A Phase I/II Study of Lenalidomide and Obinutuzumab (GA101) in Relapsed Indolent Non-Hodgkin's Lymphoma
Phase: PHASE1
Conditions: Grade 3a Follicular Lymphoma, Recurrent Follicular Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Follicular Lymphoma, Refractory Marginal Zone Lymphoma, Refractory Small Lymphocytic Lymphoma
Sponsor: M.D. Anderson Cancer Center

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MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2013-0261 
Protocol Title 
A Phase I/II study of Lenalidomide and Obinutuzumab (GA101) in 
Relapsed Indolent Non-Hodgkin’s Lymphoma 
Protocol Phase 
I/II 
Protocol Version 
MOD003 
Version Date 
11.11.2020 
Protocol PI 
Loretta Nastoupil 
Department 
Lymphoma/Myeloma 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
120166 
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MD Anderson Cancer Center 
Houston, Texas 
 
 
Study Title 
 
A Phase I/II study of Lenalidomide and Obinutuzumab (GA101) in Relapsed 
Indolent Non-Hodgkin’s Lymphoma 
 
Study Drug 
Obinutuzumab 
Lenalidomide 
Support Provided By 
Genentech, Inc. 
 
 
Sponsor Investigator 
 
Loretta Nastoupil MD 
 
 
 
 
 
 
 
 
Study Number: 
2013-0261 
 
Protocol Version Date: 
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LIST OF APPENDICES 
 
APPENDIX A: Prioritization List [located in MD Anderson’s Protocol 
Document Online (PDOL) system] 
APPENDIX B: Protocol Checklist (located in MD Anderson’s PDOL system) 
APPENDIX C: Investigator’s Brochure – Obinutuzumab IB v.7 (located in 
MD Anderson’s PDOL system) 
APPENDIX D: Calculation of Creatinine Clearance Using the Cockcroft– 
Gault Formula 
APPENDIX E: SAFETY REPORTING FAX COVER SHEET 
APPENDIX F: CURRENT NCI COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS (CTCAE) 
APPENDIX G: GUIDELINES FOR OBINUTUZUMAB PREPARATION AND 
ADMINISTRATION 
APPENDIX H: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
Abbreviation 
Definition 
 
ABC 
activated B cell 
 
ADCC 
antibody-dependent cellular cytotoxicity 
 
AE 
adverse event 
 
anti-HBc 
antibody to hepatitis B core antigen 
aPTT 
activated partial thromboplastin time 
BM 
bone marrow 
 
ASCO 
American Society of Clinical Oncology 
 
AUC 
area under the concentration−time curve 
 
BSA 
body surface area 
 
CDC 
complement-dependent cytotoxicity 
 
CHOP 
cyclophosphamide, doxorubicin, vincristine, prednisone 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration observed 
CNS 
central nervous system 
 
CR 
complete response or complete remission 
 
Cru 
unconfirmed complete response 
 
CSR 
Clinical Study Report 
 
D 
Day 
 
DFS 
disease-free survival 
 
DLBCL 
diffuse large B-cell lymphoma 
 
DLT 
dose-limiting toxicity 
 
EC 
Ethics Committee 
 
ECHO 
echocardiogram 
 
ECOG 
Eastern Cooperative Oncology Group 
 
eCRF 
electronic Case Report Form 
 
EDC 
electronic data capture 
 
EFS 
event-free survival 
 
F 
phenylalanine 
 
FACS 
fluorescent-activated cell sorter 
FcγR 
leukocyte receptors for the Fc portion of IgG 
18F-FDG 
18F-fleurodeoxyglucose 
 
FFPE 
formalin-fixed paraffin-embedded 
 
FISH 
fluorescence in situ hybridization 
 
GCB 
germinal center B cell 
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Abbreviation 
Definition 
 
GCP 
Good Clinical Practice 
 
GCSF 
granulocyte-colony stimulating factor 
 
GEP 
G 
 
gene expression profiling 
GA101(obinutuzumab) 
 
G-FC 
GA101(obinutuzumab) in combination with fludarabine 
and cyclophosphamide 
HAHA 
human anti-human antibodies 
 
HBcAb 
hepatitis B core antibodyd 
 
HBsAg 
hepatitis B surface antigen 
 
HBV 
hepatits B virus 
 
HCV 
hepatitis C virus 
 
HD 
high dose 
 
HTLV 
human T-cell leukemia virus 
 
ICH 
International Conference on Harmonisation 
 
Ig 
immunoglobulin 
 
IHC 
immunohistochemistry 
 
IND 
Investigational New Drug 
 
IMC 
Internal Monitoring Committee 
 
IRR 
infusion-related reaction 
 
IV 
intravenous 
 
IL 
interleukin 
 
IPI 
International Prognostic Index 
 
IVRS 
interactive voice response system 
 
LD 
low dose 
 
LVEF 
left ventricular ejection fraction 
 
LVSD 
left ventricular systolic dysfunction 
 
MCL 
mantle-cell lymphoma 
 
MUGA 
multigated acquisition scan 
 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
 
NHL 
non-Hodgkin’s lymphoma 
NONMEM 
Non-Linear Mixed Effect Model 
ORR 
overall response rate 
OS 
overall survival 
 
PD 
progressive disease 
 
PICC 
peripherally inserted central catheter 
 
PK 
pharmacokinetic 
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Abbreviation 
Definition 
PET 
positron emission tomography 
PFS 
progression-free survival 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response or partial remission 
R-CHOP 
rituximab in combination with cyclophosphamide, 
doxorubicin, vincristine, prednisone 
SAE 
serious adverse event 
SD 
stable disease 
SDI 
shorter duration of infusion 
SLL 
small lymphocytic lymphoma 
SOC 
Scientific Oversight Committee 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
V 
valine 
WHO 
World Health Organization 
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1. 
INTRODUCTION 
 
 
 
1.1 
DISEASE BACKGROUND 
 
1.1.1 
NON-HODGKIN’S  LYMPHOMA 
 
Non-Hodgkin’s lymphoma (NHL) is the most common hematologic malignancy in 
adults. It is estimated that in 2010 there were 93,172 new cases of NHL in Europe 
and 65,540 new cases of NHL in the United States (American Cancer Society 2010; 
GLOBOCAN 2010). The majority of NHLs 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 overexpression of the intracellular anti-apoptotic protein Bcl-2. Although 
follicular lymphoma is the most common subtype of indolent NHL, there are also 
many histological non-follicular subtypes, including marginal zone lymphoma (MZL), 
and small lymphocytic lymphoma (SLL).  Early-stage indolent NHL may be 
effectively treated with radiation therapy, but advanced stages remain incurable. 
 
1.1.2 
NATURAL HISTORY AND CURRENT MANAGEMENT OF 
INDOLENT NON-HODGKIN'S  LYMPHOMA 
 
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. 
 
a. Immunochemotherapy in Follicular Lymphoma 
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). Rituximab in combination with chemotherapy (e.g., CHOP 
[cyclophosphamide, doxorubicin, vincristine, and prednisone], CVP 
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[cyclophosphamide, vincristine, and prednisone], or purine analogue–based 
schemes such as those with fludarabine or bendamustine) for newly diagnosed 
patients with advanced Stage III and IV disease requiring treatment is strongly 
supported by both the 2009 European Society for Medical Oncology (ESMO) 
Guidelines Working Group recommendations (level of evidence: I; grade of 
recommendation: B) and the 2010 National Comprehensive Cancer Network 
(NCCN) guidelines (Category 1 recommendation based on high-level evidence, 
with a uniform NCCN consensus) (Dreyling 2009; Zelenetz et al. 2010). 
 
b. Immunochemotherapy in Non-Follicular Indolent Lymphoma 
Rituximab has also demonstrated efficacy in patients with non-follicular indolent 
lymphoma, including MZL, WM, and SLL (Foran et al. 2000; Treon et al. 2001; 
Hainsworth et al. 2003).  A Phase II trial conducted in 39 patients with MZL 
(Brown et al. 2009) showed high response rates (overall response rate [ORR] of 
85%; complete response [CR] rate of 54%) with durable responses (79.5% PFS 
after 3.1 years) following treatment with rituximab and chemotherapy. 
 
Rituximab is listed as an option for the treatment of advanced MZL in the most 
recent ESMO and NCCN Clinical Practice Guidelines (Zelenetz et al. 2010; 
Zucca et al. 2010). 
 
c. Maintenance Therapy after Induction Treatment 
In addition to immunochemotherapy induction, two randomized clinical trials have 
demonstrated the benefit of maintenance rituximab in responding patients with both 
previously untreated and relapsed follicular lymphoma.  In a clinical trial of patients 
with relapsed follicular lymphoma, responders to rituximab plus CHOP (R-CHOP) 
or CHOP underwent a second randomization to maintenance rituximab or 
observation.  Patients who received maintenance rituximab demonstrated a 
superior median PFS (52 vs. 15 months) and 3-year overall survival (85% vs. 77%) 
compared with patients who underwent observation (van Oers et al. 2006). 
Updated results from this study, with a median follow-up of 6 years, continued to 
demonstrate a significant improvement in PFS with rituximab maintenance versus 
observation (median PFS: 3.7 years vs. 1.3 years; p< 0.001; hazard ratio, 0.55) 
and in 5-year overall survival (74% vs. 64%) after either R-CHOP or CHOP 
induction (van Oers et al. 2010). More recently, a study of patients with previously 
untreated follicular lymphoma that responded to rituximab in combination with CVP, 
CHOP, or FCM (fludarabine, cyclophosphamide, and mitoxantrone) who were later 
randomized to observation or 2 years of maintenance rituximab (the Primary 
Rituximab and Maintenance [PRIMA] trial) demonstrated an improvement in PFS 
with the addition of maintenance rituximab (2-year PFS of 82% for rituximab 
maintenance compared with 66% for the observation group [p< 0.001; hazard ratio, 
0.50]) (Salles et al. 2011). 
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1.2 
OBINUTUZUMAB BACKGROUND 
 
1.2.1 
STRUCTURE AND MECHANISM OF ACTION OF OBINUTUZUMAB 
 
Obinutuzumab (RO5072759) is a novel, Type II, glycoengineered monoclonal 
antibody derived by humanization of the parental B-Ly1 mouse antibody. (Beers 
et al. 2010; Mössner et al. 2010, Aldujai et al. 2011). 
 
Obinutuzumab has an elbow hinge amino acid exchange in the Fc region of the 
antibody that results in a different angle of binding to the CD20 epitope compared 
to  Type I anti-CD20 antibodies. This Type II binding induces more potent direct 
cell death compared to Type I antibodies, including rituximab. In addition, the Fc 
portion of obinutuzumab has been glycoengineered to reduce fucosylation 
resulting in higher affinity for the FcγRIIIa receptors on natural killer cells and 
monocytes leading to enhanced ADCC. 
 
Given the significantly greater ADCC and direct cell-death induction, it is possible 
that obinutuzumab may have greater efficacy than rituximab, particularly in the 
80% to 85% of patients who are carriers of the FcγRIIIa low-affinity receptor 
polymorphism. 
 
1.2.2 
NONCLINICAL EFFICACY WITH OBINUTUZUMAB 
 
Obinutuzumab has demonstrated in vivo efficacy superior to that of rituximab in 
various human lymphoma xenograft models.  Both antibodies have been 
compared in human SUDHL-4 cells (a diffuse large B-cell lymphoma [DLBCL] 
model) that were subcutaneously injected into severe combined immunodeficient 
beige mice.  Therapy began when tumors were established and rapidly growing. 
 
It was shown that rituximab at 10 mg/kg inhibited tumor growth more than 
rituximab at 1 mg/kg; however, increasing the dose to 30 mg/kg did not result in 
increased efficacy of rituximab. In contrast, obinutuzumab showed a dose- 
dependent increase in efficacy in the range of 1−30 mg/kg and resulted in 
complete tumor regression in all animals and in lasting tumor eradication in 9 of 
10 animals at the highest dose of 30 mg/kg and in 1 of 10 animals at a dose of 
10 mg/kg. 
 
Additional studies have shown that obinutuzumab treatment was able to control 
tumor growth when vehicle- and rituximab-treated tumors were not controlled 
(Mössner et al. 2010). 
 
For more detailed nonclinical information on obinutuzumab, please refer to the 
current version of the obinutuzumab Investigator’s Brochure. 
 
 
1.2.3 
CLINICAL EXPERIENCE WITH OBINUTUZUMAB IN NON- 
HODGKIN’S LYMPHOMA 
 
As of December 2011, clinical data on obinutuzumab are available from four Phase 
I or II studies (Studies BO20999, BO21003, BO21000, and JO21900) and two 
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Phase III studies (Studies GAO4753g and BO21004/CLL-11). More than 
550 patients with CD20-positive malignant disease have been treated with 
obinutuzumab. 
 
Results from the aggressive and indolent NHL cohorts in ongoing studies are 
described below. 
 
1. Study BO20999 (Phase I/II): OBINUTUZUMAB Monotherapy 
 
 
 
Patients with Indolent Non-Hodgkin's Lymphoma 
Forty patients with relapsed or refractory indolent NHL were randomized to receive 
obinutuzumab in a low-dose cohort (n = 18) or a high-dose cohort (n = 22). The low- 
dose cohort received obinutuzumab 400 mg on Days 1 and 8 of Cycle 1 and 
400 mg on Day 1 of Cycles 2–8 (21-day cycles), and the high-dose cohort received 
obinutuzumab 1600 mg on Days 1 and 8 of Cycle 1 followed by 800 mg on Day 1 
of Cycles 2–8 (21-day cycles).  Patients had been pretreated with a median of three 
prior regimens (range, 1−11), and the majority (38 of 40) had received prior 
rituximab treatment. More than half of these patients (22 of 40) were considered to 
be rituximab refractory, and 35% (14 of 40) of all patients had previously received  
an autologous stem-cell transplant. The best overall response rate in the follicular 
lymphoma patients was 36% in the low-dose cohort (1/14 CR/CRu, 4/14  PR) and 
60% in the high-dose cohort (4/20 CR/CRu, 8/20 PR). (Salles et al. 2011) 
 
The most common adverse event of any grade was infusion-related reaction (IRR; 
72% low-dose cohort, 73% high-dose cohort). Fifty-five percent of patients had 
Grade 3 or 4 adverse events; the most common Grade 3/4 adverse events across 
cohorts were infections (14%), neutropenia (14%), and IRRs (9%), all in the high- 
dose cohort. 
 
Patients with Aggressive Non-Hodgkin's Lymphoma 
Forty patients with aggressive NHL were enrolled into the Phase II part of the 
study. Of these patients with aggressive NHL (25 with DLBCL and 15 with 
mantle-cell lymphoma [MCL]), 19 were treated in the high-dose cohort (15 with 
DLBCL and 4 with MCL) and 21 were treated in the low-dose cohort (10 with 
DLBCL and 11 with MCL). Patients were heavily pretreated (median of three  
prior therapies), with 63% of patients having not responded to or relapsed within 
6 months after a previous rituximab-containing regimen (rituximab refractory). 
The best overall response rate was 24% in the low-dose cohort (DLBCL: 2 PR, 1 
CRu); MCL: 2 CR) and 37% in the high-dose cohort (DLBCL: 3 CR, 2 PR; MCL: 
2 PR). (Morschhauser et al. 2011) 
 
The most common adverse event of any grade was IRR (81% low dose cohort, 
68% high dose cohort).  Grade 3 or 4 adverse events occurring with ≥ 5% 
frequency were anemia (10%), thrombocytopenia (8%), IRR (8%), tumor lysis 
syndrome (5%) and cardiac failure (5%).  Adverse events did not increase in the 
high-dose cohort compared to the low-dose cohort. There was one Grade 5 
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adverse event, cardiorespiratory arrest that was thought to be secondary to 
ventricular arrhythmia. 
 
b. Study BO21003 (Phase II): Obinutuzumab Monotherapy plus 
Maintenance 
Study BO21003 is an ongoing, open-label, multicenter, randomized, Phase I/II study 
to investigate the efficacy and safety of obinutuzumab monotherapy compared with 
that of rituximab monotherapy in patients with relapsed indolent NHL. 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. 2011) 
 
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. 
 
c. 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 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 
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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. 
 
d. Study GAO4753g (Phase III): Obinutuzumab in Combination with 
Chemotherapy 
Study GAO4753g is an ongoing, 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. Approximately 360 patients will be enrolled. The Data and Safety 
Monitoring Board evaluated safety of the first 20 patients without requesting 
modifications to the protocol. Since the initial review of the first 20 patients in 
April 2011, two additional Data and Safety Monitoring Board meetings have 
convened, and they recommended that the trial continue. 
 
e. Summary of Safety and Efficacy Results 
With consideration of the available obinutuzumab Phase I and II data, 
obinutuzumab has an acceptable safety profile and there is rationale to 
investigate whether obinutuzumab is an effective treatment for patients with B- 
cell malignancies. 
 
For more information relating to safety and efficacy in the NHL indication, 
please refer to the obinutuzumab Investigator's Brochure. 
 
 
1.2.4 
PHARMACOKINETIC AND PHARMACODYNAMIC OBINUTUZUMAB 
DATA 
 
A population pharmacokinetic model has been developed for Studies BO20999 
and BO21003 to characterize the pharmacokinetics of obinutuzumab and its 
variability. A two-compartment model, comprising both a linear clearance 
pathway and a non-linear time-varying clearance pathway, was fitted to the data. 
Data are available for a total of 134 patients following intravenous (IV) 
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administration of obinutuzumab in Studies BO20999 (n = 114) and BO21003 
(n = 20). 
 
Following infusion of obinutuzumab, the elimination appears to be characterized 
by a clearance that is dependent on time; that is, starting at a typical value of  
594 mL/day and then gradually decreasing to an asymptote of 112 mL/day at 
steady state. Tumor burden potentially contributes significantly to the clearance 
of obinutuzumab, especially at the beginning of treatment when there is an 
excess of CD20 cells.  As tumor burden decreases, the clearance reaches an 
asymptote, which is thought to be primarily a function of the proteolytic metabolic 
clearance. Consequently, some patients with a high tumor burden appear to 
clear the drug from the plasma faster than 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 GA101 will reduce the quantity of CD20- 
positive tumor cells. 
 
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 or after infusion, but changes have been observed in the levels of 
interleukin-6 and interleukin-8 b 
 
1.3 
LENALIDOMIDE 
 
 
 
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 non-Hodgkin’s lymphoma (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 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 
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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 5 mg and 10 mg 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. The 5 mg 
capsule shell contains gelatin, titanium dioxide and black ink. The 10 mg 
capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium 
dioxide and black ink. 
 
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 urinary excretion. The process exceeds the glomerular filtration rate and 
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therefore is partially or entirely active. Half-life of elimination is approximately 3 
hours. 
 
 
 
1.3.1 
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 
 
Wiernik et al reported preliminary results of lenalidomide monotherapy in patients 
with relapsed or refractory non-Hodgkin's lymphoma. Lenalidomide (25 mg/d)  
was administered on days 1 to 21 of a 28-day cycle and continued for 52 weeks 
as tolerated or until disease progression. Patients with various aggressive 
histologic subtypes (including diffuse large B-cell, follicular center cell, mantle cell, 
and transformed NHL) were enrolled. Forty-one of the 50 patients were 
assessable for response. Clinical responses were observed in all lymphoma 
subtypes. The ORR was 34% (n = 14) including five patients with CR 
unconfirmed (CRu), with a median progression-free survival in patients achieving 
a CRu of more than 239 (> 191 to > 373 days) days. (Witzig et al 2007) An 
ongoing multicenter clinical trial is further investigating clinical efficacy of single 
agent lenalidomide in patients with aggressive NHL. 
 
 
 
Kaufman et al first reported the clinical efficacy of thalidomide combined with 
rituximab in patients with relapsed/refractory mantle-cell lymphoma (MCL). The 
ORR and CR rate in this study was 81% and 31%, respectively with a median 
progression-free survival of 20.4 months. (Kaufman et al 2004) On the basis of 
these findings, 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 three1-4 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 the basis of the 
important single-agent activity of lenalidomide and bortezomib in MCL, CALGB is 
currently conducting a phase II trial of the combination of the two agents in 
patients with relapsed or refractory MCL. 
 
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 
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26% (n = 7) including two CRs, whereas 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 are currently conducting an investigator initiated phase II, 
single arm study with a combination of lenalidomide and rituximab in patients   
with untreated indolent NHL. Patients receive lenalidomide 20 mg/day on days 1- 
21 of each 28 day cycle. Rituximab is given at 375 mg/m2 on day 1 of each cycle. 
We have reported high overall response rates, with a complete response rate of 
over 90% 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. (Fowler N, et al 2011) 
 
 
 
 
1.4 
STUDY RATIONALE 
 
 
 
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 a 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.  Although we do not expect 
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significant additional toxicity with obinutuzumab the first cohort of patients will be 
started at dose level 1 (10mg daily) of lenalidomide. 
(Wang et al 2012) 
 
A unit dose of 1000 mg of GA101 was chosen for studies of NHL after a review  
of data from completed Phase I studies was undertaken. This unit dose of GA101 
to be used in future studies was based on the following findings: 
 
• No dose-limiting toxicities were observed and no maximum tolerated dose was 
reached in Phase I (doses from 50 mg to 2000 mg were tested). 
 
• Clinical activity (responses) was observed at all dose levels tested. 
 
• PK analyses suggested that a decreased variability of drug exposure related to 
tumor burden was achieved at doses above 800 mg given on Days 1, 8, 22 and 
every 3 weeks for nine doses. 
 
• GA101 was well tolerated with a preliminary safety profile similar to that of 
rituximab in NHL patients (i.e., mainly Grade 1−2 toxicities, with more frequent 
IRRs around the time of the first infusion, decreasing with subsequent infusions). 
 
After a comprehensive review of all safety, efficacy, and PK data obtained in 
Phase I studies, a total GA101 dose of 1000 mg for all infusions was chosen as 
the dose to be used in future Phase II and Phase III studies by the sponsor since 
it was the dose most likely to be well tolerated and efficacious in a majority of 
NHL patients regardless of their initial tumor burden. 
 
In order to coordinate the dosing of study drugs during the first 6 months of 
treatment, GA101 will be given on 28-day cycles for the first six cycles in this 
study. On cycle 1 of therapy, the dose of GA101 will be divided over 2 days; day 
1, 100mg and Day 2, 900mg. PK modeling suggests that giving additional doses 
of GA101 on Days 8 and 15 of Cycle 1, and then every 2 months beyond 6 
months, will be needed in order to saturate target-mediated clearance achieve 
and maintain a steady state of drug early and as long as possible during 
treatment. 
 
After the maximum tolerated dose is found, patients will be enrolled in two 
cohorts. Prior studies in various B cell malignancies have observed different 
response profiles in patients with SLL and marginal zone lymphoma compared to 
patients with follicular lymphoma (Fowler et al). 
 
 
 
 
 
 
 
 
2, STUDY DESIGN 
 
2.1 SCHEDULE OF STUDY ASSESSMENTS 
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SCHEDULE OF STUDY ASSESSMENTS 
Procedure 8* 
Screening 
≤ 30days from 
Baseline (First 
day study drug 
administration) 
Cycle 1 
All 
Cycles 
* 
All 
Cycles 
* 
Following 
Cycles 3, 
6, 913, 1213 
then every 4 
months during 
obinutuzumab 
maintenance*15 
Discontinuation 
From Study 
Drug 
Follow- 
Up 
Phase 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
14 
Every 36 
months 
Record prior medications, 
treatments 
X 
Record prior anti-cancer therapies 
X 
Medical History 
X 
X 
X 
HTLV1, HIV and Hepatitis B/C 
screening10 
X 
Physical examination, vital signs, 
weight 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
CT of the chest & abdomen / 
pelvis, neck, PET CT. 8* 
X 
X 
X 
X 6 
Chest x-ray 
X 
X 
Electrocardiogram (EKG) 
X 
 
Bilateral bone marrow Bx, BM 
cytogenetics. On Follicular 
lymphoma histology do BM and 
blood PCR for Bcl-2 rearrangement. 
On SLL do ZAP70, CD38 staining 
and somatic mutation analysis on 
BM and tumor tissue. 
X 2 
X2 
X2 

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Register patient into 
Revlimid REMS® program1 
X 
Prescribe lenalidomide via 
Revlimid REMS® program 1 
X 
X 
obinutuzumab infusion 12,14 
X 
X 
X 
X 
X12 
Hematology Test: hematocrit, 
platelet count, WBC count 
with differential, Absolute 
neutrophil count (ANC) and 
absolute lymphocyte count 
(ALC). 9, 11 
X 
X 
x 
X 
X 
X11 
X 
X 
Serum chemistry: Blood chemistries 
should include sodium, potassium, 
chloride, 
CO2, blood urea nitrogen (BUN), creatinine, 
glucose, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), 
total bilirubin, alkaline phosphatase, 
lactate dehydrogenase (LDH), calcium, 
S
5
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 3,4 
X4 
X 
X 
X 
X 
4 
4 
Tumor lesions assessment 
X 
X 
X 
X6 
Response assessment using 
IWG criteria 
X 
X 
Record concomitant 
therapies/procedures 
x 
X 
X 
Obtain Follow-Up anti-cancer 
treatments 
X 
X 6 
Obtain Follow-Up survival information 
X 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
* Variations of +/- 3 days of the schedule are permitted. 
** Staging CTs and BM Bx will be done up to 7 days of end of cycle 
 
 

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1. Lenalidomide must be prescribed through and in compliance with Celgene’s Revlimid REMS® program. Prescriptions must be filled within 
7 days. 
2. Repeat BM evaluation to confirm morphologic and genetic markers of disease. Zap 70 and CD38 staining will be done if tissue is available. 
Repeat BM biopsy is at investigators discretion to confirm complete remission (as determined by radiographic imaging). Screening bone marrow 
biopsy can be obtained up to 60 days prior to study entry. 
3. Pregnancy tests for females of childbearing potential. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., 
has had menses at any time in the preceding 24 consecutive months). 
4. Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled 
within 7 days). FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while 
on therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide. Females with 
irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while on therapy (including breaks in 
therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix: Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods). 
5. Thyroid Stimulating Hormone (TSH) will be drawn at baseline and prior to cycles 4 
6. Follow-up and tumor assessment – Patients will be evaluated every 3 months for one year, every 6 months for 1 year and then yearly with 
CT of neck, thorax, abdomen and pelvis and other studies as recommend by the treating physician for 1 year. Timing of imaging studies 
will be calculated from date of last scan. Tumor assessments, as well as timeline for tumor assessments are recommendations only. 
Exact timing of follow-up tumor assessments are at the discretion of the treating physician. Patients will have a minimum of imaging 
studies every 6 months for the first. Imaging can be done plus/-21 days of recommended time points. 
7. Patient evaluation and predose labs can occur up to 3 days prior to starting each cycle. If possible, patients should be seen at least 24 
hours prior to each cycle 
8. If a patient is allergic to IV contrast, non-contrast PET/CT images can be used for tumor evaluation, response assessment. If patient has a 
history of PET negative disease, repeat PET is not required prior to study entry. If patient has full CT at specified timepoint, PET is 
recommended, but not required for study entry or on follow up visits. 
9. If not reported on patients CBC, patient’s ANC and ALC can be calculated from absolute neutrophil percent and absolute lymphocyte 
percent. 
10. In the absence of a history of blood transfusion or intravenous drug use in the past 6 months, patients can have hepatitis B/C andHIV 
testing up to 8 weeks prior to study entry. 
11. Hematology testing will occur on day 1 and day 14 (+/- 4 days) of cycles 2-12. If patient discontinues lenalidomide, day 14 labs are not 
required in cycle #2 and beyond. 
12. Obinutuzumab is given on day 1, 2, 8, 15, and 22 of cycle one and on day 1 of each subsequent cycle up to 6 additional months during 
lenalidomide dosing.  In months 12 and beyond, obinutuzumab is given every 56 days. 
13. Patients can receive up to 12 cycles of lenalidomide and obinutuzumab. 
Restaging will occur every 3 cycles while the patient is on 
combination therapy, and every 112 days during obinutuzumab monotherapy (maintenance phase). 
14. Obinutuzumab will be given 100mg IV on day 1, and 900mgIV on day 2 of cycle 1. Subsequent cycles will receive 1000 mg on each dose 
day as tolerated. 
15. Cycles are 28 days long during the first 11 months of treatment (during combination and single agent dosing of 
obinutuzumab). The remaining cycles are 56 days. If the patient is on single agent obinutuzumab during cycle 7‐12, physical 
exam, labs, follow up visit, ecog, vital signs, and medical history will only be done on cycles 8, 10, and 12. 

GA101 Plus Lenalidomide in Low Grade Lymphoma 
 
 
 
 
 
2.2OBJECTIVES 
 
2.2.1 Primary Objectives 
 
Part 1 (phase 1). 
 
1. To determine the maximum tolerated dose of lenalidomide plus 
obinutuzumab in relapsed/refractory indolent lymphoma. 
 
Part 2 (phase 2). 
1. To evaluate the safety of lenalidomide in combination with obinutuzumab 
in patients with relapsed/refractory indolent lymphoma. 
 
2. To determine the overall response rate (ORR) of the combination in 
patients with relapsed/refractory indolent lymphoma. 
 
2.2.2 Secondary Objectives 
 
1. To determine the complete response rate, time to progression (TTP), and 
progression free survival in patients with indolent lymphoma following treatment 
with obinutuzumab + lenalidomide. 
 
2. To evaluate changes in immune effector cells and the tumor microenvironment 
following treatment with obinutuzumab + lenalidomide. 
 
2.3 STUDY DESIGN 
 
2.3.1 DESCRIPTION OF THE STUDY 
 
This is a single-center, open label, phase I/II study in patients with refractory or 
relapsed indolent lymphoma.  The feasibility of administrating lenalidomide in 
combination with obinutuzumab and the MTD of the combination will be 
determined in the phase I part of the study. When the MTD has been 
established, the efficacy of the combination will be further evaluated in the phase 
II part of the study in two patient cohorts simultaneously. All patients will receive 
a combination of daily lenalidomide for 21 days with IV obinutuzumab on day 1,2, 
8, 15, and 22 of cycle one (obinutuzumab will be given 100mg IV on day 1, and 
900mgIV on day 2, subsequent doses will be given over 1 day)and on day 1 of 
each subsequent cycle up to 6 cycles. Patients who do not progress following 6 
cycles and are deriving benefit from the combination in the opinion of the treating 
physician can receive up to 12 cycles of lenalidomide therapy. After completing 
combination lenalidomide therapy,patients will then enter a “maintenance phase” 
and receive obinutuzumab on day 1 of each 2 month cycle for up to 2 years or a 
total of 30 months on treatment (combination + maintenance), whichever occurs 
first. The two patient cohorts are patients with follicular lymphoma (grade 1-3a) 
and the patients with any indolent lymphoma including follicular, marginal zone or 
SLL. A maximum of 72 patients (18 in phase I and 60 in phase II; the 6 patients 
treated at the MTD in phase I will be included in analysis  
 
 
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of the first group of patients treated in phase II) will be enrolled in this study on an 
intent-to-treat basis. 
 
2.3.2 Phase I 
 
The primary objective of the phase I part of the study is to determine the 
maximum tolerated dose (MTD) of lenalidomide when given in combination 
with obinutuzumab for subsequent testing in the phase II part of the trial. 
There are three predefined dose levels for lenalidomide (10 mg, 15 mg, 20 
mg) with a fixed dose of obinutuzumab (1000 mg) as outlined in Table 1. 
 
 
Dose limiting toxicity (DLT) will be assessed during the first course of each cohort 
(28 days), and refers to a medically significant event which meets one of the 
following criteria using National Cancer Institute Common Terminology Criteria  
for Adverse Events (NCI CTCAE) version 4: 
 
 
• Grade 3 or higher non-hematologic AE which is felt to be related to 
the study drug by the investigator with the exception of the 
following: 
o Transient grade 3 or less infusion reaction that completely 
resolves within 24 hours. 
• Grade 4 hematologic toxicity (Platelet count is defined as <25,000 
for the purposes of determining DLT. 
• Grade 3 neutropenia with elevated temperature (defined as >/= 
101 degrees F to be confirmed on two occasions). 
• 
Grade 3 thrombocytopenia with bleeding. 
• Treatment delay of greater than 2 weeks due to treatment related 
toxicity. 
 
Prior to advancing/changing dose levels a cohort summary will be completed and 
submitted to the Clinical Research Monitor in the IND Office. 
 
2.3.3 Phase II 
 
The objective for the phase II part is to further evaluate the safety and efficacy of 
lenalidomide when given in combination with obinutuzumab at the MTD of 
lenalidomide determined in phase I. The maximum number of patients that will 
be recruited for the phase II part is 60 with 30 for each of the two patient cohorts: 
the patients with follicular lymphoma (grade 1-3a) and the patients with any 
indolent lymphoma.  The patients who are treated at the MTD in the phase I part 
will be counted as the first group of patients treated in phase II. 
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2.3.4 Evaluation of response 
 
Response criteria for patients enrolled onto the study will follow the guidelines 
recommended by the1999 International Workshop on Response Criteria for NHL. 
(Cheson et al.1999) All responses will be characterized as either complete 
remission (CR), unconfirmed complete remission (CRu), partial remission (PR), 
stable disease (SD), or progression of disease (POD). 
Response will be 
assessed after every three cycles of combination therapy. 
Response will be 
assessed every 4 months thereafter while the patient receives obinutuzumab 
maintenance treatment. 
 
 
3. 
STUDYPOPULATION 
 
3.1 
INCLUSIONCRITERIA 
 
Patients must meet the following criteria for study entry: 
• A diagnosis of small lymphocytic lymphoma, follicular lymphoma (grades 1- 
3a), or marginal zone lymphoma. 
 
• Evidence of progression or lack of response following at least 1 prior 
treatment for indolent lymphoma. 
 
• Able and willing to provide written informed consent and to comply with the 
study protocol 
 
• Age ≥ 18 years 
 
• Must have at least 1 node greater than 1.5cm in short axis diameter 
 
• Adequate hematologic function (unless abnormalities are related to NHL), 
defined as follows: 
 
 Hemoglobin ≥ 9.0 g/dL 
 
 Absolute neutrophil count ≥ 1.5 × 109/L 
 
 Platelet count ≥ 75 × 109/L 
 
 ANC < 1.5 x 109 /L or PLT count less than 100 x109/L if cytopenia is due 
to extensive bone marrow involvement of disease as determined by the 
treating physician. 
 
 
• For men who are not surgically sterile, agreement to use a barrier method 
of contraception for ≥ 6 months after the last obinutuzumab dose. In addition, 
male patients must agree to request that their partners use an additional 
method of contraception, such as oral contraceptives, intrauterine device, 
barrier method of contraception or spermicidal jelly 
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• For women of reproductive potential who are not surgically sterile,  agreement 
to use two adequate methods of contraception, such as oral contraceptives, 
intrauterine device, or barrier method of contraception in conjunction with 
spermicidal jelly for ≥ 18 months after the last obinutuzumab dose. 
 
• Females of childbearing potential (FCBP)† must have a negative serum 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days 
prior to and again within 24 hours of prescribing lenalidomide and must either 
commit to continued abstinence from heterosexual intercourse or begin TWO 
acceptable methods of birth control, one highly effective method and one 
additional effective method AT THE SAME TIME, at least 4 weeks before she 
starts taking lenalidomide. FCBP must also agree to ongoing pregnancy 
testing. Men must agree to use a latex condom during sexual contact with a 
female of child bearing potential even if they have had a successful 
vasectomy. 
 
• All study participants must be registered into the mandatory Revlimid 
REMS® program, and be willing and able to comply with the requirements of 
Revlimid REMS® program. 
 
For patients with bulky disease (tumors >5cm); must be able to take aspirin 
(81mg or 325 mg) daily as prophylactic anticoagulation (patients intolerant to 
ASA may use warfarin or low molecular weight heparin. 
 
• Females of reproductive potential must adhere to the scheduled pregnancy 
testing as required in the Revlimid REMS® program. Able to take aspirin (81 
or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA 
may use warfarin or low molecular weight heparin). 
 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 
24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive 
months). 
 
 
 
3.2 
EXCLUSIONCRITERIA 
 
• 
Evidence ongoing transformation into aggressive NHL. 
 
• 
History of severe allergic or anaphylactic reactions to monoclonal antibody 
therapy 
 
• 
Known hypersensitivity to thalidomide or lenalidomide. 
 
• 
Regular treatment with corticosteroids during the 4 weeks prior to the start of 
Cycle 1, unless administered for indications other than NHL at a dose 
equivalent to ≤ 30 mg/day prednisone
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• 
History of prior malignancy within the last 5 years, with the exception of 
curatively treated basal or squamous cell carcinoma of the skin and low- 
grade in situ carcinoma of the cervix 
 
• 
Evidence or history of significant, uncontrolled concomitant diseases that 
could affect compliance with the protocol or interpretation of results, including 
significant cardiovascular disease (such as New York Heart Association 
Class III or IV cardiac disease, severe arrhythmia, myocardial infarction 
within the previous 6 months, unstable arrhythmias, or unstable angina) or 
pulmonary disease (including obstructive pulmonary disease and history of 
bronchospasm) 
 
• 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) or any major episode of infection 
requiring treatment with IV antibiotics or hospitalization (relating to the 
completion of the course of antibiotics, except if for tumor fever) within 4 weeks 
prior to the start of Cycle 1 
 
Patients with suspected active or latent tuberculosis (latent tuberculosis 
needs to be confirmed by positive Interferon-gamma release assay) 
 
• 
Vaccination with live vaccines within 28 days prior to start of treatment 
 
• 
Any of the following abnormal laboratory values (unless any of these 
abnormalities are due to underlying lymphoma): 
 
Creatinine > 1.5 times the upper limit of normal (ULN) (unless creatinine 
clearance normal), or calculated creatinine clearance < 40 mL/min 
(using Cockcroft–Gault formula; see Appendix D) 
 
AST or ALT > 2.5 × ULN 
 
Total bilirubin > 1.5× ULN (or > 3 × ULN for patients with documented 
Gilbert syndrome) 
 
Any history of hepatitis B infection. 
 
• 
Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology 
testing) 
 
Patients positive for HCV antibody are eligible only if PCR is negative for 
HCV RNA 
 
• 
Known history of HIV seropositive status 
 
• 
Positive test results for human T-lymphotropic 1 (HTLV 1) virus 
HTLV testing is required in patients from endemic countries (Japan, countries in 
the Caribbean basin, South America, Central America, sub-Saharan Africa, and 
Melanesia) 
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• 
Pregnant or lactating 
 
• 
ECOG performance status greater than 2. 
 
• 
Participation in another clinical trial with drug intervention within 21 days prior 
to start of Cycle 1 and during the study 
 
• Patients with SLL/CLL will are excluded during the phase I portion of the 
study 
 
3.3 
IMMUNIZATION DURING B-CELL DEPLETION 
 
To date, no vaccination studies have been performed with obinutuzumab. No 
vaccination with live virus vaccines should be given to patients treated with 
obinutuzumab. 
 
4. 
TREATMENT PLAN 
 
4.1 Phase I 
 
Three dose levels of lenalidomide (10 mg, 15 mg, 20 mg) will be evaluated with a 
fixed dose of obinutuzumab (1000mg) as outlined in Table 1. (obinutuzumab will 
be given in divided doses on cycle 1; 100mg IV on day 1, and 900mgIV on day 2, 
subsequent doses will be given over 1 day) Up to 18 patients may participate in 
the Phase I component of the study, depending on the level at which toxicity is 
observed. Subjects will be assigned to a dose level based on the order of study 
entry and toxicities seen in prior patients.  The dose escalation process is 
described below.  There will be no intra-patient dose escalation. 
DLT will be 
assessed during the first course of each cohort (28 days), and refers to a 
medically significant event which meets criteria using National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4. (see 
section 2.3.2) 
 
Table 1. Dose levels to be tested in phase I portion 
Dose Level 
Lenalidomide Dose (days 2- 
22 followed by 6 days of no 
therapy) 
Obinutuzumab dose 
-1 
5 mg 
1000mg IV 
1 
10 mg 
2 
15 mg 
3 
20 mg 
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4. 2 Phase II 
 
Additional pts will be enrolled into two cohorts at the recommended dose level 
(MTD) established in Phase I up to a maximum of 30 patients each in two 
independently enrolling cohorts. 
 
Cohort A: 30 patients with relapsed/refractory follicular lymphoma 
Cohort B: 30 patients follicular lymphoma, marginal zone lymphoma or SLL 
 
4. 3 Treatment Schedule 
 
Lenalidomide capsules will be taken orally daily each day on days 2 - 22, 
followed by 6 days of no therapy of each 28-day cycle. Obinutuzumab will be 
given by intravenous infusion on day 1,,2, 8, 15, and 22 of cycle one and on day 
1 of each subsequent cycle up to 6 cycles. 
Patients who do not progress 
following 6 cycles and are deriving benefit from the combination in the opinion of 
the treating physician can receive further cycles of combination up to 12 cycles of 
lenalidomide therapy. (As long as the patient does not exhibit progression, the 
decision of how many cycles of combination therapy beyond 6 is at the 
discrestion of the treating team and investigator). 
 
Extended dosing of obinutuzumab will begin after combination therapy if patients 
demonstrate at least stable disease on response assessment. In the extended 
dosing schedule, obinutuzumab will be administered every 2 months, and in the 
absence of progression, will be dosed for maximum of 30 months (combination + 
maintenance). 
 
Patients that do not have at least a partial remission following 12 cycles of 
combination therapy will not continue with extended obinutuzumab treatment. 
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TREATMENT REGIMEN 
 
 
*(GA101 will be given in divided doses on first dose in cycle 1; 100mg IV on day 
1, and 900mgIV on day 2, subsequent doses will be given over 1 day) 
 
 
 
This research study protocol allows the subject to receive up to 21 infusions of 
obinutuzumab. Even if the treatment is shown to be of benefit, additional 
infusions of obinutuzumab beyond that allowed in the protocol cannot be given 
to the subject while they are participating in this study. 
 
Visit schedule and assessments 
Screening Assessments and all on study scheduled visits and assessments are 
outlined in Table of Study Assessments. All timepoints outlined in the Schedule 
of Assessments allow variation of +/- 3 days. 
 
Due to the drug delivery from an outside facility, clinicians should allow up to 72 
hours from patient assessment/evaluation to the start of each cycle. 
 
Pregnancy testing and counseling must be performed if a subject misses her 
period or if her pregnancy test or her menstrual bleeding is abnormal. Study drug 
treatment must be discontinued during this evaluation. In addition to the required 
pregnancy testing, the Investigator must confirm with FCBP that she is  
continuing to use two reliable methods of birth control at each visit. 
 
An unscheduled visit can occur at any time during the study. Source must be 
maintained for these unscheduled visits. The date for the visit and any data 
generated must be recorded on the appropriate CRF. Source documents for 
these unscheduled visits must also be maintained. 
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At treatment discontinuation, subjects will undergo off study evaluations per the 
Schedule of Assessments, Section 2. In addition, a safety assessment will be 
done approximately 28 days post the last dose of study drug. 
 
5. 
STUDYMEDICATION 
 
5.1 
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). Genentech will provide 
obinutuzumab to investigational site as an IMP. 
 
For further details, see the obinutuzumab Investigator’s Brochure. 
 
5.1.1 
OBINUTUZUMAB DOSE AND SCHEDULE 
 
Obinutuzumab 1000mg will be given IV on day 8, 15, and 22 of cycle one and 
on day 1 of each subsequent cycle up to 6 cycles during lenalidomide dosing. 
First dose of 1000mg will be split into day 1 and 2 of cycle 1 as outlined in 
section 
5.1.4. If the patient attains at least stable disease, the patient will receive 
obinutuzumab 1000mg IV every 2 months for a maximum of 2 years. For 
dosing instructions, see section 6.2. 
 
5.1.2 
OBINUTUZUMAB   PREPARATION 
 
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. 
 
5.1.3 
OBINUTUZUMAB PRE MEDICATIONS 
 
5.1.3.1 
Obinutuzumab  Pre-medications 
 
Thirty to 60 minutes prior to all obinutuzumab infusions, the following pre- 
medications will be given (unless contraindicated): 
 
• 
Oral acetaminophen (e.g., 650−1000 mg) AND 
• 
An antihistamine such as diphenhydramine (50−100 mg) 
 
• 
For Cycle 1, prophylactic corticosteroids (e.g., 100 mg IV prednisolone) 
at least one hour prior to the obinutuzumab infusion. An equivalent 
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dose of dexamethasone (15-20mg) or methylprednisolone (80mg) is 
acceptable but hydrocortisone should not be used. 
 
In subsequent cycles, steroids should be given to patients who 
experienced a severe IRR with the prior infusion of obinutuzumab or who 
are thought to be at high risk for infusion-related reactions, as assessed 
by the investigator. 
 
 
5.1.3.2 
Tumor Lysis Syndrome Prophylaxis 
 
Patients who are considered to have a high tumor burden and who are 
considered to be at risk for tumor lysis by the investigator should additionally 
receive tumor lysis prophylaxis prior to the initiation of treatment. These 
patients should be well hydrated starting 1 to 2 days before the first dose of 
obinutuzumab. In addition, all patients considered to have high tumor burden 
and who are considered to be at risk for tumor lysis should be treated with 
allopurinol 300 mg/day orally or a suitable alternative treatment starting 12 to 
24 hours prior to treatment on Day 1 of Cycle 1. These patients should 
continue to receive repeated prophylaxis with allopurinol and adequate 
hydration prior to each subsequent infusion, if deemed appropriate by the 
investigator 
 
5.1.4 
OBINUTUZUMAB  ADMINISTRATION 
 
First Infusions 
• 
First dose of obinutuzumab will be split into two days on cycle 1. Day 
1 patient will receive 100mg, day 2 patient will receive 900mg. During 
cycle 1, rate on day 1 will be 25mg/hr over 4 hours (25ml/hr at 
1mg:1ml dilution). 
 
• 
In the absence of IRRs/hypersensitivity, the rate of the infusion on cycle 1 
day 2 will be escalated in increments of 50 mg/hr (14ml/hr) every 30 minutes 
to a maximum rate of 400 mg/hr(100ml/hr). 
 
• 
The patient will receive 1000mg of obinutuzumab for the remainder of the 
cycle 1 infusions (day 8, 15, 22) at the initial rate of 50 mg/hr (12.5 ml/hr) 
and increased by 50 mg/hr (12.5 ml/hr) increments at 30 minute intervals, 
as tolerated, to a maximum rate of 400 mg/hr (100 ml/hr). 
 
• 
If a hypersensitivity or IRR develops, the infusion should be 
temporarily interrupted or slowed down and concomitant 
medication may be administered if deemed appropriate by the 
investigator. 
 
• 
Upon the resolution of symptoms, the infusion will resume at one- 
half the previous rate (the rate being used at the time that the 
hypersensitivity or IRR occurred) and infusion-rate escalation may 
resume at the increments and intervals described above. If patient 
does not demonstrate signs of acute infusion reaction 
hypotension or shortness of breath), the patient can have IV 
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discontinued prior to 1 hour on second infusion and beyond. 
 
 
 
Second cycle and Subsequent Infusions 
• 
If a patient’s previous obinutuzumab infusion(s) in cycle 1 
 
• 
were well tolerated (defined by an absence of Grade ≥ 2 IRRs during a 
final infusion rate of ≥ 100 mg/hr (25cc/hr in standard 4mg:1ml dilution), 
subsequent infusions beginning with cycle 2 will be administered at an 
initial rate of 100 mg/hr (25ml/hr) and increased by 100-mg/hr (25ml/hr) 
increments at 30-minute intervals, as tolerated, to a maximum rate of 
400 mg/hr (100ml/hr). 
 
• 
If a hypersensitivity or IRR develops, the infusion should be temporarily 
interrupted or slowed down and concomitant medication may be 
administered if deemed appropriate by the investigator. 
 
• 
Upon the resolution of symptoms, the infusion will resume at one-half the 
previous rate (the rate being used at the time that the hypersensitivity or 
infusion-related reaction occurred) and infusion-rate escalation may resume 
at the increments and intervals described above. 
 
If the previous infusion rate was not well tolerated, as defined above, instructions 
for the first cycle infusion rate will be used. 
 
 
Table 2 
 
Administration of First and Subsequent Infusions of Obinutuzumab 
 
First Infusion (Day 1 of Cycle 1) 
Subsequent Infusions 
 
• If a reaction develops, stop or slow the 
infusion. Administer medications and 
supportive care in accordance with 
institutional guidelines. If reaction has 
resolved, resume the infusion at a 50% 
reduction in rate (i.e., 50% of rate being used 
at the time that the reaction occurred). 
 
• If the patient experienced an 
infusion-related or hypersensitivity reaction 
during the prior infusion, use full 
premedication including 100 mg 
prednisone/prednisolone (or 80mg 
methylprednisolone equivalent) (until no 
further IRR occurs), begin infusion at an 
initial rate 
of 50 mg/hour (14ml/hr) and follow 
instructions for first infusion. 
• If the patient tolerated the prior infusion 
well (defined by an absence of Grade 2 
reactions during a final infusion rate of 
≥ 100 mg/hour (25ml/hr)), begin infusion 
at a rate of 100 mg/hour (25ml/hr). 
• If no reaction occurs, increase the 
infusion rate in 100-mg/hour (25ml/hr) 
increments every 30 minutes, to a 
maximum of 400 mg/hour (100ml/hr). 
If a reaction develops, stop or slow the 
infusion. Administer medications and 
supportive care in accordance with used at 
the time that the reaction occurred). 
•  
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Obinutuzumab must be administered in a clinical (inpatient or outpatient) setting. 
Full emergency resuscitation facilities should be immediately available and patients 
should be under close supervision of the investigator at all times. For the 
management of IRRs and anaphylaxis, see Section 6.1.1. 
 
Obinutuzumab should be administered as a slow IV infusion through a dedicated 
line. IV infusion pumps should be used to control the infusion rate of 
obinutuzumab. Administration sets with polyvinyl chloride, polyurethane, or 
polyethylene as product contact surface and IV bags with polyolefine, 
polypropylene, polyvinyl chloride, or polyethylene as product contact surface are 
compatible and may be used. Do not administer as an IV push or bolus. Do not 
use an additional in-line filter because of potential adsorption. 
 
After the end of the first infusion, the IV line or central venous catheter should 
remain in place for greater than or equal to 1 hour to be able to administer IV 
drugs if necessary. If no adverse events occur after 2 hours, the IV line may be 
removed or the central venous catheter may be de accessed. 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. 
 
 
 
 
5.1.5 
OBINUTUZUMAB  STORAGE 
 
Obinutuzumab drug product should be stored at 2°C–8°C and protected from 
light. For the diluted product, chemical and physical in-use stability have been 
demonstrated at concentrations of 0.2mg/ml-20mg/mL for 24 hours at 2°C–8°C 
and at ambient temperature and ambient room lighting.  The product should be 
used immediately. If not used immediately, in-use storage times and conditions 
prior to use are the responsibility of the user and would normally not be longer 
than 24 hours at 2°C–8°C.  Obinutuzumab should not be frozen or shaken.  Mix 
gently. All transfer procedures require strict adherence to aseptic techniques. 
 
For further details, see the obinutuzumab Investigator’s Brochure. 
 
5.1.6 
OBINUTUZUMAB UNUSED OR EXPIRED DRUG 
 
All unused or expired investigational drug will be destroyed in accordance 
with institutional policies. Drug accountability records will be emailed to 
ga101-gsur@gene.com at study closure. 
 
 
5.2 
LENALIDOMIDE 
 
Lenalidomide is available in 2.5 mg, 5mg and 25 mg capsule strengths 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. The 5 mg capsule shell 
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contains gelatin, titanium dioxide and black ink. The 10 mg capsule shell contains 
gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. 
 
 
5.2.1 Lenalidomide Dose and Schedule 
 
Phase I: In the phase I portion of the study the planned dose of lenalidomide for 
patients with follicular lymphoma and marginal zone lymphoma (SLL patients not 
included in phase I portion of study) will be based upon the dose escalation table. 
(table 1)  Patients will receive an oral dose daily on days 2 – 22 followed by 6 
days rest (28 day cycle). 
 
 
Table 3. Dose levels to be tested in phase I portion 
Dose Level 
Lenalidomide Dose (days 2- 
22 followed by 6 days of no 
therapy) 
Obinutuzumab dose 
-1 
5 mg 
1000mg IV 
1 
10 mg 
2 
15 mg 
3 
20 mg 
 
 
Phase II: Lenalidomide will be administered orally at the maximum tolerated 
dose (MTD) (as defined by the Phase I portion of the study) on days 2 to 22 of a 
28 day cycle in patients with follicular lymphoma and marginal zone lymphoma. 
Patients with a diagnosis of small lymphocytic lymphoma (SLL) will begin cycle 
#1 at a maximum dose of 10 mg total daily on days 2 to 22 of a 28 day cycle. 
This dose will be escalated by 5mg with each cycle up to the MTD if no toxicity is 
encountered. (see dose modification for lenalidomide table). In the absence of 
progression or toxicity, patients will remain on lenalidomide treatment for a total 
of 6-12 months/cycles. 
 
Only one cycle of study drug will be supplied to the patient each cycle. 
 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the 
same day. If it is missed for the entire day, it should not be made up. 
 
Patients who take more than the prescribed dose of lenalidomide should be 
instructed to seek emergency medical care if needed and contact study staff 
immediately. Subjects experiencing adverse events may need study treatment 
modifications. See Tables 6 and 7. 
 
Supplier 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at 
no charge through the Revlimid REMS® program. 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 
Celgene’s Revlimid REMS® program. 
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Dosage form 
Lenalidomide will be supplied as capsules for oral administration. The capsules 
are available in 2.5 mg, 5mg and 25mg capsule strengths. 
 
Packaging 
Lenalidomide will be shipped directly to the patient. Bottles will contain a 
sufficient number of capsules for one cycle of dosing. 
 
 
 
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight 
and protected from excessive heat and cold. 
 
Unused or Expired Drug 
All unused or expired investigational drug will be destroyed in accordance with 
institutional policies. Drug accountability records will be emailed to ga101- 
gsur@gene.com at study closure. 
 
Lenalidomide Prescribing Information 
 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of 
their participation in this trial at no charge to them or their insurance providers. 
Lenalidomide will be provided in accordance with the 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 Celgene’s Revlimid REMS® program. Prescriptions must 
be filled within 7 days. Only enough lenalidomide for one cycle of therapy   
will be supplied to the patient each cycle. 
 
Special Handling Instructions 
Women of childbearing potential should not handle or administer the clinical 
dosage forms unless they are wearing gloves. 
 
 
 
6. 
DOSE MODIFICATION/TOXICITY MANAGEMENT 
 
A number of measures will be taken to ensure the safety of patients participating 
in this study. These measures will be addressed through exclusion criteria (see 
Section 3.2) and routine monitoring as follows. 
 
Patients enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and during their participation in this study. Safety 
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evaluations will consist of medical interviews, recording of adverse events, 
physical examinations, blood pressure, and laboratory measurements. Subjects 
will be evaluated for adverse events (all grades for phase I section; for phase II 
portion of study: and all grades for non-hematologic events, grade 3 and 4 only 
for laboratory abnormalities.), serious adverse events, and adverse events 
requiring study drug interruption or discontinuation at each study visit for the 
duration of their participation in the study. 
 
 
 
6.1 
OBINUTUZUMAB 
 
The dose of obinutuzumab generally remains constant throughout the trial. 
Obinutuzumab infusion should be interrupted for severe reactions, e.g., rapid 
tumor lysis.  Treatment of infusion-related symptoms with diphenhydramine and 
acetaminophen is recommended. Additional treatment with bronchodilators or IV 
saline may be indicated.  Epinephrine, antihistamines, and corticosteroids should 
be available for immediate use in the event of a hypersensitivity reaction to 
obinutuzumab (e.g., anaphylaxis). In most cases, the infusion must be resumed 
at no greater than 50% of initial rate (e.g., from 100mg/hr to 50mg/hr) when 
symptoms and laboratory abnormalities have completely resolved. 
Obinutuzumab can be resumed on the following day if infusion reaction 
prevented full delivery on day 1. 
 
Infusions should be discontinued in the event of serious or life-threatening 
cardiac arrhythmias. Subjects who develop clinically significant arrhythmias 
should undergo cardiac monitoring during and after subsequent infusions. 
 
Carriers of hepatitis B and patients with a history of hepatitis B infection or 
positive serology should be excluded from clinical trials except in situations 
where the potential benefit is determined to justify the risk of possible hepatitis B 
reactivation, which can be fatal. Patients with positive serology should have viral 
DNA levels checked and a gastrointestinal consultation obtained. If treated with 
obinutuzumab, such patients should be closely monitored for clinical and 
laboratory signs of active HBV infection and for signs of hepatitis throughout their 
study participation. 
 
6.1.1 
MANAGEMENT OF INFUSION-RELATED REACTIONS AND 
ANAPHYLAXIS 
 
Medications (including epinephrine for subcutaneous injections, corticosteroids, 
diphenhydramine hydrochloride for IV injection) and resuscitation equipment 
should be available for immediate use at point of infusion. Management of 
infusion-related symptoms for obinutuzumab is summarized in Table 4. 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 and 
no additional drug should be administered. Patients who experience any of these 
reactions should receive aggressive symptomatic treatment and will be 
discontinued from study treatment. 
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Patients who experience obinutuzumab -associated, infusion-related temperature 
elevations of > 38.5°C or other minor infusion-related symptoms may be treated 
symptomatically with acetaminophen (≥ 500 mg) and/or H1- and 
H2-histamine–receptor antagonists (e.g., diphenhydramine hydrochloride, 
ranitidine).  Serious infusion-related events, manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress, should be managed with additional supportive therapies (e.g., 
supplemental oxygen, β2-agonists, epinephrine, and/or corticosteroids) 
as clinically indicated according to standard clinical practice. 
 
Table 4 
 
Guidelines for Management of Infusion-Related Symptoms Related to 
Obinutuzumab 
 
Infusion-Related Symptoms a 
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 at the investigator's discretion. c 
• 
If the same adverse event recurs with the same severity, 
treatment must be permanently discontinued. 
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. This table does not refer to management of immunoglobulin 
E−mediated allergic reactions, which should be managed as directed in Section 6.1.1. 
b Supportive treatment: Patients should be treated with acetaminophen and an antihistamine 
such as diphenhydramine hydrochloride if they have not been received in the last 4 hours. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, patients may 
require antihistamines, oxygen, corticosteroids (e.g., 100 mg of intravenous prednisolone or 
equivalent), and/or bronchodilators. For hypotension, patients may require vasopressors. 
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 50 mg/hr  
every 30 minutes to a maximum rate of 400 mg/hr. 
 
 
 
6.1.2 
MANAGEMENT OF TUMOR LYSIS SYNDROME 
 
For patients with evidence of TLS, obinutuzumab should be discontinued and the 
patients treated as clinically indicated.  Following the complete resolution of    
TLS complications, obinutuzumab may be re-administered at the full dose during 
the next infusion in conjunction with prophylactic therapy as indicated (see 
Section 5.1.3.2). 
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6.1.3 
CARDIOTOXICITY 
 
Infusions should be discontinued in the event of serious or life-threatening 
cardiac arrhythmias. Patients who develop clinically significant arrhythmias 
should undergo cardiac monitoring during and after subsequent infusion of 
obinutuzumab. Patients with preexisting cardiac conditions, including 
arrhythmias and angina, who have had recurrences of these events during 
obinutuzumab therapy should be monitored throughout the infusion and 
immediate post-infusion period. 
 
6.1.4 
HEPATITIS B VIRUS REACTIVATION 
 
Patients with a history of hepatitis B infection will be excluded from study. 
 
6.1.5 
DOSAGE MODIFICATION DURING MAINTENANCE THERAPY WITH 
OBINUTUZUMAB 
 
6.1.5.1 
NonhematologicToxicities 
 
For Grade ≥ 2 nonhematologic toxicities related to obinutuzumab, treatment with 
obinutuzumab will be delayed for a maximum of 3 weeks until resolution to Grade 
≤ 1 or baseline (see Table 4). Resumption of dosing without complete resolution 
of toxicity may be considered only upon careful weighing of the risks and benefits 
to the patient by the investigator. It is recommended that cycles be delayed in 1 
week increments. If treatment is delayed for more than 3 weeks, study treatment 
will be discontinued. 
 
There will be no dose reductions of obinutuzumab. 
 
 
6.1.5.2 
Hematologic Toxicity 
 
Note that lymphopenia is not considered to be a hematologic toxicity, because it is 
an expected outcome of therapy. 
 
For Grade ≥ 3 hematologic toxicities (defined as neutropenia, anemia, or 
thrombocytopenia), treatment with obinutuzumab will be delayed for a 
maximum of 3 weeks until resolution to Grade ≤ 2 (see Table 5). Resumption of 
dosing without complete resolution of toxicity may be considered only upon 
careful weighing of the risks and benefits to the patient by the investigator. It is 
recommended that cycles be delayed in 1-week increments. If treatment is 
delayed for more than 3 weeks, study treatment will be discontinued. 
 
There will be no dose reductions of obinutuzumab. 
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Table 5 
Guidelines for Dose Delay or Modification of Obinutuzumab 
during Maintenance Therapy 
 
Event 
Dose Delay or Modification 
Grade 2, 3, or 4 
• 
Delay doses of obinutuzumab for a maximum of 3 weeks. 
nonhematologic 
• 
If improvement to Grade ≤ 1 or baseline, administer full dose of 
toxicity a 
obinutuzumab. 
Grade 1 
• 
No dose reduction or delay. 
nonhematologic 
toxicity a 
Grade 3 or 4 
• 
Delay doses of obinutuzumab for a maximum of 3 weeks. 
hematologic toxicity 
• 
Administer myeloid growth factors for neutropenia. 
• 
Administer RBCs or platelets as required. 
• 
If improvement to Grade ≤ 2, administer full dose of obinutuzumab. 
Grade 1 or 2 
• 
No dose reduction or delay. 
hematologic toxicity 
RBC = red blood cell. 
a   For tumor lysis syndrome or hepatitis B virus reactivation, Section 6.1.2 or 6.1.4, respectively. 
b    Dose delays and interruptions will only occur of toxicity is felt to be related to 
obinutuzumab per the investigator or treating physician. 
 
6.1.6 Dosage Modification During combination Therapy 
For Grade ≥ 3 nonhematologic toxicities felt to be related to obinutuzumab by the investigator  
or treating physician, treatment with obinutuzumab will be delayed until resolution to Grade ≤ 1 
or baseline. Resumption of dosing without complete resolution of toxicity may be considered 
only upon careful weighing of the risks and benefits to the patient by the investigator. 
 
For Grade ≥ 3 hematologic toxicities (defined as neutropenia, anemia, or thrombocytopenia), 
treatment with obinutuzumab will be delayed until resolution to Grade ≤ 2. Resumption of 
dosing without complete resolution of toxicity may be considered only upon careful weighing of 
the risks and benefits to the patient by the investigator. 
 
Note that lymphopenia is not considered to be a hematologic toxicity, because it is an expected 
outcome of therapy. 
 
There will be no dose reductions of obinutuzumab. 
 
If a toxicity, hematologic or non‐hematologic is felt to be due to either lenalidomide or 
obinatuzumab, patients safety is considered paramount and either drug can be held at the 
investigator or treating physicians discretion until the investigator or treating physician feel the 
causal agent can be restarted safely. In cases of medication hold per physician, redosing must 
meet all criteria for restarting new cycle (section 6.2.2). 
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6.2 
DOSE MODIFICATION: LENALIDOMIDE 
 
Subjects will be evaluated for AEs at each visit with the NCI CTCAE v4.0, see 
below for full instruction on initiation of a new cycle of therapy and dose 
modifications during a cycle of therapy. 
 
Table 6, 7 Lenalidomide dose adjustment steps 
 
Table 6: LENALIDOMIDE Dose Adjustment Steps 
Starting Dose 
MTD mg daily for 21 days every 28 days 
Dose Level –1 
MTD -5 mg daily for 21 days every 28 days 
Dose Level –2 
MTD -10 mg daily for 21 days every 28 days 
Dose Level –3 
MTD-15 mg daily for 21 days every 28 days 
 
 
Table 7: LENALIDOMIDE Dose Adjustment Steps in SLL 
Starting Dose 
MTD or max of 10 mg daily for 21 days every 28 days 
Dose level +1 
Starting dose +5 mg daily for 21 days every 28 days 
Dose level +2 
Starting dose +10mg daily for 21 days every 28 days 
Dose level +3 
Starting dose +15mg daily for 21 days every 28 days 
Dose level -1 
Starting dose -5 mg daily for 21 days every 28 days 
Dose level -2 
Starting dose -10 mg daily for 21 days every 28 days 
Dose level -3 
Starting dose -15mg daily for 21 days every 28 days 
The minimum dose level is 15mg below MTD or 5mg daily for 21 days, 
(whichever is higher). 
Patients who cannot tolerate or require dose reduction 
below 5mg daily lenalidomide will not receive further doses of lenalidomide.
 
I
f the patient is attaining clinical benefit in the opinion of the treating physician, 
and has attained at least a partial response, obinutuzumab dosing will continue 
per study design to a maximum of 21 doses. 
 
The starting dose will be predefined during the phase I portion of the study based 
upon cohort (see Table 2). In the phase II portion of the study, the starting dose 
will be the maximum tolerated dose as defined by phase I portion. 
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6.2.1 
INSTRUCTIONS FOR LENALIDOMIDE DOSE MODIFICATIONS OR INTERRUPTION 
DURING A CYCLE. 
 
Table 8: Dose Modification for Lenalidomide 
NCI CTC Toxicity Grade 
Day 2-14 of Cycle 
≥Day 15 of Cycle 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia 
• 
Hold (interrupt dose). 
• 
Follow CBC weekly. 
• 
If neutropenia has resolved to ≤ 
grade 2 restart at next lower dose 
level and continue the cycle until 
Day 21. 
• 
Omit lenalidomide for 
remainder of cycle 
If neutropenia is the only 
toxicity for which a dose 
reduction is required. G-CSF 
may be used and the dose 
maintained for the next cycle at 
the investigators discretion. 
Thrombocytopenia 
≥Grade 3 (platelet count 
< 50,000/mm³) 
• 
Hold (interrupt dose). 
• 
Follow CBC weekly. 
• 
If thrombocytopenia resolves to ≤ 
grade 2 restart at next lower dose 
level and continue the cycle until 
Day 21. 
• 
Omit lenalidomide for 
remainder of cycle 
Erythema multiforme ≥ 
Grade 3 
• 
Discontinue lenalidomide study 
drug. 
• 
Discontinue 
lenalidomide study 
drug. 
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Sinus bradycardia/ 
other cardiac 
arrhythmia 
Grade 2 
≥ Grade 3 
• 
Hold (interrupt) dose. Follow at 
least weekly. 
• 
If the toxicity resolves to ≤ grade 1 
prior to Day 21 restart at next lower 
dose level and continue the cycle 
until Day 21. 
• 
Discontinue lenalidomide study 
drug. 
• 
Omit lenalidomide for 
the remainder of the 
cycle. 
• 
Discontinue 
lenalidomide study 
drug. 
Dose 
Allergic reaction or 
hypersensitivity 
Grade 2-3 
Grade 4 
• 
Hold (interrupt) dose. Follow at 
least weekly. 
• 
If the toxicity resolves to ≤ grade 1 
prior to Day 21 restart at next lower 
dose level and continue the cycle 
until Day 21. 
• 
Discontinue lenalidomide study 
drug. 
• 
Omit lenalidomide for 
the remainder of the 
cycle. 
• 
Discontinue 
lenalidomide study 
drug 
Venous 
thrombosis/embolism 
≥ Grade 3 
• 
Hold (interrupt) dose and start 
anticoagulation; restart at 
investigator’s discretion (maintain 
dose level). 
• 
Omit lenalidomide for 
remainder of cycle. 
Anticoagulation 
measures as 
described in 
Conncomitant therapy 
section below. 
other non-hematologic 
toxicity assessed as 
Lenalidomide-related ≥ 
Grade 3 
• 
Hold (interrupt) dose. Follow at 
least weekly. 
• 
If the toxicity resolves to ≤ grade 2 
prior to Day 21 restart at next lower 
dose level and continue the cycle 
until Day 21. 
• 
Omit lenalidomide for 
remainder of cycle. 
• 
Initiate appropriate supportive 
care, restart lenalidomide  
next cycle (decrease by one 
dose level) 
Hyperthyroidism or 
hypothyroidism 
• 
Omit lenalidomide for remainder of 
cycle, evaluate etiology, and initiate
• 
Omit lenalidomide for 
remainder of cycle,
appropriate therapy. Restart 
lenalidomide next cycle (decrease 
dose by one dose level). 
evaluate etiology, and 
initiate appropriate 
therapy. Restart 
lenalidomide next 
cycle (decrease dose 
by one dose level). 
adjustments/intervention: lenalidomide associated rash: 
 
 
Grade 
1‐2 
• 
 
 
Day 2‐14 of Cycle 
Startsupportive 
• 
 
 
Day ≥ 15 of Cycle 
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measures if grade 2 
measures if grade 2 
• 
No dose adjustment 
• 
No dose adjustment 
Non‐blisteringrash 
• 
Hold (interrupt) dose. 
• 
Omit lenalidomide for 
Grade 3 
• 
Startsupportive 
measures. 
• 
remainder of cycle. 
Startsupportive 
• 
Evaluate weekly 
measures. 
• 
If rash resolves to ≤ 
• 
Evaluate weekly until 
grade 1 prior to day 21 
restart at dose level ‐1 
• 
rash ≤ grade 1. 
Restart next cycle at 
and continue to Day 
dose level ‐1. 
21. 
• 
Restart next cycle at 
dose level ‐1. 
Grade 4* 
• 
Discontinue 
• 
Discontinue 
lenalidomide 
lenalidomide 
• 
Dermatology 
• 
Dermatology 
evaluation 
evaluation 
• 
Startsupportive 
• 
Startsupportive 
Desquamating(blistering) 
• 
measures 
Discontinue 
• 
measures 
Discontinue 
rash 
lenalidomide 
lenalidomide 
Any Grade* 
• 
Dermatology 
• 
Dermatology 
• 
evaluation 
Startsupportive 
• 
evaluation 
Startsupportive 
measures 
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Suggested supportive measures : 
 
1. Initiate daily oral antihistamines 
Examples 
 
• Loratine 10mg PO daily 
• Ceterizine 10mg PO daily 
• Diphenhydramine 25mg PO daily 
2. Short-course low-dose oral steroids 
Example 
 
• Prednisone 10mg PO x 3 days 
• Hydrocortisone 20mg PO QAM, 10mg PO QPM x 3 days 
 
 
 
6.2.2 Instruction for initiation of a New Cycle 
 
 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
 
• The ANC is ≥ 1,000/μL; 
• The platelet count is ≥ 50,000/μL; 
• Any study drug-related allergic reaction/hypersensitivity or sinus bradycardia/ 
other cardiac arrhythmia adverse event that may have occurred has resolved to ≤ 
grade 1 severity; 
• Any other study drug-related adverse event that may have occurred has 
resolved to ≤ grade 2 severity. 
 
If these conditions are not met on Day 1 of a new cycle, the subject will be 
evaluated weekly and a new cycle of the combination will not be initiated until the 
toxicity has resolved as described above. If lenalidomide dosing was halted 
during the previous cycle and was restarted with a one-level dose reduction 
without requiring an interruption for the remainder of the cycle, then that reduced 
dose level will be initiated on Day 1 of the new cycle. 
 
If lenalidomide dosing was omitted for greater than 15 days of the previous 
cycle or if the new cycle is delayed more than 7 days due to toxicity   
noted on the scheduled Day 1, then the new cycle will be started with a one- 
level dose reduction. 
 
 
 
Treatmentcompliance 
 
Subjects will be asked to maintain a diary to record the drug administration. 
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6.3 
CONCOMITANT  THERAPY 
 
Anti-cancer therapies, including chemotherapy, chemoimmunotherapy, radiation, 
thalidomide, or any other investigational agents is not permitted while subjects 
are receiving study drug during the treatment phase of the study. 
 
 
Patients can receive sargramostim (G-CSF) as treatment for grade 3 or greater 
neutropenia at the treating physicians discretion. Prophylactic growth factor is 
not permitted. 
 
 
It is recommended that patients who are at high risk for a initial or recurrent 
thromboembolic event (high risk is defined as history of a thromboembolic event 
and/or taking a concomitant medication associated with an increased risk for a 
thromboembolic event and/or a known hypercoagulable state regardless of 
thromboembolic history) receive prophylactic aspirin (70 – 325 mg) 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 subject’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. 
 
 
 
 
6.4 
DISCONTINUATION OF STUDY TREATMENT 
 
 
 
Follow-Up 
 
Subjects who discontinue treatment, will be followed for a minimum of 6 months. 
Patients who die or withdraw consent will not be followed beyond the date of the 
death or withdrawal of consent. Patients who start alternative therapy will not be 
followed beyond initiation of next line therapy except for survival. All other 
patients that remain on study (ie completion of therapy, or drug interruption due to 
toxicity) will be followed with tumor lesion assessments, imaging, and survival per 
the schedule of assessments, Section 2.1. Subjects will undergo a safety 
assessment approximately 28 days post the last dose of study drug. In addition, 
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off study evaluations, such as recording subsequent therapy, per the Schedule of 
Assessments will be done. Following completion of chemotherapy, patients will be 
evaluated every 3 months for one year, then every 6 months for a total of 2 years 
following completion of therapy with CT of neck, thorax, abdomen and pelvis and 
other studies as recommend by the treating physician. 
 
7. 
CRITERIA FOR SUBJECT DISCONTINUATION 
 
7.1 
OBINUTUZUMAB-SPECIFIC CRITERIA 
 
Subjects who meet the following criteria should be discontinued from the study: 
 
• 
• 
Active HBV infection or hepatitis 
Severe or life-threatening anaphylaxis or hypersensitivity reaction 
7.2 
GENERALCRITERIA 
• Inability of subject to comply with study requirements 
• Determination by the investigator that it is no longer safe for the 
subject to continue therapy 
8. 
CRITERIA FOR STUDY DISCONTINUATION 
Treatment will continue for six cycles of combination therapy and 12 cycles (2 
years) of maintenance obinutuzumab as per study design, or until the occurrence 
of any of the following events. 
 
Treatment with study drug is to be discontinued when any of  the following 
occurs: 
 
• Lack of therapeutic effect 
 
• Adverse event(s) that, in the judgment of the Investigator, may cause 
severe or permanent harm or which rule out continuation of study drug. 
 
• Major violation of the study protocol. 
 
• Withdrawal of consent 
 
• Lost to follow up 
 
• Death 
 
• Suspected pregnancy 
 
 
 
 
9. 
CLINICAL AND LABORATORY EVALUATIONS 
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9.1 
PRETREATMENT EVALUATIONS 
 
Please see schedule of study assessments for screening evaluations (section 
2.1). Screening evaluation will be performed within 30 days of study entry. In 
the absence of a history of blood transfusion or intravenous drug use in the past 
6 months, patients can have hepatitis B/C and HIV testing up to 8 weeks prior 
to study entry. 
 
 
 
9.2 
EVALUATIONS DURING TREATMENT 
 
Patients will undergo tumor response assessment including a CT scan of the 
neck, chest, abdomen, and pelvis, physical exam, and basic laboratory panel 
during screening, after 3 and 6, 9 and 12 cycles of combination teatment, and 
every 4 months during maintenance phase with obinutuzumab. 
 
9.3 
POST-TREATMENT EVALUATIONS 
 
Subjects who discontinue treatment for any reason, other than completion of 
therapy, will be followed for a minimum of 6 months from last dose of drug. 
Subjects will undergo a safety assessment approximately 28 days post the last 
dose of study drug. In addition, off study evaluations, such as recording 
subsequent therapy, per the Schedule of Assessments will be done. Following 
completion of chemotherapy, patients will be evaluated every 3 months for one 
year, every 6 months for 1 year and then yearly with CT of neck, thorax, 
abdomen and pelvis and other studies as recommend by the treating physician. 
When patient starts alternative treatment for lymphoma, they will no longer be 
followed pre protocol. 
 
 
 
10. 
EVALUATION OF RESPONSE 
 
 
Response criteria for patients enrolled onto the study will follow the guidelines 
recommended by the1999 International Workshop on Response Criteria for NHL 
(Cheson et al.1999) All responses will be characterized as either complete 
remission (CR), unconfirmed complete remission (CRu), partial remission (PR), 
stable disease (SD), or progression of disease (POD). 
Response will be 
assessed after every three cycles of therapy and at the completion of 
lenalidomide treatment. Response will be assessed every 4 months thereafter 
while the patient receives obinutuzumab. 
 
 
 
 
 
 
 
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11. 
STATISTICAL  CONSIDERATIONS 
 
This is a single-center, open label, phase I/II study in patients with refractory or 
relapsed indolent lymphoma.  The feasibility of administrating lenalidomide in 
combination with obinutuzumab and the MTD of the combination will be 
determined in the phase I part of the study. When the MTD has been 
established, the efficacy of the combination will be further evaluated in the phase 
II part of the study in two patient cohorts simultaneously. The two patient cohorts 
are the patients with follicular lymphoma (grade 1-3a) and the patients with either 
follicular lymphoma, marginal zone lymphoma, or SLL. A maximum of 72 
patients (18 in phase I and 60 in phase II (30 patients each cohort); the patients 
treated at the MTD in phase I will be counted as the first group of patients treated 
in phase II) will be enrolled in this study on an intent-to-treat basis. 
 
 
11.1 
STATISTICAL/STUDY  DESIGN 
 
 
11.1.1 Phase I 
 
The primary objective of the phase I part of the study is to determine the 
maximum tolerated dose (MTD) of lenalidomide when given in combination 
with obinutuzumab for subsequent testing in the phase II part of the trial. 
There are three predefined dose levels for lenalidomide (10 mg, 15 mg, 20 
mg) with a fixed dose of obinutuzumab (1000mg) as outlined in Table 2. 
 
 
Dose limiting toxicity (DLT) will be assessed during the first course of each cohort 
(28 days), and refers to a medically significant event which meets one of the 
following criteria using National Cancer Institute Common Terminology Criteria  
for Adverse Events (NCI CTCAE) version 4: 
 
 
• Grade 3 or higher non-hematologic AE which is felt to be related to 
the study drug by the investigator with the exception of the 
following: 
• Transient grade 3 or more infusion reaction that completely 
resolves within 24 hours. 
• Grade 4 hematologic toxicity (Platelet count is defined as <25,000 
for the purposes of determining DLT. 
• Grade 3 neutropenia with elevated temperature (defined as >/= 
101 degrees F to be confirmed on two occasions). 
• 
Grade 3 thrombocytopenia with bleeding. 
• Treatment delay of greater than 2 weeks due to treatment related 
toxicity. 
 
The target rate of DLT is 30%.  The standard ‘3+3’ design will be used. 
Applying the 3+3 design, the first cohort of 3 patients will be treated at dose 
level 1 and evaluated at the end of 28 days.  The algorithm is as follows: (1) 
If 0 out of 3 patients experiences DLT, the next cohort of 3 patients will be 
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treated at the next higher dose level. (2) If 1 out of 3 patients develop DLT, 
additional 3 patients will be treated at the same dose level. If no more DLT 
develops at the dose, i.e. 1 out of a total of 6 patients develops DLT, the 
dose escalation continues for the next cohort of 3 patients. (3) At any given 
dose, if greater than 1 out 3 patients or 1 out of 6 patients experience DLT, 
the dose level exceeds the MTD and 3 more patients will be treated at the 
next lower dose if there are less than 6 patients already treated at that 
dose. Following the above scheme, MTD is defined as the highest dose 
level in which 6 patients have been treated with less than 2 instances of 
DLT. Given 3 dose levels, it is anticipated that up to 18 eligible patients are 
required for the phase I part of the study. 
Safety parameters and DLTs will be summarized and listed by each dose level. 
Prior to advancing/changing dose levels a cohort summary will be completed and 
submitted to the Clinical Research Monitor in the IND Office. 
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11.1.2 Phase II 
 
The primary objective for the phase II part is to further evaluate the safety and 
efficacy of lenalidomide when given in combination with obinutuzumab at the 
MTD of lenalidomide determined in phase I. The maximum number of patients 
that will be recruited for the phase II part is 60 (include additional 54 and the 6 
patients treated at the MTD in phase I) with 30 for each of the two patient 
cohorts: the patients with follicular lymphoma (grade 1-3a) and the patients with 
either follicular lymphoma, marginal zone lymphoma or SLL. The patients who 
are treated at the MTD in the phase I part will be included in phase II (in relevant 
cohort). The objective response (complete response + partial response) after 6 
cycles and DLT after 1 cycle will be monitored simultaneously using the Bayesian 
approach of Thall, Simon, Estey (1995, 1996) as extended by Thall and Sung 
(1998). 
 
Cohort A: Patients with Follicular lymphoma 
 
Historical data on 43 patients (Witzig, 2009) with relapsed or refractory indolent 
non-Hodgkin’s lymphoma treated with lenalidomide show an objective response 
(OR) rate of 23% and DLT rate of under 30%. Independence was assumed 
between OR and DLT.  It is expected for the current trial that the two-drug 
combination will improve the OR rate by 20% to 43% while the DLT rate is 
maintained at or below 30%. A sample size of 30 patients ensures that, if the  
trial is not terminated early, a posterior 90% credible interval for OR rate will have 
width of 0.283 at most, under the assumption of a 43% of OR rate. We will claim 
that the regimen is worth of further investigation if the lower limit of the posterior 
90% credible interval for OR rate is higher than 0.23. The probabilities of OR 
and DLT for the historical data are modeled by beta distributions (Beta (9.89, 
33.11) and Beta (12.9, 30.1), respectively). The prior probabilities of OR and 
DLT for the experimental regimen are also modeled by beta distributions (Beta 
(0.46, 1.54) and Beta (0.6, 1.4), respectively), which have the same means as  
the corresponding beta distributions for the historical data. 
 
Denoting the historical probabilities of objective response rate and DLT rate by 
{p(OR,H) , p(DLT,H)}, the following decision criteria will be applied: 
 
1) Let E correspond to the experimental treatment, stop if 
Prob{p(OR,H) + δOR > p(OR,E) | data} > 0.95, where δCR =0.20 
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2) Stop if Prob{p(DLT,H) + δTOX < p(DLT,E)| data}>0.95, where δDLT =0 
 
Patients will be monitored in cohorts of 10 according to the following stopping 
boundaries for overall response and toxicity. 
Number of patients 
evaluated 
Recommend stopping if ≤ 
OR observed 
Recommend stopping if 
≥ DLT observed 
10 
1 
7 
20 
4 
11 
30 
7 
15 
 
The operating characteristics are summarized in the following table (based on 
simulations from 10,000 trials). 
True DLT Rate 
True OR Rate 
Prob(stop the trial early) 
0.10 
0.13 
0.9047 
0.23 
0.5420 
0.33 
0.2014 
0.43 
0.0491 
0.53 
0.0082 
0.20 
0.13 
0.9048 
0.23 
0.5426 
0.33 
0.2025 
0.43 
0.0503 
0.53 
0.0095 
0.30 
0.13 
0.9069 
0.23 
0.5528 
0.33 
0.2203 
0.43 
0.0715 
0.53 
0.0316 
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0.40 
0.13 
0.9186 
0.23 
0.6087 
0.33 
0.3177 
0.43 
0.1875 
0.53 
0.1526 
0.50 
0.13 
0.9461 
0.23 
0.7410 
0.33 
0.5485 
0.43 
0.4623 
0.53 
0.4392 
 
 
 
 
Cohort B: Patients with follicular lymphoma, marginal zone lymphoma or small 
lymphocytic lymphoma. 
 
Historical data on 44 patients (Ferrajoli, 2008) with relapsed or refractory chronic 
lymphocytic leukemia treated with lenalidomide show an objective response (OR) 
rate about 30% and DLT rate of under 30%. Independence was assumed 
between OR and DLT.  It is expected for the current trial that the two-drug 
combination will improve the OR rate by 20% to 50% while the DLT rate is 
maintained at or below 30%. A sample size of 30 patients ensures that, if the  
trial is not terminated early, a posterior 90% credible interval for objective 
response rate will have width of 0.287 at most, under the assumption of a 50% of 
objective response rate. We will claim that the regimen is worth of further 
investigation if the lower limit of the posterior 90% credible interval for OR rate is 
higher than 0.30. The probabilities of OR and DLT for the historical data are both 
modeled by beta distributions (Beta (13.2, 30.8)) since the historical rates are 
same for both. The prior probabilities of OR and DLT for the experimental 
regimen are then also modeled by beta distributions (Beta (0.6, 1.4)), which have 
the same mean as the corresponding beta distribution for the historical data. 
 
Denoting the historical probabilities of objective response rate and DLT rate by 
{p(OR,H) , p(DLT,H)}, the following decision criteria will be applied: 
 
1) Let E correspond to the experimental treatment, stop if 
Prob{p(OR,H) + δOR > p(OR,E) | data} > 0.95, where δCR =0.2 
2) Stop if Prob{p(DLT,H) + δDLT < p(DLT,E)| data}>0.95, where δDLT =0 
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Patients will be monitored in cohorts of 10 according to the following stopping 
boundaries for overall response and DLT. 
Number of patients 
evaluated 
Recommend stopping if ≤ 
OR observed 
Recommend stopping if 
≥ DLT observed 
10 
2 
7 
20 
6 
11 
30 
9 
15 
 
The operating characteristics are summarized in the following table (based on 
simulations from 10,000 trials). 
True DLT Rate 
True OR Rate 
Prob(stop the trial early) 
0.10 
0.30 
0.6491 
0.40 
0.3014 
0.50 
0.0889 
0.60 
0.0164 
0.70 
0.0018 
0.20 
0.30 
0.6496 
0.40 
0.3023 
0.50 
0.0901 
0.60 
0.0176 
0.70 
0.0031 
0.30 
0.30 
0.6574 
0.40 
0.3179 
0.50 
0.1104 
0.60 
0.0395 
0.70 
0.0253 
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0.40 
0.30 
0.7002 
0.40 
0.4031 
0.50 
0.2216 
0.60 
0.1596 
0.70 
0.1471 
0.50 
0.30 
0.8016 
0.40 
0.6050 
0.50 
0.4848 
0.60 
0.4438 
0.70 
0.4355 
 
 
 
 
11.2 Analysis Plans 
Phase I: 
Toxicity type and severity by dose level will be summarized using frequency 
tables. 
 
 
 
Phase II: 
The analysis for phase II will include the patients who are treated at the MTD in 
phase I. 
Toxicity type and severity will be summarized for each patient cohort using 
frequency tables. 
Summary statistics will be provided for continuous variables. Frequency tables 
will be used to summarize categorical variables. The overall response rate for 
each patient cohort will be calculated and the Clopper Pearson confidence 
interval will be provided. Chi square test or Fisher’s exact test will be used to 
evaluate the association between patient prognostic factor and response. The 
distribution of time-to-event endpoints including overall survival and progression 
free survival will be estimated using the method of Kaplan and Meier. 
Comparison of time-to-event endpoints by important subgroups will be made 
using the log-rank test. 
For the toxicity endpoint, per-treated analysis will be performed to include any 
patient who received the treatment regardless of the eligibility nor the duration or 
dose of the treatment received. For the efficacy endpoints, intend-to-treat 
analysis will be applied to the eligible patients. 
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12. 
REPORTING OF ADVERSE EVENTS 
 
12.1 
ASSESSMENT OF SAFETY 
 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) per protocol. This includes all events of death, and any 
study specific issue of concern. 
 
 
 
12.1.1 
ADVERSEEVENTS 
 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other 
protocol-imposed intervention, regardless of attribution. 
 
This includes the following:AEs not previously observed in the subject that 
emerge during the protocol-specified AE reporting period, including signs or 
symptoms associated with non-Hodgkin’s 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. 
 
12.1.2 
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 
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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. 
• 
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 timeline 
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. 
 
  
 
 
 
 
 
12.2 
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 FDA, 
appropriate IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND 
Safety Reports). 
 
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12.2.1 
ADVERSE EVENT REPORTING PERIOD 
 
The study period during which all AEs and SAEs must be reported begins after the 
first protocol intervention. 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. 
 
12.2.2 
ASSESSMENT OF ADVERSE EVENTS 
 
All AEs and SAEs whether volunteered by the subject, 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} (see 
following guidance), and actions taken. 
 
The Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for 
each event for all subjects enrolled on the trial. 
 
To ensure consistency of AE and SAE causality/attribution assessments, 
investigators should apply the following general guideline: 
 
 
           Attribution - 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). 
 
Expected adverse events are those adverse events that are listed or 
characterized in the Package Insert or current Investigator Brochure. 
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or 
current Investigator Brochure (I.B.) or not identified. This includes adverse events 
for which the specificity or severity is not consistent with the description in the P.I. 
or I.B. For example, under this definition, hepatic necrosis would be unexpected 
if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
Protocol specific data and adverse events will be entered into PDMS/CORE. 
PDMS/CORE will be used as the electronic case report form for this protocol. 
 
 
 
12.3 
PROCEDURES FOR ELICITING, RECORDING, AND 
REPORTING ADVERSE EVENTS 
 
12.3.1 
ELICITING ADVERSE EVENTS 
 
A consistent methodology for eliciting AEs at all subject evaluation time points 
should be adopted. Examples of non-directive questions include: 
 
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• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last here?” 
 
12.3.2 
SPECIFIC INSTRUCTIONS FOR RECORDING AES 
 
Investigators should use correct medical terminology/concepts when reporting 
AEs or SAEs. Avoid colloquialisms and abbreviations. 
 
a. Diagnosis vs. 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. 
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b. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 12.2.1), 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”. 
 
c. 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”). 
 
d. 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 subject 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 subject 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. 
The severity of the adverse events (AEs) will be graded according to the U.S. 
Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), Version 
4.0.  
 
Events not included in the NCI CTCAE will be scored as follows: 
• 
Grade 1: Mild: discomfort present with no disruption of daily activity, no 
treatment required beyond prophylaxis. 
• 
Grade 2: Moderate: discomfort present with some disruption of daily activity, 
require treatment. 
• 
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding 
to first line treatment.  
• 
Grade 4: Life Threatening: discomfort that represents immediate risk of death 
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The investigator (or physician designee) is 
responsible for verifying and providing source documentation for all adverse events, 
assigning the attribution  and assessing the severity of the AE, the causal relationship 
between any events and the clinical study procedure, activities or device.  Additionally, 
the Investigator is responsible for providing appropriate treatment for the event and for 
adequately following the event until resolution for all adverse events for subjects 
enrolled. 
 
Pregnancy 
If a female patient becomes pregnant while receiving obinutuzumab or within 18 
months after the last dose of obinutuzumab, or the partner of a male patient 
becomes pregnant while receiving therapy or within 6 months of completing 
therapy, a report should be completed and expeditiously submitted to the 
Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also 
occur. Abortion, whether accidental, therapeutic, or spontaneous, should always 
be classified as serious, and expeditiously reported as an SAE. Similarly, any 
congenital anomaly/birth defect in a child born to a female subject exposed to 
obinutuzumab should be reported as an SAE. 
 
Pregnancies occurring while the subject is on lenalidomide or within 4 weeks 
after the subject’s last dose of lenalidomide are considered expedited reportable 
events. If the subject is on lenalidomide, it is to be discontinued immediately and 
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the subject is to be instructed to return any unused portion of lenalidomide to the 
Investigator. The pregnancy must be reported by the investigator to MDACC IRB 
and IRB OFFICE AND to Celgene Corporation Worldwide Drug Safety 
Surveillance (WWDSS) within 24 hours of the Investigator’s knowledge of the 
pregnancy by phone and facsimile using the SAE Form. 
 
 
 
The Investigator will follow the subject until completion of the pregnancy, and 
must notify Celgene Corporation Worldwide Drug Safety Surveillance (WWDSS) 
of the outcome as specified below. The Investigator will provide this information 
as a follow-up to the initial SAE. 
 
 
 
If the outcome of the pregnancy meets the criteria for immediate classification as 
a SAE (i.e., spontaneous abortion [any congenital anomaly detected in an 
aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for reporting SAEs (i.e., 
report the event to Celgene Corporation Worldwide Drug Safety Surveillance 
(WWDSS) by facsimile within 24 hours of the Investigator’s knowledge of the 
event) and report the event to MDACC IRB and IRB OFFICE. 
 
 
 
Any suspected fetal exposure to lenalidomide must be reported to Celgene, 
MDACC IRB AND IRB OFFICE within 24 hours of being made aware of the 
event. The patient should be referred to an obstetrician/gynecologist 
experienced in reproductive toxicity for further evaluation and counseling. 
 
 
 
All neonatal deaths that occur within 30 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 30 days that the 
Investigator suspects is related to the in utero exposure to lenalidomide should 
also be reported. 
 
In the case of a live “normal” birth, Celgene Corporation Worldwide Drug Safety 
Surveillance (WWDSS), MDACC IRB AND IRB OFFICE should be advised as 
soon as the information is available. 
 
Celgene: 
 
Pregnancies 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the 
subject is on lenalidomide, or within 28 days of the subject’s last dose of 
lenalidomide, are considered immediately reportable events. Lenalidomide is to 
be discontinued immediately. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by 
facsimile or email using the Pregnancy Initial Report Form. The female subject 
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should be referred to an obstetrician-gynecologist, preferably one experienced in 
reproductive toxicity for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, 
and must notify Celgene Drug Safety immediately about the outcome of the 
pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up 
Report Form. If the outcome of the pregnancy was abnormal (e.g., spontaneous 
or therapeutic abortion), the Investigator should report the abnormal outcome as 
an AE. If the abnormal outcome meets any of the serious criteria, it must be 
reported as an SAE to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, within 24 hours of the Investigator’s knowledge of the event 
using the SAE Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the IP should also be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form. 
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taking lenalidomide should notify the Investigator, 
and the pregnant female partner should be advised to call their healthcare 
provider immediately. 
 
 
Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr.  Suite 6000 
Berkeley Heights, NJ 07922 
Fax: 
(908) 673-9115 
E-mail: drugsafety@celgene.com 
 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject  
has completed or discontinued study participation if attributed to prior 
obinutuzumab or lenalidomide exposure. If the investigator should become aware 
of the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject, including pregnancy occurring in the 
partner of a male study subject who participated in the study, this should be 
reported as an SAE adequately to Genentech drug Safety during follow up 
period  
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Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the 
Sponsor will agree to the reconciliation periodicity and format, but agree at 
minimum to exchange monthly line listings of cases received by the other party. If 
discrepancies are identified, the Sponsor and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall 
handle the matter on a case-by-case basis until satisfactory resolution. 
 
AEs of Special Interest (AESIs) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern 
specific to the product, for which ongoing monitoring and rapid communication by 
the Investigator to the Sponsor is required. Such an event might require further 
investigation in order to characterize and understand it. Depending on the nature 
of the event, rapid communication by the trial Sponsor to other parties (e.g., 
Regulatory Authorities) may also be warranted. 
           
         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: 
• Treatment-emergent ALT or AST > 3 × ULN in combination with total 
bilirubin > 2 × ULN 
• Treatment-emergent ALT or AST > 3 × ULN in combination with clinical 
jaundice 
• Data related to a suspected transmission of an infectious agent by the study 
drug (STIAMP), 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 the study drug is 
suspected. 
 
 
The obinutuzumab Events of Special Interest are: 
 
• 
TLS (all grades) 
 
• 
Second malignancy 
 
 
 
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 
• 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 
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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. 
 
 
Exchange of Single Case Reports with Genentech  
The principal Investigator will be responsible for collecting all protocol-defined Adverse 
Events (AEs)/Serious Adverse Events (SAEs), pregnancy reports (including pregnancy 
occurring in the partner of a male study subject), other Special Situation reports, AESIs 
and Product Complaints with an AE where the patient has been exposed to the Product. 
The completed MD Anderson SAE form should be sent to the Genentech contact 
specified below. Transmission of these reports (initial and follow-up) will be either 
electronically via email or by fax and within the timelines specified below: 
 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
All Product Complaints without an AE should call via: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
 
Transmission of these reports (initial and follow-up) will be either electronically or by fax 
and within the timelines specified below: 
 
Serious Adverse Drug Reactions 
(SADRs) 
15 calendar days of the awareness date 
Other SAEs 
30 calendar days of the awareness date. 
Special Situation Reports (Pregnancy)  
 
Special Situation Reports (Other)  
30 calendar days of the awareness date. 
30 calendar days of the awareness date. 
Product Complaints  
15 calendar days of the awareness date. 
AESIs 
15 calendar days of the awareness date. 
   
 
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• Serious Adverse Drug Reactions (SADRs) 
Serious AE reports that are related to the Product or where the causality is assessed as 
unknown or not provided shall be transmitted to Genentech within fifteen (15) calendar 
days of the awareness date. 
 
• Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech 
within thirty (30) calendar days of the awareness date. 
 
• Special Situation Reports 
o Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as 
defined herein, any reports of pregnancy (including pregnancy occurring in the partner of 
a male study subject), where the fetus may have been exposed to the Product, shall be 
transmitted to Genentech within thirty (30) calendar days of the awareness date. 
Pregnancies will be followed-up until the outcome of the pregnancy is known, whenever 
possible, based upon due diligence taken to obtain the follow-up information. 
 
Pregnancies in Female Partners of Male Patients   
 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 180 
days after the last dose of study drug.  A Clinical Trial Pregnancy Reporting Form should 
be completed and submitted to Genentech within thirty (30) calendar days of the 
awareness date. 
 
o Other Special Situation Reports, as defined above, shall be transmitted 
to Genentech within thirty (30) calendar days of the awareness date. 
 
• Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to Genentech within 
fifteen (15) calendar days of the awareness date. 
 
• AESIs  
 
AESIs requiring expedited reporting (related or possibly related to Genentech product or 
where the causality is assessed as unknown or not provided) shall be forwarded to 
Genentech within fifteen (15) calendar days of the awareness date. Others (non-related 
to  product) shall be sent within thirty (30) calendar days. 
 
Note: Investigators should also report events to their IRB as required. 
 
 
 
Case Transmission Verification of Single Case Reports 
 
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The Principal Investigator (PI) agrees to conduct the Case Transmission verification to 
ensure that all single case reports have been adequately received by Genentech via 
Principal Investigator emailing Genentech a Quarterly line-listing documenting single 
case reports sent by MD Anderson Cancer Center to Genentech in the preceding time 
period.  
The periodic line-listing will be exchanged within seven (7) calendar days of the end of 
the agreed time period. Confirmation of receipt should be received within the time period 
mutually agreed upon. 
                    
If discrepancies are identified, the Principal Investigatorand Genentech will cooperate 
in resolving the discrepancies. The responsible individuals for each party shall handle 
the matter on a case-by-case basis until satisfactory resolution.  The PI shall receive 
reconciliation guidance documents within the ‘Activation Package’. 
 
Following Case Transmission Verification, single case reports which have not been 
received by Genentech shall be forwarded by the PIto Genentech within five (5) 
calendar days from request by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be 
sent to Genentech. 
 
 
 
Follow-upInformation 
Additional information may be added to a previously submitted report by any of 
the following methods: 
 
• 
Adding to the original MDACC Internal SAE Report Form for Prompt 
Reporting and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up 
with the original MDACC Internal SAE Report Form for Prompt Reporting 
• 
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) 
 
 
Occasionally Genentech may contact the reporter for additional information, 
clarification, or current status of the patient for whom and adverse event was 
reported. For questions regarding SAE reporting, you may contact the 
Genentech Drug Safety representative noted above or the MSL assigned to the 
study. Relevant follow-up information should be submitted to Genentech Drug 
Safety as soon as it becomes available and/or upon request. 
 
MEDWATCH 3500A REPORTING GUIDELINES 
 
The below guidelines must also be followed when completing SAE forms different to 
MEDWATCH 3500A: 
 
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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 (or MDACC SAE form) and 
submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original  
MedWatch 3500A form (or MDACC SAE 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 
 
 
The Principal Investigator 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. 
 
 
12.3.3 
ADDITIONAL REPORTING REQUIREMENTS FOR IND 
 
For Investigator-Sponsored 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. An unexpected adverse event is one that is 
not already described in the obinutuzumab Investigator Brochure. Such reports 
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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. An
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unexpected adverse event is one that is not already described in the 
obinutuzumab 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., MDACC Internal SAE Report 
Form for Prompt Reporting, summary letter). 
 
 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
 
All written IND Safety Reports submitted to the FDA must also be faxed to 
Genentech Drug Safety: 
Fax: (650) 225-4682 or (650) 225-4630 
         Email: usds_aereporting-d@gene.com 
 
And to the Site IRB: 
U.T. MD Anderson Cancer Center 
Institutional Review Board 
1400 Pressler, Unit 1437 
Houston, TX 77030 
(713)792-2933phone 
(713) 794-4589 fax 
 
For questions related to safety reporting, please contact Genentech Drug 
Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 
OR 
(650) 225-4630 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr.  Suite 6000 
Berkeley Heights, NJ 07922 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
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12.3.4 
IND ANNUAL REPORTS 
 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor should be copied to 
Genentech.  
 
Copies of such reports should be emailed to Genentech at:  Genentech Drug Safety 
CTV mail box: ctvist_drugsafety@gene.com 
 
 
 
 
12.4 
STUDYCLOSE-OUT 
 
Any study report submitted to the FDA by the Sponsor 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  Protocols 
Email: ga101-gsur@gene.com  
 
         And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
 
 
 
13. 
MD ANDERSON REPORTING REQUIREMENTS FOR 
SERIOUS ADVERSE EVENTS AND DOSE LIMITING 
TOXICITIES: 
 
 
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• 
 
Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above. The investigator must inform 
Celgene in writing using a Celgene SAE form, MDACC 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- 
XX-PI-###) 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. 
If this is a multicenter trial, suggest including language indicating that 
participating study sites must report SAEs to Celgene as described and within 
24 hours of awareness.  Participating sites should also report SAEs to the 
primary study site. 
 
 
 
 
14. 
RETENTION OF RECORDS 
 
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP     
(see Section 4.9 of the guideline) require that records and documents pertaining 
to the conduct of clinical trials and the distribution of investigational drug, subject 
records, consent forms, laboratory test results, and medication inventory records, 
must be retained for 2 years after the last marketing application approval in an 
ICH region or after at least 2 years have elapsed since formal discontinuation of 
clinical development of the investigational product. All state and local laws for 
retention of records also apply. 
 
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with the record retention requirements set forth in the 
U.S. FDA IND regulations and the relevant national and local health authorities, 
whichever is longer. 
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REFERENCES 
 
Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for 
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Alduaij W, Ivanov A, Honeychurch J et al. Novel Type II anti-CD20 monoclonal 
antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome- 
mediated cell death in B-cell malignancies. Blood 2011; 117 (17): 4519−29. 
 
American Cancer Society. Cancer Facts & Figures 2010. Atlanta (GA): 
American Cancer Society 2010. 
 
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Dreyling M. Newly diagnosed and relapsed follicular lymphoma: ESMO clinical 
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APPENDIX D 
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. 
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APPENDIX E 
SAFETY REPORTING FAX COVER SHEET 
 
 
 
 
 
GENENTECH SUPPORTED RESEARCH 
 
AE / SAE FAX No: (650) 225-4682 
 
Alternate Fax No: (650) 225-5288 
 
 
 
Genentech Study Number 
Principal Investigator 
Site Name 
Reporter name 
Reporter Telephone # 
Reporter Fax # 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
 
(Enter a dash if patient has no 
middle name) 
 
 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
 
 
 
 
PLEASE PLACE MD ANDERSON SAE REPORTING FORM BEHIND THIS 
COVER SHEET 
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APPENDIX F: 
CURRENT NCI COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (CTCAE) 
Please refer to the following web link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_ 
applications/ctc.htm 
 
 
APPENDIX G: 
GUIDELINES FOR OBINUTUZUMAB 
PREPARATION AND ADMINISTRATION 
 
Reconstituted obinutuzumab drug product intended for IV infusion is prepared by 
dilution of the drug product into an infusion bag containing 0.9% sodium chloride, 
to the final drug concentration of 4 mg/mL. Using a 250-mL infusion bag 
containing 0.9% sodium chloride, withdraw and discard 40 mL of the sodium 
chloride. Withdraw 40 mL of obinutuzumab from a single glass vial and inject 
into an infusion bag (discard any unused portion of obinutuzumab left in the vial). 
Gently invert the infusion bag to mix the solution; do not shake. 
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Appendix H: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods 
 
Risks Associated with Pregnancy 
 
The use of lenalidomide in pregnant females and nursing mothers has not been 
studied nor has the effect of the lenalidomide on human eggs and sperm. The 
risks to a fetus are not known. However, because lenalidomide is related to 
thalidomide, and thalidomide is known to cause severe birth defects, the 
following requirements must be observed. 
 
All study participants must be registered into the mandatory Revlimid REMS® 
program, and be willing and able to comply with the requirements of Revlimid 
REMS® program. 
Females of childbearing potential (FCBP)† must agree to use two reliable forms  
of contraception simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods related to this study: 1) 
for at least 28 days before starting study drug; 2) while participating in the study; 
and 3) for at least 28 days after discontinuation from the study. The two methods 
of reliable contraception must include one highly effective method (i.e.  
intrauterine device (IUD), hormonal [birth control pills, injections, or implants], 
tubal ligation, partner’s vasectomy) and one additional effective (barrier) method 
latex condom, diaphragm, cervical cap). FCBP must be referred to a 
qualified provider of contraceptive methods if needed. 
 
Before starting study drug: 
 
Female Subjects: 
 
• FCBP must have two negative pregnancy tests (sensitivity of at least 50 
mIU/mL) prior to prescribing lenalidomide. The first pregnancy test must 
be performed within 10-14 days prior to prescribing lenalidomide and the 
second pregnancy test must be performed within 24 hours prior to 
prescribing lenalidomide (prescriptions must be filled within 7 days). The 
subject may not receive study drug until the Investigator has verified that 
the results of these pregnancy tests are negative. 
 
 
 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
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Male Subjects: 
 
• Must agree to use a latex condom during sexual contact with females of 
childbearing potential while participating in the study and for at least 28 
days following discontinuation from the study even if he has undergone a 
successful vasectomy. 
 
During study participation and for 28 days following discontinuation from 
the study: 
 
All Subjects: 
 
• If pregnancy or a positive pregnancy test does occur in a study subject or 
the partner of a male study subject during study participation, lenalidomide 
must be immediately discontinued. 
 
Female Subjects: 
 
• FCBP with regular or no menstrual cycles must agree to have pregnancy 
tests weekly for the first 28 days of study participation and then every 28 
days while on study, at study discontinuation, and at day 28 following 
discontinuation from the study. If menstrual cycles are irregular, the 
pregnancy testing must occur weekly for the first 28 days and then every 
14 days while on study, at study discontinuation, and at days 14 and 28 
following discontinuation from the study. 
 
• In addition to the required pregnancy testing, the Investigator must confirm 
with FCBP that she is continuing to use two reliable methods of birth 
control at each visit. 
 
• 
Pregnancy testing and counseling must be performed if a subject misses 
her period or if her pregnancy test or her menstrual bleeding is abnormal. 
Study drug treatment must be discontinued during this evaluation. 
 
Male Subjects: 
 
• Must agree to use a latex condom during sexual contact with females of 
childbearing potential while participating in the study and for at least 28 
days following discontinuation from the study even if he has undergone a 
successful vasectomy. 
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