Clinical trial NCT01243190
Conditions: Chronic Lymphocytic Leukemia
Keywords: leukemia small lymphocytic leukemia SLL CLL ofatumumab untreated early stage high-risk
Sponsor: M.D. Anderson Cancer Center
Start date: 2011-03-01; Completion date: 2023-03-28
Enrollment: 44 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if ofatumumab can help to control CLL/SLL that has not yet been treated. The safety of this drug will also be studied.

Detailed description:
The Study Drug:

Ofatumumab is designed to bind to the surface of some of the white blood cells (B-cells). It may destroy cancer cells that come from B-cells.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive a "loading dose" (a lower dose given first, to lower the risk of a bad reaction to the study drug) of ofatumumab by vein on Day 1 of Cycle 1. The loading dose is less than one-third (1/3) of the normal dose. You will then receive the normal dose over 4 hours 1 time each week (+/- 3 days). The doses may be given more slowly, if your doctor thinks it is needed. All doses of the study drug will be given at M. D. Anderson.

Benadryl (diphenhydramine) and glucocorticoids (steroids such as prednisolone) will be given by vein 30 minutes to 2 hours before you receive ofatumumab to help prevent side effects. You will also take pills of acetaminophen (Tylenol) to help prevent side effects. If no side effects occur, these "pre-medications" may be reduced or not given after the second infusion.

Study Visits:

One (1) time each week, before you receive ofatumumab:

* You will have a physical exam, including measurement of your vital signs.
* You will be asked about how you are feeling, about any side effects you may be having, and about any changes in your health since the last visit.
* Blood (about 2 teaspoons) will be drawn for routine tests.

Length of Study:

You may continue taking the study drug until Day 50, as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, if you develop hepatitis B, or if you decide to go off study.

End-of-Treatment Visit:

On the day of your last treatment or after you stop receiving the study drug for any reason, the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your vital signs.
* You will be asked about how you are feeling, about any side effects you may be having, and about any changes in your health since the last visit.
* Blood (about 2 teaspoons) will be drawn for routine tests.
* If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn for hepatitis testing.

Follow-Up:

About 3 months (+/- 2 weeks) after the end-of-treatment visit, the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your vital signs.
* You will be asked about how you are feeling, about any side effects you may be having, and about any changes in your health since the last visit.
* You will have a bone marrow aspirate and biopsy, as well as CT scans of the chest, abdomen, and pelvis, to check the status of the disease.
* Blood (about 2 teaspoons) will be drawn for routine tests.
* If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn for hepatitis testing.

Every 3 months (+/- 4 weeks) after the end-of-treatment visit for 6 months:

* You will have a physical exam, including measurement of your vital signs.
* You will be asked about how you are feeling, about any side effects you may be having, and about any changes in your health since the last visit.
* Blood (about 2 teaspoons) will be drawn for routine tests.
* If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn for hepatitis testing.

Every year (+/- 4 weeks) after the end-of-treatment visit:

* You will have a physical exam, including measurement of your vital signs.
* You will be asked about how you are feeling, about any side effects you may be having, and about any changes in your health since the last visit.
* Blood (about 2 teaspoons) will be drawn for routine tests.
* You will have a bone marrow aspirate and biopsy, as well as CT scans of the chest, abdomen, and pelvis, to check the status of the disease.

This is an investigational study. Ofatumumab is FDA approved and commercially available for use in the treatment of CLL. The use of ofatumumab as an early treatment for patients with CLL/SLL who have not received other treatment is investigational.

Up to 44 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Loading dose 300 mg by vein on Day 1 of Cycle 1; and full dose 1000 mg over 4 hours 1 time each week for 7 additional weekly doses (8 doses).
Interventions: intervention 1: Ofatumumab
Intervention descriptions: intervention 1: Loading first dose 300 mg by vein on Day 1 of Cycle 1; and full dose 1000 mg over 4 hours 1 time each week for 7 additional weekly doses (8 doses).

Protocol documents:
Prot_SAP_000.pdf: 
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Ofatumumab Early Treatment for High-Risk, Treatment-
Naïve, Early Stage (0-II) Patients with Chronic Lymphocytic 
Leukemia (CLL)/ Small Lymphocytic Leukemia (SLL) 
 
Version 8 
 
March 26, 2014 
 
William G. Wierda, M.D.,Ph.D. 
Associate Professor of Medicine 
Department of Leukemia 
Division of Cancer Medicine 
UT MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX  77030 
(713) 745-0428 (ph) 
(713) 794-1602 (fax) 
 
 
 
 
Short Title: 
Ofatumumab for High-Risk CLL/SLL 
 


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1.0 
OBJECTIVES 
Primary objective: 
1. Determine the response rate (2008 IWCLL/NCI-WG criteria) to treatment 
with single-agent ofatumumab in previously untreated, early-stage, high-
risk patients with CLL/SLL. 
 
Secondary objectives: 
1. Determine the time-to-progression for high-risk patients treated with 
ofatumumab. 
2. Determine the time-to-next chemoimmunotherapy or alternative therapy. 
3. Evaluate the pharmacokinetics of single-agent ofatumumab in high-risk, 
previously untreated patients with CLL/SLL. 
4. Evaluate for circulating CD20+ cells through treatment and in follow-up in 
high-risk patients treated with ofatumumab. 
5. Evaluate safety and toxicities of ofatumumab in previously untreated high-
risk patients with CLL/SLL. 
 
2.0 
BACKGROUND 
 
Rationale 
Ofatumumab has significant single-agent activity in treating patients with CLL 
refractory to fludarabine and alemtuzumab (FA-ref) and fludarabine-refractory 
patients with bulky (>5cm) lymph nodes (BF-ref), as demonstrated by the interim 
analysis of the pivotal trial1. The overall response rate (ORR) for FA-ref (n=59) and 
BF-ref (n=79) was 58% and 47%, respectively. The median duration of response 
(median) for both populations was approximately 6 months. Treatment with 
ofatumumab was very well tolerated. This fully human monoclonal antibody against 
CD20 binds to a unique epitope composed of the small- and large-loop domains and 
is highly effective at fixing complement for complement-dependent cytotoxicity (CDC). 
In vitro studies demonstrated higher levels of CDC against primary CLL cells and cell 
lines with ofatumumab compared to rituximab2,3.  In addition, a phase I/II trial of 
single-agent ofatumumab in relapsed patients with CLL demonstrated an ORR of 
50% in the 26 patients treated with ofatumumab 500 mg followed by 3 weekly doses 
of 2000 mg (4 total doses). This treatment was well tolerated with the most common 
side effect being infusion-related reactions4. 
 
Ofatumumab was combined with fludarabine (F) and cyclophosphamide (C) (O-FC) 
in a multi-center, Phase II randomized trial of 2-dose levels ofatumumab (500 versus 
1000 mg) for treatment of previously untreated patients with CLL5.  First course 
ofatumumab was 300 mg in both dose cohorts and both cohorts received F 25 mg/m2 
and C 250 mg/m2, both daily for 3 days of each 4-wk course.  There were 31 patients 
and 30 patients randomized to the 500 and 1000mg cohorts, respectively.  This 
chemoimmunotherapy regimen was active and well tolerated.  There were no 
statistically significant differences in efficacy or safety parameters between the dose 
cohorts.  The CR rate for the 500 and 1000 mg cohorts was 32 and 50%, 
respectively; the ORR for the 500 and 1000 mg cohorts was 77 and 73%, 


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respectively.  There were no ofatumumab infusion-related reactions ≥ grade 3.  
Myelosuppression was the most frequent adverse event with O-FC regimen.  This is 
a promising chemoimmunotherapy regimen and merits further study in frontline and 
previously treated patients with CLL. 
 
Prior clinical trials demonstrated activity for rituximab in treating early-stage, 
treatment-naïve high-risk (β2M ≥ 3 mg/L) CLL6.  The treatment was 8 weekly doses 
of rituximab 375mg/m2.  Patients were previously untreated, high-risk by elevated 
β2M (≥ 3 mg/L).  There were 34 patients enrolled and treated.  The CR rate was 9%, 
nPR was 21%, and PR was 53% (ORR 82%).  The median time to treatment failure 
(N=34) was 27 months and the median time to progression for responders (N-28) 
was 43 months. Responses and response duration will be compared to this historical 
trial. Time to first chemoimmunotherapy will be evaluated based on observed versus 
expected (O/E) ratio using the MDACC CLL database and multivariable models with 
nomograms developed to predict time to chemoimmunotherapy based in presenting 
characteristics.  Given the activity and tolerability of ofatumumab, it is an ideal 
candidate to evaluate for single-agent activity in early-stage, high-risk patients with 
CLL. 
 
The overall objective of this phase II study is to evaluate the efficacy of ofatumumab 
in treating high-risk, watch-and-wait, treatment-naïve patients with CLL/SLL to delay 
time to first chemoimmunotherapy treatment.  For this clinical trial, patients will be 
defined as high-risk for progression based on the presence of one of the following: 
Rai stage II, serum beta-2 microglobulin (β2M) of ≥ 3 mg/L, absolute lymphocyte 
count ≥ 25,000/µL, unmutated (≤ 2%) IGHV gene or mutated IGHV3-21, ZAP70 
positive, CD38 positive (≥ 30%), or 11q or 17p deletion by FISH. 
 
3.0 
BACKGROUND DRUG INFORMATION 
 
Ofatumumab FDA-Labeled Indication:  refractory chronic lymphoid leukemia 
 
Ofatumumab is currently under development by GlaxoSmithKline for the treatment of 
relapsed or refractory B-cell follicular lymphoma (FL) for previously untreated FL, for 
the treatment of relapsed or refractory B-cell chronic lymphocytic leukemia (CLL), for 
previously untreated CLL and for the treatment of active rheumatoid arthritis and 
other related autoimmune diseases. 
 
US Trade Name:  Arzerra 
 
Dosing & Indications 
How Supplied:  Intravenous solution, 20 mg/mL 
Adult Single-Agent Dosing 
• Refractory chronic lymphoid leukemia:  300 mg IV, followed 1 week later by 
2000 mg IV weekly for 7 doses (dose 2 to 8), followed 4 weeks later by 2000 
mg every 4 weeks for 4 doses (dose 9 to 12); premedicate 30 min to 2 hr 


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before each dose with acetaminophen (1000 mg or equivalent), oral or IV 
antihistamine (cetirizine 10 mg or equivalent), and IV corticosteroid 
(prednisolone 100 mg or equivalent). 
o Corticosteroid premedication dose may be gradually reduced for doses 
3 through 8, if grade 3 or greater infusion reaction did not occur with the 
preceding dose. 
o Corticosteroid premedication dose may be reduced to prednisolone 50 
to 100 mg or equivalent for doses 10 through 12, if grade 3 or greater 
infusion reaction did not occur with dose 9. 
o Initiate dose 1 at an initial rate of 12 mL/hr (3.6 mg/hr), if infusion is 
well-tolerated, rate may be escalated in 2-fold increments at 30 min 
intervals to a maximum of 200 mL/hr. 
o Initiate dose 2 at an initial rate of 12 mL/hr (24 mg/hr), if infusion is well-
tolerated, rate may be escalated in 2-fold increments at 30 min intervals 
to a maximum of 200 mL/hr 
o Initiate (dose 3 through 12) at an initial rate of 25 mL/hr (50 mg/hr), if 
infusion is well-tolerated, rate may be escalated in 2-fold increments at 
30 min intervals to a maximum of 400 mL/hr 
 
Mechanism of Action/Pharmacokinetics 
Mechanism of Action 
Ofatumumab is a human IgG1-kappa monoclonal antibody that binds to the CD20 
molecule on normal B lymphocytes and on B-cell chronic lymphocytic leukemia, 
resulting in B-cell lysis. 
 
Pharmacokinetics (single-agent in refractory CLL) 
• Distribution:  1.7 to 5.1 L 
• Excretion:  total body clearance, mean: 0.01 L/hr 
• Elimination half life:  approximately 14 days  
 
Administration/Monitoring 
Administration 
Intravenous 
• Do NOT shake, mix by gentle inversion. 
• Do NOT mix ofatumumab with other drugs. 
• Colorless solution with small amounts of visible, translucent-to-white, 
amorphous, ofatumumab particles is normal; do not use if discolored, cloudy, 
or if foreign particulate matter is present. 
• Total volume of prepared solution should be 1000 mL; withdraw appropriate 
volume of 0.9% sodium chloride solution to accommodate volume of 
ofatumumab. 
• Do NOT administer as an intravenous push or bolus. 
• Do NOT administer ofatumumab with other drugs. 
• Administer with an infusion pump, the in-line filter supplied with product, and 
polyvinyl chloride administration sets. 


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• Infusion should be started within 12 hr of preparation; discard prepared 
solution after 24. 
• Initiate dose 1 at an initial rate of 12 mL/hr (3.6 mg/hr), if infusion is well-
tolerated, rate may be escalated in 2-fold increments at 30 min intervals to a 
maximum of 200 mg/hr. 
• Initiate dose 2 at an initial rate of 12 mL/hr (24 mg/hr), if infusion is well-
tolerated, rate may be escalated in 2-fold increments at 30 min intervals to a 
maximum of 200 mg/hr. 
• Initiate dose 3 through 12 at an initial rate of 25 mL/hr (50 mg/hr), if infusion is 
well-tolerated, rate may be escalated in 2-fold increments at 30 min intervals to 
a maximum of 400 mg/hr  
Monitoring 
• Evidence of tumor response is indicative of efficacy. 
• CBC regularly, including platelet count and differential. 
• CBC more frequently in patients who develop grade 3 or 4 cytopenias, 
including platelet count and differential. 
• Hepatitis B virus (HBV) infection; clinical and laboratory screening before 
initiation of therapy for those at high risk of HBV infection; hepatitis B carriers, 
signs of active HBV for 6 to 12 months after therapy. 
• Infusion reaction (bronchospasm, dyspnea, laryngeal edema, pulmonary 
edema, flushing, hypertension, hypotension, syncope, cardiac 
ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and 
angioedema), especially with first 2 infusions. 
 
Dose Adjustments 
• body weight: no dose adjustment is recommended 
• gender: no dose adjustment is recommended 
• infusion reaction, grade 1 or 2: interrupt infusion and if reaction resolves or 
remains less than or equal to grade 2, resume at one-half the previous infusion 
rate; resume infusion at normal infusion rate as tolerated 
• infusion reaction, grade 3: interrupt infusion and if reaction resolves or remains 
less than or equal to grade 2, resume infusion at a rate of 12 mL/hr; resume 
infusion at normal infusion rate as tolerated 
• infusion reaction, grade 4: discontinue the infusion and do not resume  
 
Contraindications 
• Specific contraindications have not been determined  
 
Precautions 
• 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 


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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 (eg. 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 intestine 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 vaccination, live; do not use in patients who recently received 
ofatumumab therapy. 
 
Potential Side Effects 
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 
• Other:  complication of infusion (first infusion, 44%; second infusion, 29%) 
 
Disposition of Unused Drug 
Upon termination of the study all unused materials provided by GSK shall be 
promptly returned at GSK’s expense, or, at GSK’s option, destroyed with the 
destruction certified in writing according to MDACC Institutional Drug 
Destruction Policy. 
 
4.0 
PATIENT ELIGIBILITY 
 
4.1 
Inclusion criteria: 


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1. Diagnosis of chronic lymphocytic leukemia (CLL) / small lymphocytic 
lymphoma (SLL), previously untreated, Rai stage 0-II 
2. At least 1 of the following high-risk features for previously untreated 
patients: 
• Rai stage II disease 
• Rai stage 0-I with disease-related fatigue 
• Serum β2M ≥ 3 mg/L 
• Absolute lymphocyte count ≥ 25,000/µL 
• Unmutated IGHV gene or IGHV3-21 
• ZAP70 positive (≥ 20% by flow cytometry or positive by 
immunohistochemistry) 
• CD38 positive (≥ 30% by flow cytometry) 
• Deletion 11q or 17p by FISH 
3. ECOG PS ≤ 2 
4. Age ≥ 18 years 
5. Patients must have adequate renal and hepatic function (creatinine 
<2mg/dL, total bilirubin <2mg/dL).  Patients with renal or liver dysfunction 
due to organ infiltration with CLL/SLL may be eligible after discussion with 
the study chairman 
6. Provide informed consent 
 
7.   Female patients (including those <1 year post-menopausal) and male  
           patients who have not undergone previous surgical sterilization must agree  
           to use contraception. 
          
 
 
4.2 
Exclusion Criteria: 
1. Presence of 2008 IWCLL/NCI-WG indication for CLL treatment: 
• Constitutional symptoms related to CLL/SLL: 
o Fever > 100.5°F for ≥ 2 weeks or night sweats for > 1 mo, 
both without evidence of infection 
o Unintentional weight loss of ≥ 10% body weight in previous 6 
months 
o Extreme fatigue (ECOG PS > 2; inability to work or perform 
usual activities) 
• Lymphocyte doubling time of ≤ 6 months or 50% increase in 
absolute lymphocyte count within 2 months 
• Progressive anemia (Rai stage III) or thrombocytopenia (Rai stage 
IV) 
• Recurrent infections unrelated to hypogammaglobulinemia 
• Autoimmune phenomenon poorly responsive to corticosteroids or 
other standard therapy 
• Massive, progressive or symptomatic lymphadenopathy (> 10 cm in 
longest diameter) or splenomegaly (> 6 cm below left costal margin) 
2. Prior or concurrent chemotherapy, radiotherapy, or immunotherapy for CLL 


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3. Active infection (febrile and requiring IV/PO antibiotics) including hepatitis 
C or HIV, or significant medical illness including renal, cardiac, pulmonary 
disease, or current active hepatic or biliary disease (with exception of 
patients with Gilbert's syndrome, asymptomatic gallstones, liver 
metastases or stable chronic liver disease per investigator assessment) 
4. Positive serology for Hepatitis B virus (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 
patient will be excluded. 
A. Consult with a physician experienced in care and management of 
subjects with hepatitis B to manage/treat subjects who are anti-HB 
positive. 
5. Pregnant or breast feeding females are not eligible  
 
5.0 
TREATMENT PLAN 
This is a single-arm, open label, phase II trial of single-agent ofatumumab. 
 
Patients will receive ofatumumab 300 mg dose 1, then 1000 mg weekly for 7 
additional weekly doses (8 doses). All doses will be administered at MDACC. 
Allopurinol 300 mg PO daily for the first 7 days of course 1 is recommended for tumor 
lysis prophylaxis. 
 
There are no required prophylactic antibiotics.  Herpes virus and PCP prophylaxis 
may be given at the discretion of the treating physician but is recommended for 
patients with recent or concurrent corticosteroid use. 
 
Growth factors (neutrophil, erythrocyte, platelet) may be used at the discretion of the 
treating physician, if clinically indicated. 
 
Pre-medication for each ofatumumab infusion must be given within 30 minutes to 2 
hours prior to the infusion: 
 
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 
AEs, pre-medication with corticosteroid may be reduced or omitted before the 3rd to Nth 
infusion at the discretion of the treating physician.  
 
First Infusion of 300 mg ofatumumab 


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The first dose administered of ofatumumab will be 300 mg to minimize infusion 
reactions.  The initial rate of the first infusion of 300 mg ofatumumab (0.3mg/ml) 
should be 12mL/h.  If no infusion reactions occur the infusion rate can be increased 
every 30 minutes, to a maximum of 200 mL/h, according to Table 2.   
 
Table 2. 
Infusion rate at 1st Ofatumumab Infusion 
Time 
mL/hour 
0 – 30 minutes 
12 
31 – 60 minutes 
25 
61 – 90 minutes 
50 
91 – 120 minutes 
100 
121 – 150+minutes 
200 
 
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 (1000 mg) ofatumumab 
If the previous infusion was 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 can 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 was completed with grade ≥ 3 infusion-associated AEs, the 
subsequent infusion should start at a rate of 12 mL/hour according to Table 3. 
 
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. 
 


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There are no proposed or planned ofatumumab dose reductions for toxicities. 
Toxicities will be addressed by escalating premedication, slowing the infusion rate or 
delaying planned dose as determined by the treating physician. 
 
6.0 
PRETREATMENT EVALUATION (To Be Done Day ≤ -21; TABLE 4) 
 
6.1 
Patients will have a complete history and physical examination. 
 
6.2 
Laboratory studies will include CBC, platelet count, differential count, blood 
chemistries (SMA 12) (bilirubin, creatinine, albumin, LDH), serum β-2 
microglobulin, pregnancy test for women of childbearing potential, bone 
marrow aspirate (flow cytometry) and biopsy with samples sent for 
morphology. Hepatitis B (HB) serologies will be performed including HBsAg, 
HBsAb, and HBcAb.  For HBcAb+ (HBsAb+/-) individuals, HB virus DNA PCR 
will be performed. 
  
6.3 
Prognostic factors will be characterized including immunoglobulin heavy chain 
variable gene (IGHV) family and mutation status; leukemia cell expression of 
ZAP-70, CD38, and CD49d; thymidine kinase; chromosome abnormalities by 
FISH (13q del, +12, 11q del, and 17p del); and p53 expression.  If bone 
marrow evaluation is done within 3 months of enrollment, this will not need to 
be repeated.  In these cases, if there is any prognostic factor information 
missing, this can be obtained from blood.  If IGHV mutation status and ZAP70 
were previously determined at any time, they do not need to be repeated. 
 
6.4 
Staging CT of chest, abdomen, and pelvis will be done within 2 months of 
treatment.  Any other appropriate radiological and radioisotope examinations 
should be performed as clinically indicated. 
 
6.5 
Pretreatment optional blood (20 ml) will be taken to isolate and store 
mononuclear cells, DNA, RNA, and plasma.  Also, pretreatment optional bone 
marrow will be taken (5 ml) to isolate and store cells, DNA, RNA and marrow 
plasma. Not all samples will be collected in all patients at all time points. 
 
7.0 
EVALUATION DURING STUDY 
 
7.1 
Monitoring during treatment will consist of weekly (±3 days) blood counts and 
chemistries (through C1D50), then every 3 months (±2 weeks) during follow-
up until alternative treatment for CLL/SLL or death, whichever occurs first.  A 
physician will see patients at least monthly (±5 days) during treatment.  A mid-
level provider may evaluate patients weekly (±2 days) during treatment (8 
weeks) when not seen by the physician.   
 
7.2 
Follow-up visits will include PE with vital signs, interval history, toxicity/adverse 
event assessment, CBC with differential, and SMA12.  Bone marrow 
examinations (aspirate, biopsy, and MRD evaluation) will be done at response 


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assessment (at least 2 months after last dose of ofatumumab) to confirm 
complete remission, then annually. 
 
7.3 
Patients will be followed at MDACC for all visits including follow-up, response 
assessment 3 months after the last ofatumumab dose, and at least annually.  
Patients will be considered off study when they start alternative treatment for 
their CLL. 
 
7.4 
For patients who are HBsAg-, HBcAb+, HBsAb+/-, and HBV DNA- on enrollment 
and who proceeded with treatment, HBV DNA PCR testing will be done every 
2 months while on treatment, then every 3 months during follow-up for 6 
months.  Consult with a physician experienced in care and management of 
subjects with hepatitis B to manage/treat subjects who are anti-HBc positive.  
Initiate anti-viral therapy if required.  If a subject’s HBV DNA becomes positive 
during the study, notify the GSK medical monitor.  For subjects who have not 
completed planned ofatumumab therapy, discuss with the medical monitor the 
risks and benefits of continuing or discontinuing ofatumumab before 
appropriate treatment decisions are made for that individual subject. 
 
7.5  
Information regarding concomitant medications will not be collected for 
patients on this study.  This information is routinely collected and recorded as 
part of the patient’s electronic record.  If there is a need to refer to this, it will 
be available. 
 
The schedule of events is detailed in Table 4. 
 


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Table 4.  Schedule of Events 
Test and Evaluations 
Screening Visit 
Day ≤ -21 
C1 
D1 
C1 
D8 
C1 
D15 
C1 
D22 
C1 
D29
C1 
D36 
C1 
D43
C1 
D50 
(EOT)
C1 
D140
FU 
Q3 
MO
ANNUAL
FU 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Interval history, including 
adverse events and toxicity 
 
X 
Xa Xa 
Xa 
Xa Xa Xa 
Xa 
Xb 
Xc 
Xc 
PE including VS 
X 
X 
Xa Xa 
Xa 
Xa Xa Xa 
Xa 
Xb 
Xc 
Xc 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
β2 Microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
Screening BM asp/bxd 
X 
 
 
 
 
 
 
 
 
 
 
 
Zap70, CD38, CD49d, 
thymidine kinasee, IGHV, FISH 
(13q del, +12, 11q del, and 17p 
del); and p53 expressiond 
X 
 
 
 
 
 
 
 
 
 
 
 
Staging CT of chest, abdomen, 
pelvis (Day ≤-2 mo) 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B surface Ag and  
surface and core Ab serology 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC with diff, PLT 
X 
X 
Xa Xa 
Xa 
Xa Xa Xa 
Xa 
Xb 
Xc 
Xc 
SMA 12 
X 
X 
Xa Xa 
Xa 
Xa Xa Xa 
Xa 
Xb 
Xc 
Xc 
Ofatumumab 
 
X 
Xa Xa 
Xa 
Xa Xa Xa 
Xa 
 
 
 
For Pts HBsAg-, HBcAb+, 
HBsAb+/-, HBV DNA- on 
enrollment, HBV DNA PCR 
testing will be done 
X 
 
 
 
 
 
 
 
Xa 
Xb 
Xc 
 
PK & PD, optional samples 
X 
X 
Xa Xa 
Xa 
Xa Xa Xa 
Xa 
Xb 
Xc 
Xc 
Response assessment (IWCLL 
criteria, staging CT scan, and 
BM for MRD) 
 
 
 
 
 
 
 
 
 
Xb 
 
Xc 
BM=bone marrow evaluation; C=course; D=day; EOT=end of treatment; FU=follow-up; MO=months; 
PE=physical examination; VS=vital signs; CBC=complete blood count; PK=pharmacokinetic; 
PD=pharmacodynamic; IWCLL=International Working Group for CLL; MRD=minimal residual disease; 
aindicates ± 3 days; bindicates ± 2 weeks; cindicates ± 4 weeks; dif bone marrow evaluation is done 
within 3 months of enrollment, this will not need to be repeated.  In these cases, if there is any 
prognostic factor information missing, this can be obtained by blood.  If IGHV mutation status and 
ZAP70 were previously determined at any time, they do not need to be repeated. ewhen testing is 
available at MDACC. 
 
8.0 
RESPONSE CRITERIA AND TOXICITY EVALUATION 
Responses will be assessed according to the 2008 IWCLL guidelines (Table 5)7 at 
MDACC.  Reponses will be evaluated by physical examination; CBC; CT of chest, 
abdomen, pelvis; and for individuals in complete remission bone marrow aspirate and 
biopsy with evaluation of residual disease (MRD) by 4-color flow cytometry at least 3 
months after completing ofatumumab. 
 


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Table 5.  2008 IWCLL Response Assessment 
SITE 
CR 
PR 
Nodes*† 
None > 1.5 cm 
Decrease ≥ 50% 
Liver/Spleen 
Not palpable 
Decrease ≥ 50% 
Symptoms 
None 
N/A 
PMN 
>1,500/µL 
N/A 
Platelet count 
> 100,000/µL 
>100,000/µl or increase  
≥ 50% over baseline 
Hemoglobin 
(untransfused) 
>11.0 g/dL 
>11.0 g/dl or increase  
≥ 50% over baseline 
Blood Lymphocytes 
<4,000/µL 
Decrease ≥ 50% 
Bone Marrow 
     Aspirate** 
 
     Biopsy 
Normocellular 
<30% lymphocytes 
 
No lymphocyte infiltrate or 
nodules 
 
 
> 50% decrease in marrow 
infiltrate or B lymphoid 
nodules 
* CT scan of neck, chest, abdomen, and pelvis to confirm CR is recommended. 
† Sum of the product of multiple lymph nodes. 
** Evaluation for MRD will be performed either by 4-color flow cytometry or by molecular evaluation. 
N/A=not applicable 
 
Non-hematologic toxicity will be assessed, summarized and graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  
Hematologic toxicity will be assessed, summarized and graded according to the 2008 
IWCLL Guidelines (Table 6). 
 
8.1    ADVERSE EVENT DOCUMENTATION 
Adverse events will be documented in the medical record and entered into the case 
report form (CRF) according to the Leukemia –Specific Adverse Event Recording and 
Reporting Guidelines (Appendix E). PDMS/Core will be used as the CRF 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. The Investigator will 
sing and date the PDMS CRF toxicity pages for each patient at the completion of 
each course.  Following signature, the CRF will be used as source documentation for 
the adverse events attribution. 
 


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Table 6.  2008 IWCLL Grading for Hematological Toxicity 
Grade 
Decrease in PLT* or 
HGB** (nadir) from 
pretreatment value, % 
Absolute neutrophil 
count (ANC)/µl*** (nadir) 
0 
≤ 10% 
≥ 2000 
1 
11 – 24% 
≥ 1500 – < 2000 
2 
25 – 49% 
≥ 1000 – < 1500 
3 
50 – 74% 
≥ 500 – < 1000 
4 
≥ 75% 
< 500 
Death occurring as a result of toxicity at any level of decrease from pretreatment will be 
recorded as grade 5. 
* 
PLT counts must be below normal levels for grades 1-4.  If, at any level of decrease, the 
PLT count is < 20K/µl, this will be considered grade 4 toxicity, unless there was severe or 
life-threatening low initial PLT count (< 20K/µl) pretreatment, in which case the patient is 
not evaluable for toxicity referable to PLT count. 
** HGB levels must be below normal levels for grades 1-4.  Baseline and subsequent HGB 
determinations must be performed before any given transfusions. 
*** If the absolute neutrophil count (ANC) reaches <1000/µl, it should be judged to be grade 
3 toxicity.  If the ANC was <1000/µl before therapy, the patient is not evaluable for toxicity 
referable to the ANC. 
 
9.0 
REMOVAL FROM STUDY 
 
9.1 
Progressive or Relapsed Disease 
Progressive disease (PD) will be characterized by at least one of the following: 
 
a. ≥ 50% increase in the sum of the products of at least two nodes or 
appearance of new palpable lymph nodes noted on two consecutive 
examinations at least two weeks apart (at least one node must be > 2 cm). 
 
b. ≥ 50% increase in the size of liver and/or spleen as determined by 
measurement below the respective costal margin; appearance of palpable 
hepatomegaly or splenomegaly which was not previously present. 
 
c. ≥ 50% increase in absolute number of circulating lymphocytes over 
baseline with ≥ 5,000 B cells/µL. 
 
d. Transformation to a more aggressive histology (Richter syndrome) 
documented with biopsy. 
 
e. PLT or HGB decrease ≥ 50% from baseline secondary to CLL/SLL. 
 
9.2 
Active HBV infection or hepatitis. 
 
9.3 
Patient request. 
 


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10.0 STATISTICAL CONSIDERATIONS 
This is a phase II, open label, single-arm study. Sample size calculation will be based 
on the CR rate. The objective is to demonstrate a 20% CR rate for patients treated 
with single-agent ofatumumab. A CR rate of 9% was achieved in a previous phase II 
clinical trial with single-agent rituximab in a similar patient population. Simon’s two-
stage MinMax design will be used to assess efficacy in this study. In particular, a 
sample size of 44 is chosen to differentiate between a good response rate of 20% 
and a poor response rate of 9% at the significance level of 0.10 with 80% power. In 
particular, 25 patients will be enrolled at the first stage. If there is 1 or fewer 
responders among 25, the trial will be terminated due to lack of efficacy; otherwise an 
additional 19 patients will be treated resulting in a total of 44 patients. If there are 6 or 
fewer responses among 44 patients, the treatment will be concluded ineffective. The 
probability of early termination due to futility is 0.33. 
 
The probability of toxicity will be monitored based on a beta-binomial model, 
assuming a priori that p = Prob(toxicity) ~ beta(1, 1). The trial will be terminated if 
Prob(p> .15| data) ≥ .9. This rule will stop the trial if [#patients with toxicity]/[#patients 
evaluated] ≥ 3/7, 4/12, 5/17,6/22, 7/27, 8/32, 9/37, or 10/42. The operating 
characteristics for toxicity are summarized in Table 7. 
 
Table 7. Operating characteristics based on 1000 simulation study 
true Prob(tox) Pr(stop)  Median # Pts (25%, 75%)  
0.05 
0.004 
44 (44, 44) 
0.10 
0.07 
44 (44, 44) 
0.15 
0.25 
44 (44, 44) 
0.20 
0.49 
44 (12, 44) 
0.30 
0.89 
12 (7, 22) 
0.40 
0.99 
7 (7, 12) 
 
Toxicity events, for purposes of safety monitoring, will be defined as ofatumumab-
related grade ≥ 4 toxicity by CTCAE V 4.0 that persist longer than 1 week despite 
holding drug and/or dose reduction. 
 
Descriptive statistical analysis will be used to explore the data, including histograms 
or box-plots, proportions, means, standard deviations. The Fisher’s exact test or Chi-
square test will be used for the univariable analysis on categorical variables 
(response variable with Yes versus No, for example). The t-test or Wilcoxon test will 
be used for continuous variables. The Kaplan-Meier survival analysis will be 
performed to estimate the overall survival and event-free-survival. The log-rank test 
will be used to assess the difference of survival functions between two groups.  
Toxicity will be reported by type, frequency and severity. 
 
11.0 PHARMACODYNAMIC AND PHARMACOKINETIC ENDPOINTS 
Ofatumumab levels, normal blood B cell counts, leukemia cells in blood (CD5-
/CD19+/CD20+/- and light chain restricted-CD5+/19+/20+/-) and soluble CD20 and 


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CD52 will be quantitated weekly during treatment (pre-dose), then at response 
assessment and at 6 months follow-up (3 months after response assessment). 
 
The following is the schedule of sample acquisition for pharmacokinetic analyses. 
Ofatumumab levels will be measured by a central lab. 
 
Table 8.  PK/PD Sample Collections 
Day 
Sampling time relative to ofatumumab infusion 
1 
Predose, End of Infusion (EOI), 1 h and 2 h post-EOI 
2 
Any time of study day (+1 d) 
4 
Any time of study day (+3 d) 
6 
Any time of study day (+5 d) 
8 
Predose, EOI, 1 h post-EOI 
15 
Predose 
22 
Predose, EOI, 1 h post-EOI 
29 
Predose 
36 
Predose 
43 
Predose 
50 (EOT) 
Predose, EOI, 1 h and 2 h post-EOI 
51 
Any time of study day (+1 d) 
54 
Any time of study day (+4 d) 
57 
Any time of study day (+7 d) 
 
1 month after last ofatumumab dose1 
 
3 months after last ofatumumab dose1 
 
6 months after last ofatumumab dose1 
EOT = end of treatment 
1  Collect relative to last dose of ofatumumab, regardless of number of doses.  Collect at any time of 
study day. 
 
The actual date and time of each sample collection will be recorded on a 
pharmacokinetic sample collection form. 
 
PK, PD and bone marrow samples will be collected and sent to:  Attention of Ruth 
LaPushin, MD Anderson Cancer Center, 1515 Holcombe Blvd., T6.3849, Houston, 
Texas 77030. Phone 713-792-3690. All samples will be frozen and stored for batched 
processing.  Not all samples will be collected on all patients at all time points. 
 
12.0   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 


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be retained for as long as is required by law and by institutional regulations, and at 
that point will be destroyed. 
 
13.0 SERIOUS ADVERSE EVENT REPORTING REQUIREMENTS 
Serious Adverse Event Reporting (SAE) 
A serious adverse event is – any adverse drug experience occurring at any dose that results 
in any of the following outcomes:  
 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/incapacity – a substantial disruption of a person’s 
ability to conduct normal life functions. 
• 
A congenital anomaly/birth defect. 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical 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 (21 
CFR 31+ 2.32). 
 
• 
Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, 
MDACC IND Office. 
 
• 
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 “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 MDACC IND Office, 
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 
MDACC IND Office.   
 
• 
The MDACC “Internal SAE Report Form for Prompt Reporting” will be used for 
reporting to MDACC IND Office.  
 


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• 
Serious adverse events will be captured from the time the patient signs consent 
until 30 days after the last dose of drug. 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 MDACC IND Office. 
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 MDACC IND Office) 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. 
 
All serious adverse events will also be forwarded to GSK according to their guidelines. 
 
14.0  REFERENCES 
1. 
Wierda WG, Kipps T Immunotherapy in Fludarabine-Refractory Chronic 
Lymphocytic Leukemia. J Clin Oncol. 2010;In Press. 
2. 
Teeling JL, French RR, Cragg MS, et al. Characterization of new human CD20 
monoclonal antibodies with potent catalytic activity against non-Hodgkin 
lymphomas. Blood. 2004;104:1793-1800. 
3. 
Teeling JL, Mackus WJ, Wiegman LJ, et al. The biological activity of human 
CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol. 
2006;177:362-371. 
4. 
Coiffier B, Lepretre S, Pedersen LM, 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;111:1094-1100. 
5. 
Wierda WG, Kipps TJ, Durig J, et al. Ofatumumab Combined with Fludarabine 
and Cyclophosphamide (O-FC) Shows High Activity in Patients with Previously 
Untreated Chronic Lymphocytic Leukemia (CLL): Results From a Randomized, 
Multicenter, International, Two-Dose, Parallel Group, Phase II Trial. Blood. 
2009;114:(Abstract #207). 
6. 
Thomas DA, O'Brien S, Giles FJ, et al. Single agent Rituxan in early stage 
chronic lymphocytic leukemia (CLL). Blood. 2001;98:364a (Abstract 1533). 
7. 
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and 
treatment of chronic lymphocytic leukemia: a report from the International 
Workshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute-Working Group 1996 guidelines. Blood. 2008;111:5446-5456.