Clinical trial NCT01497496
Conditions: Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Keywords: leukemia lymphoma consolidative therapy combination regimen Chronic Lymphocytic Leukemia (CLL) Small Lymphocytic Lymphoma (SLL)
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2012-01-26; Completion date: 2020-03-20
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to see if the combination of ofatumumab with high dose methylprednisolone followed by additional treatment with ofatumumab and lenalidomide can help people with relapsed or refractory CLL/SLL get rid of their CLL/SLL for a long period of time. Researchers also want to find out if the combination of ofatumumab with methylprednisolone followed by additional treatment with ofatumumab and lenalidomide is safe and tolerable.

Detailed description:
This is a phase II, single institution, and non-randomized study of patients with relapsed or refractory CLL/SLL, utilizing a two-stage trial design. The primary endpoint for this trial is the combined complete and partial response rate at 3 months (after the end of cycle 3) to the protocol therapy. Investigators anticipate this trial will have a complete response and partial response (CR+PR) rate of at least 55%.

A two-stage design is employed for this trial. The null/unacceptable CR+PR response rate is ≤35% while the anticipated true response rate to the protocol treatment is at least 55% for each disease cohort. At the first stage, 25 patients will be accrued to the trial. If 9 or fewer of these patients respond, then the trial will be terminated early and the response rate to the protocol treatment will be deemed unacceptable (≤35%). Otherwise, if more than 9 patients respond during the first stage, an additional 31 patients will be enrolled to this trial during stage 2 for a total of 56 patients. If 25 or fewer of these 56 patients respond to the protocol treatment at the end of stage 2, no further investigation of the protocol treatment is considered warranted. On the other hand, if more than 25 patients out of the 56 enrolled patients respond, the protocol treatment will be considered promising. If the true response rate is ≤35%, the probability of ending the trial at stage 1 is 0.63. If, however, the true response rate is at least 55%, then the probability of ending the trial at stage 1 is only 0.04. This two-stage design has an overall alpha level of 0.047 and a power of 0.90.

For the purpose of interim analysis at the end of stage 1, the objective response will be measured by the end of 3 months (or end of cycle 3) from the start of the protocol treatment prior to the initiation of the combination of ofatumumab with lenalidomide. The accrual will not be suspended while waiting for the results of the interim analysis unless the observed objective response rate among those patients whose objective response data are available is below 30%.

Arms: arm 1: Combination regimen consisting of high dose methylprednisolone combined with ofatumumab, followed by consolidative therapy with lenalidomide in combination with ofatumumab.
Interventions: intervention 1: High Dose Methylprednisolone (HDMP) intervention 2: Ofatumumab intervention 3: Lenalidomide
Intervention descriptions: intervention 1: 1000 mg/m\^2 on Cycle 1: Day 1, 8, 15, 22; Cycle 2: Day 1, 15; Cycle 3: Day 1, 15 intervention 2: Ofatumumab infusion will be administered immediately after HDMP. 300 mg on Cycle 1 Day 1. 2000 mg on Cycle 1: Day 8, 15, 22; Cycle 2: Day 1, 15; Cycle 3: Day 1, 15; Cycle 6: Day 1; Cycle 8: Day 1; Cycle 10: Day 1: Cycle 12: Day 1 intervention 3: The lenalidomide treatment will start with cycle 4. 5-10 mg pd Days 1-28 as per Creatinine Clearance (CrCl)

Protocol documents:
Prot_SAP_000.pdf: 
 
Phase II Study of Ofatumumab in Combination with High Dose 
Methylprednisolone Followed by Ofatumumab and Lenalidomide 
Consolidative Therapy for the Treatment of Relapsed or Refractory 
CLL/SLL The HiLOG Trial 
 
NCT01497496 
 
Amendment 7 
February 2, 2017 


Amendment 7 Dated 02/02/2017 
Protocol Title: Phase II Study of Ofatumumab in Combination with High Dose 
Methylprednisolone followed by Ofatumumab and Lenalidomide consolidative therapy 
for the treatment of Relapsed or Refractory CLL/SLL: The HiLOG trial. 
 
Study Location:  H. Lee Moffitt Cancer Center & Research Institute 
 
Principal Investigators:  Celeste Bello, M.D.. 
                                         Address:  12902 Magnolia Drive 
                                                         Tampa, FL  33612-9497 
                                         Telephone:  (813) 745-3880 
                                         Fax: (813) 979-7264 
                                         E-mail: Celeste.bello@moffitt.org  
 
 
 
Protocol Numbers:  
MCC: 16631 
                                 
Celgene Reference #: RV-CLL-PI-0560 
                                 
NOVARTIS study identifier: COMB157AUS08T 
 
 
Version: 
Amendment 7  02/02/2017 
 
Amendment 6   03/03/2016  
 
Amendment 5  03/23/2015 
 
Amendment 4 2/17/2012 
 
Amendment 3 1/23/2012 
 
Amendment 2 1/12/2012 
 
Amendment 1 dated 12/15/2011 
 
Version 3, 10/5/11    
                                 
Version 2, 8/19/11 (Original draft:  02/25/2011) 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent 
necessary to obtain informed consent, may not be disclosed to another party unless law or regulations 
require such disclosure.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
 
 
 


 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
Principal Investigator: 
 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/EC procedures, instructions from Celgene representatives, 
the Declaration of Helsinki, ICH Good Clinical Practices guidelines, and 
the applicable parts of the United States Code of Federal Regulations or 
local regulations governing the conduct of clinical studies. 
 
 
 
 
 
 
 
 
 
 


 
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STUDY PERSONNEL 
 
Supporters: 
 
Celgene Corporation 
Novartis 
 
Study Location:  
 
H. Lee Moffitt Cancer Center & Research Institute 
Principal Investigator: 
 
Celeste Bello, MD  
Study Coordinator: 
 
 
Elyce Turba, RN 
 
 
 
 
 
 


 
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Table of Contents 
 
 
 
 
                                          Section 
Number 
Protocol Synopsis…………..……………………………………..……………….…………..….1 
Schedule of Study Assessments…………………………..………………………..………….….2 
Background and Rationale……………………………….…………………………………....….3 
3.1: Introduction: CLL/SLL 
 
3.2: Ofatumumab 
 
3.3: HDMP 
3.4: Lenalidomide 
3.5: Rationale for the combination regimen in CLL/SLL  
Study Objectives and End Points…………………………………………………………….…...4 
Investigational Plan……………………………………………………………………….………5 
 
5.1: Overall design 
5.2: Protocol Therapy 
 
5.3: Screening and eligibility 
 
5.4: Visit schedule and assessments 
 
5.5: Drug administration 
 
5.6: Concomitant therapy 
 
5.7: Discontinuation of study treatment 
 
5.8  Lenalidomide Maintenance Therapy (MT) 
 
5.9:  Follow-up 
Adverse Events……………………………………………………………….……………….…..6 
 
6.1: Adverse events reporting to Celgene Corporation 
 
6.2: Adverse events reporting to Novartis 
 
6.3: Report of adverse events to IRB 
 
6.4: Investigator reporting to FDA 
6.5: Adverse events updates/IND safety reports 
Response Criteria…………………………………………………………………………….……7 
Protocol Amendments and Deviations………………………………………………………….…8 
Data Management……………………………………………………………………………..…...9 
Biostatistical Considerations…..…………………………………………………………….…...10 
Regulatory Considerations………………………………………………………………..………11 
Appendices……………………………………………………………………………………..…12 


 
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A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods 
B: ECOG Performance Status 
C: Cockcroft-Gault Estimation of Creatinine Clearance (CrCl) 
D: Tumor Staging 
E: Criteria for Treatment 
F:  Response Criteria 
G: NCI CTC Version 4.0 
H: Cairo-Bishop Definition of Tumor Lysis Syndrome 
References……………………………………………………………………………………..….13 
 
 


 
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1  Protocol Synopsis 
PROTOCOL TITLE: Phase II Study of Ofatumumab in Combination with High Dose 
Methylprednisolone followed by Ofatumumab and Lenalidomide consolidative therapy 
for the treatment of Relapsed or Refractory CLL/SLL: The HiLOG trial. 
DATE PROTOCOL FINAL: 
June 20, 2011 
INDICATION: 
Relapsed or refractory CLL/SLL 
STUDY PHASE: 
Phase II 
BACKGROUND AND RATIONALE: Chronic lymphocytic leukemia (CLL), the most 
common leukemia in the Western countries, is characterized by a progressive 
accumulation of functionally incompetent monoclonal B lymphocytes. CLL is considered 
to be identical (same disease at different stages) to the mature B-cell small lymphocytic 
lymphoma (SLL).(1) CLL is typically considered a disease of the elderly, with a median 
age at diagnosis of 72 years.(2, 3) The disease remains non curable by current treatment 
options with the possible exception of allogeneic hematopoietic stem cell transplantation. 
In addition, the vast majority of patients diagnosed with CLL are older than 65 and many 
times have significant co-morbidities.  This makes it difficult for most patients with CLL 
to tolerate traditional chemotherapy regimens due to the associated toxicities.  A non-
chemotherapeutic regimen that provides high efficacy with less toxicity than 
conventional regimens would be desirable in this population. We are proposing a 
combination regimen consisting of high dose methylprednisolone combined with 
ofatumumab, followed by consolidative therapy with lenalidomide in combination with 
ofatumumab. (See Table 1 for dosing and details of treatment regimen). The rationale for 
exploring this combination regimen is based on the following previously published trials: 
 
Results of a phase II study combining Rituximab, an anti CD20 monoclonal antibody, 
with high dose methylprednisolone as a salvage regimen for the treatment of patients 
with fludarabine refractory CLL showed an overall response rate (ORR) of 93% with a 
complete remission rate (CR) of 36%. The regimen was well tolerated, and serious 
adverse events were rare. All patients were able to complete the scheduled treatment 
without delays or dosage reductions. (4) Another recent paper from the same group 


 
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showed similar efficacy in the front line setting using a reduced dose of steroids.  They 
showed an ORR of 96% with a CR rate of 32%. (5) 
 
Ofatumumab (Arzerra®) is a human monoclonal antibody that targets a unique small-
loop epitope on CD20 and elicits potent in vitro complement-dependent cytotoxicity, even 
in malignant B cells with low levels of CD20 expression. Ofatumumab is currently 
approved by the FDA for fludarabine and alemtuzumab refractory CLL.  It is also under 
development by Novartis for the treatment of untreated, relapsed or refractory B-cell 
follicular lymphoma, for the treatment of untreated CLL, for the treatment of active 
rheumatoid arthritis, and other autoimmune diseases. 
 
Ofatumumab has been studied in patients with fludarabine and alemtuzumab refractory 
CLL (FA-ref) or refractory to fludarabine with bulky (>5cm) lymphadenopathy (BF-ref). 
(6) Ofatumumab was given weekly x 8 doses followed by monthly infusions x 4. Results 
of a planned interim analysis included 138 treated patients with FA-ref (n = 59) and BF-
ref (n = 79) CLL. The overall response rates (primary end point) were 58% [corrected] 
and 47% in the FA-ref and BF-ref groups, respectively. Complete resolution of 
constitutional symptoms and improved performance status occurred in 57% and 48% of 
patients, respectively. Median progression-free survival and overall survival times were 
5.7 and 13.7 months in the FA-ref group, respectively, and 5.9 and 15.4 months in the 
BF-ref group, respectively. The most common adverse events during treatment were 
infusion reactions and infections, which were primarily, grade 1 or 2 events. Hematologic 
events during treatment included anemia and neutropenia. These encouraging results in 
patients with refractory CLL warrant further investigation of ofatumumab in combination 
with other agents, and as maintenance for the treatment of patients with CLL.  
 
Lenalidomide is a novel immunomodulating anticancer agent that was designed to 
enhance immunologic and anticancer properties while potentially decreasing neurotoxic 
and teratogenic adverse effects of the parent compound thalidomide. Its exact antitumor 
mechanism remains elusive. However, its antitumor activity seems to be mediated 
through its ability to modulate production of various key survival cytokines such as TNF-


 
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α, IL-6, IL-8 and VEGF in the tumor microenvironment. Lenalidomide has also been 
shown to affect other components of the tumor microenvironment, including the immune 
cellular compartment. Preclinical studies demonstrated that lenalidomide enhances NK-
cell mediated and monocyte-mediated tumor cell ADCC for a variety of rituximab treated 
NHL cell lines in vitro. (7) A Phase II trial of single agent lenalidomide in patients with 
relapsed or refractory CLL revealed an ORR of 47% with a CR rate of 9%. (8) Another 
phase II trial of single agent lenalidomide for the treatment of relapsed or refractory CLL 
revealed an ORR of 32% with 7% CR, 25% stable disease. The most common toxicity 
was myelosuppression, and the median daily dose of lenalidomide tolerated was 10 mg. 
(9) More recently two combination trials of lenalidomide and rituximab have been 
reported in abstract form from our center (10) and the MDACC. (11) Both of these studies 
evaluated patients with relapsed disease and showed an overall response rate of 60%. 
 
Our hypothesis is that ofatumumab will produce higher rates of CR in this setting. The 
consolidation with lenalidomide is based on the fact that this drug has activity in CLL but 
is not immunosuppressive. In addition, there is evidence that lenalidomide can improve 
the immune system of patients with CLL as well as increase the rates of CR in this 
population. The reason for incorporating lenalidomide after debulking patients with high 
dose steroids and ofatumumab is based on the experience with lenalidomide as a single 
agent in the relapsed and front line setting.  In this setting tumor lysis syndrome and 
tumor flare were observed. We believe that this sequence of drugs will carry less toxicity 
and will be better tolerated.  
 
Table 1. HiLOG Clinical Study Dosing Schema 
Week 
Study Day 
HDMP 
Ofatumumab 
Lenalidomide 
1 
Cycle 1 Day 1 
1000 mg/m2 
300 mg 
 
2 
Cycle 1 Day 8 
1000 mg/m2 
2000 mg 
 
3 
Cycle 1 Day 15 
1000 mg/m2 
2000 mg 
 
4 
Cycle 1 Day 22 
1000 mg/m2 
2000 mg 
 
5 
Cycle 2 Day 1 
1000 mg/m2 
2000 mg 
 
6 
Cycle 2 Day 8 
 
 
 
7 
Cycle 2 Day 15 
1000 mg/m2 
2000 mg 
 
8 
Cycle 2 Day 22 
 
 
 
9 
Cycle 3 Day 1 
1000 mg/m2 
2000 mg 
 
10 
Cycle 3 Day 8 
 
 
 


 
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11 
Cycle 3 Day 15 
1000 mg/m2 
2000 mg 
 
12 
Cycle 3 Day 22 
 
 
 
Response assessment (BM with four color flow and CT scans) 
13 
Cycle 4 Day 1 
 
 
5-10 mg pd Days 1-
28 as per Cr Cl 
17 
Cycle 5 Day 1 
 
 
5-10 mg pd Days 1-
28 as per Cr Cl 
21 
Cycle 6 Day 1 
 
2000 mg 
5-10 mg pd Days 1-
28 as per Cr Cl 
25 
Cycle 7 Day 1 
 
 
5-10 mg pd Days 1-
28 as per Cr Cl 
29 
Cycle 8 Day 1 
 
2000 mg 
5-10 mg pd Days 1-
28 as per Cr Cl 
33 
Cycle 9 Day 1 
 
 
5-10 mg pd Days 1-
28 as per Cr Cl 
37 
Cycle 10 Day 1 
 
2000 mg 
5-10 mg pd Days 1-
28 as per Cr Cl 
41 
Cycle 11 Day 1 
 
 
5-10 mg pd Days 1-
28 as per Cr Cl 
45 
Cycle 12 Day 1 
 
2000 mg 
5-10 mg pd Days 1-
28 as per Cr Cl 
Response assessment (BM with four color flow and CT scans) 
STUDY OBJECTIVES: 
Primary:   
1. To estimate the objective response rate for the combination of ofatumumab with 
high dose methylprednisolone followed by consolidative therapy with 
lenalidomide and ofatumumab for patients with relapsed or refractory (relapse 
within six months of completion of or failure to respond to current treatment) 
CLL/SLL. 
  
Secondary:   
      To collect preliminary efficacy data on: 
1. Progression/relapse free survival. 
2. Overall survival. 
 


 
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STUDY DESIGN: 
This is a phase II, single institution, and non-randomized study of patients with relapsed 
or refractory CLL/SLL, utilizing a two-stage trial design. The primary endpoint for this 
trial is the combined complete and partial response rate (at 3 months, after the end of 
cycle 3) to the protocol therapy. We anticipate this trial will have a CR+PR response rate 
of at least 55%.  
 
A two-stage design is employed for this trial. The null/unacceptable CR+PR response 
rate is ≤35% while the anticipated true response rate to the protocol treatment is at least 
55% for each disease cohort. At the first stage, 25 patients will be accrued to the trial. If 9 
or fewer of these patients respond, then the trial will be terminated early and the response 
rate to the protocol treatment will be deemed unacceptable (≤35%). Otherwise, if more 
than 9 patients respond during the first stage, an additional 31 patients will be enrolled to 
this trial during stage 2 for a total of 56 patients. If 25 or fewer of these 56 patients 
respond to the protocol treatment at the end of stage 2, no further investigation of the 
protocol treatment is considered warranted. On the other hand, if more than 25 patients 
out of the 56 enrolled patients respond, the protocol treatment will be considered 
promising. If the true response rate is ≤35%, the probability of ending the trial at stage 1 
is 0.63. If, however, the true response rate is at least 55%, then the probability of ending 
the trial at stage 1 is only 0.04. This two-stage design has an overall alpha level of 0.047 
and a power of 0.90. 
 
For the purpose of interim analysis at the end of stage 1, the objective response will be 
measured by the end of 3 months (or end of cycle 3) from the start of the protocol 
treatment prior to the initiation of the combination of ofatumumab with lenalidomide. 
The accrual will not be suspended while waiting for the results of the interim analysis 
unless the observed objective response rate among those patients whose objective 
response data are available is below 30%. 


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2 Schedule of Study Assessments *  
All visits/assessments may be scheduled + 3 business days 
 
 
Procedure 
1.1.1.1.1. 
Screening 
12 
 28 days from 
Baseline (First day 
drug administration) 
 
 
Cycle 
1  
 
 
 
Cycles 
2 - 3   
 
 
Cycle 4 13 
 
Cycles 
5-12 
Lenalidomide 
Maintenance 
Therapy 
 
Discontinuation 
From Protocol 
Therapy 15 
Follow-
Up 
Phase 
 
Days 
1, 8, 
15, 
and 22 
Days 
1, and 
15 
Day 
1 
 
Day 3 or 4 
1.1.1.1.2. 
At 
in
ve
sti
ga
to
r 
di
sc
re
ti
on 
See footnote 6 
Day 
8 
Day 
15 
Day 
22 
Day 1 
and 
15 
Labs 
 
Every 
3 
months 
Study drug administration** 
 
X 
X 
X 
 
 
 
 
X 
X 
 
 
Record prior medications, 
treatments 
X 
 
 
 
 
 
 
 
 
 
 
 
Record prior anti-cancer 
therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital 
signs, weight 
X 
X10 
X 10 
X10 
 
 
 
 
X 
 
 
X 
ECOG performance status 
X 
X10 
X 10 
X10 
 
 
 
 
X 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
Assess lymphadenopathy, spleen 
/ liver1 
 
X 1 
X 1 
X1 
 
X1 
X1 
 
X1 
 
 
 
Peripheral blood for FISH, ZAP 
70, -2 microglobulin, and 
IgHV, research samplesa, 
mutational status2 
X 
 
 
X 
 
 
 
 
 
 
 
 
Baseline lesion assessment 
X 
 
 
X 
 
 
 
 
 
 
 
 
Bone marrow3 
X 
 
 
X 
 
 
 
 
X 
X 
 
X3 


 
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CT of the neck, chest, abdomen 
& pelvis4 
X 
 
 
X 
 
 
 
 
X 
X 
 
X4 
Hematology5 
X 
X 
X 
X5 
 
X5 
X5 
X5 
X5 
X 14 
 
X 
Serum chemistry6 
X 
X 
X 
X6 
X6 
X6 
X6 
X6 
X6 
X 14 
 
X 
Hepatitis B and C serology, 
HBV DNA PCR7 
X7 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing8  
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
Register patient into RevAssist® 
program 11 
X 
 
 
 
 
 
 
 
 
 
 
 
Prescribe lenalidomide via 
RevAssist® 11 
 
 
 
X 
 
 
 
 
X 
 
 
 
Record adverse events9 
 
X 
X 
X 
 
 
 
 
X 
X 14 
 
 
Record concomitant 
therapies/procedures 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
Obtain Follow-Up anti-cancer 
treatments 
 
 
 
 
 
 
 
 
 
 
 
X 
Obtain Follow-Up survival 
information 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* An unscheduled visit can occur at any time during the study.  Source must be maintained for these unscheduled visits. The date for the visit and any data generated must 
be recorded on the appropriate CRF.  Source documents for these unscheduled visits must also be maintained.   
** See Table 1 for detailed study drug administration schedule. 
1 Physical examination of lymphadenopathy, the spleen and liver will be performed on Days 1,and 15 of Cycle 1 to access for tumor flare reaction, and on Day 1 of 
subsequent cycles to assess response. 
2 Peripheral blood for FISH, ZAP 70, IgVH mutational status, beta-2 microglobulin analyses and research samples for storage will be drawn during screening, day 1 of 
Cycle 4, and end of treatment.   
3 Bone marrow studies will be performed for all subjects at baseline at the end of cycle 3 (day 21-28 prior to Cycle 4) and after completion of cycle 12.  During 
lenalidomide maintenance therapy it will be done every 6 months  for two years. Bone marrow studies at any other time point will be performed at the discretion of the 
treating physician. 
4 CT of the neck, chest, abdomen & pelvis will be performed for response assessment at the end of cycle 3 (day 21-28 prior to cycle 4), after the end of cycle 12 (7-10 
days after discontinuation of  lenalidomide) and every 6 months for two years during lenalidomide maintenance therapy. At any other time point, CT scans will be 
performed at the discretion of the treating physician. 5 Hematology – CBC with differential WBC and platelet counts.  Hematology profiles are required weekly during 
Cycle 4 (which corresponds to Cycle 1 of lenalidomide-containing therapy), and during any cycle in which the dose of lenalidomide is escalated or re-escalated.  For 
subjects who are on a stable lenalidomide dose (without dose escalation or interruption of the planned dosing schedule) for ≥ 1 cycle of treatment, hematology profiles are 
required on Days 1 and 15 of the cycle. 
6 Chemistry includes sodium, potassium, chloride, CO2, calcium, magnesium, phosphorus, BUN, creatinine, glucose, albumin, total protein, alkaline phosphatase, total 
bilirubin, AST/SGOT, ALT/SGPT, LDH, and uric acid.  At a minimum, for tumor lysis syndrome (TLS) monitoring purposes, subjects will have chemistry assessments 
weekly during at least the first 2 cycles of lenalidomide-containing treatment. Chemistry assessments  on Day 3 or 4 of Cycle 1 of lenalidomide-containing treatment are 
at the investigator’s discretion.  In addition, because the risk for TLS may be elevated when lenalidomide is re-started after treatment interruptions or when the 
lenalidomide dose is escalated, in any cycle in which the lenalidomide dose is escalated or re-escalated or treatment is interrupted for more than 1 week, subjects will have 


 
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weekly chemistry assessments performed for at least 4 consecutive weeks as well as an additional chemistry assessment on day 3 or 4 during the first week of escalating, 
re-escalating or re-initiating lenalidomide therapy.  If TLS occurs, subjects will have additional chemistry assessments weekly for at least 4 consecutive weeks as well as 
on Day 3 or Day 4 following re-initiation of lenalidomide.  For subjects who do not experience any abnormalities in serum chemistry assessments for 2 consecutive cycles 
while on a stable lenalidomide dose (without dose escalation or interruption of the planned dosing schedule) throughout these 2 cycles, the timing of chemistry 
assessments may be reduced to Day 1 and Day 15 in subsequent cycles.  See section 5.6.1.1 for TLS prophylaxis instructions.  To include Thyroid Stimulating Hormone 
(TSH) at Screening, at treatment discontinuation, and whenever clinically indicated.  T3 and T4 levels may be assessed as clinically indicated. 
7 Hepatitis B Virus DNA by PCR will be tested at screening.  If it is positive then it will be tested every 2 weeks during cycle1, every 4 weeks during cycles 2 ad 3, and 
then every 2 to 3 months thereafter. 
8 Pregnancy test for females of childbearing potential.  A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy 
or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 
consecutive months).  Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled 
within 7 days).  FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on lenalidomide therapy 
(including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide.  Females with irregular menstruation must have a 
pregnancy test weekly for the first 28 days and then every 14 days while on lenalidomide therapy (including breaks in therapy), at discontinuation of lenalidomide and at 
Day 14 and Day 28 post the last dose of lenalidomide (see Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).    
9An additional safety assessment will be done 28 days (+/- 2 days) following the last dose of protocol therapy. 
10 If physical examination, vital signs, weight and ECOG performance status were done within 7 days of Day 1, they do not need to be repeated on Day 1. 
11 Lenalidomide must be prescribed through and in compliance with the RevAssist® program of Celgene Corporation.  Prescriptions must be filled within 7 days.  
Consideration should be given to prescribing lenalidomide 5 to 7 days in advance of Day 1 of each cycle to allow time for required patient and prescriber surveys, and 
drug shipment to patient.  Any unused Revlimid® (lenalidomide) should be returned to the patient for disposition in accordance with the RevAssist® program. 
12 Any required screening  tests that have been performed as standard of care prior to consent and are within 28 days of starting study treatment may be used for screening 
and do not need to be repeated. A bone marrow biopsy performed within 6 weeks of starting study treatment does not need to be repeated during screening.  
13 Cycle 4 may begin up to 14 days after cycle 3 bone marrow biopsy to allow for results of response assessments to be available. 
14 CBC and CMP only every 4 weeks. See Section 5.8. Any grade 3 or 4 cytopenia will be recorded as an adverse event during Maintenance Therapy.  No other adverse 
events will be recorded during Maintenance Therapy 
15 Upon discontinuation of study therapy, any diagnostic testing will be at the discretion of the physician.  
 
 
 


 
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3 
Background and Rationale 
3.1 
Introduction: Chronic lymphocytic leukemia / Small lymphocytic lymphoma 
Chronic lymphocytic leukemia (CLL), a monoclonal B-cell malignancy with a low level 
of proliferation, is characterized by a progressive accumulation of mature-appearing but 
functionally incompetent, malignant B lymphocytes. CLL is the most common form of 
leukemia diagnosed in the Western countries. (1) It accounts for over 15,000 new 
diagnoses (almost 40% of all leukemias) and over 4,000 deaths per year in the United 
States. CLL is a disease of the elderly with a median age at diagnosis of 72 years and 
more than two-thirds of patients are over 65 years of age. (2, 3) 
 
The cells are characterized by having mature B-cell markers such as CD19, CD20, and 
CD22 but also express CD5 which is a T-cell marker. (2) The spectrum of this disease 
varies from a simple lymphocytosis to splenomegaly and/or cytopenias.  Some patients 
have an indolent course while others have a more accelerated course.  In either case, the 
disease relapses frequently once treatment is initiated, and there is considerable morbidity 
from the disease and the treatments themselves. (12) 
 
Several predictive factors have been identified in CLL In addition to clinical staging, 
traditional prognostic factors for identifying high risk of disease progression have 
included elevated serum levels of beta-2 microglobulin, soluble CD23, diffuse bone 
marrow infiltration, short lymphocyte doubling time, and high levels of zeta-associated 
protein (ZAP-70) on the surface of malignant cells. (13, 14) More recently, the presence of 
certain cytogenetic abnormalities identified by fluorescence in situ hybridization (FISH) 
analysis and mutational status of immunoglobulin heavy chain (IgHV) have become a 
more meaningful predictor of disease progression and duration of response to therapy. (15) 
 
CLL remains non curable by current treatment options with the possible exception of 
allogeneic hematopoietic stem cell transplantation. Previously, when the need for 
treatment was established, chlorambucil with or without corticosteroids was often used as 
first line treatment and purine analogues such as fludarabine as second line treatment. 


 
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However, first line treatment in most centers is either fludarabine combined with 
cyclophosphamide or these 2 compounds combined with rituximab. Other treatment 
options include combination chemotherapy or alemtuzumab. Previously, rituximab has 
been administered as monotherapy, but due to the low response rates this treatment is 
now abandoned. Despite having a first line combination regimen of fludarabine, 
cyclophosphamide and rituximab with an excellent complete response rate of 44%, these 
patients do relapse and require further treatments. Patients without a complete response 
also progress and require further therapy. Considering that the vast majority of patients 
diagnosed with CLL are older than 65 years of age, there is a need to search for a non-
chemotherapeutic regimen that provides high efficacy with less toxicity than 
conventional regimens. We are proposing a combination regimen consisting of high dose 
methylprednisolone combined with ofatumumab, followed by consolidative therapy with 
lenalidomide in combination with ofatumumab (See Section 1 Table 1 for dosing schema 
and details of regimen). 
3.2 
Ofatumumab 
Ofatumumab (Arzerra®) is a human monoclonal antibody that targets a unique small-
loop epitope on CD20 and elicits potent in vitro complement-dependent cytotoxicity, even 
in malignant B cells with low levels of CD20 expression. Ofatumumab is currently 
approved by the FDA for fludarabine and alemtuzumab refractory CLL. It is also under 
development by Novartis for the treatment of untreated, relapsed or refractory B-cell 
follicular lymphoma, for the treatment of untreated CLL, for the treatment of active 
rheumatoid arthritis, and other autoimmune diseases. 
3.2.1 Ofatumumab Indications 
Ofatumumab was approved by the FDA on October 27th, 2009 for the treatment of 
patients with CLL whose cancer is no longer being controlled by other forms of 
chemotherapy. It has also shown potential in treating follicular non-Hodgkin’s lymphoma 
(FL), diffuse large B cell lymphoma, rheumatoid arthritis (RA) and relapsing remitting 
multiple sclerosis. 


 
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3.2.2 Ofatumumab Adverse Events  
During clinical trials of ofatumumab in FL, CLL and RA subjects, adverse events 
occurring during the infusions of trial drug have been reported. The following reactions 
should be regarded as expected infusion-related adverse reactions in connection with the 
use of ofatumumab probably as a consequence of B cell depletion and cytokine release: 
pruritus, dyspnea, bronchospasm, throat irritation, cough, pharyngolaryngeal pain, 
flushing, 
hyperhidrosis, 
nausea 
and 
vomiting, 
abdominal 
pain, 
hypotension, 
rash/urticaria, influenza-like-illness, fatigue, fever, chills, headache, dizziness, myalgia 
and arthralgia.  
 
The incidence of infusion-related symptoms was highest during the first infusion and 
decreased substantially with subsequent infusions. Implementation of pre-medication 
before infusions has reduced the number as well as the severity of infusion related 
adverse events. One serious case of cytokine release complicated with laryngeal edema 
and one case of anaphylactoid-like reaction have been observed; both events were fully 
reversible after cessation of the infusion and proper treatment. It should be noted that 
none of these subjects received premedication with prednisolone. 
 
During the ongoing study in subjects with CLL refractory to alemtuzumab and 
fludarabine, infusion related adverse events have been reported in approximately 30% of 
subjects. Only 2-3 % were serious adverse events. All subjects received pre-medication 
with prednisolone, acetaminophen and antihistamine. In the completed CLL trial 402 in 
patients with relapsed or refractory CLL, 15% of the subjects had serious infections. In 
the ongoing CLL 406 trial in subjects refractory to both alemtuzumab and fludarabine an 
increased frequency of serious infections (25-30%) have been reported.  
 
One case of Progressive Multifocal Leukoencephalopathy (PML) has been reported in a 
very ill CLL subject previously treated with alemtuzumab and fludarabine and with a 
very low CD4 cell count. Leukopenia, including neutropenia, anemia, and 
thrombocytopenia have been reported in CLL subjects. These events are most likely 


 
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related to the patients’ baseline disease; however, a causal relationship to ofatumumab 
cannot be excluded. 
3.3 
High Dose Methylprednisolone 
Methylprednisolone is a corticosteroid that has been on the market for several years and 
is available in generic form. 
 
Results of a phase II study combining Rituximab, an anti CD20 monoclonal antibody, 
with high dose methylprednisolone as salvage regimen for the treatment of patient with 
fludarabine refractory CLL showed an overall response rate (ORR) of 93% with a 
complete remission rate (CR) of 36%. The regimen was well tolerated and serious 
adverse events were rare. All patients were able to complete the scheduled treatment 
without delays or dosage reductions. (4) Another recent paper from the same group 
showed a similar efficacy in the front line setting using a reduced dose of steroids.  They 
showed an ORR of 96% with a CR rate of 32%. (5)  
 
3.3.1 Methylprednisolone Adverse Effects 
The following adverse events have been reported with the use of methylprednisolone and 
are common to most corticosteroids: arrhythmias, bradycardia, cardiac arrest, 
cardiomegaly, circulatory collapse, congestive heart failure, edema, fat embolism, 
hypertension in premature infants, myocardial rupture (post MI), syncope, tachycardia, 
thromboembolism, vasculitis, delirium, depression, emotional instability, euphoria, 
hallucinations, headache, intracranial pressure increased, insomnia, malaise, mood 
swings, nervousness, neuritis, personality changes, psychic disorders, pseudotumor 
cerebri (usually following discontinuation), seizure, vertigo, acne, allergic dermatitis, 
alopecia, 
dry 
scaly 
skin, 
ecchymoses, 
edema, 
erythema, 
hirsutism, 
hyper-
/hypopigmentation, hypertrichosis, impaired wound healing, petechiae, rash, skin 
atrophy, sterile abscess, skin test reaction impaired, striae, urticaria, adrenal suppression, 
amenorrhea, carbohydrate intolerance increased, Cushing's syndrome, diabetes mellitus, 
fluid retention, glucose intolerance, hyperglycemia, hyperlipidemia, hypokalemia, 
hypokalemic alkalosis, menstrual irregularities, negative nitrogen balance, pituitary-


 
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adrenal axis suppression, protein catabolism, sodium and water retention, abdominal 
distention, appetite increased, gastrointestinal hemorrhage, gastrointestinal perforation, 
nausea, pancreatitis, peptic ulcer, perforation of the small and large intestine, ulcerative 
esophagitis, vomiting, weight gain, leukocytosis (transient), hepatomegaly, increased 
transaminases, arthralgia, arthropathy, aseptic necrosis (femoral and humoral heads), 
fractures, muscle mass loss, muscle weakness, myopathy (particularly in conjunction 
with 
neuromuscular 
disease 
or 
neuromuscular-blocking 
agents), 
neuropathy, 
osteoporosis, parasthesia, tendon rupture, vertebral compression fractures, weakness, 
cataracts, exophthalmoses, glaucoma, intraocular pressure increased, glycosuria, 
pulmonary edema, abnormal fat disposition, anaphylactoid reaction, anaphylaxis, 
angioedema, avascular necrosis, diaphoresis, hiccups, hypersensitivity reactions, 
infections, secondary malignancy  
 
3.4 Lenalidomide 
Lenalidomide (Revlimid®) is a proprietary IMiD® compound of Celgene Corporation.  
IMiD® compounds have both immunomodulatory and anti-angiogenic properties which 
could confer antitumor and antimetastatic effects.  Lenalidomide has been demonstrated 
to possess anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-α 
induced endothelial cell migration, due at least in part to inhibition of Akt 
phosphorylation response to bFGF (16).  In addition, lenalidomide has a variety of 
immunomodulatory effects.  Lenalidomide stimulates T cell proliferation, stimulates the 
production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6, and modulates 
IL-12 production.(17) Up regulation of T cell derived IL-2 production is achieved at least 
in part through increased AP-1 activity. (18) 
Although the exact antitumor mechanism of action of lenalidomide is unknown, a 
number of mechanisms are postulated to be responsible for lenalidomide’s activity 
against multiple myeloma.  Lenalidomide has been shown to increase T cell proliferation, 
which leads to an increase in IL-2 and IFN-γ secretion.  The increased level of these 
circulating cytokines augment natural killer cell number and function, and enhance 
natural killer cell activity to yield an increase in multiple myeloma cell lysis. (19)  In 


 
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addition, lenalidomide has direct activity against multiple myeloma and induces 
apoptosis or G1growth arrest in multiple myeloma cell lines and in multiple myeloma 
cells of patients resistant to melphalan, doxorubicin and dexamethasone.  (20) 
Lenalidomide Indications and Usage: 
 Lenalidomide is indicated for the treatment of patients with transfusion-dependent 
anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a 
deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.  
Revlimid® is also approved in combination with dexamethasone for the treatment of 
patients with multiple myeloma that have received at least one prior therapy.  
Lenalidomide Adverse Events 
Most frequently reported adverse events reported during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of presumed 
relationship to study medication include: anemia, neutropenia, thrombocytopenia and 
pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, rash, itching, 
infections, sepsis, pneumonia, UTI, upper respiratory infection, atrial fibrillation, 
congestive heart failure, myocardial infarction, chest pain, weakness, hypotension, 
hypercalcemia, hyperglycemia, back pain, bone pain, generalized pain, dizziness, mental 
status changes, syncope, renal failure, dyspnea, pleural effusion, pulmonary embolism, 
deep vein thrombosis, CVA, convulsions, dizziness, spinal cord compression, syncope, 
disease progression, death not specified and fractures.  Tumor flare reactions (TFR) have 
been reported frequently in CLL patients treated with lenalidomide.  Tumor lysis 
syndrome (TLS) has been reported in CLL patients treated with lenalidomide.  
Precautions must be taken to prevent TLS including proper selection of patients with 
regard to renal function, correction of electrolyte abnormalities, and TLS prophylaxis and 
monitoring. 
Complete and updated adverse events are available in the Investigational Drug Brochure 
and the IND Safety Letters. 


 
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3.5  Rationale for Combination Regimen in CLL/SLL 
The rationale for exploring this combination regimen is based on the following 
previously published trials. Results of a phase II study combining Rituximab, an anti 
CD20 monoclonal antibody, with high dose methylprednisolone as salvage regimen for 
the treatment of patient with fludarabine refractory CLL showed an overall response rate 
(ORR) of 93% with a complete remission rate (CR) of 36%. The regimen was well 
tolerated and serious adverse events were rare. All patients were able to complete the 
scheduled treatment without delays or dosage reductions. (4)  
 
Ofatumumab single agent has been studied in patients with fludarabine and alemtuzumab 
refractory CLL (FA-ref) or refractory to fludarabine with bulky (>5cm) lymphadenopathy 
(BF-ref). (6) Ofatumumab was given weekly x 8 doses followed by monthly infusions x 4. 
Results of a planned interim analysis included 138 treated patients with FA-ref (n = 59) 
and BF-ref (n = 79) CLL. The overall response rates (primary end point) were 58% 
[corrected] and 47% in the FA-ref and BF-ref groups, respectively. Complete resolution 
of constitutional symptoms and improved performance status occurred in 57% and 48% 
of patients, respectively. Median progression-free survival and overall survival times 
were 5.7 and 13.7 months in the FA-ref group, respectively, and 5.9 and 15.4 months in 
the BF-ref group, respectively. The most common adverse events during treatment were 
infusion reactions and infections, which were primarily, grade 1 or 2 events. Hematologic 
events during treatment included anemia and neutropenia. These encouraging results in 
patients with refractory CLL warrant further investigation of ofatumumab in combination 
with other agents and as maintenance for the treatment of patients with CLL.  
 
 
A Phase II trial of single agent lenalidomide in patients with relapsed or refractory CLL 
revealed an ORR of 47% with a CR rate of 9%. (8) Another phase II trial of single agent 
lenalidomide for the treatment of relapsed or refractory CLL revealed an ORR of 32% 
with 7% CR, 25% stable disease. The most common toxicity was myelosuppression, and 
the median daily dose of lenalidomide tolerated was 10 mg. (9) More recently two 
combination trials of lenalidomide and rituximab have been reported in abstract form 


 
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from our center (10) and MDACC.(11) Both these studies evaluated patients in the relapsed 
setting and had an overall response rate of 60%.  
 
Our hypothesis is that ofatumumab will produce higher rates of CR when combined with 
lenalidomide and high dose steroids. The consolidation with lenalidomide is based on the 
fact that this drug has activity in CLL but is not immunosuppressive. In addition, there is 
evidence that lenalidomide can improve the immune system of patients with CLL as well 
as increase the rates of CR in this population. The reason for incorporating lenalidomide 
after debulking patients with high dose steroids and ofatumumab is based on the 
experience with lenalidomide as a single agent in the relapsed and front line setting.  In 
this setting tumor lysis syndrome and tumor flare were observed. We believe that this 
sequence of drugs will carry less toxicity and will be better tolerated.    
4 Study Objectives and Endpoints 
4.1 Objectives 
4.1.1 Primary objective 
 To estimate the response rate for the combination of ofatumumab with high dose 
methylprednisolone followed by consolidative therapy with lenalidomide and 
ofatumumab for patients with relapsed or refractory CLL/SLL. 
 
 


 
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4.1.2 Secondary study objective 
      To collect preliminary efficacy data on: 
 Progression/relapse free survival. 
 
Overall survival. 
4.2 Endpoints 
4.2.1 Primary Endpoint 
 Objective response (CR+PR) rate 
4.2.2 Secondary Endpoints 
 Progression/relapse free survival. 
 
Overall survival. 
5 
Investigational Plan 
5.1 
Overall design 
This is a phase II study, single institution, non randomized study involving patients with 
relapsed or refractory CLL/SLL receiving a combination treatment of ofatumumab and 
high dose methylprednisolone, followed by ofatumumab and lenalidomide consolidative 
therapy. 
The study has 2 stages (see study schema in section 1).  Stage 1 is an induction phase and 
incorporates cycles 1-3 (see table1 for drug dosing).  Stage 2 is a consolidation phase and 
incorporates cycles 4-12.  After stage 1 (cycle 3) all patients will be assessed for response 
(see section 7, Response criteria).  Patients with a CR, PR, or SD will then proceed to the 
2nd stage of treatment (cycles 4-12).  Patients will then be reassessed at the end of 
treatment.   
 


 
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5.2 
Protocol Therapy  
5.2.1 Lenalidomide  
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent 
with anti-angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -
2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:  
Chemical Structure of Lenalidomide 
 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3.  
Lenalidomide is off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in 
organic solvents and low pH solutions. Solubility was significantly lower in less acidic 
buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon 
atom and can exist as the optically active forms S(-) and R(+), and is produced as a 
racemic mixture with a net optical rotation of zero. 
5.2.1.1 Clinical Pharmacology 
Mechanism of Action:  
The mechanism of action of lenalidomide remains to be fully characterized. 
Lenalidomide 
possesses 
immunomodulatory 
and 
antiangiogenic 
properties.  
Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the 
secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells.  
Lenalidomide inhibited cell proliferation with varying effectiveness (IC50s) in some but 
not all cell lines.  Of cell lines tested, lenalidomide was effective in inhibiting growth of 
Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) 
N
N
H
O
O
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but was much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell 
line, also with a deletion of one chromosome 5) and other cell lines without chromosome 
5 deletions.  Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) but not 
COX-1 in vitro.   
5.2.1.2 Pharmacokinetics and Drug Metabolism: 
Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration 
with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. 
Co-administration with food does not alter the extent of absorption (AUC) but does 
reduce the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic 
disposition of lenalidomide is linear. Cmax and AUC increase proportionately with 
increases in dose. Multiple dosing at the recommended dose-regimen does not result in 
drug accumulation. 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the 
phase I studies.  Absorption was found to be rapid on both Day 1 and Day 28 with time to 
maximum blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 
25mg, and 50mg).  No plasma accumulation was observed with multiple daily dosing.  
Plasma lenalidomide declined in a monophasic manner with elimination half-life ranging 
from 2.8 to 6.1 hours on both Day 1 and 28 at all 4 doses.  Peak and overall plasma 
concentrations were dose proportional over the dosing range of 5mg to 50mg.  Exposure 
(AUC) in multiple myeloma patients is 57% higher than in healthy male volunteers.  
Pharmacokinetic Parameters: 
Distribution: 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
 
 


 
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Metabolism and Excretion: 
The metabolic profile of lenalidomide in humans has not been studied. In healthy 
volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through 
urinary excretion. The process exceeds the glomerular filtration rate and therefore is 
partially or entirely active.  Half-life of elimination is approximately 3 hours.  
5.2.1.3 
Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no 
charge through the RevAssist® program.   
5.2.1.4 
Dosage form 
Lenalidomide will be supplied as capsules for oral administration.   
5.2.1.5 
Packaging 
Lenalidomide will be shipped directly to patients.   Bottles will contain a sufficient 
number of capsules for one cycle of dosing.    
5.2.1.6 
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold.     


 
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5.2.1.7 
Prescribing Information  
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide 
will be provided in accordance with the RevAssist® program of Celgene Corporation.  
Per standard RevAssist® requirements all physicians who prescribe lenalidomide for 
research subjects enrolled into this trial, and all research subjects enrolled into this trial, 
must be registered in and must comply with all requirements of the RevAssist® program.  
Prescriptions must be filled within 7 days.  Only enough lenalidomide for one cycle of 
therapy will be supplied to the patient each cycle. 
5.2.2 Ofatumumab  
Ofatumumab (ARZERRA) is an IgG1ĸ human monoclonal antibody (mAb) that 
specifically recognizes epitopes on the human CD20 molecule on B cells. The antibody is 
generated via transgenic mouse and hybridoma technology and produced in a 
recombinant murine cell line (NS0) using standard mammalian cell cultivation and 
purification technologies.  
 
Ofatumumab represents a novel anti-CD20 mAb, as it binds to a CD20 epitope distinct 
from the epitope recognized by rituximab. Ofatumumab is superior in CDC and its ability 
to kill rituximab resistant tumors as compared to rituximab. Based on the data from the 
non-clinical investigations of ofatumumab it is suggested that ofatumumab may deplete B 
cells for a longer period of time than rituximab, which may lead to a longer duration of 
treatment response and could potentially result in less dose needed. Ofatumumab is a 
human mAb with an anticipated very low immunogenicity. Therefore, subjects are not 
expected to produce human anti-human antibodies (HAHA) to the same degree as to the 
human anti-chimeric antibodies (HACA) seen in some subjects following rituximab 
treatment. 
 
 


 
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5.2.2.2 
Clinical Pharmacology 
Mechanism of Action: 
Ofatumumab binds specifically to epitopes which encompass the amino acid residues 163 
and 166 in the second extracellular loop of CD20. Ofatumumab induces cross linking of 
CD20 molecules and relocation of these CD20 molecules to the so-called lipid rafts. The 
translocation of CD20 into lipid rafts is considered important for induction of cell 
signaling and more effective complement activation. Differences in antibody function 
between various anti-CD20 antibodies might be explained by their distinct ability to 
induce relocation of the CD20 molecules within the lipid rafts. The binding of 
ofatumumab induces cell death, primarily through CDC and ADCC and not by apoptosis. 
Thus, depletion of B cells by ofatumumab treatment may provide clinical benefits to 
subjects with CD20-expressing cell tumors. In the treatment of FL and CLL, the goal is 
to achieve a complete B-cell depletion in blood and to induce an objective tumor 
response in lymph nodes.  
 
In patients with CLL refractory to fludarabine and alemtuzumab, the median decrease in 
circulating CD19-positive B cells was 91% (n = 50) with the 8
th infusion and 85% (n = 
32) with the 12
th 
infusion. The time to recovery of lymphocytes to normal levels has not 
been determined. 
5.2.2.2 Pharmacokinetic and Drug Metabolism  
Pharmacokinetic data were obtained from 146 patients with refractory CLL who received 
a 300-mg initial dose followed by 7 weekly and 4 monthly infusions of 2,000 mg. The 
C
max and AUC
(0-∞) after the 8
th 
infusion in Study 1 were approximately 40% and 60% 
higher than after the 4
th 
infusion in Study 2. The mean volume of distribution at steady-
state (V
ss) values ranged from 1.7 to 5.1 L.  
 
Ofatumumab is eliminated through both a target-independent route and a B cell-mediated 
route. Ofatumumab exhibited dose-dependent clearance in the dose range of 100 to 2,000 
mg. Due to the depletion of B cells, the clearance of ofatumumab decreased substantially 


 
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after subsequent infusions compared to the first infusion. The mean clearance between 
the 4
th 
and 12
th 
infusions was approximately 0.01 L/hr and exhibited large inter-subject 
variability with CV% greater than 50%. The mean t
1/2 between the 4
th 
and 12
th 
infusions 
was approximately 14 days (range: 2.3 to 61.5 days).  
 
Special Populations: Cross-study analyses were performed on data from patients with a 
variety of conditions, including 162 patients with CLL, who received multiple infusions 
of ofatumumab as a single agent at doses ranging from 100 to 2,000 mg. The effects of 
various covariates (e.g., body size [weight, height, and body surface area], age, gender, 
baseline creatinine clearance) on ofatumumab pharmacokinetics were assessed in a 
population pharmacokinetic analysis.  
Body Weight: Volume of distribution and clearance increased with body weight. 
However, this increase was not clinically significant. No dosage adjustment is 
recommended based on body weight.  
Age: Age did not significantly influence ofatumumab pharmacokinetics in patients 
ranging from 21 to 86 years of age.  
Gender: Gender had a modest effect on ofatumumab pharmacokinetics (14% to 25% 
lower clearance and volume of distribution in female patients compared to male patients) 
in a cross-study population analysis (41% of the patients in this analysis were male and 
59% were female). These effects are not considered clinically important, and no dosage 
adjustment is recommended.  
Renal Impairment: Creatinine clearance at baseline did not have a clinically important 
effect on ofatumumab pharmacokinetics in patients with calculated creatinine clearance 
values ranging from 33 to 287 mL/min. 
5.2.2.3 Supplier  
Novartis will supply ofatumumab to H. Lee Moffitt Cancer Center at no charge to study 
participants.  


 
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5.2.2.4 Ofatumumab Dosage Form  
The quantitative composition in acetate formulation is 20 mg/mL.  This is available in 
two 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 
 
5.2.2.5 Packaging  
Ofatumumab will be shipped from Novartis directly to H. Lee Moffitt Cancer Center 
Pharmacy Department. Novartis will supply ofatumumab to the investigator as vials 
presented as either 100 mg – acetate formulation, 20 mg/mL, 5 mL fill vials, or 1000 mg 
– acetate formulation, 20 mg/mL, 50 mL fill vials.  
 
The investigational medical product, ofatumumab, is a liquid concentrate for solution for 
intravenous infusion presented in glass vials. Ofatumumab will be dosed as described in 
dosing schema in section 1. 
 
The ofatumumab infusions will be prepared in 1000 mL NaCl sterile, pyrogen free 0.9% 
NaCl to yield a 0.3 mg/mL, 1 mg/mL, or 2 mg/mL ofatumumab concentration for 
infusions of 300 mg, 1000 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 


 
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infusion. The site is responsible for labeling individual vials for investigational use. All 
items required for administration of study medication (e.g., infusion bags, filters, etc.) are 
to be provided by the site. 
5.2.2.6 Storage 
The product should be stored in a refrigerator at a temperature between +2ºC and +8ºC 
(36° to 46°F). Do not freeze. Vials should be protected from light and may not be utilized 
after the expiry date printed on label. 
 
5.2.2.7 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 48 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 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: 
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 


 
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Filter Extension Set 
Sterilizing-grade (0.22 m) 
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) 
 
5.2.2.8 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 48 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) supplied by study site 
Intravenous (IV) cannula (not required if subject has central venous access) supplied by 
study site 
Infusion pump and infusion tubing set supplied by study site 
In-line low protein binding, polyether sulfone filter 0.2 m (please make sure a spare 
filter is available in case the filter needs to be changed) supplied by study site  Please 
note that the commercial filters are sterilizing-grade (0.22 m) hydrophilic Durapore by 
Millipore. 


 
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5.2.2.9 
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 2 or Table 3 below 
 Draw the required amount of ofatumumab according to Table 2 (100 mg vials) or 
Table 3 (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 
 
 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) 
1000 mg 
1000 mL 
50 mL 
50 mL  
(10 vials, 5 mL/vial)  
2000 mg 
1000 mL 
100 mL 
100 mL 
(20 vials, 5 mL/vial) 
 
 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) 
1000 mg 
1000 mL 
50 mL 
50 mL  
(1 vial, 50 mL/vial)  
2000 mg 
1000 mL 
100 mL 
100 mL 
(2 vials, 50 mL/vial) 
 


 
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5.2.3.0  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. 
Please note that the infusion site can be used for blood sampling only if there is no 
risk of contamination of the infusion needle with the saline, infusion solutions, or 
any other fluid(s).  Only a newly inserted needle can be used for the predose blood 
samples.   
 
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 
48 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 Error! 
Reference source not found.). 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. 
 
Collect the pre-dose blood samples, if required. 
 
Check the backflow from the i.v. cannula according to routine practice at site 


 
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 
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 infusion rates described in drug administration section 
5.5.2. 
5.3 
Screening and Eligibility 
The Investigator is responsible for keeping a record of all subjects who sign an Informed 
Consent Form for entry into the study.  All subjects will be screened for eligibility.  
Screening procedures are outlined in Section 2, Schedule of Study Assessments. Unless 
otherwise specified, screening must take place within 28 days prior to initiation of 
therapy.  
Approximately 56 subjects with relapsed or refractory CLL/SLL will be screened for 
enrollment and must meet the eligibility criteria below. 
5.3.1 Inclusion Criteria 
Subjects must meet the following inclusion/exclusion criteria to be eligible for the study. 
Inclusion criteria  
1. Understand and voluntarily sign an informed consent form. 
2. Age 18 years at the time of signing the informed consent form. 
3. Able to adhere to the study visit schedule and other protocol requirements. 
4. Patients must have histologically or cytologically confirmed CD5+/CD20+ B-Cell 
chronic lymphocytic leukemia or small lymphocytic lymphoma. The diagnosis of 
CLL is based upon the NCCN guidelines.  Any outside pathology slides used as 
inclusion criteria for the patient will be reviewed at this institution to confirm the 
diagnosis.  The patient must meet all of the following CLL criteria to participate 
in this study: 
 absolute lymphocyte count > 5000/μL 
 CD20+ and CD5+ 


 
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 Bone marrow lymphocytes ≥ 30% 
 Or previous confirmed diagnosis of CLL/SLL with less than 
5000/µl or less than 30% lymphocytes in BM 
 
5. Patients are eligible if they have relapsed or refractory CLL/SLL (See also 
Appendix E: Criteria for Treatment) 
6. All previous cancer therapy, including radiation, hormonal therapy and surgery, 
must have been discontinued at least 4 weeks prior to treatment in this study.  
7. ECOG performance status of  2 at study entry (see Appendix B). 
8. Laboratory test results within these ranges: 
 Absolute neutrophil count  1000/mm³  
 Platelet count 50,000 /mm³  
(Adequate baseline platelet and neutrophil levels must be present, unless there is 
clear evidence of extensive bone marrow involvement with tumor infiltration 
Extensive bone marrow involvement is defined as:  
-Bone marrow lymphocytes > 30%  
-Platelets <50,000 and/or neutropenia <1,000 at least 4 weeks since previous 
  cancer therapy ). 
 
 Renal function assessed by calculated creatinine clearance ≥ 30ml/min by 
Cockcroft-Gault formula. (see Appendix: Cockcroft-Gault estimation of CrCl)   
 Total bilirubin  1.5 x ULN 
 AST (SGOT) and ALT (SGPT)  2.5 x ULN. 
 Alkaline phosphatase <2.5 x ULN 
9. Disease free of prior malignancies for  5 years with exception of currently 
treated basal cell, squamous cell carcinoma of the skin, or carcinoma “in situ” of 
the cervix or breast.  
10. All study participants must be registered into the mandatory RevAssist® program, 
and be willing and able to comply with the requirements of RevAssist®. 


 
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11. Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days and 
again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions 
must be filled within 7 days) and must either commit to continued abstinence 
from heterosexual intercourse or begin TWO acceptable methods of birth control, 
one highly effective method and one additional effective method AT THE SAME 
TIME, at least 28 days before she starts taking lenalidomide.  FCBP must also 
agree to ongoing pregnancy testing.  Men must agree to use a latex condom 
during sexual contact with a FCBP even if they have had a successful vasectomy.  
See Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods. 
12. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients 
intolerant to ASA may use warfarin or low molecular weight heparin). 
5.3.2 Exclusion criteria   
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form. 
2. Pregnant or breast feeding females. (Lactating females must agree not to breast 
feed while taking lenalidomide).  
3. Any condition, including the presence of laboratory abnormalities, which places 
the subject at unacceptable risk if he/she were to participate in the study or 
confounds the ability to interpret data from the study. 
 
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† A female of childbearing potential is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
 
 


 
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4. Evidence of laboratory TLS by Cairo-Bishop Definition of Tumor Lysis 
Syndrome (see Appendix H).  Subjects may be enrolled upon correction of 
electrolyte abnormalities.  
5. Use of any other experimental drug or therapy within 28 days of baseline. 
6. Known hypersensitivity to thalidomide. 
7. The development of erythema nodosum if characterized by a desquamating rash 
while taking thalidomide or similar drugs. 
8. Any prior use of lenalidomide. 
9. Concurrent use of other anti-cancer agents or treatments. 
10. Known seropositive for or active viral infection with human immunodeficiency 
virus (HIV)  
11. Positive serology for hepatitis B (HB) defined as a positive test for HBsAg. In 
addition, if negative for HBsAg but HBcAb positive and HBsAb negative, a HB 
DNA test will be performed and if positive the subject will be excluded. Note: If 
HBcAb positive and HBsAb positive, which is indicative of a past infection, the 
subject can be included. Patients who are seropositive because of hepatitis B virus 
vaccine are eligible. 
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. Subjects who have current active hepatic or biliary disease (with exception of 
patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or 
stable chronic liver disease per investigator assessment) are ineligible. 
14. 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. 
15. History of significant cerebrovascular disease in the past 6 months or ongoing 
event with active symptoms or sequelae 


 
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16. 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. 
17. 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. 
5.4 
Visit schedule and assessments 
Screening Assessments and all on study scheduled visits and assessments are outlined in 
Section 2: Table of Study Assessments.  
At treatment discontinuation, subjects will undergo off study evaluations per the 
Schedule of Assessments, Section 2.  Study subjects who have completed the 12 cycles of 
treatment protocol, have not progressed while on therapy, and do not continue on 
lenalidomide maintenance therapy (MT) will be followed every 3 months until disease 
progression, study closure, withdrawal of consent, or death. Subjects who progress while 
on MT and discontinue treatment will have the end of treatment testing. If the bone 
marrow biopsy and CT scans have been performed in the past 28 days to determine 
progression of disease, it is not necessary to repeat these tests.  
  
5.5 
Drug Administration 
Treatment will be administered at the outpatient H. Lee Moffitt Cancer Center Infusion 
Center. The patients will receive combination of high dose methylprednisolone IV and 
ofatumumab IV infusion for 3 cycles. This regimen will be followed by a combination of 
lenalidomide and ofatumumab starting on cycle 4-12 of a 28-day cycle in patients with 
CR, PR or stable disease. 
 
 
   


 
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5.5.1 High dose methylprednisolone (HDMP) 
HDMP will be administered at 1 gm/m2 IV over 90 minutes daily with ofatumumab 
infusions 1-8. The patients will be premedicated with cimetidine (or equivalent) 300mg 
IV, acetaminophen 1000mg orally, and diphenhydramine (or equivalent) 50mg po or IV 
before receiving HDMP.  See Section 5.6.1.5 for concomitant antimicrobial prophylactic 
therapy. 
5.5.2 Ofatumumab 
Ofatumumab infusion will be administered immediately after HDMP. Please refer to 
dosing schema in Section 1 for ofatumumab dosing. Patients will be pre-medicated prior to 
infusion of HDMP as above on day 1 and before each ofatumumab infusions 2-8 within 
30 minutes to 2 hours prior to the treatment. The last four doses of ofatumumab will 
follow the standard premedication regimen. Pre-medication before each ofatumumab 
infusion 9-12 must be given within 30 minutes to 2 hours prior to the treatment: 
 
Pre-medication Requirements prior to Ofatumumab Infusions 
 
Infusion # 
Acetaminophen 
(po) 
or equivalent 
Antihistamine (iv or 
po) diphenhydramine  
or equivalent 
Glucocorticoid (iv) 
 prednisolone  
or equivalent  
9th 
1000 mg 
50 mg 
50 mg 
10th  
1000 mg  
50 mg 
50 mg 
11th-12th  
1000 mg 
50 mg 
0 – 50 mg 
 
First Infusion of 300 mg Ofatumumab  
The first dose administered of ofatumumab in CLL should be 300 mg to minimize 
infusion reactions. The initial rate of the first infusion of 300 mg ofatumumab (0.3 
mg/mL) should be 12 mL/h. If no infusion reactions occur the infusion rate should be 
increased every 30 minutes, to a maximum of 400 mL/h, according to the following table. 
If this schedule is followed, the infusion duration will be approximately 4.67 hours. 


 
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Infusion rate at 1st Ofatumumab infusion (300mg) 
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 
 
If an infusion reaction develops, the infusion should be temporarily slowed or interrupted. 
Upon restart, the infusion rate should be half of the infusion rate at the time the infusion 
was paused. If, however, the infusion rate was 12 mL/hour before the pause, the infusion 
should be restarted at 12 mL/hour. Thereafter, the infusion rate may be increased 
according to the judgment of the investigator, in the manner described in this section. 
 
Subsequent Infusions of Ofatumumab 2000 mg 
If the previous infusion has been completed without grade ≥ 3 infusion-associated 
adverse effects (AEs), the subsequent infusion of the 2000 mg ofatumumab (2 mg/mL) 
can start at a rate of 25 mL/hour and should be doubled every 30 minutes up to a 
maximum of 400 mL/h, according to the following table. Duration of the infusion will be 
approximately 4 hours if this schedule is followed. If the previous infusion has been 
completed with grade ≥ 3 infusion associated AEs, the subsequent infusion should start at 
a rate of 12 mL/hour according to table “Infusion rate at 1st Ofatumumab infusion 
(300mg)” 
 
 
Infusion rate at subsequent ofatumumab infusion 
Time 
mL/hour  


 
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0 – 30 minutes 
25 
31 – 60 minutes 
50 
61 – 90 minutes 
100 
91 – 120 minutes 
200 
121+ minutes 
400 
 
During infusion the patient should be monitored closely and appropriate measurements 
should be performed whenever judged necessary. See Section 5.6.1.5 for concomitant 
antimicrobial prophylactic therapy 
5.5.2.1 Ofatumumab Dose Interruptions or Discontinuation 
Liver chemistry stopping and follow-up criteria have been designed to assure subject 
safety and evaluate liver event etiology. 
 
5.5.2.1.1 Liver Chemistry Stopping Criteria: 
1. ALT > 3xULN and bilirubin  2xULN (>35% direct bilirubin; bilirubin 
fractionation required)* 
2. ALT > 8xULN 
3. ALT  5xULN for more than 2 weeks 
 
*NOTE: serum bilirubin fractionation should be performed if testing is available. 
If testing is unavailable and a subject meets the criterion of total bilirubin >2.0 x 
ULN, then the following actions must still be performed. 
When any of the liver chemistry stopping criteria is met, do the following: 
 
Immediately withdraw investigational product 
 
Report the event to NOVARTIS and Celgene Corporation within 24 hours of 
learning its occurrence 
 
All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin), termed 
‘Hy’s Law’, must be reported as an SAE. 


 
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NOTE: 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. 
 
Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below.  
 
Withdraw the subject from the study (unless further safety follow up is required) 
after completion of the liver chemistry monitoring as described below. 
 
Do not re-challenge with investigational product. 
 
In addition, for criterion 1: 
 
Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
monitoring 
 
A specialist or hepatology consultation is recommended 
 
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values 
 
For criteria 2 and 3: 
 
Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below) 
 
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible. 
 
Subjects with ALT 5xULN which exhibit a decrease to ALT x3xULN, but <5xULN 
and bilirubin <2xULN without hepatitis symptoms or rash, and who can be monitored 
weekly for 4 weeks: 


 
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 
Can continue ofatumumab 
 
Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline  
 
If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above 
 
If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
5.5.2.1.2 Liver Chemistry Follow-up Assessments: 
Make every attempt to carry out the liver event follow up assessments described below: 
 
Viral hepatitis serology including: 
o Hepatitis A IgM antibody; 
o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);  
o Hepatitis C RNA; 
o Cytomegalovirus IgM antibody; 
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); 
o Hepatitis E IgM antibody (if subject resides outside the US or Canada, or has 
traveled outside US or Canada in past 3 months); 
 
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 of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form 


 
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 
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form. 
 
Record alcohol use on the liver event alcohol intake case report form 
 
The following 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. 
5.5.3 Lenalidomide 
The lenalidomide starting dose will be based on baseline calculated creatinine clearance 
as follows: 
Lenalidomide Starting Dose (Cycle 4) Based on Renal Function Prior to Cycle 4 of 
Treatment 
Baseline Calculated 
Creatinine Clearance (by 
Cockcroft-Gault) 
Starting Lenalidomide Dose 
 60 ml/min 
10mg daily on Days 1-28 of each 28-day cycle 
 30 and < 60 ml/min 
5mg daily on Days 1-28 of each 28-day cycle 
At investigator discretion, subjects who have a CrCl between 30-60ml/min may have 
their lenalidomide dose increased from 5mg to 10mg at the start of cycle 5 or at the start 
of subsequent treatment cycles, if they tolerated the prior treatment cycle without 
requiring dose modifications, interruptions or delays due to toxicity. The maximum 
allowable target dose for all study subjects is 10 mg daily on Days 1-28 of each 28-day 
cycle.  


 
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Dosing should be at approximately the same time each day but the time of day may be 
determined per patient to manage any side effects.  Only enough lenalidomide for one 
cycle of therapy will be supplied to the patient each cycle.  Prescriptions must be filled 
within 7 days. If a dose of lenalidomide is missed, it should be taken as soon as possible 
on the same day.  If it is missed for the entire day, it should not be made up. Patients who 
take more than the prescribed dose of lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately. 
Subjects experiencing adverse events may need study treatment modifications (See 
section 5.5.3.6). 
See Section 5.6.1.1 for allopurinol and oral hydration requirements as prophylaxis against 
tumor lysis syndrome (TLS). 
See Section 5.6.1.2 for prophylactic anti-coagulation. 
See Section 5.6.1.5 for concomitant antimicrobial prophylactic therapy 
5.5.3.1 Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless 
they are wearing gloves. 
5.5.3.2 Record of administration 
Accurate records will be kept in the source documents of all drug administration 
(including prescribing and dosing).   
5.5.3.3 Lenalidomide Dose Continuation, Modification and Interruption    
Once study subjects start the lenalidomide-containing cycle of the treatment protocol 
(Cycle 4) they will be evaluated for AEs at each visit with the NCI CTCAE v4.0 (see 
Appendix G: NCI CTCAE v4.0) used as a guide for the grading of severity.  Sections 
below describe dose reduction steps, instructions for initiation of a new cycle of therapy 
and dose modifications during a cycle of therapy.    


 
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Additionally, at the discretion of the investigator, lenalidomide may be continued beyond 
cycle 12 on all patients who have achieved a complete response, partial response or stable 
disease. 
5.5.3.4 Dose Modification Steps 
Lenalidomide dose reductions should be taken one dose level at a time per the table 
below.  Similarly, if lenalidomide dose escalation (or re-escalation) is permitted, it should 
be done one dose level at a time according to the table below (reverse of the dose 
reduction steps).  See Section 5.5.3.6 for instructions related to lenalidomide dose re-
escalation. 
 
Table 1: Lenalidomide Dose Modification Steps 
Current Lenalidomide Dose 
One Level Dose Reduction 
10 mg daily on Days 1-28 every 28 days 
5 mg daily on Days 1-28 every 28 days 
5 mg daily on Days 1-28 every 28 days 
5 mg every other day during Days 1-28 
every 28 days* 
5 mg every other day during Days 1-28 
every 28 days* 
See * below 
 
* Lenalidomide 5 mg every other day is the minimum lenalidomide dose.  Lenalidomide 
will be discontinued in patients who cannot tolerate this dose.  However, patients who 
experience toxicity requiring dose reduction while receiving lenalidomide 5 mg every 
other day may, at the discretion of their physician, have their dose held until toxicity 
resolves as described in Sections 5.5.3.6, and then restart lenalidomide 5 mg every other 
day.  If the same toxicity recurs at lenalidomide 5 mg every other day, consideration 
should be given to discontinuing lenalidomide. 
5.5.3.5 Instructions for Initiation of a New Lenalidomide Cycle  
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 


 
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 The ANC is ≥ 500/mm³; 
 The platelet count is ≥ 25,000/mm³;  
 Any drug-related rash or neuropathy that may have occurred has resolved to ≤ 
grade 1 severity; 
 Tumor lysis syndrome (TLS) has not exceeded grade 1 severity during previous 
cycle (see Appendix: Cairo-Bishop Definition of Tumor Lysis Syndrome); 
 If TLS ≥ grade 2 during previous cycle (see Appendix: Cairo-Bishop Definition 
of Tumor Lysis Syndrome), electrolyte abnormalities have resolved to ≤ grade 0 
severity; 
 Any other drug-related adverse events that may have occurred have resolved to ≤ 
grade 2 severity.  
If these conditions are not met on Day 1 of a new lenalidomide cycle, the subject will be 
evaluated weekly and a new cycle of treatment will not be initiated until the toxicity has 
resolved as described above.   
5.5.3.6 Instructions for lenalidomide dose modifications or interruption  
Dose delay and dose reduction rules are as follows and in the table below. 
 Lenalidomide dose reduction steps are outlined in Section 5.5.3.4   
 For treatment interruptions during a cycle, the 28-day schedule of each cycle will 
continue to be followed.  Missed doses of lenalidomide are not made up.   
 For treatment interruptions that delay the scheduled start of a new cycle, when 
toxicity has resolved as required to allow the start of a new cycle (Section 
5.5.3.5), the restart day of therapy becomes Day 1 of the next cycle. 
Dose re-escalation following dose reductions due to neutropenia, thrombocytopenia, 
tumor lysis syndrome, or tumor flare: 
 If the dose of lenalidomide has been reduced for neutropenia or 
thrombocytopenia, lenalidomide dose re-escalation is permitted if the subject 


 
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completes one full cycle without experiencing any toxicity that requires dose 
interruption or reduction.   
 If the dose of lenalidomide has been dose reduced for tumor lysis syndrome, 
lenalidomide dose re-escalation is permitted if the subject completes one full 
cycle without experiencing a laboratory TLS or ≥ Grade 1 TLS (see Appendix H: 
Cairo-Bishop Definition of Tumor Lysis Syndrome), unless the subject requires a 
dose interruption/reduction for other toxicity.   
 If the dose of lenalidomide has been dose reduced for tumor flare, lenalidomide 
dose re-escalation is permitted if the subject completes one full cycle without 
experiencing ≥ Grade 1 tumor flare, unless the subject requires a dose 
interruption/reduction for other toxicity.   
 If any of the above conditions are met, the lenalidomide dose may be increased by 
one dose level at the initiation of a new cycle of therapy up to the maximum 
allowable target dose (see Section 5.5.3 for the maximum allowable target dose 
and Section 5.5.3.4, Table 1, for appropriate dose escalation steps [reverse of the 
dose reduction steps in Table 1 
 Serum chemistry and uric acid should be closely monitored for signs of laboratory 
or clinical TLS (see Appendix H: Cairo-Bishop Definition of Tumor Lysis 
Syndrome) following lenalidomide dose re-escalation (see Section 2, Schedule of 
Study Assessments, for details regarding serum chemistry and uric acid 
monitoring).   
 TLS prophylaxis with allopurinol and hydration as described in Section 5.6.1.1 
should be considered with each dose re-escalation. 
 
 
 
 
 


 
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Table 2: Dose Modifications  
NCI CTC Toxicity 
Grade 
Dose Modification Instructions 
(also see Instructions for Initiation of a New Cycle above) 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º 
C) or Grade 4 
neutropenia 
 Hold (interrupt) lenalidomide dose.  Omitted doses are 
NOT made up. 
 Follow CBC weekly. 
 First episode: If neutropenia resolves to ≤ grade 3 
without fever prior to the scheduled end of the current 
cycle, restart lenalidomide at the current dose level and 
continue through the scheduled end of the current cycle.   
Otherwise, omit for remainder of cycle and restart 
lenalidomide at the current dose level at the start of the 
next cycle.   
 Second and subsequent episodes: If neutropenia resolves 
to ≤ grade 3 without fever prior to the scheduled end of 
the current cycle, restart lenalidomide at the next lower 
dose level and continue through the scheduled end of the 
current cycle.  Otherwise, omit for remainder of cycle 
and restart lenalidomide at the next lower dose level at 
the start of the next cycle.    
Thrombocytopenia 
≥Grade 4 (platelet 
count < 25,000/mm³) 
 Hold (interrupt) lenalidomide dose.  Omitted doses are 
NOT made up. 
 Follow CBC weekly. 
 If thrombocytopenia resolves to ≤ grade 3 prior to the 
scheduled end of the current cycle, restart lenalidomide 
at next lower dose level and continue through the 
scheduled end of the current cycle.  Otherwise, omit for 
remainder of cycle and restart lenalidomide at the next 
lower dose level at the start of the next cycle. 
Platelet count < 
50,000/mm³ 
 Hold prophylactic anti-coagulation, if applicable. 
 Restart prophylactic anti-coagulation when platelet count 
is ≥ 50,000/mm³. 
Laboratory Tumor 
Lysis Syndrome 
(TLS) and Grade 1 
TLS  
(see Section 5.6.1.3 
and Appendix H: 
Cairo-Bishop 
Definition of TLS) 
 Continue treatment as planned.  Maintain current dose. 
 Institute vigorous intravenous hydration and consider 
rasburicase therapy as needed to reduce hyperuricemia, 
until correction of electrolyte abnormalities. 
 Other TLS prophylaxis measures outlined in Section 
5.6.1.1 should be continued or re-instituted. 


 
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Table 2: Dose Modifications  
NCI CTC Toxicity 
Grade 
Dose Modification Instructions 
(also see Instructions for Initiation of a New Cycle above) 
Tumor Lysis 
Syndrome (TLS) 
≥Grade 2 
(see Section 5.6.1.3 
and Appendix H: 
Cairo-Bishop 
Definition of TLS) 
 Hold (interrupt) lenalidomide dose.  Maintain schedule 
of cycle.  Omitted doses are NOT made up. 
 First episode: If electrolyte abnormalities resolve to 
Grade 0 prior to the scheduled end of the current cycle, 
restart lenalidomide at the current dose with appropriate 
TLS prophylaxis (Section 5.6.1.1) and continue through 
the scheduled end of the current cycle.  Otherwise, omit 
for remainder of cycle and restart lenalidomide at the 
current dose at the start of the next cycle with 
appropriate TLS prophylaxis (Section 5.6.1.1).   
 Subsequent episodes: If electrolyte abnormalities resolve 
to Grade 0 prior to the scheduled end of the current 
cycle, restart lenalidomide with appropriate TLS 
prophylaxis (Section 5.6.1.1) and continue through the 
scheduled end of the current cycle.  Otherwise, omit for 
remainder of cycle and restart lenalidomide at the start of 
the next cycle with appropriate TLS prophylaxis 
(Section 5.6.1.1).  At physician discretion, the 
lenalidomide dose may be restarted at the current dose or 
lenalidomide may be reduced by 1 dose level.   
 First or subsequent episodes: subjects should be closely 
monitored for signs of TLS after resuming treatment.  To 
monitor for TLS, serum chemistry and uric acid tests 
should be performed at least every week following re-
initiation of lenalidomide for 4 consecutive weeks and 
on Day 3 or Day 4 following re-initiation of 
lenalidomide.  See Section 2, Schedule of Study 
Assessments, for additional specifics regarding serum 
chemistry and uric acid testing. 


 
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Table 2: Dose Modifications  
NCI CTC Toxicity 
Grade 
Dose Modification Instructions 
(also see Instructions for Initiation of a New Cycle above) 
Non-blistering rash 
 
Grade 3 
 
 
 
 
             Grade 4 
 
 If Grade 3, hold (interrupt) lenalidomide dose.  Follow 
weekly. 
 If the toxicity resolves to ≤ grade 1 prior to the 
scheduled end of the current cycle, restart lenalidomide 
at next lower dose level and continue through the 
scheduled end of the current cycle.  Otherwise, omit for 
remainder of cycle and reduce the dose of lenalidomide 
by 1 dose level at the start of the next cycle.  Omitted 
doses are not made up. 
 
 
 If Grade 4, discontinue lenalidomide.  Remove patient 
from study. 
Desquamating 
(blistering) rash- any 
Grade  
 Discontinue lenalidomide.  Remove patient from study. 
Neuropathy 
 
Grade 3 
 
 
 
 
Grade 4 
 
 If Grade 3, hold (interrupt) lenalidomide dose.  Follow at 
least weekly. 
 If the toxicity resolves to ≤ grade 1 prior to the 
scheduled end of the current cycle, restart lenalidomide 
at next lower dose level and continue through the 
scheduled end of the current cycle.  Otherwise, omit for 
remainder of cycle and reduce the dose of lenalidomide 
by 1 dose level at the start of the next cycle.  Omitted 
doses are not made up. 
 
 
 If Grade 4, discontinue lenalidomide.  Remove patient 
from study. 
Venous 
thrombosis/embolism 
≥ Grade 3 
 Hold (interrupt) lenalidomide and start therapeutic 
anticoagulation, if appropriate. 
 Restart lenalidomide at investigator’s discretion 
(maintain dose level).   
 See Anticoagulation Consideration (Section 5.6.1.2). 
Hyperthyroidism or 
hypothyroidism 
 Omit lenalidomide for remainder of cycle, evaluate 
etiology, and initiate appropriate therapy.  
 See Instructions for Initiation of a New Cycle and reduce 
the dose of lenalidomide by 1 dose level*. 


 
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Table 2: Dose Modifications  
NCI CTC Toxicity 
Grade 
Dose Modification Instructions 
(also see Instructions for Initiation of a New Cycle above) 
other non-
hematologic toxicity 
≥ Grade 3 
 Hold (interrupt) lenalidomide dose.  Follow at least 
weekly. 
 If the toxicity resolves to ≤ grade 2 prior to the 
scheduled end of the current cycle, restart lenalidomide 
and continue through the scheduled end of the current 
cycle.  Otherwise, omit for remainder of cycle.  Omitted 
doses are not made up.  For toxicity attributed to 
lenalidomide, reduce the lenalidomide dose by 1 dose 
level when restarting lenalidomide. 
 
5.5.3.7 Treatment adherence 
Research center personnel will review the dosing instructions with subjects. Subjects will 
be asked to maintain a diary to record lenalidomide administration. Subjects will be asked 
to bring any unused lenalidomide and empty drug containers to the research center at 
their next visit.  Research personnel will count and record the number of used and unused 
drug at each visit and reconcile with the patient diary.   
Any unused Revlimid® (lenalidomide) should be returned to the patient for disposition in 
accordance with the RevAssist® program. 
5.6 
Concomitant therapy   
5.6.1 Recommended concomitant therapy   
Subjects should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, hematopoietic growth factors, analgesics, and antiemetics when 
appropriate.  
 
5.6.1.1 Tumor Lysis Syndrome (TLS) Prophylaxis (allopurinol and hydration) 
Tumor lysis syndrome (TLS), characterized by hyperkalemia, hyperuricemia, and 
hyperphosphatemia resulting from the rapid release of potassium, uric acid, and 
phosphate, has been reported in CLL patients treated with lenalidomide necessitating 


 
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TLS prophylaxis including allopurinol and oral hydration.  The risk of TLS is highest 
during the first cycle of therapy and decreases after resolution of lymphocytosis. 
Allopurinol 300mg po daily will be given at the beginning at least 3 days before cycle 1 
and continuing through the end of cycle 1. TLS prophylaxis is required for all subjects in 
cycle 1.  It can be considered prior to initiation of lenalidomide in subsequent cycles at 
the discretion of the investigator.  Subjects should be instructed to maintain adequate 
hydration and maintain urinary output as an additional measure to prevent TLS.  To 
maintain fluid intake, subjects should be instructed to drink 8 to 10 eight ounce glasses of 
water each day for the first 14 days of Cycle 1.  Hydration levels should be adjusted 
according to age and clinical status, and lowered if the subject’s cardiovascular status 
indicates the possibility of volume overload.  Based on clinical and laboratory 
parameters, TLS prophylaxis may be continued or restarted as needed at the 
Investigator’s discretion. 
5.6.1.2 Anticoagulation Consideration   
Lenalidomide increases the risk of thrombotic events in patients who are at high risk or 
with a history a thrombosis, in particular when combined with other drugs known to 
cause thrombosis. When lenalidomide is combined with other agents such as steroids 
(e.g. dexamethasone, prednisone), anthracyclines (Doxil, Adriamycin) and erythropoietin 
the risk of thrombosis is increased.  For information on the risk of venous 
thromboembolism with combined oral contraception see Appendix: Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods. 
All patients should receive prophylactic anti-coagulation.  Aspirin (81 or 325 mg) is the 
recommended agent for anti-coagulation prophylaxis.  Low molecular weight heparin 
may be utilized in patients that are intolerant to ASA. Coumadin should be used with 
caution and close monitoring of INR. 
Patients with a history of venous thromboembolism should be closely monitored 
throughout the study, especially during periods of fluctuating platelet counts. 
Prophylactic anti-coagulation should be held for platelet counts < 50,000/mm³ 
and then restarted when platelet counts are above this level.  


 
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Full therapeutic anti-coagulation should be considered for patients who have a history of 
venous thromboembolism.   
5.6.1.3 Treatment and Dose Modification for Tumor Lysis Syndrome 
All subjects meeting criteria of laboratory TLS or ≥ Grade 1 TLS according to the Cairo-
Bishop Definition of Tumor Lysis Syndrome (see Appendix) should receive vigorous 
intravenous hydration and should be considered for rasburicase therapy as needed to 
reduce hyperuricemia, until correction of electrolyte abnormalities.   
5.6.1.4 Tumor Flare Reaction (TFR):  
Prophylaxis for (TFR) is not recommended.  Grade 1 TFR may be treated with NSAIDs 
(i.e. ibuprofen 400-600 mg orally every 4-6 hours as needed).  TFR ≥ Grade 2 may be 
treated with corticosteroids.  Narcotic analgesics may be added as needed for pain control 
in subjects experiencing ≥ Grade 2 tumor flare.  If corticosteroids are used, the following 
dosage schedule is recommended; prednisone 20mg PO QD x 7 days followed by 10mg 
PO QD x 7 days.   
Tumor flare occurring during the first 2 weeks of Cycle 4 of treatment protocol should be 
recorded as an adverse event and not as progressive disease (PD).  For tumor flare 
occurring after the first 2 weeks of Cycle 4 of treatment protocol, differentiate tumor flare 
from progression.   
5.6.1.5 Prophylaxis of infections 
Patients will receive prophylaxis for Pneumocystis carini pneumonia with trimethoprim-
sulfamethoxazole or equivalent, prophylaxis for herpes virus with acyclovir 400mg twice 
per day or equivalent and antifungal prophylaxis with fluconazole 100mg daily or 
equivalent. Prophylaxis will be administered throughout the treatment period until end of 
cycle 5. 
 
5.6.1.6  Growth Factor Support  


 
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Patients may receive growth factor support in the form of granulocyte colony stimulating 
factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), or 
erythropoietin at the discretion of the treating physician. 
 
5.6.2 Prohibited concomitant therapy 
Concomitant use of other anti-cancer therapies, including radiation, thalidomide, or other 
investigational agents is not permitted while subjects are receiving protocol therapy 
during the treatment phase of the study. 
5.7 
Discontinuation of Study Treatment (See Also Section 5.5.3.5 and 5.5.3.6) 
Treatment will continue as per dosing schema. Treatment will be discontinued at the 
occurrence of any of the following events.   
 Disease progression  
 Adverse event(s) that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of the treatment regimen. 
 Discontinuation of treatment protocol for any reason. 
 Major violation of the study protocol. 
 Withdrawal of consent 
 Lost to follow up 
 Death 
 Pregnancy or a positive pregnancy test 
5.8 Lenalidomide Maintenance Therapy (MT) 
 At the discretion of the investigator, any subject completing 12 cycles of protocol 
therapy who has achieved a complete response, partial response or stable disease may 
begin Lenalidomide Maintenance Therapy (MT). 
 
During MT the following study procedures will be initiated: 


 
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1. The subject will have a safety CBC with differential and CMP every four weeks 
which will not be recorded in the database.   
2. Physical examinations will be at the discretion of the investigator or per standard 
of care.  The physical exam results will not be recorded in the database. 
3. For the purpose of the study, vital signs, weight, and concomitant medications are 
not required to be recorded in the database. 
4. No subject pill diary or source documentation of dosing will be maintained.  The 
patient report of daily dosing will be sufficient to document adherence.  
5. The only adverse events collected and entered into the database will be grade 3 or 
grade 4 cytopenias and any event considered a serious adverse event. 
6. All standard of care guidelines as outlined by the Celgene Corporation for 
lenalidomide administration, including prophylactic anticoagulation, pregnancy 
prevention, and counseling through the Revlimid REMS program will continue to 
be followed. 
7. Serious adverse events will be collected and reported as outlined by NOVARTIS 
and Celgene in section 6.  
8. A bone marrow biopsy and CT scan will be performed every six months for the 
first two years. After that these tests will be performed at the discretion of the 
treating physician.  
 
At the discretion of the investigator: 
1. Lenalidomide dose may be maintained at the subject’s current dose or if 
previously dose reduced, may be escalated to the maximum of 10 mg daily.  
2. Lenalidomide dose reductions may be initiated to 5 mg daily or 5 mg every other 
day.  
 
 
 


 
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5.9 
Follow-Up   
If a subject discontinues study treatment at any time during cycles 1-12, “Discontinuation 
from Protocol Therapy” on the Schedule of Assessments, Section 2 will be performed.  
If a subject enters Maintenance Therapy (MT) after cycle 12, the follow-up period will 
begin after any discontinuation of lenalidomide in MT. If a subject completes 12 cycles 
and does not enter MT, follow-up will begin at the completion of cycle 12.  
6 
Adverse Events 
Adverse events will be captured from the time the patient receives the first dose of study 
drug. 
All adverse events will be followed for 30 days after the last dose in cycle 12 of study 
treatment, unless the subject withdraws consent, or begins other CLL treatment. If a 
subject completes all 12 cycles of the protocol therapy and enters lenalidomide 
Maintenance Therapy (MT), any unresolved adverse events will be considered ongoing. 
During MT only grade 3 or 4 cytopenias and any serious adverse events will be captured 
as adverse events and recorded in Oncore.  
 
6.1 
Serious adverse event reporting to Celgene Corporation 
Celgene Corporation must be notified according to Celgene serious adverse event (SAE) 
definition. A serious adverse event is one that at any dose (including overdose): 
    Results in death 
 Is life-threatening
1 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity
2 
 Is a congenital anomaly or birth defect 
 Is an important medical event
3 
 Pregnancy 


 
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 1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious adverse event; it 
does not refer to a serious adverse event that hypothetically might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability to 
carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in 
situations where none of the outcomes listed above occurred.  Important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above should also usually be considered serious.  Examples 
of such events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.  A new diagnosis of cancer during the course of a treatment should be considered as medically important.  
6.1.1 Adverse Event Reporting 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE Version 4.0 can be downloaded from the CTEP 
homepage (HTTP://CTEP.INFO.NIH.GOV).  All appropriate treatment areas should 
have access to a copy of the CTCAE Version 4.0.  All adverse clinical experiences, 
whether observed by the investigator or reported by the patient, must be recorded, with 
details about the duration and intensity of each episode, the action taken with respect to 
the test drug, and the patient’s outcome.  The investigator must evaluate each adverse 
experience for its relationship to the test drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical 
significance.  If any abnormal laboratory result is considered clinically significant, the 
investigator must provide details about the action taken with respect to the test drug and 
about the patient’s outcome. 
6.1.2 Pregnancies 
Pregnancy of a female subject or the female partner of a male subject occurring while the 
subject is on lenalidomide or within 4 weeks after the subject’s last dose of lenalidomide 
are considered expedited reportable events.  If the subject is on lenalidomide, it is to be 
discontinued immediately and the subject is to be instructed to return any unused portion 
of lenalidomide to the Investigator.  The pregnancy must be reported to Celgene and 


 
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Novartis Drug Safety within 24 hours of the Investigator’s knowledge of the pregnancy 
by phone and facsimile using the SAE Form. 
 
The Investigator will follow the pregnant female until completion of the pregnancy, and 
must notify Celgene and Novartis Drug Safety of the outcome as specified below.  The 
Investigator will provide this information as a follow-up to the initial SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE 
(i.e., spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly), the Investigator should 
follow the procedures for Expedited Reporting of SAEs to Celgene and Novartis (i.e., 
report the event to Celgene and Novartis Drug Safety by facsimile within 24 hours of the 
Investigator’s knowledge of the event). 
 
Any suspected fetal exposure to lenalidomide must be reported to Celgene and Novartis 
within 24 hours of being made aware of the event.  The pregnant female should be 
referred to an obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs.  In addition, any infant death after 30 days that the Investigator 
suspects is related to the in utero exposure to lenalidomide should also be reported. 
 
In the case of a live “normal” birth, Celgene and Novartis Drug Safety should be advised 
as soon as the information is available. 
 
6.1.3 Celgene Drug Safety Contact Information: 
Celgene Corporation 
Drug Safety 
86 Morris Avenue 


 
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Summit, N.J. 07901 
Toll Free:   
(800)-640-7854 
Phone:  
(908) 673-9667 
Fax: 
 
(908) 673-9115 
e-mail:  
drugsafety@celgene.com 
 
6.1.4 Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
 
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an 
annual report is provided to the FDA within 60-days of the IND anniversary date.  21 
CRF 312.33 provides the data elements that are to be submitted in the report.  The 
Annual Report should be filed in the study's Regulatory Binder, and a copy provided to 
Celgene Corporation as a supporter of this study as follows. 
 
 
Celgene Corporation 
 
Attn: Medical Development 
 
86 Morris Avenue 
 
Summit, NJ  07901 
 
Tel: (908) 673-9000 
 
All adverse experience reports must include the patient number, age, sex, weight, severity 
of reaction (e.g. mild, moderate, severe), relationship to drug (e.g. probably related, 
unknown relationship, definitely not related), date and time of administration of test 
medications and all concomitant medications, and medical treatment provided.   The 
investigator is responsible for evaluating all adverse events to determine whether criteria 
for “serious” and as defined above are present.  The investigator is responsible for 
reporting adverse events to Celgene as described below. 


 
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6.1.5 Expedited reporting by investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 
24 hours of being aware of the event. The written report must be completed and supplied 
to Celgene by facsimile within 24 hours/1 business day.  The initial report must be as 
complete as possible, including an assessment of the causal relationship between the 
event and the investigational product(s), if available.  Information not available at the 
time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number (RV-CLL-PI-
0560) and the institutional protocol number should be included on SAE reports (or on the 
fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE 
report to Celgene should be attached to the SAE and retained with the patient records.  
 
6.2 
Serious Adverse Events Reporting to Novartis  
NOVARTIS must be informed according to NOVARTIS Serious Adverse Event 
definitions. 
 
Adverse Events: 
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: 
 
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 medial 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 


 
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 
New conditions detected or diagnosed after investigational 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 
investigational 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 
6.2.1 Definition of a Serious Adverse Event (SAE) 
A SAE is  an Adverse Event,  that, at any dose: 
a. 
Results in death 


 
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b. Is life-threatening 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
An overnight hospital stay due to slow infusion rates will not be considered a Serious 
Adverse Event. 
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. 
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 


 
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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. 
6.2.2 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. 
 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. 
6.2.3 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 


 
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with investigational product or protocol design/procedures and the disease progression, 
then this must be reported as an SAE. 
6.2.4 Time Period and Frequency of Detecting and SAEs 
Once an investigator determines that an event meets the protocol definition of an SAE, 
the SAE will be reported to NOVARTIS within 24 hours of being notified of the event.  
All SAEs regardless of relationship to investigational product will be collected from the 
first dose of investigational product to after the last dose of investigational product 
(minimum of 6 months or until the end of the follow-up period which ever is longer). All 
SAEs regardless of causality will be collected until the end of the follow-up period.   
 
From the time a subject consents to participate in and completes the study all SAEs 
assessed as related to study participation (e.g., protocol-mandated procedures, invasive 
tests, or change in existing therapy) or related to NOVARTIS concomitant medication, 
will be reported promptly to NOVARTIS. 
 
Any SAE brought to the investigator’s attention after the subject has completed the study 
and considered by the investigator as possibly related to investigational product must be 
reported to NOVARTIS. 
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. 
Any SAEs experienced after the follow-up period should only be reported to Novartis if 
the investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up information. 
A SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event.  The 
end date of the first event must be provided. 
The original copy of the SAE Report and the fax confirmation sheet must be kept within 
the Trial Master File at the study site. 


 
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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 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. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements.  
 
 
For medical emergencies, the contact is: 
 
Gaetano Bonifacio MD 
Medical Director 
US CD MA Hematology 
Novartis Pharmaceuticals Corporation                                    
One Health Plaza, 345/4th 
East Hanover, NJ 07936-1080 
Mobile  +1 610 427 3613 
gaetano.bonifacio@novartis.com 
 
6.2.5 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 investigational product, must be promptly reported to NOVARTIS. 


 
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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. 
6.2.6         Novartis Drug Safety Contact Information:   
 
SAEs should be reported to Novartis by fax, using the FAX coversheets provided by 
Novartis.  
Fax to:   U.S. Drug Safety & Epidemiology  at  Fax #: 877-778-9739 
Email:   Should the designated SAE Fax# be non-functional please send SAEs to the 
designated SAE mailbox: clinicalsafetyop.phuseh@novartis.com) 
SAE Submissions must reference your Novartis Study Code:  COMB157AUS08T 
 
For medical emergencies, the contact is: 
 
Gaetano Bonifacio MD 
Medical Director 
US CD MA Hematology 
Novartis Pharmaceuticals Corporation                                    
One Health Plaza, 345/4th 
East Hanover, NJ 07936-1080 
Mobile  +1 610 427 3613 
gaetano.bonifacio@novartis.com 
 
6.3 
Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) 
of a serious adverse event according to institutional policy.   
6.4 
Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the 
Food and Drug Administration (FDA) by telephone or by fax.  Fatal or life threatening 
SAEs that meet the criteria for reporting to the FDA must be reported to the FDA within 
7 calendar days after awareness of the event.  All other SAEs that meet the criteria for 
reporting to the FDA must be reported to the FDA within 15 calendar days after 
awareness of the event.  A clear description of the suspected reaction should be provided 
along with an assessment as to whether the event is drug or disease related.    


 
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6.5 
Adverse event updates/IND safety reports 
The supporters (NOVARTIS and Celgene Corporation) shall notify the Investigator via 
an IND Safety Report of the following information: 
 
 Any AE associated with the use of drug in this study or in other studies that is 
both serious and unexpected. 
 Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. 
 
The Investigator must keep copies of all AE information, including correspondence with 
the supporters and the IRB/EC, on file (see Section 11.4 for records retention 
information). 
7 
Response Criteria 
Baseline lesion assessments must occur within  28 days of protocol therapy initiation or 
as indicated in Section 2, Schedule of Study Assessments. 
Efficacy assessments will be performed as delineated in Section 2, Schedule of Study 
Assessments Table.   
All partial and complete responses must be confirmed with another efficacy assessment 
no less than 4 weeks apart.  
Assessment for response will be made following the NCIWG 2008 CLL criteria for 
response (See Appendix F: NCIWG 2008 CLL Criteria for Response). 


 
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8 
Protocol Amendments/Deviations 
8.1 
Protocol amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and 
reviewed by Celgene Corporation and Novartis.  Amendments should only be submitted 
to IRB/EC after consideration of Celgene Corporation and Novartis review.  Written 
verification of IRB/EC approval will be obtained before any amendment is implemented.   
8.2 
Protocol deviations 
When an emergency occurs that requires a deviation from the protocol for a subject, a 
deviation will be made only for that subject.  A decision will be made as soon as possible 
to determine whether or not the subject (for whom the deviation from protocol was 
effected) is to continue in the study.  The subject’s medical records will completely 
describe the deviation from the protocol and state the reasons for such deviation.  In 
addition, the Investigator will notify the IRB/EC in writing of such deviation from 
protocol. 
Non-emergency minor deviations from the protocol will be permitted with approval of 
the Principal Investigator.  
9 
Data Management 
9.1 
Analyses and Reporting 
Data will be analyzed and reported after completion of treatment protocol. All subsequent 
data collected will be analyzed and reported in a follow-up clinical report.  
9.2 
Study auditing 
9.2.1 Investigator responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice 
(GCP) and in the US Code of Federal Regulations. 


 
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Investigators must enter study data onto CRFs or other data collection system.  The 
Investigator will permit study-related audits by Celgene or its representatives, IRB/EC 
review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to 
the facilities where the study took place, to source documents, to CRFs, and to all other 
study documents. 
 
9.2.2  Internal Monitoring 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database.  The Case Report 
Forms will be reviewed by Moffitt’s Internal Monitors, periodically, approximately every 
3 months, throughout the conduct of the trial.  The monitoring will include source data 
verification utilizing research subjects’ medical records. 
 
10   Statistical Considerations 
10.1 
Study Design/Endpoints 
This is a phase II, single institution, and non-randomized study of patients with Relapsed 
or Refractory CLL/SLL, utilizing a two-stage trial design. The primary endpoint for this 
trial is the combined complete and partial response rate (at 3 months-the end of cycle 3) 
to the protocol therapy. We anticipate this trial will have a CR+PR response rate of at 
least 55%.  
A two-stage design is employed for this trial. The null/unacceptable CR+PR response 
rate is ≤35% while the anticipated true response rate to the protocol treatment is at least 
55% for each disease cohort. At the first stage, 25 patients will be accrued to the trial. If 9 
or fewer of these patients respond, then the trial will be terminated early and the response 
rate to the protocol treatment will be deemed unacceptable (≤35%). Otherwise, if more 
than 9 patients respond during the first stage, an additional 31 patients will be enrolled to 
this trial during stage 2 for a total of 56 patients. If 25 or fewer of these 56 patients 
respond to the protocol treatment at the end of stage 2, no further investigation of the 
protocol treatment is considered warranted. On the other hand, if more than 25 patients 


 
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out of the 56 enrolled patients respond, the protocol treatment will be considered 
promising. If the true response rate is ≤35%, the probability of ending the trial at stage 1 
is 0.63. If, however, the true response rate is at least 55%, then the probability of ending 
the trial at stage 1 is only 0.04. This two-stage design has an overall alpha level of 0.047 
and a power of 0.90. 
10.2 
Sample Size/Accrual Rate  
Up to 56 patients will be enrolled into this study. During the interim analysis at the end of 
stage 1, the patient accrual to the trial will be not suspended while pending the interim 
analysis results unless the observed objective response rate among those patients whose 
objective response data are available is below 30%. The accrual rate will be 
approximately 2-3 patients per month. The entire accrual for this trial should be 
completed in about 1.5 years.  
10.3 
Stratification Factors 
There are no stratification factors planned for this study. 
10.4 
Data Analysis, Reporting and Exclusions Regarding Efficacy Endpoints 
The objective response (CR+PR) rate and clinical benefit rate (CR +PR +SD) will be 
summarized using both a point estimate and its exact confidence interval based on the 
binomial distribution.  
Progression-free survival (PFS), defined as the time from study entry to disease 
progression, relapse or death due to any cause, whichever is earlier, will be summarized 
with the Kaplan-Meier curve. Confidence intervals for the median and survival rates at 
different time points will be constructed if needed. The other secondary endpoint, overall 
survival (OS), will be analyzed similarly. Both of these two secondary endpoints will be 
reported descriptively. 
The intent-to-treat approach will be used for data analysis of this trial. That means all 
patients who receive at least one dose of the protocol treatment will be included in the 
interim and final data analyses. Patients who are lost to follow-up or drop out of study 
prior to their scheduled response evaluation time due to any reason will be treated as non-
responders for response determination and censored for time-to-event type of endpoints 


 
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at the time of their last assessment/follow-up if no relevant event has occurred by then. A 
secondary analysis that includes only all eligible patients may be conducted in addition to 
the primary analysis described above at the discretion of the trial PI and study 
biostatistician. Other subanalyses may also be considered on the basis of a subset of 
patients, excluding those for whom major protocol deviations have been identified (e.g., 
early discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.   
10.5 
Toxicity Monitoring and Stopping Rules 
All patients will be evaluable for toxicity and adverse events from the time of their first 
protocol treatment. Toxicity will be reported by type and severity according to the 
CTCAE version 4.0. 
During the entire study period, toxicity will be closely monitored by the PI and clinical 
trial coordinator of this study, even though no formal stopping rules are stipulated in this 
protocol. In the event that toxicity is thought to be excessive for the study patient 
population at any point of the trial, the patient accrual to the trial will be suspended 
immediately, pending a review of all toxicity data. A final decision will be made by the 
PI and sponsor as to whether the trial should be amended, terminated or continue accrual. 
Such decision should be filed with and pre-approved by the institutional Protocol 
Monitoring Committee. 
10.6 
Evaluation of Response 
All patients treated on the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note: By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.]  


 
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Patients in response categories 4-9 should be considered as failing to respond to treatment 
(disease progression).  Thus, an incorrect treatment schedule or drug administration does 
not result in exclusion from the analysis of the response rate.  
11 
Regulatory Considerations 
11.1 
Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki.  The review of this protocol by the 
IRB/EC and the performance of all aspects of the study, including the methods used for 
obtaining informed consent, must also be in accordance with principles enunciated in the 
declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations 
(CFR), Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to the 
relevant IRB/EC and obtaining written approval for this study.  The approval will be 
obtained prior to the initiation of the study. 
The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by 
the Investigator to the IRB/EC for approval.  The Investigator is also responsible for 
notifying the IRB/EC of any serious deviations from the protocol, or anything else that 
may involve added risk to subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved 
by the IRB/EC prior to use. 
11.2 
Informed consent 
The Investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study 
and the informed consent process should be recorded in the subject’s source documents.  


 
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The original consent form signed and dated by the subject and by the person consenting 
the subject prior to the subject’s entry into the study, must be maintained in the 
Investigator’s study files. 
11.3 
Subject confidentiality 
Celgene affirms the subject’s right to protection against invasion of privacy.  In 
compliance with United States federal regulations, Celgene requires the Investigator to 
permit representatives of Celgene Corporation and, when necessary, representatives of 
the FDA or other regulatory authorities to review and/or copy any medical records 
relevant to the study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Investigator to 
obtain such permission in writing from the appropriate individual. 
11.4 
Study records requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of 
the study and the distribution of the protocol therapy, that is copies of CRFs and source 
documents (original documents, data, and records [e.g., hospital records; clinical and 
office charts; laboratory notes; memoranda; subject’s diaries or evaluation checklists; 
SAE reports, pharmacy dispensing records; recorded data from automated instruments; 
copies or transcriptions certified after verification as being accurate copies; microfiches; 
photographic negatives, microfilm, or magnetic media; x-rays; subject files; and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical study; documents regarding subject treatment and drug accountability; 
original signed informed consents, etc.]) be retained by the Investigator for as long as 
needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval).  The 
Investigator agrees to adhere to the document/records retention procedures by signing the 
protocol. 


 
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11.5 
Premature discontinuation of study 
The Principal Investigator, institution, Celgene, and Novartis have the right to 
discontinue this study at any time for reasonable medical or administrative reasons.  
Possible reasons for termination of the study could be but are not limited to: 
 Unsatisfactory enrollment with respect to quantity or quality. 
 Inaccurate or incomplete data collection. 
 Falsification of records. 
 Failure to adhere to the study protocol. 
Any possible premature discontinuation would be documented adequately with reasons 
being stated, and information would have to be issued according to local requirements 
(e.g., IRB/EC, regulatory authorities, etc.). 


 
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12 Appendices 
Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied 
nor has the effect of the lenalidomide on human eggs and sperm.  Lenalidomide is 
structurally related to thalidomide.  Thalidomide is a known human teratogenic active 
substance that causes severe life-threatening birth defects.  An embryofetal development 
study in animals indicates that lenalidomide produced malformations in the offspring of 
female monkeys who received the drug during pregnancy.  The teratogenic effect of 
lenalidomide in humans cannot be ruled out.  Therefore, a risk minimization plan to 
prevent pregnancy must be observed. 
All study participants must be registered into the mandatory RevAssist® program, and be 
willing and able to comply with the requirements of RevAssist®. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been 
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months). 
The investigator must ensure that: 
 Females of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that she has an adequate level of 
understanding 
 Females NOT of childbearing potential acknowledge that she understands the 
hazards and necessary precautions associated with the use of lenalidomide 
 Male patients taking lenalidomide acknowledge that he understands that traces of 
lenalidomide have been found in semen, that he understands the potential 


 
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teratogenic risk if engaged in sexual activity with a female of childbearing 
potential, and that he understands the need for the use of a condom even if he has 
had a vasectomy, if engaged in sexual activity with a female of childbearing 
potential.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods related to this study: 1) for at 
least 28 days before starting lenalidomide; 2) throughout the entire duration of 
lenalidomide treatment; 3) during dose interruptions; and 4) for at least 28 days after 
lenalidomide discontinuation.  
The two methods of reliable contraception must include one highly effective method and 
one additional effective (barrier) method. FCBP must be referred to a qualified provider 
of contraceptive methods if needed. The following are examples of highly effective and 
additional effective methods of contraception:   
o Highly effective methods: 
 Intrauterine device (IUD) 
 Hormonal (birth control pills, injections, implants) 
 Tubal ligation 
 Partner’s vasectomy 
o Additional effective methods: 
 Male condom 
 Diaphragm 
 Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are 
not recommended.  If a patient is currently using combined oral contraception the patient 


 
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should switch to one of the effective method listed above.  The risk of venous 
thromboembolism continues for 4−6 weeks after discontinuing combined oral 
contraception. The efficacy of contraceptive steroids may be reduced during co-treatment 
with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding. 
Prophylactic antibiotics should be considered particularly in patients with neutropenia.  
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing 
potential who commit to complete abstinence, as outlined below. 
Before starting lenalidomide 
Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
prescribing lenalidomide.  The first pregnancy test must be performed within 10-14 days 
prior to prescribing lenalidomide and the second pregnancy test must be performed 
within 24 hours prior to prescribing lenalidomide.  The patient may not receive 
lenalidomide until the Investigator has verified that the results of these pregnancy tests 
are negative. 
Male Patients: 
Must agree to practice complete abstinence or agree to use a condom during sexual 
contact with pregnant females or females of childbearing potential throughout the entire 
duration of lenalidomide treatment, during dose interruptions and for at least 28 days 
following lenalidomide discontinuation, even if he has undergone a successful 
vasectomy.   
During study participation and for 28 days following lenalidomide discontinuation  
Female Patients: 


 
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 FCBP with regular or no menstrual cycles must agree to have pregnancy tests 
weekly for the first 28 days of lenalidomide treatment, including dose 
interruptions and then every 28 days throughout the remaining duration of 
lenalidomide 
treatment, 
including 
dose 
interruptions, 
at 
lenalidomide 
discontinuation, and at Day 28 following lenalidomide discontinuation.  If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for the 
first 28 days of lenalidomide treatment, including dose interruptions, and then 
every 14 days throughout the remaining duration of lenalidomide treatment, 
including dose interruptions, at lenalidomide discontinuation, and at Day 14 and 
Day 28 following lenalidomide discontinuation.   
 At each visit, the Investigator must confirm with the FCBP that she is continuing 
to use two reliable methods of birth control at each visit during the time that birth 
control is required.   
 If pregnancy or a positive pregnancy test does occur in a study patient, 
lenalidomide must be immediately discontinued. 
 Pregnancy testing and counseling must be performed if a patient misses her period 
or if her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide 
treatment must be temporarily discontinued during this evaluation. 
 Females must agree to abstain from breastfeeding during study participation and 
for at least 28 days after lenalidomide discontinuation. 
Male Patients: 
 Must practice complete abstinence or use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire 
duration of lenalidomide treatment, during dose interruptions and for at least 28 
days following lenalidomide discontinuation, even if he has undergone a 
successful vasectomy.   
 If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 


 
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Additional precautions 
 Patients should be instructed never to give lenalidomide to another person. 
 Female patients should not donate blood during therapy and for at least 28 days 
following discontinuation of lenalidomide. 
 Male patients should not donate blood, semen or sperm during therapy or for at 
least 28 days following discontinuation of lenalidomide. 
 Only enough lenalidomide for one cycle of therapy may be prescribed with each 
cycle of therapy.  
 
 
 


 
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Appendix B: ECOG Performance Status Scale 
 
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry 
out any work activities.  Up and about more than 50% of 
waking hours. 
3 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 


 
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Appendix C:  Cockcroft-Gault estimation of CrCl 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl):  
(Cockcroft, 1976; Luke 1990) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)__           
   (Males) 
 
72 x (serum creatinine, mg/dL) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)_    x 0.85         
   (Females) 
 
72 x (serum creatinine, mg/dL) 
 
 
 
 


 
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Appendix D:  Staging of Chronic Lymphocytic Leukemia 
 
Modified Rai clinical staging system  
Risk 
Stage 
Description 
Low 
0 
Lymphocytosis in blood or bone marrow 
Intermediate 
I 
Lymphocytosis + enlarged lymph nodes 
II 
Lymphocytosis + enlarged liver or spleen with or without 
lymphadenopathy 
High 
III 
Lymphocytosis + anemia (Hgb <11 g/dL) with or without 
enlarged liver, spleen, or lymph nodes 
IV 
Lymphocytosis + thrombocytopenia (platelet count 
<100,000/µL) with or without anemia or enlarged liver, spleen, 
or lymph nodes 
 
Binet Staging System  
Stage  
Description  
A 
Two or less lymphoid bearing areas enlarged*  
B 
Three or more lymphoid bearing areas enlarged*  
C 
Presence of anemia (Hgb <10.0 g/dL) or thrombocytopenia (platelet count 
<100,000/microL)  
* Five lymphoid bearing areas are possible: cervical, axillary, inguino-femoral, spleen, and liver. 
 
 


 
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Appendix E: Criteria for Treatment of CLL 
1. Weakness, night sweats, weight loss of ≥ 10% over a six month period, 
painful lymphadenopathy, or fever.  
2. Symptomatic anemia and/or thrombocytopenia (Rai stages III or IV; Binet 
stage C) 
3. Autoimmune hemolytic anemia and/or thrombocytopenia poorly responsive to 
corticosteroid therapy. 
4.  Progressive disease, as demonstrated by increasing lymphocytosis with a 
lymphocyte doubling time less than six months, and/or rapidly enlarging 
lymph nodes, spleen, and liver.  
5. Repeated episodes of infection. Hypogammaglobulinemia without repeated 
episodes of infection is not a clear indication for therapy.  


 
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Appendix F: NCIWG 2008 Response Criteria 
 
 
 
 Group A criteria define the tumor load, Group B criteria define the functions of the hematopoietic system (or marrow). 
*CR (complete remission): all of the criteria have to be met, and patients have the lack disease-related constitutional 
symptoms: PR (partial remission): at least two of the criteria of Group A plus one of the criteria of group B have to be met; SD 
is the absence of progressive disease (PD) and failure to achieve at lease a PR; PD: at least one of the above criteria of Group 
A or Group B has to be met. 
 Sum of the products of multiple lymph nodes (as evaluated by CT scans in clinical trials, or by physical examination in 
general practice). 
‡ These parameters are irrelevant for some response categories. 
 
 
PARAMETER 
Group A 
Lymphadenopathy 
 
Hepatomegaly 
 
Splenomegaly 
 
Blood Lymphocytes 
 
Marrow 
 
 
Group B 
 
Platelet count 
 
 
 
Hemoglobin 
 
 
Neutrophils‡ 
 
 
 
 
CR* 
 
None> 1.5 cm 
 
None 
 
None 
 
<4000/uL 
 
Normocellular, 
<30% 
lymphocytes, no B-lymphoid 
nodules, Hypocellular marrow 
defines Cri (5.1.6). 
 
 
>100 000/uL 
 
 
 
> 11.0 g/dL 
 
 
> 1500/uL 
 
 
PR* 
 
Decrease > 50% 
 
Decrease > 50% 
 
Decrease > 50% 
 
Decrease > 50% over baseline 
 
50% 
reduction 
in 
marrow 
infiltrate or B-lymphoid nodules 
 
 
 
> 100 000/uL or increase > 50% 
over baseline 
 
 
 
> 11 g/dL or increase > 50% 
over baseline 
 
> 
1500/uL 
or 
> 
50% 
improvement over baseline 
PD* 
 
Increase > 50% 
 
Increase > 50% 
 
Increase > 50% 
 
Increase > 50% over baseline 
 
 
 
 
 
 
Decrease of  > 50% from 
baseline secondary to CLL 
 
 
 
Decrease 
> 
2 
g/dL 
from 
baseline secondary to CLL 
 


 
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Appendix G:  NCI CTC Version 4.0 
 
Toxicity will be scored using NCI CTC Version 4.0 for toxicity and adverse event 
reporting.  A copy of the NCI CTC Version 4.0 can be downloaded from the CTEP 
homepage: (http://ctep.info.nih.gov).  All appropriate treatment areas have access to a 
copy of the CTC Version.  
 
 
 


 
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APPENDIX H:  Cairo-Bishop Definition of Tumor Lysis Syndrome 
(Cairo MS et al. Br J Haematol 2004) 
Table:  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (LTLS) 
Uric Acid 
≥ 476 μmol/l (≥ 8.0 mg/dl) or 25% increase from baseline 
Potassium 
≥ 6.0 mmol/l (≥ 6.0 mEq/l) or 25% increase from baseline 
Phosphorous 
≥1.45 mmol/l  (≥ 4.5 mg/dl) or 25 % increase from baseline 
Calcium 
≤ 1.75 mmol/l (≤ 7.0 mg/dl) or 25% decrease from baseline 
Laboratory tumor lysis syndrome (LTLS) is defined as either a 25% change or level above or below normal, as 
defined above, for any two or more serum values of uric acid, potassium, phosphate, and calcium within 3 days 
before or 7 days after the initiation of chemotherapy.  This assessment assumes that a patient has or will receive 
adequate hydration (± alkalinization) and a hypouricemic agent(s). 
Table:  Cairo-Bishop Definition of Clinical TLS 
The presence of laboratory TLS and one or more of the following criteria: 
1. Creatinine:  ≥ 1.5 ULN (age > 12 years or age adjusted) 
2. Cardiac arrhythmia / sudden death 
3. Seizure* 
ULN, Upper limit of normal 
*Not directly attributable to a therapeutic agent 
Table:  Cairo-Bishop Grading System for TLS 
Grade 
LTLS 
Creatinine 
Cardiac Arrhythmia 
Seizure 
0 
- 
≤ 1.5 x ULN 
None 
None 
1 
+ 
1.5 x ULN 
Intervention not 
indicated 
None 
2 
+ 
> 1.5 – 3.0 x ULN 
Non-urgent medical 
intervention indicated 
One brief generalized seizure; seizure(s) 
well controlled or infrequent; focal motor 
seizures not interfering with ADL 
3 
+ 
> 3.0 – 6.0 x ULN 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device 
Seizure in which consciousness is altered; 
poorly controlled seizure disorder; 
breakthrough generalized seizures despite 
medical intervention 
4 
+ 
> 6.0 x ULN 
Life-Threatening 
Seizures of any kind that are prolonged, 
repetitive, or difficult to control 
5 
+ 
Death* 
Death* 
Death* 
LTLS, laboratory tumor lysis syndrome; ULN, upper limit of normal; ADL, activities of daily living 
*Probably or definitely attributable to clinical TLS 
 


 
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