Clinical trial NCT02225275
Conditions: Recurrent Chronic Lymphocytic Leukemia Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Small Lymphocytic Lymphoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2016-03-31; Completion date: 2021-05-19
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well lenalidomide and obinutuzumab work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that has come back (recurrent) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as obinutuzumab, may interfere with the ability of cancer cells to grow and spread. Giving lenalidomide and obinutuzumab may work better in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. Overall response defined as achievement of complete response (CR) or partial response (PR).

SECONDARY OBJECTIVES:

I. Safety of the combination. II. Response according to prognostic markers at diagnosis. III. Time to next treatment. IV. Overall survival.

OUTLINE:

Patients receive obinutuzumab intravenously (IV) over 3-4 hours on days 1, 2, 8, and 15 of course 1 and day 1 of courses 2-6 and lenalidomide orally (PO) once daily (QD) on days 9-28 of course 1 and days 1-28 of all subsequent courses. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may continue to receive lenalidomide PO QD in the absence of disease progression or unacceptable toxicity.

Arms: arm 1: Patients receive obinutuzumab IV over 3-4 hours on days 1, 2, 8, and 15 of course 1 and day 1 of courses 2-6 and lenalidomide PO QD on days 9-28 of course 1 and days 1-28 of all subsequent courses. Treatment with obinutuzumab repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may continue to receive lenalidomide PO QD in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Lenalidomide intervention 2: Obinutuzumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2014-0115 
Protocol Title 
Combination of Lenalidomide and Obinutuzumab (GA101) in patients 
with Recurrent Chronic Lymphocytic Leukemia/Small Lymphocytic 
Lymphoma (CLL/SLL) 
Protocol Version 
16 
Version Date 
05/29/2019 
 
Protocol PI 
Alessandra Ferrajoli, MD 
Department 
Leukemia 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
123987 
 
 
 


PROTOCOL
TITLE:
STUDY NUMBER:
VERSION NUMBER:
TEST PRODUCTS:
INVESTIGATOR:
COMBINATION OF LENALIDOMIDE AND
OBINUTUZUMAB (GA101) IN PATIENTS WITH
RECURRENT CHRONIC LYMPHOCYTIC
LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA 
(CLL/SLL)
2014-0115
9 
Obinutuzumab (GA101) Lenalidomide
Alessandra Ferrajoli
Department of Leukemia, The University of Texas,M
D Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428,
Houston TX 77030
 Telephone: (713) 792 -206
Fax: (713) 794-4297
E-mail: aferrajo@mdanderson .org
SUB-INVESTIGATORS:   
STUDY COORDINATOR: 
Ana B Ayala
SUPPORT PROVIDED
BY:
PROTOCOL DATE:
Genentech, Inc.
Celegene Co.
06/11/2015
CONFIDENTIAL
This is a MD Anderson Cancer Center document that contains confidential 
information.  It is intended solely for the recipient clinical investigator(s) and 
must not be disclosed to any other party. This material may be used only 
forevaluating or conducting clinical investigations;any other proposed use
requires written consent from MD Anderson Cancer Center
Obinutuzumab (GA101) and Lenalidomide-MD Anderson Cancer Center
Protocol,Version 2014-0115


TABLE OF CONTENTS 
1. INTRODUCTION AND BACKGROUND ........................................................................ 3 
2. OBJECTIVES ............................................................................................................. 7 
3. STUDY DESIGN ........................................................................................................ 8 
4. PATIENT ELEGIBILITY .................................................................................................. 9 
5. TREATMENT PLAN ................................................................................................. 11 
6. STUDY MEDICATION ............................................................................................. 11 
7. CRITERIA FOR PATIENT DISCONTINUATION ........................................................ 19 
8. CLINICAL AND LABORATORY EVALUATIONS ....................................................... 19 
9. EVALUATION OF RESPONSE. .............................................................................. 21 
10. STATISTICAL  CONSIDERATIONS ........................................................................... 21 
11. REPORT!NG OF ADVERSE EVENTS .................................................................. 22 
12. AMENDMENTS  DEVIATIONS AND REGULATORY .............................................. 26 
REFERENCES ....................................................................................................................... 28 
LIST OF TABLES 
    Table 1 
Table 2 
 
Table 3 
Table 4 
Table 5 
Table 6 
Table 7 
Table 8 
 
 
 
 
 
Appendix 1 
Appendix 2 
Appendix 3 
 
Appendix 4    
           
      
     Appendix 5                    
Appenidx D 
Appendix E 
 
CLL11 study results .................................................................................. 5 
NCI grading scale for hematological toxicity in CLL/SLL 
studies  ........................................................................................................ 13 
Dose Modification for Cytopenia  ............................................................... 14 
Management of Obinutuzumab Infusion-Related Symptoms  .................. 15 
Dosage modifications for lenalidomide study drug  ................................. 16 
Dose level for lenalidomide  ...................................................................... 18 
Interim futility stopping boundaries  ........................................................... 22 
Interim toxicity stopp ing boundaries  ......................................................... 22 
LIST OF APPENDICES 
ECOG Performance Status ....................................................................... 31 
 Study Calendar  .......................................................................................... 32 
Current NCI Common Terminology Criteria for Adverse 
Events (CTCAE)  ........................................................................................ 33 
     Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
     Acceptable Birth Control Methods                                                          34 
  
 
     FDA  MDACC SAE reporting   ...................................................................... 39 
Obinutuzumab package insert ……………………………………………..40 
Revlimid package insert……………………………………………………….55


 
•
.
 
 
 
 
 
1. 
INTRODUCTION CHRONIC LYMPHOCYTIC LEUKEMIA 
Chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLLISLL) is a 
lymphoproliferative disorder that accounts for approximately 30% of adult leukemias and 25% 
of non-Hodgkin's lymphomas (NHLs). In 2010, there were approximately 14,900 new cases 
in the United States (U.S.: American Cancer Society 2010) . The median age at diagnosis is 
72 years . 
 
CLL/SLL is a disease of B-cell origin, with a characteristic immunophenotype (CDS 
positive, CD23 positive, weak surface expression of CD19, CD20, CD79b, and lgM or 
lgD) and blood smear morphology (mature lymphocytes, Gumprecht shadows) 1 
 
Natural History 
CLL/SLL often is an indolent disease that does not need treatment for many years . Many 
CLL/SLL patients initially present with lymphocytosis in the absence of other symptoms . 
However, when the disease advances , there is the appearance of lymphadenopathy , 
hepatomegaly or splenomegaly , and bone marrow failure . B-symptoms (i.e., fever , night 
sweats, and weight loss), general fatigue , and recurrent infections are common in patients 
with late-stage CLLISLL but can occasionally be found earlier in the course of the disease . 
 
The individual survival time of CLLISLL patients is highly variable, with a range of less than 2 
years to 20 years or more. There are two clinical staging systems (Rai and Binet) currently in 
use for CLLISLL that allow a rough division of patients into three prognostic groups : good, 
intermediate, and poor prognosis. In the Rai staging system , the low-risk (Rai Stage 0) group 
accounts for 31% of all patients with CLL/SLL , and these patients 
have a median survival of more than 10 years 2. Intermediate-risk (Rai Stages I and II) 
patients (61% of all CLLISLL patients) have a median survival of 7 to 9 years . High-risk (Rai 
Stages Ill and IV) patients (8% of all CLL/SLL patients) have a median survival of 5 
years 3 In the Binet staging system, CLL/SLL is divided into three stages of A, B, and C 
4 
 
 
Current Management 
Because there is no survival benefit associated with early intervention 5, asymptomatic 
patients with early-stage CLL/SLL (Binet Stages A and B) are usually not treated but are 
followed with a "watch and wait" approach. Treatment is usually initiated when patients 
become symptomatic or progress to late stage; 50% of CLL/SLL patients ultimately require 
therapy . 
 
In the recent past, first-line treatment of CLLISLL has evolved from single-agent therapy with 
alkylating drugs (e.g., chlorambucil [Cib]) to combination therapy incorporating 


 
-
 
 
 
 
 
purine analogues (i.e., fludarabine , pentostatin, and cladribine) and monoclonal 
antibodies (i.e., rituximab and alemtuzumab) 6 9. Currently , fludarabine , 
cyclophosphamide , and rituximab (FCR) is the standard of care in fit  previously 
untreated patients with CLLISLL requiring treatment 9. 
 
In patients with recurrent disease the choice of the treatment depends on the duration of the 
first or previous lines of treatment, age, comorbidities, cytogenetic abnormalities (absence of 
del11q and 17p) and donor availability. The options include retreatment as in first line 
therapy in patients with long response to first line therapy (>3 years) or treatment with other 
agents with activity in this disease . The National Comprehensive Cancer Care Network, 
CLL/SLL Guidelines , 2013 include: bendamustine ± rituximab, high dose methylprednisolone  
(HDMP) + rituximab; ofatumumab; alemtuzumab ± 
rituximab and lenalidomide ± rituximab) . 
 
OBINUTUZUMAB 
 
Obinutuzumab (GA 101, R05072759), is a glycoengineered, humanized, type II anti- CD20 
monoclonal antibody (mAb). Obinutuzumab was derived by humanization of the parental B-
Ly1 mouse antibody and subsequent glycoengineering leading to the following 
characteristics : high antibody-dependent cellular cytotoxicity (ADCC); high affinity binding to 
the CD20 antigen ; low complement-dependent cytotoxicity (CDC) activity ; and antibody 
dependent cellular phagocytosis (ADCP) through recruitment of FcyRIII positive immune 
effector cells such as natural killer (NK) cells, macrophages and monocytes; and high direct 
cell death induction. Given the direct cell death inducing 
properties of obinutuzumab and the significantly enhanced ADCC in preclinical assays, it is 
possible that obinutuzumab may have greater efficacy than the widely used anti- 
CD20-mAb rituximab. 
 
Obinutuzumab has been approved by the FDA in combination with chlorambucil for the initial 
treatment of patients with CLL/SLL.  Please refer to Appendix D (Obinutuzumab package 
insert) for additional information. Phase I-III studies have been conducted and demonstrated 
safety and efficacy of obinutuzumab as single agent.  8021004 (CLL11; NCT01010061)   is a 
large randomized phase 3 trial investigating first-line chemoimmunotherapy  in 663 CLUSLL 
patients with comorbidities , i.e. patients typically treated in daily practice. Treatment-na"ive  
CLL/SLL patients with a Cumulative Illness Rating Scale (CIRS) total score >6 and/or an 
estimated creatinine clearance (CrCI) <70 mllmin were eligible. Patients received Clb alone 
(0.5 mg/kg po d1, d15 q28 days, 6 cycles), GCib (100 mg iv d1, 900 mg d2, 1000 mg d8, d15 
of cycle 1, 1000 mg d1 cycles 
2-6), or RCib (375 mg/m2 iv d1 cycle 1, 500 mg/m2 d1 cycles 2-6) . Primary endpoint was 
investigator-assessed progression-free survival (PFS). Response rates, minimal residual 
disease (MRD) , and overall survival (OS) were key secondary efficacy endpoints. Final 
results of the stage 2 analysis: Median observation time was 19 months. The GCib and RCib 
treatment arms were well balanced for baseline characteristics . Median age, CIRS 


 
THerronscore, and CrCI at baseline were 73 years , 8, and 63 mllmin respectively. Key efficacy 
and safety results are shown in the table 1. 
 
Table 1 CLL11 study results. 
 
            Stage 
                                GCib                                           RCib 
 
 
 Stage                  
                                                               
  
Total N = 663 
N = 333 
N = 330  
 
Overall response rate,%* 
Complete response rate, 
%* 
MedianPFS,month
s HR, Cl, p 
Median OS, 
months HR, Cl, 
p 
Grade 3-5 adverse events, 
%** Infusion-related 
reaction*** Neutropenia*** 
Infections 
 
 
78 
65 
21 
7 
 
26,7# 
15.2 
0.39, 0.31-0.49 , <.0001 
 
NR 
NR 
0.66, 0.41-1.06, 0.09 
 
66 
47 
20 
4 
33 
27 
7 
7 
 
• At the end of treatment 
•• During treatment 
 ••• No deaths (grade 5 AE) in these categories  
# Still immature, 10% at risk at time of median 
 
The PFS benefit of GCib over RCib was supported by all pre-planned subgroup analyses 
(including the cytogenetic subgroups 17p-, 11q-, 12+, 13q-). The number of patients with 
MRD negative blood samples at end-of-treatment was more than 10-fold higher with GCib 
compared with RCib (63/214 [29.4%] vs. 6/243 [2.5%]). Grade 3-4 
infusion-related reactions with GCib occurred at first infusion only. Updated results of the 
stage 1 analysis: Median observation time was 23 months. Confirming the primary stage 1 
results, GCib or RCib compared with Clb alone was associated with statistically significant 
and clinically meaningful improvement in PFS (GCib vs. Clb: HR 0.18 , Cl 
0.13-0.24, p<.0001, RCib vs. Clb: HR 0.44, Cl 0.34-0.57 , p<.0001). The updated median 
PFS in GCib, RCib and Clb were 26.7 , 16.3 and 11.1 months, respectively . Updated OS 
analysis demonstrated a benefit of GCib over Clb (HR 0.41, Cl 0.23-0.74, p=0.002). OS 
analysis for RCib over Clb showed HR 0.66, Cl 0.39-1.11 , p=0.113. At the data cut-off, 9%, 
15%, and 20% of the patients in the GCib, RCib, and Clb arms, respectively, had died. OS 
medians were not reached. In this study, obinutuzumab , in combination with Clb (GCib 
regimen) demonstrated statistically significant and clinically meaningful prolongation of PFS, 
and higher complete response rate and MRD negativity rate compared with RCib in 
previously untreated CLL patients with comorbidities . Infusion- related reactions and 
neutropenia were more common with GCib without an increase in infections . Furthermore , 
GCib vs. Clb alone demonstrated a prolongation of OS10. 


 
 
.
. 
.
 
 
 
     Lenalidomide 
 
Lenalidomide is an immunomodulatory agent with activity in the treatment of activity in 
multiple myeloma and various lymphoproliferative disorders 11. In CLLISLL, lenalidomide 
alters the tumor microenvironment by modulating cytokine production by dendritic cells as 
well as modifying expression of co-stimulatory molecules by T-cells , potentially repairing 
defective humoral immunity and defective T -cell to B-cell synapse format ion characteristic 
of CLL12. 
 
Please refer to Appendix E (lenalidomide package insert) for additional information 
 
In 2006 Chanan-Khan et al published the results of a phase II trial with lenalidomide in 
relapsed or refractory 8-cell CLL/SLL patients. Lenalidomide was administered orally at 25 
mg on days 1through 21 of a 28-day cycle. Patients were to continue treatment until disease 
progression, unacceptable toxicity , or complete remission. Rituximab was added to 
lenalidomide on disease progression. The overall response rate was 47%, with 9% of the 
patients attaining a complete remission. Fatigue, thrombocytopenia , and neutropenia were the 
most common adverse effects noted in 83%, 78%, and 78% of the patients, 
respectively  
NCT00267059 study investigated the activity of lenalidomide in patients CLLISLL. 
Lenalidomide was given at 10 mg daily with dose escalation up to 25 mg daily . Three patients 
(7%) achieved a complete response (CR), one a nodular partial remission, and 10 patients a 
PR, for OR rate of 32%. The most common toxicity was myelosuppression , and the median 
daily dose of lenalidomide tolerated was 10 mg 14 
 
Chen and collaborators conducted a trial with lenalidomide in untreated patients as single-
agent. Using a starting dose of lenalidomide 10 mg/d for 21 days of a 28-day cycle and 
weekly 5-mg dose escalations to a target of 25 mg, they encountered severe 
toxicities (tumor lysis, fatal sepsis) in the first two patients enrolled. The study was halted and 
the protocol amended to a more conservative regimen: starting dose of lenalidomide 
2.5 mg with monthly escalations to a target dose of 10 mg, and extended tumor lysis 
prophylaxis and monitoring. Twenty-five patients were enrolled on the amended protocol. No 
further tumor lysis events were reported. Tumor flare was common (88%) 
but mild. Grade 3 to 4 neutropenia occurred in 72% of patients, with only five episodes of 
febrile neutropenia. The overall response rate was 56% (no complete responses) 15 
 
Lenalidomide in combination with Rituximab (NCT00759603) (Phase II) 
In a multicenter phase II study of the CLL Research Consortium , previously untreated 
patients with CLLISLL (69 patients) were treated with lenalidomide (initial dose of 2.5 mg/d, 
with dose escalation up to 10 mg/d; given 21 days of a 28-day cycle) combined with 
rituximab (dose escalated to 375 mg/m2 cycle 1; 375 mg/m2 weekly for 4 weeks in 


 
 
. 
. 
 
 
 
 
 
cycle 2, then on day 1for cycles 3-7) (James et al. abst Blood 2011; 118:3489-3498) . 
Patients in this trial were stratified by age group (age< or 65 years) . Only 59% of the 
older patient group completed the planned 7 cycles of therapy compared with 90% of 
patients younger than 65 years . Tumor flare reactions occurred in 71% of patients, but were 
grade 1 or 2 in nearly all cases . The most common grade 3 or 4 toxicity was neutropenia , 
which was reported in 49% of patients. Neutropenic fever occurred in 4 patients (6%). 
Among evaluable patients, the ORR in those younger than 65 years was 94% (CR in 20%) 
and the ORR in older patients was 77% (CR in 9%). 
 
NCT00759603 is a single center, phase II trial for previously treated patients . Rituximab was 
administered intravenously on days 1, 8, 15, and 22 during cycle one and once every 4 
weeks on day 1 for cycle two to 12. Lenalidomide was started on day 9 of cycle one at 10 
mg per day and administered continuously . Treatment duration was planned 12 cycles but 
could continue lenalidomide indefinitively beyond 12 cycles if there was a significant clinical 
benefit, such as ongoing partial or complete response. 
 
The OR was 66%, including 12% complete responses and 12% nodular partial remissions. 
Time to treatment failure was 17.4 months. Median OS has not been reached; estimated 
survival at 36 months is 71%. The most common grad 3 or 4 toxicity was neutropenia (73% 
of patients) . Fourteen patients (24%) experienced a grade 3 to 4 infection and febrile episode 
. There was one episode of grade 3 tumor lysis; one patient experienced renal failure during 
the first cycle of therapy , and one venous 
thromboembolic event occurred during the study 16. 
 
STUDY  RATIONALE 
 
Monoclonal antibody therapy has been found to potentiate the activity of 
chemotherapeutic agents . There is sinergystic activity between rituximab and 
lenalidomide against CLLISLL and non-Hodgkin lymphoma in vitro 11 
Furthermore, the 
results our phase II trial of lenalidomide in combination with rituximab in relapsed or refractory 
CLL/SLL support the clinical activity of this combination 16 
 
Based on the promising results from the lenalidomide plus rituximab combination in terms of 
both efficacy and safety in relapsed/refractory patients and on the increasing data suggesting 
the higher efficacy of the second generation of anti CD20 monoclonal antibodies in B cell 
malignancies , we aim to test the effect of combining lenalidomide to obinutuzumab in 
patients with recurrent CLLISLL of all ages. 
 
 
2. PRIMARY OBJECTIVES 
 
The primary end point will be overall response defined as CR or PR. 


 
 
 
 
 
 
 
SECONDARY 
 
The secondary end points will be safety of the combination , response according to 
prognostic markers at diagnosis, time to next treatment and overall survival. 
 
3. 
STUDY DESIGN DESCRIPTION OF THE STUDY 
This is a single arm phase II study of Combination of Lenalidomide and Obinutuzumab in 
Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL-SLL) with 
recurrent disease . Up to 30patients will be enrolled from M. D. Anderson Cancer Center, at a 
rate of 1-3patients per month. The primary efficacy endpoint is overall response and safety is 
one of the secondary endpoints. We will monitor futility and safety of the treatment 
combination using a Bayesian design by Thall, Simon and Estey, in cohort size of 10. 
 
Response to treatment will be assessed according to NCI-WG 2008 working group criteria 
at 3, 6 months from the beginning of therapy and every 6 months thereafter . The investigator 
assessment of response and progression will be considered primary for all endpoints 
described in the study. 
 
The estimated patient accrual is 1-3 per month. And the trial accrual time is estimated to be 
about 10-20 months. The end of study is defined as 5 years after the last patient was 
enrolled (unless all patients have died) . 
 
OUTCOME  MEASURES 
 
Efficacy Outcome Measures 
 
Response will be assessed by means of clinic visits , complete blood counts, imaging if 
clinically indicated  radiographic images as clinically indicated). 
 
 
Clinic visits (this will include vital signs and physical exam) at the University of Texas, M D 
Anderson Cancer Center (UTMDACC) are required after 3, 6 cycles (obinutuzumab and 
lenalidomide) and 12 cycles (lenalidomide) and once every 6 cycles thereafter . Hematology 
complete blood counts (white blood cells , hemoglobin, platelets and differential) will be 
monitored once weekly for the first five weeks and once every two weeks in case of dose 
increase until a stable, dose of lenalidomide has been established for the specific patient. 
Blood will be drawn for routine tests. 
 
Bone marrow biopsy and aspiration will be performed and evaluated by flow cytometry after 
3, 6 cycles (obinutuzumab and lenalidomide) and after 12 cycles (lenalidomide) . If patients 
stay on the study past 12 cycles, once every 6 cycles , they will have if clinically indicated a 
bone 


 
 
 
 
 
 
 
marrow biopsy and aspirate evaluated by flow cytometry to check the status of the 
disease . 
 
Safety Outcome Measures 
 
Hematology complete blood counts (white blood cells, hemoglobin, platelets and differential) 
will be monitored once weekly for the first five weeks and once every two weeks in case of 
dose increase until a stable dose of lenalidomide has been established for the specific patient 
(the once every two weeks laboratory monitoring will not apply if the dose is decreasing for 
non-hematological or laboratory measurable toxicity), and then every four weeks thereafter. 
Serum chemistry basic metabolic profile (sodium, potassium, BUN, creatinine and glucose) 
will be monitored once a week for the first five 
weeks and then once every two weeks until a stable dose of lenalidomide has been 
established for the specific patient and then every four weeks thereafter . 
 
Additionally , beta-2-microglobulin , lymphocyte subsets, immunoglobulin levels will be 
performed and evaluated by flow cytometry after 3, 6 cycles (obinutuzumab and 
lenalidomide) and after 12 cycles (lenalidomide). 
 
4. 
PATIENT ELEGIBILITY INCLUSION CRITERIA 
 
Patients must meet the following criteria for study entry: 
 
• 
Age 18 years or older at the time of signing informed consent. Able to understand and 
to provide voluntarily informed consent; 
 
• 
Have documented CLL/SLL according to NCI criteria; 
 
• 
Recurrent or refractory disease according to NCI criteria; 
 
• 
Patient are eligible if they have received one or more prior treatment ; 
 
• 
ECOG performance status of 0-2 (Appendix 1); 
 
• 
Life expectancy > 6 months; 
 
• 
Adequate renal function indicated by serum creatinine less or equal to 2 mg/dl; 
 
• 
Adequate hepatic function indicated as total bilirubin less or equal to 2 mg/dl and 
ALT/GPT less or equal to two times the upper normal limit; 
 
• 
Disease free of prior malignancies for 3 years with exception of currently treated basal 
cell squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast. 
Patients with malignancies with indolent behavior such as prostate cancer treated with 
radiation or surgery can be enrolled in the study as long as they have a reasonable 
expectation to have been cured with the treatment modality received; 
 
• 
No prior history of myelodysplastic syndrome or other myeloid malignancy ; 


 
 
 
 
 
 
• 
All participants must be registered into the mandatory Revlimid REMS® program, and 
be willing and able to comply with the requirements of the  Revlimid REMS® ; 
• 
Females of childbearing potential (FCBP) must have a negative serum and/or urine 
pregnancy test with a sensitive of at least 50 miU/mL within 10-14 days and again within 
24 hours prior to prescribe lenalidomide for cycle 1 (prescriptions must be filled within 7 
days as required by Revlimid REMS®) 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. 
 
 
Revlimid(REMS) is available to patients through a restricted distribution program called 
the REVLIMID Risk Evaluation and Mitigation Strategy (REMS)™ (formerly known as the 
RevAssist® program). 
 
Upon consent and confirmation of protocol eligibility, patients will be required to complete a 
Revlimid REMS enrollment form in order to receive their clinical trial supply of Revlimid 
directly from Celgene. 
 
For more information visit www .Cel geneRi skManagement.com or call the Celgene 
Customer Care Center at 1-888-423-5436 
 
 
EXCLUSION CRITERIA 
 
Patients who meet any of the follow ing criteria will be excluded from study entry: 
 
• 
Known sensitivity to lenalidomide or other thalidomide derivatives or anti CD20; 
 
• 
Documented prolymphocytic leukemia (prolymphocytes more than 55% in the 
blood); 
• 
Known history of infection with Human immunodeficiency virus (HIV) or Human T Cell 
Leukemia Virus  1 (HTLV-1); 
 
• 
Serologic status reflecting active hepatitis B or C. Patients with hepatitis B (HBV) 
antibody positive but who have positivity for Hepatitis B surface antigen (HBsAg) or anti 
Hepatitis B core antibody (anti-HBc) and patients who are positive for anti-HCV will need 
to have a negative PCR (viral HBV DNA or HCV RNA) result prior to enrollment. Those 
who are HBsAg positive or HBV DNA positive and those who are positive for HCV 
(RNA) will be excluded; 
 
• 
Pregnant or breast feeding females ; 
 
• 
History of tuberculosis treated within the last five years or recent exposure to 
tuberculosis ; 


 
 
 
 
 
 
 
• 
Any serious medical condition, laboratory abnormality, or psychiatric illness that 
places the subject unacceptable risk if he/she were to participate to the study; 
 
• 
Patients with a recent history of deep vein thrombosis or pulmonary embolus , in the six 
months prior to enrollment are not eligible for this study. 
 
 
5. 
TREATMENT PLAN 
 
This is a single arm phase II study of Combination of Lenalidomide and Obinutuzumab in 
Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL-SLL) with 
recurrent disease. 
 
Obinutuzumab will be given 100 mg iv d1, 900 mg iv d2 and 1000 mg d8(+/-3 days) and d15 
(+/-3 days) for the first cycle, and 1000 mg d1(+/-10 days) along cycles 2-6 in a 28 days cycle. 
Lenalidomide will be given at  5 mg per day from day 9 until day 56 and at 10 mg per/day from 
day 57 until progression or excessive toxicity. See Study Calendar (Appendix 2). 
 
Patients will self-administer lenalidomide daily. 
 
This research study protocol allows the patient to receive up to 9 infusions of Obinutuzumab . 
 
Response will be evaluated after three , six and twelve cycles and every 6 months 
thereafter . 
 
The estimated patient accrual is 3-6 per month. And the trial accrual time is estimated to be 
about 10-20 months. The end of study is defined as 5 years after the last patient was 
enrolled (unless all patients have died). 
 
 
 
6. 
STUDY MEDICATION FORMULATION , STORAGE , AND PREPARATION 
 
 
Obinutuzumab 
Formulation 
Obinutuzumab is provided as a single-use vial. Each vial contains a sterile liquid formulation 
in a 50-mL pharmaceutical-grade glass vial containing a nominal dose of 1000 mg of 
obinutuzumab . 
 
Storage 
The recommended storage conditions for the obinutuzumab drug product are between 2°C 
and 8°C, protected from light. Chemical and physical in-use stability for obinutuzumab 
dilutions in 0.9% sodium chloride (NaCI) at concentrations of 
0.2 -20 mg/mL have been demonstrated for 24 hours at 2°C -8°C and an additional 24 
hours at ambient temperatu re and ambient room lighting. 


 
 
 
 
 
 
 
Split dosing 
Split dosing: Splitting the first dose of obinutuzumab  in Cycle 1 is mandatory. The first dose 
(1000 mg) must be administered over Days 1 and 2 (100 mg on Day 1 and 900 mg 
on Day 2). 
 
 
Obinutuzumab drug product intended for IV infusion is prepared by dilution of the drug product 
into an infusion bag containing 0.9% NaCI. 
 
Lenalidomide 
 
 
Formulation and Storage 
Lenalidomide is provided as pills. Lenalidomide will be obtained by the Revlimid REMS 
program  
 
DOSAGE AND ADMINISTRATION 
 
Obinutuzumab 
 
Obinutuzumab administered by IV infusion for up to 6 cycles (28-day cycles): 
 
• 
On Cycle 1, Day 1, 100 mg obinutuzumab will be administered 
 
• 
On Cycle 1, Day 2, 900 mg of obinutuzumab will be administered 
 
• 
On Cycle 1, Days 8 (+/-3 days) and 15 (+/-3 days), 1000 mg of obinutuzumab will be 
administered. 
 
• 
On Cycles 2 -6, Day 1 (+/-10 days), 1000 mg of obinutuzumab will be administered 
 
 
 
Obinutuzumab should be given as a slow IV infusion through a dedicated line. IV infusion 
pumps should be used to control the infusion rate of obinutuzumab . Do not administer as an 
IV push or bolus. 
 
Premedication Requirements 
 
 
Infusion-Related Reactions (IRR) 
Since some patients may develop hypersensitivity or other IRRs to obinutuzumab , pre- 
medication is recommended to reduce the risk of infusion reactions as outlined below: 
• 
Cycle 1, Days 1 and 2, all patients require pre-medication with: 
 
IV glucocorticoid : dexamethasone (20 mg) or methylprednisolone (80 mg) 
administered at least one hour prior to obinutuzumab infusion. 
An oral acetaminophen (1000 mg) and an antihistamine such as diphenhydramine 
(50 mg) administered at least 30 minutes before starting each obinutuzumab 
infusion. 


 
 
 
 
 
 
 
 
 
If a patient experiences any grade infusion reaction during infusion, adjust the infusion as 
outlined below: 
• 
Grade 4 (life threatening): Stop infusion and discontinue therapy. 
 
• 
Grade 3 (severe): Temporarily interrupt infusion and treat symptoms. Upon resolution 
of symptoms, restart infusion at no more than half the previous rate (the rate being 
used at the time that the infusion reaction occurred) and, if patient does not experience 
any infusion reaction symptoms, infusion rate escalation may resume at the increments 
and intervals as appropriate for the treatment dose. 
• 
Grade 1-2 (mild to moderate): Reduce infusion rate and treat symptoms. Upon 
resolution of symptoms, continue infusion and, if patient does not experience any 
infusion reaction symptoms, infusion rate escalation may resume at the increments and 
intervals as appropriate for the treatment dose. 
 
Dosage Modification and Toxicity Management 
Assessment of Hematologic Toxicities 
Dose modification decisions for patients with cytopenia (below the lower limit of the normal 
range) at baseline will be based on the NCI sponsored Working Group (NCI-WG) grading 
scale for hematologic toxicity in CLL/SLL studies9  (Table 2). For patients with a 
normal neutrophil count, platelet count , and/or hemoglobin value at baseline, the NCI 
CTCAE, v4.0, will be used. 
 
Table 2  NCI grading scale for hematological toxicity in CLLISLL studies. 
 
Decrease in 
platelets or Hb from 
pretreatment 
Grades 
ANC/IJL 
No change to 10% 
0 
2000 
11%-24% 
1 
1500 and <2000 
25%-49% 
2 
1000 and <1500 
50%-74% 
3 
500 and <1000 
75% 
4 
<500 
 
Dosage Modifications 
No reduction in the dose of obinutuzumab is allowed. Splitting the first dose of 
obinutuzumab in Cycle 1 is mandatory. The first dose (1000 mg) must be administered 
over Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2) . Infusions should be 
interrupted or slowed if patients experience infusion reactions (see "Management of 
infusion related reactions and anaphylaxis" paragraph). If a planned dose of obinutuzumab 
is missed, it should be administered as soon as possible. 


 
 
 
 
 
 
 
The guidelines for obinutuzumab dose delay due to Grade 3 or 4 cytopenia are outlined 
in Table 3. 
 
Table 3 
Dose Modification for Cytopenia 
 
Grade 
Obinutuzumab 
Grade 3 or 
4 cytopenia 
No reduction in the dose of obinutuzumab is allowed. A dose 
delay is allowed if clinically indicated. If improvement to Grade 
2, administer full dose 
Grade 1 or 
2 cytopenia 
No dose reduction or delay 
a   In patients with cytopenia at baseline, dose modifications will be based on the NCI 
grading scale for hematological toxicity in CLL/SLL studies (see Appendi x 3) 
b 
Or baseline 
 
  Administration of Granulocyte Colony-Stimulating Factor 
  G-CSF may be administered as primary prophylaxis in each cycle of therapy, as per the 
  American Society of Clinical Oncology (ASCO) guidelines or each site's institutional  
  standards. 
 
Hepatitis 8 Virus Reactivation 
Positive serology for Hepatitis B is defined as positivity for Hepatitis B surface antigen 
(HBsAg) or Hepatitis B core antibody (anti-HBc). Patients who are positive for anti-HBc may 
be considered for inclusion in the study on a case-by-case basis if they are Hepatitis B viral 
DNA negative and are willing to undergo ongoing HBV DNA testing by real-time PCR. 
Patients with positive serology may be referred to a specialist for appropriate monitoring and 
management. 
 
For the subset of patients who are Hepatitis B viral DNA negative and anti-HBc positive and 
have undetectable Hepatitis B viral DNA levels at screening, Hepatitis B viral DNA levels 
must be followed regularly. 
 
 
Management of Infusion-Related Reactions and Anaphylaxis 
Please refer to Section "Premedication requirements" for information relating to concomitant 
medications. Medications (including subcutaneous epinephrine , corticosteroids, and 
intravenous diphenhydramine) and resuscitation equipment should be available for 
immediate use. 
 
Life-Threatening Infusion-Related Reactions and Anaphylaxis 
In the event of a life-threatening IRR (which may include pulmonary or cardiac events) or lgE-
mediated anaphylactic reaction, obinutuzumab should be discont inued and no additional 
obinutuzumab should be administered (see Table 4). Patients who 
experience any of these reactions should receive aggressive treatment of symptoms and will 
be discontinued from study treatment. 


 
 
 
 
 
 
 
Table 4 
Management of Infusion-Related Symptoms 
 
Infusion-Related Symptoms 
Guidance 
Grades 1-2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
Grade 4
• Slow or hold infusion 
• Give supportive treatment 
• Upon symptom resolution, may resume infusion 
rate escalation at the investigator's discretion c 
 
• Discontinue infusion 
• Give supportive treatment b 
• Upon symptom resolution, may resume infusion rate 
escalation, at investigator discretion 
• Note:  If the same adverse event recurs with the 
same severity , treatment must be permanently 
discontinued. 
 
 
Tumor Lysis Syndrome 
For patients with evidence of TLS, obinutuzumab should be discontinued and the patient 
treated as clinically indicated. Following the complete resolution of TLS complications , 
obinutuzumab may be re administered at the full dose during the next infusion in conjunction 
with prophylactic therapy . 
 
Lenalidomide 
 
Lenalidomide will be provided to research subjects for the duration of their participation in 
this trial at no charge to them or their insurance providers and in accordance with the 
Revlimid REMS® program of Celgene Corporation . Per standard Revlimid REMS ® 
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 be 
filled within 14 days, unless the patient is a female of childbearing potential, in which case 
the prescription must be filled within 7 days. Only enough lenalidomide for one cycle will be 
supplied to the patient each cycle. 
 
Lenalidomide will be given at 5  mg per day, day 9-56, followed by 10 mg per day, 
day 57 until end of treatment. Lenalidomide will start on day 9 and continued for one 
year with the possibility to prolong the end of treatment until progression or excessive 
toxicity. Patients will self administer lenalidomide daily, per mouth. 
 
Dosage modification and Toxicity management of lenalidomide 
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 . 
 
 
The dose of lenalidomide will be adapted depending on the assessment of toxicity . The 
evaluation of potential treatment-induced toxicity, in particular of hematological toxicity, in 
patients with advanced CLLISLL required careful consideration. At diagnosis, in fact, 
cytopenia could be the expression of progressive bone marrow failure. As a consequence, 
dose modification decisions for patients with cytopenia (below the lower limit of the normal 
range) at baseline will be based on the NCI grading scale for haematological toxicity in 
CLL!SLL studies (see Table 2). For patients with a normal neutrophils count, platelet count 
and or hemoglobin value at baseline, the NCI common terminology criteria for adverse 
events (CTCAE) version 4.0 will be used (Appendix 3). 
 
For lenalidomide the dose reduction is describe below. 
 
Table 5 Dosage modifications for lenalidomide study drug. 
 
 
Lenalidomide 
Sustained (>7 days) Grade 3 neutropenia 
or Grade 3 associated to fever > 38.5 C 
or Grade 4 neutropeniaa 
• administer G-CSF as clinical indicated 
• Follow CBC weekly until resolution 
or stabilization 
• If improvement to  </= Grade 2*, implement 
one 
d
d
ti
t
d
ti
th
Thrombocytopeniaa 
Grade 4 
• 
Hold (interrupt dose) for a maximum of 4 
weeks and eventually transfuse platelets 
• 
Follow CBC weekly until resolution 
or stabilization 
• 
If improvement to  </= 5 Grade 2*, 
implement one dose reduction step 
and continue therapy 
Not desquamating (blistering) 
rash Grade 3 
 
 
 
 
 
 
Grade 4
• 
Hold (Interrupt) the dose and follow weekly 
until resolution or stabilization 
• 
If the toxicity resolved to grade 1, 
implement one dose reduction step 
and 
continue therapy 
Desquamating (blistering) rash 
Any grade 
•
Discontinue lenalidomide study drug
Erythema multiforme 
Grade 3-4 
•
Discontinue lenalidomide study drug 
Neuropathy 
Grade 3 
 
 
 
 
Grade 4 
• 
Hold(interrupt) the dose and follow 
weekly until resolution or stabilization 
• 
If toxicity resolves to  grade 2, implement 
one dose reduction and continue therapy 
 
• 
Discontinue lenalidomide study drug 


 
 
 
 
 
 
 
 
Sinus bradycardia/other cardiac arytmia 
Grade 2 
• Hold (interrupt) the dose and follow at least 
weekly until resolution and stabilization 
If the toxicity resolves to >grade 1, 
implement one dose reduction step and 
continue therapy 
Sinus bradycardia/other cardiac arytmia 
Grade 3 
•
Discontinue lenalidomide study drug 
Allergic reaction or 
hypersensitivity Grade >/=  3 
 
 
 
 
 
Grade 4
• 
Hold (interrupt) the dose and follow at least 
weekly until resolution and stabilization 
• 
If the toxicity resolves to !>grade 1, 
implement one dose reduction step 
and 
continue therapy 
Constipation 
Grade 1-2 
• 
Initiate bowel regimen and maintain 
dose level 
• 
If the toxicity resolves to  </= grade2, 
implement one dose reduction step and 
continue therapy
Grade 3 
• 
Discontinue lenalidomide study drug 
Venous  thrombosis/embolism 
grade 3 
• 
Hold (interrupt) dose and start 
anticoagulant ; restart at investigator's 
discretion (maintain dose level) 
Hepatic or other non-hematologicic 
toxicity 
assessed  as  lenalidomide-related c 
>/= grade 3 
• Hold (interrupt) the dose and follow at 
least weekly until resolution and 
stabilization 
• 
If the toxicity resolves to </= grade 2, 
implement the dose reduction step
Tumor flair refractory to oral pain 
medications 
Hold (interrupt) dose and differentiate 
tumor flare from progression. 
• 
Restart therapy at the 
investigator's discretion 
a In patients with cytopenia at baseline, dose modifications will be based on the NCI grading 
scale for 
haematological toxicity in CLL/SLL studies (see Table 2). 
 
b Once toxicity has resolved, lenalidomide dose can be increased to 10 mg/daily at the 
discretion of the investigator or the dose that is clinically indicated. 
c Further dose reduction will be allowed at the discretion of the investigator in case of 
persistent non haematological toxicity of grade 3 or less and in case of a change in laboratory 
evaluation such as platelet count , ANC, or hemoglobin count that indicates upcoming 
myelosuppre ssion or as clinically indicated. 
 
d For patients who experienced TFRs while treated with lenalidomide-containing  


 
 
 
 
regimens, steroids will be allowed to manage lymph node enlargement and inflammation, 
and anthistamines to manage rash/pruritus. For patients with bulky(> 5 em) lymph-nodes 
before the start of therapy ,tumor flair prophylaxis with steroids may be considered for the 
first 10-14 days of therapy. 


 
 
 
 
 
 
 
Table 6  Dose· level for lenalidomide . 
 
Level 
10 mg Dose 
5 mg Dose 
-1 
5 mg daily 
5 mg daily, day 1-21 of a 28 days 
cycle or 5 mg every other day for 28
-2 
5 mg daily, day 1-21 of a 28 days 
cycle or 5 mg every other day for 28 
days 
5 mg twice a week 
-3 
5 mg twice a week 
5 mg once a week 
-4 
5 mg once a week 
 N/A 
 
CONCOMITANT MEDICATIONS 
 
Concomitant therapy 
All concomitant medications should be recorded in the patient electronic records. 
 
 
 
Prophylaxis for Tumor Lysis Syndrome 
All patients should then be carefully monitored during the initial weeks of treatment. Patients 
still considered at risk for TLS because of persistently high tumor burden before the second 
and subsequent infusions of obinutuzumab should continue TLS prophylaxis until the risk is 
abated, as determined by the investigator. 
 
 
Other Concomitant Medications 
Necessary supportive measures for optimal medical care will be given throughout the study 
as clinical indicated, including the use of growth factors if clinically indicated. 
 
 
Anticoagulant Prophylaxis 
 
Lenalidomide has been associated with increased risk for venous thromboembolism 
(deep vein thrombosis or pulmonary embolism) in patients with myelodisplastic or 
multiple myeloma, particularly when combined with dexamethasone or 
chemotherapeutic agents. 
Routine prophylaxis for venous thromboembolic events is not recommended in patients with 
CLL/SLL undergoing lenalidomide-containing regimens. However, NCCN NHL Panel 
recommend prohylaxis with daily low-dose aspirin in patients with extremely high platelet 
counts at baseline (National Comprehensive Cancer Care Network, CLLISLL Guidelines , 
2013). Thus, the investigator may consider the use of aspirin (81 mg or 325 mg/daily per 
mouth) or LMWH subcutaneously at prophylactic dose in patients at high risk for thrombotic 
events . 


 
 
 
 
 
 
 
7. CRITERIA FOR STUDY DISCONTINUATION GENERAL 
CRITERIA 
• 
Inability of patient to comply with study requirements 
 
• 
Determination by the investigator that it is no longer safe for the patient to continue 
therapy 
 
• 
Disease progression 
 
• 
Patient’s preference 
 
The responsible local clinical Investigator as well as  MDACC IND Office, Celgene and 
Genentech have the right to discontinue this study at any time for reasonable medical or 
administrative reasons in any single center . Possible reasons for termination of the study 
could be but are not limited to: 
 
• 
Unsatisfactory enrollment with respect to quantity or quality 
 
• 
Inaccurate or incomplete data collection 
 
• 
Falsification of records 
 
• 
Failure to adhere to the study protocol. 
 
 
 
8. 
CLINICAL AND LABORATORY EVALUATIONS 
PRETREATMENT E V A L U A T I O N S  
Pretreatment evaluation will include: 
 
 
• Medical history and a physical examination including vital signs ECOG performance 
status , height and weight and recording of concurrent medications (within 7 days of 
day 1). 
 
• Hematology: complete CBC and differential , peripheral blood lymphocyte subsets 
(CD4, CD8, NK) and immunoglobulin levels (within 7 days of registration) . 
 
• Serum chemistry . This will include sodium, potassium , calcium , BUN, creatinine, 
glucose, albumin, total protein, alkaline phosphatase, LDH, total bilirubin, 
ALT(SGPT), uric acid, and TSH. Beta-2-microglobulin (within 7 days of day 1). 
 
• Serology for HBV, HIV and HCV (within 3 months of registration). 
 
Bone marrow aspiration and biopsy within one month from registration. Bone marrow will be 
evaluated for flow cytometry , for clonality and for lgVH mutational status (unless known), ZAP-
70 (unless known) and CD38 expression, cytogenetic and genomic abnormalities by FISH (unless 
known). 
 
• CT SCAN or/and PET and/or US and/or MRI within 30 days of registration if clinically 
indicated. 


 
 
 
 
 
 
 
• For FCBP (female of childbearing potential) serum and/or urine pregnancy test 
must be done within 10 -14 days prior to start therapy and 24 hours prior to 
prescribe lenalidomide for cycle 1. Females of childbearing potential (FCBP) is a 
sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; 2) has not been naturally postmenopausal for at least 24 consecutive 
months (i.e., has not had menses at any time in the preceding 24 consecutive 
months). 
 
EVALUATIONS DURING TREATMENT 
 
• Clinic visits (this will include vital signs and physical exam) at the University of Texas 
, MD Anderson Cancer Center (UTMDACC) are required for treatment initiation and at 
the start of cycles 2-6 (+/10 days from Day 1).  Clinic visits (this will include vital signs 
and physical exam) at UTMDACC are required after 3, 6 cycles (obinutuzumab and 
lenalidomide) and 12 cycles (lenalidomide) and once every 6 cycles thereafter (+/-14 
days from Day 1 of subsequent cycle). Hematology complete blood counts (white 
blood cells, hemoglobin , platelets and differential) will be monitored once weekly for 
the first five weeks and once every two weeks in case of dose increase until a stable 
dose of lenalidomide has been established for the specific patient (the once every 
two weeks laboratory monitoring will not apply if the dose is decreasing for non-
hematological or laboratory measurable toxicity) , and every two or four weeks 
thereafter . 
 
• Serum chemistry basic metabolic profile (sodium, potassium , BUN, creatinine 
and glucose) will be monitored once a week for the first five weeks and then once 
every two weeks until a stable dose of lenalidomide has been established for the 
specific patient and then every two or  four weeks thereafter . 
 
• TSH, beta-2-microglobulin , lymphocyte subsets, immunoglobulin levels, bone 
marrow biopsy and aspiration , flow cytometry will be performed and evaluated 
after 3, 6 cycles (obinutuzumab and lenalidom ide) and after 12 cycles 
(lenalidomide). 
 
• If patient stay on the study past 12 cycles , once every 6 cycles, he will have a 
bone marrow biopsy and aspirate evaluated by flow cytometry to check the status 
of the disease if clinically indicated. 
 
• Blood lymphocyte subsets (CD4, CD8, NK) and immunoglobulin levels every 3 
months for the first year, and once every 6 months thereafter. 
 
• CT scan and/or PET, and/or US and/or MRI  as clinical indicated 
 
 
• Response to treatment will be assessed according to IW-CLL 2008 criteria . 


 
 
 
 
 
 
 
• FCBP with regular or no menstruation must have a pregnancy test weekly for the first 
28 days and then every 28 days while on therapy (including breaks in therapy); at 
discontinuation of lenalidomide and at day 28 post the last dose of lenalidomide. 
Females with irregular menstruation must have a pregnancy test weekly for the first 
28 days and then every 14 days while on therapy (including breaks in therapy), at 
discontinuation of lenalidomide and at day 14 and day 28 post the last dose of 
lenalidomide (see Appendix 4 Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods). 
 
• In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed until they have returned to the normal range, 
baseline value and/or an adequate explanation of the abnormality is found. If a clear 
explanation is established it should be recorded on the eCRF. 
 
 
 
9. 
EVALUATION OF RESPONSE 
 
The primary efficacy endpoint is overall response, defined as CR or PR. The secondary 
endpoints will be safety of the combination, response according to prognostic markers at 
diagnosis, time to next treatment and overall survival. Response to treatment will be assessed 
according to NCI-WG 2008 working group criteria at 3 months from the beginning of therapy 
and every 6 months thereafter. 
 
10. 
STATISTICAL C O N S I D E R A T I O N S  
DETERMINATION OF SAMPLE SIZE 
The patient sample size will be 30 patients and the Bayesian method of Thall, Simon and 
Estey 21 will be employed to perform interim futility and safety monitoring. 
 
PLANNED EFFICACY EVALUATIONS 
 
The primary efficacy endpoint is overall response, defined as CR or PR. The secondary 
endpoints will be safety of the combination, response according to prognostic markers at 
diagnosis, time to next treatment and overall survival. Response to treatment will be assessed 
according to NCI-WG 2008 working group criteria at 3, 6 months from the beginning of 
therapy and every 6 months thereafter. 
 
PRIMARY EFFICACY VARIABLES 
 
Overall response, defined as CR or PR. 
 
SECONDARY EFFICACY VARIABLES 
 
The secondary endpoints will be safety of the combination, response according to prognostic 
markers at diagnosis, time to next treatment and overall survival. 


 
 
 
 
 
 
 
METHOD OF ANALYSIS 
 
We will monitor futility and safety of the treatment combination using a Bayesian design by 
Thall, Simon and Estey, in cohort size of 10. Specifically, assuming a beta (0.8, 1.2) prior 
for the overall response (OR) rate, we will stop trial if Prob {p(OR) > 0.40 data} < 0.05, 
where p(OR) is the probability of overall response. That is, if at any time during the trial we 
determine that there is less than 5% chance that the overall response rate is at least 40%, 
we will stop the trial. For futility monitoring purpose, we will assess patients' OR rate at 3 
months post treatment, and at each planned cohort (i.e., 10, 20, 30, etc.) for interim look, if 
there is not enough number of responders (such as 1 or fewer out of the first 10, 4 or fewer 
out of the first 20, etc.) we will temporarily suspend accrual until all patients in the current 
cohort has been fully evaluated. Similarly, we will stop the trial if Prob{p(TOX) > 0.50 data} 
> 0.95, where p(TOX) is the probability of grade 3 or higher non-hematological toxicity and 
a beta(1, 1) prior was used for toxicity rate. That is, if at any time during the trial we 
determine that there is more than 95% chance that the toxicity rate is at least 50%, we will 
stop the trial due to safety concern. The corresponding stopping boundaries for futility and 
safety are shown in Tables 7 and 8 respectively.  The operating characteristics of the 
design are illustrated in Table 9. Multc Lean Desktop (v2.1.0) was used for generating the 
stopping boundaries and the OC table. 
 
If the trial did not stop due to either futility or toxicity, then with a total sample size of 30, 
the 95% credible interval for the overall response rate will be (0.24, 0.57), assuming an 
OR rate of 0.40and a beta(0.8 , 1.2) prior. 
 
The proportion of patients achieving OR and its 95% credible interval will be presented. In 
addition, we will compute the posterior probability of OR rate being greater than 40%. 
Similar methods will be used to analyze the toxicity data. Univariate and multivariable 
logistic regression models will be fit to assess the association between OR and prognostic 
biomarkers. The time-to-event outcomes (such as time to next treatment or overall 
survival) will be estimated using the Kaplan-Meier method. 
 
 
 
Table 7. Interim futility stopping boundaries in cohort size of 10. 
 
Number of Patients Evaluated 
Stop the trial if </= OR Observed 
10 
1 
20 
4 
30 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 8. Interim toxicity stopping boundaries in cohort size of 10. 
 


 
 
Among These Number of Patients 
Stop the trial if >/= Toxicity Observed 
10 
8 
 
 
 
  
20 
14 __ 
  
30 
20 __ 
  
  
__ 
 
 
 
Table 9 The operating characteristics of futility and toxicity monitoring. 
 
 
True OR rate 
True Toxicity 
Rate 
Prob (stop early) 
Average number of 
patients 
0.3 
0.3 
0.28 
25.6 
0.3 
0.5 
0.35 
24.5 
0.3 
0.7 
0.75 
17.8 
 
0.4 
0.3 
0.08 
28.7 
0.4 
0.5 
0.16 
27.4 
0.4 
0.7 
0.68 
19.1 
 
0.5 
0.3 
0.02 
29.7 
0.5 
0.5 
0.10 
28.3 
0.5 
0.7 
0.65 
19.6 
 
 
 
In addition, we will monitor the grade 4 and grade 5 non-hematological toxicities separately, 
throughout the study and in cohort size of 10. Specifically, the trial will be stopped if Prob{p(TOX4) > 
0.25 | data} > 0.95 or Prob{p(TOX5) > 0.10 | data} > 0.95 , where p(TOX4) a n d  p(TOX5) are the 
probabilities of grade 4 and grade 5 non-hematological toxicities, respectively. A beta(0.5, 1.5) prior 
is assumed for p(TOX4) a n d  a beta(0.2, 1.8) prior is assumed p(TOX5). Based on these 
stopping criteria, the trial will be stopped early if [#patients with grade 4 
toxicities]/[#patients evaluated] >= 6/10, 9/20, 12/30OR [#patients with grade 5 toxicities]/[#patients 
evaluated] >= 4/10, 5/20, 7/30. 
 
 
This protocol will use PDMS and CORE as database repositories 
 
 
REPORTING OF ADVERSE EVENTS ASSESSMENT OF SAFETY 
 
Safety assessments will consist of monitoring and reporting AEs and SAEs that are considered 
related to obinutuzumab or/and lenalidomide, all events of death, and any study specific issue of 
concern. 
 
 
 
 
 
Adverse  Events 
 
An AE is any unfavorable and unintended sign,  temporarily associated with the use of an 


 
 
investigational medicinal product (IMP) or other protocol- imposed intervention, regardless of 
attribution . 
 
Serious Adverse Event Reporting for MD Anderson- Sponsored IND Protocols 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
  
 
Death 
A life-threatening adverse drug experience – any adverse experience that places the patient, in the 
view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. It 
does not include an adverse experience that, had it occurred in a more severe form, might have 
caused death. 
Inpatient hospitalization or prolongation of existing hospitalization 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
 
A congenital anomaly/birth defect. 
  
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse (21 CFR 312.32). 
 
Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate by 
the Principal Investigator or the INDIND Sponsor, IND Office. 
 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlined in “The University of 
Texas M. D. Anderson Cancer Center Institutional Review Board Policy for Investigators on Reporting 
Unanticipated Adverse Events for Drugs and Devices”.  Unless stated otherwise in the protocol, all 
SAEs, expected or unexpected, must be reported to the IND Office, regardless of attribution (within 5 
working days of knowledge of the event). 
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB for participants enrolled at MDACC.  
  
Reporting for all sites: 
 
x 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of the 
event to the Safety Project Manager in the IND Office.   
x 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the event has stabilized, 
or there has been acceptable resolution of the event. 
x 
Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
x 
All events reported to the supporting company must also be report to the IND 
Office. 
  
Reporting to FDA: 
x 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
  
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 


 
 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
Genetech requested reporting: 
 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of 
attribution. 
This includes the following: 
AEs not previously observed in the patient that emerge during the protocol-specified AE reporting 
period, including signs or symptoms associated with CLL/SLL that were not present prior to the 
AE reporting period. 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive procedures 
such as cardiac catheterizations). 
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention. 
Preexisting medical conditions (other than the condition being studied) judged by the investigator to 
have worsened in severity or frequency or changed in character during the protocol-specified AE 
reporting period. 
 
Serious Adverse Events 
 
An AE should be classified as an SAE if the following criteria are met: 
It results in death (i.e., the AE actually causes or leads to death). 
It is life threatening (i.e., the AE, in the view of the investigator, places the patient at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, might have caused 
death.). 
It requires or prolongs inpatient hospitalization. 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of 
the patient’s ability to conduct normal life functions). 
 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. 
It is considered a significant medical event by the investigator based on medical judgment (e.g., may 
jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above). 
 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES  
The investigator is responsible for ensuring that all AEs and SAEs, that are observed or reported 
during the study, are collected and reported to the U.S. Food and Drug Administration (FDA), 
appropriate IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports).  
Adverse Event Reporting Period 
 
The study period during which all AEs and SAEs must be reported begins after informed consent is 
obtained and initiation of study treatment and ends 30 days following the last administration of study 
treatment or study discontinuation/termination, whichever is earlier. After this period, investigators 
should only report SAEs that are attributed to prior study treatment. 
Assessment of Adverse Events 
 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be reported 
appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and end dates), 
regulatory seriousness criteria if applicable, suspected relationship to the obinutuzumab (see following 
guidance), and actions taken. 


 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the following 
general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of the 
obinutuzumab  and the AE cannot be readily explained by the patient’s clinical state, intercurrent 
illness, or concomitant therapies; and/or the AE follows a known pattern of response to the 
obinutuzumab and/or the AE abates or resolves upon discontinuation of the obinutuzumab or 
dose reduction and, if applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the obinutuzumab (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the 
AE has no plausible temporal relationship to obinutuzumab administration (e.g., cancer 
diagnosed 2 days after first dose of obinutuzumab). 
 
Expected AEs are those AEs that are listed or characterized in the Package Insert or current 
Investigator Brochure.  
Unexpected AEs are those not listed in the Package Insert (P.I.) or current Investigator’s Brochure or 
not identified.  This includes AEs for which the specificity or severity is not consistent with the 
description in the P.I. or Investigator’s Brochure.  For example, under this definition, hepatic necrosis 
would be unexpected if the P.I. or Investigator’s Brochure only referred to elevated hepatic enzymes 
or hepatitis. 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS  
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all patient evaluation timepoints should be adopted.  
Examples of non-directive questions include:  
“How have you felt since your last clinical visit?” 
“Have you had any new or changed health problems since you were last here?  
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  Avoid 
colloquialisms and abbreviations. 
Diagnosis versus Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report the 
information that is currently available.  If a diagnosis is subsequently established, it should be reported 
as follow-up information. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period regardless of attribution, will be 
reported to the appropriate parties.  When recording a death, the event or condition that caused or 
contributed to the fatal outcome should be reported as the single medical concept.  If the cause of 
death is unknown and cannot be ascertained at the time of reporting, report “Unexplained Death”. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study.  Such conditions should 
be reported as medical and surgical history.  A preexisting medical condition should be re-assessed 
throughout the trial and reported as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When reporting such events, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”). 


 
 
Hospitalizations for Medical or Surgical Procedures 
 
Any AE that results in hospitalization or prolonged hospitalization should be documented and reported 
as an SAE.  If a patient is hospitalized to undergo a medical or surgical procedure as a result of an 
AE, the event responsible for the procedure, not the procedure itself, should be reported as the SAE.  
For example, if a patient is hospitalized to undergo coronary bypass surgery, record the heart 
condition that necessitated the bypass as the SAE. 
- 
Hospitalizations for the following reasons do not require reporting: 
- 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
preexisting conditions 
- 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study or 
- 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the 
study. 
 
Pregnancy 
 
If a female patient becomes pregnant while receiving obinutuzumab or within one year after the last 
dose of obinutuzumab, or the partner of a male patient becomes pregnant while receiving therapy or 
within three months of completing therapy, a report should be completed and expeditiously submitted 
to the Genentech, Inc.  Follow-up to obtain the outcome of the pregnancy should also occur.  
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as serious, 
and expeditiously reported as an SAE.  Similarly, any congenital anomaly/birth defect in a child born 
to a female patient exposed to obinutuzumab should be reported as an SAE. 
Post-Study Adverse Events 
 
The investigator should expeditiously report any SAE occurring after a patient has completed or 
discontinued study participation if attributed to prior obinutuzumab exposure.  If the investigator should 
become aware of the development of cancer or a congenital anomaly in a subsequently conceived 
offspring of a female patient who participated in the study, this should be reported as an SAE.  
Safety Reconciliation 
 
The Sponsor agrees to conduct reconciliation for the product.  Genentech and the Sponsor will agree 
to the reconciliation periodicity and format, but agree at minimum to exchange monthly line listings of 
cases received by the other party.  If discrepancies are identified, the Sponsor and Genentech will 
cooperate in resolving the discrepancies.  The responsible individuals for each party shall handle the 
matter on a case-by-case basis until satisfactory resolution. 
Adverse Events of Special Interest (AESIs) 
 
AEs of special interest (AESIs) are defined as a potential safety problem, identified as a result of 
safety monitoring of the Product. 
The following AEs are considered of special interest and must be reported to the Sponsor 
expeditiously irrespective of regulatory seriousness criteria:  
x 
TLS (Tumor Lysis Syndrome; all grades) 
x 
Abnormal Liver Functions Tests 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with 
either an elevated bilirubin or clinical jaundice, as defined by Hy’s law. 
The finding of an elevated ALT or AST (! 3 u ULN) in combination with either an elevated total 
bilirubin (! 2 u ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury.  Therefore, investigators must 
report as an adverse event the occurrence of either of the following: 
x 
Treatment-emergent ALT or AST ! 3 u ULN in combination with total bilirubin ! 2 u ULN 


 
 
x 
Treatment-emergent ALT or AST ! 3 u ULN in combination with clinical jaundice 
x 
Suspected transmission of an infectious agent by the study drug, as defined below: 
– 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings that indicate an infection in a patient exposed to a medicinal product.  
This term applies only when contamination of the study drug is suspected. 
 
 
 Investigator Communications with Genentech: 
 
Investigators must report all SAEs to Genentech within the timelines described below.  The completed 
MDACC SAE reporting form/case report should be faxed immediately upon completion to Genentech 
Drug Safety at: 
(650) 225 4682 
OR 
(650) 225 5288 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it becomes 
available. 
Serious AE reports that are related to obinutuzumab and AEs of Special Interest (regardless of 
causality) will be transmitted to Genentech within fifteen (15) calendar days of the Awareness Date. 
Serious AE reports that are unrelated to obinutuzumab will be transmitted to Genentech within thirty 
(30) calendar days of the Awareness Date. 
Additional reporting requirements to Genentech include the following: 
Any reports of pregnancy following the start of administration with the obinutuzumab and within the 
follow-up period (for female patients within one year after the last dose of obinutuzumab or the 
partner of a male patient within three months of completing therapy) will be transmitted to 
Genentech within 30 days of the Awareness Date.  
All non-serious obinutuzumab AEs originating from the study will be forwarded Genentech quarterly 
 
Note: Investigators should also report events to their IRB as required. 
 
Follow-Up Information 
 
Additional information may be added to a previously submitted report by any of the following methods: 
Adding to the original MDACC SAE report and submitting it as follow-up 
Adding supplemental summary information and submitting it as follow-up with the original MDACC 
SAE reporting form. Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e., D.O.B. initial, patient number), protocol description and number, if assigned, brief AE  
description, and notation that additional or follow-up information is being submitted (The patient  
identifiers are important so that the new information is added to the correct initial report). Occasionally 
Genentech may contact the reporter for additional information, clarification, or current status of the 
patient for whom and AE was reported.  For questions regarding SAE reporting, you may contact  
the Genentech Drug Safety representative noted above or the MSL assigned to the study.  Relevant  
follow-up information should be submitted to Genentech Drug Safety as soon as it becomes available 
and/or upon request. 
 
 
Investigator Communications with Celgene: 
Pregnancies 


 
 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on lenalidomide, or within  28 days of 
the subject’s last dose of lenalidomide, are considered immediately reportable events. Lenalidomide is 
to be discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy test 
must be reported to Celgene Drug Safety immediately by facsimile or email using the Pregnancy Initial 
Report Form. The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must notify 
Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form.  If the outcome of the pregnancy was 
abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should report the abnormal 
outcome as an AE. If the abnormal outcome meets any of the serious criteria, it must be reported as 
an SAE to Celgene Drug Safety immediately by facsimile, or other appropriate method, within 24 
hours of the Investigator’s knowledge of the event using the SAE Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to causality, 
as SAEs. In addition, any infant death after 28 days that the Investigator suspects is related to the in 
utero exposure to the IP should also be reported to Celgene Drug Safety immediately by facsimile, or 
other appropriate method, within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form.  
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking lenalidomide should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: 
(908) 673-9115 
E-mail: drugsafety@celgene.com 
 
Expedited Reporting by Investigator to Celgene 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events of being related to lenalidomide based on the Investigator Brochure.  In the United States, all 
suspected unexpected serious adverse reactions (SUSARs) will be reported in an expedited manner 
in accordance with 21 CFR 312.32. 
 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in writing 
using the MDACC SAE reporting   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).  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-CL-CLL- PI-004319) 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. 
 
REFERENCES 
 
1. 
Matutes E, Polliack A Morphological and immunophenotypic features of chronic 
lymphocytic leukemia . Reviews in clinical and experimental hematology 2000 ; 4(1): 22- 47. 
2. 
Dighiero G, Binet JL. When and how to treat chronic lymphocytic leukemia . The New 
England journal  of medicine 2000 ; 343(24) : 1799-801. 
3. 
Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored 


 
 
Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis 
and treatment. Blood 1996; 87(12): 4990-7 . 
4. 
Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic 
lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48(1): 198-
206. 
5. 
Shustik C, Mick R, Silver R, Sawitsky A , Rai K, Shapiro L. Treatment of early chronic 
lymphocytic leukemia : intermittent chlorambucil versus observation . Hematol Onco/1988; 
6(1): 7-12. 
6. 
Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil 
as primary therapy for chronic lymphocytic leukemia. N Eng/ J Med 2000; 343(24): 1750-7. 
7. 
Hillmen P, Skotnicki AB , Robak T, et al. Alemtuzumab compared with chlorambucil as 
first-line therapy for chronic lymphocytic leukemia . J Clin Oneal 2007; 25(35) : 5616-23 . 
8. 
Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus 
cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a 
randomised controlled trial. Lancet 2007; 370(9583) : 230-9. 
9. 
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and 
treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. 
Blood 2008; 111(12): 5446-56 . 
10. 
Goede V, Fischer K, Busch R, et al. Obinutuzumab plus Chlorambuc il in Patients with 
CLL and Coexisting Conditions. The New England journal  of medicine 2014. 
11. 
Lapalombella R, Andritsos L, Liu Q, et al. Lenalidomide treatment promotes CD154 
expression on CLL cells and enhances production of antibodies by normal B cells through a 
Pl3-kinase-dependent pathway. Blood 2010; 115(13): 2619-29 . 
12. 
Shanafelt TD, Ramsay AG , Zent CS, et al. Long-term repair ofT-cell synapse 
activity in a phase II trial of chemoimmunotherapy followed by lenalidomide consolidation in 
previously untreated chronic lymphocytic leukemia (CLL). Blood 2013 ; 121(20): 4137- 41. 
13. 
Chanan-Khan A, Miller KC, Musial L, et al. Clinical efficacy of lenalidomide in patients 
with relapsed or refractory chronic lymphocyt ic leukemia: results of a phase II study. J  Clin 
Onco/2006 ;  24(34): 5343-9. 
14. 
Ferrajoli A, Lee BN, Schlette EJ, et al. Lenalidomide induces complete and partial 
remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood2008 ;   
111(11): 5291-7. 
15. 
Chen Cl, Bergsagel PL, Paul H, et al. Single-agent lenalidomide in the treatment of 
previously untreated chronic lymphocytic leukemia. J C!in Onco/2011; 29(9): 1175-81. 
16. 
Badoux XC, Keating MJ, WenS , et al. Phase II study of lenalidomide and rituximab as 
salvage therapy for patients with relapsed or refractory chronic lymphocyt ic 


 
 
 
 
 
 
leukemia. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2013; 31(5): 584-91. 
17. 
Bennett CL, Angelotta C, Yarnold PR, et al. Thalidomide- and lenalidomide- 
associated thromboembolism among patients with cancer. JAMA 2006 ; 296(21) : 2558- 60. 
18. 
Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose 
dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for 
newly diagnosed  multiple myeloma: an open-label randomised controlled trial. Lancet 
Oncol2010 ;    11(1): 29-37. 
19. 
Palumbo A , Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and 
lenalidomide-associated thrombosis in myeloma . Leukemia 2008; 22(2) : 414-23. 
20. 
Gay F, Hayman SR, Lacy MQ, et al. Lenalidomide plus dexamethasone versus 
thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative 
analysis of 411 patients. Blood 2010; 115(7): 1343-50. 
21. 
Thall PF, Simon RM, Estey EH. New statistical strategy for monitoring safety and 
efficacy in single-arm clinical trials. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 1996; 14(1): 296-303 . 


 
 
I
1
 
Appendix 1 ECOG Performance Status 
 
 
 
 
 
 
 
; Grade   ECOG 
ECOG    PERFORMANCE     STATUS* 
j 
------1 
  
J 
IFully active, able t;-carry on l pre-disease performance without 
   I restriction 
 
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 
I 
r 2 
Ambulatory and   apable of all selfcare but unable to carry out any work 
, 
I activities.  Up and about more than 50% of waking hours 
 
; 3 
Capable of onl;"limited selfcare, confined to bed or chair more than 50%- ; 
! 
I of waking   hours 
 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
 
Dead 
 
*As published in Am . J. Clin. 
Oneal: 
------------------ 
Oken, M.M., Creech, R.H., Tanney, D.C., Horton, J., Davis, T.E., McFadden, E. T., Carbone, 
P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 


 
 
 
Appendix 2 Treatment Schedule 
Cycle 1(28-day cycles) 
Cycles 2 - 6 Obinutuzumab 
(mg) 
 
 
100 900 1000 
1000 
1000 
 
. 
Day 
1 
2 
8 
15 
1 
Day 9 - 56 Lenalidomide 10 mg daily Day 57 until progression


 
 
 
Appendix 3 Current NCI Common Terminology Criteria for Adverse Events (CTCAE) 
 
In the present study, toxicities will be graded according NCI CTCAE , version 4.0. 
 
 
Please use the following link to the NCI CTCAE website : 
 
http://ctep.cancer .gov/protocolDevelopment/electronic    applications/ etc.htm 


 
 
Appendix 4 Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods. 
 
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 Revlimid REMS® program , 
and be willing and able to comply with the requirements of Revlimid REMS®. 
 
Criteria for females of childbearing potential (FCBP) 
 
 
This protocol defines a female of childbearing potential as a sexually mature woman who : 
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months) . 
 
Counseling 
 
 
For a female of childbearing potential, lenalidomide is contraindicated  unless all of the 
following   are met (i.e.,  all females   of childbearing   potential   must be counseled 
concerning the following risks and requirements prior to the start of lenalidomide study 
therapy): 
 
• 
She understands the potential teratogenic risk to the unborn child 
 
 
• 
She understands the need for effective contraception , without interruption, 4 weeks 
before starting study treatment , throughout the entire duration of study treatment , dose 
interruption and 28 days after the end of study treatment 
 
She should be capable of complying with effective contraceptive measures 
 
 
• 
She is informed and understands the potential consequences  of pregnancy 
and the  need to notify  her study  doctor  immediately  if there  is a risk of pregnancy 
 
• 
She understands the need to commence the study treatment  as soon as 
study drug is dispensed following a negative pregnancy test 
 
• 
She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol 


 
 
• 
She   acknowledges 
that   she   understands   the   hazards   and   necessary 
precautions associated with the use of lenalidomide 
 
The investigator must ensure that for females of childbearing potential: 
 
 
• 
Complies with the condition for pregnancy risk minimization including 
confirmation that she has an adequate level of understanding 
 
• 
Acknowledge the aforementioned  requirements 
 
 
• 
For a female NOT of childbearing potential, lenalidomide  is contraindicated unless 
all of the following are met (i.e., all females NOT of childbearing potential must 
be counseled concerning  the following risks and requirements prior to the start 
of lenalidomide  study therapy): 
 
• 
She  acknowledges 
that  she  understands  the  hazards  and  necessary 
precautions associated with the use of lenalidomide 
 
Traces of lenalidomide have been found in semen.  Male patients taking lenalidomide must 
meet the following conditions (i.e., all males must be counseled concerning the following risks 
and requirements prior to the start of lenalidomide study therapy) : 
 
Understand the potential teratogenic risk if engaged in sexual activity with a 
pregnant female or a female of childbearing potential 
 
• 
Understand the  need for the  use of a condom  even  if he has had a 
vasectomy , if engaged in sexual activity with a pregnant female or 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 contact  during  the following  time periods  related to this study : 1) for at least 
28 days before starting study drug; 2) while participating in the study; 3) dose interruptions; 
and 4) for at least 28 days after study treatment 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 : 
 
• 
Highly effective methods: 
 
 
Intrauterine device (IUD) 


 
 
Hormonal (birth control pills, injections , implants) Tubal 
ligation 
Partner's vasectomy 
 
• 
Additional effective methods: 
 
 
Male condom 
Diaphragm Cervical 
Cap 
 
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 study drug 
 
Female Patients: 
 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 miU/mL) prior to 
starting study drug. The first pregnancy test must be performed within 10 to 14 days prior to 
the start of study drug and the second pregnancy test must be performed within 24 hours 
prior to the start of study drug. The patient may not receive study drug until 
the study doctor has verified that the results of these pregnancy tests are negative. 
 
Male Patients: 
 
Must practice complete abstinence or  agree to use a condom during sexual contact with 
a pregnant female or a female of childbearing  potential while participating in the study,   
during   dose   interruptions  and for 
at least 28 days following 
study drug 
discontinua tion, even if he has undergone a successful vasectomy . 
 
During study participation and for 28 days following study drug discontinuation Female 
Patients: 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests 
weekly for the first 28 days of study participation and then every 28 days while on study, at 
study discontinuation , and at day 28 following study drug discontinuation . If menstrual cycles 
are irregular, the pregnancy testing must occur weekly for the first 28 


 
 
days and then every 14 days while on study, at 
study14and   28   following   study   drug 
discontinuation. 
discontinuation, and at days 
 
At  each  visit , the  Investigator   must  confirm  with  the  FCBP  that  she  is 
continuing to use two reliable methods of birth control. 
 
• 
Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted at a minimum of every 28 days. 
 
• 
If pregnancy or a positive pregnancy test does occur in a study patient, study 
drug 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. Study drug 
treatment must be discontinued during this evaluation. 
 
Females must agree to abstain from breast feeding during study participation and for 
at least 28 days after study drug discontinuation . 
 
Male Patients : 
• 
Counseling about the requirement for complete abstinence or condom use during 
sexual contact with a pregnant female  or a female  of childbearing potential 
and the potential risks of fetal exposure to lenalidomide must be conducted at a 
minimum of every 28 days. 
 
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. 
 
Additional  precautions 
 
Patients should be instructed never to give this medicinal product to another person 
and to return any unused capsules to the study doctor at the end of treatment. 
 
• 
Female patients should not donate blood during therapy and for at least 28 days 
following discontinuation of study drug. 
 
• 
Male patients should not donate blood, semen or sperm during therapy or for at 
least 28 days following discontinuation of study drug. 
 
• 
Only enough study drug for one cycle of therapy may be dispensed with each 
cycle of therapy. 
 
Pregnancies: 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female subject occurring while the subject is on IP (Investigational 
Product) , or within (insert time-frame which must be at least 28 days of the subject's last dose 
of IP), are considered immediately reportable events. IP is to be discontinued immediately . 
The pregnancy, suspected pregnancy, or positive pregnancy 


 
 
test  must  be  reported  to  Celgene  Drug  Safety  immediately  by  facsimile ,  or  other 
appropriate   method,  using the Pregnancy   Initial Report Form, or approved  equivalent form. 
The female subject should be referred to an obstetrician-gynecologist , preferably one 
experienced in reproductive toxicity for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either 
normal or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved   
equivalent   form. If the outcome of the pregnancy   was  abnormal  (e.g., spontaneousor 
therapeutic  abortion) , the Investigator shouldreport the abnormal outcome as an AE. If 
the abnormal outcome meets any of the serious criteria , it must be reported as an SAE to 
Celgene Drug Safety  immediately  by facsimile , or other appropriate method, within 24 
hours of the Investigator's knowledge of the event using the SAE Report Form, or approved 
equivalent form . 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition , any infant death after 28 days that the Investigator suspects 
is related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile , or other appropriate method, within 24 hours of the Investigator's 
knowledge of the event using the SAE Report Form, or approved equivalent form. 
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, the  
male  subject  taking  IP  should  notify  the  Investigator, and the pregnant  female partner 
should be advised to call their healthcare provider immediately. 


 
 
Appendix 5 FDA  MDACC SAE reporting   
 
http://www  .fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm