A Phase II Study of Obinutuzumab and Lenalidomide in Previously Untreated Subjects With Follicular Lymphoma
Phase: PHASE2
Conditions: Ann Arbor Stage II Grade 1 Follicular Lymphoma, Ann Arbor Stage II Grade 2 Follicular Lymphoma, Ann Arbor Stage III Grade 1 Follicular Lymphoma, Ann Arbor Stage III Grade 2 Follicular Lymphoma, Ann Arbor Stage IV Grade 1 Follicular Lymphoma, Ann Arbor Stage IV Grade 2 Follicular Lymphoma, Bulky Disease, Fatigue, Fever, Grade 3a Follicular Lymphoma, Night Sweats, Splenomegaly, Weight Loss
Sponsor: M.D. Anderson Cancer Center

CONFIDENTIAL 
This is a MDACC 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 for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from MDACC.
 
Obinutuzumab + lenalidomide untreated FL
MDACC Protocol 2015- 0464Version11 
1
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2015-0464 
Protocol Title 
A Phase 2 Study of Obinutuzumab and Lenalidomide in Previously 
Untreated Subjects with Follicular Lymphoma 
Protocol Phase 
I/II 
Protocol Version 
MOD 001 
Version Date 
11.09.2020 
Protocol PI 
Loretta Nastoupil, MD 
Department 
Lymphoma/Myeloma 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
130992 
 
 
 
 
Proprietary Information of MD Anderson

CONFIDENTIAL 
 
This is a MDACC 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 for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from MDACC.
 
 
Obinutuzumab + lenalidomide untreated FL
MDACC Protocol 2015- 0464Version11 
2 
TITLE: 
A Phase II Study of Obinutuzumab and 
Lenalidomide in Previously Untreated 
Subjects with Follicular Lymphoma  
STUDY 
NUMBER: 
2015- 0464 
VERSION 
NUMBER: 
11 
TEST 
PRODUCTS
: 
Obinutuzumab (Gazyva, GA101) 
Lenalidomide (Revlimid) 
INVESTIGAT
OR: 
Loretta Nastoupil, MD 
Department of Lymphoma and Myeloma 
The University of Texas M.D. Anderson Cancer Center 
1515 Holcombe Blvd, Unit 429 
Houston, TX 77030 
Telephone:  713- 745- 4017 
Fax: 713- 794- 5656 
E- mail: lnastoupil@mdanderson.org 
CO- PI: 
Nathan Fowler, MD 
 
STUDY 
NURSE: 
STUDY 
DATA 
COORDINA
TOR: 
IND:                
Lacey Anderson, RN BSN 
Karina Grimaldo 
130992 
SUPPORT 
PROVIDED 
BY: 
Genentech, Inc. 
Celgene 
PROTOCOL 
DATE: 
11.09.2020 
 
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Obinutuzumab + lenalidomide in untreated FL
MDACC 
Protocol 2015- 0464 Version11 
3 
TABLE OF CONTENTS 
1. 
Introduction 
16 
1.1 
Non- Hodgkin lymphoma 16 
1.1.1 
Natural History and Current Management of Indolent Non
- Hodgkin 
Lymphoma 16 
1.1.1.1 
Natural History 
16 
1.1.1.2 
Current Management 
16 
1.2 
Obinutuzumab Background 
17 
1.2.1 
Structure and Mechanism of Action of Obinutuzumab
 17 
1.2.2 
Clinical Experience with Obinutuzumab
 
17 
1.2.2.1 
Tolerability and Efficacy of Obinutuzumab in NHL 
17 
1.2.3 
Overview of Safety of Obinutuzumab
 19 
1.2.4 
Risks Associated with Obinutuzumab Therapy
 21 
1.2.4.1 
Hepatitis B Virus Reactivation 
21 
1.2.4.2 
Progressive Multifocal Leukoencephalopathy 21 
1.2.4.3 
Infusion- Related Reactions 22 
1.2.4.4 
Tumor Lysis Syndrome 
22 
1.2.4.5 
Infection 22 
1.2.4.6 
Neutropenia 
22 
1.2.4.7 
Thrombocytopenia 23 
1.2.5 
Summary of Pharmacokinetic and Pharmacodynamic Data for 
Obinutuzumab 23 
1.3 
lenalidomide BackGround 23 
1.3.1 
Lenalidomide Description 
24 
1.3.2 
Pharmacokinetics and Drug Metabolism: Absorption: 
24 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
4 
1.3.3 
Pharmacokinetic Parameters: Distribution: 
24 
1.3.4 
Metabolism and Excretion 
24 
1.3.5 
Lenalidomide in NHL 
25 
1.3.5.1 
Aggressive NHL 
25 
1.3.5.2 
Indolent NHL 
25 
1.3.5.2.1 
Lenalidomide plus Rituximab in Indolent Lymphoma 
26 
1.4 
Study Rationale 26 
1.4.1 
Obinutuzumab Plus Lenalidomide in Untreated Follicular Lymphoma
 
26 
1.4.2 
Novel Endpoints 
27 
2. 
Objectives 
27 
2.1 
Primary 27 
2.2 
Secondary 
27 
2.3 
exploratory 
28 
3. 
Study Design 
28 
3.1 
Description of the Study 28 
3.2 
Study Endpoints 28 
3.2.1 
Primary Efficacy Outcome Measure
 28 
3.2.2 
Secondary Efficacy Outcome Measures
 
28 
3.2.3 
Safety Outcome Measures
 
29 
3.2.4 
Exploratory Endpoints 
29 
3.3 
Evaluation of response 
29 
3.4 
Safety plan 
29 
3.5 
Statement of compliance 29 
4. 
Study Population 
29 
4.1 
Inclusion Criteria 29 
4.2 
Exclusion Criteria 
32 
5. 
Treatment of subjects 
34 
5.1 
enrollment and blinding 
34 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
5 
5.2 
treatment schedule 
34 
5.3 
dosage and administration 35 
5.3.1 
Obinutuzumab 
36 
5.3.1.1 
Obinutuzumab Administration
 
36 
5.3.1.2 
Obinutuzumab Storage
 
37 
5.3.2 
Lenalidomide 
38 
5.3.2.1 
Lenalidomide administration
 
38 
5.3.2.1.1 
Lenalidomide Dose Adjustment for Renal Impairment
 
38 
5.3.2.2 
Lenalidomide Storage 
39 
5.4 
Dose Reduction, Delay and Discontinuation 40 
5.4.1 
Toxicities Necessitating Dose Modification or Delay
 
40 
5.4.2 
Obinutuzumab Dose Reduction or Delay
 
43 
5.4.3 
Lenalidomide Dose Reduction or Delay
 
44 
5.5 
Overdose Instruction 
44 
5.6 
Permanent Discontinuation of Study Drug 45 
6. 
Concomitant medications 
45 
6.1 
permitted supportive care 45 
6.2 
Thromboembolism prophylaxis 
46 
6.3 
Tumor lysis prophylaxis 46 
6.4 
Obinutuzumab pre- medication 
46 
6.5 
Hepatitis B Prophylaxis 
47 
6.6 
prohibited concomitant therapy 
47 
7. 
Study procedures 
48 
7.1 
screening Phase 48 
7.2 
Treatment phase 49 
7.2.1 
Cycle 1/Day 1 
49 
7.2.2 
Cycle 1/Day 8 
50 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
6 
7.2.3 
Cycle 1/Day 15 
50 
7.2.4 
Cycle 2/Day 1and every 4 weeks until Cycle 18 or Treatment 
Termination 50 
7.2.5 
Cycle 20/Day 1 and every 4 weeks until Cycle 30 or Treatment 
Termination 51 
7.3 
End of Treatment Visit 
51 
7.4 
Response evaluation 
52 
7.5 
follow up phase 52 
7.5.1 
Survival Follow up 53 
7.6 
Missed evaluations 
53 
7.7 
Description of Procedures 53 
7.7.1 
Medical History 
53 
7.7.2 
Physical Examination
 
53 
7.7.3 
Vital Signs 54 
7.7.4 
ECOG PS 54 
7.7.5 
Concomitant Medications 
54 
7.7.6 
Adverse Events 
54 
7.7.7 
CT, PET/CT, MRI scans 
55 
7.7.8 
Response Assessment
 
55 
7.7.9 
Hematology 
55 
7.7.10 
Serum Chemistry 
55 
7.7.11 
Coagulation Studies 55 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
7 
7.7.12 
Hepatitis Serologies 55 
7.7.13 
HIV serologies 
55 
7.7.14 
Creatinine Clearance 
56 
7.7.15 
Pregnancy Test 
56 
7.7.16 
Bone Marrow Biopsy and Aspirate
 
56 
7.7.17 
ECG 
56 
7.7.18 
Determination of FLIPI Score 
56 
7.7.19 
Determination of Tumor Burden Status
 
56 
7.7.20 
Blood Sampling and Tumor Tissue Collection for Correlative Studies
 
57 
8. 
SUBJECT COMPLETION AND WITHDRAWAL 
57 
8.1 
Completion 
57 
8.2 
Treatment Discontinuation 
57 
8.3 
Study Exit/ Withdrawal 
58 
9. 
Statistical 
58 
9.1 
General Considerations 
58 
9.1.1 
Response Assessment
 
58 
9.1.2 
Safety Monitoring 58 
9.2 
Definition of Analysis Populations 59 
9.3 
Endpoint Data Analysis 
60 
9.3.1 
Baseline Characteristics 
60 
9.3.2 
Primary Efficacy Endpoint 
60 
9.3.2.1 
Analysis Methods 60 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
8 
9.3.3 
Secondary Efficacy Endpoints
 
60 
9.3.4 
Safety Analysis 
61 
9.4 
Handling of Missing Data 61 
9.5 
Determination of Sample Size 
61 
9.6 
Trial Monitoring 62 
10. 
Reporting of Adverse Events 
63 
10.1 
Assessment of Safety 
63 
10.1.1 
Adverse Events 
63 
10.1.2 
Serious Adverse Events
 
64 
10.2 
Methods and Timing for Assessing and Recording Safety Variables 
65 
10.2.1 
Adverse Event Reporting Period
 
65 
10.2.2 
Assessment of Adverse Events
 
65 
10.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events 
66 
10.3.1 
Eliciting Adverse Events 
66 
10.3.2 
Specific Instructions for Recording Adverse Events
 
66 
10.3.2.1 
Diagnosis versus Signs and Symptoms 
66 
10.3.2.2 
Deaths 66 
10.3.2.3 
Preexisting Medical Conditions 
66 
10.3.2.4 
Hospitalizations for Medical or Surgical Procedures 67 
10.3.2.5 
Pregnancy 
67 
10.3.2.6 
Post- Study Adverse Events 
68 
10.3.2.7 
Adverse Events of Special Interest (AESIs) 68 
10.3.2.8 
Serious Adverse Event Reporting Error! Bookmark not defined. 
10.4 
Product Complaint Reporting 
Error! Bookmark not defined. 
10.5 
Expedited Reporting by Investigator to Celgene Study Close- Out 
71 
10.6 
Maintenance of safety information 71 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
9 
10.7 
Study Close- Out 72 
11. 
Study administration 
72 
11.1 
Regulatory and Ethical Compliance 
72 
11.2 
Informed Consent 
72 
11.3 
Quality Control and Quality Assurance 
72 
11.4 
Protected Subject Health Information Authorization 73 
11.5 
Record Retention 
73 
11.6 
Investigational Drug Accountability 
73 
11.7 
Investigator Responsibilities 
73 
11.8 
Publication of Study Results 
74 
11.9 
Study Completion 
74 
References 
75 
 
 
 
 
 
LIST OF APPENDICES 
Appendix 1 
Study Flowchart 79 
Appendix 2 
Calculation of Creatinine Clearance Using the Cockcroft- Gault Formula 
82 
Appendix 3  
FLIPI Score 
82 
Appendix 4  
Determination of Tumor Burden 
82 
Appendix 5 Response Assessment 83 
Cheson Revised Response Criteria 2007 
84 
Appendix 6 
Safety Reporting Fax Cover Sheet 84 
Appendix 7 
FDA MedWatch 3500 Form 
85 
Appendix 8 
Current NCI Common Terminology Criteria for Adverse Events (CTCAE) 
86 
 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
10 
List of Abbreviations and Definition of Terms  
• 
Ab
br
evi
ati
on 
• 
Definition 
• 
A
B
C 
• 
activated B cell 
• 
A
D
C
C 
• 
antibody- dependent cellular cytotoxicity 
• 
A
E 
• 
adverse event 
• 
an
ti-
H
Bc 
• 
antibody to hepatitis B core antigen 
• 
aP
T
T 
• 
activated partial thromboplastin time 
• 
B
M 
• 
bone marrow 
• 
AS
C
O 
• 
American Society of Clinical Oncology 
• 
A
U
C 
• 
area under the concentration−time curve 
• 
BS
A 
• 
body surface area 
• 
C
D
C 
• 
complement- dependent cytotoxicity 
• 
C
H
O
P 
• 
cyclophosphamide, doxorubicin, vincristine, 
prednisone 
• 
C
LL 
• 
chronic lymphocytic leukemia 
• 
Cm
ax 
• 
maximum   concentration observed 
• 
C
NS 
• 
central nervous system 
• 
C
R 
• 
complete response or complete remission 
• 
Cr
u 
• 
unconfirmed complete response 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
11 
• 
Ab
br
evi
ati
on 
• 
Definition 
• 
CS
R 
• 
Clinical Study Report 
• 
D 
• 
day 
• 
D
FS 
• 
disease- free survival 
• 
D
LB
C
L 
• 
diffuse large B- cell lymphoma 
• 
D
LT 
• 
dose- limiting toxicity 
• 
E
C 
• 
Ethics Committee 
• 
E
C
H
O 
• 
echocardiogram 
• 
E
C
O
G 
• 
Eastern Cooperative Oncology Group 
• 
eC
RF 
• 
electronic Case Report Form 
• 
E
D
C 
• 
electronic data capture 
• 
EF
S 
• 
event- free survival 
• 
F 
• 
phenylalanine 
• 
F
A
CS 
• 
fluorescent- activated cell sorter 
• 
Fc
γR 
• 
leukocyte receptors for the Fc portion of IgG 
• 
F
D
A 
• 
Food and Drug Administration 
• 
18F
-
F
D
G 
• 
18F- fleurodeoxyglucose 
• 
FF
PE 
• 
formalin- fixed paraffin- embedded  
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
12 
• 
Ab
br
evi
ati
on 
• 
Definition 
• 
FI
SH 
• 
fluorescence in situ hybridization 
• 
FL 
• 
Follicular lymphoma 
• 
G
C
B 
• 
germinal center B cell 
• 
G
C
P 
• 
Good Clinical Practice 
• 
G
CS
F 
• 
granulocyte- colony stimulating factor 
• 
G
EP 
• 
G 
• 
gene expression profiling 
• 
GA101 
• 
G-
F
C 
• 
GA101 in combination with fludarabine 
and cyclophosphamide 
• 
H
A
H
A 
• 
human anti- human antibodies 
• 
H
Bc
Ab 
• 
hepatitis B core antibody 
• 
H
Bs
Ag 
• 
hepatitis B surface antigen 
• 
H
B
V 
• 
hepatitis B virus 
• 
H
C
V 
• 
hepatitis C virus 
• 
H
D 
• 
high dose 
• 
H
TL
V 
• 
human T- cell leukemia virus 
• 
IC
H 
• 
International Conference on Harmonisation 
• 
Ig 
• 
immunoglobulin  
• 
IH
C 
• 
immunohistochemistry 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
13 
• 
Ab
br
evi
ati
on 
• 
Definition 
• 
IN
D 
• 
Investigational New Drug 
• 
IM
C 
• 
Internal Monitoring Committee 
• 
IR
R 
• 
infusion- related reaction 
• 
IV 
• 
intravenous 
• 
IL 
• 
interleukin  
• 
IPI 
• 
International Prognostic Index 
• 
IV
RS 
• 
interactive voice response system 
• 
L
D 
• 
low dose 
• 
L
V
EF 
• 
left ventricular ejection fraction 
• 
L
VS
. 
D 
• 
left ventricular systolic dysfunction 
• 
M
C
L 
• 
mantle- cell lymphoma 
• 
M
RI 
• 
magnetic resonance imaging 
• 
M
U
G
A 
• 
multigated acquisition scan 
• 
N
CI 
C
T
C
A
E 
• 
National Cancer Institute Common Terminology 
Criteria for Adverse Events 
• 
N
H
L 
• 
non- Hodgkin’s lymphoma 
• 
N
O
N
M
E
M 
• 
Non- Linear Mixed Effect Model 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
14 
• 
Ab
br
evi
ati
on 
• 
Definition 
• 
O
RR 
• 
overall response rate 
• 
O
S 
• 
overall survival 
• 
P
D 
• 
progressive disease  
• 
PI
C
C 
• 
peripherally inserted central catheter 
• 
PK 
• 
pharmacokinetic 
• 
PE
T 
• 
positron emission tomography 
• 
PF
S 
• 
progression- free survival 
• 
P
M
L 
• 
progressive multifocal leukoencephalopathy 
• 
PR 
• 
partial response or partial remission 
• 
R-
C
H
O
P 
• 
rituximab in combination with cyclophosphamide, 
doxorubicin, vincristine, prednisone 
• 
SA
E 
• 
serious adverse event 
• 
SD 
• 
stable disease 
• 
SD
I 
• 
shorter duration of infusion 
• 
SL
L 
• 
small lymphocytic lymphoma 
• 
S
O
C 
• 
TF
R 
• 
Scientific Oversight Committee 
• 
Tumor flare reaction 
• 
TL
S 
• 
tumor lysis syndrome 
• 
U
L
N 
• 
upper limit of normal 
• 
U.
S. 
• 
United States 
• 
V 
• 
valine  
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
15 
• 
Ab
br
evi
ati
on 
• 
Definition 
• 
W
H
O 
• 
World Health Organization 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
16 
Introduction 
Non-Hodgkin lymphoma 
Non- Hodgkin lymphoma (NHL) is the most common hematologic malignancy in adults. The 
majority of NHL are of B- cell origin and are characterized by the expression of membrane 
antigen CD20 which is important in cell cycle initiation and differentiation (Anderson et al. 
1984). 
 
Indolent NHLs are a heterogeneous group of malignant lymphomas and account for about 
one- third of all NHLs. Follicular lymphoma is the most common subtype of indolent NHL in 
the Western hemisphere and is associated with follicle center B cells that typically contain 
the BCL2 chromosome translocation t(14:18), which  leads to overexpresion of the 
intracellular anti- apoptotic protein Bcl- 2.  
 
Early- stage indolent NHL may be effectively treated with radiation therapy, but advanced 
stages remain incurable and there is no established standard of care for previously untreated 
follicular lymphoma (Friedber
g et al. 2009). 
 
Natural History and Current Management of Indolent Non-Hodgkin Lymphoma 
Natural History 
The clinical course of indolent NHL is characterized by remission and relapse 
(Gallagher et al. 1986). The disease often initially responds to immunochemotherapy, 
but most patients eventually suffer multiple relapses distinguished by increasing 
resistance and decreasing duration of response in subsequent lines of therapy.  
Patients with advance- stage disease are not usually cured with conventional treatment 
and ultimately die from recurrent disease or treatment- related toxicity. 
 
Current Management 
There is no standard treatment for the management of advanced follicular lymphoma, and 
data from the National LymphoCare registry demonstrate that practice varies widely 
among physicians (Friedberg et al. 2009).  For follicular lymphoma patients requiring 
treatment, immunochemotherapy with rituximab, a monoclonal antibody directed against 
CD20, plus chemotherapy has demonstrated improvements in response rates, 
progression- free survival (PFS), and overall survival compared with chemotherapy alone in 
four studies (Hiddemann et al. 2005; Herold et al. 2007; Marcus et al. 2008; Salles et al. 
2008). Despite high response rates, and median PFS exceeding 5 years with the addition 
of maintenance rituximab (Salles et al. 2011), chemoimmunotherapy is not considered 
curative in FL, as patients continue to relapse.  In addition, the side effect profile 
associated with cytotoxic therapy raises the question, what is the optimal frontline 
strategy for FL? 
 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
17 
Obinutuzumab Background 
Structure and Mechanism of Action of Obinutuzumab 
Obinutuzumab (GA101, RO5072759), 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 (Beers et al. 2010; Mössner et al. 2010): 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 FcγRIII 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 (Rituxan).  
Clinical Experience with Obinutuzumab 
Clinical data on obinutuzumab are available from four Phase I or II studies (Studies BO20999, 
BO21003, BO21000, and JO21900) and two Phase III studies (Studies GAO4753g and 
BO21004/ CLL- 11). Results from the ongoing studies are described below. For the most up-
to- date information on obinutuzumab, please refer to the current version of the Investigator’s 
Brochure. 
 
Tolerability and Efficacy of Obinutuzumab in NHL 
Study BO20999 (GAUGUIN; NCT00517530) (Phase I) 
BO20999 was an open- label, multicenter, Phase I/ II study to explore obinutuzumab 
safety and activity in relapsed/ refractory NHL and CLL. Patients have received 
obinutuzumab at doses with a range of 400−2000 mg (given as a flat dose) across 
four cohorts (Morschhauser et al. 2009).  There were no dose- limiting toxicities 
(DLTs) and no requirement for dose reductions.  Infusion- related reactions (IRRs) 
occurred in all CLL patients and were characterized predominantly by National 
Cancer Institute Common Terminology Criteria (NCI- CTC) Grade 1−2 toxicities:  
chills, nausea, vomiting, fever, pyrexia, hypertension, hypotension, dyspnea, and 
dizziness.  Two patients experienced four NCI- CTC Grade 3 toxicities:  sweats, 
flushing, asthenia, and hepatic cytolysis.  
Although the safety profile appears otherwise similar between NHL and CLL, there was 
an increase in NCI- CTC v3.0 Grade 3−4 neutropenia noted in CLL patients, which 
were observed in 9 patients across the four dose levels administered.  Five patients 
experienced NCI- CTC Grade 4 neutropenia and 4 patients experienced NCI- CTC 
Grade 3 neutropenia as the maximum severity.  Of the 9 patients, 7 had 
one NCI- CTC Grade 3−4 event and 2 patients experienced more than one event.  
Granulocyte colony- stimulating factor (G- CSF) support was administered to 6 of the 
9 patients, and these patients responded quickly to G- CSF support.  For the 
3 patients who did not receive G- CSF, neutrophil counts normalized spontaneously.  
Furthermore, it is important to note that these neutropenia events did not appear to 
be accompanied by a higher incidence of infections.  No deaths were reported in 
Phase I of this study for CLL. 
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Obinutuzumab + lenalidomide in untreated FL 
MDACC Protocol 2015- 0464 Version 11 
 
18 
As assessed by the International Workshop on CLL (IWCLL) criteria, the 
end- of- treatment response rate with obinutuzumab monotherapy was 62% 
(8 of 13 patients with partial response [PR]) (Morschhauser et al. 2009). 
Study BO20999 (GAUGUIN; NCT00517530) (Phase II) 
Twenty patients with relapsed/refractory CLL have received 1000 mg of 
obinutuzumab.  The most commonly reported adverse event (AE) during the 
treatment period was IRR, reported in 19 (95%) of 20 patients.  Fifteen patients 
experienced Grade 3−4 AEs of whom 14 patients had treatment- related Grade 3−4 
AEs (investigator assessment).  Treatment- related Grade 3−4 AEs were IRR 
(6 patients), neutropenia (4 patients), lymphopenia (2 patients), thrombocytopenia (2 
patients), and anemia, pure red cell aplasia, pancytopenia, febrile neutropenia, herpes 
zoster, and interstitial lung disease (1 patient each).  Eleven serious adverse events 
(SAEs) in 9 patients were reported during treatment, 9 of which were assessed by the 
investigator as related to obinutuzumab:  IRR (4 patients) and febrile neutropenia, 
pancytopenia, pure red cell aplasia, interstitial lung disease and pyrexia (1 patient 
each).  Three patients withdrew from further study treatment after the first infusion 
due to IRR.  One death has been reported during follow- up from colon cancer.  The 
most common AE in follow- up was nasopharyngitis, reported in 2 patients.  End- of-
treatment response assessment showed that four patients (20%) achieved a clinical 
response, with a best overall response rate (ORR) of 25% in evaluable patients (Salles 
et al. 2011). 
Study BO21003 (GAUSS; NCT00576758) (Phase I) 
BO21003 is an open- label, dose- escalating, multicenter Phase I/ randomized Phase II study 
in patients with relapsed/ refractory CD20+ malignant disease.  In the Phase II portion of the 
study 175 patients (149 follicular, 26 non- follicular) were randomized to receive 4 weekly 
infusions of obinutuzumab (1000 mg) or rituximab (375mg/ m2). 
 
Patients without progression continued therapy with obinutuzumab or rituximab every 2 
months for 2 years. The ORR at the end of treatment in the follicular lymphoma cohort was 
45% for obinutuzumab and 33% for rituximab, as assessed by the investigators. A blinded 
central review was also performed and the ORR was 45% for obinutuzumab and 27% for 
rituximab. (Sehn et al. 2015) 
 
More IRRs were reported in the obinutuzumab arm (any grade: 72% vs. 49%, Grade 3/ 4: 
11% vs. 5%, for obinutuzumab and rituximab, respectively). Other AEs of any grade that 
occurred with ≥ 5% frequency with obinutuzumab compared to rituximab were fatigue, 
cough, back pain, and decreased appetite. 
 
Study BO21000 (Phase Ib): Obinutuzumab in Combination with Chemotherapy 
Study BO21000 is an ongoing, open- label, randomized Phase I/ II trial investigating two 
doses of obinutuzumab (400 mg in all cycles and 1600 cycle 1/ 800 mg subsequent cycles) 
in combination with chemotherapy given every 4 weeks for a maximum of six cycles 
(obinutuzumab plus fludarabine and cyclophosphamide [G- FC]) or a maximum of eight 
cycles (obinutuzumab plus CHOP [G- CHOP]) in patients with relapsed or refractory 
follicular lymphoma. Patients with a PR or CR who complete a minimum of four cycles of 
G- FC or six cycles of G- CHOP have the option of receiving maintenance therapy with 
obinutuzumab alone every 3 months for up to 2 years. All patients (28/ 28) who received 
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G- CHOP and 22/ 28 who received G- FC completed treatment. Reasons for withdrawal 
from the G- FC arm were PD (1 patient), neutropenia (3 patients) and rash and infection 
(1 patient each). (Radford et al. 2011) 
 
Overall, the rate of adverse events was similar between the high- dose and low-  dose 
arms. The most common AE in both groups was IRRs, mostly during cycle 1. The rate 
of IRRs was 64% of patients in the G- CHOP arm and 79% of patients in the G- FC arm; 
7% of IRR events were Grade 3 or 4 events in both chemotherapy arms.  There were 
fewer dose delays, dose reductions, and neutropenia in the G- CHOP versus the G- FC 
cohorts. Grade 3/ 4 neutropenia was seen in 39% of the G- CHOP patients and 50% of 
the G- FC patients. In the G- CHOP arm 6% of cycles were delayed due to neutropenia 
or infection and the dose of any CHOP component was reduced in 29% of patients. In 
the G- FC arm, 10% of cycles were delayed due to neutropenia or infection with dose 
reductions in 36% of patients. Three deaths were reported following G- FC induction 
treatment (progressive disease, n=1; underlying Parkinson’s disease, n=1; and chronic 
obstructive pulmonary disease during maintenance, n=1) with none considered to be 
treatment- related. 
 
The overall response rate (ORR) at the end of induction was 96% in the G- CHOP group (39% 
CR) and 93% in the G- FC group (50% CR). Data from the G- CHOP cohort were compared in a 
matched- pair analysis to the rituximab plus CHOP (R-  CHOP) arm from study M39022 
(EORTC 20981) in a similar patient population. Response rates to G- CHOP compared 
favorably to response rates to R- CHOP. 
 
The protocol was amended to include obinutuzumab at a flat dose of 1000 mg plus 
bendamustine (G- bendamustine) or CHOP in previously untreated patients with follicular 
lymphoma.  Again, patients with a PR or CR who complete a minimum of six cycles of G-
CHOP or four cycles of G- bendamustine have the option of receiving maintenance therapy 
with GA101 alone every 3 months for up to 2 years. The Data and Safety Monitoring Board 
evaluated safety of the first 20 patients without requesting modifications to the protocol. 
 
Study GAO4753g (Phase III): Obinutuzumab in Combination with Chemotherapy 
Study GAO4753g (GADOLIN) is an open- label, multicenter, randomized, Phase III study to 
investigate the efficacy and safety of bendamustine compared with bendamustine plus 
obinutuzumab in patients with rituximab- refractory indolent NHL. Preliminary results have 
been presented at ASCO and Lugano 2015. The study was terminated early given 
recommendations from the IDMC as the primary endpoint had been reached with superior 
PFS with bendamustine plus obinutuzumab vs. bendamustine alone. (Sehn et al. 2015). 
 
 
Overview of Safety of Obinutuzumab 
Obinutuzumab has been administered to approximately 1310 patients with 
CD20- positive malignancies.  Both in patients with NHL and with CLL, IRR was the 
most common AE in clinical trials conducted to date.  They were predominantly 
associated with the first infusion, generally occurring early during the infusion, 
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shortly after, or in some cases up to 24 hours after the completion of the infusion 
with obinutuzumab.  The incidence and intensity of IRRs decreased with subsequent 
infusions of obinutuzumab.  In a few patients, concurrent signs of tumor lysis 
syndrome (TLS) were observed.  Other frequently observed AEs include infections 
and neutropenia.  These events appeared to be more common in patients with CLL 
compared to NHL. 
In trials investigating the combination of obinutuzumab and CHOP, FC, chlorambucil 
or bendamustine, the incidence of AEs in the treatment arms with combined use was 
consistent with the known safety profiles of the individual study drugs.  So far, no 
maximum tolerated dose, no dose- limiting toxicities, and no clear dose- related 
trends in the incidence of AEs have been determined. 
A pooled analysis of safety data for obinutuzumab collected during the monotherapy 
studies BO20999 and BO21003 was conducted in patients with NHL (aggressive 
[aNHL] and indolent []iNHL]) or CLL who participated in those two studies (both 
Phase I and Phase II) and received monotherapy treatment with obinutuzumab and 
included a total 205 patients with NHL (49 aNHL and 156 iNHL patients) and 38 
patients with CLL. 
In the group of 38 patients with CLL treated with obinutuzumab monotherapy, the 
majority of patients (25 [66%]) were treated for ≥  4 weeks to <  6 months.  Eleven 
patients (29%) were exposed for 6 to  < 12 months, and two patients (5%) were 
exposed for 12 months or longer.  Eight of 38 patients (21%) with CLL were 
withdrawn during the treatment phase; 4 patients (11%) were withdrawn due to AEs, 
which indicates that AEs were mostly manageable.  Almost all patients (37/ 38 [97%]) 
experienced an IRR.  The number of patients with Grade 3−4 IRRs was 11/ 38 (29%).  
As is typical for patients with CLL, blood and lymphatic system disorders were 
among the most frequently reported AEs, in particular neutropenia (13/ 38 patients 
[34%]), febrile neutropenia (5/ 38 patients [13%]), and thrombocytopenia (7/ 38 
patients [18%]). 
Infections and infestations were common AEs, occurring in 21/ 38 patients (55%).  
Infections reported in more than one patient were nasopharyngitis (6 patients), 
bronchitis and sinusitis (4 patients each), influenza and lung infection (3 patients 
each), and herpes zoster and oral herpes (2 patients each). 
Thirteen patients (34%) died, 8 of these due to disease progression.  One patient died 
from an unspecified cause after withdrawal from the study for lack of response.  This 
patient had received subsequent experimental therapies and had stable CLL at the 
time she died.  For 4 additional patients, the cause of death was reported as colon 
cancer, lung adenocarcinoma, metastasis, and septic shock, and all were considered 
not to be related to treatment. 
In the two studies investigating obinutuzumab as monotherapy, BO20999 and 
BO21003, patients with CLL appeared to be at a higher risk of experiencing an AE 
of special interest than patients with NHL.  The largest difference in the incidences 
was seen for neutropenia (occurring in 47% of patients with CLL [18/ 38] vs. 8% of 
patients with aNHL [4/ 49] and 8% of patients with iNHL [13/ 156]) and treatment-
related AEs associated with the infusion (100% [38/ 38] vs. 80% (39/ 49) and 83% 
[129/ 156]). 
To date, a very small number of patients have experienced TLS (six in total); four 
patients in the aNHL population (population including MCL) and one patient each in 
the CLL and iNHL populations. 
Infections have been reported in 20/ 49 aNHL patients (41%), 74/ 156 iNHL patients 
(47%), and 21/ 38 CLL patients (55%).  One iNHL patient was withdrawn from the 
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study because of an infection.  In addition, one CLL patient and one iNHL patient 
died from an infection (septic shock in both cases) during survival follow- up 671 days 
and 494 days after last dose of treatment, respectively. 
Three CLL and 3 iNHL patients were withdrawn from treatment due to an AE of 
special interest, all for IRRs.  An additional patient in the iNHL group discontinued 
treatment because of an infection.  This indicates that these events were generally 
manageable. 
Risks Associated with Obinutuzumab Therapy 
Hepatitis B Virus Reactivation 
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, 
hepatic failure, and death, can occur in patients treated with anti- CD20 antibodies 
such as obinutuzumab.  HBV reactivation has been reported in patients who are 
hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg 
negative but are hepatitis B core antibody (anti- HBc) positive.  Reactivation has 
also occurred in patients who appear to have resolved hepatitis B infection (i.e., 
HBsAg negative, anti- HBc positive, and hepatitis B surface antibody [anti- HBs] 
positive).  HBV reactivation is defined as an abrupt increase in HBV replication 
manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a 
person who was previously HBsAg negative and anti- HBc positive.  Reactivation of 
HBV replication is often followed by hepatitis, i.e., increase in transaminase levels 
and, in severe cases, increase in bilirubin levels, liver failure, and death.  
Screen all patients for HBV infection by measuring HBsAg and anti- HBc before 
initiating treatment with obinutuzumab. For patients who show evidence of hepatitis 
B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but 
anti- HBc positive), consult physicians with expertise in managing hepatitis B 
regarding monitoring, and consider HBV antiviral therapy.  
Monitor patients with evidence of current or prior HBV infection for clinical and 
laboratory signs of hepatitis or HBV reactivation during and for several months 
following treatment with obinutuzumab.  HBV reactivation has been reported for 
other CD20- directed cytolytic antibodies following completion of therapy.  
In patients who develop reactivation of HBV while receiving obinutuzumab, immediately 
discontinue obinutuzumab and any concomitant chemotherapy, and institute 
appropriate treatment.  Resumption of obinutuzumab in patients whose HBV 
reactivation resolves should be discussed with physicians with expertise in managing 
hepatitis B.  Insufficient data exist regarding the safety of resuming obinutuzumab in 
patients who develop HBV reactivation.  
Progressive Multifocal Leukoencephalopathy  
JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which 
can be fatal, was observed in patients treated with obinutuzumab.  Consider the 
diagnosis of PML in any patient presenting with new onset or changes to pre-
existing neurologic manifestations.  Evaluation of PML includes, but is not limited to, 
consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar 
puncture.  Discontinue obinutuzumab therapy and consider discontinuation or 
reduction of any concomitant chemotherapy or immunosuppressive therapy in 
patients who develop PML.  
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Infusion-Related Reactions  
Obinutuzumab can cause severe and life- threatening IRRs.  Two- thirds of patients 
experienced a reaction to the first 1000 mg of obinutuzumab infusion.  IRRs can also 
occur with subsequent infusions.  Symptoms may include hypotension, tachycardia, 
dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, 
wheezing, and laryngeal edema).  Other common symptoms include nausea, vomiting, 
diarrhea, hypertension, flushing, headache, pyrexia, and chills.  
Pre- medicate patients with acetaminophen, antihistamine, and a glucocorticoid.  
Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, 
and/ or oxygen) for IRRs as needed.  Closely monitor patients during the entire 
infusion.  IRRs within 24 hours of receiving obinutuzumab have occurred.  
For patients with any Grade 4 IRRs, including but not limited to anaphylaxis, acute 
life- threatening respiratory symptoms, or other life- threatening infusion reaction, 
stop the obinutuzumab infusion.  Permanently discontinue obinutuzumab therapy.  
For patients with Grade 1, 2, or 3 IRRs, interrupt obinutuzumab for Grade 3 reactions 
until resolution of symptoms.  Interrupt or reduce the rate of the infusion for Grade 
1 or 2 reactions and manage symptoms. 
For patients with pre- existing cardiac or pulmonary conditions, monitor more 
frequently throughout the infusion and the post- infusion period because these 
patients may be at greater risk of experiencing more severe reactions.  Hypotension 
may occur as part of the obinutuzumab IRR.  Consider withholding antihypertensive 
treatments for 12 hours prior to, during, and for the first hour after administration of 
each obinutuzumab infusion until blood pressure is stable.  For patients at increased 
risk of hypertensive crisis, consider the benefits versus the risks of withholding their 
hypertensive medication as is suggested here.  
Tumor Lysis Syndrome  
Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/ or 
hyperphosphatemia from TLS can occur within 12 − 24 hours after the first infusion.  
Patients with high tumor burden and/ or high circulating lymphocyte count 
( > 25 × 109/ L) are at greater risk for TLS and should receive appropriate tumor lysis 
prophylaxis with anti- hyperuricemics (e.g., allopurinol) and hydration beginning 
12 − 24 hours prior to the infusion of obinutuzumab.  For treatment of TLS, correct 
electrolyte abnormalities, monitor renal function and fluid balance, and administer 
supportive care, including dialysis as indicated.  
Infection  
Serious bacterial, fungal, and new or reactivated viral infections can occur during and 
following obinutuzumab therapy.  Do not administer obinutuzumab to patients with 
an active infection.  Patients with a history of recurring or chronic infections may be 
at increased risk of infection.  
Neutropenia  
Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 neutropenia in 
34% of patients in clinical trials.  Patients with Grade 3 to 4 neutropenia should be 
monitored frequently with regular laboratory tests until resolution.  Anticipate, 
evaluate, and treat any symptoms or signs of developing infection.  Neutropenia can 
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also be of late onset (occurring more than 28 days after completion of treatment) 
and/ or prolonged (lasting longer than 28 days).  
Patients with neutropenia are strongly recommended to receive antimicrobial 
prophylaxis throughout the treatment period.  Antiviral and antifungal prophylaxis 
should be considered.  
Thrombocytopenia  
Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia 
in 12% of patients in clinical trials.  In 5% of patients, obinutuzumab caused an acute 
thrombocytopenia occurring within 24 hours after the obinutuzumab infusion.  In 
patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more 
frequently until resolution.  Transfusion of blood products (i.e., platelet transfusion) 
may be necessary. 
Summary of Pharmacokinetic and Pharmacodynamic Data for Obinutuzumab 
A two- compartment model comprising a time- varying clearance pathway and a linear 
clearance pathway provides an adequate description of the pharmacokinetics of 
obinutuzumab following intravenous (IV) administration in Studies BO20999 and 
BO21003.  Following the infusion of obinutuzumab, the elimination appears to be 
characterized by a clearance pathway that is dependent on time (i.e., starting at a 
typical value of 630 mL/ day and then gradually decreasing to an asymptote of 
60 mL/ day at steady state) and a linear clearance pathway.  Tumor burden may 
potentially contribute significantly to the clearance of obinutuzumab, especially at 
the beginning of treatment when CD20- positive tumor cells are most abundant.  
As tumor burden decreases, the clearance reaches an asymptote, which is believed 
to be primarily a function of the proteolytic metabolic clearance.  Consequently, 
some patients with a high tumor burden may appear to clear the drug from the 
plasma faster than do patients with a low tumor burden because obinutuzumab binds 
to the CD20- positive tumor cells and is effectively removed from the plasma.  
Therefore, the clearance of the drug will vary with time, since repeated treatments 
with obinutuzumab will reduce the quantity of CD20- positive tumor cells.  
Consequently, the number of obinutuzumab administrations during the first cycle of 
treatment may be expected to reduce the number of CD20- positive tumor cells, thus 
minimizing the impact of the time varying clearance pathway on obinutuzumab 
exposure. 
Treatment with obinutuzumab resulted in extensive B- cell depletion, with all patients 
showing a reduction in cell count to absolute zero at some stage of their treatment 
cycle.  Overall, there has been no notable increase in complement levels before and 
after infusion, but changes have been observed in the levels of interleukin (IL)- 6 and 
IL- 8 before and after infusion. 
lenalidomide BackGround 
Lenalidomide, an oral agent, is a thalidomide derivative that belongs to a new class of agents 
known as immunomodulatory drugs (IMiDs). Lenalidomide has clinical activity in NHL and has 
been shown to possess several immunomodulatory properties. Despite the clinical activity of 
the IMiDs in various malignant diseases, the exact mechanism of their antitumor activity 
remains elusive. In addition to its known effect on various cytokines, lenalidomide may affect 
the immune cellular component of the tumor microenvironment. Potential effects include 
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inducing lymphocyte proliferation, increasing the production of IL- 2/ INF- g by effector cells 
and angiogenesis inhibition. 
 
 
Lenalidomide Description 
 
The chemical name is 3- (4- amino- 1- oxo 1,3- dihydro - 2H- isoindol- 2- yl) piperidine- 2,6- dione 
. The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3. 
 
Lenalidomide is off- white to pale- yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 
to 0.5 mg/ ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically 
active forms S(- ) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero. 
 
Lenalidomide is available in 2.5mg, 5 mg, 10 mg, 15mg, 20mg, and 25mg capsules
 for oral 
administration. Each capsule contains lenalidomide as the active ingredient and the following 
inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate.  
 
Pharmacokinetics and Drug Metabolism: Absorption: 
Lenalidomide, in healthy volunteers,
 is rapidly absorbed following oral administration 
with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-
dose. Co- administration with food does not alter the extent of absorption (AUC) but 
does reduce the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic 
disposition of lenalidomide is linear. Cmax and AUC increase proportionately with 
increases in dose. 
Multiple dosing at the recommended dose
- regimen does not result in drug accumulation. 
Pharmacokinetic sampling in myelodysplastic syndrome (MDS) patients was not performed. In 
multiple myeloma patients maximum plasma concentrations occurred between 0.5 and 4.0 
hours post- dose both on Days 1 and 28. AUC and Cmax values increase proportionally with 
dose following single and multiple doses. Exposure (AUC) in multiple myeloma patients is 57% 
higher than in healthy male volunteers.
 
 
Pharmacokinetic Parameters: Distribution: 
In vitro (14C)- lenalidomide binding to plasma proteins is approximately 30%. 
 
Metabolism and Excretion 
The metabolic profile of lenalidomide in humans has not been studied. In healthy 
volunteers, approximately two- thirds of lenalidomide is eliminated unchanged through 
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urinary excretion. The process exceeds the glomerular filtration rate and therefore is 
partially or entirely active. Half- life of elimination is approximately 3 hours. 
 
 
Lenalidomide in NHL 
 
Lenalidomide induced growth arrest and apoptosis of lymphoma cell lines as well as 
enhancing NK- cell–mediated antibody- dependent cellular cytotoxicity (ADCC) of rituximab. 
(Wu et al 2006) In addition, using a lymphoma xenograft mouse model (Hernandez-
Ilizaliturri et al 2005) demonstrated that IMiD molecules enhanced the antitumor activity of 
rituximab, resulting in improved survival of tumor- bearing animals. 
 
 
Aggressive NHL 
Witzig et al reported the Phase II results of lenalidomide monotherapy in patients with 
relapsed or refractory aggressive NHL. Lenalidomide (25 mg/ d) was administered on days 1 
to 21 of a 28- day cycle and continued as tolerated or until disease progression. (Witzig et al 
2011) Patients with various aggressive 
histologic subtypes (including diffuse large B- cell, grade 3 follicular lymphoma, mantle cell, 
and transformed NHL) were enrolled. 277 patients were enrolled, the ORR was 35%. Clinical 
responses were observed in all lymphoma subtypes. Median PFS was 3.7 months. The most 
common adverse event was myelosuppresion with grade 4 neutropenia and thrombocytopenia 
in 17 and 6%, respectively. A multicenter clinical trial has been completed investigating 
clinical efficacy of single agent lenalidomide vs. investigator’s choice in patients with 
relapsed/ refractory DLBCL and preliminary findings suggest clinically activity of lenalidomide 
in relapsed/ refractory DLBCL with more pronounced efficacy in ABC DLBCL. (Czucman et 
al. 2014)  
 
 
A phase I clinical trial of lenalidomide (5 to 25 mg) in combination with rituximab was 
initiated for MCL. The MTD was 20 mg/ d, 21 of 28 days. The DLT was prolonged 
neutropenia. Thirteen of 15 patients were assessable and had a median of three (range 1- 4) 
prior therapies. Although there were no responses in the 10-  and 15- mg dose cohorts, five 
of six patients in the 20- mg cohort responded including a complete response. (Wang et al 
2007) On this basis, a multicenter Phase II trial of lenalidomide in patients with relapsed or 
refractory MCL after bortezomib was conducted demonstrating an ORR of 28%, median PFS 
of 4 month, median OS of 19 months, and led to the indication of lenalidomide in 
relapsed/ refractory MCL. (Goy et al. 2013) 
 
 
Indolent NHL 
Witzig et al reported a phase II study of lenalidomide (25 mg/ d for 21 of 28 days) in patients 
with relapsed or refractory indolent NHL.70 Among 27 assessable patients with a median of 
three (range, one to 17) prior therapies, the ORR was 26% (n = 7) including two CRs, whereas 
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the overall clinical benefit (stable disease or better response) was observed in 59% of the 
patients. (Witzig 2007) A large, randomized, multicenter clinical trial conducted by the Cancer 
and Leukemia Group B (CALGB) is investigating the clinical benefit of lenalidomide versus 
lenalidomide/ rituximab in patients with relapsed follicular NHL. 
 
 
Lenalidomide plus Rituximab in Indolent Lymphoma 
At MD Anderson, we conducted a phase II, single arm study with a combination of 
lenalidomide and rituximab in patients with untreated indolent NHL. (Fowler et al. 2014) 
Patients receive lenalidomide 20 mg/ day on days 1- 21 of each 28 day cycle. Rituximab was 
given at 375 mg/ m2 on day 1 of each cycle. We reported high overall response rates, with a 
complete response rate of 87% in patients with follicular lymphoma. Toxicity has been mild to 
moderate, with the most common non- hematologic adverse event reported as grade 1- 2 
fatigue and rash. Hematologic toxicity included 35% ≥grade 3 neutropenia and 4% with 
≥grade 3 thrombocytopenia. These results were validated by a recently reported Phase II 
cooperative group study of lenalidomide and rituximab in untreated indolent NHL, 
demonstrating similar response rates and toxicity.  (Martin P, et al ASH 2013). 
 
 
Study Rationale 
Obinutuzumab Plus Lenalidomide in Untreated Follicular Lymphoma 
We hypothesize that the high clinical responses noted in indolent lymphoma patients 
following lenalidomide and rituximab is related to the combination’s ability to augment the 
immune response, and subsequent ADCC through alteration of immune cell subsets in the 
tumor and peripheral blood. Lenalidomide has been shown to activate NK cells, T cells, or 
both and leads to expansion of immune effector cells in- vivo in NHL and CLL models. In 
preclinical models, we have also shown the synergistic anti- tumor effect of combining 
lenalidomide with anti- CD20 molecules. 
 
As noted above, obinutuzumab is a new, humanized anti- CD20 monoclonal antibody which 
binds to a unique type II epitope on the cell surface. Obinutuzumab has demonstrated 
increased affinity to the FCgRIIIa receptor, and may have increased ADCC when compared 
to rituximab. 
Preliminary 
studies also suggest the obinutuzumab is effective in patients with relapsed/ refractory 
indolent lymphoma. (Salles et al 2011) 
 
Combining an anti- CD20 antibody with increased affinity for the FCgRIIIa receptor with an 
immunomodulatory agent that increases ADCC is rational and has the potential to build 
upon the anti- lymphoma characteristics of both agents. Both agents are well tolerated, and 
the expected toxicity profile is mild. 
 
The starting dose of lenalidomide is based upon the initial dose finding study by Wang et 
al., which determined the maximum tolerated dose of lenalidomide with rituximab was 
20mg daily in relapsed NHL.   This dose was also shown to be safe in a recently 
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presented phase I study of obinutuzumab and lenalidomide in relapsed NHL. 
(Morschhauser F, et al ASH 2014) In addition, we are conducting a Phase I/II study of 
obinutuzumab and lenalidomide in relapsed/refractory indolent NHL (
NCT01995669). 
No DLTs were observed in the Phase I dose escalation portion of the study and the 
Phase II cohort is currently enrolling with obinutuzumab dosed at 1000mg and 
lenalidomide at 20mg.
 
Novel Endpoints 
With the prolonged natural history of follicular lymphoma, identifying optimal endpoints or 
surrogates for overall survival for frontline studies is an evolving field. In an analysis of the 
National LymphoCare Study, previously untreated patients with FL who experienced 
progressive disease within 2 years of initial treatment were identified as a high risk group, 
“early progressors”. Early progression was dramatically associated with inferior overall 
survival, 5 year OS estimates of 50% versus 90% in the reference group. (Casulo et al. JCO 
2015) After adjusting for FLIPI score, early progression was associated with an increased risk 
of death (hazard ratio [HR] =6.44 (95% confidence interval [CI] 4.33- 9.58). This suggests that 
a landmark progression- free survival at 2 years may predict for a high risk population and 
discern a difference in survival outcomes. Another proposed efficacy endpoint includes the 
complete response rate at 30 months which has been shown to correlate with PFS in follicular 
lymphoma (Sargent et al, ASCO 2015). Both approaches serve as surrogate endpoints for 
overall survival. 
 
We are proposing a novel frontline, open- label, Phase II clinical trial for previously 
untreated patients with follicular lymphoma, a non- cytotoxic approach based on 
sound scientific rationale with emerging clinical endpoints. We are proposing the 
next generation of immune therapy with obinutuzumab in combination with 
lenalidomide to enhance ADCC and direct cell death to improve outcomes for our 
patients with an anticipated acceptable toxicity profile.  We aim to explore the 
efficacy and safety of the novel combination of obinutuzumab and lenalidomide in 
previously untreated patients with follicular lymphoma to influence practice patterns. 
Objectives 
Primary 
The primary objective is to evaluate the efficacy of obinutuzumab combined with 
lenalidomide in patients with previously untreated follicular lymphoma (determined by 
PFS at 2 years). 
Secondary 
The secondary objectives are: 
 
1. 
To evaluate the safety of obinutuzumab in combination with lenalidomide 
in patients with untreated follicular lymphoma. 
2. 
To evaluate the efficacy of obinutuzumab in combination with 
lenalidomide in subjects with follicular lymphoma as assessed by CR at 
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28 
30 months, ORR, DOR, EFS, and OS 
 
exploratory 
The exploratory objective are to evaluate prognostic and predictive biomarkers relative 
to treatment outcomes. 
Study Design 
Description of the Study 
This is a single center, Phase II, open label study designed to assess the efficacy and safety of 
obinutuzumab combined with lenalidomide in previously untreated subjects with follicular 
lymphoma. The study will include approximately 90 subjects in one treatment arm.  
 
Once a patient provides written informed consent, the patient may enter the screening period, 
which is permitted to last up to 4 weeks. During the screening period, the patient will undergo 
safety and other assessments to determine eligibility for the study. The patient eligibility will be 
based on investigator assessment. The patient will enter the treatment period once the patient 
has fulfilled the required assessment in the screening period. The treatment period for each 
patients starts with study day 1 of cycle 1. The treatments will be given as described in Section 
5. The patients will receive protocol- specified treatments, until: 
 
1) Failure to achieve at least a partial response after 6 cycles of therapy 
2) Relapse or progression of disease 
3) Withdrawal of consent,  
4) Unacceptable toxicity, or 
5) End of study.  
 
Upon completion of the required treatments, the patient will enter the follow- up period. During 
the follow- up period, patients will be followed for disease progression, next lymphoma 
treatment, and OS.  
 
Study Endpoints 
Primary Efficacy Outcome Measure 
Progression- free survival (PFS) at 2 years as assessed by the investigator  
 
Secondary Efficacy Outcome Measures 
• 
Complete response rate ([CR], based on Cheson, Lugano classification 2014) at 30 
months or 120 weeks as assessed by the investigator 
• 
Overall response rate ([ORR] CR + partial response [PR]) based on Cheson, Lugano 
2014 as assessed by the investigator 
• 
ORR, CR, and PR based on Cheson 2007. 
• 
Duration of response (DOR) 
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• 
Event free survival (EFS) 
• 
Overall survival (OS) 
 
Safety Outcome Measures 
• 
Frequency, severity, and relatedness of treatment- emergent adverse events (AEs) 
• 
Frequency of treatment- emergent AEs requiring discontinuation of study drug or dose 
reductions 
 
Exploratory Endpoints 
• 
Immunophenotyping of PBMCs to determine alteration in immune cell subsets  
• 
Identification of signaling pathways or biomarkers that predict sensitivity or resistance 
by gene expression profiling 
 
 
Evaluation of response 
Response assessment will be completed by the Principal Investigator using Cheson 2014 
Lugano Criteria. At screening, up to 6 target lesions will be selected and followed for the 
duration of the study as outlined in Section 7.7.8. Information on extranodal involvement can 
also be recorded. The best response will be documented.  
 
Safety plan 
This study will be monitored by the Principal Investigator and in accordance with all 
FDA safety reporting requirements. AEs and SAEs will be reviewed on an ongoing 
basis to identify potential safety concerns. The Investigator will record the action 
taken with the study drugs as a result of an AE or SAE, as applicable (e.g., 
discontinuation, interruption, or reduction of study drugs, as appropriate) and report 
if concomitant and/ or additional treatments were given for the event. The principal 
Investigator is required to notify his/ her Institutional Review Board (IRB) of a 
serious adverse event according to institutional policy. Enrolled subjects will be 
evaluated clinically including vital signs and standard laboratory test assessment. 
Statement of compliance 
The study will be conducted in compliance with this protocol, principles of International 
Conference on Harmonization (ICH), Good Clinical Practice (GCP), Declaration of 
Helsinki, and all applicable national and local regulations governing clinical studies. 
Study Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. A diagnosis of follicular lymphoma (grades 1, 2, or 3a), untreated 
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2. Able and willing to provide written informed consent and to comply with 
the study protocol 
3. Must be ≥18 years of age 
4. Bi- dimensionally measurable disease, with at least one mass lesion ≥ 2 cm 
in longest diameter by CT, PET/ CT, and/ or MRI. 
5.  Must be in need of therapy as evidenced by at least one of the following 
criteria: 
a. Bulky disease defined as: 
i. A nodal or extranodal (except spleen) mass > 7 cm in its 
greater diameter or, 
ii. At least 3 nodal or extranodal sites  ≥ 3 cm in diameter 
b. presence of at least one B symptom: 
i. fever (>38 C) not due to infectious etiology 
ii. night sweats 
iii. weight loss >10% in the past 6 months 
c. Fatigue due to lymphoma 
d. Splenomegaly (>13 cm) 
e. Compression syndrome (ureteral, orbital, gastrointestinal) 
f. Any of the following cytopenias due to lymphoma: 
i. Hemoglobin ≤ 10 g/ dL 
ii. Platelets ≤ 100 x 109/ L 
iii. absolute neutrophil count (ANC) < 1.5x109/ L 
g. Pleural or peritoneal effusion 
h. LDH > ULN or β2 microglobulin > ULN 
6. Stage II, III, or IV disease 
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2  
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8. Adequate hematologic function defined as follows: 
a. Absolute neutrophil count  (ANC) >1.0x109/ L 
b. Platelet count > 75x109/ L 
9. Adequate organ function, including: 
a. Serum aspartate transaminase (AST) and alanine transaminase 
(ALT) < 3 x upper limit of normal (ULN) 
b. Creatinine clearance >30 ml/ min calculated by modified 
Cockcroft- Gault formula. 
c. Bilirubin < 1.5 x ULN unless bilirubin is due to Gilbert’s 
syndrome, documented liver involvement with lymphoma, or of 
non- hepatic origin, in which case bilirubin should not exceed 
3g/ dL. 
10. Women of childbearing potential and men who are sexually active must 
practice reliable contraceptive measures started at least 4 weeks before 
study therapy and continued for at least 18 months for female subjects 
and 6 months for male subjects following discontinuation of therapy. 
Females of childbearing potential must either completely abstain from 
heterosexual sexual contact or must use 2 methods of reliable 
contraception. Reliable contraceptive methods include 1 highly effective 
method [intrauterine device, birth control pills, hormonal patches, 
injections, vaginal rings, or implants] and at least 1 additional method 
[condom, diaphragm, or cervical cap] every time they have sex with a 
male. Males who are sexually active must be practicing complete 
abstinence or agree to a condom during sexual contact with a pregnant 
female or female of child bearing potential.  Men must agree to not 
donate sperm during and after the study.  
11. Women of childbearing potential must have a negative serum (beta-
human chorionic gonadotropin [β- hCG]) pregnancy test at screening. 
Women who are pregnant or breastfeeding are ineligible for this study. 
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a. Females of reproductive potential must adhere to the scheduled 
pregnancy testing as required in the Revlimid REMS® program.  
12. All study participants must be registered into the mandatory Revlimid 
REMS® program, and be willing and able to comply with the 
requirements of the REMS® program. 
13. Sign (or their legally- acceptable representatives must sign) an informed 
consent document indicating that they understand the purpose of and 
procedures required for the study, including biomarkers, and are willing 
to participate in the study. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Known active central nervous system lymphoma or leptomeningeal disease.  
2. Follicular lymphoma with evidence of diffuse large B- cell transformation 
3. Grade 3b follicular lymphoma 
4. Any prior history of other malignancy besides follicular lymphoma, unless 
the patient has been free of disease for ≥ 5 years and felt to be at low risk 
for recurrence by the treating physician, except: 
a. Adequately treated non- melanoma skin cancer or lentigo maligna 
without evidence of disease.  
b. Adequately treated cervical carcinoma in situ without evidence of 
disease. 
5. Any life- threatening illness, medical condition, or organ system 
dysfunction which, in the investigator’s opinion, could compromise the 
subject’s safety, interfere with the absorption or metabolism of 
lenalidomide capsules, or put the study outcomes at undue risk 
6. Known history of human immunodeficiency virus (HIV), active Hepatitis C 
Virus, active Hepatitis B Virus infection, or any uncontrolled active 
systemic infection 
a. Patients with inactive hepatitis B infection must adhere to hepatitis 
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B reactivation prophylaxis unless contraindicated. 
7. Prior use of lenalidomide 
8. Concurrent systemic immunosuppressant therapy (e.g., cyclosporine, 
tacrolimus, etc., or chronic administration glucocorticoid equivalent of 
>10mg/ day of prednisone) within 28 days of the first dose of study drug 
9. Known anaphylaxis or IgE- mediated hypersensitivity to murine proteins or 
to any component of rituximab 
10. Clinically significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or myocardial infarction 
within 6 months of Screening, or any Class 3 (moderate) or Class 4 
(severe) cardiac disease as defined by the New York Heart Association 
Functional Classification. 
11. Significant screening electrocardiogram (ECG) abnormalities including left 
bundle branch block, 2nd degree atrioventricular (AV) block, type II AV 
block, or 3rd degree block. QT prolongation is not a significant ECG 
abnormality that would warrant exclusion.  
12. Vaccinated with live, attenuated vaccines within 4 weeks of study entry 
13. Lactating or pregnant subjects 
14. Administration of any investigational agent within 28 days of first dose of 
study drug. 
15. Patients who have undergone major surgery within 14 days. 
16. Patients with the following: 
a. bleeding diathesis or patients in whom prophylactic antithrombotic 
therapy is otherwise contraindicated 
b. patients with prior DVT, PE, or arterial thromboembolism 
c. patients with ischemic stroke or TIA 
 
 
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Treatment of subjects 
enrollment and blinding 
This is an open- label, Phase II study with one treatment arm. Subjects will not be blinded to 
study drug nor will they be randomized. Enrolled subjects will receive open- label capsules of 
lenalidomide in combination with IV obinutuzumab.  
 
treatment schedule 
 
± After cycle 6, obinutuzumab will be administered every 2 cycles until cycle 30 (8, 10, 12, 14, 
16, 18, 20, 22, 24, 26, 28, 30) 
+ For subjects with CrCL >60mL/ min, see Table 2 for dose modification for CrCL≤60 mL/ min. 
* For subjects who achieve a CR prior to cycle 12, these subjects will proceed to 10mg of 
lenalidomide, days 1- 21 for the remainder of 18 cycles. For subjects who maintain a PR, after 
12 cycles, they will receive 10mg of lenalidomide for the remainder of 18 cycles. 
# For subjects who fail to achieve at least a partial response after 6 cycles of therapy, they will 
discontinue study drug. Subjects with earlier evidence of nonresponse that warrants change in 
therapy in the opinion of the treating physician will discontinue study drug. 
 
• 
Lenalidomide dosing:  
o Patients will receive a maximum of 18 cycles of lenalidomide. 
  
o Cycles 1- 6: 
 
 
Patients with a CrCl >60 mL/ min, will receive 6 cycles of lenalidomide, 20mg 
daily on days 1- 21 of a 28 day cycle (± 2days). For patients with a CrCl ≤ 60 
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mL/ min, see Section 5.3.2.1 /  Table 1 for dose adjustment for renal 
impairment. 
 
o 
Cycles 7- 18: 
 
Patients with a CrCl >60 mL/ min exhibiting a CR after six cycles will then receive 12 
additional cycles of 10mg of lenalidomide daily on days 1- 21 every 28 days (± 2days) 
for a total of 18 cycles.  
 
Patients who fail to achieve at least a PR after 6 cycles will discontinue study 
drug. 
 
 
Patients with a CrCl >60 mL/ min with a PR after six cycles will continue 20mg of 
lenalidomide on days 1- 21 every 28 days (± 2days) for 3 to 6 more cycles until they 
achieve a CR at which time they will receive 10mg lenalidomide on days 1- 21 every 28 
days (± 2days) for the remainder of 18 cycles.  
 
Patients with a CrCl >60 mL/ min with a PR after 12 cycles will then receive 10mg of 
lenalidomide on days 1- 21 every 28 days (± 2days) for the remainder of 18 cycles. 
• 
Obinutuzumab dosing: 
o Cycle length is 28 days. 
 
o Cycles 1- 6: 
 
Patients will receive obinutuzumab, 1000 mg on days 1, 8 (± 2days), and 
15 (± 2days) of cycle 1, and day 1 (± 2days) of cycles 2 through 6.  
 
 
Patients who fail to achieve at least a PR after 6 cycles will discontinue 
study drug. 
 
o Cycles 7- 30: 
 
 
Patients will receive 1000mg of obinutuzumab on day 1 (± 2days) of cycle 
8, 10, and 12. 
 
 
Patients will receive obinutuzumab, 1000 mg on day 1 (± 7 days) of cycle 
14, 16, 18, 20, 22, 24, 26, 28, and 30. 
 
 
 
Obinutuzumab is continued for 30 cycles or until disease progression, 
unacceptable toxicity, or voluntary withdrawal whichever occurs first. 
 
 
dosage and administration 
Below are specific administration instructions for drugs used within this study. 
 
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Obinutuzumab  
Obinutuzumab is provided as a single dose, sterile liquid formulation in 50 mL pharmaceutical 
grade glass vials containing a nominal 1000 mg of obinutuzumab. The formulated drug product 
consists of 25 mg/ mL drug substance (G3 material) formulated in histidine, trehalose, and 
poloxamer 188.  The vials contain 41 mL (with 2.5% overfill).  Obinutuzumab will be supplied 
to research subjects by Genentech for the duration of this trial at no charge to participants or 
their insurance providers. 
 
Obinutuzumab drug product intended for IV infusion is prepared by dilution of the drug 
product into an infusion bag containing 0.9% NaCl to the final drug concentration of 4 mg/ mL. 
Using a 250- mL infusion bag containing 0.9% NaCl, withdraw and discard 40 mL of the NaCl. 
Withdraw 40 mL of obinutuzumab from a single glass vial and inject into the infusion bag 
(discard any unused portion of obinutuzumab left in the vial). Gently invert the infusion bag to 
mix the solution; do not shake. 
 
Do not use obinutuzumab beyond the expiration date stamped on the carton. 
 
Obinutuzumab Administration 
Obinutuzumab 1000mg will be given as outlined in Section 5.2. 
 
First Infusion of obinutuzumab: 
 
Thirty to 60 minutes prior to all obinutuzumab infusions, the following pre-  medications will be 
given (unless contraindicated): 
 
• 
Oral acetaminophen (1000 mg) AND 
 
• 
An antihistamine such as diphenhydramine (50−100 mg) 
 
• 
For Cycle 1, day 1 prophylactic corticosteroids (e.g., 20 mg IV dexamethasone) 
at least one hour prior to the obinutuzumab infusion. An equivalent dose of 
methylprednisolone (80mg) is acceptable but hydrocortisone should not be used. 
 
 
Obinutuzumab will be administered at an initial rate of 12.5mL/ hr (50mg/ hr) for 60 minutes, 
and then the infusion rate may be escalated by 12.5mL/ hr increments every 30 minutes to a 
maximum of 100mL/ hr as tolerated. If hypersensitivity or an infusion reaction develops, the 
infusion should be interrupted until symptoms resolve or improve, see Section 6.4, Table 4. 
For management of infusion reaction, please refer to the institution’s hypersensitivity reaction 
order sheet. The infusion can continue at one- half the previous rate upon improvement in 
symptoms, and the escalation of 12.5mL/ hr increments every 30 minutes resumes to a 
maximum rate of 100mL/ hr. 
 
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After the end of the first infusion, the IV line or central venous catheter should remain in place 
for ≥ 1 hour to be able to administer IV drugs if necessary. If no adverse events occur after 1 
hour, the IV line may be removed or the central venous catheter may be de accessed. 
 
Subsequent infusions of obinutuzumab: 
 
Thirty to 60 minutes prior to all obinutuzumab infusions, the following pre-  medications will be 
given (unless contraindicated): 
 
• 
Oral acetaminophen (1000 mg) AND 
 
• 
An antihistamine such as diphenhydramine (50−100 mg) 
In subsequent cycles, steroids (dexamethasone 20mg IV 30- 60 minutes before obinutuzumab) 
should be given to patients who experienced a severe IRR (≥ grade 3) with the prior infusion of 
obinutuzumab or who are thought to be at high risk for infusion- related reactions, as assessed 
by the investigator. 
 
If subjects tolerated the previous infusion well, the subsequent infusions can start at an initial 
rate of 25mL/ hr and increase by 25mL/ hr increments every 30 minutes to a maximum of 
100mL/ hr as tolerated. If subjects did not tolerate the first infusion well, follow the guidelines 
for the first infusion.  
 
If hypersensitivity or an infusion reaction develops, the infusion should be interrupted until 
symptoms resolve or improve, see Table 4. For management of infusion reaction, please refer 
to the institution’s hypersensitivity reaction order set. The infusion can continue at one- half 
the previous rate upon improvement in symptoms, and the escalation of 25mL/ hr increments 
every 30 minutes resumes to a maximum rate of 100mL/ hr. 
 
For subsequent infusions, the IV line or central venous catheter should remain in place 
for at least 1 hour after the end of the infusion. If no adverse events occur after 1 
hour, the IV line may be removed or the central venous catheter may be de 
accessed. 
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 (NaCl) 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 temperature and ambient room lighting.  The prepared diluted 
product should generally be used immediately.  If not used immediately,  the infusion 
should be stored under refrigerated conditions due to microbiology stability and 
should not be longer than 24 hours at 2°C − 8°C unless reconstitution/ dilution has 
taken place in controlled and validated aseptic conditions.  Obinutuzumab should not 
be frozen or shaken.  Mix gently.  All transfer procedures require strict adherence to 
aseptic techniques.   
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All unused or expired investigational drug will be destroyed in accordance with institutional 
policies. 
 
For further details, see the obinutuzumab Investigator’s Brochure. 
Lenalidomide 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide will 
be provided in accordance with the Celgene Corporation’s Revlimid REMS® program.  Per 
standard Revlimid REMS® program requirements,  all physicians who prescribe lenalidomide 
for research subjects enrolled into this trial, and all research subjects enrolled into this trial, 
must be registered in, and must comply with, all requirements of the Revlimid REMS® 
program. 
 
Further information about the Revlimid REMS® program is available at 
www.celgeneriskmanagement.com. 
 
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site for IND 
studies. Only enough lenalidomide for one cycle of therapy will be supplied to the patient each 
cycle. 
 
Lenalidomide administration 
Patients with creatinine clearance (CrCl) >60 mL/ min as determined by modified 
Crockcroft- Gault (see Appendix 2) will receive a total of 18 cycles as outlined in 
Section 5.2. 
Lenalidomide Dose Adjustment for Renal Impairment 
 
Subjects with renal impairment (CrCl ≤ 60 ml/ min) will be dosed based on Table 1.  CrCL 
assessment will occur on: Day 1, 8, and 15 for cycle 1 and Day 1 of cycles 2- 18. However, if a 
subject has a creatinine obtained at any time during the administration of lenalidomide on 
study because it was clinically indicated, a dose reduction based on CrCL and Table 1 should 
be performed.  
 
Subjects with moderate renal impairment, CrCL of 30- 60mL/ min, will initiate 10mg of 
lenalidomide daily on days 1- 21 of a 28 day cycle.  Subjects with severe renal impairment, 
CrCL of <30 mL/ min, will initiate 15mg of lenalidomide every 48 hours on days 1- 21 of a 28 
day cycle.  
 
For subjects with renal impairment (CrCl ≤ 60 ml/ min) necessitating dose adjustment on Day 1 
of a cycle according to Table 1, but then stably improves, a dose increase based on CrCL will 
not occur until day 1 of the next cycle. At any point, should a patient require dose reduction 
due to reduced CrCl, and the CrCl then stably improves, dose escalation will not occur until 
day 1 of the next cycle.   
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Table 1. Lenalidomide Dose Adjustment for Patients with Renal Impairment
 
Category 
Renal Function 
(modified Cockcroft-
Gault) 
Cycles 1-6 
 Cycles 7-18 
Mild or no renal 
Impairment 
CrCl > 60 mL/min 
20 mg once daily 
10 mg once daily for 
subjects with a CR after 6 
cycles 
OR 
20mg once daily for subjects 
with PR after 6 cycles 
Moderate renal 
impairment 
CrCl 30-60 mL/min 
10 mg every 24 
hours* 
5mg every 24 hours  
Severe renal 
impairment 
CrCl <30mL/min (not 
requiring dialysis) 
15 mg every 48 
hours* 
10mg every 48 hours  
* If CrCl is ≤ 60 ml/ min necessitating dose reduction of lenalidomide but then stably improves 
to >60 mL/ min, proceed to lenalidomide 20 mg once daily with subsequent cycle, day 1. 
 
 
Lenalidomide should be taken orally at about the same time each day, either with or without 
food. Lenalidomide capsules should be swallowed whole with water, and should not be opened, 
broken, or chewed. If a dose is missed, it can be taken as soon as possible on the same day 
with a return to the normal schedule the following day. No extra capsules to make up the 
missed dose should be taken. Females of childbearing potential should not handle or administer 
lenalidomide unless they are wearing gloves. 
 
Additional prescribing information can be found at www.revlimid.com/wp-
content/uploads/2013/11/PI.pdf 
 
 
Lenalidomide Storage 
Lenalidomide is available in capsule doses of 2.5mg, 5mg, 10mg, 15mg, 20mg, and 25mg. 
Lenalidomide should be stored as directed on the respective package labels. Lenalidomide 
should be stored at room temperature away from direct sunlight and protected from excessive 
heat and cold.  
 
All unused or expired investigational drug will be destroyed in accordance with institutional 
policies. 
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Dose Reduction, Delay and Discontinuation 
Toxicity necessitating dose modification or delay is based on NCI CTCAE v 4.03 Toxicity 
Grade. The Principal Investigator will assess whether each AE is related or not to each of the 
study drugs. Events that are judged definitely, probably or possibly related are considered 
related AEs. Events that are considered unlikely or definitely not related are considered not 
related AEs. Factors to be taken into consideration include the temporal relationship between 
administration of study drug and the onset of the AE, other potential causes of the AE 
including the subject’s underlying medical condition and concomitant medications, whether the 
AE is consistent with known AEs previously attributed to a study drug, whether the AE 
decreases or resolves upon withholding or reducing the dose of the study drug, or whether the 
AE recurs upon reintroduction of the study drug. AEs defined below (Sections 5.4.1), unless 
the Principal Investigator considers the event clearly unrelated to study drug, will be 
considered a toxicity that necessitates dose modification or delay. 
 
Toxicities Necessitating Dose Modification or Delay 
Toxicities necessitating dose modification or delay will be defined as any non- hematologic or 
hematologic toxicity listed below. Study treatment should be discontinued in the event of a 
toxicity lasting more than 28 days despite appropriate medical management, unless reviewed 
and approved by the Principal Investigator. The action in Table 2 should be taken for the 
following toxicities: 
 
Non- hematologic toxicity will be defined as any of the following: 
 
• 
Any unmanageable Grade 3 or 4 non- hematologic toxicity with failure to improve (< 
Grade 2) or recover to baseline within 14 days of withholding drug  
• 
Grade 3 non- blistering rash that does not resolve to < Grade 2 within 14 days 
• 
Any desquamating (blistering) or grade 4 rash 
• 
Any grade Stevens- Johnson syndrome or toxic epidermal necrolysis 
• 
Grade 3 or 4 thrombosis/ embolism 
• 
Grade 3 or 4 peripheral neuropathy which began or worsened while on study 
 
Hematologic toxicity will be defined as any of the following: 
 
• 
Grade 3 neutropenia with infection or fever (single temperature of > 38.3 ºC, or with a 
sustained temperature of ≥ 38 º C lasting > 1 hour). 
• 
Grade 4 neutropenia (ANC<500/ µL) lasting > 7 days.  
• 
Grade 4 thrombocytopenia (<25,000/ µL) 
 
The following action in Table 2 should be taken for any unmanageable toxicity that is 
consistent with the rules outlined above: 
 
 
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Table 2. Dose Modification for Toxicity
 
Toxicity Grade 
Action to be Taken 
Grade 3 neutropenia 
associated with fever 
(single temperature of > 
38.3 ºC, or with a 
sustained temperature 
of ≥ 38 º C lasting > 1 
hour) 
 
OR 
 
Grade 4 neutropenia 
lasting > 7 days. 
• Hold lenalidomide. 
• Follow CBC weekly. 
• If neutropenia has resolved to < Grade 2 prior to Day 21 of 
the current cycle, restart lenalidomide at next lower 
dose level, (see Table 3) and continue through the 
scheduled Day 21 of the current cycle.  Otherwise, omit 
for remainder of cycle and reduce the dose of 
lenalidomide by 1 dose level at the start of the next 
cycle.   
• Withhold obinutuzumab until recovery to < Grade 2 or 
baseline. 
• Omitted doses are not made up.   
• G- CSF may be used. 
Grade 3 
thrombocytopenia 
• 
Follow CBC weekly. 
• 
Hold prophylactic anti- coagulation including aspirin, if 
applicable. 
• 
Restart prophylactic anti- coagulation and/ or aspirin when 
platelet count is ≥ 50,000/ mm³. 
≥ Grade 4 
thrombocytopenia 
• 
Hold lenalidomide. 
• 
Follow CBC weekly. 
• 
If thrombocytopenia resolves to < Grade 2 prior to Day 21 
of the current cycle, restart lenalidomide at next lower dose 
level and continue through the scheduled Day 21 of the 
current cycle.  Otherwise, omit for remainder of cycle and 
reduce the dose of lenalidomide by 1 dose level at the start 
of the next cycle.   
• 
Withhold obinutuzumab until recovery to < Grade 2 or 
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baseline. 
• 
Omitted doses are not made up. 
• 
Hold prophylactic anti- coagulation including aspirin, if 
applicable. 
• 
Restart prophylactic anti- coagulation and/ or aspirin when 
platelet count is ≥ 50,000/ mm³. 
Non- blistering rash 
Grade  3 
 
 
 
 
  
• 
If Grade 3, hold lenalidomide.   
• 
Follow weekly.  
• 
If the toxicity resolves to < Grade 2 prior to Day 21 of the 
current cycle, restart lenalidomide at original dose level (for 
first occurrence) and continue through the scheduled Day 
21 of the current cycle.  Otherwise, omit for remainder of 
cycle.   
• 
Omitted doses are not made up. 
• 
For the second occurrence of Grade 3, hold lenalidomide, 
and follow weekly. If the toxicity resolves to ≤ Grade 2 
prior to Day 21 of the current cycle, restart lenalidomide at 
next lower dose level and continue through the scheduled 
Day 21 of the current cycle.  Otherwise, omit for remainder 
of cycle and reduce the dose of lenalidomide by 1 dose level 
at the start of the next cycle.  Omitted doses are not made 
up. 
• 
Treatment with 10mg of prednisone or equivalent for 10 
days (with or without taper) and/ or antihistamines PO daily 
is recommended.  
• If Grade 3 rash has not improved to at least Grade 2 within 
14 days of drug being withheld and administration of 
10mg of steroids and/ or antihistamines daily, the subject 
will discontinue study treatment.  
Desquamating 
(blistering) rash 
• 
Discontinue study drugs. Remove patient from study. 
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Any grade 
 
Or grade 4 rash 
• 
Start supportive care: daily antihistamine, 10mg or higher of 
prednisone or corticosteroid equivalent as clinically 
indicated 
≥ Grade 3 
thrombosis/ embolism 
• Hold lenalidomide and start therapeutic anticoagulation.   
• Restart lenalidomide at investigator’s discretion (maintain 
dose level) after anticoagulation is initiated. 
• See anticoagulation considerations, Section 6.2. 
Peripheral neuropathy 
Grade 3 
 
 
 
 
 
Grade 4 
• If Grade 3, hold lenalidomide dose.  Follow at least weekly. 
• If the toxicity resolves to ≤ grade 1 prior to Day 21 of the 
current cycle, restart lenalidomide at next lower dose 
level and continue through the scheduled Day 21 of the 
current cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at 
the start of the next cycle.  Omitted doses are not made 
up. 
• If Grade 4, discontinue lenalidomide.  Remove patient from 
study. 
Other non- hematologic 
toxicity ≥ Grade 3  
• 
Hold lenalidomide.  Follow at least weekly. 
• 
If the toxicity resolves to < Grade 2 prior to Day 21 of the 
current cycle, restart lenalidomide and continue through 
the scheduled Day 21 of the current cycle.  Otherwise, 
omit for remainder of cycle.  Omitted doses are not made 
up.  For toxicity attributed to lenalidomide, reduce the 
lenalidomide dose by 1 dose level when restarting 
lenalidomide. 
• 
Withhold obinutuzumab until recovery to < Grade 2 or 
baseline. 
 
Obinutuzumab Dose Reduction or Delay 
The obinutuzumab dose should be held for any unmanageable toxicity that is consistent with 
the rules outlined in Table 2. A missed dose of obinutuzumab on the weekly schedule for any 
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reason will not be made up (the visit window for this visit and Day 1 of Cycles 2 - 12 is ±2 
days, and ±7 days for cycles 14- 30). 
 
Lenalidomide Dose Reduction or Delay 
The lenalidomide dose should be held for any unmanageable toxicity that is consistent with the 
rules outlined in Table 2. 
 
The dose of lenalidomide may be reduced successively by one level from starting dose, Table 
3. Once a patient’s dose has been reduced, no dose re- escalation is permitted. Patients who 
cannot tolerate the lowest applicable dose level are to be discontinued from the Treatment 
Phase. Dose modification should also meet the specifications outlined for those subjects with 
renal insufficiency as outlined in Table 1. If patients with renal impairment are currently 
receiving 10mg every 24 hours and need a dose modification, they will then be dose reduced to 
15mg every 48 hours. If they need further dose reduction due to toxicity, they will be 
discontinued due to being unable to tolerate the lowest applicable dose. Similarly, patients 
starting at 15mg every 48 hours who need further dose reduction will be discontinued due to 
being unable to tolerate the lowest applicable dose.  
 
 
Table 3. Dose Reduction Levels for Lenalidomide
 
Dose Level 
Lenalidomide 10 mg starting 
dose* 
Lenalidomide 20 mg starting dose
 
Level - 1 
5mg daily on Days 1- 21, every 
28 days 
15mg daily on Days 1- 21, every 28 days 
Level - 2 
Discontinue Lenalidomide 
10mg daily on Days 1- 21, every 28 days 
Level - 3 
Discontinue lenalidomide 
5mg daily on Days 1- 21, every 28 days 
• 
If patients with renal impairment are currently receiving 10mg every 24 hours and need 
a dose modification, they will then be dose reduced to 15mg every 48 hours. If they 
need further dose reduction due to toxicity, they will discontinue lenalidomide. 
 
Overdose Instruction 
Overdose, as defined for this protocol, refers to obinutuzumab and lenalidomide dosing only.   
 
On a per dose basis, an overdose is defined as the following amount over the protocol-
specified dose of obinutuzumab and lenalidomide assigned to a given patient, regardless of any 
associated adverse events or sequelae. 
PO 
any amount over the protocol- specified dose 
IV 
10% over the protocol- specified dose   
SC 
10% over the protocol- specified dose 
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On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.   
 
On an infusion rate basis, an overdose is defined as any rate faster than the protocol- specified 
rate.  Complete data about drug administration, including any overdose, regardless of whether 
the overdose was accidental or intentional, should be reported in the case report form 
 
 
Permanent Discontinuation of Study Drug 
Investigators are encouraged to keep a subject who is experiencing a clinical benefit on study 
unless significant toxicity puts the subject at risk or routine noncompliance puts the study 
outcomes at risk. If a subject meets any of the following criteria, then withdrawal from the 
study treatment is mandatory: 
 
• 
Subject has failed to achieve at least a partial response (PR) after 6 cycles of therapy. 
Subjects with earlier evidence of nonresponse that warrants change in therapy in the 
opinion of the treating physician will discontinue study drug at any time. 
• 
Subject has confirmed progressive disease (PD) 
• 
Subject has an intercurrent illness or AE that prevents further treatment 
administration beyond 28 days 
• 
Subject decides to withdraw from study 
• 
Subject becomes pregnant 
• 
Subject is routinely noncompliant with study procedures and/ or scheduled evaluations 
• 
Subject requires a prohibited concomitant medication 
• 
Investigator considers withdrawal to be in the best interest of the subject. 
 
A safety follow up visit is required for all subjects except those who have withdrawn full 
consent. 
 
 
Concomitant medications 
permitted supportive care 
Supportive medications (such as for emesis, diarrhea, constipation, etc.) should be delivered in 
accordance with standard practice. Use of neutrophil growth factors (granulocyte colony-
stimulating factor [G- CSF] such as filgrastim or pegfilgrastim) is permitted for management of 
neutropenia in accordance with the American Society of Clinical Oncology (ASCO) guidelines. 
Preemptive or prophylactic G- CSF during cycle 1 is not required, but can be used at the 
discretion of the investigator if the subject is felt to be of high risk according to the current 
ASCO guidelines.  
 
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Transfusions may be given in accordance with institutional policy. Short courses of 
corticosteroids (<14 days) for treatment of non- lymphoma related medical reasons (e.g. rash, 
arthritis, asthma) or for tumor flare reaction (TFR) at doses that do not exceed 10mg per day 
of prednisone or equivalent are permitted.  However, if clinically indicated, higher doses of 
corticosteroids (>10mg per day) are permissible. 
 
Thromboembolism prophylaxis 
It is recommended that patients receive prophylactic aspirin (81mg) daily unless 
contraindicated. If aspirin is contraindicated, use of low molecular weight heparin or warfarin 
(or equivalent Vitamin K antagonist) to keep the international normalized ratio (INR) in the 
range of 2- 3, or use of other anti- thrombotic therapy according to hospital guidelines, or 
physician preference, is acceptable. However, the choice of anticoagulant for prophylaxis for 
VTE relies upon the investigator’s discretion and should be tailored to the patient’s individual 
risk/ benefit profile by taking into account the individual thrombotic risk (e.g., history of 
venous thrombosis), bleeding risk, and the quality of compliance with antithrombotic 
treatment. In the setting of thrombocytopenia, thromboembolism prophylaxis should be held in 
accordance with the guidelines established in Table 2.  
 
All patients who develop a deep venous thromboembolism in any location must be treated 
appropriately with low molecular weight heparin. Heparin should continue for at least 3 
months, however treating physician discretion is allowed. Study treatment is to continue 
during heparin use. For subjects in whom low molecular weight heparin is contraindicated (i.e., 
renal impairment), a vitamin K antagonist anti- coagulant can be used instead where medically 
appropriate. 
 
 
Tumor lysis prophylaxis 
Patients with high tumor burden or those considered to be high risk for tumor lysis by the 
investigator should receive TLS prophylaxis (allopurinol, rasburicase or equivalent as per 
institutional guidelines) during the first cycle of lenalidomide administration or as clinically 
indicated. To monitor for TLS, the patients will have chemistries drawn on Days 1, 8, and 15 
of the first cycle and additionally as clinically indicated. 
 
Obinutuzumab pre-medication 
Premedication consisting of acetaminophen and an antihistamine should be administered before 
each obinutuzumab infusion as outlined in Section 5.3.1.1. Steroids (dexamethasone or 
prednisone) can also be administered as clinically indicated before obinutuzumab.  
 
Management of infusion- related symptoms for obinutuzumab is summarized in Table 4 
and in accordance with institution policy outlined in the hypersensitivity order set. 
In the event of a life- threatening IRR (which may include pulmonary or cardiac 
events) or an IgE- mediated anaphylactic reaction, obinutuzumab should be 
discontinued. 
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Table 4. Guidelines for Management of Infusion- Related Symptoms Related to 
Obinutuzumab 
 
Infusion-Related 
Symptomsa 
 Guidance 
Grade 4 
• 
Discontinue infusion immediately, treat symptoms  
        aggressively, and do not resume treatment. 
Grade 3 
• 
Hold infusion. 
• 
Give supportive treatment.b 
• 
Upon symptom resolution, may resume infusion 
rate escalation as outlined in 5.3.1.1.c 
• 
If the same adverse event recurs with the same 
severity despite aggressive supportive treatment, 
treatment must be discontinued. Retreatment at the 
Grade 1-2 
• 
Slow or hold infusion. 
• 
Give supportive treatment.b 
• 
Upon symptom resolution, may resume infusion 
rate escalation at the investigator’s discretion.c 
a Refer to National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0 for the grading of symptoms.  
b Supportive treatment: Please refer to hypersensitivity order set 
c Escalation of the infusion rate after re- initiation: Upon complete resolution of 
symptoms, the infusion may be resumed at 50% of the rate achieved prior to interruption. 
In the absence of infusion- related symptoms, the rate of infusion may be escalated in 
increments of 12.5mL/ hr (or 25mL/ hr for subsequent infusions) every 30 minutes to a 
maximum rate of 100mL/ hr. 
 
Hepatitis B Prophylaxis 
Patients with inactive hepatitis B infection must adhere to hepatitis B reactivation prophylaxis 
unless contraindicated. 
 
prohibited concomitant therapy 
Systemic corticosteroid use at doses above 10 mg /  day (prednisone or equivalent) is 
prohibited during the Treatment Phase. For patients receiving systemic corticosteroids at 
doses above 10 mg/ day (prednisone or equivalent), a 28 day washout period prior to Cycle 1 
Day 1 study drug dosing is required. Systemic doses above 10 mg/ day (prednisone or 
equivalent) are allowed for the exceptions of tumor flare reaction (TFR) treatment at any time, 
for obinutuzumab cytokine release syndrome prophylaxis on C1D1, and treatment of infusion 
related reactions at any time. 
 
Experimental therapy or radiotherapy is prohibited during the Treatment phase. 
 
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Study procedures 
Before study entry (Screening Phase), throughout the Treatment Phase, and during 
Follow- up, various clinical and diagnostic laboratory evaluations are outlined. The 
purpose of obtaining these measurements is to ensure adequate safety and 
tolerability. Clinical evaluations and laboratory studies may be repeated more 
frequently if clinically indicated. The Study Flow Chart is provided in Appendix 1. 
screening Phase 
Screening procedures will be performed up to 28 days before Cycle 1 Day 1, unless otherwise 
specified. All subjects must first read, understand, and sign the IRB- approved informed 
consent form (ICF) before any study- specific screening procedures are performed. After 
signing the ICF, completing all screening procedures, and being deemed eligible for entry, 
subjects will be enrolled in the study. Procedures that are performed prior to signing the ICF 
and are considered standard of care may be used as screening assessments if they fall within 
the 28 day screening window.  
 
The following procedures will be performed during the Screening Phase: 
 
• 
Informed consent 
• 
Review of eligibility criteria 
• 
Medical history and demographics 
• 
Record the Follicular Lymphoma International Prognostic Index (FLIPI) score 
(Appendix 3) and tumor burden (Appendix 4) 
• 
Review of AEs and concomitant medications 
• 
Complete physical exam 
• 
ECOG performance status 
• 
Vital signs, weight, and height 
• 
12 lead ECG 
• 
Imaging by CT/ PET/ or MRI 
• 
Bone marrow aspirate and biopsy (can be done within 90 days of study entry) 
• 
Clinical laboratory tests for: 
 Hematology (CBC with differential) 
 Serum chemistry (electrolytes [Na, K, Cl, bicarbonate, Ca], glucose, blood 
urea nitrogen [BUN], creatinine, alkaline phosphatase, AST, ALT, total 
protein, albumin, total bilirubin, lactate dehydrogenase [LDH], β2-
microglobulin), uric acid 
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 Coagulation (PT/ INR, aPTT) 
 Serum pregnancy test (for women of childbearing potential only) will be 
performed 10- 14 days and again 24 hours prior to writing an initial 
prescription for lenalidomide. 
 Hepatitis serologies (hepatitis B surface antigen [HBsAg], hepatitis B core 
antibody [anti- HBc, hepatitis C antibody]) 
 HIV 1 and 2 antibody 
 TSH 
• 
Optional core needle or fine needle aspiration (FNA) biopsy will be obtained by 
Interventional Radiology from an accessible lymph node under ultrasound or CT- scan 
guidance within 28 days prior to the first infusion of obinutuzumab.  
• 
Optional research blood sample, 10ml EDTA tube to be collected prior to infusion of 
obinutuzumab.  
• 
Determination of creatinine clearance (modified Cockcroft- Gault estimate, Appendix 2) 
utilizing actual body weight 
 
Treatment phase 
Cycle 1/Day 1 
Subjects who are deemed eligible will return to the clinic on Cycle 1, Day 1. The following 
procedures will be performed on Day 1: 
 
Pre- Dose 
• 
Confirmation of eligibility 
• 
Complete physical exam 
• 
ECOG performance status 
• 
Vital signs and weight 
• 
Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o Determination of creatinine clearance (modified Cockcroft- Gault estimate) 
utilizing actual body weight 
• 
Review of AEs and concomitant medications 
• 
Dispense lenalidomide 
 
Dosing 
• 
In- clinic administration of obinutuzumab 
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Cycle 1/Day 8 
The following procedures will be performed on Cycle 1, Day 8 (±2 days): 
 
Pre- Dose 
• 
Complete physical exam 
• 
ECOG performance status 
• 
Vital signs and weight 
• 
Clinical laboratory tests for: 
 Hematology 
 Serum chemistry 
• 
Optional research blood draw, 10 ml EDTA tube 
• 
Optional research FNA of an accessible lymph node  
• 
Determination of creatinine clearance (modified Cockcroft- Gault estimate) utilizing 
actual body weight 
• 
Review of AEs and concomitant medications 
 
Dosing 
• 
In- clinic administration of obinutuzumab 
 
Cycle 1/Day 15 
The following procedures will be performed on Cycle 1, Day 15 (±2 days): 
 
Pre- Dose 
• 
Complete physical exam 
• 
ECOG performance status 
• 
Vital signs and weight 
• 
Clinical laboratory tests for: 
 Hematology 
 Serum chemistry 
 Determination of creatinine clearance (modified Cockcroft- Gault estimate) utilizing 
actual body weight 
• 
Review of AEs and concomitant medications 
 
Dosing 
• 
In- clinic administration of obinutuzumab 
Cycle 2/Day 1and every 4 weeks until Cycle 18 or Treatment Termination 
Visits will be performed every 4 weeks (± 2 days) starting at Cycle 2, Day1. Visit windows are 
relative to Day 1 visit date. The following procedures will be performed: 
 
Pre- Dose 
• 
Complete physical exam 
• 
ECOG performance status 
• 
Vital signs and weight 
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• 
Clinical laboratory tests for: 
 Hematology 
 Serum chemistry 
 Determination of creatinine clearance (modified Cockcroft- Gault estimate) utilizing 
actual body weight 
• 
Review of AEs and concomitant medications 
• 
Drug accountability 
• 
Dispense lenalidomide 
• 
CT/ PET/ or MRI on Cycle 4/ Day 1, Cycle 7/ Day 1, Cycle 10/ Day 1 only, Cycle 
14/ Day 1 
• 
Optional research blood draw on Cycle 4/ Day 1 only, 10 ml EDTA tube 
 
Dosing 
 
• In- clinic administration of obinutuzumab on Day 1 of Cycle 2, 3, 4, 5, 6, 8, 10,12, 
14, 16, 18 
 
Cycle 20/Day 1 and every 4 weeks until Cycle 30 or Treatment Termination 
Visits will be performed at Cycle 20, Day 1, Cycle 22, Day 1, Cycle 24, Day 1, Cycle 26, Day 
1, Cycle 28, Day 1, Cycle 30, Day 1 (± 7 days).  Visit windows are relative to Day 1 visit 
date. The following procedures will be performed: 
 
Pre- Dose 
 
• 
Complete physical exam 
• 
ECOG performance status 
• 
Vital signs and weight 
• 
Clinical laboratory tests for: 
 Hematology 
 Serum chemistry 
• 
Review of AEs and concomitant medications 
• 
CT/ PET/ or MRI on Cycle 14/ Day 1, Cycle 20/ Day 1, and Cycle 26, Day1 only 
 
Dosing 
• 
In- clinic administration of obinutuzumab on Day 1 of Cycle 14, 16, 18, 20, 22, 24, 26, 
28, and 30. 
 
End of Treatment Visit 
The end of treatment visit will occur approximately 4 weeks (±14 days) from last dose of study 
drug (end of cycle 30) for patients who complete the planned study treatment. If the subject 
comes in for a regular study visit and the investigator suspects PD, or if the subject wants to 
discontinue treatment for any other reason outlined in Section 5.6, the regular visit will 
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become the termination visit. Adverse events and hospitalizations will be recorded up to 30 
days after the last dose of study drugs. 
 
The following procedures will be performed: 
 
• 
Complete physical exam 
• 
ECOG performance status 
• 
Vital signs 
• 
Clinical laboratory tests for: 
 Hematology 
 Serum chemistry 
 TSH 
• 
For consenting patients and those undergoing a biopsy at PD as part of standard of 
care, a research sample will also be collected 
• 
Optional research blood draw at the time of PD only, 10 ml EDTA tube 
• 
Review of AEs and concomitant medications 
• 
Drug accountability 
• 
CT/ PET/ or MRI 
 
Response evaluation 
Response Evaluation visits will be performed at the following timepoints: 
• 
At approximately cycle 4, day 1, cycle 7, day 1, cycle 10, day 1, cycle 14, day 1, cycle 
20, day 1,  cycle 26, day 1 (±7 days).  
• 
At the End of treatment visit (±2 weeks), this will also serve as the 120 week response 
assessment. 
• 
Every 24 weeks during the follow up phase for 3 assessments, then annually until the 
subject exhibits disease progression (± 4 weeks).  
• 
If clinical suspicion for PD is raised at any time outside of a pre- determined response 
evaluation, imaging can be requested at the discretion of the investigator. 
 
The following procedures will be performed in conjunction with standard visits as follows: 
• 
Radiologic exam by CT, PET/ CT, or MRI scan  
• 
Bone marrow biopsy and/ or aspirate, to be done once to confirm CR if marrow was 
involved with lymphoma at screening 
• 
Overall response assessment 
 
follow up phase 
The follow up period will start at the end of treatment visit (after cycle 30) Patients will be 
assessed every 24 weeks (± 4 weeks) for 3 assessments, and then annually (± 4 weeks) up to 
the end of the follow up period, 2 years after the last subject’s last study drug dose. 
 
For patients who have completed treatment the follow up assessments will include: 
• 
Physical exam including vital signs and ECOG PS 
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• 
Clinical laboratory tests for hematology and serum chemistry  
• 
Second primary malignancy (SPM) 
• 
Adverse events and hospitalization up to 30 days after last study drug 
• 
Overall survival 
• 
Radiologic assessment (CT, PET/ CT, or MRI) 
 
For patients who discontinue treatment due to progressive disease or relapse, follow up 
assessments will include: 
• 
Overall survival 
• 
Subsequent anti- lymphoma therapy (including the time of initiation of therapy and best 
response to first subsequent anti- lymphoma treatment utilized after discontinuation 
from this study) 
• 
Adverse events and hospitalization up to 30 days after last study drug (Safety visit) 
• 
SPM 
Survival Follow up 
Once subject progresses or starts use of alternative antineoplastic therapy (for 
subjects who have not withdrawn consent), they will be contacted approximately q 12 
weeks (± 2 weeks) for 1 year and then q 24 weeks (± 4 weeks) from the last dose of 
study drug by clinic visit or telephone to assess survival and the use of alternative 
antineoplastic therapy and stem cell transplant. Subjects will be contacted until: 
death, consent withdrawal, lost to follow up, or study termination, whichever comes 
first. 
Missed evaluations 
Missed evaluations should be rescheduled and performed as close to the original scheduled 
date as possible.  An exception is made when rescheduling becomes, in the opinion of the 
investigator, medically unnecessary or unsafe. In that case the missed evaluation should be 
abandoned. 
 
Description of Procedures 
Medical History 
The subject’s medical history through review of the medical records and by interview will be 
collected and recorded. A disease history including date of initial diagnosis and baseline 
symptoms and severity should be recorded. 
 
Physical Examination 
The physical exam should include the general state of the subject, examination of the skin, 
eyes, ear, nose, throat, lungs, heart, abdomen, extremities, lymphatic system. Nervous system 
should be included if clinically indicated. 
 
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Vital Signs 
Vital signs including weight, blood pressure, heart rate, respiratory rate, and temperature will 
be recorded. Height will only be recorded during the screening phase, Visit 1.  
 
ECOG PS 
Table 5: Performance status definitions
 
Status 
ECOG PS Definition 
0 
Fully active, able to carry on all pre- disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (ie, light housework, office 
work) 
2 
Ambulatory and capable of all self- care, but unable to carry out any 
work activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self- care, confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled. Cannot carry on any self- care. Totally confined to 
bed or chair 
5 
Dead 
 
Concomitant Medications 
All concomitant medications including over the counter medications and supplements should 
be recorded starting during the screening phase and continued through the treatment phase as 
well as up to 30 days after last study drug dose. Concomitant medications will be captured in 
the electronic medical record. 
 
Adverse Events 
Only laboratory abnormalities which result in signs or symptoms that require intervention or 
follow up and are considered clinically significant should be recorded as AEs.  See Section 10 
for more details. All other AEs whether serious or non- serious will be entered in 
RedCap/ CORe (the electronic case report form) from the time of first protocol intervention up 
until 30 days after the last dose of study drugs.  The Principal Investigator or designee will be 
responsible for assigning attribution to the study drugs. 
 
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CT, PET/CT, MRI scans 
A CT scan (with contrast unless contraindicated) of the neck, chest, abdomen and pelvis are 
required for disease assessment. A “diagnostic quality” combined PET/ CT with IV and PO (or 
water) contrast is an acceptable alternative to CT scans.  In addition, if independent CTs are 
performed, a PET can also be used to augment tumor assessment. In the case where a CT with 
contrast is contraindicated, an alternative would be an MRI of the chest, abdomen, and pelvis.  
 
In general, follow- up assessments will be done by CT scans. PET- CT scan is encouraged and 
should be done at baseline and repeated to confirm complete remission and/ or at treatment 
discontinuation, unless the subject’s insurance will not cover a PET as part of standard of 
care. In this situation, CTs are acceptable alternatives. For lymphomas that are not FDG- avid 
at screening, PET does not need to be repeated in subsequent assessments. 
 
Response Assessment 
Response assessment will be completed by the Principal Investigator using Cheson 2014 
Lugano Criteria. At screening, up to 6 target lesions will be selected and followed for the 
duration of the study. Information on extranodal involvement can also be recorded. The best 
ORR will be documented.  
 
Hematology 
Hematology studies must include a complete blood count (CBC) with differential. Coagulation 
studies performed at screening will include a PT and PTT.   
 
Serum Chemistry 
Chemistry must include electrolytes (sodium, potassium, chloride, bicarbonate), blood urea 
nitrogen, creatinine, glucose, calcium, alkaline phosphatase, ALT, AST, total bilirubin, 
albumin, total protein, LDH, β2- microglobulin), and uric acid.  
 
Coagulation Studies 
Coagulation studies performed at screening will include PT/ INR and activated PTT. 
 
Hepatitis Serologies 
Hepatitis serologies include Hepatitis C antibody, Hepatitis B surface antigen, Hepatitis B 
core antibody. For patients with a positive Hepatitis C antibody, Hepatitis C viral PCR should 
be performed to evaluate for active infection.  
 
HIV serologies 
HIV serologies include antibodies to HIV 1 and 2.  
 
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Creatinine Clearance 
Determination of creatinine clearance using the modified Cockcroft- Gault estimate (utilizing 
actual body weight) should be calculated during the Screening phase and at the start of each 
cycle to determine dose of lenalidomide (Section 5.4.3). 
 
Pregnancy Test 
During screening, two serum pregnancy tests will be required for women of childbearing 
potential. Females of childbearing potential are defined as: all females who are menstruating, 
amenorrheic from previous treatments, under 50 years of age, and/ or perimenopausal, and do 
not qualify for the females not of reproductive potential category.   
 
Females not of reproductive potential are defined as: females who have been in natural 
menopause for at least 24 consecutive months, or who have had a hysterectomy and/ or 
bilateral oophorectomy, or female children who have not started menstruating. 
 
Females of reproductive potential must also adhere to the scheduled pregnancy testing as 
required in the Revlimid REMS® program.  
Urine pregnancy tests should be performed as clinically indicated for women of childbearing 
potential.  
 
Bone Marrow Biopsy and Aspirate 
An unilateral bone marrow biopsy and aspirate will be done at screening or up to 90 days 
before the first dose of study drug. Thereafter, bone marrow biopsy and aspirate will only be 
required to confirm CR if it was positive at screening.  
 
ECG 
An electrocardiogram will be conducted during screening to evaluate for clinically significant 
cardiac arrhythmias.  
 
Determination of FLIPI Score 
During the screening phase, subject’s FLIPI score will be calculated and recorded as outlined 
in Appendix 3. 
 
Determination of Tumor Burden Status 
During the screening phase, subject’s tumor burden, either high or low will be determined 
using the GELF criteria as outlined in Appendix 4.  
 
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Blood Sampling and Tumor Tissue Collection for Correlative Studies 
Blood and tumor sample collection for biomarker studies is optional. In consenting subjects, 10 
ml of blood sample (purple top, EDTA) will be collected within 28 days prior to the first 
infusion of obinutuzumab, C1D8 (± 2 days), C4D1 (± 2 days), and at the time of disease 
progression (±14 days). These samples will be transported within 6 hours of collection to Dr. 
Neelapu’s laboratory for processing at the South Campus Research Building I, Room 4.3206, 
at M. D. Anderson Cancer Center (MDACC).  
 
In consenting patients, core needle biopsies and FNA will be obtained by Interventional 
Radiology from an accessible lymph node under ultrasound or CT- scan guidance within 28 
days prior to the first infusion of obinutuzumab, on C1D8 (±2 days), and at the time of disease 
progression (±14 days). Whenever feasible, up to 3 cores will be obtained using 18 or 20 gauge 
needles as deemed appropriate by an Interventional Radiologist. The three cores will be placed 
into normal saline and transported within 6 hours of collection on ice to Dr. Neelapu’s 
laboratory for processing at the South Campus Research Building I, Room 4.3206, at MDACC. 
The cores will be processed as follows: i) the first core will be disaggregated and analyzed by 
flow cytometry and single cell RNA sequencing, ii) second core will be formalin- fixed and 
paraffin- embedded for IHC, iii) third core will be snap frozen for DNA, RNA, or protein 
isolation. If fresh biopsies are not feasible, archival tissue from prior tumor biopsy may be used 
for biomarker studies. 
Samples will be maintained until the study has been terminated. 
 
SUBJECT COMPLETION AND WITHDRAWAL 
Completion 
A subject will be considered to have completed the study if he or she has died before the end 
of the study, has not been lost to follow up, or has not withdrawn consent before the end of 
the study.  
 
Treatment Discontinuation 
 
Study treatment will be discontinued in any of the following events: 
• 
SD after 6 cycles of therapy.  
• 
Confirmed PD 
• 
Unacceptable toxicity: an intercurrent illness or AE that prevents further study 
drug administration beyond 28 days 
• 
Treatment discontinuation by subject beyond 28 days 
• 
Investigator decision 
• 
Subject becomes pregnant 
 
All subjects, regardless of reason for discontinuation of study treatment will undergo a 
treatment termination visit and followed for progression and survival.  
 
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Study Exit/Withdrawal 
 
Exit from study (including all follow up) will occur under the following circumstances: 
• 
Withdrawal of consent for follow- up observation by the subject 
• 
Lost to follow up 
• 
Study termination by the Investigator 
• 
Death 
 
If a subject is lost to follow up, every reasonable effort should be made by the study personnel 
to contact the subject. The measures taken should be documented. 
 
When a subject withdraws before the completing the study, the following information should be 
documented: 
• 
Reason for withdrawal 
 
Whether the subject withdraws full consent (withdraws consent for treatment and all follow up 
including further contact) or partial consent (withdraws consent to treatment but agrees to 
participate in follow up visits). 
 
Statistical 
General Considerations 
This is an open- label, Phase II study investigating the efficacy and safety of obinutuzumab and 
lenalidomide in previously untreated subjects with FL. The study will include 90 subjects in 
one treatment arm.  
 
Response Assessment 
 
Response assessments will be done and recorded by the Principal Investigator. The response 
criteria are based on the revised criteria for malignant lymphoma described in the Lugano 
Criteria, international Working Group for NHL (Cheson 2014). In addition, will examine 
response assessment based on the Cheson 2007 response criteria for historical comparison.  
 
Safety Monitoring 
 
The Principal Investigator or a physician designee will assess each subject to evaluate for 
potential new or worsening AEs as specified in the Trial Flow Chart, Appendix 1 and more 
frequently if clinically indicated. Adverse experiences will be graded and recorded throughout 
the study and during the follow- up period according to NCI CTCAE Version 4.03. Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment. The study investigators and data coordinators are 
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responsible for entering the data and safety for this study including causality. For both AEs 
and SAEs, the Investigator will provide a record of the start and stop dates of the event. 
 
Safety data will be monitored by the Principal Investigator and in accordance with institutional 
policies. The Investigator will record the action taken with the study drugs as a result of an 
AE or SAE, as applicable (e.g., discontinuation, interruption, or reduction of study drugs, as 
appropriate) and report if concomitant and/ or additional treatments were given for the event. 
AEs and SAEs will be reviewed on an ongoing basis to identify safety concerns.  
 
For subjects with a history of Hepatitis B or C, standard of care monitoring for viral 
reactivation will be conducted. Subjects with a history of Hepatitis B will be required to 
undergo hepatitis B reactivation prophylaxis unless contraindicated. 
 
All SAEs that have not resolved upon discontinuation of the subject’s participation in the 
study must be followed until recovered, recovered with sequelae, not recovered or death (due 
to the SAE). 
 
Genentech and Celgene shall notify the Investigator via an IND Safety Report of the following 
information: 
 
Any AE associated with the use of study drug in this study or in other studies that is both 
serious and unexpected, any changes on the investigational brochure or any other safety 
information that changes the risk/ benefit profile of obinutuzumab or lenalidomide during the 
conduct of the study; any finding from tests in laboratory animals that suggests a significant 
risk for human subjects; including reports of mutagenicity, teratogenicity, or carcinogenicity. 
The Principal Investigator shall notify his/ her IRB promptly of these new serious and 
unexpected AEs or significant risks to subjects. The Investigator must keep copies of all AE 
information, including correspondence with Genentech, Celgene, and the IRB, on file. 
 
Definition of Analysis Populations 
 
The following definitions will be used for the efficacy and safety analysis: 
 
All treated population: The subjects who enrolled in the study and had at least 1 dose of study 
drug. 
 
Response evaluable population: The subjects in the all treated population who have measurable 
disease at baseline and have at least one adequate post- treatment disease assessment by the 
investigator. 
 
Safety analysis population: All enrolled subjects who receive at least 1 dose of study drug 
(same as the all treated population). 
 
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The all treated population will be used for analyzing efficacy endpoints unless specified 
otherwise. The response evaluation population will be used for sensitivity analysis of efficacy 
endpoints. The safety population will be used for safety analysis. 
 
Endpoint Data Analysis 
 
Baseline Characteristics 
 
Subject demographics (age, sex, race/ ethnicity) and other baseline characteristics (ECOG PS, 
tumor burden, FLIPI score) will be summarized. Summary statistics will include means, 
standard deviations, and medians for continuous variables and proportions for categorical 
variables. Compliance parameters including number of completed cycles, number of dose 
modifications, and reasons for discontinuation will also be similarly summarized. 
 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint is PFS rate at 2 years. Response will be assessed by the 
investigator based on the 2014 Cheson Lugano criteria. The 2- year PFS rate will be calculated 
and corresponding 95% CI will be derived.  
 
Analysis Methods 
 
The primary analysis for all efficacy endpoints will be conducted based on the all treated 
population. PFS is defined as the time from the treatment start date (Cycle 1, Day 1) until the 
first date of objectively documented progressive disease or date of death from any cause. 
Patients will be censored at the last follow- up date if progression or death has not occurred 
during follow- up.   If a patient has missing data (incomplete CT scan), all other available CT, 
PET/ CT or MRI of the patient will be used for the analysis.  Kaplan- Meier method will be 
used to estimate the PFS.  Corresponding 95% CI will be summarized. Cox proportional 
hazards models will be used to assess the effects of patient prognostic factors on time- to-
event endpoints. The final analysis will be performed when the last patient is followed for 3 
years after last study drug dose.  
 
Secondary Efficacy Endpoints 
 
CR rate at 120 weeks (± 4 weeks) will be determined by the PI (Cheson, Lugano classification 
2014). The number and percentage of subjects with a CR at 120 weeks will be tabulated.   
 
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ORR (CR + PR) will be assessed by the investigator based on Cheson, Lugano 2014. The 
number and percentage of subjects with an ORR will be tabulated. The best ORR will be 
recorded.  
 
DOR will be measured from the time by which measurement criteria for CR or PR, whichever is 
recorded first, is met until death or the first date by which progressive disease is documented. 
Subjects who are progression free and alive at the time of clinical cut- off or have unknown 
status will be censored at the last tumor assessment. Subjects with no baseline disease 
assessment will be censored on cycle 1, day 1. Non- responders will be excluded from the 
analysis for DOR. Kaplan- Meier methodology will be used to estimate event- free curves, 
median, and 95% CI.  
 
EFS will be measured from the date of cycle 1, day 1 to the date of first documented 
progression, transformation to diffuse large B- cell lymphoma, initiation of new anti- lymphoma 
treatment, or death. Kaplan- Meier methodology will be used to estimate event- free curves, 
median, and 95% CI. 
 
OS will be measured from the date of cycle 1, day 1 to the date of death regardless of cause. 
For subjects who have not died, subjects will be censored at the time of last contact. Kaplan-
Meier methodology will be used to estimate event- free curves, median, and 95% CI. 
 
Safety Analysis 
 
Analysis of safety data will be conducted on the safety population. Safety summaries will 
include tabulations in the form of tables and listings. The frequency (number and percentage) 
of treatment- emergent AEs will be reported. Additional AE summaries will include AE 
frequency by AE severity and by relationship to study drug.  
 
Clinically significant abnormal laboratory values will be summarized.  
 
 
Handling of Missing Data 
 
Subjects lost to follow up will be included in the statistical analyses up to the point of their last 
evaluation or contact. 
 
Data for subjects without disease progression or death will be censored at the date of the last 
tumor assessment and before the date of initiation of alternative anticancer therapy. Subjects 
with no post- baseline assessment will be censored on cycle 1, day 1.  
 
Determination of Sample Size 
 
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The primary endpoint is PFS.  It is expected that the experimental regimen will achieve better 
efficacy compared to the standard of care for this population. It was reported that the standard 
of care of lenalidomide and rituximab in this patient population had a two- year PFS rate of 
86.5% (95% CI: 77%-  97.2%). We will enroll a total of 90 patients with an accrual rate of 4 
patients per month.  All patients will be followed for at least 3 years or until death.  The final 
analysis will be performed when the last patient is followed for 3 years.  When the sample size 
is 90, a two- sided 95% CI for the PFS rate at 2 years will extend 0.087 from the observed rate 
for an expected rate of 77% (nQuery Advisor 7.0). According to our previous experience, we 
will be able to obtain biomarker data from about 30% of patients enrolled.  We will explore the 
correlation between the biomarkers and clinical outcomes. 
 
Trial Monitoring 
Due to the fast accrual planned for the study and long median PFS time expected for the 
experimental regimen, a formal futility monitoring rule is not feasible. 
Because of the limited number of patients who have received the combination treatment, for 
patient safety we will monitor the prohibitive toxicity, defined as frequent discontinuation (>2 
discontinuations) of treatment during cycles 1 and 2. The prohibitive toxicity rate of 15% or 
higher will be considered unacceptable. The prior probability of the rate is assumed to follow a 
Beta (0.3, 1.7) distribution with two patients worth of information. We will monitor patients by 
a cohort size of 10.  At any time after at least 10 patients have completed toxicity evaluations, 
the trial will be stopped if the following statement is true 
 
Pr[prohibitive toxicity rate > 15% | data]  > 0.95, 
 
which means that the trial will be stopped for toxicity if the posterior probability of the rate 
being greater than 15% is greater 95%.  
 
Patients will be monitored by a cohort size of 10 according to the following stopping 
boundaries for prohibitive toxicity at cycles 1 and 2: 
 
Number of patients evaluated 
Stop if ≥ prohibitive toxicities observed 
10 
4- 10 
20 
7- 20 
30 
9- 30 
40 
11- 40 
50 
13- 50 
60 
15- 60 
70 
16- 70 
80 
18- 80 
90 
Always stop with this many patients 
 
 
Operating characteristics for the stopping rules 
For prohibitive toxicity monitoring 
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True Prohibitive 
Toxicity Rate 
Probability Stop Early 
Average sample size
 
0.05 
0.0011 
89.92 
0.10 
0.0166 
88.78 
0.15 
0.1226 
83.13 
0.20 
0.4483 
67.77 
0.25 
0.8052 
47.27 
0.30 
0.9639 
31.40 
 
 
Toxicity and response summaries will be submitted to the IND Office Medical Affairs & Safety 
after the first 10 evaluable participants are treated in the study and every 10 evaluable 
participants thereafter. 
 
To ensure patient safety, we will also utilize an additional monitoring rule for treatment-
related death.  Any treatment- related death occurring at any time will result in pause in 
accrual pending complete evaluation and discussion between the Principal Investigator and the 
FDA.  
Any second malignancy other than non- melanoma skin cancer that occurs anytime during the 
study will result in pause in accrual pending complete evaluation and discussion between the 
Principal Investigator and the FDA.  
 
The above stopping boundaries and operating characteristics are calculated using MultcLean 
(v.2.1.0) design software downloaded from 
http://biostatistics.mdanderson.org/SoftwareDownload.   
 
Reporting of Adverse Events 
Assessment of Safety 
Timely, accurate, and complete reporting and analysis of safety information is the 
responsibility of the PI and will be conducted in accordance with Institution policies.   
 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) that are considered related to obinutuzumab or 
lenalidomide per protocol, all events of death, and any study specific issue of 
concern. 
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: 
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AEs not previously observed in the patient that emerge during the protocol- specified AE reporting 
period, including signs or symptoms associated with follicular lymphoma 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 
Serious Adverse Event (SAE) Reporting Requirements for M D Anderson Sponsor Single Site 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 event 
• 
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 IND 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 on 
Reporting Adverse Events for Drugs and Devices”. 
• 
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. 
• 
All SAEs, expected or unexpected/  initial or follow up, must be reported to the IND Office 
within 5 working days of knowledge of the event
 regardless of the attribution. 
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• 
Death or life- threatening events that are unexpected, possibly, probably or definitely related to 
drug must be reported (initial or follow up) to the IND Office within 24 hours of knowledge of 
the event 
• 
Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
• 
The electronic SAE application (eSAE) will be utilized for safety reporting to the IND Office 
and MD Anderson IRB.  
• 
All events reported to the supporting company must also be reported to the IND Office 
 
Reporting to FDA: 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor 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
. 
 
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 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 study drug (obinutuzumab and lenalidomide, 
see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the following 
general guideline: 
Attribution is the determination of whether an adverse event is related to a medical treatment or 
procedure.  
• 
Definite -  the adverse event is clearly related to the investigational agent(s). 
• 
Probable -  the adverse event is likely related to the investigational agent(s). 
• 
Possible -  the adverse event may be related to the investigational agent(s). 
• 
Unlikely -  The adverse event is doubtfully related to the investigational agent(s). 
• 
Unrelated -  The adverse event is clearly NOT related to the investigational agent(s).  
 
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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 (see 
Section 10.2.1), 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”). 
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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. 
 
Assessment of Severity of Adverse Events
 
 
 
  
The adverse event severity grading scale for the NCI CTCAE v4.0. 
 
Pregnancy 
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 
obinutuzumab or lenalidomide, or within 18 months of the subject’s last dose of 
obinutuzumab and 3 months of the last dose lenalidomide, are considered 
immediately reportable events.  Obinutuzumab or lenalidomide is to be discontinued 
immediately. The pregnancy, suspected pregnancy, or positive pregnancy test must 
be reported to Genentech, Inc. and Celgene Drug Safety immediately by facsimile, or 
other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form. The female subject may be referred to an obstetrician- gynecologist 
(not necessarily one with reproductive toxicity experience) or another appropriate 
healthcare professional for further evaluation. 
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., 
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 OTHERAPPROPRIATE 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 
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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 lenalidomide should notify the Investigator, and the pregnant 
female partner should be advised to call their healthcare provider immediately.  
If the female partner of a male study subject becomes pregnant while the study 
subject is receiving obinutuzumab or within 6 months of the last dose of 
obinutuzumab, a report should be completed and expeditiously submitted to 
Genentech. 
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.  
Adverse Events of Special Interest (AESIs) 
The following AEs are considered of special interest and must be reported to the
 Sponsor expeditiously
 
(see Section 10.3.2.9 for reporting instructions) irrespective of regulatory seriousness criteria: 
 
Adverse events of special interest for this study include the following: 
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 and based on the following observations: -  Treatment-
emergent ALT or AST > 3 x baseline value in combination with total bilirubin 
> 2 x ULN (of which > 35% is direct bilirubin) -  Treatment- emergent ALT or 
AST > 3 x baseline value in combination with clinical jaundice 
Suspected transmission of an infectious agent by the study treatment, 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 a contamination of study treatment is 
suspected 
The obinutuzumab Events of Special Interest are: 
Tumor Lysis Syndrome (serious and non- serious events) 
Second malignancies 
 
Other Special Situations Reports
 
 
The following other Special Situations Reports should be collected even in the absence of an 
Adverse Event and transmitted to Genentech: 
• 
Data related to the Product usage during breastfeeding 
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• 
Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors) 
• 
In addition, reasonable attempts should be made to obtain and submit the age or age 
group of the patient, in order to be able to identify potential safety signals specific to a 
particular population 
Product complaints 
 
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, 
durability, effectiveness, or performance of a product after it has been released and distributed 
to the commercial market or clinical trial. 
 
 
MedWatch 3500A Reporting Guidelines 
 
In addition to completing appropriate patient demographic (Section A) and suspect 
medication information (Section C & D), the report should include the following information 
within the Event Description (Section B.5) of the MedWatch 3500A form: 
 
• 
Protocol number and title description  
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics (Section B.6) 
• 
Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
Follow- Up Information 
 
• 
Additional information may be added to a previously submitted report by any of the 
following methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow- up 
• 
Adding supplemental summary information and submitting it as follow- up with the 
original MedWatch 3500A 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 adverse event 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) 
 
 
MedWatch 
3500A 
(Mandatory 
Reporting) 
form 
is 
available 
at 
https://www.fda.gov/media/69876/download 
 
• 
Reporting to Regulatory Authorities, Ethics Committees and Investigators
 
 MD Anderson Cancer Center, as the Sponsor of the Study, will be responsible 
for the expedited reporting of safety reports originating from the Study to 
the Regulatory Authorities (FDA) where it has filed a clinical trial approval, 
in compliance with local regulations.
 
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MD Anderson Cancer Center will be responsible for the expedited reporting of safety reports 
originating from the Study to the Ethics Committees and Institutional Review Boards (IRB), 
where applicable. 
MD Anderson Cancer Center will be responsible for the distribution of safety information to 
its own investigators, where relevant, in accordance with local regulations. 
 
Additional Reporting Requirements for IND Holders (if applicable):  
 
For Investigator- Initiated IND Studies, some additional reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR § 
600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports according to the following 
guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report: 
 
The Investigator is required to notify the FDA of any fatal or life- threatening adverse event 
that is unexpected and assessed by the Investigator to be possibly related to the use of 
obinutuzumab or lenalidomide. An unexpected adverse event is one that is not already 
described in the obinutuzumab or lenalidomide Investigator Brochure. Such reports are to 
be telephoned or faxed to the FDA and Genentech within 7 calendar days of first learning of 
the event. 
 
 
15 Calendar Day Written Report 
 
The Investigator is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered reasonably or 
possibly related to the use of obinutuzumab or lenalidomide. An unexpected adverse event 
is one that is not already described in the obinutuzumab or lenalidomide investigator 
brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of 
the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the 
event. The FDA prefers these reports on a MedWatch 3500 form, but alternative formats are 
acceptable (e.g., summary letter). 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed to 
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Genentech Drug Safety: 
 
Fax: (650) 225- 4682 or (650) 225- 4630 
Email: usds_aereporting-d@gene.com 
 
And MD Anderson Cancer Center will be responsible for the distribution of safety 
information to Site IRB. 
For questions related to safety reporting, please contact Genentech Drug Safety:
 
 
Tel: (888) 835- 2555 
Fax: (650) 225- 4682 or (650) 225- 4630 
 
Expedited Reporting by Investigator to Celgene Study Close-Out 
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.SAEs are defined above, Section 10.1.2.  
The investigator must inform Celgene in writing using a Celgene SAE form or MEDWATCH 
3500A form of any SAE within 24 hours of being aware of the event.  The written report must 
be completed and supplied to Celgene by facsimile within 24 hours/ 1 business day.  The initial 
report must be as complete as possible, including an assessment of the causal relationship 
between the event and the investigational product(s).  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- FL- PI- 005632) 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. 
 
Investigator Communications with Celgene:    
 
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 
Maintenance of safety information 
Safety information will be maintained in RedCap/ CORe. At a minimum, at the end of the 
treatment phase (=”last patient off treatment”) as well as the end of the follow- up phase 
(=”last patient out”) of the Study, the Principal Investigator shall provide all adverse events, 
both serious and non- serious, in report format. However, in certain circumstances more 
frequent review of the safety data may be necessary, e.g. to fulfill a regulatory request, and as 
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such the data shall be made available within a reasonable timeframe at Genentech and/ or 
Celgene’s request.  The data must also be available at the request of the FDA and the IRB. 
 
Study Close-Out 
Any study report submitted to the FDA by the Sponsor- Investigator should be copied to Genentech.  
This includes all IND annual reports and the Clinical Study Report (final study report).  Additionally, 
any literature articles that are a result of the study should be sent to Genentech.  Copies of such 
reports should be mailed to the assigned Clinical Operations contact for the study: 
Obinutuzumab (GA101) Protocols 
Email:  ga101-gsur@gene.com  
 
 
Study administration 
Regulatory and Ethical Compliance 
This clinical study was designed and will be implemented in accordance with the protocol, the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with the ethical principles 
laid down in the Declaration of Helsinki, and in compliance with our IRB guidelines. 
 
The Investigator or his/ her authorized representative will be provided a copy of the IRB letter 
that grants formal approval and a copy of the IRB approved lCF before entering subjects in 
this study. 
 
Informed Consent 
The ICF will document the study- specific information the Investigator or his/ her designee 
provides to the subject and the subject’s agreement to participate. 
The Investigator or designee (designee must be listed on the Delegation of Authority log), 
must explain in terms understandable to the subject the purpose and nature of the study, 
study procedures, anticipated benefits, potential risks, possible AEs, and any discomfort 
participation in the study may entail. Each subject must provide a signed and dated ICF before 
any study- related (nonstandard of care) activities are performed. The original and any 
amended signed and dated ICFs must remain in the subject’s file. A copy of each signed 
consent form must be given to the subject. 
 
Quality Control and Quality Assurance 
This study shall be conducted in accordance with the provisions of the Declaration of Helsinki 
and in accordance with FDA regulations and the guidelines of Good Clinical Practices. 
 
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Protected Subject Health Information Authorization 
Information on maintaining subject confidentiality in accordance with our local and national 
subject privacy regulations must be part of the informed consent process. A HIPPA consent 
form will be used. The investigator or designee must explain to each subject that for the 
evaluation of study results, the subject’s protected health information obtained during the 
study may be shared with the Principal Investigator and his/ her designees, regulatory 
agencies, and the IRB. The Investigator will not use the subject’s protected health information 
or disclose it to a third party without applicable subject authorization. If a subject withdraws 
permission to use protected health information, it is the Investigator’s responsibility to obtain 
the withdrawal request in writing from the subject and to ensure no further data will be 
collected from the subject. Any data collected before withdrawal will be used in the analysis of 
the study results. 
 
Record Retention 
The Investigator/ study staff must maintain adequate and accurate records to enable the 
conduct of the study to be fully documented and the study data to be subsequently verified. 
Essential documentation includes, but is not limited to, the package insert signed protocols 
and amendments, IRB approval letters, signed ICFs (including subject confidentiality 
information), drug dispensing and accountability records, signed (electronically), dated and 
completed CRFs, and documentation of CRF corrections, SAE forms transmitted to 
Genentech and/ or Celgene, or designee, and notification of SAEs and related reports, source 
documentation, and all relevant correspondence and other documents pertaining to the 
conduct of the study. 
 
Investigational Drug Accountability 
Obinutuzumab and lenalidomide must be kept in a locked limited access room. The study drug 
must not be used outside the context of the protocol. Under no circumstances should the 
Investigator or other site personnel supply obinutuzumab or lenalidomide to other 
Investigators, subjects, or clinics or allow supplies to be used other than as directed by this 
protocol without prior authorization from Genentech/ Celgene.  
 
Accountability records for obinutuzumab and lenalidomide must be maintained and readily 
available for inspection by representatives of Genentech or Celgene and are open to 
inspections by regulatory authorities at any time.  
 
Investigator Responsibilities 
 
The Annual Report should be filed in the study's Regulatory Binder, and a copy provided to 
Genentech and Celgene Corporation as a supporter of this study as follows. 
 
Genentech Drug Safety Fax: (650) 225- 4682 OR (650) 225- 5288 
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Celgene Corporation 
 
Attn: Medical Affairs Operations 
 
Connell Corporate Park  
 
400 Connell Drive Suite 700 
 
Berkeley Heights, NJ  07922 
 
 
The investigator is responsible for evaluating all adverse events to determine whether criteria 
for “serious” and as defined above (Section 10.1.2) are present.  The investigator is 
responsible for reporting adverse events to Genentech and Celgene as described. 
 
The investigator will forward a copy of the Final Study Report to Genentech upon completion 
of the Study. 
 
Publication of Study Results 
The results of this study may be used for papers, abstracts, posters, or other material 
presented at scientific meetings or published in professional journals or as part of an academic 
thesis by an Investigator. In all cases, to avoid disclosures that could jeopardize proprietary 
rights and to ensure accuracy of the data, Genentech and Celgene reserve the right to preview 
all manuscripts and abstracts related to this study, allowing the Investigator sufficient time to 
make appropriate comments before submission for publication. The Investigators shall be listed 
as lead authors on manuscripts and reports of study results. The Principal Investigator will 
forward a copy of the Publication to Genentech upon completion of the Study. 
 
Study Completion 
 
The study is expected to be completed approximately 2 years after the last subject’s last 
study drug dose. 
 
Any study report submitted to the FDA by the Principal Investigator should be copied to 
Genentech.  This includes all IND annual reports and the Clinical Study Report (final study 
report).  Additionally, any literature articles that are a result of the study should be sent to 
Genentech.  Copies of such reports should be mailed to the assigned Clinical Operations 
contact for the study: 
 
Obinutuzumab (GA101) Protocols 
Email:  ga101- gsur@gene.com  
Fax:  866- 706- 3927 
 
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Appendix 1 
Study Flowchart 
 
Screening  
Phase 
Treatment phase 
End of Treatment 
Follow up Phase 
Treatment Cycle/ Title 
Screening 
Visit 
1a 
2a 
3 
To be repeated up to 18 cycles 
Cycles 20- 30 
End of Treatment 
Visit 
Follow up visitsb 
4 
5 
6 
 
 
 
Scheduling Windowc (Days) 
- 28 to - 1 
± 2  
± 2  
± 2  
± 2  
± 2  
± 2  
± 7 
± 14 
q 24 weeks x 3 visits, and then 
annually (± 4 weeks) 
Clinical/Administrative Assessments
 
Informed Consentd 
X 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
 
 
 
Record FLIPI score and GELF 
tumor burden 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
Reviewe 
X 
Day 1, 8, 
15 
X 
X 
X 
X 
X 
X 
X 
 
Drug accountability 
 
 
X 
X 
X 
X 
X 
 
 
 
Obinutuzumab Administration
f 
 
Day 1, 8, 
15 
X 
X 
X 
X 
X 
X 
 
 
Lenalidomide prescriptiong 
 
X 
X 
X 
X 
X 
X 
 
 
 
Review Adverse Events
h 
 
Day 1, 8, 
15 
X 
X 
X 
X 
X 
X 
Xh 
Xh 
Physical Examination 
X 
Day 1, 8, 
15 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weight
i 
X 
Day 1, 8, 
15 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
Day 1, 8, 
15 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
Laboratory Assessment
 
Pregnancy Test –  Serum b-
HCG
j 
X 
 
 
 
 
 
 
 
 
 
PT/ INR and aPTT
k 
X 
 
 
 
 
 
 
 
 
 
HIV 1 and 2 antibody 
X 
 
 
 
 
 
 
 
 
 
HBsAg, anti- Hep Bc, Hep C 
Ab
l 
X 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
Day 1, 8, 
15 
X 
X 
X 
X 
X 
X 
X 
X 

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Comprehensive Serum 
Chemistry Panel 
X 
Day 1, 8, 
15 
X 
X 
X 
X 
X 
X 
X 
X 
Creatinine clearance (modified 
Cockcroft- Gault) 
X 
 Day 1, 8, 
15 
X 
X 
X 
X 
X 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
X 
 
Bone marrow biopsy and 
aspirate
m 
X 
 
 
 
 
 
 
 
 
 
Optional research Biopsy (core 
needle or FNA)n 
X 
Day 8 
 
 
 
 
 
 
X 
 
Optional research blood 
sampleo 
X 
Day 8 
 
 
Day 1 
 
 
 
X 
 
Radiologic Assessment
 
Response Assessment: 
CT/ PET/ or MRIp 
X 
 
 
 
X 
 
 
X 
X 
X 
 
a. 
For each Cycle, assessment is assumed to be on Day 1 unless otherwise specified.  
b. 
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status as per the follow- up schedule 
until (1) the start of new anti- cancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, whichever occurs first. Survival assessments will continue up 
to 3 years after the last study drug.  
c. 
Treatment cycles are 28 days; however the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines provided in Section 5.4. If the interval 
is increased, all procedures except for response assessment should be performed based on the new dosing schedule 
d. 
Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of trial treatment). Screening number will be 
assigned when the study informed consent is signed. 
e. 
Record all medications taken within 28 days of screening visit. Concomitant medications – Enter new medications started through the treatment phase as well as up to 30 days after the 
last study drug dose. Record all medications taken for SAEs as defined in Section 10.1.2. 
f. 
Obinutuzumab administration will occur on day 1, 8, and 15 of Cycle 1; Day 1 of cycles 2- 6; Day 1 of cycles 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, and 30. Hypersensitivity reaction 
should be managed according to institution policy and as outlined in Section 6.4. 
g. 
Patients with creatinine clearance (CrCl) >60 mL/ min as determined by modified Crockcroft- Gault will receive 6 cycles of lenalidomide, 20mg daily on days 1- 21 of a 28 day cycle (± 
2days). Patients with a CR after 6 cycles will then receive 10mg of lenalidomide daily on days 1- 21 every 28 days (± 2days) for a total of 18 cycles. Patients with a PR after 6 cycles will 
continue 20mg of lenalidomide on days 1- 21 every 28 days (± 2days) for 3 to 6 more cycles until they achieve a CR at which time they will receive 10mg lenalidomide on days 1- 21 every 
28 days (± 2days) for the remainder of 18 cycles. Patients with a PR after 12 cycles will then receive 10mg of lenalidomide on days 1- 21 every 28 days (± 2days) for the remainder of 18 
cycles. Patients that fail to achieve at least a PR after 6 cycles with discontinue study drug. For subjects with earlier evidence of nonresponse that warrants change in therapy in the 
opinion of the treating physician, will discontinue study drug. 
h. 
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.03. All AEs, will also be evaluated for seriousness and handled as discussed in Section 10.1. 
Unresolved abnormal labs that are drug related AEs should be followed weekly until resolution. Labs do not need to be repeated after the end of treatment if labs are within normal range. 
AEs will be monitored until 30 days after last study drug dose.  
i. 
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at Screening visit 1 only. 
j. 
For women of child- bearing potential, a serum pregnancy test should be performed10- 14 days and 24 hours prior to the initial prescription of lenalidomide.  . Females of reproductive 
potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program. 

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k. 
Coagulation factors (PT/ INR and aPTT) should be tested as part of the screening procedures for all subjects. For subjects requiring anticoagulation during the study, appropriate 
coagulation tests should be done when clinically indicated to monitor anticoagulation. 
l. 
These screening tests need to be finalized prior to the first dose of obinutuzumab. HCV RNA will be performed if Hep C Ab is positive. 
m. 
All subjects will have bone marrow biopsy/ aspirate performed at baseline (within 90 days of cycle 1, day 1). Subsequent bone marrow assessments will only be performed in subjects who 
have bone marrow involvement at baseline to confirm disease response (CR). 
n. 
In consenting patients, a fresh tumor biopsy can be collected. If this is not possible, archival tumor tissue (paraffin embedded) when available should be collected at Screening for 
biomarker analyses. On C1D8 (± 2 days) an optional research biopsy should be performed. At the time of confirmed PD, if a tumor biopsy is planned as part of routine clinical practice, 
for consenting patients, a fresh tumor sample should be collected and processed. 
o. 
Biomarker blood samples will be collected and processed. During screening or within 28 days of the first infusion of obinutuzumab, on cycle 1, day 8 (± 2 days), cycle 4, Day 1 (± 2 days), 
and at the time of documented PD (±14 days), blood biomarker collection should be performed. 
p. 
Disease response assessment is based upon Cheson 2014 lymphoma response criteria and Cheson 2007 revised response criteria. “Diagnostic quality” PET- CT with oral contrast/ or 
water and IV contrast should be performed at Screening unless there is a contraindication. If CT scans have already been completed, a PET can be performed at Screening. PET/ CT or 
CT and PET should be repeated to confirm complete remission and/ or at treatment discontinuation. For lymphomas that are not FDG- avid, PET does not need to be repeated in 
subsequent assessments. CTs of the neck, chest, abdomen, and pelvis with IV contrast will otherwise be conducted at baseline for those who do not undergo diagnostic quality PET- CT, 
at approximately Cycle 4, Day 1 (± 7 days), Cycle 7, Day 1 (± 7 days), Cycle 10, Day 1 (± 7 days), Cycle 14, Day 1 (± 7 days), Cycle 20, Day 1 (± 7 days), Cycle 26, Day 1 (± 7 days), 
and at the completion of treatment. During the follow- up phase, response assessment will occur every 24 weeks (±4 weeks) x 3 assessments, and then annually (±4 weeks) until study 
completion, PD, withdrawal of consent, death, or lost to follow up, whichever comes first. When a contraindication prevents CT, an MRI of the chest, abdomen/ pelvis can be substituted. 
In subjects who discontinue study therapy without confirmed disease progression, a radiological assessment should be performed at the time of treatment discontinuation (i.e. date of 
discontinuation ± 2 weeks). If previous scan was obtained within 4 weeks prior to the date of discontinuation, then a repeat scan at treatment discontinuation isn’t mandatory.

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Appendix 2 
Calculation of Creatinine Clearance Using the Cockcroft- Gault Formula 
 
Creatinine Clearance (men) = (140- Age) × Lean Body Weight [kilograms] 
Serum Creatinine (mg/ dL) × 72 
 
Creatinine Clearance (women) = 0.85 × (140- Age) × Lean Body Weight [kilograms] 
Serum Creatinine (mg/ dL) × 72 
Reference: 
Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted serum 
creatinine (editorial). Nephron 1992;62:249. 
 
Appendix 3  
FLIPI Score 
FLIPI (Solal- Celigny, 2004) 
 
Score 1 point for each of the following risk factors: 
 
• Hemoglobin, g/ dL < 12 g/ L 
• Number of nodal areas >4 (The spleen is considered as an extranodal site 
and not a nodal area) 
• Age, years > 60 
• LDH level > normal 
• Ann Arbor Stage III/ IV 
 
RISK GROUPS 
 
Number of Factors 
 
Low   
 
 
0- 1 
Intermediate   
 
2 
High   
 
 
3- 5 
 
 
Appendix 4  
Determination of Tumor Burden 
 
If patients meet all the above criteria and are without B symptoms (drenching night 
sweats, fever that is non- infectious, weight loss > 10% of body weight, fatigue, or 
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pruritus), they are considered low tumor burden by the Groupe D’Etude des 
Lymphomes Folliculares (GELF) criteria. (Khal. ASH Education 2012) If they do not 
meet all of the above criteria, they are considered high tumor burden. 
 
Appendix 5 Response Assessment 
Cheson Lugano Criteria 2014. 
 
 
 
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Cheson Revised Response Criteria 2007
 
 
Appendix 6 
Safety Reporting Fax Cover Sheet 
 
Genentech Supported Research 
AE/ SAE FAX No:  (650) 225- 4682 
Alternate Fax No:  (650) 225- 4630 
 
Page 1 of ___ 
Genentech Study Number 
 
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Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
Initial Report Date 
 
 
/  
/  
 
 
dd /  mmm /  yyyy 
Follow- up Report Date 
 
 
/  
/  
 
 
dd /  mmm /  yyyy 
Patient Initials 
(Please enter a dash if the patient has no 
middle name) 
____ -  ____ - ____ 
 
SAE or Safety Reporting questions, contact 
Genentech Safety: (888) 835- 2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET 
Appendix 7 
FDA MedWatch 3500 Form 
This form is included in the study start- up zip file to be sent to sites via email. 
 
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Appendix 8 
Current NCI Common Terminology Criteria for Adverse Events (CTCAE) 
 
Please use the following link to the NCI CTCAE website: 
http:/ / ctep.cancer.gov/ protocolDevelopment/ electronic_applications/ ctc.htm 
 
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