, Berdeja 
JG, Byrd JC. Phase II Trial of Ofatumumab (OFA) for older Patients and Patients 
who refuse Fludarabine-Based Regimens with Previously untreated Chronic 
Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Blood 
120(21), 2012.