Clinical trial NCT01716208
Conditions: Chronic Lymphocytic Leukemia
Keywords: Fresh Frozen Plasma Complement Monoclonal Antibody
Sponsor: Joseph Tuscano
Start date: 2013-01-14; Completion date: 2020-10-01
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
It has been shown that many patients with lymphoma or chronic lymphocytic leukemia (CLL)have low levels of complement. Several drugs have been approved by the Food and Drug Administration (FDA) for use in this cancer. However, these drugs are often used as combination therapies which means two or more drugs are part of the treatment. Many people, especially elderly patients, cannot put up with the use of multiple drugs because of the side effects.

The main purpose of this study is to see if patients respond to therapy with human plasma (known as fresh frozen plasma or FFP) and ofatumumab. Another purpose of the study is to find out if this therapy will increase chances of getting rid of leukemia. This study will also look at the levels of complement in your blood. The levels of complement may allow better understanding of whether increasing the levels of complement by giving FFP may help control leukemia.

Detailed description:
The vast majority of patients with CLL are elderly and often they cannot tolerate standard multi-agent chemotherapeutic or biochemotherapeutic approaches. Based on this, less toxic and more effective treatment options are needed.

Ofatumumab has proven to be effective in patients with relapsed and/or refractory CLL. Previous studies have shown that ofatumumab is more effective than rituximab at activating complement and utilizing complement-dependent cytotoxicity (CDC).

This study will investigate treating relapsed/refractory CLL patients with FFP in combination with ofatumumab. The hypothesis is that patients with CLL have low complement levels and when they get treated with humanized antibodies like rituximab or ofatumumab these levels drop even further. Both these antibodies utilize complement to exert their cytotoxic effect, thus we hypothesize that by replacing complement levels with FFP we can enhance the efficacy of ofatumumab.

Arms: arm 1: Ofatumumab will be infused intravenously on day 1 (300 mg initial dose), followed one week later by 2000 mg weekly for 7 doses, followed 4 weeks later by 2000 mg every 4 weeks for 4 doses. Two units (approximately 200 or 250 ml) of FFP will be administered prior to ofatumumab(with the exception of the first dose). A unit of fresh frozen plasma is approximately 250ml (or half a pint).
Interventions: intervention 1: Ofatumumab + Fresh Frozen Plasma
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
PHASE II TRIAL OF OFATUMUMAB AND FRESH FROZEN PLASMA IN PATIENTS 
WITH RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA 
 
 
 
 
 
 
 
Protocol Number: 
UCDCC#232 
 
Funding Source Identifier:  
COMB157AUS19T (Novartis) 
 
Principal Investigator:  
Joseph Tuscano, M.D. 
 
University of California Comprehensive Davis Cancer Center 
 
 
 
 
 
Co-Investigator(s): 
Mehrdad Abedi, M.D. 
 
 
 
Statistician:  
Laurel Beckett, Ph.D. 
 
 
 
 
 
Protocol Version Number:  
10.0 
Protocol Version Date:  
March 20, 2018 
 
 
Date of Amendment/Revisions: Original/January 17, 2012 
1.0/June 4, 2012 
2.0/April 17, 2013 
3.0/June 20, 2013 
4.0/October 30, 2013 
5.0/March 10, 2014 
6.0/June 23, 2015 
7.0/July 6, 2015 
8.0/November 3, 2015 
9.0/ May 9, 2017 
 
  
 
 
  
 
 
 
 
 
 


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TABLE OF CONTENTS  
 
LIST OF IN-TEXT TABLES .................................................................................................................... 3 
LIST OF FIGURES ................................................................................................................................. 3 
PROTOCOL SIGNATURE PAGE ........................................................................................................... 4 
PROTOCOL SUMMARY ........................................................................................................................ 5 
1.0 
STUDY Objectives ....................................................................................................................... 6 
2.0 
BACKGROUND AND RATIONALE.............................................................................................. 6 
2.1 
Chronic Lymphocytic Leukemia (CLL) ...................................................................................... 6 
2.2 
Current Treatment for CLL ....................................................................................................... 7 
2.3  
Ofatumumab ............................................................................................................................ 7 
2.4 
 Fresh Frozen Plasma (FFP) .................................................................................................... 8 
2.5 
Rationale .................................................................................................................................. 8 
3.0 
SUBJECT SELECTION ............................................................................................................... 9 
3.1 
Number of Subjects .................................................................................................................. 9 
3.2 
Inclusion Criteria ...................................................................................................................... 9 
3.3 
Exclusion Criteria ................................................................................................................... 10 
3.4 
Withdrawal Criteria ................................................................................................................. 11 
4.0 
INVESTIGATIONAL PLAN ........................................................................................................ 12 
Study Design ..................................................................................................................................... 12 
5.0         STUDY TREATMENT ............................................................................................................. 12 
5.1 
Ofatumumab .......................................................................................................................... 12 
5.1.1 
Ofatumumab Pre-Medication........................................................................................... 13 
5.1.2 
Composition of Ofatumumab Injection 20 mg/mL ............................................................ 13 
5.1.3 
Preparation of Ofatumumab Infusion ............................................................................... 13 
5.1.4 
Ofatumumab Infusion Set up ........................................................................................... 15 
6.0  
Fresh Frozen Plasma Administration ......................................................................................... 17 
7.0 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................ 18 
7.1 Study Calendar and Assessment Schedule ................................................................................. 18 
7.2 
 Efficacy ................................................................................................................................. 20 
7.3 
 Safety Assessments .............................................................................................................. 21 
7.3.1 
 Liver chemistry stopping and follow-up criteria ............................................................... 21 
7.4. 
 Adverse Events ..................................................................................................................... 23 
7.4.1 
 Definition of an AE ......................................................................................................... 23 
7.4.2 
 Definition of a SAE ......................................................................................................... 24 
7.4.3 
Toxicity Assessments of AEs and SAEs .......................................................................... 25 
7.4.4 
Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs .... 25 
7.4.5 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs ..... 26 
7.4.6 
SAE Reporting ................................................................................................................ 26 
7.4.7 
Pregnancy ....................................................................................................................... 27 
8.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 28 
8.1 
Datasets to be Analyzed ........................................................................................................ 28 
8.2 
Statistical Methodology .......................................................................................................... 28 
8.3 
Analysis Plan ......................................................................................................................... 28 
8.4 
Safety Evaluation ................................................................................................................... 28 


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9.0  
STUDY CONDUCT CONSIDERATIONS ................................................................................... 29 
9.1 
Registration Guidelines .......................................................................................................... 29 
9.1.1 
Study Registration ........................................................................................................... 29 
9.1.2 
Protocol Deviations ......................................................................................................... 29 
9.2 
Minority and Gender Statement .............................................................................................. 29 
9.3 
Ethical and Regulatory Considerations ................................................................................... 29 
9.4 
Quality Assurance .................................................................................................................. 29 
9.5 
Record Retention ................................................................................................................... 29 
9.5.1 
Confidentiality of Records ............................................................................................... 29 
9.5.2 
Patient Consent Form ..................................................................................................... 29 
9.5.3 
Registration Eligibility Worksheet .................................................................................... 30 
9.6 
Data and Safety Monitoring .................................................................................................... 30 
10.0 REFERENCES .......................................................................................................................... 31 
11.0 APPENDICES ........................................................................................................................... 34 
Appendix 1: Performance Status Scale ............................................................................................. 34 
Appendix 2: Arzerra®  (Ofatumumab) Prescribing Information .......................................................... 35 
Appendix 3: Data Submission Schedule ............................................................................................ 36 
Appendix 4: Drug Request Form ....................................................................................................... 37 
 
 
LIST OF IN-TEXT TABLES 
Table 5-1  
Pre-medication Requirements Prior to Ofatumumab Infusions 
Table 5-2 
Dosing Components for Ofatumumab in Clinical Studies 
Table 5-3  
Preparation of Ofatumumab Infusion:  100 mg vials 
Table 5-4  
Preparation of Ofatumumab Infusion:  1000 mg vials 
Table 5-5 
Infusion rate of 1st ofatumumab infusion (300 mg) 
Table 5-6 
Infusion rate of subsequent ofatumumab infusion 
 
LIST OF FIGURES 
Figure 1   
Infusion Set-Up Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
 
Protocol Number: UCDCC#232 
 
 
Protocol Title: PHASE II TRIAL OF OFATUMUMAB AND FRESH FROZEN PLASMA IN PATIENTS 
WITH RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA 
 
 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated, in 
accordance with all stipulations of the protocol and in accordance with Good Clinical Practices, local 
regulatory requirements, and the Declaration of Helsinki.  
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study agent(s) and the conduct of the study.  
 
 
 
__________________________              
Investigator Name (print)                          
 
 
__________________________________ 
Investigator Signature  
 
 
 
_____________________________________ 
Institution Name  
 
 
 
_____________________ 
Date 
 
 
 
 
 
 
 
 
 


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PROTOCOL SUMMARY  
 
 
Rationale 
 
Despite progress in therapy, chronic lymphocytic leukemia (CLL) remains incurable. Response rates 
are promising but remain transient and all patients eventually relapse. Many patients are elderly and 
thus cannot tolerate multi-agent chemotherapeutic regimens. Less toxic and more effective non-
chemotherapeutic approaches are needed.  
 
An impaired complement system is thought to be involved in the pathophysiology of CLL and of its 
infectious complications. This study builds on the fact that the anti-CD20 monoclonal antibody, 
ofatumumab, effectively fixes and activates complement and complement levels in patients with CLL.  
 
 
Objectives 
 
The primary objective is to evaluate response to therapy (defined as complete, or partial response, and 
progression-free survival) in subjects with refractory or relapsed CLL who have relapsed after at least 
one prior therapy. 
 
Secondary objectives are to evaluate toxicity, overall survival (OS), and complement levels (CH20 and 
C2) in subjects with refractory or relapsed CLL.  
 
 
Study Design 
 
This is an open-label, Phase II study of the combination of ofatumumab and fresh frozen plasma (FFP) 
in patients with relapsed or refractory CLL. 
 
Approximately 12 subjects will be enrolled. 
 
Treatment: 12 doses of ofatumumab as currently approved over a 24 week period with 2 units of FFP 
with each dose (with the exception of the first dose). 
 
Patients will be followed for 2 years after the last dose of ofatumumab. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 
STUDY OBJECTIVES 
 
Primary Objective:  
• 
To evaluate the response to therapy (complete response (CR), or partial response (PR), and 
progression-free survival (PFS)) of subjects with refractory or relapsed CLL who have relapsed 
after at least one prior therapy. 
 
 
Secondary Objectives:  
• 
To determine the toxicity and safety of administration of the combination of ofatumumab and 
FFP 
 
• 
To evaluate overall survival 
 
• 
To evaluate complement levels in subjects with CLL receiving ofatumumab before and after the 
administration of FFP 
 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Chronic Lymphocytic Leukemia (CLL) 
 
Chronic Lymphocytic Leukemia is the most common type of leukemia in the Western world, accounting 
for 40% of all leukemia types in people over the age of 65 [Oscier, 2004]. It is estimated that in the US 
alone 15,110 adults (8,750 men and 6,360 women) were diagnosed and 4,390 adults will die of CLL in 
2008 [Jemal, 2008]. The prevalence of CLL increases with age and the median age at the time of 
diagnosis is 65 to 70 years [Redaelli, 2004]. Approximately 50% of patients are initially asymptomatic 
and are observed for several years before treatment is needed, therefore more than half of patients 
who finally require therapy are older than 70 years. The disease is a hematological neoplasm of 
unknown etiology, characterized by accumulation of monomorphic small, round mature-appearing B 
lymphocytes in the peripheral blood, bone marrow, and lymph nodes that aberrantly co-express T-cell 
(CD5+) and B-cell (CD19+, CD23+) cell surface markers, with a low expression of CD20. Over the past 
decade, new information suggests B-CLL originates from antigen-stimulated mature B-lymphocytes, 
which either avoid cell death through the effect of external signals, or die by apoptosis, but are 
replenished by proliferating precursor cells [Chiorazz, 2005]. CLL follows a variable clinical course with 
overall survival times ranging from months to decades. Median survival from diagnosis is approximately 
10 years in the overall CLL population, but is only 18 months for patients with advanced disease 
[Nabhan, 2004]; and 9-13 months for CLL cases refractory to fludarabine [Byrd, 2004]. 
 
Clinical staging systems devised by Rai and Binet are the best validated for evaluating CLL patients 
[Rai, 1975; Binet, 1981]; however, there is heterogeneity in the course of the disease within defined 
stages. In recent years, molecular and cellular markers have been correlated with disease 
aggressiveness. These allow further stratification of subjects into risk groups such as: abnormal 
cytogenetics, CD38, ZAP-70, beta-2-microglobulin, IgVH mutational status [Oscier, 2004; Abbott, 2006; 
Shanafelt, 2007; Zenz, 2007]. Unfortunately, so far, these parameters have only limited use in 
determining when and what type of therapy to use [Binet, 2006]. One exception is that p53 deletion was 
shown to be predictive for non-response to purine analogues like fludarabine and for poor clinical 
outcome, but is not predictive for response to a particular therapy [Dohner, 1995]. 
 
 
 
 


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2.2 
Current Treatment for CLL 
 
Over the last two decades, the treatment goal of CLL has undergone a paradigm shift changing from 
simple symptom palliation to attainment of maximal disease control and consequently prolonged 
survival [Tam, 2007]. Clinical trials assessing single agent chemotherapy were followed by studies 
investigating combination chemotherapies which showed no significant difference in overall survival 
[Shanafelt, 2007]. Subjects receiving monotherapy or combination chemotherapy experience a range of 
different levels of toxicity [Abbott, 2006]. Currently, fludarabine and cyclophosphamide combined with 
Rituxan (FCR) seems to be the most potent regimen, both in previously untreated and relapsed 
patients [Hallek, 2008; Tam 2008]. In general, as with most clinical studies, all these trials endorse strict 
eligibility criteria often excluding subjects older than 65 plus those with inferior organ function.  This 
causes a limitation in assessing the suitability of these studied therapy regimens regarding their efficacy 
and tolerability for the treatment of unselected patients in practice of which the majority is older and in 
poor health.  
 
Despite numerous studies with various therapies demonstrating overall and complete response rates in 
both previously untreated and relapsed or refractory CLL patients [Hallek, 2001; Huhn, 2001; O'Brien, 
2001a; O'Brien, 2001b; Keating, 2002; Wierda, 2005], there is no curative treatment and the disease 
often relapses. There is no current maintenance therapy to extend the time between relapses. 
 
The biological behavior of CLL is similar to follicular lymphoma (FL), wherein the disease is incurable 
and the clinical course is characterized by a high relapse rate. After relapse, both the response rate and 
progression-free survival after subsequent salvage regimens steadily decrease [Montoto, 2002]. 
Recently, in relapsed FL patients, maintenance treatment with the chimeric CD20 mAb, rituximab, 
resulted in a median PFS of 51.5 months versus 14.9 months with observation only (p<.001). 
Significantly improved PFS was noted regardless of induction treatment (CHOP vs R-CHOP). 
Additionally, rituximab maintenance also improved overall survival at 3 years (85% vs 77%, p=.011) 
[van Oers, 2006]. Similar results of improved PFS and overall survival with rituximab maintenance in FL 
patients have been noted [Forstpointner, 2006; Hochster, 2009].  
 
While rituximab monotherapy is not very effective in previously untreated or relapsed CLL patients, 
possibly due to the relatively low CD20 expression on CLL cells [Byrd, 2001], a recent small phase II 
study with rituximab consolidation and maintenance treatment showed a significantly longer response 
duration in patients with minimal residual disease (MRD)-positive CLL in first remission after fludarabine 
induction [Del Poeta, 2008]. 
 
2.3  
Ofatumumab    
 
Ofatumumab is a fully human monoclonal antibody (mAb), IgG1κ, targeting a unique epitope on the 
CD20 molecule expressed on human B-cells, resulting in increased binding affinity to CD20, prolonged 
dissociation rate, and increased cell kill due to greater complement dependent cytotoxicity (CDC) 
activity and similar antibody dependent cell mediated cytotoxcity (ADCC) activity, especially in low 
CD20 expressing cells [Teeling, 2006]. Thus, depletion of B-cells by ofatumumab treatment may 
provide clinical benefits to subjects with CD20-expressing cell tumors. In B-CLL, the goal of treatment is 
to achieve complete abnormal B-cell depletion in the blood and to induce an objective tumor response 
in the lymph nodes. 
 
In a Phase I dose-ranging trial of ofatumumab 500mg (n=3), 1000mg (n=3), or 2000mg (n=27) given 
weekly x 4, 50% PR was observed in the 2000mg dose amongst relapsed CLL patients [Coiffier, 2008]. 
Objective response significantly correlated with maximum observed concentration (Cmax), minimum 
observed concentration (Cmin), area under the concentration-time curve (AUC), and half-life (t½) and 
survival endpoints correlated with exposure. The maximum tolerated dose (MTD) was not reached and 


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treatment was well tolerated. Adverse events were limited to grade 1-2 infusion reactions and easily 
managed with premedication. Grade 3-4 neutropenia occurred in only 6% of patients. Non-opportunistic 
grade 1-2 infections were observed in 51% of patients. 
 
Interim analysis for the pivotal trial evaluated 154 patients with refractory CLL (Study Hx-CD20-406). In 
the 138 evaluable patients, approximately half were refractory to both fludarabine and alemtuzumab 
and the other patients were refractory to fludarabine and considered inappropriate for alemtuzumab 
due to bulky disease of the lymph nodes. An objective response rate of approximately 50% consisting 
of 30 partial responses was achieved in the fludarabine and alemtuzumab refractory group and an 
objective response rate of approximately 44% was achieved in the fludarabine refractory group 
including 1 complete response and 34 partial responses. In this study, ofatumumab was generally well 
tolerated by the patients. The most frequently reported adverse events (>15% frequency) were pyrexia, 
diarrhea, fatigue, cough, neutropenia, anemia and pneumonia. There were no unexpected safety 
findings. Studies clearly indicate monoclonal antibodies (mAbs) play an important role in the treatment 
of CLL. Anti-CD20 mAbs with a low toxicity can be applied advantageously in subjects who cannot 
tolerate highly toxic treatments (i.e. advanced age), in combination with chemotherapy and as 
maintenance treatment. Ofatumumab preclinical data demonstrates superior CDC activity in CLL 
compared to rituximab. Based on this, therapeutic combinations that may exploit the enhanced CDC 
potential would be hypothesized to improve outcome. 
 
2.4 
 Fresh Frozen Plasma (FFP) 
 
FFP is the fluid portion of one unit of human blood that has been centrifuged, separated, and frozen 
solid at −18 °C (−0 °F) or colder within eight hours of collection. FFP contains the labile as well as 
stable components of the coagulation, fibrinolytic and complement systems.  In 
addition, fats, carbohydrates and minerals are present in concentrations similar to those in circulation. 
Although well-defined indications exist for the use of FFP in single or multiple coagulation deficiencies, 
indications for many of its other uses may be empiric. These indications generally are limited to the 
treatment of deficiencies of coagulation proteins for which specific factor concentrates are unavailable 
or undesirable. In addition, circumstances exist in which FFP has been employed and is believed to be 
of therapeutic value, but data supporting its efficacy are limited or unavailable (e.g., multiple 
coagulation protein deficiencies in the uncontrollably bleeding patient). Because such patients are often 
critically ill and satisfactory alternative therapy may not be at hand, FFP may be appropriate. FFP is 
efficacious for treatment of deficiencies of factors II, V, VII, IX, X, and XI when specific component 
therapy is neither available nor appropriate. FFP is also a rich source of complement proteins and 
previous studies have demonstrated effective replacement in patients with hereditary complement 
deficiencies, autoimmune disease and cancer.  Complement is crucial for the physiological processing 
of immune complexes and the beneficial effect of reconstituting the deficient complement component is 
likely to be at least in part the result of temporarily restoring this biological role. Evidence to support this 
includes the demonstrations that: (i) the uptake of immune complexes by the spleen is absent in 
complement C2 deficiency but restored after the administration of FFP; and (ii) circulating levels of 
immune complexes fell in a C2-deficient individual following plasma infusion [Rudmann, 2005]. 
 
2.5 
Rationale  
 
While there have been significant advances in the understanding of the pathogenesis of CLL and 
innovative new strategies are being explored, few have resulted in a significant change in the survival.  
The vast majority of patients with this disease are elderly and often they cannot tolerate standard multi-
agent chemotherapeutic or biochemotherapeutic approaches. Based on this, less toxic and more 
effective treatment options are needed. Ofatumumab has proven to be effective in patients with 
relapsed and/or refractory CLL. A phase II study found that patients treated with ofatumumab that were 
refractory to fludarabine and alemtuzumab had an overall response rate of 42% with a median duration 


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of response of 6.5 months. While this is a significant improvement in this patient population, 
improvements in efficacy without substantially increasing toxicity are needed. Previous studies have 
shown that ofatumumab is more effective than rituximab at activating complement and utilizing 
complement-dependent cytotoxicity (CDC) [Pawluczkowycz, 2008].  It has been also shown that 
patients with CLL are complement deficient, especially those that are heavily pretreated [Varga, 1995l, 
Schlesinger, 1996]. While not thoroughly examined, it is hypothesized that complement levels drop 
even lower after treatment with large doses of humanized antibodies. Based on this principle, a 
previous study gave 5 highly refractory CLL patients two units of  FFP (as a source of complement) with 
rituximab (375 mg/m2) as a single agent, repeated every 1-2 weeks, as needed. All 5 patients had a 
“rapid and dramatic clinical and laboratory response.” In fact, 3 of the patients were rituximab refractory 
[Kelpfish, 2008]. Toxicity was minimal and the treatment was well-tolerated in all cases. Based on these 
principles, we propose treating relapsed/refractory CLL patients with FFP in combination with 
ofatumumab. 
 
 
3.0 
SUBJECT SELECTION 
 
3.1 
Number of Subjects 
 
Subjects who meet all the following inclusion/exclusion criteria will be eligible for enrollment into the 
study. Approximately 42 subjects will be screened to obtain 12 evaluable subjects (assuming 15 % 
screen failure and 5 % drop out rates). 
 
3.2 
Inclusion Criteria 
 
Subjects eligible for enrollment in the study must meet all of the following criteria: 
 
1. 
Patients must have a pathological diagnosis of B-cell CLL 
 
2. 
Patients must have received prior rituximab therapy and must have recovered from all non-
hematologic toxicities. (Previous radiation is allowed as long as patients have recovered from all 
treatment related toxicities) 
 
3. 
Patients must meet the following laboratory values: 
 
• 
Hgb > 9.0 g/dl 
• 
Platelets > 50,000/mm3 
• 
Creatinine < 2.0 times the institutional upper limit of normal 
• 
SGOT/SGPT < 2.5 times the institutional upper limit of normal (unless due to disease 
involvement of liver) 
• 
Total Bilirubin <1. 5 times the institutional upper limit of normal  
• 
Alkaline phosphatase <2.5 times upper limit of normal (unless due to disease 
involvement of the liver or bone marrow)   
 
4. 
Patients must be at least 18 years of age.  
5. 
Patients must have a performance status of 0-2 by ECOG criteria (see Appendix I). 


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6. 
All patients must be informed of the investigational nature of this study and must sign and give 
written consent in accordance with institutional and federal guidelines. 
 
3.3 
Exclusion Criteria 
 
Subjects meeting any of the following criteria must not be enrolled in the study: 
 
1. 
Subjects who have current active hepatic or biliary disease (with the exception of patients with 
Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease 
per investigator assessment). 
 
2. 
Having received rituximab  within the prior 2 months 
 
3. 
Treatment with any known therapeutic or experimental therapy within 4 weeks prior to 
enrollment,  or currently participating in any other interventional clinical study 
 
4. 
Other past or current malignancy.  Subjects who have been free of malignancy for at least 5 
years, have a history of completely resected non-melanoma skin cancer, successfully treated in 
situ carcinoma, adequately treated basal or squamous cell skin cancer, adequately treated 
Stage I or II cancer from which the patient is currently in complete remission, or any other 
cancer for which the patient has been disease-free for 5 years are eligible. 
5. 
Prior treatment with anti-CD20 monoclonal antibody or alemtuzumab within 2 months prior to 
start of therapy.   
 
6. 
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, tuberculosis and active Hepatitis C. 
7. 
History of significant cerebrovascular disease in the past 6 months or ongoing event with active 
symptoms or sequelae 
 
8. 
Known HIV positive 
 
9. 
Clinically significant cardiac disease including unstable angina, acute myocardial infarction 
within six months prior to randomization, congestive heart failure (NYHA III-IV), and arrhythmia 
unless controlled by therapy, with the exception of extra systoles or minor conduction 
abnormalities. 
 
10. 
Significant concurrent, uncontrolled medical condition including, but not limited to, renal, 
hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease 
which in the opinion of the investigator may represent a risk for the patient. 
 
11. 
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. HBsAg negative, HBsAB negative, 
HBsAB positive subjects can be included, * See Monitoring criteria for HBcAb+ and HBV DNA 
negative subjects on next page. 
• 
Consult with a physician experienced in care & management of subjects with hepatitis B to 
manage/treat subjects who are anti-HBc positive 
 


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12. 
Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case 
reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result 
 
13. 
Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy 
test at screening. **women of child bearing potential must undergo pregnancy testing prior to 
each dose if the previous pregnancy test was greater than 14 days prior and a pregnancy test at 
6 months after the last dose. 
 
14. 
Women of childbearing potential, including women whose last menstrual period was less than 
one year prior to screening, unable or unwilling to use adequate contraception from study start 
to one year after the last dose of protocol therapy. Adequate contraception is defined as 
hormonal birth control, intrauterine device, double barrier method or total abstinence. 
 
15. 
Male subjects unable or unwilling to use adequate contraception methods from study start to 
one year after the last dose of protocol therapy. 
 
16. 
Receiving warfarin 
 
*Monitoring criteria for HBcAb+ and HBV DNA negative subjects: 
• 
If HBV DNA is negative, subject may be included but must undergo at least every 2 month HBV 
DNA PCR testing from the start of treatment during the treatment course.  
 
• 
Monitoring during the follow-up period will be performed during routine study visits for a 
minimum follow-up period of six months after the last dose, as long as the subject remains on 
study. Monitoring frequency during follow-up should occur at a minimum of every 2-3 months.  
Whenever possible, the monitoring should occur as part of the routine follow-up visit  (Note: for 
most studies, the follow-up visits are 1 month post-dose, 3 months post-dose and 6 months 
post-dose. 
 
• 
Prophylactic antiviral therapy may be initiated at the discretion of the investigator. 
 
 
3.4 
Withdrawal Criteria 
 
Subjects may be withdrawn from the study at any time if it is the wish of the subject (or their legally 
acceptable representative) for any reason, the investigator judges it necessary due to medical reasons 
including disease progression or the subject becomes pregnant. (See also Section 7.4.7) The subject 
will be evaluated for disease status and survival per the follow-up visit schedule outlined in Section 7.1. 
 
The reason for withdrawal from study participation must be documented. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.0 
INVESTIGATIONAL PLAN 
 
Study Design 
 
TREATMENT SCHEMA 
 
FFP 
 
 
Ofa 
 
          
           300 mg                                      2000 mg                                                                     2000 mg 
          
           
           Dose 1                                     Doses  2-8                                                                   Doses 9-12  
 
Week  
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
20 
24 
 
 
 
This is an open-label, Phase II study of ofatumumab in patients with relapsed or refractory CLL. 
Twelve doses of ofatumumab as currently approved over a 24 week period with 2 units of FFP with 
each dose (with exception of the first dose) will be administered. Ofatumumab will be infused 
intravenously on day 1 (300 mg initial dose), followed one week later by 2000 mg weekly for 7 doses, 
followed 4 weeks later by 2000 mg every 4 weeks for 4 doses. Two units (approximately 200 or 250 ml) 
of FFP will be administered prior to ofatumumab.  
 
The study period will consist of screening, treatment, and follow-up (see Section 7.1 for study calendar 
and assessments schedule). 
 
 
5.0         STUDY TREATMENT 
 
5.1 
Ofatumumab  
 
Novartis will supply ofatumumab vials presented as 100 mg – acetate formulation, 20 mg/mL, 5 mL fill 
vials, and 1000 mg – acetate formulation, 20 mg/mL, 50 mL fill vials.  
 
The study medical product, ofatumumab, is a liquid concentrate for solution for infusion presented in 
glass vials. Ofatumumab will be infused intravenously on day 1 (300 mg initial dose), followed one 
week later by 2000 mg weekly for 7 doses, followed 4 weeks later by 2000 mg every 4 weeks for 4 
doses. 
 
The ofatumumab infusions will be prepared in 1000 mL NaCl sterile, pyrogen free 0.9% NaCl to yield a 
0.3 mg/mL, or 2 mg/mL ofatumumab concentration for infusions of 300 mg or 2000 mg, respectively.  
 
Ofatumumab vials must be stored at 2-8°C. Protect from light and do not freeze. No special packaging 
components, other than the outer white cardboard carton in which the vials are placed, will be used to 
afford light protection.  
 
Ofatumumab open-labeled product will be for intravenous infusion. Our site is responsible for labeling 
individual vials for study use.  
 
All items required for administration of study medication (e.g., infusion bags, filters, etc.) will be 
provided by University of California Davis Comprehensive Cancer Center. 


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5.1.1 Ofatumumab Pre-Medication 
 
Pre-medication before each ofatumumab infusion must be given within 30 minutes to 2 hours prior to 
the treatment (Table 5-1). 
  
 
Table 5-1 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 mg*  
 
        *If the 2nd infusion has been completed without the subject experiencing any grade = 3 AEs, 
        pre-medication with glucocorticoid may be reduced or omitted before the 3rd to Nth infusion  
        at the discretion of the investigator. 
 
 
5.1.2 Composition of Ofatumumab Injection 20 mg/mL 
 
The quantitative composition of acetate formulation is 20 mg/mL.  This is available in two fill volumes, 5 
mL / vial (100 mg/vial) and 50 mL/vial (1000 mg/vial). 
 
 
Ingredient  
Quantity/ mL 
Ofatumumab 
20.0 mg 
Sodium Acetate, Trihydrate 
6.80 mg 
Edetate Disodium, Dihydrate 
(EDTA) 
0.019 mg 
Polysorbate 80 
0.20 mg 
L-Arginine 
10.0 mg 
Sodium Chloride 
2.98 mg 
Hydrochloric Acid 
to give pH 5.5 
Water for Injection 
q.s. to 1.0 mL 
 
5.1.3 Preparation of Ofatumumab Infusion 
 
Ofatumumab will be prepared as 1000 mL dilution of ofatumumab in sterile, pyrogen-free 0.9% NaCl. 
The exact time of dilution into the 0.9% NaCl must be written on the label of the infusion bag. 
Once diluted into saline, the product is stable for up to 24 hours at ambient temperature. However, the 
product contains no preservative and should be used as soon as possible after dilution. 
 
Preparation of drug solution for intravenous injection by the site pharmacist or designee will be done in 
accordance with the protocol, and in these dilution instructions. Ofatumumab intravenous solution will 


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be prepared using standard dilution methods and following general aseptic practice standard to 
preparation of IV medications. Eyes and hands should be protected when handling ofatumumab.  
 
For intravenous administration, compatibility of the following components for ofatumumab in clinical 
studies (i.e., not for commercial product) has been established: 
Table 5-2 
Dosing Components for Ofatumumab in Clinical Studies 
Dosing component 
Material of construction 
Suggested Vendor 
1L Saline Bags 
Polyvinyl Chloride (PVC) 
Baxter 
 
Polyolefin [polyethylene* 
(PE)/polypropylene (PP)] 
Baxter, B. Braun 
Administration Set 
PVC 
Baxter 
 
PVC lined with Polyethylene 
B. Braun 
Filter Extension Set 
Sterilizing-grade (0.22 µm) 
hydrophilic filter 
Durapore brand by Millipore 
 
Lines made of PVC, filter 
membrane material polyether 
sulfone 
Baxter 
 
Lines made of PVC lined with 
Polyethylene, filter membrane 
material polyether sulfone 
Alaris/Cardinal Health 
 
Preparation of the 1000 mL infusion bags should be done on the day of planned infusion.  
* polyethylene (IUPAC name: polyethene) 
 
5.1.3.1 Materials for Preparation and Administration of Infusion 
 
The following materials are needed when preparing and administering the infusion: 
 
1000 mL sterile pyrogen free 0.9% saline (NaCl) infusion bag(s).  The solution can be kept at ambient 
temperature for a maximum of 24 hours after preparation; however, the product does not contain a 
preservative and dosing should begin as soon as possible after dose preparation.  
Ofatumumab 100 mg and 1000 mg vials (supplied by Novartis) 
Needles and syringes (50 mL sterile syringe) not supplied by Novartis 
Intravenous (IV) cannula (not required if subject has central venous access) [not supplied by Novartis] 
Infusion pump and infusion tubing set (not supplied by Novartis) 
In-line low protein binding, polyether sulfone filter 0.2 µm (please make sure a spare filter is available in 
case the filter needs to be changed) [not supplied by Novartis].  Please note that the commercial 
filters are sterilizing-grade (0.22 µm) hydrophilic Durapore by Millipore. 
 
 


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5.1.3.2 Dilution of Ofatumumab  
 
• 
Ensure the correct container number is used. 
• 
Take a 1000 mL infusion bag (sterile pyrogen free 0.9%  saline), remove and dispose of the 
appropriate amount of saline according to Table 5-3 or Table 5-4  
• 
Draw the required amount of ofatumumab according to Table 5-3 (100 mg vials) or Table 5-4 (1000 
mg vials) below 
• 
Inject ofatumumab into the saline bag 
• 
Invert the infusion bag slowly 3 times, avoiding formation of any foam 
• 
Label the infusion bag with the completed label 
 
Table 5-3 
Preparation of Ofatumumab Infusion:  100 mg vials  
Dose of 
Ofatumumab 
Infusion bag 
size 
Volume of NaCl to be 
removed from infusion 
bag 
Volume ofatumumab  
(number of ofatumumab vials) 
300 mg 
1000 mL 
15 mL 
15 mL 
(3 vials, 5 mL/vial) 
2000 mg 
1000 mL 
100 mL 
100 mL 
(20 vials, 5 mL/vial) 
 
Table 5-4 
Preparation of Ofatumumab Infusion:  1000 mg vials 
Dose of 
Ofatumumab 
Infusion bag 
size 
Volume of NaCl to be 
removed from infusion 
bag 
Volume ofatumumab  
(number of ofatumumab vials) 
2000 mg 
1000 mL 
100 mL 
100 mL 
(2 vials, 50 mL/vial) 
 
5.1.4 Ofatumumab Infusion Set up 
 
Ofatumumab must be administered by i.v. infusion through an in-line filter and through a well-
functioning i.v. catheter (i.v. cannula) into a vein in the arm (or other venous access) by an infusion 
pump. 
 
Please Note:   It is mandatory to use an in-line low protein binding 0.2 micron polyether sulfone 
filter for all IV dosing of ofatumumab drug product. 
 
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
 
Ofatumumab should not be mixed with any other medication.  If ofatumumab is to be dosed 
through an in-dwelling catheter, then, any previous medication should be removed by flushing 
with normal saline prior to dosing with ofatumumab. 
 


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• 
Check subject ID against the label on the infusion bag and ensure the expiry of the solution. The 
solution must be administered in its entirety to the subject within 24 hours from time of 
preparation.   
• 
Attach the 1000mL infusion bag to the infusion set (if not done at the pharmacy). 
• 
Attach the in-line filter to the infusion set (closest to the subject; see Figure 1). Note: The in-line 
filter must be used during the entire infusion. 
• 
Prime the infusion set and filter with ofatumumab (if not done at the pharmacy). 
• 
In case of a problem with the filter (i.e. clogging/blockage), please change, re-prime the new 
filter, and continue the infusion. 
• 
In case of problem with infusion set, follow local procedures. 
• 
Check the backflow from the i.v. cannula according to routine practice at site 
• 
Set the pump at the initial infusion rate 12mL/hr for the first infusion and 25mL/hr for the 
subsequent infusions (if no grade ≥ 3 infusion-associated AEs were observed in the previous 
infusion)  
• 
Start the infusion using the following infusion rates  
 
Table 5-5 
 
Infusion rate of 1st ofatumumab infusion (300 mg) 
Time 
mL/hour 
0 – 30 minutes 
12 
31 – 60 minutes 
25 
61 – 90 minutes 
50 
91 – 120 minutes 
100 
121 - 150 minutes 
200 
151 - 180 minutes 
300 
181+ minutes 
400 
 
Table 5-6 
 
Infusion rate of 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 
 
No ofatumumab dose modifications are permitted. 
 


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Figure 1 
Infusion Set-Up Schematic 
 
 
 
 
 
6.0  
FRESH FROZEN PLASMA ADMINISTRATION 
 
Fresh frozen plasma will be administered per University of California Davis Health System 
GUIDELINES FOR ADULT TRANSFUSION (Patient Care Standards, XIII-12) (Approved by Medical 
Staff Executive Committee 11/06). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ofatumumab infusion bag  
infusion pump 
infusion set 
In-line filter 
i.v. cannula 
subject 


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7.0 
STUDY ASSESSMENTS AND PROCEDURES 
 
7.1 Study Calendar and Assessment Schedule 
All visits should be +/- 7 business days with the exception of day 1 of cycle 1. 
 
 
Procedures 
< 14 days prior to 
registration† 
Treatment 
Follow-up 
 
 
Doses 1-4 
(Every week – 
Week 1, 2, 3, 
4 ) 
Doses 5-8 
(Every week – 
Week 5, 6, 7, 
8 ) 
Doses 9-12 
(Every 4 weeks -
- Week  12, 16, 
20, 24) 
Treatment 
withdrawal 
1,3, 6 months 
following last 
ofatumumab dose 
9, 12, 15, 18, 21, 24 
months following last 
ofatumumab dose 
Medical History 
X 
 
 
 
 
 
 
Disease History 
X 
 
 
 
 
 
 
Therapy History 
X 
 
 
 
 
 
 
Efficacy Assessments  
1Bone marrow/ 
aspirate biopsy 
X 
 
 
 
 
X 
 
2CT/PET 
X 
 
 
 
 
X 
X 
Safety Assessments  
3Physical Exam or 
Evaluation 
X 
3X 
3X 
3X 
 
X 
X 
3ECOG 
X 
3X 
3X 
3X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
X 
Vital Signs 
X 
X 
X 
X 
 
X 
 
12-lead ECG  
X 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
4FFP (2 units) 
 
4X 
X 
X 
 
 
 
Dispense Study Medication 
Ofatumumab 
 
X 
X 
X 
 
 
 
Lab Assessments  
5Hematology  
X 
X 
X 
X 
 
X 
X 
6Chemistry 
X 
X 
X 
X 
 
X 
X 
7Liver chemistry 
X 
X 
X 
X 
 
 
 
8Complement 
levels 
X 
X 
 
X 
 
X 
X 


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Procedures 
< 14 days prior to 
registration† 
Treatment 
Follow-up 
 
 
Doses 1-4 
(Every week – 
Week 1, 2, 3, 
4 ) 
Doses 5-8 
(Every week – 
Week 5, 6, 7, 
8 ) 
Doses 9-12 
(Every 4 weeks -
- Week  12, 16, 
20, 24) 
Treatment 
withdrawal 
1,3, 6 months 
following last 
ofatumumab dose 
9, 12, 15, 18, 21, 24 
months following last 
ofatumumab dose 
9B-cells, IgG, IgA 
and IgM 
X 
 
 
 
 
X 
 
10HIV Test 
X 
 
 
 
 
 
 
11Serum 
Pregnancy Test 
X 
 
 
 
 
 
 
Hepatitis B&C* 
X 
 
 
 
 
 
X 
Survival 
X 
 
 
 
 
X 
X 
*REQUIRED- Subjects who are HBcAb positive must undergo at least every 2 month HBV DNA PCR testing during the treatment course.  Monitoring must also occur 
during the follow-up period for a minimum of 6 months after the last dose as long as the subject remains in the study at a minimum frequency of every 2 to 3 months.    
† Bone marrow/aspirate biopsy and CT/PET performed within 28 days of registration. 
 
1. BM biopsy will be performed for staging at baseline and if clinically warranted after completion of therapy. If the BM biopsy is positive at baseline it must be 
repeated once to confirm CR. This will include flow cytometry for minimal residual disease (MRD) status. Bone marrow (or peripheral blood if bone marrow is 
unavailable must be sent to the cytogenetics laboratory for analysis. If the BM biopsy is negative at baseline, it will not be repeated.  
2. CT/PET will be performed for staging at baseline and if clinically warranted after completion of therapy. 
3. Patient will see treating physician for physical exam/evaluation and ECOG evaluation every 4 weeks.  
4. Two units of FFP will be given with each dose of ofatumumab with the exception of the first dose of ofatumumab.  
5. During the treatment phase, obtain hematology pre-treatment and every 2 weeks for the first month, then every month thereafter for at least 6 months after the last 
dose of ofatumumab. 
6. Chemistries include electrolytes, BUN, creatinine and lactate dehydrogenase (LDH). During the treatment phase, obtain chemistries pre-treatment and every 2 
weeks for the first month, then every month thereafter for at least 6 months after the last dose of ofatumumab or up to discretion of investigator. 
7. Liver chemistries consist of albumin, INR,  ALT, AST, total bilirubin, and alkaline phosphatase. During the treatment phase, obtain liver chemistries pre-treatment 
and every 2 weeks for the first month, then every month thereafter for at least 6 months after the last dose of ofatumumab. 
8. Complement will be measured at baseline, before and after the first and second dose of ofatumumab, at week 12, 16, 20 and 24, at completion of therapy, and at 
follow up only in patients with low complement levels at baseline or after treatment.  
9. B-cells, IgG, IgA and IgM will be monitored until they return to baseline or up to two years after the last dose of ofatumumab, or until the subject starts other B-cell 
depleting therapy.  
10. Human Immunodeficiency Virus (HIV) test; If status is unknown. 
11. Women of childbearing potential must have a negative pregnancy test at screening. **women of child bearing potential must undergo pregnancy testing prior to 
each dose if the previous pregnancy test was greater than 14 days prior and a pregnancy test at 6 months after the last dose. 
 
 
 


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7.2 
 Efficacy 
 
Efficacy analyses will be performed on data from the Intent-to-Treat Population. 
 
Definition of Response 
 
Response criteria 
NCI-WG 
National Cancer Institute – 
Working Group 
IWCLL 
International Workshop on Chronic 
Lymphocytic Leukemia 
Complete Response (CR): 
 
Physical exam  
(nodes, and/or liver, spleen) 
Normal 
Normal 
Symptoms 
None 
None 
Lymphocytes (x 109/L) 
<4 
<4 
Neutrophils (x 109/L) 
>1.5 
 
Platelets (x 109/L) 
> 100 
 
Hb (g/dL) 
>11 (untransfused) 
Not stated 
Bone marrow lymphocytes (%) 
>30; no nodules 
Normal, allowing nodules or focal 
infiltrates 
Partial Response (PR): 
 
Physical exam  
(nodes, and/or liver, spleen) 
>50% decrease 
Downshift in stage 
Plus >1 of: 
 
 
Neutrophils (x 109/L) 
>1.5 
 
Platelets (x 109/L) 
>100 
 
Hemoglobin (g/dL) 
>11 or 50% improvement 
 
Duration of CR or PR 
>2 months 
Not stated 
Progressive disease (PD):  
 
Upshift in stage 
Physical exam  
(nodes, liver, spleen) 
>50% increase or new 
 
Circulating lymphocytes 
>50% increase 
 
Other 
Richter's syndrome 
 
Stable disease (SD):  
All others 
No change in stage 


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Bone Marrow Examination 
A bone marrow aspirate and biopsy are generally not required to make the diagnosis of CLL. 
Nevertheless, CLL is a disease of the bone marrow, and it is appropriate to evaluate a major site of 
involvement. The aspirate smear must show >= 30% of all nucleated cells to be lymphoid. A bone 
marrow examination also provides useful prognostic information by determining whether there is diffuse 
or non-diffuse involvement, and permits an assessment of the erythroid precursors and 
megakaryocyte. 
 
 
7.3 
 Safety Assessments 
 
7.3.1  Liver chemistry stopping and follow-up criteria 
 
Liver chemistry stopping and follow-up criteria have been designed to assure subject safety and 
evaluate liver event etiology. The sponsor-investigator will review all events which meet liver chemistry 
stopping criteria to determine if the event was due to:  
 
• 
tumor lysis, disease related liver involvement 
• 
other identified cause and to exclude drug induced liver injury (DILI) due to ofatumumab 
The criteria are relevant for all Ofatumumab studies because transient elevations in LFTs may be due 
to tumor lysis which is of clinical benefit, disease related liver involvement or due to other 
chemotherapy rather than drug induced liver injury from ofatumumab. 
If the event is determined to be due to causes other than ofatumumab DILI and improvement is 
observed after withdrawal of ofatumumab, rechallenge may be attempted if deemed appropriate by the 
sponsor-investigator and in addition to consent of the subject.  
7.3.1.1 Liver chemistry interruption/stopping criteria 
 
1. ALT >3xULN and bilirubin > 2 x ULN (>35% direct bilirubin; bilirubin fractionation required*) 
 
2. ALT >8xULN 
 
3. ALT >5xULN for more than 2 weeks 
 
*NOTE: If serum bilirubin fractionation not immediately available, study drug should be discontinued if 
ALT > 3 x ULN and bilirubin > 2 X ULN. Serum bilirubin fractionation should be performed if testing is 
available. . If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating 
direct bilirubin elevations and suggesting liver injury. 
 
When any of the liver chemistry stopping criteria is met, do the following: 
 
• 
Immediately stop study treatment 
• 
Hold Ofatumumab for two weeks, repeat liver chemistry testing at least twice weekly, and report 
to sponsor-investigator to discuss the possibility of re-challenging with ofatumumab. Note:  The 
2 week time point for stopping medication was chosen because it will distinguish from LFT 
elevations due to tumor lysis which should have resolved within this time period.  Medication is 
interrupted and it is a clinical and patient decision if ofatumumab may be re-started.  The risk: 
benefit ratio is different in an oncology setting and an efficacious therapy may be life-saving.   
• 
Report SAE to Novartis within 24 hours 


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• 
All events of ALT > 3xULN and bilirubin > 2xULN (>35% direct bilirubin) (or ALT>3xULN and 
INR>1.5, if INR measured; INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis). 
• 
NOTE: if serum bilirubin fractionation is not immediately available, study treatment should be 
discontinued if ALT > 3xULN and bilirubin > 2xULN. Serum bilirubin fractionation should be 
performed if testing is available. If testing is unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
Liver chemistry follow-up assessments are to be followed until liver chemistries resolve, stabilize or 
return to baseline values. 
7.3.1.2. Liver Chemistry Follow-up Assessments 
 
Chemistry tests/ assessments below are to be performed at the time of the event and then continued 
and/or discontinued at the discretion/judgment of the sponsor-investigator; please refer to stopping 
criteria within this document. 
Viral hepatitis serology including: 
• 
Hepatitis A IgM antibody; 
• 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);  
• 
Hepatitis C RNA;  
• 
Cytomegalovirus IgM antibody;   
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody 
or monospot testing);   
• 
Hepatitis E IgM antibody  
• 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) 
• 
Fractionate bilirubin, if total bilirubin >2xULN 
• 
Obtain complete blood count with differential to assess eosinophilia 
• 
Record the  appearance or worsening clinical symptoms of hepatitis, or hypersensitivity, fatigue, 
decreased appetite, nausea, vomiting, abdominal pain, jaundice, fever, or rash  
• 
Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter 
medications, or putative hepatotoxins 
• 
Increased  alcohol use  
The following assessments are required for subjects with ALT >3xULN and bilirubin >2xULN (.35% 
direct) but are optional for other abnormal liver chemistries:  
• 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal 
antibodies 
• 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver 
disease.  
 
 
 


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Stopping Criteria: 
• 
For subject meeting liver stopping criteria 1:  
o A repeat of  liver chemistries within 24 hours, liver event follow-up assessments and 
close monitoring 
o A specialist or hepatology consultation is recommended 
o Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values. 
• 
For subjects meeting criteria 2 or 3:  
o A repeat of  liver chemistries within 24 to 72 hours for repeat liver chemistries and liver 
event follow-up assessments  
o Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values 
• 
After holding ofatumumab for two weeks:  
o If the treatment is exhibiting efficacy and the subject wants to continue therapy after 
being informed of the results of liver chemistry testing, then the ofatumumab may be re-
started.  
o Liver chemistries and follow-up assessments should be monitored at a minimum of 
every 2 weeks until resolution, stabilization, or a return to baseline values, at which point 
monitoring should be continued per protocol 
• 
Subjects with ALT >3xULN but <5xULN and bilirubin <2xULN without hepatitis symptoms or 
rash, and who may be monitored weekly for at least 4 weeks, then the following actions should 
be taken: 
o Subjects can continue ofatumumab 
o Weekly repeat of liver chemistries until they resolve, stabilize, or return to baseline 
values, then monitor liver chemistries as per protocol assessment schedule 
If at any time the subject meets any of the liver chemistry stopping criteria, then proceed as described 
above. 
If after 4 weeks of monitoring, ALT<3xULN and bilirubin<2xULN monitor twice monthly until liver 
chemistries normalize or return to within baseline values 
 
7.4. 
 Adverse Events 
 
The investigator or site staff will be responsible for detecting, documenting and reporting events that 
meet the definition of an AE or SAE. 
 
7.4.1  Definition of an AE 
 
Any untoward medical occurrence in a subject or clinical investigation subject, temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product. 
 
Events meeting the definition of an AE include: 
 
 


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• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments e.g., ECGs, radiological scans, vital signs measurements), including those that 
worsen from baseline, and felt to be clinically significant in the medical and scientific judgment of 
the investigator 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition 
• 
New conditions detected or diagnosed after study product administration even though it may have 
been present prior to the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study product or a 
concomitant medication (overdose per se will not be reported as an AE/SAE) 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or 
SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be 
reported if they fulfill the definition of an AE or SAE. 
 
Events that do not meet the definition of an AE include: 
• 
Any clinically significant abnormal laboratory finding or other abnormal safety assessments that is 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the subject’s condition.  
• 
The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the 
procedure is an AE 
• 
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen 
• 
B cell depletion and hypogammaglobulinemia due to ofatumumab treatment 
 
7.4.2  Definition of a SAE 
 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
 
a. 
Results in death 
b. 
Is life-threatening 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization 
is for:  
• 
routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition (specify what this includes) 
• 
elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication 
under study and has not worsened since the start of study drug 
• 
treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a 
SAE given above and not resulting in hospital admission 


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• 
social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
d. 
Results in disability/incapacity, or 
NOTE:  The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.  This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but 
do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
is medically significant, i.e., defined as an event that jeopardizes the patient or may require medical 
or surgical intervention to prevent one of the outcomes listed above.  
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition.  These should also 
be considered serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse. 
 
7.4.3 Toxicity Assessments of AEs and SAEs 
 
The investigator is required to make an assessment of the toxicity grade of each AE or SAE reported. 
In this protocol, the maximum toxicity grade of each non-hematologic AE/SAEs will be evaluated 
according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) 
version 4.0. 
 
It is important to consider low blood counts at the initiation of therapy when evaluating hematologic 
toxicity of CLL subjects.  
 
 
7.4.4 Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs 
 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline, and felt to be clinically significant in the medical and scientific 
judgment of the investigator are to be recorded as AEs or SAEs. 
 
• 
All events meeting liver stopping criteria must be recorded as an SAE.  
 
• 
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the subject’s 
condition, are not to be reported as AEs or SAEs. 
 
• 
B cell depletion, IgG below LLN, low CD19+ count, and hypogammaglobulinemia due to 
treatment with ofatumumab are not to be reported as AEs or SAEs. 
 


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• 
Infusion related AEs may lead to a prolonged infusion time. Overnight stay at the hospital due to 
slow infusion rate is not to be reported as a SAE. 
 
 7.4.5 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs 
 
An event which is part of the natural course of the disease under study (i.e., disease progression) does 
not need to be reported as an SAE.  However, if the progression of the underlying disease is greater 
than that which would normally be expected for the subject, or if the investigator considers that there 
was a causal relationship between treatment with study product or protocol design/procedures and the 
disease progression, then this must be reported as an SAE. 
 
7.4.6 SAE Reporting 
 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, and 
Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E). 
 
Reporting to the FDA  
 
All serious, unlabeled, (unexpected) adverse events will be reported to the FDA as required by 21 CFR 
312.32. (Investigational New Drug)  https://www.accessdata.fda.gov/scripts/medwatch/. All events 
reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A (MedWatch Form).  
 
Reporting to the Institutional Review Board 
 
Both serious and non-serious adverse events will be reported in accordance with UCD IRB 
Administration and UCD Cancer Center Clinical Trial Support Unit (CTSU) or participating site policies.  
The UC Davis IRB can be reached at (916) 703-9151.  
 
Reporting to Novartis 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
• 
after the patient has provided informed consent and up to a minimum of 6 months after the last 
dose of study product or until the end of the follow-up period whichever is longer. All SAEs 
regardless of causality will be collected until the end of the follow-up period.  SAEs are no longer 
required to be reported if a subject begins treatment with another therapy.  
• 
after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-blind 
treatment, etc.) and 30 days after the patient has stopped study treatment 
• 
after the start of any period in which the study protocol interferes with the standard medical 
treatment given to a patient (e.g., treatment withdrawal during washout period, change in treatment 
to a fixed dose of concomitant medication) and until 30 days after the patient has stopped study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. This includes 
serious, related, not related, labeled (expected) and, unlabeled (unexpected) adverse experiences. 
All deaths during treatment or within 30 days following completion of active protocol therapy must 
be reported within24 hours.  
 
 
Send SAE Reports to Novartis via Fax: 
 
Novartis Drug Safety and Epidemiology 
Fax: 877-778-9739 
 


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Should the designated SAE Fax# be non-functional please send SAEs to the designated SAE 
mailbox: 
 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept within the Trial Master 
File at the study site. 
 
Follow-up information is sent to the same fax number as the original SAE Report Form was sent, using 
a new fax cover sheet, stating that this is a follow-up to the previously reported SAE, and giving the 
date of the original report. Each re-occurrence, complication, or progression of the original event should 
be reported as a follow-up to that event regardless of when it occurs. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not (if applicable), and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Ofatumumab Investigator Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study drug, a DS&E associate may 
urgently require further information from the investigator for Health Authority reporting. Novartis may 
need to issue an Investigator Notification (IN), to inform all investigators involved in any study with the 
same drug that this SAE has been reported.  
 
Subjects who are HBsAg negative, anti-HBc positive and HBV DNA negative may be included in the 
study but must undergo HBV DNA monitoring. Consult with a physician experienced in care & 
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 
Novartis Clinical Team.  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. 
 
7.4.7 Pregnancy 
 
Any pregnancy that occurs during study participation must be reported to Novartis.   To ensure subject 
safety, each pregnancy must be reported to Novartis within 2 weeks of learning of its occurrence.  The 
pregnancy must be followed up to determine outcome (including premature termination) and status of 
mother and child.  Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
 
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after the 
subject has completed the study and considered by the investigator as possibly related to the study 
product, must be promptly reported to Novartis. 
 
In addition, the investigator must attempt to collect pregnancy information on any female partners of 
male study subjects who become pregnant while the subject is enrolled in the study. Pregnancy 
information must be reported to Novartis as described above. 
 
Novartis Drug Safety and Epidemiology 
Fax: 
 
Should the designated SAE Fax# be non-functional please send SAEs to the designated SAE 
mailbox: 
 
 
 
 
 
 
 
 


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8.0 STATISTICAL CONSIDERATIONS 
 
8.1 Datasets to be Analyzed 
 
The primary study endpoint is response to therapy (defined as a CR, or PR, and progression free 
survival).  The secondary endpoints are toxicity, overall survival, complement levels (CH50 and C2 
levels) will be measured from the time of entry into the clinical trial.   
 
Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the 
probable association with the study regimen.  Tables will be constructed to summarize the observed 
incidence by severity and type of toxicity.   
 
8.2 
Statistical Methodology 
 
Thirty-six patients will be treated with ofatumumab and FFP at dose levels previously established to be 
safe. Objective response (CR + PR) will be monitored using Simon’s optimal 2-stage minimax design. 
This study design is optimal in that sense that it minimizes the expected sample size among competing 
designs. The OR rate of ofatumumab in patients that have failed fludarabine and alemtuzumab is 
approximately 42% respectively. However, patients enrolled on this study will have received prior 
rituximab therapy and the objective response rate in such patients retreated with rituximab is estimated 
to be 25%. A 20% increase in the objective response rate with the addition of FFP to 45% would justify 
evaluation of this regimen in larger, more definitive trials. We assume a one-sided type I error rate of 
5% and desire at least 80% power to conclude that this regimen elicits and objective response rate 
significantly greater than 25% if the true response rate of this regimen is 45% or higher. Under these 
assumptions, if 4 or fewer OR’s are observed in the first 17 patients, the principal investigator may 
conclude that the regimen is insufficiently active to warrant further study. Otherwise, accrual will 
continue to a total of 12 patients. If 14 or more OR’s are observed in 36 patients, this regimen will be 
deemed sufficiently active to warrant further study. 
 
8.3 
Analysis Plan 
 
Continuous variables (e.g., age, hematology values, complement levels) will be summarized using the 
mean (s.d.) or median (range). Frequency tables will be used to summarize categorical variables. 
Logistic regression will be used to assess the impact of patient characteristics (e.g., low/high 
complement levels) on the objective response rate. The distribution of time-to-event endpoints (e.g., CR 
duration, overall survival) will be estimated using the method of Kaplan and Meier. Comparison of time-
to-event endpoints by important subgroups of patients (based on known prognostic factors, e.g 
cytogenetics, CD38, Ig mutational status) will be made using the logrank test. Cox (proportional 
hazards) regression will be used to evaluate multivariable predictive models of time-to-event outcomes. 
 
8.4 
Safety Evaluation 
 
Data from all subjects who receive any study drug will be included in the safety analyses. The severity 
of the toxicities will be graded according to the NCI CTCAE v4.0 whenever possible. Unacceptable 
toxicity (> grade 3) experienced in patients will be monitored according to guidelines for monitoring 
toxicity in pilot/phase II trials using sequential probability ratio test based criteria.  The guidelines will be 
used to raise a flag if the number of patients who experience unacceptable toxicity is greater than 20%.  
Toxicity information recorded will include the type, severity, date of onset, date of resolution, and the 
probable association with the study regimen. Tables will be constructed to summarize the observed 
incidence by severity and type of toxicity.  Baseline information (e.g. the extent of prior therapy, extent 
of disease) and demographic information will be presented, as well, to describe the patients treated in 
this Phase II study.   


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9.0  
STUDY CONDUCT CONSIDERATIONS 
 
9.1 
Registration Guidelines 
 
9.1.1 Study Registration  
 
Once signed, informed consent has been obtained and all pretreatment evaluations have been 
performed, patients will be entered on study according to UCD Clinical Trials Support Unit (CTSU) 
policy. To register a patient, the data manager must complete the Eligibility Checklist and the Patient 
Registration Form. A patient accession number will then be assigned.  Administration of study product 
may not be initiated until the patient is registered. 
 
9.1.2 Protocol Deviations 
 
All protocol deviations will be reported in accordance with UCD IRB Administration and UCD Cancer 
Center CTSU policies or participating site policies. 
9.2 
Minority and Gender Statement 
 
Recruitment is open to all minorities and both genders.  Although distributions may vary by disease 
type, our recruitment procedures have been developed to enroll patients who are representative of the 
respective target population. 
 
 
9.3 
Ethical and Regulatory Considerations 
 
All patients will have signed an informed consent for participation in research activities in accordance 
with all institutional, NCI and Federal regulations, and will have been given a copy of the Experimental 
Subject's Bill of Rights. 
 
 
9.4 
Quality Assurance 
 
Quality assurance audits of select patients and source documents may be conducted by the UC Davis 
Cancer Center Quality Assurance Committee as outlined in the UC Davis Cancer Center Data and 
Safety Monitoring Plan. 
 
Quality control will be maintained by the CTSU Quality Assurance team according to CTSU policy. 
 
9.5 
Record Retention  
 
9.5.1 Confidentiality of Records 
 
The original data collection forms will be stored in secure cabinets in the UCD Clinical Trials Support 
Unit. 
 
9.5.2 Patient Consent Form  
 
In accordance with UCD CTSU policy, an original signed and dated participant Informed Consent 
document will reside in a secured location within the UCD CTSU. Copies of the signed and dated 
Informed Consent document will be provided to the study participant and UCD Health System 


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Information Management for inclusion in the participant’s UCD Health System Medical Record or 
participating site’s medical record.  
 
 
9.5.3 Registration Eligibility Worksheet   
 
At the time of registration, the information requested on the Eligibility Checklist will be submitted to the 
Protocol Coordinator.  
 
 
9.6 
Data and Safety Monitoring 
 
In addition to the requirements for adverse event reporting as outlined in Section 7.4, this protocol is 
also subject to the UC Davis Cancer Center’s (UCDCC) Data and Safety Monitoring Plan. The UCDCC 
is committed to pursuing high-quality patient-oriented clinical research and has established 
mechanisms to ensure both scientific rigor and patient safety in the conduct of clinical research studies. 
The UCDCC relies on a multi-tiered committee system that reviews and monitors all cancer clinical 
trials and ensures the safety of its participants, in compliance with institutional and federal requirements 
on adverse event reporting, verification of data accuracy, and adherence to protocol eligibility 
requirements, treatment guidelines, and related matters. The Scientific Review Committee (SRC) 
assumes overall oversight of cancer studies, with assistance and input from two independent, but 
interacting, committees: the Quality Assurance Committee and the Data Safety Monitoring Committee. 
A multi-level review system strengthens the ability of the UCDCC to fulfill its mission in conducting high 
quality clinical cancer research. 
 
As per University of California Davis Cancer Center (UCDCC) Clinical Trials Support Unit (CTSU) SOP 
AM 506: Protocol Specific Meetings, the principal investigator (PI) and clinical research coordinator 
(CRC), meet at least monthly for ongoing study information, to discuss patient data and adverse events 
and to determine if dose escalation is warranted, when applicable.   
 
According to the UCDCC Data and Safety Monitoring Plan (DSMP), any new serious adverse events 
related to the drug being used on this trial are reviewed monthly by the UCDCC Data and Safety 
Monitoring Committee (DSMC) and any applicable changes to the study are recommended to the PI, if 
necessary. 
 
The UCDCC Scientific Review Committee (SRC) determines if a UCDCC Data and Safety Monitoring 
Board (DSMB) is required.  If required, the DSMC will appoint a DSMB. The DSMB is responsible for 
reviewing study accrual logs, adverse event information and dose escalation meeting minutes (where 
applicable) to ensure subject safety and compliance with protocol defined guidelines. 
 
 
 
 
 


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10.0 
REFERENCES 
 
 
 
Aivado M, Shulte K, Henze L, et al. Bendamustine in the Treatment of Chronic Lymphocytic Leukemia: 
Results and Future Perspectives. Semin Oncol. 2002;29 Suppl 13:19-22. 
 
Bergmann M, Goebeler M, Herold M et al. Efficacy of Bendamustine in patients with relapsed or 
refractory chronic lymphocytic leukemia: results of a phase I/II study of the German CLL Study Group. 
Hematologica. 2005:90(10):1357-64. CAMPATH (alemtuzumab) prescribing information, Bayer 
Healthcare, October 2008. 
 
Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for 
patients with chronic lymphocytic leukemia (the LRF CLL4 Trial): a randomized controlled trial. Lancet. 
2007;370:230-239. 
 
Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR. National Cancer Institute-
Sponsored Working Group Guidelines for Chronic Lymphocytic Lymphoma: Revised Guidelines for 
Diagnosis and Treatment. Blood. 1996;87:4990- 4997. 
 
Coiffier B, 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 I-II study. Blood 2008; 
111:1094-1100. 
 
Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic 
leukemia. N Engl J Med 2000;343:1910-1916 
 
Fiegl M, et al. Routine clinical use of alemtuzumab in patients with heavily pre-treated B-cell chronic 
lymphocytic leukemia. Cancer. 2006;107:2408-16. 
 
Hallek M, Fingerle-Rowson G, Fink A, et al. Immuochemotherapy with fludarabine 
(F),cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine and cyclophosphamide (FC) 
improves response rtaes and progression-free survival (PFS) of previously untreated patients (pts) with 
advanced chronic lymphocytic leukemia (CLL). Blood (ASH Annual Meeting Abstracts) 2008;112: 
Abstract 325. 
 
Hallek, M, Cheson BD, Catovsky C et al , Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia: a report from the InternationalWorkshop on Chronic Lymphocytic Leukemia 
updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111:5446-5456 
 
Hallek MH, Schmitt BS, Wilhelm MW, Busch RB, Krober AK, Fostitsch HPF, Sezer OS, Herold MH, et 
al. Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic 
leukemia (CLL): results of a phase II study of the German CLL Study Group. Br J Haematol. 
2001;114:342-348. 
 
Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab 
compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 
2007;25:5616-5623. 
 
Huhn D, von Schilling C, Wilhelm M, et al. Rituximab therapy of patients with B-cell chronic lymphocytic 
leukemia. Blood. Huhn, D., et al. 2001;98:1326-1331. 
 
Jemal, A., et al., Cancer statistics, 2006. CA Cancer J Clin, 2006. 56(2): p. 106- 30. 


UCDCC#232 
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Kath R, Blumenstengel K, Fricke H, Höffken K. Bendamustine monotherapy in advanced and refractory 
chronic lymphocytic leukemia. J Cancer Res Clin Oncol. 2001;127:48-54.- 83  
 
Kay, NE, Hamblin, TJ, Jelinek, DF, et al. Chronic Lymphocytic Leukemia. Hematology 2002;1:193-213. 
 
Keating MJ, O’Brien S, Kontoyiannis D et al. Results of first salvage therapy for patients refractory to a 
fludarabine regimen in chronic lymphocytic leukemia. Leuk Lymphoma. 2002a; 43:755-1762. 
 
Keating MJ, Flinn IF, Jain VJ, Binet JB, Hillmen PH, Byrd JB, Albitar MA, Brettman LB, Santabarbara 
PS, Wacker BW, Rai KR. Therapeutic role of alemtuzumab (Campath- 1H) in patients who have failed 
fludarabine: results of a large international study. Blood. 2002b;99:3554-3561. 
 
Keating MJ. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 
2001a;19:2165-2170. 
 
Klepfish A, Rachmilewitz, EA, Kotsianidis I. Adding fresh frozen plasma to rituximab for the treatment of 
patients with refractory advanced CLL. Q J Med 2008; 101:737–740 
 
Knauf WU, et al. Bendamustine Versus Chlorambucil in Treatment-Naïve Patients with B-Cell Chronic 
Lymphocytic Leukemia (B-CLL): Results of an International Phase III Study. Blood. (ASH Annual 
Meeting Abstracts) November, 2007;110:2043. 
 
Moreton P, Kennedy B, Lucas G. et al. Eradication of minimal residual disease in B-cell chronic 
lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 
2005;23: 2971-2979. 
 
Morrison V, Management of Infectious Complications in Patients with Chronic Lymphocytic Leukemia, 
Hematology 2007;332-338 
 
Nabhan C, Gartenhaus RB, Tallman MS. Purine nucleoside analogues and combination therapies in B-
cell chronic lymphocytic leukemia: dawn of a new era. Leuk Res. 2004; 28:429-442. 
 
O'Brien SO, Kantarjian HK, Cortes JC, Beran MB, Koller CK, Giles FG, Lerner SL, Keating MK. Results 
of the Fludarabine and Cyclophosphamide Combination Regimen in Chronic Lymphocytic Leukemia. J 
Clin Oncol. 2001(a);19:1414-1420. 
 
O’Brien SM, Kantarjian H, Thomas DA, Giles FJ, Freireich EJ, Cortes J, Lerner S, Results of 
fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. JCO. 
2001b:19:1414-20 
 
Oscier D, Fegan C, Hillmen P, Illidge T, Johnson S, Maguire P, Matutes E, Milligan D. Guidelines on 
the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol. 2004;125:294-317. 
 
Pawluczkowycz AW, Beurskens FJ, Beum PV, Lindorder MA, van de Winkel JG, Pareen PW, Taylor 
RP.  Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells 
opsonized with anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of 
CDC are induced by OFA than by RTX. J Immunol. 2009: 183(1):749-758. 
 
Perkins JG, Flynn JM, Howard RS, Byrd JC. Frequency and type of serious infections in fludarabine-
refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma: implications for clinical 
trials in this patient population. Cancer. 2002;94:2033-2039. 


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Rai, KR, et al. Clinical Staging of Chronic Lymphocytic Leukemia. Blood 1975;46:219-234. 
 
Rai KR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic 
leukemia. NEJM 2000;343:1750-7. 
 
Rai KR, Freter CE, Mercier RJ et al. Alemtuzumab in previously treated chronic lymphocytic leukemia 
patients who also had received fludarabine. J Clin Oncol. 2002; 20: 3891-3897. 
 
Redaelli, A., et al. The Clinical and Epidemiological Burden of Chronic Lymphocytic Leukaemia. Eur J 
Cancer Care. 2004;13:279-287. 
 
Robak T, et al. Rituximab, fludarabine, and cyclophosphamide (R-FC) prolongs progression free 
survival in relapsed or refractory chronic lymphocytic leukemia (CLL) compared to FC alone: final 
results from the international randomized phase III REACH trial. Blood (ASH Annual Meeting Abstracts) 
2008; 112: Late-Breaking Abstract 1 
 
Rudmann  SV(18 February 2005). Textbook of blood banking and transfusion medicine. Elsevier Health 
Sciences. pp. 247-52 ISBN 9780721603841 
 
Schlesinger M, Broman I, Lugassy G. The complement system is defective in chronic lymphocytic 
leukemia patients and in their healthy relatives. Leukaemia. 1996:10 1509-1513. 
 
Shanafelt TS, Kay NK, Morrison VM, Goldin LG. Comprehensive Management of the CLL Patient: A 
Holistic Approach. Hematology 2007;1:324-331. 
 
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. 
 
Teeling JL, French RR, Cragg MS, et al. Characterization of new human CD20 monoclonal antibodies 
with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 2004;104:1793-800. 
 
Varga L, Czink E, Miszlai Z, Paloczi K, Banyai A, Szegedi G, et al. Low activity of the classical 
complement pathway predicts short survival of patients with chronic lymphocytic leukemia. Clin Exp 
Immunol 1995: 99:112-116. 
 
Wierda WW, O'Brien SO, Wen SW, Faderl SF, Garcia-Manero GG, Thomas DT et al. 
Chemoimmunotherapy with Fludarabine, Cyclophoshamide, and Rituximab for Relapsed and 
Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2005; 23: 4070. 
 
Zenz TZ, Dohner HD, Stilgenbauer SS. Genetics and Risk-Stratified Approach to Therapy in Chronic 
Lymphocytic Leukemia. Best Pract Res Clin Haematol. 2007;20:439-453. 
 
 
 
 
 
 
 


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11.0 
APPENDICES 
 
Appendix 1: Performance Status Scale  
 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable 
assistance and frequent medical 
care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: Arzerra®  (Ofatumumab) Prescribing Information 
 
  
(The hyperlink below is to the revised Prescribing Information document, Revised: 04/2015) 
 
http://www.pharma.us.novartis.com/product/pi/pdf/arzerra.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3: Data Submission Schedule 
 
All data will be collected using UC Davis data collection forms. Copies of the completed forms will be 
submitted to UC Davis data coordinating center for data entry and storage in a secure location. The 
original data collection forms will reside at the originating institution in secure location.  
 
 
 SUBMIT WITHIN 24 HOURS OF REGISTRATION:  
Patient Registration Form  
 
 SUBMIT WITHIN 14 DAYS OF REGISTRATION:  
In‐House Pre‐Study Evaluation Form (IH‐102)  
 
 SUBMIT WITHIN 7 DAYS OF SCREENING FAILURE:  
Patient Screen Failure Form  
 
 SUBMIT WITH 14 DAYS OF CYCLE COMPLETION:  
Adverse Event/Drug Relationship Form  
 
 
 SUBMIT WITHIN 14 DAYS OF END OF EACH TREATMENT CYCLE:  
In‐House Treatment Cycle Form (IH‐201)  
 
 SUBMIT WITHIN 14 DAYS OF EACH RESPONSE ASSESSMENT:  
Tumor Measurement Log  
 
 SUBMIT WITHIN 14 DAYS OF OFF TREATMENT:  
Off Treatment/In Follow-up/Off Study/Expiration Form (IH‐301)  
 
 SUBMIT WITHIN 14 DAYS OF KNOWLEDGE OF DEATH IF PATIENT IS STILL ON STUDY 
OR 30–DAYS IF OFF STUDY:  
Off Treatment/In Follow-up/Off Study/Expiration Form (IH‐301)  
 
 SUBMIT WITHIN 2 DAYS OF KNOWLEDGE OF PROTOCOL DEVIATION:  
Clinical Trials Support Unit: Notice of Protocol Deviation  
 
 SUBMIT WITHIN 14 DAYS OF EACH REQUIRED FOLLOW‐UP ENCOUNTER:  
Follow‐Up Form (IH‐302)  
 
 ALL SERIOUS ADVERSE EVENTS MUST BE REPORTED AS OUTLINED IN THE 
PROTOCOL.  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 4: Drug Request Form 
Drug Supply Request Form  
 
PI:  Joseph Tuscano, MD 
Novartis Study Number: COMB157AUS19T 
 
Title of Study:  PHASE II TRIAL OF OFATUMUMAB AND FRESH FROZEN PLASMA IN PATIENTS WITH 
RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA 
 
 
Read carefully.  For Investigator Sponsored Studies (ISS), the PI may need to hold an IND.  You are responsible 
for following CFR and GCP for labeling and dispensing (21 CFR 312.6) study medication.   
 
Novartis will provide content labeled-Ofatumumab  vials presented as either 100mg – acetate formulation, 
20mg/mL, 5mL fill vials or 1000mg – acetate formulation 20mg/mL, 50mL fill vials. 
 
Ofatumumab vials must be stored at 2-8°C. Protect from light and do not freeze. No special packaging 
components, other than the outer white cardboard carton in which the vials are placed, will be used to afford light 
protection.  The prepared solution remains stable for up to 24 hours at ambient temperature. Since the product 
contains no preservative, it should be used as soon as possible after dilution. 
 
Ofatumumab  open-labeled product will be for intravenous infusion.  The site is responsible for labeling individual 
vials for study use.  All other items required for administration of study medication, e.g. infusion bags, filters etc, 
are to be provided by the site. 
 
PLEASE NOTE: UPON NOVARTIS RECEIPT OF ALL REQUIRED DOCUMENTION, IT MAY TAKE UP TO 2 
WEEKS FOR DRUG TO BE SENT TO YOU. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The full shipping address for drug supply: 
Pharmacist:  Name, 
(shipping) address, contact 
info (email and phone) of the 
pharmacist or person 
handling the study drug 
add contact info here 
Please complete the following 3 items. 
Step 1: 
Total Number 
of Subjects 
Best Estimate 
of Patient 
accrual/mo 
Dose(s) in mg 
Total dose 
(mg) per 
patient;  
Life of Study 
Total # vials 
(100mg/vial); per 
patient 
Total Duration 
of study (mos) 
 
 
__________ 
 
 
__________ 
 
 
 
__________ 
 
 
__________ 
 
 
__________ 
Step 2: 
TOTAL VIALS REQUIRED FOR STUDY (# subjects x total # vials per patient) 
__________ 
Step 3: 
Specific number of vials 
for initial study shipment 
(i.e., 3 month supply) 
 
Estimated # of patients (3 months) =              ___________ 
 
1. 
Total # vials requested for first shipment = _________ 
(NB: 1 vial x 5 mL fill = 100mg dose) 
 
2. 
Total # vials requested for first shipment = _________ 
(NB: 1 vial x 50 mL fill = 1000mg dose) 
Best estimate of Study Start (First Subject First Visit)_____________________(dd/mmm/yyyy) 
 
SEND TO: