Conditions: Lymphoma
Keywords: Lymphoma Diffuse Large B Cell Lymphoma DLBCL Lenalidomide CC-5013 Revlimid Obinutuzumab GA101 Gazyva Cyclophosphamide Cytoxan Neosar Doxorubicin Doxorubicin Hydrochloride Adriamycin PFS Adriamycin RDF Adriamycin Rubex Vincristine Prednisone
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 59
Healthy volunteers: no

Brief summary:
There are 2 parts to this study: Part 1 (dose de-escalation) and Part 2 (dose expansion).

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of lenalidomide in combination with obinutuzumab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) that can be given to patients with diffuse large B cell lymphoma.

The goal of Part 2 of this clinical research study is learn if the dose of lenalidomide found in Part 1 can help to control the disease.

The safety of this drug combination will be studied in both parts.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study phase based on when you join this study. Up to 3 groups of up to 6 participants will be enrolled in Phase 1 of the study, and up to 50 participants will be enrolled in Phase 2.

If you are enrolled in Phase 1, the dose of lenalidomide you receive will depend on when you join this study. The first group of participants will receive the highest dose level of lenalidomide. Each new group will receive a lower dose of lenalidomide than the group before it, if intolerable side effects are seen. This will continue until the most tolerable dose of lenalidomide is found.

If you are enrolled in Phase 2, you will receive lenalidomide at the highest dose that was tolerated in Phase 1.

All participants will receive the same dose of CHOP and obinutuzumab.

Study Drug Administration:

Each study cycle is 21 days.

You will take lenalidomide pills by mouth on Days 1-14 of each cycle.

You will receive obinutuzumab by vein over 3-4 hours on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2-6.

You will receive cyclophosphamide by vein over about 1 hour on Day 1 of all cycles.

You will receive doxorubicin and vincristine by vein over about 15 minutes each on Day 1 of all cycles.

Study Visits:

Within 3 days before Day 1 of Cycles 1-6:

* You will have a physical exam.
* Blood (about 8-9 teaspoons) will be drawn for routine tests and to check for PBMCs.

One (1) time each week during Cycle 1 and then at any time the doctor thinks it is needed, blood (about 2-3 teaspoons) will be drawn for routine tests.

At the end of Cycle 1 but before the start of Cycle 2, blood (about 6 teaspoons) will be drawn to check for PBMCs.

At the end of Cycle 3 but before the start of Cycle 4, you will have a PET/CT scan.

If you can become pregnant, blood (about 2-3 teaspoons) will be drawn for a pregnancy test 1 time before Cycle 1 and then 1 time during each cycle after that.

Length of Treatment:

You may receive lenalidomide, obinutuzumab, and CHOP therapy for up to 6 cycles. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on this study will be over after follow-up.

End-of-Treatment Visit:

Within 3-4 weeks after your last dose of study drugs:

* You will have a physical exam.
* Blood (about 8-9 teaspoons) will be drawn for routine tests and to check for PBMCs.
* You will have a PET/CT scan.
* If the doctor thinks it is needed, you will have a bone marrow biopsy to check the status of the disease.
* If the doctor thinks it is needed and the tumor is accessible, you will have a core needle biopsy to check the status of the disease. To perform a core biopsy, a sample of tissue is removed using a hollow core needle that has a cutting edge.

Follow-Up:

Every 3 months (+/- 4 weeks) during the first year after the End-of-Treatment Visit and then every 4 months (+/- 9 weeks) during the second year:

* You will have a physical exam.
* Blood (about 2-3 teaspoons) will be drawn for routine tests.
* You will have a PET/CT scan.

This is an investigational study. Lenalidomide is FDA approved and commercially available for the treatment of multiple myeloma (MM) and myelodysplastic syndrome (MDS). Obinutuzumab is FDA approved and commercially available for the treatment of chronic lymphocytic leukemia (CLL). CHOP is FDA approved and commercially available for the treatment of lymphoma and non-Hodgkin's lymphoma.

The combination of lenalidomide, CHOP, and obinutuzumab to treat DLBCL is considered investigational.

Up to 59 participants will be enrolled in this study. All will take part at MD Anderson.

Arms:
arm 1: Phase I: Participants take Lenalidomide by mouth on Days 1 - 14 of each cycle. Participants receive Obinutuzumab by vein over 3 - 4 hours on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 - 6. Participants receive Cyclophosphamide by vein over about 1 hour on Day 1 of all cycles. Participants receive Doxorubicin and Vincristine by vein over about 15 minutes each on Day 1 of all cycles.

Phase II: Participants treated at the recommended phase II dosing (RP2D) of Lenalidomide determined in the Phase Ib portion for 6 cycles of therapy. Dose of Obinutuzumab, Cyclophosphamide, Doxorubicin and Vincristine remain the same as in Phase I.

Each study cycle is 21 days.

Interventions: intervention 1: Lenalidomide intervention 2: Obinutuzumab intervention 3: Cyclophosphamide intervention 4: Doxorubicin intervention 5: Vincristine intervention 6: Prednisone
Intervention descriptions: intervention 1: Phase I Starting Dose Level: 15 mg by mouth on Days 1 - 14 of each 21 day cycle.

Phase II Starting Dose Level: Maximum tolerated dose from Phase I. intervention 2: Phase I and II: 1000 mg by vein on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 - 6. intervention 3: Phase I and II: 750 mg/m2 vein over about 1 hour on Day 1 of all cycles. intervention 4: Phase I and II: 50 mg/m2 by vein over about 15 minutes each on Day 1 of all cycles. intervention 5: Phase I and II: 1.4 mg/m2 by vein on Day 1 of all cycles. intervention 6: Phase I and II: 100 mg by mouth daily on Days 1 - 5 of each 21 day cycle.

Protocol document:
Prot_SAP_000.pdf: 
Protocol 2015-0069 
Version 1.4 April 5, 2018 
CONFIDENTIAL 
 
This is an MD Anderson Cancer Center document that contains confidential information.  It is 
intended solely for the recipient clinical investigator(s) and must not be disclosed to any other 
party.  This material may be used only for evaluating or conducting clinical investigations; any 
other proposed use requires written consent from MD Anderson Cancer Center. 
 
Lenalidomide and Obinutuzumab with CHOP for Diffuse Large B Cell Lymphoma 
 
1 
PROTOCOL 
TITLE: 
A Phase I/II Study of Lenalidomide and Obinutuzumab 
with CHOP for Diffuse Large B Cell Lymphoma 
 
STUDY NUMBER: 
2015-0069 
VERSION NUMBER: 
1 
TEST PRODUCTS: 
Obinutuzumab (Gazyva, GA101) 
Lenalidomide (Revlimid) 
 
INVESTIGATOR: 
Jason Westin 
University of Texas 
M.D. Anderson Cancer Center 
Department of Lymphoma & Myeloma 
1400 Holcombe Blvd, Unit 0429 
Houston, TX 77030 
Telephone:       713-792-3750 
Fax:                  713-745-5656 
E-mail:              jwestin@mdanderson.org 
 
SUB-INVESTIGATORS: 
Luis Fayad 
Fredrick Hagemeister 
Nathan Fowler 
Michael Wang 
STUDY COORDINATOR: Shapatra Parker 
 
SUPPORT PROVIDED 
BY: 
Genentech, Inc. 
Celgene, Inc. 
 
PROTOCOL DATE: 
15 May 2015 
 


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Lenalidomide and Obinutuzumab with CHOP for Diffuse Large B Cell Lymphoma 
 
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TABLE OF CONTENTS 
1. Introduction ................................................................................................ 88 
1.1 Diffuse Large B-Cell Lymphoma ......................................................... 88 
1.2 PET/CT Scans in lymphoma ................................................................ 88 
1.3 Non-imaging based disease monitoring ............................................. 98 
1.4 Biological and Clinical Significance of DLBCL Typing ..................... 99 
1.4.1 GCB versus ABC Gene Expression Profiling Assay Used in This 
Protocol .................................................................................................. 1010 
1.5 Biomarkers in DLBCL ....................................................................... 1010 
1.5.1 Biomarkers in DLBCL Pathogenesis ......................................... 1010 
1.5.2 Minimal Residual Disease and Clonal Heterogeneity .............. 1110 
1.5.3 Mechanistic Biomarkers ............................................................. 1111 
1.6 Lenalidomide ..................................................................................... 1211 
1.6.1 Preclinical Data on Lenalidomide in DLBCL ............................. 1212 
1.6.2 Lenalidomide Clinical Pharmacology: ...................................... 1414 
1.6.3 Lenalidomide Pharmacokinetics and Drug Metabolism .......... 1414 
1.6.4 Clinical Efficacy Data on Lenalidomide in DLBCL ................... 1515 
1.6.5 Clinical Efficacy Data Conclusion ............................................. 2121 
1.7 Obinutuzumab ................................................................................... 2221 
1.7.1 Obinutuzumab Preclinical Data ................................................. 2222 
1.7.2 Obinutuzumab Clinical Pharmacology ...................................... 2323 
1.7.3 Summary of Pharmacokinetic and Pharmacodynamic Data for 
Obinutuzumab ....................................................................................... 2424 
1.7.4 Clinical Experience with Obinutuzumab ................................... 2525 
1.7.5 Rationale for Use of Flat Dosing of Obinutuzumab ................. 2727 
1.7.6 Rationale for Administration of Additional Doses of 
Obinutuzumab on Days 1 and 8 ........................................................... 2727 
1.7.7 Overview of Safety of Obinutuzumab ........................................ 2827 
1.7.8 Risks Associated with Obinutuzumab Therapy ....................... 3030 
1.8 Study Rationale ................................................................................. 3232 
2. Objectives ............................................................................................... 3534 
2.1 Primary .............................................................................................. 3534 
2.2 Secondary ......................................................................................... 3534 
3. Design ..................................................................................................... 3635 
3.1 Description of the Study .................................................................. 3635 
3.2 Screening Period .............................................................................. 3635 
3.3 Treatment Period .............................................................................. 3635 
3.4 Follow-up Period ............................................................................... 3736 
3.5 Rationale For Study Design ............................................................. 3736 
3.6 Outcome Measures ........................................................................... 3837 


TABLE OF CONTENTS (CONT.) 
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3.6.1 Primary Efficacy Outcome Measure .......................................... 3837 
3.6.2 Secondary Efficacy Outcome Measures ................................... 3837 
4. Study Population.................................................................................... 3938 
4.1 Eligility Criteria ................................................................................. 3938 
4.1.1 Inclusion Criteria ......................................................................... 3938 
4.2 Exclusion Criteria ............................................................................. 4039 
5. Treatment Plan ....................................................................................... 4241 
5.1 Phase Ib ............................................................................................. 4241 
5.2 Phase II .............................................................................................. 4342 
6. Clinical trial Medications ....................................................................... 4443 
6.1.1 Obinutuzumab ............................................................................. 4443 
6.1.2 Lenalidomide ............................................................................... 5049 
6.1.3 CHOP Chemotherapy .................................................................. 5352 
6.1.4 Pre-medications .......................................................................... 5352 
6.1.5 Pre-phase Treatment .................................................................. 5352 
6.1.6 Consolidation Treatment (Pre-Specified) .................................. 5452 
6.2 Concomitant and Excluded Therapies ............................................ 5453 
6.2.1 Concomitant Therapy ................................................................. 5453 
7. Study Evaluations .................................................................................. 5755 
7.1 Screening Evaluations ..................................................................... 5755 
7.2 Pre-treatment evaluations ................................................................ 5755 
7.3 Evaluations during Therapy ............................................................. 5856 
7.4 Evaluations performed after completion of therapy ...................... 5957 
8. Evaluation of Response ........................................................................ 6159 
9. Statistical Considerations ..................................................................... 6361 
9.1 Determination of Sample Size ......................................................... 6361 
9.2 Planned Efficacy Evaluations .......................................................... 6361 
9.2.1 Phase Ib ....................................................................................... 6361 
9.2.2 Phase II ........................................................................................ 6361 
9.3 Method of Analysis ........................................................................... 6361 
9.3.1 Clinical Outcomes Analysis ....................................................... 6361 
9.3.2 Analysis Plan: ............................................................................. 6462 
9.3.3 Correlative Assay Analysis ........................................................ 6663 
10. Reporting of Adverse Events .............................................................. 7068 
10.1 Assessment of Safety..................................................................... 7068 
10.1.1 Adverse Events ......................................................................... 7068 


TABLE OF CONTENTS (CONT.) 
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10.1.2 Serious Adverse Events ........................................................... 7068 
10.2 Methods for Assessing and Recording Safety Variables ............ 7168 
10.2.1 Adverse Event Reporting Period ............................................. 7169 
10.2.2 Assessment of Adverse Events ............................................... 7169 
10.3 Procedures for Recording, and Reporting Adverse Events ........ 7371 
10.3.1 Specific Instructions for Recording Adverse Events ............. 7471 
10.3.2 Additional Reporting Requirements for IND ........................... 7874 
10.4 Study Close-Out .............................................................................. 7975 
11. Retention of Records ........................................................................... 8077 
12. References ........................................................................................... 8682 
 
 
LIST OF TABLES 
Table 1 Obinutuzumab Dosing Schedule ..................................................... 4645 
Table 2 Management of Hepatitis B Reactivation ........................................ 4948 
 
 
LIST OF APPENDICES 
Appendix 1 Study Flowchart ........................................................................ 8178 
Appendix 2 Calculation of Creatinine Clearance Using the Cockcroft-Gault 
Formula ................................................................................... 8379 
Appendix 3 Safety Reporting Fax Cover Sheet ............................................ 8480 
Appendix 4 FDA MedWatch 3500 Form ...................................................... 8581 
Appendix 5 Current NCI Common Terminology Criteria for Adverse 
Events (CTCAE) ..................................................................... 8682 
 
Appendix 1 Study Flowchart ........................................................................ 8178 
Appendix 2 Calculation of Creatinine Clearance Using the Cockcroft-Gault 
Formula ................................................................................... 8379 
Appendix 3 Safety Reporting Fax Cover Sheet ............................................ 8480 
Appendix 4 FDA MedWatch 3500 Form ...................................................... 8581 
Appendix 5 Current NCI Common Terminology Criteria for Adverse 
Events (CTCAE) ..................................................................... 8682 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
ABC 
activated B cell 
ADCC 
antibody-dependent cellular cytotoxicity 
ADCP 
antibody dependent cellular phagocytosis 
AE 
adverse event 
anti-HBc 
aNHL 
antibody to hepatitis B core antigen 
aggressive Non-Hodgkin lymphoma 
aPTT 
activated partial thromboplastin time 
BCR 
B-cell receptor 
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 
COO 
cell of origin 
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 
FcR 
leukocyte receptors for the Fc portion of IgG 
FDA 
Food and Drug Administration 
18F-FDG 
18F-fleurodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded  
FISH 
fluorescence in situ hybridization 


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Abbreviation 
Definition 
FL 
GCB 
GCP 
Follicular Lymphoma 
germinal center B cell 
Good Clinical Practice 
GCSF 
granulocyte-colony stimulating factor 
GEP 
G 
gene expression profiling 
GA101 
G-FC 
GA101 in combination with fludarabine 
and cyclophosphamide 
HAHA 
human anti-human antibodies 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HD 
high dose 
HTLV 
human T-cell leukemia virus 
ICH 
International Conference on Harmonisation 
Ig 
immunoglobulin  
IgH 
Immunoglobulin heavy chain 
IHC 
immunohistochemistry 
IND 
Investigational New Drug 
IMC 
Internal Monitoring Committee 
IRR 
infusion-related reaction 
IV 
intravenous 
IL 
interleukin  
iNHL 
Indolent non-Hodgkins lymphoma 
IPI 
International Prognostic Index 
IVRS 
interactive voice response system 
LD 
low dose 
LVEF 
left ventricular ejection fraction 
LVS. D 
left ventricular systolic dysfunction 
MCL 
mantle-cell lymphoma 
MM 
multiple myeloma 
MRD 
minimal residual disease 
MTD 
maximum tolerated dose 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition scan 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 


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Abbreviation 
Definition 
NGS 
next generation sequencing 
NHL 
non-Hodgkin’s lymphoma 
NONMEM 
Non-Linear Mixed Effect Model 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease  
PICC 
peripherally inserted central catheter 
PK 
pharmacokinetic 
PET 
PFS 
positron emission tomography 
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 
SNPs 
single nucldeotide polymorphisms 
SOC 
Scientific Oversight Committee 
TCR 
T-cell receptor 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
U.S. 
United States 
V 
valine  
WHO 
World Health Organization 


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1. 
INTRODUCTION 
Although this protocol contains sufficient information regarding the medications utilized in this 
clinical trial, for additional information please refer to the Investigator’s Brochures for 
lenalidomide and obinutuzumab, Appendix A and B, for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) 
profiles. 
1.1 
DIFFUSE LARGE B-CELL LYMPHOMA 
Diffuse large B-cell Lymphoma (DLBCL) is a distinct histological type within mature B-cell non-
Hodgkin lymphoma (NHL) that is characterized by large tumor cells and aggressive clinical 
behavior. This type accounts for approximately 31% of all newly diagnosed malignant 
lymphomas.(1) 
 
CHOP chemotherapy in combination with the anti-CD20 monoclonal antibody rituximab on a 
21-day schedule is a standard of care in newly diagnosed cases in most countries 
worldwide.(2-4) In the GELA study of R-CHOP versus CHOP front line therapy in elderly 
subjects, following R-CHOP treatment the 5-year event-free survival (EFS) was 47%, the 5-
year progression free survival (PFS) was 54%, and the 5-year overall survival (OS) was 
58%.(5) While approximately 50% to 60% of patients are cured, for those patients who are 
refractory or who progress following R-CHOP, treatment options are limited and outlook is 
poor; most die within the next two years. Since roughly 40% to 50% of patients are not cured 
on initial therapy, evaluating other front line treatment options is warranted. Other attempts to 
improve cure rate, including R-ACVBD, CHOEP, dose dense regimens (R-CHOP14), and high 
dose regimens (DA-EPOCH), have not replaced R-CHOP21 as a standard of care.(4) 
1.2 PET/CT SCANS IN LYMPHOMA 
18F-fluorodeoxyglucose positron emission tomography (FDG PET) scans are used in NHL to 
evaluate residual masses detected on CT after completion of chemotherapy, with the negative 
predictive values for outcome of 80% to 100%.(6, 7) Results from a FDG PET scan after one 
cycle of chemotherapy were essentially equivalent to results from a FDG PET scan obtained at 
the completion of chemotherapy in predicting PFS in NHL and HD.(8)  
Moskowitz et al evaluated the predictive value of an FDG PET in patients with high risk 
untreated DLBCL after 3 cycles of conventional chemotherapy.(9) Of the 38 patients with a 
positive interim FDG PET, only 5 (13%) had biopsy-confirmed persistent disease. Interestingly, 
the patients with positive interim FDG PET and negative biopsy had no significant difference in 
long-term outcomes from patients with negative interim FDG PET (p=0.27). As a result of this 
important trial, the positive predictive value of an interim FDG PET is considered low enough 
that a biopsy for confirmation is mandatory prior to altering the treatment plan. Essentially, 
interim FDG PET scans have an excellent negative predictive value, however the positive 
predictive value is not clinically viable. 


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1.3 NON-IMAGING BASED DISEASE MONITORING 
A novel technology (LymphoSIGHT, Sequenta) has been shown to allow a detection of a 
tumor-specific clonotype (DoC) in blood and to correlate with therapeutic response and 
identification of relapse prior to imaging findings.(10-12) This novel technology amplifies the 
immunoglobulin (Ig) gene segments from tumor biopsy DNA, and subsequent quantification of 
the same clonotype in blood. Genomic DNA from tumor is isolated using standard kits from 
Qiagen, and is subsequently amplified using locus-specific primer sets for all known alleles of 
germine line immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) sequences.(10) The 
tumor-specific sequences identified at diagnosis are then used as a target to assess the 
presence of tumor-specific clonotype in follow-up samples. For quantitation, multiple 
sequencing reads (~10X coverage) are generated for each rearranged B cell in the reaction.  
 
To determine the absolute measure of the tumor-specific clonotype present in the follow-up 
sample, a known quantity of reference IgH sequence is added into the reaction and the 
associated sequencing reads are counted. The resulting number of reference IgH reads per 
sequence are then applied to the tumor-specific clonotype reads to obtain an absolute 
measure of the total tumor-specific clonotype in the reaction.  
 
The tumor-specific clonotype reads and the absolute number of total leukoctyes in the reaction 
metrics can be combined to calculate a final tumor-specific clonotype measurement, which is 
the number of tumor-specific clonotype reads divided by the total leukocytes in the sample. 
 
 
1.4 
BIOLOGICAL AND CLINICAL SIGNIFICANCE OF DLBCL TYPING 
As initially described by Staudt and colleagues, DLBCL is composed primarily of two 
biologically distinct disease subtypes.(13) The authors successfully classified DLBCL by gene 
expression profiling (GEP) into the germinal center B-cell (GCB) and the activated B cell (ABC) 
types, derived from their putative cells of origin (COO). Subsequently, an additional type was 
noted by GEP called type III,(14) which has since been renamed as unclassifiable type. 
Although GEP is fully capable of discerning all three types, GCB, ABC, and unclassifiable; 
immunohistochemistry (IHC) is capable of discerning only two, GCB and non-GCB, via the 
algorithm described by Hans.(15) The less precise, though widely utilized, IHC method groups 
ABC and unclassifiable together as the non-GCB type. The Lymphoma/Leukemia Molecular 
Profiling Project reported approximately 60% GCB and 40% non-GCB (including ABC and 
unclassifiable) in 240 newly diagnosed DLBCL subject biopsy samples examined by GEP.(14, 
16, 17)  
 
The different DLBCL types have been reported to have distinct clinical outcomes with 
CHOP(14) and R-CHOP(17) therapy, further supporting that these are distinct clinical and 
molecular subtypes. With frontline CHOP therapy, the 5-year OS rates for the GCB, 


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unclassifiable, and ABC types were 60%, 39%, and 35%, respectively.(14) With frontline R-
CHOP therapy, the 3-year EFS for GCB and non-GCB subtypes was 67% and 52% 
respectively, and the 3-year OS was 85% and 69%, respectively.(17) With RCHOP therapy for 
predominantly higher risk patients (International Prognostic Index, IPI 0/1 = 21%, IPI 2/3 = 
63%, and IPI 4/5 = 15%) the median PFS for the ABC type was only 1.5 years.(18, 19) In the 
relapsed setting, the prognosis for the COO subtype appears to be approximately equal,(20, 
21) which may reflect the selection of GCB subjects with adverse biology not cured initially by 
R-CHOP. 
 
1.4.1 GCB versus ABC Gene Expression Profiling Assay Used in This Protocol 
The COO as characterized by GEP and performed on fresh tissue biopsy samples is 
considered the gold standard for disease subtyping. However, defining COO is not performed 
currently in routine clinical practice and is often not a practical method for subject selection in 
clinical trials due to the fresh biopsy sample requirement, technological expertise, and 
bioinformatics required to perform and interpret the assay. 
 
This protocol will utilize a validated GEP based assay performed on NanoString’s nCounter® 
Analysis System with formalin-fixed paraffin-embedded (FFPE) biopsy material to identify 
eligible subjects with the required ABC type. The NanoString 20-gene assay, referred to as 
Lymph2Cx, was validated against the original COO model defined by Lenz(18) using an 
independent cohort of 68 FFPE biopsies. In the validation cohort the assay was highly 
accurate, as only one case with definitive COO was incorrectly assigned by NanoString; and 
robust, with >95% concordance of COO determination between two independent 
laboratories.(22) 
 
1.5 
BIOMARKERS IN DLBCL 
1.5.1 Biomarkers in DLBCL Pathogenesis 
In recent years a number of chromosomal rearrangements, acquired mutations, or aberrant 
expression of genes) have been identified in DLBCL. Many are associated with a particular 
DLBCL COO subtype or yield prognostic information. As an example, BCL2 is a commonly 
translocated or mutated gene in the GCB subtype, and EZH2 is also mutated in the GCB 
subtype.(23, 24) Activation of NF-κB is critical for the ABC subtype survival, and mutation of 
MYD88 is more common in the ABC type).(25, 26) Coexpression of MYC/BCL2 as defined by 
FISH or IHC is associated with a very aggressive clinical course in both subtypes, although it 
has been reported to be more common in the ABC type.(27-30) Additionally, mutations in 
MYC, CDKN2A, SOCS1, MYD88, CARD11, TP53, and other genes have demonstrated 
prognostic information in patients with DLBCL receiving front line treatment. (31-34) Single 
nucleotide polymorphisms (SNPs) are also reported to be associated with prognosis in DLBCL 
patients. (35, 36) 
 


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1.5.2 Minimal Residual Disease and Clonal Heterogeneity 
In order to be able to adapt treatment intensity, extend duration of response, and prolong PFS, 
more sensitive clinical assessment methods are necessary to better define treatment 
outcomes at the molecular level. Recently, investigators from the National Cancer Institute 
evaluated samples from untreated DLBCL patients treated with DA-EPOCH +/- rituximab to 
assess for minimal residual disease (MRD) using a next generation sequencing (NGS) based 
test with DNA present in the tumor biopsy and serum.(10) IgH variable, diversity, and joining 
segments as well as immunoglobulin light chain gene segments from genomic DNA were 
sequenced, and analysis of these data demonstrated that NGS MRD measurement detected 
relapse of DLBCL a median of 7.4 months before the disease was detected via CT scan.(37) 
 
This study will evaluate the ability of NGS sequencing to assess MRD status compared to CT 
scan in a larger sample size to help determine quality of treatment and detection of relapse. 
The MRD and clonality assessments will be conducted according to the laboratory manual. 
 
1.5.3 Mechanistic Biomarkers 
Research on the mechanism of action of lenalidomide, pomalidomide, and thalidomide suggest 
that in tumor cells and T cells, cereblon, a component of E3 ubiquitin ligase complexes, is a 
critical target for binding by these compounds.(38-40) These and other studies showed that the 
loss of cereblon or a binding partner, such as DDB1, decreases or eliminates the antitumor 
and immunomodulatory activity of lenalidomide and pomalidomide. A number of recent studies 
have reported a correlation between pre-treatment levels of cereblon measured by GEP or by 
IHC methods and clinical outcomes in subjects treated with regimens containing lenalidomide, 
pomalidomide or thalidomide. In addition, multiple groups have described Aiolos (IKZF3) and 
Ikaros (IKZF1) as two direct substrates of the CRL4 CRBN E3 ligase complex. These proteins 
act as transcriptional repressors in T-cells and are also drivers of proliferation in multiple 
myeloma (MM) cells.(41)  
 
This study will explore the functions of Aiolos and Ikaros by examining their expression levels 
in DLBCL patient samples and evaluate for correlation with clinical outcomes, as well as 
genetic mutations that could have functional consequences. Validated assays for both GEP 
and IHC methods will be used to measure baseline and treatment levels of cereblon, Aiolos 
and Ikaros to investigate whether there is any potential correlation between their expression 
level and clinical outcome. Additional biomarkers may be included in the analysis based on 
accumulated evidence for their inclusion. 
 
Mechanistic biomarker measurements for cereblon and other potential biomarkers, including 
substrates of the CRL4-CRBN complex, gene expression, DNA mutational analysis, and 
metabolic factors, will be performed as appropriate. The mechanistic biomarker assessments 
will be conducted according to the laboratory manual. 


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1.6 
LENALIDOMIDE 
REVLIMID®  (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti-
angiogenic properties. Lenalidomide is indicated for the treatment of patients with transfusion-
dependent anemia due to low- or Intermediate-1-risk myelodysplastic syndromes (MDS) 
associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic 
abnormalities.  Revlimid® is also approved in combination with dexamethasone for the 
treatment of patients with multiple myeloma that have received at least one prior therapy.  
 
Lenalidomide, 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. 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. 
 
The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-2, 6-dione 
and it has the following chemical structure:  
Figure 1 Chemical Structure of Lenalidomide 
 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3. Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in 
organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, 
ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can 
exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with a 
net optical rotation of zero. 
 
1.6.1 Preclinical Data on Lenalidomide in DLBCL 
There is biological plausibility and also preclinical data that provide strong support for why 
lenalidomide should be expected to significantly enhance the efficacy of the current standard 
of care R-CHOP in the treatment of the ABC type of DLBCL. 
N
N
H
O
O
O
NH2


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In DLBCL cell line models, lenalidomide preferentially suppresses the proliferation of ABC cells 
in vitro and delays tumor growth in a human tumor xenograft model, with minimal effect on 
GCB cells.(42) The synthetically lethal effect was associated with down-regulation of interferon 
regulatory factor 4 (IRF4, also known as MUM1), a hallmark of ABC cells.(43) IRF4 inhibition 
by lenalidomide induced down-regulation of B-cell receptor (BCR)-dependent NF-κB, and this 
effect was reported to require co-expression of cereblon, a molecular target of lenalidomide. It 
has also been reported that NF-κB mediates resistance to chemotherapy and that decreased 
NF-κB expression may restore sensitivity to chemotherapy and targeted agents.(44, 45) The 
ability of lenalidomide to kill ABC DLBCL cell lines by augmenting autocrine interferon beta 
(IFN-ß) production is dependent on oncogenic MYD88 mutations.(42) In a cereblon-dependent 
fashion, lenalidomide downregulated IRF4 and SPIB transcription factors which repress IFN-ß 
production. 
 
In addition to affecting lymphoma cells directly, lenalidomide exerts potent immunomodulatory 
activity and thus modulates immune responses. Preclinical studies have shown an 
enhancement of antibody dependent cell mediated cytotoxicity and antitumor effects in vivo 
when lenalidomide was combined with rituximab.(46-48) In a murine NHL model, lenalidomide 
induced a significant increase in the recruitment of NK cells to tumor sites, resulting in 
enhanced antitumor activity of rituximab.(49) When combined with rituximab, lenalidomide 
improved survival in a mouse NHL model and the antitumor activity was shown to be NK cell-
mediated.(50)  
 
Lenalidomide reverses immunosuppression of T cells by tumor cells of MM, chronic 
lymphocytic leukemia (CLL), and follicular lymphoma (FL).(51-53) Impaired T-cell 
immunological synapse formation has been reported in CLL, FL and DLBCL patients and is 
thought to be a mechanism of cancer immune evasion. Lenalidomide increases expression of 
T cell co-stimulatory molecules, T cell activating cytokines, and the number of cytotoxic T cells 
in MM patient samples. In indolent lymphomas including FL, we found that R-lenalidomide 
activated many different immune cell subsets, including T and natural killer cells, and 
enhanced tumor infiltration by CD8+ T cells.(54, 55) Lenalidomide treatment of the T-cells and 
the tumor cells collected from these patients repaired the immune synapse defects by 
enhancement of the F-actin synapse. In vitro studies have shown that lenalidomide induced 
actin cytoskeleton reorganization and polarization of NHL cells as early as 30 minutes, a 
process termed “capping,” which is considered an important subcellular component of the 
immune synapse formation.(56)  
 
Additionally it has been shown that the combined use of lenalidomide and rituximab enhances 
NK cell-mediated immune synapse formation and the resultant cytotoxicity, versus using each 
agent alone.(56) Lenalidomide induces CD20-localization within the “cap,” and the addition of 


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rituximab can enhance immune synapse formation. The capping of CD20 is accompanied by 
redistribution of other proteins that become part of the immune synapse complex. Therefore, 
the capping process induced by lenalidomide appears integral to immune synapse formation 
and may coordinately enhance the clustering of both the CD20 antigen and the attached 
rituximab, potentially further enhancing its activity, which would support the clinical 
combination of these agents. Additional agents which target CD20, including obinutuzumab, 
should have a similar mechanism of potential synergy. 
 
1.6.2 Lenalidomide Clinical Pharmacology: 
Mechanism of Action:  
The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide 
possesses immunomodulatory and antiangiogenic properties.  Lenalidomide inhibited the 
secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory 
cytokines from peripheral blood mononuclear cells.  Lenalidomide inhibited cell proliferation 
with varying effectiveness (IC50s) in some but not all cell lines.  Of cell lines tested, 
lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell lymphoma cell 
line with a deletion of one chromosome 5) but was much less effective in inhibiting growth of 
KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and other 
cell lines without chromosome 5 deletions.  Lenalidomide inhibited the expression of 
cyclooxygenase-2 (COX-2) but not COX-1 in vitro.   
 
Metabolism and Excretion 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. 
The process exceeds the glomerular filtration rate and therefore is partially or entirely active.  
Half life of elimination is approximately 3 hours.  
 
1.6.3 Lenalidomide Pharmacokinetics and Drug Metabolism:  
 
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 area under the concentrated 
time curve (AUC) but does reduce the maximal plasma concentration (Cmax) by 36%. The 
pharmacokinetic (PK) disposition of lenalidomide is linear. Cmax and AUC increase 
proportionately with increases in dose. Multiple dosing at the recommended dose-regimen 
does not result in drug accumulation. 
 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the 
phase I studies.  Absorption was found to be rapid on both Day 1 and Day 28 with time to 
maximum blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, and 
50mg).  No plasma accumulation was observed with multiple daily dosing.  Plasma 


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lenalidomide declined in a monophasic manner with elimination half-life ranging from 2.8 to 6.1 
hours on both Day 1 and 28 at all 4 doses.  Peak and overall plasma concentrations were dose 
proportional over the dosing range of 5mg to 50mg (5).  Exposure (AUC) in multiple myeloma 
patients is 57% higher than in healthy male volunteers.  
 
Multiple dosing at the recommended dose-regimen does not result in drug accumulation. 
Pharmacokinetic sampling in 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.  
 
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 therefore is partially or entirely active. 
Half-life of elimination is approximately 3 hours. 
 
1.6.4 Clinical Efficacy Data on Lenalidomide in DLBCL 
1.6.4.1 
Relapsed / Refractory DLBCL 
Single agent lenalidomide activity in relapsed or refractory DLBCL subjects has been noted in 
two Celgene-sponsored single arm clinical trials in aggressive NHL (aNHL): study CC-5013-
NHL-002 and study CC-5013-NHL-003.(57, 58) Data from both studies were combined for a 
revised analysis of 134 DLBCL subjects as study design was nearly identical and subject 
baseline characteristics were similar. Results showed an overall response rate (ORR) of 
26.1% (35/134), a median PFS of 2.7 months, and a median response duration of 6.0 
months.(59) In these clinical trials, COO typing was not conducted. 
 
Hernandez-Ilizaliturri et al reported in a retrospective analysis of 40 relapsed/refractory aNHL 
subjects (34 DLBCL, 6 composite/transformed DLBCL) treated with single agent lenalidomide 
at Roswell Park Cancer Institute, Mayo Clinic, University of Bologna, and Hackensack 
University that there was a preferential clinical activity of lenalidomide in patients with the non-
GCB subtype DLBCL.(47) The tumor response rate was an impressive 52.9% (5 CR, 4 PR) in 
the non-GCB subtype although with the caveat of a small sample size (n=17) compared with 
only 8.7% (1 CR, 1 PR) in the GCB subtype (n=23). The median PFS for lenalidomide was 6.2 
months for the non-GCB and 1.7 months for the GCB subtype (p=0.004). Importantly, there 
were no significant differences in the age, disease stage at time of treatment, international 


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prognostic index (IPI) scores, or number of prior therapies between the 
COO groups. 
 
These observations led to the CC-5013-DLC-001 phase II/III randomized clinical trial of single 
agent lenalidomide versus investigator’s choice in subjects with relapsed/refractory DLBCL in 
GCB and non-GCB subtypes. In this trial, subjects with relapsed DLBCL underwent COO 
typing during the screening phase, which was used to assign subjects to two different cohorts 
defined by the subtype. The subjects were subsequently randomized to receive lenalidomide 
or single agent of investigator choice, and the ongoing as of December 2014. At the time of the 
planned final analysis (N=102 intention to treat patients (ITT) who were randomized, received 
at least one dose of therapy; 54 non-GCB, 48 GCB), the CC-5013-DLC-001 study showed a 
statistically significant improvement of median PFS for lenalidomide versus investigator’s 
choice treatment in the non-GCB subtype as assessed by the imaging and response 
assessment core (IRAC, control 7.1 weeks versus lenalidomide 15.2 weeks; p = 0.021, HR 
[95% CI] = 0.50 [0.27, 0.92]). In addition, there was a favorable trend in ORR as assessed by 
IRAC (control 11.5% versus lenalidomide 28.6%, p=0.179)). There was also a favorable trend 
in median OS in the non-GCB subtype (control 20.4 weeks versus lenalidomide 32.3 weeks; p 
= 0.253, HR [95% CI] = 0.70 [0.38, 1.30]). Potentially influencing the OS data, 16/26 (61.5%) of 
non-GCB subjects in the control arm crossed over to lenalidomide upon radiological evidence 
of disease progression on the comparator treatment. 
 
The CC-5013-DLC-001 study also included exploratory objectives related to gene expression 
profiling. If medically feasible, subjects were required to provide a fresh frozen lymph node or 
tumor biopsy at study enrollment; biopsies for 65 subjects were provided. Samples were then 
typed as ABC, GCB, or unclassifiable using Affymetrix U133 Plus 2.0 GeneChip microarrays. 
At the time of planned final analysis (N= 65 ITT who were randomized, received at least one 
dose of therapy, 27 ABC type, 8 unclassifiable type, 30 GCB type) the study showed a 
favorable trend in median PFS for lenalidomide versus investigator’s choice treatment in the 
ABC type as assessed by IRAC (control 6.3 weeks versus lenalidomide 82.0 weeks; p = 0.105, 
HR [95% CI] = 0.44 [0.15 – 1.23]). There was also a favorable trend in median OS in the ABC 
type (control 18.6 weeks versus lenalidomide 108.4 weeks; p = 0.144, HR [95% CI] = 0.47 
[0.17, 1.33]). 
 
Taken together, these data of lenalidomide single agent in subjects with relapsed DLBCL 
suggest that lenalidomide has preferential activity in non-GCB and ABC types of DLBCL. 
Further evidence supporting this preferential activity in the non-GCB subtype is observed in 
preclinical models (Section 1.4). 
 
1.6.4.2 
Front Line DLBCL 
The chemo-immunotherapeutic regimen of R-CHOP is a standard of care worldwide for the 


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treatment of patients with newly diagnosed DLBCL.(4) Two academic clinical research groups 
have developed the combination regimen of lenalidomide + rituximab + CHOP (R2-CHOP) in 
patients with newly diagnosed DLBCL: the Mayo Clinic Cancer Center in the US and the Italian 
cooperative group, Fondazione Italiana Linfomi (FIL). 
 
1.6.4.2.1 
Mayo Clinic R2-CHOP Data 
Protocol MC078E is an investigator initiated Phase 1/2 study of R2-CHOP in subjects with 
newly diagnosed, previously untreated DLBCL and follicular grade IIIA/B B-cell lymphoma, 
sponsored by the Mayo Clinic. 
 
The objective of the Phase 1 cohort of this study was to establish the maximum tolerated dose 
(MTD) of lenalidomide that could be combined with R-CHOP. A total of 24 subjects with newly 
diagnosed, untreated CD20-positive DLBCL or follicular grade III NHL were enrolled. Twenty of 
these 24 subjects had DLBCL. Subjects received oral lenalidomide on Days 1-10 with standard 
dose R-CHOP every 21 days. The lenalidomide dose levels tested were 15, 20, and 25 mg. 
The median age was 65 (35-82) years and 54% were over 60 years. Three subjects received 
15 mg, 3 received 20 mg, and 18 received 25 mg of lenalidomide. No dose-limiting toxicity 
(DLT) was found, and 25 mg on Days 1-10 was the recommended dose for the Phase 2 
portion of this study. The incidence of Grade 4 neutropenia and thrombocytopenia was 67% 
and 21%, respectively. Febrile neutropenia was rare (4%) and there were no deaths due to 
toxicity. The ORR was 100% with a CR rate of 77%. It was concluded that lenalidomide at the 
dose of 25 mg/day administered on Days 1 to 10 of 21-day cycle can be safely combined with 
R-CHOP in the initial chemotherapy of aggressive B-cell lymphoma.(60)  
 


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Based on these phase 1 results, the phase 2 cohort of the study was conducted to assess the 
efficacy of this combination. Response was evaluated using PET/CT by standard criteria.(6) 
The final results were recently reported with a total of sixty four subjects with DLBCL accrued 
to the Phase 2 cohort with median follow up of 23.5 months.(61) All subjects received R-
CHOP21 for 6 cycles plus lenalidomide 25 mg (R2-CHOP) on Days 1 – 10 of each cycle. 
Although not prospectively planned, subjects were retrospectively subtyped by IHC using the 
Hans algorithm (Hans, 2004). In the 60 evaluable patients, the overall response rate was 98%, 
with 80% achieving a complete response. Furthermore, 87 consecutive subjects with DLBCL 
and similar clinical characteristics participating in the Mayo Clinic Lymphoma Database and 
treated with standard R-CHOP alone served as a contemporaneously matched control. Table 
Table 1.  Patient Characteristics from Nowakowski et al 
 
 
 
Characteristics 
 
 
R2CHOP 
(n = 64) 
 
Contemporary 
Cohort of 
R-CHOP 
(n = 87) 
 
 
 
 
 
No. 
% 
 
No. 
% 
 
P 
Age, years 
Median 
Range 
 
65.0 
22.0-87.0 
 
 
61.0 
41.0-86.0 
 
.0132* 
Sex 
 
Female 
Male 
 
 
24 
40 
 
 
 37.5 
 62.5 
 
 
 
 37 
 50 
 
 
 42.5 
 57.5 
 
.5337† 
IPI 
Low 
Intermediate-low 
Intermediate-high 
High 
 
 
7 
 24 
 24 
 
9 
 
 10.9 
 37.5 
 37.5 
 14.1 
 
 
 18 
 16 
 38 
 15 
 
 20.7 
 18.4 
 43.7 
 17.2 
 
.0508† 
Ann Arbor stage 
2 
3 
4 
 
 
7 
 19 
 38 
 
 10.9 
 29.7 
 59.4 
 
 
 20 
 14 
 53 
 
 23.0 
 16.1 
 60.9 
 
.0467† 
ECOG PS 
0 
1 
2 
3 
 
 30 
 28 
 
6 
 
0 
 
 46.9 
 43.8 
 
9.4 
 
0.0 
 
 
 32 
 41 
 11 
 
3 
 
 36.8 
 47.1 
 12.6 
 3.4 
 
.36350‡ 
Abbreviations:  ECOG PS, Eastern Cooperative Oncology Group performance score; IPI, International Prognostic Index, R-
CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R2CHOP, lenalidomide added to R-CHOP. 
*Kruskal-Wallis test. 
†2  test. 
‡ Fisher’s exact test


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1 below describes the baseline characteristics of the DLBCL subjects treated with R2-CHOP in 
the Mayo Clinic phase 2 trial and the 87 subjects treated with R-CHOP as matched control.(61) 
Subjects treated with R2-CHOP had fewer subjects with low IPI score and were also older as 
compared to the R-CHOP cohort.  
 
Safety data of the R2-CHOP regimen showed the most common Grade 3 and 4 toxicities with 
R2-CHOP were neutropenia (12% Grade 3, 74% Grade 4), thrombocytopenia (30% Grade 3, 
16% Grade 4), anemia (20% Grade 3, 0% Grade 4), febrile neutropenia (12% Grade 3, 0% 
Grade 4), pneumonia (2% Grade 3, 0% Grade 4), sepsis (0% Grade 3, 2% Grade 4), venous 
thrombosis (0% Grade 3, 2% Grade 4), fatigue (2% Grade 3, 0% Grade 4) and dehydration 
(2% Grade 3, 0% Grade 4). Overall, R2-CHOP is considered well tolerated and has promising 
efficacy.(61)  
 
It is noted that an unplanned COO subtype cohort analysis, as defined by IHC testing, found 
that combination of lenalidomide with RCHOP appears to have improved outcomes, especially 
in the non-GCB subtype in comparison with the historical control patients. The 2-year PFS in 
the RCHOP control group was only 52% (95% CI: 43% – 64%), and the median follow up for 
patients still alive was 41.2 months (range: 11.6 – 78.3 months). By COO subtype, the 
historical RCHOP therapy achieved a 2-year PFS of 28% (95% CI: 15% – 51%) for the non-
GCB subtype, and 64% (95% CI: 53% - 78%) for the GCB subtype (log-rank p<0.001). In the 
patients treated with lenalidomide and RCHOP (R2CHOP), there was no difference in 2-year 
PFS between non-GCB (60%, 95% CI: 41% - 81%) and GCB (59%, 95% CI: 44% - 80%). In 
the RCHOP group, the 2-year OS in the non-GCB was 46%, as compared with 78% in the 
GCB group. In the R2CHOP group, the 2-year OS was improved to 83% in the non-GCB 
group, as compared to 75% in the non-GCB group. The implication of this evaluation of a 
prospective clinical trial and historical control is that the PFS and OS for non-GCB DLBCL 
patients is significantly improved with the addition of lenalidomide to RCHOP. An additional 
finding is that the outcome for patients with GCB DLBCL did not appear to have worsened 
outcomes with the addition of lenalidomide to standard immunochemotherapy. 
  
1.6.4.2.2 
FIL R2-CHOP Data 
The Italian cooperative group FIL conducted a prospectively designed multicenter phase 1/2 
study to evaluate the toxicity and efficacy of lenalidomide plus R-CHOP21 in untreated elderly 
DLBCL subjects, the REAL07 trial.(62) 
 
The objective of the Phase 1 cohort of the REAL07 trial was to determine the maximum 
tolerated dose of this combination. Four lenalidomide doses (5, 10, 15, and 20 mg/day on 
Days 1-14) using the continual reassessment method were planned in combination with each 
course of R-CHOP for a total of 6 courses. Seven subject cohorts (n=3 each) were treated 
(total n=21) at 10, 20, 15, 15, 15, 10, and 10 mg of lenalidomide. Dose-limiting toxicities 


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occurred in seven subjects during the first three treatment courses. The third dose-level of 
lenalidomide (15 mg/day) was selected as the maximum tolerated dose, with an estimated 
DLT probability of 0.345 (95% credibility interval 0.164-0.553). Grade 3-4 hematologic adverse 
events were: neutropenia in 28% of the courses, thrombocytopenia in 9%, and anemia in 3%. 
Non-hematologic toxicities were moderate: grade 4 increase of creatinine phosphokinase 
(n=1), grade 3 cardiac (n=2), grade 3 neurologic (n=3), and grade 3 gastrointestinal (n=1). In 
this phase 1 study, 90% of subjects achieved an overall response with 81% achieving 
complete remission. It was concluded that this combination is tolerable in elderly DLBCL 
subjects, and lenalidomide given at 15 mg on Days 1-14 of each cycle in combination with 
standard R-CHOP21 was the recommended dosing schedule for Phase 2 study.(63, 64) Nine 
subjects were treated at this dosing schedule in the Phase 1 cohort. 
 
Phase 2 of the REAL07 trial was a study to investigate the efficacy of R2-CHOP in CD20+ 
elderly DLBCL or FL grade IIIB subjects. Key inclusion criteria included age 60-80, Ann Arbor 
stage II-IV, and IPI > 2. The primary endpoints were ORR and CR rate after 6 courses of R2-
CHOP by using Cheson, 2007 criteria and included PET negativity as a requirement for CR. 
The secondary endpoints were 2-year OS, 2-year PFS, and relationship between response 
and histopathological features. Subjects were treated with lenalidomide given at 15 mg on 
Days 1-14 of each cycle in combination with standard R-CHOP21 for 6 cycles. Subjects were 
retrospectively subtyped by IHC using the Hans algorithm, although this analysis was not 
prospectively planned.(15) 
 
Forty-nine subjects were enrolled. The phase 2 cohort data analyses included these 40 
subjects plus 9 subjects from the phase 1 cohort treated at the recommended phase 2 
dose/schedule (total N=49). The most significant common hematological toxicities recorded in 
277 cycles of treatment were neutropenia (9% grade 3, 22% grade 4), leukocytopenia (15% 
grade 3, 13% grade 4), febrile neutropenia (3% grade 3, 1%, grade 4), thrombocytopenia (5% 
grade 3, 7% grade 4), and anemia (4% grade 3, < 0.5% grade 4) The most significant common 
hematological toxicities recorded in 277 cycles of treatment were neutropenia (9% grade 3, 
22% grade 4), leukocytopenia (15% grade 3, 13% grade 4), febrile neutropenia (3% grade 3, 
1%, grade 4), thrombocytopenia (5% grade 3, 7% grade 4), and anemia (4% grade 3, < 0.5% 
grade 4).  
 
The overall results for all 49 subjects showed a CR rate of 86%, ORR 92%, 2-year PFS 80%, 
and 2-year OS 92%. Among these 49 subjects, GCB vs. non-GCB typing assignment was 
achieved in 34 subjects (17 subjects with GCB, and 17 subjects with non-GCB) by Hans 
criteria.(15) The CR rate in subjects with non-GCB subtype appears to be essentially 
equivalent to that of the in GCB subtype subjects (88% vs. 81%). In addition, as was observed 
in the Mayo Clinic study, among the subjects treated with R2-CHOP regimen, the PFS and OS 
curves of the subjects with the non-GCB subtype appear to be about the same as or better 


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than the GCB subtype subjects. The 2-year PFS of patients with COO subtyping available was 
not different from those who did not have tissue available for subtyping. Among the patients 
with non-GCB DLBCL, the 2-year PFS was 81% (95% CI: 51-93) compared with 71% (95% CI: 
51-93) for the patients with GCB DLBCL, with a hazard ratio of 0.78 (95% CI: 0.21 - 2.9, 
p=0.705).  The 2-year OS was 94% (95% CI: 63 – 99) in non-GCB DLBCL, and 88% (95% CI: 
59 – 97) in GCB DLBCL, with a hazard ratio of 0.51 (95% CI: 0.05 – 5.63, p=0.58). Together, 
these data suggest that adding lenalidomide to standard therapy improved treatment outcome 
in non-GCB subjects who have a poor prognosis and typically have a worse outcome to 
treatment. 
 
1.6.5 Clinical Efficacy Data Conclusion 
In summary, the R2-CHOP efficacy data from the Mayo Clinic MC078E study and the FIL 
REAL07 study compare favorably to historical R-CHOP21 data with a better CR rate at the end 
of induction therapy and better PFS. Furthermore, promising efficacy results were also 
demonstrated in the non-GCB subtype, which generally has a poorer outcome when treated 
with R-CHOP alone. Clinically meaningful improvements as demonstrated by higher CR rate 
and longer PFS in non-GCB DLBCL subjects are considered significant in this difficult to treat 
sub-population (Table 2).(61, 62) This data is not direct comparison, but supports the 
hypothesis that lenalidomide is able to overcome the adverse outcomes associated with non-
GCB DLBCL. 
Table 2. Pooled outcomes from Mayo and FIL R2CHOP studies 
and Mayo RCHOP control 
  
  
  
Non-GCB 
  
GCB 
FIL 
  
  
  
  
  
  
2y PFS 
  
81% 
  
71% 
  
2y OS 
  
94% 
  
88% 
Mayo R2CHOP 
  
  
  
  
  
  
2y PFS 
  
60% 
  
59% 
  
2y OS 
  
83% 
  
75% 
Mayo RCHOP 
  
    
    
  
2y PFS 
  
28% 
  
64% 
  
2y OS 
  
46% 
  
78% 
 
The combination of lenalidomide and RCHOP is tolerable, without unexpected toxicities. The 
Grade 3 and 4 toxicities are primarily hematological, and manageable with supportive care. 


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1.7 
OBINUTUZUMAB  
Obinutuzumab (GA101, RO5072759), is a glycoengineered, humanized, type II anti-CD20 
monoclonal antibody (mAb).  Obinutuzumab was derived by humanization of the parental B-
Ly1 
mouse 
antibody 
and 
subsequent 
glycoengineering 
leading 
to 
the 
following 
characteristics(65, 66):  high antibody-dependent cellular cytotoxicity (ADCC); high affinity 
binding to the CD20 antigen; low complement-dependent cytotoxicity (CDC) activity; and 
antibody dependent cellular phagocytosis (ADCP) through recruitment of FcRIII positive 
immune effector cells such as natural killer (NK) cells, macrophages and monocytes; and high 
direct cell death induction.  
 
Given the direct cell death inducing properties of obinutuzumab and the significantly enhanced 
ADCC in preclinical assays, it is possible that obinutuzumab may have greater efficacy than 
the widely used anti-CD20-mAb rituximab (Rituxan).  
 
1.7.1 Obinutuzumab Preclinical Data 
Non-clinical in vitro studies show that obinutuzumab mediates superior induction of direct cell 
death and effector cell-mediated ADCC and ADCP on a panel of NHL cell lines as compared 
to the Type I CD20 antibodies rituximab and ofatumumab. Its potency to mediate CDC is 
significantly reduced as compared to these two antibodies. In ex vivo autologous whole blood 
B-cell depletion studies with blood from healthy volunteers as well as CLL patients, 
obinutuzumab mediated superior B-cell depletion when compared with rituximab. 
 
These properties of obinutuzumab translated into superior anti-tumor efficacy in direct 
comparison to rituximab against a number of aggressive SC and disseminated NHL xenograft 
models. Obinutuzumab induced complete tumor remission and long term survival (cures) and 
increased the overall survival in disseminated NHL xenograft models. The efficacious and 
optimal dose range of obinutuzumab in xenograft models was in the range of 10-30 mg/kg, 
corresponding to trough levels of 300-600 μg/mL. In addition, obinutuzumab showed efficacy in 
combination with classical chemotherapeutic agents, such as chlorambucil, fludarabine and 
bendamustine. Importantly, the combination of obinutuzumab with chemotherapeutic agents 
was superior to the combination of these agents with rituximab. Treatment with obinutuzumab 
also resulted in potent and superior depletion of B-cells in the peripheral blood and in lymphoid 
tissues of hCD20 transgenic mice and cynomolgus monkeys. Vaccination studies in 
cynomolgus monkeys and human CD20 transgenic mice showed that the enhanced efficacy in 
terms of B-cell depletion of obinutuzumab translated into suppression of de novo antibody 
responses, but left the protective humoral memory responses intact. 
 
The data generated to date imply that obinutuzumab represents a novel therapeutic CD20 
antibody with outstanding efficacy compared to classical Type I and non-ADCC enhanced 


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CD20 antibodies, such as rituximab and ofatumumab. Based on these non-clinical data it can 
be anticipated that the combination of the recognition of a Type II epitope together with 
improved ADCC and ADCP potency exclusive to obinutuzumab may translate into superior 
clinical efficacy. 
 
1.7.2 Obinutuzumab Clinical Pharmacology 
The clinical pharmacology properties of obinutuzumab have been characterized in a number of 
clinical studies, in patients with CLL or NHL. These studies include Phase 1 and 2 
monotherapy studies (BO20999 and BO21003), a Phase Ib combination study (BO21000) and 
a Phase 3 combination study (BO21004). A serum sampling scheme for the quantitation of 
obinutuzumab was undertaken in these studies to enable population PK analysis. 
 
Population PK modeling was undertaken on all available serum concentration data from 
studies BO20999, BO21003, BO21000 and BO21004/CLL11 to provide a robust description of 
the PK behavior of obinutuzumab. This demonstrated that a two compartment PK model 
comprising both a linear clearance pathway and a non-linear time varying clearance pathway 
adequately described serum obinutuzumab concentration data. The initial clearance of 
obinutuzumab was 2.85 times higher than the steady state clearance which is consistent with a 
decrease in the time varying clearance component, which is high at the start of treatment and 
which declines with repeated cycles of obinutuzumab treatment. The time varying clearance 
pathway is consistent with target mediated drug disposition, such that at the start of treatment 
when there is a large quantity of CD20 positive cells, this binds obinutuzumab. With repeated 
dosing of obinutuzumab this saturates the pool of CD20 positive cells, hence reducing this 
component in clearance. The linear clearance pathway is consistent with catabolism of IgG 
antibodies, and is therefore independent of CD20 positive cells. This analysis further supports 
the need to minimize the time varying clearance component quickly, and has lead to the 
proposed dose and regimen of 1000 mg in both induction and extended treatment. In the 
Phase II part of study BO21003, which investigated the 1000 mg obinutuzumab dose taken 
into Phase III, the PK of obinutuzumab was assessed in patients with indolent non-Hodgkin’s 
lymphoma (iNHL) who received weekly administrations of 1000 mg of obinutuzumab during the 
induction phase (4 administrations; Cycle 1 – Cycle 4) followed by an extended maintenance 
treatment phase of 1000 mg obinutuzumab every 2 months until disease progression. The 
mean obinutuzumab serum concentration increased markedly over the 4 treatment cycles. 
Following the final (i.e., fourth) administration of the induction treatment, obinutuzumab serum 
levels decreased. Overall, mean Ctrough serum levels of obinutuzumab observed during the 
maintenance regimen were similar across the 12 maintenance cycles. 
 
In study BO21004/CLL11, a pivotal Phase III study in CLL patients, mean serum 
obinutuzumab concentrations increased from Cycle 1 to Cycle 2 following administration of 
obinutuzumab on Day 1/2 (45 patients in Stage 1a received the first 1000 mg dose over 2 


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days: 100 and 900 mg on Days 1 and 2, respectively), Day 8 and Day 15 of Cycle 1. From 
Cycle 3 until Cycle 6, pre- and post-infusion serum concentrations remained constant during 
the course of treatment. Having the first 1000 mg administered over 2 days did not impair the 
rapid minimization of the time varying clearance component indicative of depletion of CD20+ 
tumor cells. 
 
In Phase Ib study BO21000, the PK of obinutuzumab in combination with cyclophosphamide, 
doxorubicin, vincristine, and prednisone (CHOP) or fludarabine and cyclophosphamide (FC) is 
being investigated in patients with relapsed/refractory FL. Based on preliminary PK data, for 
both combinations, obinutuzumab serum concentrations increased with increases in dose. In 
this same study, the effect of obinutuzumab on the PK of bendamustine was investigated in 
first-line NHL patients. The 2 cohorts (obinutuzumab + bendamustine and obinutuzumab + 
CHOP) showed similar PK profiles (serum obinutuzumab serum concentrations versus time), 
similar increases in systemic exposure (Cmax and AUC7 days) from Cycle 1 (Day 1 and Day 
8) to end of treatment cycle, total clearance, and volume of distribution (Vc). The effect of 
obinutuzumab on the PK of bendamustine is also being investigated in an ongoing Phase III 
study in rituximab-refractory iNHL patients. Based on preliminary data, there were no 
differences in bendamustine clearance when given with obinutuzumab compared to 
bendamustine alone following single administration. Similarly, no changes in half-life were 
observed for bendamustine when given in combination with obinutuzumab compared to 
bendamustine alone. 
 
Consistent with the mechanism of action of obinutuzumab, extensive B-cell depletion was 
observed both in patients with NHL and CLL. In most patients receiving obinutuzumab 
monotherapy, there was no notable increase in complement levels during or following an 
infusion. Changes in the levels of IL-6 and IL-8 were observed, i.e., increases during the 
course of the first infusion followed by a decrease to pre-infusion levels 7 days later. 
 
1.7.3 Summary of Pharmacokinetic and Pharmacodynamic Data for Obinutuzumab 
A two-compartment model comprising a time-varying clearance pathway and a linear 
clearance pathway provides an adequate description of the PK of obinutuzumab following 
intravenous (IV) administration in Studies BO20999 and BO21003.  Following the infusion of 
obinutuzumab, the elimination appears to be characterized by a clearance pathway that is 
dependent on time (i.e., starting at a typical value of 630 mL/day and then gradually 
decreasing to an asymptote of 60 mL/day at steady state) and a linear clearance pathway.  
Tumor burden may potentially contribute significantly to the clearance of obinutuzumab, 
especially at the beginning of treatment when CD20-positive tumor cells are most abundant.  
As tumor burden decreases, the clearance reaches an asymptote, which is believed to be 
primarily a function of the proteolytic metabolic clearance.  Consequently, some patients with a 
high tumor burden may appear to clear the drug from the plasma faster than do patients with a 


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low tumor burden because obinutuzumab binds to the CD20-positive tumor cells and is 
effectively removed from the plasma.  Therefore, the clearance of the drug will vary with time, 
since repeated treatments with obinutuzumab will reduce the quantity of CD20-positive tumor 
cells.  Consequently, the number of obinutuzumab administrations during the first cycle of 
treatment may be expected to reduce the number of CD20-positive tumor cells, thus 
minimizing the impact of the time varying clearance pathway on obinutuzumab exposure. 
Treatment with obinutuzumab resulted in extensive B-cell depletion, with all patients showing a 
reduction in cell count to absolute zero at some stage of their treatment cycle.  Overall, there 
has been no notable increase in complement levels before and after infusion, but changes 
have been observed in the levels of interleukin (IL)-6 and IL-8 before and after infusion. 
 
1.7.4 Clinical Experience with Obinutuzumab 
For the most up-to-date information on obinutuzumab, please refer to the current version of the 
Investigator’s Brochure. 
 
Table 3 shows the end-of-treatment response in patients with relapsed or relapsed/refractory 
NHL treated with obinutuzumab as monotherapy or in combination chemotherapy. 
 
1.7.4.1 
Obinutuzumab Monotherapy 
In the monotherapy setting, the proportion of patients who had a CR or PR at the end of 
treatment ranged from 28% to 58%. Although this was a population with treatment-refractory or 
relapsed disease, some patients in studies BO20999 and JO21900 achieved a CR by the end-
of-treatment assessment. The Phase I of study BO20999 recruited 21 NHL patients; 
lymphoma subtypes were follicular (n=13), mantle cell (n=4), diffuse large B-cell (n=1), small 
lymphocytic 
(n=1), 
lymphoplasmacytic 
lymphoma 
(n=1) 
and 
Waldenström’s 
macroglobulinaemia (n=1). In the Phase I part of the study, 7 patients (33%) had a response at 
the end of treatment. In the Phase II part, 11 patients (28%) with aNHL and 15 patients (38%) 
with iNHL had a response at the end of treatment. In Phase II, end-of-treatment response for 
iNHL was 17% (3 PR) for patients receiving 400/400 mg (n=18) obinutuzumab and 55% (2 CR, 
10 PR) in the 1600/800 mg cohort (n=22). The Phase I part of study BO21003 included 17 
patients: 10 with FL, 3 with DLBCL, 2 with lymphocytic lymphoma, and one each with mantle 
cell lymphoma (MCL) and marginal zone lymphoma. At the end of the (induction) treatment 
period, no patients had CR, 5 patients (29%) had PR, 2 patients had progressive disease (PD), 
and 1 patient had no data. 
 
1.7.4.2 
Obinutuzumab Combination Therapy 
In the Phase Ib chemotherapy combination study, BO21000, 53/56 relapsed/refractory patients 
(95%) had a response (CR+PR) at the end of treatment; one had PD, one had stable disease 
(SD) and one had no response assessment due to early withdrawal. In patients with previously 
untreated B-cell FL, 76/81 patients (94%) responded at the end of treatment; one each had SD 


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and PD, and 3 patients had no response assessment as they withdrew prior to the first 
response assessment. The proportion of patients with a CR was higher in this chemotherapy 
combination study than for the monotherapy studies (relapsed/refractory setting: 39% [11/28 
patients] in the obinutuzumab + CHOP arm and 50% [14/28 patients] in the obinutuzumab + 
FC arm; first-line setting: 39% [16/41 patients] in the obinutuzumab + bendamustine arm and 
35% [14/40 patients] in the obinutuzumab + CHOP arm). 
 
Table 3 Summary of Response in Patients with NHL Treated with Obinutuzumab  
 
Number of Patients (%) with 
 
Response 
 
(CR + PR) 
CR 
PR 
SD 
PD 
No Data 
Monotherapy 
 
 
 
 
 
 
BO20999 Phase I 
 N=21 (relapsed/refractory NHL) 
7 (33) 
4 (19) 
3 (14) 
5 (24) 
8 (38) 
1 (5) 
BO20999 Phase II 
 N=40 (relapsed/refractory aNHL) 
11 (28) 
3 (8) 
8 (29) 
4 (10) 
24 (60) 
1 (3) 
BO20999 Phase II N=40 
(relapsed/refractory iNHL) 
15 (38) 
2 (5) 
13 (33) 
12 (30) 
13 (33) 
- 
BO21003 Phase I 
N=17 (relapsed/refractory NHL) 
5 (29) 
- 
5 (29) 
9 (53) 
2 (12) 
1 (6) 
BO21003 Phase II* 
N=87 (relapsed/refractory iNHL) 
39 (45) 
10 (11) 
29 (33) 
37 (47) 
8 (9) 
4 (5) 
JO21900 Phase I 
 N=12 (relapsed/refractory NHL) 
7 (58) 
2 (17) 
5 (42) 
5 (42) 
- 
- 
Combination Therapy 
 
 
 
 
 
 
BO21000 (relapsed/refractory FL) 
 Obinutuzumab + CHOP: N=28 
 
Obinutuzumab + FC: N=28 
 
27 (96) 
26 (93) 
 
11 (39) 
14 (50) 
 
16(57) 
12 (43) 
 
1 (4) 
- 
 
- 
1 (4) 
 
- 
1 (4) 
BO21000 (first line FL) 
 Obinutuzumab + Bendamustine: 
N=41 
Obinutuzumab + CHOP: N=40 
 
38 (93) 
 
38 (95) 
 
16 (39) 
 
14 (35) 
 
22 (54) 
 
24 (60) 
 
1 (2) 
 
- 
 
1 (2) 
 
- 
 
1 (2) 
 
2 (5) 
 
 
 
 
 
 
 
CR:  complete response; PR: partial response; SD: stable disease; PD: progressive 
disease. 
Table shows the primary efficacy analysis at the end of treatment period (BO20999, 
JO21900)/ end of induction treatment period (BO21003, BO21000) 
*: analysis includes all patients, both follicular and non-follicular lymphoma, bur primary 
efficacy endpoint was only based on FL patients 
 
To date, more than 470 patients have been enrolled into one of the six ongoing or completed 


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studies with obinutuzumab for patients with CD20-positive B-cell malignancies. Obinutuzumab 
monotherapy has been well tolerated, with a preliminary safety profile similar to that of 
rituximab in NHL patients (i.e., mainly Grade 1 and 2 toxicities, with more frequent IRRs 
occurring in patients around the time of the first infusion, and decreasing with subsequent 
infusions). Obinutuzumab has been administered to patients at doses ranging between 50 and 
2000 mg, reaching cumulative doses per treatment regimen of up to 17,200 mg. Responses 
have been observed in all cohorts, with B-cell depletion being observed already at the lowest 
cohort. No dose-limiting toxicities have been observed. A high intra-individual and inter-
individual degree of antibody clearance has been observed. 
 
1.7.5 Rationale for Use of Flat Dosing of Obinutuzumab 
Similar to most current monoclonal antibodies, a flat dose (not adapted to body weight or body 
surface area [BSA]) has been chosen for obinutuzumab combination trials. The rationale for 
use of flat dosing was based on the fact that antibody clearance is mostly determined by target 
volume and target access, i.e., tumor burden and accessibility to normal or malignant tumor 
cells in various compartments, such as blood, bone marrow, and lymphatic organs, rather than 
body weight or surface area. In contrast, the dose of the first monoclonal antibody licensed for 
the treatment of B-cell malignancies was calculated on the basis of BSA.  
 
In the 1990s, determination of the dose for monoclonal antibodies followed an approach typical 
for cytotoxic drugs, for which an upper dose-limiting toxicity is usually determined. The toxicity 
is generally a function of the capacity to eliminate the drug by organs such as liver and spleen, 
limiting and narrowing the therapeutic window, and thereby requiring an adaptation of the dose 
using body weight or BSA. In effect, most monoclonal antibodies, including those targeting 
CD20, reveal a wide therapeutic window without the need to adjust dosing by BSA or body 
weight. However, because quantifying the target and adjusting individual dosing according to 
target has been notoriously difficult, the currently accepted approach for most monoclonal 
antibodies, including nearly all of those targeting CD20 in various stages of development, is flat 
dosing 
 
1.7.6 Rationale for Administration of Additional Doses of Obinutuzumab on Days 1 and 8 
In the Phase II part of Study BO20999, the first two doses of obinutuzumab in the HD cohort 
were set at 1600 mg. Although well tolerated by patients, the dosing scheme resulted in 
administration times of up to and exceeding 5 hours. With the goal in mind to maintain the 
loading dose concept, and to provide a significant amount of antibody early on during the 
treatment course, it was decided to split obinutuzumab administration and to change the 
schedule and dose during the first 2 weeks of any future studies from 1600 mg on Days 1 and 
8 to 1000 mg on Days 1, 8, and 15, providing comparably fast rising PK exposure and early 
target saturation, while avoiding the practical challenges of delivering 1600 mg of drug in a 
single day together with chemotherapy. The dose for subsequent cycles is also set at 1000 


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mg. This dose and schedule result in an obinutuzumab exposure of 3000 mg during the first 2 
weeks for a cumulative exposure of 10,000 mg and is therefore very close to the regimen that 
has delivered the best results thus far for obinutuzumab in both indolent and aggressive 
lymphoma. There is no indication that the additional obinutuzumab doses on Days 8 and 15 in 
the first cycle would negatively affect the safety of patients. 
 
1.7.7 Overview of Safety of Obinutuzumab 
Obinutuzumab has been administered to approximately 1310 patients with CD20-positive 
malignancies.  Both in patients with NHL and with CLL, infusion-related reactions (IRR) were 
the most common AE in clinical trials conducted to date.  They were predominantly associated 
with the first infusion, generally occurring early during the infusion, shortly after, or in some 
cases up to 24 hours after the completion of the infusion with obinutuzumab.  The incidence 
and intensity of IRRs decreased with subsequent infusions of obinutuzumab.  In a few patients, 
concurrent signs of tumor lysis syndrome (TLS) were observed.  Other frequently observed 
AEs include infections and neutropenia.  These events appeared to be more common in 
patients with CLL compared to NHL. 
 
In trials investigating the combination of obinutuzumab and CHOP, FC, chlorambucil or 
bendamustine, the incidence of AEs in the treatment arms with combined use was consistent 
with the known safety profiles of the individual study drugs.  So far, no maximum tolerated 
dose, no DLT, and no clear dose-related trends in the incidence of AEs have been determined. 
 
A pooled analysis of safety data for obinutuzumab collected during the monotherapy studies 
BO20999 and BO21003 was conducted in patients with NHL (aNHL] and iNHL) or CLL who 
participated in those two studies (both Phase I and Phase II) and received monotherapy 
treatment with obinutuzumab and included a total 205 patients with NHL (49 aNHL and 156 
iNHL patients) and 38 patients with CLL. 
 
In the group of 38 patients with CLL treated with obinutuzumab monotherapy, the majority of 
patients (25 [66%]) were treated for  4 weeks to  6 months.  Eleven patients (29%) were 
exposed for 6 to  12 months, and two patients (5%) were exposed for 12 months or longer.  
Eight of 38 patients (21%) with CLL were withdrawn during the treatment phase; 4 patients 
(11%) were withdrawn due to AEs, which indicates that AEs were mostly manageable.  Almost 
all patients (37/38 [97%]) experienced an IRR.  The number of patients with Grade 34 IRRs 
was 11/38 (29%).  As is typical for patients with CLL, blood and lymphatic system disorders 
were among the most frequently reported AEs, in particular neutropenia (13/38 patients 
[34%]), febrile neutropenia (5/38 patients [13%]), and thrombocytopenia (7/38 patients [18%]). 
 
Infections and infestations were common AEs, occurring in 21/38 patients (55%).  Infections 
reported in more than one patient were nasopharyngitis (6 patients), bronchitis and sinusitis (4 


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patients each), influenza and lung infection (3 patients each), and herpes zoster and oral 
herpes (2 patients each). 
 
Thirteen patients (34%) died, 8 of these due to disease progression.  One patient died from an 
unspecified cause after withdrawal from the study for lack of response.  This patient had 
received subsequent experimental therapies and had stable CLL at the time she died.  For 4 
additional patients, the cause of death was reported as colon cancer, lung adenocarcinoma, 
metastasis, and septic shock, and all were considered not to be related to treatment. 
 
In the two studies investigating obinutuzumab as monotherapy, BO20999 and BO21003, 
patients with CLL appeared to be at a higher risk of experiencing an AE of special interest than 
patients with NHL.  The largest difference in the incidences was seen for neutropenia 
(occurring in 47% of patients with CLL [18/38] vs. 8% of patients with aNHL [4/49] and 8% of 
patients with iNHL [13/156]) and treatment-related AEs associated with the infusion (100% 
[38/38] vs. 80% (39/49) and 83% [129/156]). 
 
To date, a very small number of patients have experienced tumor lysis syndrome (TLS) (six in 
total); four patients in the aNHL population (population including MCL) and one patient each in 
the CLL and iNHL populations. 
 
Infections have been reported in 20/49 aNHL patients (41%), 74/156 iNHL patients (47%), and 
21/38 CLL patients (55%).  One iNHL patient was withdrawn from the study because of an 
infection.  In addition, one CLL patient and one iNHL patient died from an infection (septic 
shock in both cases) during survival follow-up 671 days and 494 days after last dose of 
treatment, respectively. 
 
Three CLL and 3 iNHL patients were withdrawn from treatment due to an AE of special 
interest, all for IRRs.  An additional patient in the iNHL group discontinued treatment because 
of an infection.  This indicates that these events were generally manageable. 
 
In the Phase III Study BO21004 (CLL11), comparison of obinutuzumab + chlorambucil to 
chlorambucil alone showed that the most common AEs (all grades, Grades 3 − 4), 
respectively, were IRRs (69% vs. 0, 21% vs. 0), neutropenia (40% vs. 18%, 34% vs. 16%), 
thrombocytopenia (15% vs. 7%, 11% vs. 3%), anemia (12% vs. 10%, 4% vs. 5%), leukopenia 
(7% vs. 0, 5% vs. 0), pyrexia (10% vs. 7%,   1 vs. 0), and cough (10% vs. 7%, 0 vs.   1%). 
The incidence of IRRs was 69% with the first infusion of obinutuzumab.  The incidence of 
Grade 3 or 4 IRRs was 21%, with 8% of patients discontinuing therapy.  The incidence of 
reactions with subsequent infusions was 3%, with the second 1000-mg dose and <1% 
thereafter.  No Grade 3 or 4 IRRs were reported beyond the first 1000- mg infusion.  Of the 
first 53 patients receiving obinutuzumab in the trial, 47 (89%) experienced an IRR.  After this 


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occurrence, study protocol modifications were made to require pre-medication with a 
corticosteroid, antihistamine, and acetaminophen.  The first dose was also divided into two 
infusions (100 mg on Day 1 and 900 mg on Day 2).  Of the 45 patients for whom these 
mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 
1000-mg dose and <2% thereafter. 
 
The incidence of neutropenia reported as an AE was 40% in the obinutuzumab-treated arm 
and 18% in the chlorambucil-alone arm, with the incidence of serious adverse events (SAEs) 
being 1% and 0%, respectively.  Cases of late-onset neutropenia (occurring 28 days after 
completion of treatment or later) were 16% in the obinutuzumab-treated arm and 12% in the 
chlorambucil-alone arm.  
The incidence of infections was similar between arms.  Thirty-eight percent of patients in the 
obinutuzumab- treated arm experienced an infection, 9% were Grade 3 − 4, and none were 
fatal.  
 
The incidence of thrombocytopenia reported as an AE was 15% in the obinutuzumab-treated 
arm and 7% in the chlorambucil-alone arm.  Five percent of patients in the obinutuzumab-
treated arm experienced acute thrombocytopenia (occurring within 24 hours after the 
obinutuzumab infusion).  
 
The incidence of Grade 3 or 4 TLS was 2% in the obinutuzumab-treated arm vs. 0% in the 
chlorambucil-alone arm.  
 
AEs related to musculoskeletal disorders, including pain (System Organ Class), have been 
reported with obinutuzumab with higher incidence than with the comparator (17% vs. 13%, 
respectively).(67) 
 
1.7.8 Risks Associated with Obinutuzumab Therapy 
1.7.8.1 
Hepatitis B Virus Reactivation 
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic 
failure, and death, can occur in patients treated with anti-CD20 antibodies such as 
obinutuzumab.  HBV reactivation has been reported in patients who are hepatitis B surface 
antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core 
antibody (anti-HBc) positive.  Reactivation has also occurred in patients who appear to have 
resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface 
antibody [anti-HBs] positive).  HBV reactivation is defined as an abrupt increase in HBV 
replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a 
person who was previously HBsAg negative and anti-HBc positive.  Reactivation of HBV 
replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe 
cases, increase in bilirubin levels, liver failure, and death.  


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In patients who develop reactivation of HBV while receiving obinutuzumab, immediately 
discontinue obinutuzumab and any concomitant chemotherapy, and institute appropriate 
treatment.  Resumption of obinutuzumab in patients whose HBV reactivation resolves should 
be discussed with physicians with expertise in managing hepatitis B.  Insufficient data exist 
regarding the safety of resuming obinutuzumab in patients who develop HBV reactivation.  
 
1.7.8.2 
Progressive Multifocal Leukoencephalopathy  
JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be 
fatal, was observed in patients treated with obinutuzumab.  Consider the diagnosis of PML in 
any patient presenting with new onset or changes to pre-existing neurologic manifestations.  
Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain 
magnetic resonance imaging (MRI), and lumbar puncture.  Discontinue obinutuzumab therapy 
and 
consider 
discontinuation 
or 
reduction 
of 
any 
concomitant 
chemotherapy 
or 
immunosuppressive therapy in patients who develop PML.  
 
1.7.8.3 
Infusion-Related Reactions  
Obinutuzumab can cause severe and life-threatening IRRs.  Two-thirds of patients 
experienced a reaction to the first 1000 mg of obinutuzumab infusion.  IRRs can also occur 
with subsequent infusions.  Symptoms may include hypotension, tachycardia, dyspnea, and 
respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, and 
laryngeal edema).  Other common symptoms include nausea, vomiting, diarrhea, 
hypertension, flushing, headache, pyrexia, and chills.  
 
Pre-medicate patients with acetaminophen, antihistamine, and a glucocorticoid.  Institute 
medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for 
IRRs as needed.  Closely monitor patients during the entire infusion.  IRRs within 24 hours of 
receiving obinutuzumab have occurred.  
 
For patients with any Grade 4 IRRs, including but not limited to anaphylaxis, acute life-
threatening respiratory symptoms, or other life-threatening infusion reaction, stop the 
obinutuzumab infusion.  Permanently discontinue obinutuzumab therapy.  
For patients with Grade 1, 2, or 3 IRRs, interrupt obinutuzumab for Grade 3 reactions until 
resolution of symptoms.  Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions 
and manage symptoms. 
 
For patients with pre-existing cardiac or pulmonary conditions, monitor more frequently 
throughout the infusion and the post-infusion period because these patients may be at greater 
risk of experiencing more severe reactions.  Hypotension may occur as part of the 
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during, and for the first hour after administration of each obinutuzumab infusion until blood 
pressure is stable.  For patients at increased risk of hypertensive crisis, consider the benefits 
versus the risks of withholding their hypertensive medication as is suggested here.  
 
1.7.8.4 
Tumor Lysis Syndrome  
Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia 
from TLS can occur within 12 − 24 hours after the first infusion.  Patients with high tumor 
burden and/or high circulating lymphocyte count (  25  109/L) are at greater risk for TLS and 
should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) 
and hydration beginning 12 − 24 hours prior to the infusion of obinutuzumab.  For treatment of 
TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer 
supportive care, including dialysis as indicated.  
 
1.7.8.5 
Infection  
Serious bacterial, fungal, and new or reactivated viral infections can occur during and following 
obinutuzumab therapy.  Do not administer obinutuzumab to patients with an active infection.  
Patients with a history of recurring or chronic infections may be at increased risk of infection.  
 
1.7.8.6 
Neutropenia  
Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 neutropenia in 34% of 
patients in clinical trials.  Patients with Grade 3 to 4 neutropenia should be monitored 
frequently with regular laboratory tests until resolution.  Anticipate, evaluate, and treat any 
symptoms or signs of developing infection.  Neutropenia can also be of late onset (occurring 
more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 
days).  
 
Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis 
throughout the treatment period.  Antiviral and antifungal prophylaxis should be considered.  
 
1.7.8.7 
Thrombocytopenia  
Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 
12% of patients in clinical trials.  In 5% of patients, obinutuzumab caused an acute 
thrombocytopenia occurring within 24 hours after the obinutuzumab infusion.  In patients with 
Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution.  
Transfusion of blood products (i.e., platelet transfusion) may be necessary. 
 
1.8 
STUDY RATIONALE 


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Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy with 
~30,000 new cases in the US annually, is uniformly treated with a combination (CHOP) which 
remains essentially unchanged over the past 30+ years.(1) DLBCL biology now includes the 
definition of two distinct subtypes with unique gene expression programs,(2-4) genomic 
abnormalities,(5) microRNA profiles,(6-8) signaling pathways,(9-12) and response to targeted 
therapies.(13,14) These substantial advances in understanding DLBCL biology do not yet 
influence the frontline therapy of DLBCL patients, which achieves 5-year overall survival rates 
in activated B-cell (ABC) and germinal center B-cell subtypes (GCB) DLBCL of ~50% and 
~70%, respectively. The ABC subtype requires constitutive activity of the targetable B-cell 
receptor and NF-κB pathways for survival. Recent work has demonstrated the subtype-
selective activity of lenalidomide in ABC DLBCL comes from inhibition of the expression of the 
survival-critical transcription factor IRF4 (Figure 2). When lenalidomide reduces IRF4 
expression, a synthetically lethal interferon response occurs in ABC DLBCL cell lines.  
 
Figure 2. The BCR pathway and target for lenalidomide 
The clinical activity of lenalidomide in DLBCL has been shown to be significant, as a single 
agent (ABC DLBCL ORR 52%, 14, 16) or in combination with R-CHOP. (ORR 92%, CR 86%, 
equivalent in ABC and GCB DLBCL, 17-19). Equally impressive is that both lenalidomide was 
able to be dose escalated to its maximal studied level without significant toxicity when 
combined with R-CHOP. Based on the promising efficacy and toxicity data, lenalidomide is 
being evaluated in two randomized trials in combination with R-CHOP, and may file for an FDA 
indication/registration. 
 
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increased direct cell death and antibody dependent cell-mediated cytotoxicity when compared 
with rituximab. Obinutuzumab has shown promising single agent activity in relapsed DLBCL 
(ORR: 24 – 37% in a Phase I study, 20). Obinutuzumab has also been combined successfully 
with chemotherapy including CHOP in indolent lymphomas (21) and aggressive lymphomas 
(22). A randomized trial comparing rituximab and obinutuzumab with CHOP has recently 
completed accrual, with highly anticipated results expected in 2015 (23). 
 
The hypothesis of this clinical trial is that the combination of lenalidomide + obinutuzumab 
with CHOP will be tolerable and result in an ORR at least even to lenalidomide + rituximab with 
CHOP. Based upon the above data, we propose to conduct a Phase Ib/II trial to evaluate the 
combination of lenalidomide, obinutuzumab, and CHOP in patients with DLBCL  
 
 


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2. 
OBJECTIVES 
2.1 
PRIMARY 
The primary objective of the phase Ib portion of the trial will be to determine the maximum 
tolerated dose of lenalidomide + obinutuzumab with CHOP.  
 
The primary objectives of the Phase II portion of the trial will be to determine the efficacy 
(complete and overall response rate). 
 
2.2 
SECONDARY 
The secondary objectives of the Phase Ib portion will include the efficacy (overall and 
complete response rate) and tolerability of lenalidomide + obinutuzumab with CHOP. 
 
The secondary objectives of the Phase II portion will include determination of the survival 
outcomes (progression free and overall survival), and safety.  
 
Exploratory objectives will include the comprehensive genomic profiling of patient tumor 
and blood samples to attempt correlation with response, evaluation of immune cell subsets in 
peripheral blood at diagnosis and end of therapy to attempt correlation with response, and use 
of novel technology to evaluate for circulating tumor DNA of the lymphoma immunoglobulin 
heavy chain to attempt correlation with response. 
 
 


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3. 
STUDY DESIGN 
This will be a single arm, single institution, open-label phase Ib/II clinical trial of lenalidomide, 
obinutuzumab, and CHOP to evaluate the safety and efficacy in subjects with previously 
untreated CD20+ DLBCL. This study is divided into Screening (3.2), Treatment (3.3) and 
Follow-up Periods (3.4). Details of the study treatments are described in Section 5. 
 
3.1 
DESCRIPTION OF THE STUDY 
During Phase Ib, patients will receive previously demonstrated tolerable doses of lenalidomide 
with planned fixed dosing of obinutuzumab and CHOP to determine if the toxicity data from 
R2CHOP remains relevant. In the unlikely event that obinutuzumab and lenalidomide are 
found to result in unexpected toxicity, we may explore lower dosing levels of obinutuzumab. 
Patients will be evaluated in a standard 3+3 design. 
 
During Phase II, patients will receive lenalidomide + obinutuzumab with CHOP for a total of 6 
cycles.  
  
It is anticipated that a total of 59 patients will be enrolled in the Phase Ib/Phase II trial. The 
study will be conducted in compliance with Good Clinical Practice (GCP). 
 
3.2 
SCREENING PERIOD 
Screening for eligibility determination may begin after the subject signs the informed consent 
form. All screening assessments must be completed within 28 days prior to enrollment. The 
only exceptions to the 28-day time period are for the lymph node / tumor biopsy and the bone 
marrow biopsy / optional aspirate, which may occur up to 6 weeks prior to Cycle 1 Day 1.  
 
During the Screening Period, subjects will undergo safety and other assessments to determine 
eligibility for the study as shown in Section 7.1. 
Key aspects of screening include MD Anderson Pathology assessment of disease diagnosis, 
CD20+ status; local assessment of bone marrow involvement by lymphoma; documentation of 
measurable disease by CT scan; collection of a PET scan; and verification of adequate liver, 
renal, cardiac, and bone marrow function. 
 
3.3 
TREATMENT PERIOD 
The Treatment Period begins with Cycle 1 Day 1 dosing of the chemotherapy drugs as 
described in Section 5. Subjects will receive protocol-specified treatments for 6 cycles. 
Treatment will continue to completion, or until the outcome of the mid-therapy PET scan 
between Weeks 7 – 9 (after Cycle 3 but before Cycle 4) indicates a treatment change; disease 
progression; unacceptable toxicity; death; or withdrawal of consent, whichever occurs first. 
 
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and modification rules will be followed (Section 5.1 and 6). Key aspects of ongoing safety 
monitoring include physical exam, AE assessment, and hematology / chemistry laboratory 
testing prior to the initiation of every cycle, and at additional time points as shown in the 
Section 7. 
 
Key aspects of ongoing efficacy assessment include physical exam; CT scans at screening, 
once between 3 – 4 weeks after completing Cycle 6, and in follow-up at specified time points; 
and PET scans at Screening, between Weeks 7 – 9 (after Cycle 3 but before Cycle 4), and 
once 3 – 4 weeks after start of Cycle 6.  
 
The treatment will be defined in Section 5, but in brief the starting dosage level in the phase I 
trial will be: 
Dose level 1 (cycle is q21 days) 
 
Lenalidomide 15mg po daily 1 – 14 
 
Obinutuzumab 1000mg IV day 1, 8, 15 C1, day1 C2-6 
 
Cyclophosphamide 750mg/m2 IV on day 1 
 
Doxorubicin 50mg/m2 IV on day 1 
 
Vincristine 1.4mg/m2 (max 2mg) IV on day 1 
 
Prednisone 100mg po daily on days 1-5  
 
3.4 
FOLLOW-UP PERIOD 
The Follow-up Period begins upon study treatment discontinuation for all subjects. This 
includes subjects who complete the full course of treatment, who discontinue treatment due to 
progression or toxicity, as well as those who discontinue before progression to pursue a new 
anti-lymphoma / salvage therapy (chemotherapy, SCT, radiotherapy, etc.).  
 
3.5 
RATIONALE FOR STUDY DESIGN 
The CHOP regimen is well established as efficacious in our target population, as it has 
remained the standard therapy for nearly 40 years. The dosing for lenalidomide is based on 
the previous lenalidomide + RCHOP trials.(60, 62, 68). The dosing for obinutuzumab will be 
based on the Gather Study (NCT01414855)(69): 1000mg IV on day 1, 8, and 15 of cycle 1, 
then on day 1 of cycles 2 – 6. 
 
The rationale for conducting a phase Ib trial portion is to confirm that there is no adverse 
increase in toxicity from the previous Obinutuzumab-CHOP and Rituximab-Lenalidomide-
CHOP trials. Based on the large number of patients treated on these similar trials, it is 
anticipated that the Phase Ib portion will be limited in size. 
 
Although there has been compelling data that lenalidomide may have increased activity in the 
ABC subtype of DLBCL, we will allow all patients with newly diagnosed DLBCL to enroll in this 


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study. There is no suggestion that adding lenalidomide worsens outcomes in the GCB DLBCL 
subtype, and the combination of Obinutuzumab with lenalidomide-CHOP has not previously 
been explored. 
 
3.6 
OUTCOME MEASURES 
Outcome measurements will be detailed in Section 7. In brief, CT scans will be obtained at 
screening, once between 3 – 4 weeks after start of Cycle 6, and in follow-up at specified time 
points; and PET scans at Screening, between Weeks 7 – 9 (after Cycle 3 but before Cycle 4), 
and once 3 – 4 weeks after start of Cycle 6.  
 
3.6.1 Primary Efficacy Outcome Measure 
Phase Ib: Maximum Tolerated Dose as defined in Section 5.1 
Phase II: CR and ORR rate after 6 courses as defined in Section 8 
 
3.6.2 Secondary Efficacy Outcome Measures 
Phase Ib: ORR and CR rate and tolerability after 6 courses as defined in Section 8 
Phase II: Survival outcomes (progression free and overall survival), and safety after 6 courses 
as defined in Section 8 
 
 


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4. 
STUDY POPULATION 
Untreated CD20+ Diffuse Large B Cell Lymphoma, including both non-GCB/ABC and GCB 
patients. 
 
4.1 
ELIGILITY CRITERIA 
4.1.1 Inclusion Criteria 
Patients must meet all of the following criteria for study entry: 
4.1.1.1 
Confirmed treatment-naïve de novo CD20+ DLBCL, regardless of cell 
of origin, with Stage II-IV disease, or Stage I disease if 6 cycles of 
chemotherapy are planned.  
4.1.1.2 
Measurable disease on cross section imaging that is at least 1.5 cm in 
the longest diameter and measurable in two perpendicular dimensions 
4.1.1.3 
Appropriate candidate for systemic immune-chemotherapy such as the 
standard RCHOP21 6 cycles as determined by the treating physician 
4.1.1.4 
Age ≥18  
4.1.1.5 
Adequate organ function (normal cardiac ejection fraction of >45%, 
serum bilirubin <1.5 mg/dl, AST or ALT  5  ULN, and creatinine 
clearance  30 mL/min (Calculated according to Cockcroft–Gault 
formula) unless due to lymphoma with documentation of normal 
function prior to onset of lymphoma. In the case of Gilberts Syndrome, 
or documented liver or pancreatic involvement by lymphoma, the 
requirement for total bilirubin is ≤ 5.0 mg/dl  
4.1.1.6 
ANC >1000/mm3, hemoglobin >8.0, and platelets >100,000/mm3. If 
bone marrow is involved with lymphoma and normal marrow function 
prior to onset of lymphoma is documented: ANC of >750, any 
hemoglobin, and platelets of >50,000/mm3. 
4.1.1.7 
Performance status <3 (unless previous performance status was 0 or 1 
and deterioration is due to lymphoma which treating MD expects to 
reverse with therapy)  
4.1.1.8 
Consent to potential need for transfusion of blood products  
4.1.1.9 
Able to give informed consent 
4.1.1.10 
Ability and willingness to comply with the requirements of the study 
protocol 
 


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4.2 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from study entry: 
4.2.1.1 
Prior history of low grade lymphoma with transformation to DLBCL. If a 
patient has a composite diagnosis of DLBCL and low grade without a 
prior history of lymphoma, they will not be considered ineligible.  
4.2.1.2 
Pregnant or lactating females 
4.2.1.3 
Symptomatic CNS lymphoma involvement  
4.2.1.4 
Significant comorbidity (cirrhosis, severe coronary artery disease, 
significant psychiatric illness, or other that may compromise the ability 
to safely administer the therapy at the discretion of the primary 
investigator)  
4.2.1.5 
HBV:  Patients with positive serology for Hepatitis B defined as 
positivity for HBsAg or anti-HBc.  Patients who are positive for anti-HBc 
may be considered for inclusion in the study on a case-by-case basis if 
they are hepatitis B viral DNA negative and are willing to undergo 
ongoing HBV DNA testing by real-time PCR.  Patients with positive 
serology may be referred to a hepatologist or gastroenterologist for 
appropriate monitoring and management. 
4.2.1.6 
Hepatitis C (HCV):  Patients with positive hepatitis C serology unless 
HCV RNA is confirmed negative and may be considered for inclusion 
in the study on a case-by-case basis. 
4.2.1.7 
Known HIV or HTLV infection  
4.2.1.8 
Previous malignancy with diagnosis or suspicion of recurrence within 
the past 2 years, not including non-melanoma skin cancers or in situ 
malignancies. 
4.2.1.9 
History of severe allergic or anaphylactic reactions to monoclonal 
antibody therapy  
4.2.1.10 
Known hypersensitivity to any of the study drugs  
4.2.1.11 
Known active bacterial, viral, fungal, mycobacterial, or other infection 
(excluding fungal infections of nail beds) or any major episode of 
infection requiring treatment with IV antibiotics or hospitalization 
(related to the completion of the course of antibiotics) within 4 weeks 
before the start of Cycle 1 
4.2.1.12 
Major surgery (within 4 weeks prior to the start of Cycle 1), other than 
for diagnosis 
4.2.1.13 
Fertile men or women of childbearing potential unless 1) surgically 
sterile or 2) using an adequate measure of contraception such as oral 
contraceptives, intrauterine device, or barrier method of contraception 
in conjunction with spermicidal jelly. 


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4.2.1.14 
Vaccination with a live vaccine a minimum of 28 days prior to the start 
of treatment  
4.2.1.15 
Peripheral neuropathy ≥ Grade 2  
4.2.1.16 
Subjects who are unwilling to take VTE prophylaxis 
 
 
 


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5. 
TREATMENT PLAN 
This will be a single arm, single institution, open-label phase Ib/II clinical trial of lenalidomide, 
obinutuzumab, and CHOP to evaluate the safety and efficacy in subjects with previously 
untreated CD20+ DLBCL.   
 
5.1 
PHASE IB 
In the Phase Ib portion of the trial, the standard 3+3 design will be employed. Three patients 
will be enrolled in the Dose Level 1 cohort with dosing as: 
 
Dose level 1 (cycle is q21 days) 
 
Lenalidomide 15mg po daily 1 – 14 
 
Obinutuzumab 1000mg IV day 1, 8, 15 C1, day1 C2-6 
 
Cyclophosphamide 750mg/m2 IV on day 1 
 
Doxorubicin 50mg/m2 IV on day 1 
 
Vincristine 1.4mg/m2 (max 2mg) IV on day 1 
 
Prednisone 100mg po daily on days 1-5  
 
Drug dosing should occur at the above schedule unless it is not feasible due to 
patient travel delays, holiday schedule, or other unforeseen circumstance. In that 
event, the schedule may be modified for a therapeutic cycle to be between 20 
and 23 days (range of -1 day - +2 days). For obinutuzumab cycle 1 dosing, the 
day 8 and day 15 dosing can administered +/-1 day if necessary for similar to 
above issues.  
 
If zero of the initial 3 patients experiences a dose limiting toxicity (DLT, as defined below), an 
additional three patients will be treated at this dose level.  If 0 or 1 DLT is observed out of the 
total 6 patients treated at Dose Level 1, then Dose Level 1 will be selected for the Phase II 
portion of the trial and no further patients will be accrued to the phase Ib portion of the trial. 
 
The DLT evaluation period will be cycle 1. DLT will be defined as grade ≥ 3 non-hematologic 
toxicity per NCI CTCAE 4.0 unmanageable with aggressive supportive care or toxicity resulting 
in a delay of over 7 days of cycle 2. The incidence of neutropenic fever will be carefully 
monitored, but will not be considered a DLT as neutropenic fever is known to occur with R-
CHOP. 
 
If 1 out of the initial 3 patients develops a DLT, an additional 3 patients will be treated at the 
same dose level.  If no more DLTs develop at this dose (i.e., 1 out of a total of 6 patients 
develops a DLT), Dose Level 1 will be selected for the Phase II portion of the trial and no 
further patients will be accrued to the phase Ib portion of the trial. 
 


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At any given dose, if greater than 1 out of 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.  
 
Lower dose levels are defined as: 
 
Dose level 0 
Lenalidomide 10mg po daily 1 – 14 
Obinutuzumab 1000mg IV day 1, 8, 15 C1, day1 C2-6 
CHOP standard dosing 
 
Dose level -1 
Lenalidomide 10mg po daily 1 – 10 
Obinutuzumab 1000mg IV day 1, 8, 15 C1, day1 C2-6 
CHOP standard dosing 
 
Dose level -2 
Lenalidomide 5mg po daily 1 – 10 
Obinutuzumab 1000mg IV day 1, 8, 15 C1, day1 C2-6 
CHOP standard dosing 
 
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 the history of good tolerance of 
lenalidomide with RCHOP (including 2 planned/ongoing Phase III trials comparing RCHOP vs 
R2CHOP), and Obinutuzumab with CHOP, it is anticipated that a maximum of 15 will be 
enrolled in the phase Ib portion of the trial. The MTD identified in the Phase Ib portion of the 
trial will be selected as the recommended phase II dosing (RP2D) for further evaluation in the 
Phase II portion of the trial 
 
The 6 patients treated at the MTD in the phase Ib component of the trial will be included in the 
efficacy analysis of patients treated in the Phase II trial. 
 
5.2 
PHASE II 
In the Phase II portion of the trial, patients will be treated at the RP2D determined in the Phase 
Ib potiion for 6 cycles of therapy.  The trial plans to enroll 50 patients at the RP2D. 
 
A Bayesian toxicity monitoring rule will be used to ensure patient safety. The patient enrollment 
will be stopped at any time when excessive toxicity is observed. If the trial is halted prior to 
planned completion due to increased incidence of DLTs, the principle investigator would 
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If there is a minor modification that is estimated to likely correct the etiology of DLTs (e.g., 
addition of a specific prophylactic antibiotic as mandatory for all patients), the trial will resume 
at the previously determined MTD, with the same monitoring strategy as detailed above.   
 
If the etiology of the increased DLTs in unknown or not correctable with a minor modification, 
the trial will resume at the next lower dosing level from the Phase Ib portion of the trial if 
deemed appropriate by the principle investigator. If the increased DLTs are significant and 
unavoidable, the principle investigator may elect to end the trial before full enrollment is 
completed.  
 
6. 
CLINICAL TRIAL MEDICATIONS 
6.1.1 Obinutuzumab 
6.1.1.1 
Formulation 
Obinutuzumab is provided as a single-use vial.  Each vial contains a sterile 
liquid formulation in a 50-mL pharmaceutical-grade glass vial containing a 
nominal dose of 1000 mg of obinutuzumab (G3 material).  The formulated drug 
product consists of 25 mg/mL drug substance formulated in histidine/histidine-
HCl, trehalose, and poloxamer 188.  The vial contains 41 mL (with 2.5% overfill). 
 
6.1.1.2 
Storage 
The recommended storage conditions for the obinutuzumab drug product are 
between 2C and 8C, protected from light.  Chemical and physical in-use 
stability for obinutuzumab dilutions in 0.9% sodium chloride (NaCl) at 
concentrations of 0.2 − 20 mg/mL have been demonstrated for 24 hours at 
2C − 8C and an additional 24 hours at ambient temperature and ambient room 
lighting.  The prepared diluted product should generally be used immediately.  If 
not used immediately, 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 unless reconstitution/dilution has taken place in controlled and 
validated aseptic conditions.  Obinutuzumab should not be frozen or shaken.  
Mix gently.  All transfer procedures require strict adherence to aseptic 
techniques.  Do not use an additional in line filter because of potential 
adsorption. 
 
6.1.1.3 
Preparation 
Obinutuzumab drug product intended for IV infusion is prepared by dilution of 
the drug product into an infusion bag containing 0.9% NaCl.  
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should be 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 it 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. 
Administration sets with polyvinyl chloride, polyurethane, or polyethylene as 
product contact surface and IV bags with polyolefin, polypropylene, polyvinyl 
chloride, or polyethylene as product contact surface are compatible and may be 
used.  Use of a port or peripherally inserted central catheter line is acceptable. 
Do not use obinutuzumab beyond the expiration date stamped on the carton. 
6.1.1.4 
Dosage and Administration 
Obinutuzumab administered by IV infusion for up to 6 cycles (21-day cycles): 
• 
On Cycle 1, Days 1, 8 and 15, 1000 mg of obinutuzumab will be administered.  
• 
On Cycles 2 − 6, Day 1, 1000 mg of obinutuzumab will be administered 
(see Table Table 4) 
 
Obinutuzumab must be administered in a clinical setting (inpatient or outpatient).  
Full emergency resuscitation facilities should be immediately available, and 
patients should be under close supervision by the investigator or designated 
infusion team at all times.  Obinutuzumab should be given as a slow IV infusion 
through a dedicated line.  IV infusion pumps (such as Braun Infusomat Space) 
should be used to control the infusion rate of obinutuzumab.  Do not administer 
as an IV push or bolus.  After the end of the first infusion, the IV line should 
remain in place for at least 2 hours in order to be able to administer IV drugs if 
necessary.  If no AEs occur after 2 hours, the IV line may be removed.  For 
subsequent infusions, the IV line should remain in place for at least 1 hour from 
the end of infusion; if no AEs occur after 1 hour, the IV line may be removed. 
The rate of infusion and time of IV removal should be documented in the 
medical record. 
 
Formatted: Font: 12 pt


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Table 4 
Obinutuzumab Dosing Schedule 
Cycle and Day of 
Administration 
Dose of 
Obinutuzumab 
Rate of Infusion (in the Absence of Infusion 
Reactions/ Hypersensitivity during Previous 
Infusions) 
Cycle 1 
Day 1 
1000 mg 
• Administer at 50 mg/hour over 4 hours.  If no 
infusion 
reaction 
occurs, 
increase 
the 
infusion rate in 50-mg/hr increments every 
30 minutes, to a maximum of 400 mg/hr.  
• If an infusion reaction develops, stop or slow 
the infusion. Administer infusion-reaction 
medications 
and 
supportive 
care 
in 
accordance 
with 
institutional 
protocol. 
Resume the infusion at a 50% reduction in 
rate (the rate being used at the time that the 
hypersensitivity or infusion-related reaction 
occurred) if the reaction has resolved. 
Day 8 
1000 mg 
• If the patient tolerated the prior infusion well 
(defined as an absence of Grade 2 reactions 
during a final infusion rate of ≥ 100 mg/hr), 
begin the infusion at a rate of 100 mg/hr.  
• If a patient experienced an infusion reaction 
during the prior infusion, start at the same 
rate as the first infusion (50 mg/hr) and 
follow directions as noted. 
• If no infusion reaction occurs, increase the 
infusion rate in 100-mg/hr increments every 
30 minutes, to a maximum of 400 mg/hr. 
• If an infusion reaction develops, stop or slow 
the infusion. Administer infusion-reaction 
medications 
and 
supportive 
care 
in 
accordance 
with 
institutional 
protocol. 
Resume the infusion at a 50% reduction in 
rate (the rate being used at the time that the 
hypersensitivity or infusion-related reaction 
occurred) if the reaction has resolved. 
 
Day 15 
1000 mg 
Cycles 2−6 
Day 1 
1000 mg 
 
6.1.1.5 
Premedication Requirements 
Infusion-Related Reactions 
Since some patients may develop hypersensitivity or other IRRs to 


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obinutuzumab, pre-medication is recommended to reduce the risk of infusion 
reactions as outlined below: 
• 
Cycle 1, Day 1, all patients require pre-medication with:  
– 
IV glucocorticoid: dexamethasone (20 mg) or methylprednisolone (80 mg) 
administered at least one hour prior to obinutuzumab infusion.  Hydrocortisone 
should not be used as it has not been effective in reducing rates of IRR.  
– 
An oral acetaminophen (1000 mg) and an antihistamine such as 
diphenhydramine (50 mg) administered at least 30 minutes before starting each 
obinutuzumab infusion. 
• 
Cycle 1, Days 8 and 15 and Cycles 2-6, Day 1:  
– 
All patients require pre-medication with oral acetaminophen (1000 mg) 
administered at least 30 minutes before starting each obinutuzumab infusion. 
– 
Patients who experience an IRR (Grade 1 or more) with the previous infusion 
will require pre-medication with an antihistamine such as diphenhydramine 
(50 mg) administered at least 30 minutes before starting each subsequent 
obinutuzumab infusion. 
– 
Patients who experience a Grade 3 IRR with the previous infusion or who have 
lymphocyte counts of  25  109/L prior to the next treatment will require pre 
medication 
with 
IV 
glucocorticoid: 
dexamethasone 
(20 
mg) 
or 
methylprednisolone (80 mg) administered at least one hour prior to 
obinutuzumab infusion.  Hydrocortisone should not be used as it has not been 
effective in reducing rates of IRR.  
 
Hypotension may be expected to occur during obinutuzumab infusions.  
Withholding of antihypertensive treatments should be considered for 12 hours 
prior to and throughout each obinutuzumab infusion and for the first hour after 
administration.  Patients at acute risk of hypertensive crisis should be evaluated 
for the benefits and risks of withholding their hypertensive medication. 
For TLS prophylaxis, see Section 6.1.1.8. 
 
If a patient experiences any grade infusion reaction during infusion, adjust the 
infusion as outlined below: 
• 
Grade 4 (life threatening): Stop infusion and discontinue therapy. 
• 
Grade 3 (severe): Temporarily interrupt infusion and treat symptoms.  Upon 
resolution of symptoms, restart infusion at no more than half the previous rate 
(the rate being used at the time that the infusion reaction occurred) and, if 
patient does not experience any infusion reaction symptoms, infusion rate 
escalation may resume at the increments and intervals as appropriate for the 
treatment dose. 
• 
Grade 1 − 2 (mild to moderate): Reduce infusion rate and treat symptoms.  


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Upon resolution of symptoms, continue infusion and, if patient does not 
experience any infusion reaction symptoms, infusion rate escalation may 
resume at the increments and intervals as appropriate for the treatment dose. 
 
6.1.1.6 
Toxicity Management 
If a patient experiences an IRR of any grade during infusion, adjust the infusion 
as follows:  
• 
Grade 4 (life-threatening):  Stop infusion immediately and permanently 
discontinue obinutuzumab therapy.  
• 
Grade 3 (severe):  Interrupt infusion and manage symptoms.  Upon resolution of 
symptoms, consider restarting obinutuzumab infusion at no more than half the 
previous rate (the rate being used at the time that the IRR occurred) and, if the 
patient does not experience any further infusion-reaction symptoms, the infusion 
rate escalation may resume at the increments and intervals appropriate for the 
treatment cycle dose.  Permanently discontinue treatment if a patient 
experiences a Grade 3 infusion-related symptom at re-challenge.  
• 
Grade 1 − 2 (mild to moderate):  Reduce the infusion rate or interrupt infusion 
and treat symptoms.  Upon resolution of symptoms, continue or resume infusion 
and, if the patient does not experience any further infusion-reaction symptoms, 
infusion rate escalation may resume at the increments and intervals appropriate 
for the treatment cycle dose.  
 
6.1.1.7 
Hepatitis B Virus Reactivation 
Positive serology for Hepatitis B is defined as positivity for Hepatitis B surface 
antigen (HBsAg) or Hepatitis B core antibody (anti-HBc).  Patients who are 
positive for anti-HBc may be considered for inclusion in the study by the Medical 
Monitor on a case-by-case basis if they are Hepatitis B viral DNA negative and 
are willing to undergo ongoing HBV DNA testing by real-time PCR.  Patients 
with positive serology may be referred to a hepatologist or gastroenterologist for 
appropriate monitoring and management.   
For the subset of patients who are Hepatitis B viral DNA negative and anti-HBc 
positive and have undetectable Hepatitis B viral DNA levels at screening, 
Hepatitis B viral DNA levels must be followed approximately every 4 weeks.  
Guidelines for the management of hepatitis B reactivation are outlined in 
Table Table 5. 
Formatted: Font: 12 pt


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Table 5 
Management of Hepatitis B Reactivation 
Hepatitis B Viral DNA 
Level by Real-Time 
PCR 
Guideline 
 100 IU/mL 
• 
Hold obinutuzumab  
• 
Begin anti-viral medication and treat for at least 
1 year after the last dose of obinutuzumab. 
• 
Immediately 
refer 
the 
patient 
to 
a 
gastroenterologist 
or 
hepatologist 
for 
management. 
• 
Resume obinutuzumab once Hepatitis B viral 
DNA levels decrease to undetectable levels. 
 100 IU/mL while on 
anti-viral medication 
Discontinue obinutuzumab. 
29−100 IU/mL 
Retest within 2 weeks. 
If still hepatitis B viral DNA positive: 
• 
Hold obinutuzumab  
• 
Begin anti-viral medication and treat for at least 
1 year after the last dose of obinutuzumab. 
• 
Immediately 
refer 
the 
patient 
to 
a 
gastroenterologist 
or 
hepatologist 
for 
management 
• 
Resume obinutuzumab once Hepatitis B viral 
DNA levels decrease to undetectable levels 
 
6.1.1.8 
Management of Infusion-Related Reactions and Anaphylaxis 
Please refer to Section 6.2.1 for information relating to concomitant medications.  
Medications 
(including 
subcutaneous 
epinephrine, 
corticosteroids, 
and 
intravenous diphenhydramine) and resuscitation equipment should be available 
for immediate use. 
Life-Threatening Infusion-Related Reactions and Anaphylaxis 
In the event of a life-threatening IRR (which may include pulmonary or cardiac 
events) or IgE-mediated anaphylactic reaction, obinutuzumab should be 
discontinued and no additional obinutuzumab should be administered (see 
10.3).  Patients who experience any of these reactions should receive 
aggressive treatment of symptoms and will be discontinued from study 
treatment. 
Tumor Lysis Syndrome 
For patients with evidence of TLS, obinutuzumab should be discontinued and 
the patient treated as clinically indicated.  Following the complete resolution of 


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TLS complications, obinutuzumab may be re administered at the full dose during 
the next infusion in conjunction with prophylactic therapy. 
 
6.1.2 Lenalidomide 
6.1.2.1 
Formulation 
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.  
 
6.1.2.2 
Storage 
Lenalidomide will be packaged in bottles, and each bottle will contain 14 capsules. 
The label for lenalidomide will include sponsor name, address and telephone 
number, the protocol number, lenalidomide name, dosage form and strength 
(where applicable), amount of lenalidomide per container, lot number, expiry date 
(where applicable), medication identification/kit number, dosing instructions, 
storage conditions, and required caution statements and/or regulatory statements 
as applicable. Additional information may be included on the label as applicable 
per local regulations. 
 
6.1.2.3 
Dosing and administration 
Lenalidomide is initiated on Day 1 of Cycle 1 at a dose of 15 mg (oral 
administration) PO once daily for 14 days in each 21-day cycle. Lenalidomide 
should be taken at approximately the same time each day. There is no 
requirement for taking lenalidomide with or without food, or with or without certain 
types of foods or liquids. 
 
A rest period of at least 6 days following the 14 days of dosing is required. A rest 
period may be extended for toxicity as needed (Table 6). 
 
If a subject misses a dose of lenalidomide and it is within 12 hours of their normal 
dosing time, the subject should be instructed to make up the missed dose, and to 
then take their next dose according to their regular schedule. Lenalidomide 
concentration is low at 12 hours post dose, therefore making up a missed dose 
and then resuming regular dosing with a greater than or equal to (≥) 12 hour 
interval between the two doses will not cause considerable drug accumulation. 
 
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addition to those listed in Table 6 per investigator discretion. If a dose is reduced, 
re-escalation is not permitted. 
 
6.1.2.4 
Drug Dispensing Requirements 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of 
their participation in this trial at no charge to them or their insurance providers.  
Lenalidomide will be provided in accordance with the Celgene Corporation’s 
Revlimid REMS™ program. Patients will be enrolled in the REMS program after 
they have provided informed consent for the trial.  Per standard Revlimid REMS™ 
program requirements, all physicians who prescribe lenalidomide for research 
subjects enrolled into this trial, and all research subjects enrolled into this trial, 
must be registered in, and must comply with, all requirements of the Revlimid 
REMS™ program.   
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic 
site for Investigational New Drug (IND) studies. Only enough lenalidomide for one 
cycle of therapy will be supplied to the patient each cycle 
 
6.1.2.5 
Toxicity Management 
As the DLT evaluation period is cycle 1, the below events will be monitored but 
will not be considered DLT unless they occur within cycle 1. The dose 
modifications for lenalidomide mentioned below are identical to ongoing trials 
evaluating the combination of lenalidomide or placebo with RCHOP, and thus will 
be considered acceptable as long as below modifications are able to mitigate non-
DLT issues delineated below. 
Table 6 
NCI CTCAE Toxicity Grade v 4.0 
Action Required 
Neutropenia* 
Sustained (≥ 7 days) Grade 3 
    OR 
≥Grade 3 associated with fever (temperature ≥ 
38.5°C) 
    OR 
Grade 4 *unless secondary to lymphoma bone 
marrow 
involvement 
per 
investigator 
assessment 
 Withhold dose 
 Monitor CBC at least every seven days 
 If neutropenia has resolved to ≤ Grade 2 on first 
occurrence, restart at the same dose level 
 If neutropenia has resolved to ≤ Grade 2 on subsequent 
occurrences, restart at the next lower dose level 
Thrombocytopenia* 
≥Grade 3 (platelet count <50,000 /mm³ 
*unless secondary to lymphoma 
bone marrow involvement per 
investigator assessment 
 Withhold dose 
 Monitor CBC at least every seven days 
 If thrombocytopenia resolves to ≤ Grade 2 on first 
occurrence, restart at the same dose level 
 If thrombocytopenia resolves to ≤ Grade 2 on subsequent 
occurrences, restart at next lower dose level 
Rash 
Grade 2 or 3 non-desquamating (blistering) 
 
 Determine causative investigational product and if 
attributable to lenalidomide then: 
- Hold dose; administer antihistamines or short course of ≤ 


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------------ 
Desquamating (blistering) ≥ Grade 3 
OR 
Non-desquamating Grade 4 
20 mg prednisone (or equivalent) 
- When toxicity resolves to ≤ Grade 1, restart at the same 
dose level 
----------------- 
 Determine causative investigational product and if 
attributable to lenalidomide then: 
- Discontinue lenalidomide 
Allergic reaction or hypersensitivity 
Grade 2 
 
 
 
------------ 
Grade 3–4 
 Determine causative investigational product and if 
attributable to lenalidomide then: 
- Withhold dose. Follow at least every seven days 
- When the toxicity resolves to ≤ Grade 1, restart 
lenalidomide at next lower dose level 
----------------- 
- Discontinue lenalidomide 
Constipation 
Grade 1–2 
----------------- 
≥ Grade 3 
 Initiate bowel regimen and maintain dose level 
----------------- 
 Withhold dose. Follow at least every seven days 
 When the toxicity resolves to ≤ Grade 2, restart at 
same dose level 
Venous thrombosis/embolism 
≥ Grade 3 
 Withhold dose and start therapeutic anticoagulation; 
restart at investigator’s discretion (maintain dose level) 
Tumor Lysis Syndrome 
(TLS) Grading is per Cairo-Bishop, and not 
per NCI CTCAE, for TLS only 
Laboratory TLS or Grade 1 TLS 
 
 
 
----------------- 
Grade 2 – 4 
 Continue lenalidomide (maintain dose), or at the 
investigator’s discretion, continue lenalidomide and 
reduce dose by one level 
 Provide vigorous IV hydration and appropriate 
medical management, until electrolyte abnormalities 
are corrected. Rasburicase therapy is allowable. 
 Hospitalization will be at investigator’s discretion 
----------------- 
 Withhold dose 
 When symptoms resolve to Grade 0, restart at same 
dose level 
 If lenalidomide is resumed prior to the start of the 
subsequent cycle, a chemistry test should be 
performed every other day for the first week following 
re-initiation of lenalidomide 
Abnormal Liver Function: 
AST or ALT > 3 x ULN 
 Withhold lenalidomide dose; re-test at least weekly 
until AST or ALT < 2.5 x ULN or return to baseline 
 If the event is considered related to lenalidomide, 
restart lenalidomide at next lower dose level 
 If the event is considered NOT related to 
lenalidomide, restart the same dose of lenalidomide 
Abnormal Liver Function: 
Bilirubin > 3 x ULN 
 Withhold lenalidomide dose; re-test at least weekly 
until bilirubin < 1.5x ULN 
 If the event is considered related to lenalidomide, 
restart lenalidomide at next lower dose level 
 If the event is considered NOT related to 
lenalidomide, restart the same dose of lenalidomide 


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Other lenalidomide related 
non-hematologic AEs ≥ 
Grade 3 
 Withhold dose 
 When the AE resolves to ≤ Grade 2, restart at the 
same or next 
lower dose level per the investigator’s discretion 
 
6.1.3 CHOP Chemotherapy 
The CHOP regimen will be administered over a 21-day cycle. Treatment will continue until the 
CHOP regimen has completed 6 cycles, or until unacceptable toxicity, inadequate response to 
treatment is determined, disease progression, or withdrawal of consent, whichever occurs first. 
 
CHOP is a standard chemotherapy which has been employed routinely worldwide over the 
past 39 years. The dosing and schedule will be as per standard practice: 
Cyclophosphamide 750mg/m2 IV on day 1 
Doxorubicin 50mg/m2 IV on day 1 
Vincristine 1.4mg/m2 (max 2mg) IV on day 1 
Prednisone 100mg po daily on days 1-5  
 
6.1.4 Pre-medications: 
6.1.4.1 
Supportive Care 
Anti-emetics are required to be administered prior to each dosage of CHOP 
chemotherapy and may be administered with additional pre-medications given 
prior to obinutuzumab. However, the dosage and medication choice will not be 
mandated and will be at the discretion of the treating physician, but there will be 
suggested dosing on the order sets. Subsequent anti-emetics after start of a 
chemotherapy cycle will be given to as needed per the discretion of the treating 
physician. 
6.1.5 Pre-phase Treatment 
For subjects with bulky disease, systemic symptoms, compressive disease, elevated bilirubin 
due to lymphoma, or rapidly progressing adenopathies, pre-phase treatment with 1 mg/kg/day 
prednisone, or equivalent, for a maximum of 7 days is permitted prior to beginning the 
Treatment Period, at the discretion of the investigator.  
 
In the case of pre-phase corticosteroid treatment, there is no protocol specified definition of 
bulky disease. A washout period is not required; prophase treatment may be given, 
immediately followed by the prednisone as part of CHOP, and then a corticosteroid taper is 
allowed if the treating physician feels indicated. However, the Screening PET, CT, lymph node 
biopsy, and bone marrow biopsy (and if applicable, also the bone marrow aspirate) should be 
completed before initiating corticosteroids. 
 
Pre-phase treatment with vincristine or any other chemotherapy is prohibited. 
 


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6.1.6 Consolidation Treatment (Pre-Specified) 
The investigator may prospectively choose to give local radiotherapy after study chemotherapy 
for the treatment of a particular site of bulky disease or a large mass. In the case of 
consolidation treatment, bulky disease is defined as ≥ 7.0 cm. However, the decision to treat 
and the location to be treated must be determined during the Screening Period. In this case, 
the consolidation radiotherapy will not count as a treatment event for the EFS endpoint. 
 
If the investigator should decide at anytime after Cycle 1 Day 1 to give consolidation treatment, 
or to switch treatment to a different lesion, receipt of consolidation treatment will count as an 
EFS event. 
 
6.2 
CONCOMITANT AND EXCLUDED THERAPIES 
6.2.1 Concomitant Therapy 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient between the 14 days preceding the study entry evaluation and the early 
study treatment termination visit/study treatment completion visit.  All concomitant medications 
should be reported to the investigator and recorded on the appropriate electronic Case Report 
Form (eCRF). 
 
Patients who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use.  Effective contraception is required while receiving 
obinutuzumab and/or lenalidomide.  For women, effective contraception is required to continue 
for  12 months after the last dose of obinutuzumab and/or lenalidomide.  For men, effective 
contraception is required to continue for  3 months after the last dose of obinutuzumab and/or 
lenalidomide. 
 
6.2.1.1 
Prophylaxis for Tumor Lysis Syndrome 
All patients with peripheral blood lymphocyte counts of  25  109/L or bulky 
lymphadenopathy must receive prophylaxis for TLS prior to the initiation of study 
treatment.  This includes appropriate hydration consisting of a fluid intake of 
approximately 3 L/day starting 1 day prior to the first dose of obinutuzumab and 
administration of allopurinol (300 mg/day orally) or a suitable alternative 
treatment starting prior to the first infusion of obinutuzumab (Cycle 1, Day 1).  All 
patients should then be carefully monitored during the initial weeks of treatment.  
Patients still considered at risk for TLS because of persistently high tumor 
burden (i.e., peripheral blood lymphocyte counts  25  109/L) before the second 
and subsequent infusions of obinutuzumab should continue TLS prophylaxis 
with allopurinol and adequate hydration until the risk is abated, as determined by 
the investigator.   
 


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6.2.1.2 
Venous Thrombosis: 
Based upon prior trial data, it will be required for all patients to receive either 
aspirin (81 – 325 mg PO daily) or another prophylaxis agent while on 
lenalidomide. Exceptions will be made if a patient has a previous history of 
significant bleeding or other condition which makes anticoagulation unsafe in the 
determination of the principle investigator. 
The choice of VTE prophylaxis agent 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, bleeding risk, and the quality of 
compliance with the VTE prophylaxis. 
The use of clopidogrel or ticolpidine alone is not recommended as VTE 
prophylaxis in this trial. 
VTE prophylaxis may need to be held during therapy due the potential of 
thrombocytopenia associated with either CHOP, lenalidomide, or obinutuzumab. 
For guidelines regarding VTE management related to thrombocytopenia, refer to 
Table 7. 
 
Table 7 
NCI CTCAE Toxicity Grade v 4.0 
Action Required 
Thrombocytopenia* 
≥Grade 3 (platelet count <50,000/mm³ 
 
 Withhold anticoagulation 
 Monitor CBC at least every seven days 
 If thrombocytopenia resolves to < Grade 3 
(>50,000/mm3), restart anticoagulation unless other 
contraindication 
 
6.2.1.3 
Administration of Granulocyte Colony-Stimulating Factor 
Neutropenia prophylaxis with either granulocyte-colony stimulating factor (G-
CSF) is required. However, the selection of a particular drug, for example 
filgrastim, pegfilgrastim, or other is per treating physician discretion.  
 
6.2.1.4 
Infections Prophylaxis 
Pneumocystis jirovecii pneumonia prophylaxis is required. However, the drug, 
dose and schedule selection are per treating physician discretion.  
Additional antibiotic, antiviral, and antifungal prophylaxis is not required. 
However, treating physicians will be allowed to administer antibiotic, antiviral, 
and antifungal prophylactic medications if they desire. The use of live viral 
vaccines is contraindicated. 
 
6.2.1.5 
CNS Lymphoma Prophylaxis 
Subjects at risk for CNS involvement may receive CNS lymphoma prophylaxis 
treatment. At risk for CNS involvement is defined as high LDH with ≥2 


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extranodal disease sites, testicular, vertebral body, bone marrow, paranasal 
sinus, renal, or adrenal involvement, or at the discretion of the treating 
physician. The following may be considered by the investigator: 4 – 8 doses of 
intrathecal methotrexate and/or cytarabine administered during the systemic 
treatment. CNS prophylaxis with IV drugs is not permitted. 
 
 
 


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7. 
STUDY EVALUATIONS 
7.1 SCREENING EVALUATIONS 
• A history and physical examination, including determination of height, weight and 
performance status should be performed within 28 days prior to enrollment 
• The following laboratory studies should be performed within 28 days prior to enrollment: 
o CBC with differential, Serum chemistries – sodium (Na), potassium (K), chloride 
(Cl), glucose, bicarbonate (CO2), blood urea nitrogen (BUN), creatinine (Cr), 
calcium (Ca), magnesium (Mg), phosphorus, total protein, albumin, alkaline 
phosphatase, aspartate transaminase (AST), alanine transaminase (ALT), total 
bilirubin, uric acid, lactate dehydrogenase (LDH), -2 microglobulin, and urine 
analysis.  
• Females undergo pregnancy testing within 28 days prior to enrollment.  
• Quantitative immunoglobulins (IgG, IgA, and IgM) within 28 days prior to enrollment. 
• HIV, Hepatitis C viral antibody, Hepatitis B surface antigen, Hepatitis B core antibody 
within 28 days prior to enrollment. 
• The following staging studies should be performed within 28 days prior to enrollment:  
o CT scans of neck, chest, abdomen, and pelvis;  
o PET/CT Scan 
o Chest X-ray – PA and lateral; 
o An echocardiogram or MUGA scan 
 
7.2 PRE-TREATMENT EVALUATIONS 
The below testing may use the same data as Section 7.1 as long the test was performed within 
the below time windows 
• A history and physical examination, including determination of vital signs, height, weight 
and performance status should be performed within 3 working/business days prior to 
the start of therapy 
• The following laboratory studies should be performed within 3 working/business days 
prior to the start of therapy: 
o CBC with differential, Serum chemistries – sodium (Na), potassium (K), chloride 
(Cl), glucose, bicarbonate (CO2), blood urea nitrogen (BUN), creatinine (Cr), 
calcium (Ca), magnesium (Mg), phosphorus, total protein, albumin, alkaline 
phosphatase, aspartate transaminase (AST), alanine transaminase (ALT), total 
bilirubin, uric acid, and lactate dehydrogenase (LDH) 
• Females must follow pregnancy testing requirements as outlined in the Revlimid 
REMS™ program.  
• For correlative studies, 30 ml of blood sample [one purple top tube (10 ml) and 2 
heparin containing green top tubes (20 ml)] will be collected within 14 working/business 
days prior to the first dose of therapy. These samples will be transported within 6 hours 


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of collection to Dr. Neelapu’s laboratory for processing at the South Campus Research 
Building I, Room 2.2206, at M. D. Anderson Cancer Center (MDACC). Blood from red 
top and green top tubes will be processed for isolation of serum and peripheral blood 
mononuclear cells (PBMC), respectively using standard laboratory protocols.  
• For correlative studies, an optional core needle biopsy and fine needle aspiration may 
be requested from an accessible FDG avid lymph nodes. These samples will be 
transported within 6 hours of collection to Dr. Neelapu’s laboratory for processing at the 
South Campus Research Building I, Room 2.2206, at M. D. Anderson Cancer Center 
(MDACC). 
• Unilateral Bone marrow biopsy and aspirate 
• Standard of care testing not required by the protocol will include lumbar puncture for 
flow cytometry, glucose, protein, cell count and cytology if deemed necessary by the 
treating physician as part of initial disease workup. 
 
7.3 EVALUATIONS DURING THERAPY 
• A lymphoma therapy focused history and physical examination, including vital signs, 
height, weight and performance status assessment, should be performed within 3 
working/business days prior to the start of each therapeutic cycle 
• The following laboratory studies should be performed within 3 working/business days 
prior to the start of each therapeutic cycle: 
o CBC with differential, Serum chemistries – sodium (Na), potassium (K), chloride 
(Cl), glucose, bicarbonate (CO2), blood urea nitrogen (BUN), creatinine (Cr), 
calcium (Ca), magnesium (Mg), phosphorus, total protein, albumin, alkaline 
phosphatase, aspartate transaminase (AST), alanine transaminase (ALT), total 
bilirubin, uric acid, lactate dehydrogenase (LDH). Serum -HCG in women of 
child-bearing potential. 
• The following staging studies should be performed at the conclusion of cycle 3 and 
before the start of cycle 4 of therapy:  
o FDG PET/CT scan. Interim imaging can be CT scans when PET/CT scans 
cannot be obtained.  
• The following laboratory studies should be performed once weekly after the completion 
of therapy during the first treatment cycle, and in additional cycles at the treating 
physician’s discretion: 
o CBC with differential. Additional laboratory studies can be obtained at the 
discretion of the treating physician. 
• For correlative studies, 30 ml of blood sample [one purple top tube (10 ml) and 2 
heparin containing green top tubes (20 ml)] will be collected 21 days (+/- 72 hours) after 
the first cycle of therapy, prior to start of cycle 2. An additional purple top tube (10ml) 
will be obtained prior to the start of each additional cycle of therapy. These samples will 
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the South Campus Research Building I, Room 2.2206, at M. D. Anderson Cancer 
Center (MDACC). Blood from red top and green top tubes will be processed for isolation 
of serum and peripheral blood mononuclear cells (PBMC), respectively using standard 
laboratory protocols. The isolation of serum from red top tubes may also be performed 
at the CTRC Laboratory at MDACC using standard laboratory protocols. 
 
7.4 EVALUATIONS PERFORMED AFTER COMPLETION OF THERAPY 
• A history and physical examination should be performed within 3 - 4 weeks after the 
start of Cycle 6 
• The following laboratory studies should be performed within 3 - 4 weeks after the start 
of Cycle 6: 
o CBC with differential, Serum chemistries – sodium (Na), potassium (K), chloride 
(Cl), glucose, bicarbonate (CO2), blood urea nitrogen (BUN), creatinine (Cr), 
calcium (Ca), magnesium (Mg), phosphorus, total protein, albumin, alkaline 
phosphatase, aspartate transaminase (AST), alanine transaminase (ALT), total 
bilirubin, uric acid, lactate dehydrogenase (LDH). 
• The following staging studies should be performed within 3 – 4 weeks after the start of 
Cycle 6 (scan at end of therapy, EOT) :   
o PET/CT scan  
o Combined PET/CT and CT with IV contrast is acceptable, if applicable  
o Unilateral Bone marrow biopsy and aspirate (only if positive at the pre-treatment 
bone marrow obtain in 6.1.6 was positive for lymphoma) 
o Core needle biopsy of lymph nodes with suspicion of residual lymphoma (only if 
biopsy site is accessible by interventional radiology) 
• A lymphoma specific history and physical examination should be performed every 3 
months (+/- 4 weeks) during the first year after the EOT scan 
• The following laboratory studies should be performed every 3 months (+/- 4 weeks) 
during the first year after the EOT scan: 
o CBC with differential, Serum chemistries – sodium (Na), potassium (K), chloride 
(Cl), glucose, bicarbonate (CO2), blood urea nitrogen (BUN), creatinine (Cr), 
calcium (Ca), magnesium (Mg), phosphorus, total protein, albumin, alkaline 
phosphatase, aspartate transaminase (AST), alanine transaminase (ALT), total 
bilirubin, uric acid, lactate dehydrogenase (LDH). 
• The following staging studies should be performed every 3 months (+/- 4 weeks) during 
the first year after the EOT scan:  
o PET/CT Scan or CT Scan with IV/oral contrast (CT is preferred if EOT PET/CT 
showed no FDG avid or suspicious lesions) 
• A history and physical examination should be performed every 4 months (+/- 9 weeks) 
during the second year after the EOT scan 
• The following laboratory studies should be performed every 4 months (+/- 9 weeks) 


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during the second year after the EOT scan: 
o CBC with differential, Serum chemistries – sodium (Na), potassium (K), chloride 
(Cl), glucose, bicarbonate (CO2), blood urea nitrogen (BUN), creatinine (Cr), 
calcium (Ca), magnesium (Mg), phosphorus, total protein, albumin, alkaline 
phosphatase, aspartate transaminase (AST), alanine transaminase (ALT), total 
bilirubin, uric acid, lactate dehydrogenase (LDH). 
• The following staging studies should be performed every 4 months (+/- 9 weeks) during 
the second year after the EOT scan:  
o PET/CT Scan or CT Scan with IV/oral contrast (CT is preferred if EOT PET/CT 
showed no FDG avid or suspicious lesions) 
• Beyond the second year after EOT scan: restaging imaging, laboratory studies, and 
history and physical examination schedule will be determined by the treating physician. 
• For correlative studies, 30 ml of blood sample [one purple top tube (10 ml) and 2 
heparin containing green top tubes (20 ml)] will be collected within 3-4 weeks after the 
last cycle of therapy. An additional purple top tube (10ml) will be obtained at future visits 
at the discretion of the principle investigator if there is suspicion for relapse or other new 
disease related complaint. These samples will be transported within 6 hours of 
collection to Dr. Neelapu’s laboratory for processing at the South Campus Research 
Building I, Room 2.2206, at MDACC. Blood from red top and green top tubes will be 
processed for isolation of serum and peripheral blood mononuclear cells (PBMC), 
respectively using standard laboratory protocols. The isolation of serum from red top 
tubes may also be performed at the CTRC Laboratory at MDACC using standard 
laboratory protocols. 
 
 


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8. 
EVALUATION OF RESPONSE 
Response assessment testing will be detailed in Section 7. In brief, CT scans will be obtained 
at screening, once between 3 – 4 weeks after start of Cycle 6, and in follow-up at specified 
time points. FDG PET/CT scans will be obtained at screening, between Weeks 7 – 9 (after 
Cycle 3 but before Cycle 4), and once 3 – 4 weeks after start of Cycle 6. Obtaining FDG PET 
concurrently with CT scans will be allowable as long as the CT imaging is sufficient for 
response assessment. 
 
The primary endpoint of the phase II trial and patients treated at the MTD in the phase Ib trial 
will be the response rate, complete and overall, at the EOT scan, as defined by the Lugano 
Criteria and will be assessed by a dedicated Radiology collaborator.(70) For full details, please 
see the reference.  
 
Table 8 
Response  
PET-CT Based Response 
CT-Based Responses 
CR 
Complete metabolic response 
Score 1, 2, or 3 with or without a residual mass on 5 
point scale 
It is recognized that in Waldeyer’s ring or extranodal 
sites with high physiologic uptake or with activation 
within spleen or marrow (eg, with chemotherapy or 
myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the tissue 
has high physiologic uptake 
Complete Radiographic Response 
Target Nodes/nodal masses must regress to <= 1.5cm in 
longest dimension 
No extralymphatic sites of disease 
 
PR 
Partial Metabolic Response 
Score 4 or 5 with reduced uptake compared with 
baseline and residual masses of any size 
At interim, these findings suggest responding disease 
As end of treatment, these findings indicate residual 
disease 
Partial Remission (all of the following): 
>=50% decrease in sum of the product of diameters of up 
to 6 target measureable nodes and extranodal sites 
When a lesion is too small to measure on CT, assign 5 
mm x 5mm as default value 
When no longer visible on CT, assign 0 x 0 mm 
For a node 5 mm x 5mm, but smaller than normal, use 
actual measurement 
 
SD 
No metabolic response 
Score 4 or 5 with no significant change in FDG uptake 
from baseline at interim or end of treatment 
Stable disease  
< 50% decrease in sum of the product of diameters of up 
to 6 target measureable nodes and extranodal sites, no 
criteria for disease progression are met 
 
PD 
Progressive metabolic disease 
Score 4 or 5 with an increase in intensity of uptake from 
baseline and/or 
New FDG-avid foci consistent with lymphoma at interim 
or 
end-of-treatment assessment 
Progressive disease requires at least one of the following: 
An individual node/lesion must be abnormal with: 
LDi _ 1.5 cm and 
Increase by _ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions _ 2 cm 
1.0 cm for lesions _ 2 cm 
In the setting of splenomegaly, the splenic length must 
increase by >=50% of the extent of its prior increase 
beyond baseline (e.g, a 15-cm spleen must increase to 
>=16 cm). If no prior splenomegaly, must increase by at 
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The complete response rate is calculated as the proportion of subjects who have achieved CR 
prior to any treatment change. The overall response rate is defined as the proportion of 
subjects who have achieved either CR or PR prior to any treatment change. Of note, patients 
who had an initial positive bone marrow biopsy during testing in Section 7.1 will need to have a 
bone marrow biopsy repeated after therapy to confirm response. 
 
The secondary endpoint of the phase II and patients treated at the MTD in the phase Ib trial 
will be the survival outcomes (progression free and overall survival), and safety after 6 
courses.  
 
Progression free survival is defined as the time from study entry to objective disease 
progression or death from any cause, whichever occurs first. Objective disease progression 
will be evaluated utilizing the Lugano criteria.(70) Subjects who did not experience disease 
progression and who did not die before the clinical data cut-off date will be censored at the 
time of the last visit with adequate response assessment. 
 
Overall survival is defined as the time between study entry and death from any cause. Subjects 
who complete the study and are still alive at the time of the clinical data cutoff date will be 
censored at the last visit date or the last contact date, whichever is later. Subjects who were 
lost to follow-up prior to the clinical data cut-off date will also be censored at the time of the last 
contact. 
 
Safety is defined as a description of the significant toxicities encountered by patients, as 
defined in section 10. 
 
 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1 
DETERMINATION OF SAMPLE SIZE 
The maximum sample size for this phase Ib/II study is 59 with 15 for the phase Ib portion and 
additional 44 for the phase II portion.  The 6 patients treated at the MTD in the phase Ib portion 
will be included in the analysis for the phase II portion to reach the sample size of 50 (6+44).  
The phase II trial will determine the complete response rate after completion of therapy at the 
recommended phase 2 dosing levels. The obinutuzumab-CHOP trial (Gather) found an ORR 
of 83%, and CR rate of 55%. It is hypothesized that the combination of lenalidomide, 
obinutuzumab and CHOP should result in a CR rate of >75%. With a sample size of 45, the 
study will have a power of 0.8 to detect the difference between the null hypothesis response 
rate of 0.55 and the alternative hypothesis response rate of 0.75 assuming a two-sided type I 
error rate of 0.05. We would plan to enroll 50 patients in the phase II portion and MTD cohort 
of the of the Phase Ib portion of the trial to account for potential dropout or other issues 
impacting our final numbers for efficacy evaluation. 
 
9.2 
PLANNED EFFICACY EVALUATIONS 
The planned efficacy evaluations will be defined by each portion of the trial: 
9.2.1 Phase Ib: 
The primary endpoint of the phase Ib trial is not efficacy, but determination of the MTD. The 
patients treated at the MTD in the phase Ib component of the trial will be included in the 
efficacy analysis of patients treated in the Phase II trial. 
 
The MTD determination is defined in Section 5.1 
9.2.2 Phase II:  
The efficacy evaluation in patients treated at the MTD in phase Ib and in phase II portions of 
the trial will occur by evaluation of the end of treatment and subsequent follow up PET/CT 
scans, as defined in Sections 7.4 and 8. 
9.3 
METHOD OF ANALYSIS 
9.3.1 Clinical Outcomes Analysis: 
Summary statistics will be provided for continuous variables.  Frequency tables will be used to 
summarize categorical variables.  Logistic regression will be utilized to assess the effect of 
patient prognostic factors on the response rate and the toxicity rate.  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.  Cox proportional hazard regression may be 
employed for multivariate analysis on time-to-event outcomes. 
 
Toxicity data will be summarized by frequency tables for all patients.  For the efficacy 


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endpoints, intend-to-treat analysis will be applied to the eligible patients.  For the toxicity 
endpoint, per-treated analysis will be performed to include any patient who received the 
treatment regardless of the eligibility or the duration or dose of the treatment received.  
 
9.3.1.1 
Phase Ib:  
The primary objectives of phase 1b are to determine the MTD of lenalidomide, obinutuzumab, 
and CHOP. The secondary objectives are to determine the efficacy (complete and overall 
response rate) and tolerability.  Dose de-escalation will be guided by standard 3+3 design. The 
first cohort of 3 patients will be treated at Dose Level 1 and evaluated for DLT (definition in 
section 5.1) at the end of the first cycle (21 days per cycle).  The algorithm is as follows:  (1) As 
this trial has a high expectation of dosing safety, dosing will start at the anticipated MTD level 
(i.e., Dose Level 1). At Dose Level 1, if 0 or 1 out of 3 patients experiences DLT, an additional 
3 patients will be treated in this cohort.  (2) If no more DLTs develop at this dose (i.e., < 2 out 
of a total of 6 patients develops a DLT), Dose Level 1 will be the MTD and used in the Phase II 
portion of the trial.  (3) At any given dose, if greater than 1 out of 3 patients or 1 out of 6 
patients experience DLT, the dose level exceeds the MTD and 3 patients will be treated at the 
next lower dose.  (4)  If 0 or 1 out of 3 patients experiences DLT, an additional 3 patients will 
be treated at this dose level.  (5)  If no more DLTs develop at this dose level, then the current 
dose level will be the MTD and used in the Phase II portion of the trial.  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.  MTD will be used in the Phase II portion of the trial. 
Given the prior tolerance of R2CHOP and Obinutuzumab-CHOP, it is anticipated that eligible 
number of patients are required for the phase 1b part will be a maximum of 15 patients, and 
possibly only six patients.  
 
9.3.1.2 
Phase II 
Once the MTD is determined, a planned 50 patients will be treated at the RP2D (6 patients will 
be from the phase Ib who are treated at the MTD).  
 
To ensure treatment efficacy and patient safety, end of therapy complete response rate and 
DLT at 1 cycle during the Phase II portion of the trial will be monitored simultaneously using 
the Bayesian approach of Thall, Simon, Estey(71) as extended by Thall and Sung(72). The 
stopping boundaries will be calculated based on conjugate beta-binomial distribution. The trial 
will be stopped early if  
Pr (CR rate < 0.55 |data) > 0.95 
or 
Pr(DLT rate > 0.30 | data)  > 0.95 
That is, the trial will be stopped early if there is more than a 95% probability that the CR rate is 
lower than 55% or if there is more than a 95% probability that the DLT rate is higher than 30%. 
We assume that CR and DLT follow a prior distribution of beta (0.55, 0.45) and beta (0.3, 0.7), 


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respectively. 
 
The above futility and toxicity monitoring rules will be implemented by a cohort size of 10, 
starting from the 10th patient in Phase 2 have been enrolled. The corresponding stopping 
boundaries are listed in Table 9.1. For example, the patient enrollment will be stopped if more 
than 5 DLTs or less than 3 complete responses are observed among the first 10 patients. The 
patient enrollment will be halted for interim toxicity look if the number of non-DLT required for 
continuing the trial to next stage has not been achieved, but will not be halted for interim 
efficacy look. 
 
Table 9.1: The stopping boundaries of Phase II trial 
Number of 
patients 
evaluated 
Stop the trial if there are 
this many responses observed 
Stop the trial if there are 
this many toxicities observed 
10 
0-2 
6-10 
20 
0-7 
10-20 
30 
0-11 
13-30 
40 
0-16 
17-40  
50 
Always stop with this many patients 
Always stop with this many patients 
 
Table 9.2: The operating characteristics are summarized in the following table (based on 
simulations from 10,000 trials). 
 
True CR Rate 
True Toxicity 
Rate 
Prob(stop the trial 
early) 
Average number of 
patients treated 
0.40 
0.10 
0.652 
32.1 
 
0.30 
0.686 
30.5 
 
0.50 
0.947 
18.9 
0.55 
0.10 
0.096 
47.2 
 
0.30 
0.185 
44.4 
 
0.50 
0.862 
23.0 
0.70 
0.10 
0.003 
49.9 
 
0.30 
0.102 
46.8 
 
0.50 
0.848 
23.7 
 
 
 
The above stopping boundaries and operating characteristics were calculated using MultcLean (v.2.1.0) 
design software downloaded from http://biostatistics.mdanderson.org/SoftwareDownload.   


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9.3.2 Analysis Plan: 
Data analysis will be performed using SAS or R, as appropriate. The overall and complete 
response rates, DLT rate, and OS/PFS rate at 1 year will be summarized by relative frequency 
and 95% confidence interval. Patients who received at least one dose of the treatment drug 
will be evaluable for toxicity outcomes.  Toxicities will be summarized by dose levels, by grade 
and by their relationship to the treatment. The intent-to-treat patients will be used for the 
primary efficacy analysis; patients who are lost-to-follow up in the first 3 cycles will be treated 
as failures. The distribution of time-to-event endpoints including OS and PFS will be estimated 
by the method of Kaplan and Meier Analysis. Comparison of time-to-event endpoints by 
important subgroups will be made using the log-rank test.  Cox proportional hazard regression 
will be employed for multivariate analysis on time-to-event outcomes. 
9.3.3 Correlative Assay Analysis: 
The following correlative studies will be performed in Dr. Neelapu, Dr. Davis, or an MD 
Anderson Core laboratory using the blood, serum, and biopsy samples.  
 
9.3.3.1 
To determine whether obinutuzumab, lenalidomide, and CHOP 
enhance the frequency and function of tumor-specific T-cells in the 
peripheral blood, the phenotype and function of T cells will be 
assessed as follows: 
Phenotypic studies for T cells. PBMC (1 x 105 per tube) will be 
analyzed by multiparametric flow cytometry on 6-color, 8 parameter 
FACS Canto (BD Pharmingen) after staining with a panel of antibodies 
in 2 separate tubes. Tube 1: PBMC will be stained with CD3, CD4, 
CD8, CD45RO, CD69, and PD-1 to determine the percentage of total T 
cells, CD4+ T cells, CD8+ T cells, effector/memory (CD45RO+) T cells 
within each subset, activation status (CD69+) of T cells within each 
subset, and PD-1 expression within each subset. Tube 2: PBMC will 
be stained with CD3, CD4, CD8, CD45RO, CD62L, CD27, CD127 and 
CCR7 to determine the percentage of effector memory T cells 
(CD45RO+CD27-CCR7-, CD62L-CD127+) and central memory T cells 
(CD45RO+CD27+CCR7+, CD62L+CD127+) within CD4+ and CD8+ T-
cell subsets. The absolute number of each of these T-cell subsets in 
the peripheral blood of the patients will be calculated using the 
following formula: (absolute number of lymphocytes per l of blood on 
the CBC analysis) x (% of T-cell subset in lymphocyte gate).  
 


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9.3.3.2 
Statistical considerations for 9.3.3.1. The percentage of various T-cell 
subsets will be collected at each of the planned time points. Spaghetti 
plots will be used to show the biomarker measurements change 
overtime. Longitudinal analysis including mixed effects model for time-
dependent variables will be performed. The percentage change for the 
biomarkers from baseline to the various time points will be calculated. 
The correlations among the percentage changes for different 
biomarkers will be assessed by scatter plots and Spearman’s 
correlation coefficient. The association between the percentage 
change and patient’s clinical outcome such as complete and overall 
response will be evaluated. Wilcoxon rank sum test will be used to test 
the difference in percentage change of biomarker between the 
response group and the non-response group. The percentage change 
will also be dichotomized into two categories (high vs. low) based on a 
cutoff point which will be determined after examination of the data.  
Fisher’s exact test will be used to assess the associations between the 
dichotomized variables for percentage change and clinical response. 
 
To evaluate changes in T-cell subsets by phenotypic studies before 
and after obinutuzumab, lenalidomide, and CHOP treatment at the 
different time points, we will perform a two-sided paired t-test or 
Wilcoxon signed rank test for the experiments proposed under 9.3.3.1.  
 
9.3.3.3 
To evaluate the mutational and gene expression data from RNA-Seq of 
tumor biopsy material, the following analyses will be performed. The 
baseline biopsy will be evaluated with RNA sequencing (RNA-
Seq)(73), in comparison with germline DNA, to determine gene 
expression, translocations, and mutations including those known to 
correlate with ibrutinib resistance (e.g., BTK, PLCγ2, MYD88, 
CARD11, CD79A/B).(18, 74-77) To attempt correlation of GEP data 
with clinical responses to obinutuzumab, lenalidomide, and CHOP by 
comparing baseline aggregate expression data between responders 
and non-responders, a regression analysis will be performed. Data 
from RNA-Seq will be processed using published methods, including 
standard quality assessments and R software packages.(73, 78, 79) 
Gene expression will be compared against the continuous variable of 
tumor regression percentage and/or changes in LymphoSIGHT values, 
and analyzed using Gene Set Enrichment Analysis (GSEA)(80) to 
evaluate for processes in the tumor cells and microenvironment which 
are associated with response to R-CHOP, but have an unknown 


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relevance to obinutuzumab, lenalidomide, and CHOP.(18) We will also 
perform RNA-Seq on biopsies of residual disease, and potentially 
perform focused deep sequencing of DNA from residual tumor, PBMC 
(germline), and initial biopsy. Based upon findings in 9.3.3.1 and from 
RNA-Seq of biopsy material, we may elect to perform gene expression 
profiling or RNA-Seq on PBMC, was employed in our previous 
rituximab and lenalidomide trials. 
 
9.3.3.4 
Analysis of LymphoSIGHT data 
Minimum Residual Disease (MRD) will be determined by NGS method 
as MRD negative or MRD positive at each MRD assessment time 
point. MRD status of subjects will be assessed by an NGS-based 
method and compared with results from imaging based assessments. 
Correlation of MRD status from both types of assessment with clinical 
outcomes will be analyzed. In order to evaluate how well the MRD 
assay predicts clinical outcome, its sensitivity and specificity in 
predicting disease progression will be calculated. 
 
The sensitivity and specificity of MRD in predicting disease progression 
is described in the table below. 
 
 
 


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In subjects who achieve CR, the MRD test results will also be 
evaluated to assess time to achieve MRD status, duration of MRD 
status, and their correlation to clinical progression. 
 
The sensitivity and specificity of MRD in predicting clinical outcomes 
such as PFS and OS will be similarly analyzed. 
 
 


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10. 
REPORTING OF ADVERSE EVENTS 
10.1 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and reporting AEs and SAEs that are considered 
related to obinutuzumab or lenalidomide, all events of death, and any study specific issue of 
concern. 
 
10.1.1 Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of an investigational medicinal product (IMP) or other protocol-imposed 
intervention, regardless of attribution. 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with DLBCL 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. 
 
10.1.2 Serious Adverse Events 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred 
in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 


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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 for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
 
10.2 
METHODS FOR ASSESSING AND RECORDING SAFETY VARIABLES  
The investigator is responsible for ensuring that all AEs and SAEs, that are observed or 
reported during the study, are collected and reported to the U.S. Food and Drug Administration 
(FDA), appropriate IRB(s), Celgene, and Genentech, Inc. in accordance with CFR 312.32 (IND 
Safety Reports).  
 
10.2.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier. 
After this period, investigators should only report SAEs that are attributed to prior study 
treatment. 
 
10.2.2 Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start 
and end dates), regulatory seriousness criteria if applicable, suspected relationship to 
obinutuzumab, lenalidomide, or CHOP (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of 
obinutuzumab, lenalidomide, or CHOP, and the AE cannot be readily explained by the 
patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a 


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known pattern of response to the [study drug}; and/or the AE abates or resolves upon 
discontinuation of the [study drug} or dose reduction and, if applicable, reappears upon re-
challenge. 
No 
Evidence exists that the AE has an etiology other than the [study drug} (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or 
the AE has no plausible temporal relationship to obinutuzumab, lenalidomide, or CHOP 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
 
Expected AEs are those AEs that are listed or characterized in the Package Inserts or current 
Investigator Brochures.  
 
Unexpected AEs are those not listed in the Package Inserts or current Investigator’s Brochures 
or not identified.  This includes AEs for which the specificity or severity is not consistent with 
the description in the Package Inserts or Investigator’s Brochures.  For example, under this 
definition, hepatic necrosis would be unexpected if the Package Inserts or Investigator’s 
Brochures only referred to elevated hepatic enzymes or hepatitis. 
 
10.2.2.1 
Second Primary Malignancies 
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events regardless of the treatment arm the subject is in. This includes any 
second primary malignancy, regardless of causal relationship to obinutuzumab, lenalidomide, 
or CHOP, occurring at any time for the duration of the study, from the time of signing the 
informed consent document (ICD) for at least 5 years from the date the last subject is entered 
into the study. Events of second primary malignancy are to be reported using the SAE report 
form and must be considered an “Important Medical Event” if no other serious criteria apply; 
these events must also be documented in the appropriate page(s) of the CRF (i.e., AE and 
SPM CRF) and subject’s source documents. Documentation on the diagnosis of the second 
primary malignancy must be provided at the time of reporting as a serious adverse event (e.g., 
any confirmatory histology or cytology results, X-rays, CT scans, etc.). 
10.2.2.2 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age 
or disease state) of a female subject occurring while the subject is on lenalidomide, or within 
28 days of the subject’s last dose of lenalidomide, are considered immediately reportable 
events. Lenalidomide is to be discontinued immediately. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety immediately 
by facsimile or email using the Pregnancy Initial Report Form. The female subject should be 
referred to an obstetrician-gynecologist, preferably one experienced in reproductive toxicity for 
further evaluation and counseling. If a female patient becomes pregnant while receiving 
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and/or lenalidomide, or the partner of a male patient becomes pregnant while receiving therapy 
or within three months of completing therapy, a report should be completed and expeditiously 
submitted to Genentech and Celgene, Inc.   
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety and Genentech, Inc. 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 and 
Genentech, Inc. 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 lenalidomide should also be reported to Celgene Drug 
Safety and Genentech, Inc. immediately by facsimile, or other appropriate method, within 24 
hours of the Investigator’s knowledge of the event using the SAE Report Form. 
If a female partner of a male subject taking investigational product becomes pregnant, the 
male subject taking lenalidomide or obinutuzumab should notify the Investigator, and the 
pregnant female partner should be advised to call their healthcare provider immediately. 
 
10.3 
PROCEDURES FOR RECORDING, AND REPORTING SERIOUS ADVERSE 
EVENTS  
• All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of 
the event to the Safety Project Manager in the IND Office.   
 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• 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. 
 
• Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 


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Reporting to FDA: 
 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
 
10.3.1 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations. 
 
10.3.1.1 
Diagnosis versus Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, it is 
acceptable to report the information that is currently available.  If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
 
10.3.1.2 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 10.2.1), 
regardless of attribution, will be reported to the appropriate parties.  When recording a death, 
the event or condition that caused or contributed to the fatal outcome should be reported as 
the single medical concept.  If the cause of death is unknown and cannot be ascertained at the 
time of reporting, report “Unexplained Death”. 
 
10.3.1.3 
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”). 
 
10.3.1.4 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE.  If a patient is hospitalized to undergo a medical or surgical procedure as 
a result of an AE, the event responsible for the procedure, not the procedure itself, should be 


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reported as the SAE.  For example, if a patient is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study. 
 
10.3.1.5 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient has completed 
or discontinued study participation if attributed to prior obinutuzumab exposure.  If the 
investigator should become aware of the development of cancer or a congenital anomaly in a 
subsequently conceived offspring of a female patient who participated in the study, this should 
be reported as an SAE.  
 
10.3.1.6 
Safety Reconciliation 
The investigator agrees to conduct reconciliation for the product.  Genentech and Celgene 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 
investigator 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. 
 
10.3.1.7 
Adverse Events of Special Interest (AESIs) 
AEs of special interest (AESIs) are defined as a potential safety problem, identified as a result 
of safety monitoring of the Product. 
 
The following AEs are considered of special interest and must be reported to the Sponsor 
expeditiously (see Section 10.3.1.8 for reporting instructions) irrespective of regulatory 
seriousness criteria: 
  
• 
Tumor Lysis Syndrome (TLS - all grades) 
 
10.3.1.8 
Serious Adverse Event Reporting 
Investigators must report all SAEs to Genentech and Celgene within the timelines described 
below.  The completed MedWatch/case report should be faxed immediately upon completion 
to Genentech Drug Safety at: 
(650) 225 4682 


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OR 
(650) 225 5288 
Email: us_drug.safety@gene.com 
 
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 
 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available. 
 
Serious AE reports that are related to obinutuzumab and AEs of Special Interest (regardless of 
causality) will be transmitted to Genentech within 15 calendar days of the Awareness Date. 
 
Serious AE reports that are unrelated to obinutuzumab will be transmitted to Genentech within 
thirty (30) calendar days of Awareness Date. 
 
 
 
Additional reporting requirements to Genentech include the following: 
• 
Any reports of pregnancy following the start of administration with the obinutuzumab and 
within the follow-up period (for female patients within one year after the last dose of 
obinutuzumab or the partner of a male patient within three months of completing therapy) 
will be transmitted to Genentech within thirty (30) calendar days of the Awareness Date.  
• 
All non-serious obinutuzumab AEs originating from the study will be forwarded Genentech 
quarterly. 
 
Expedited Reporting by Investigator to Celgene 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness 
of events of being related to lenalidomide based on the Investigator Brochure.  In the United 
States, all suspected unexpected serious adverse reactions (SUSARs) will be reported in an 
expedited manner in accordance with 21 CFR 312.32. 
 


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Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of 
being aware of the event.  The written report must be completed and supplied to Celgene by 
facsimile within 24 hours/1 business day.  The initial report must be as complete as possible, 
including an assessment of the causal relationship between the event and the investigational 
product(s).  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 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. 
 
Note: Investigators should also report events to their IRB as required. 
 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (item 5) of the 
MedWatch 3500A form: 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the AE to each investigational product and 
suspect medication 
 
Follow-Up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form  
• 
Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e., D.O.B. initial, patient number), protocol description and number, if assigned, brief AE 
description, and notation that additional or follow-up information is being submitted (The 
patient identifiers are important so that the new information is added to the correct initial 
report) 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom and AE was reported.  For questions regarding SAE 
reporting, you may contact the Genentech Drug Safety representative noted above or the 
medical science lisason 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. 


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MedWatch 3500A (Mandatory Reporting) form is available at: 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm 
 
10.3.2 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 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 AE that is 
unexpected and assessed by the investigator to be possibly related to the use of 
obinutuzumab.  An unexpected AE is one that is not already described in the Obinutuzumab 
Investigator Brochure.  Such reports are to be telephoned or faxed to the FDA and Genentech 
within 7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered reasonably or 
possibly related to the use of obinutuzumab.  An unexpected AE 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., summary letter).  
Contact Information for IND Safety Reports 
FDA fax number for IND safety reports: 
Fax: 1 (800) FDA 0178 
 
All written IND safety reports submitted to the FDA by the investigator must also be faxed to 
the following: 
Genentech Drug Safety Fax:  (650) 225 4682 or (650) 225 5288 
Site’s IRB:  [(713)794-4589 Contact info/fax] 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682    OR    (650) 225-5288 


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10.4 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech and Celgene.  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 and Celgene.  Copies of such reports should be mailed to the assigned 
Clinical Operations contact for the study: 
 
Obinutuzumab (GA101) Protocols 
Email:  ga101-gsur@gene.com  
Fax:  866-706-3927 
 
 
 


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11. 
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, patient 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. It is the policy of MD Anderson to maintain records from 
clinical research indefinitely. A storage location memo will be provided to the MD Anderson 
IND office at the time of protocol close out. 
For studies conducted outside the U.S. 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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Appendix 1 Study Flowchart 
 
During 
Screening 
Obtain ≤ 28 
days of cycle 1 
Obtain ≤ 3 d 
of cycle 1 - 6 
start 
Obtain at the end 
of cycle 3 and prior 
to start of cycle 4 
Obtain within 3 to 4 
weeks after start of 
cycle 6  
(End of Therapy) 
Obtain every 3 months 
during year 1 and every 4 
months during year 2 after 
End of Therapy testing  
Informed Consent 
 
X 
 
 
 
 
Lymphoma-relevant 
History and Physical 
 
X 
X 
 
X 
X 
Performance status 
Assessment 
 
X 
X 
 
 
 
Vital Signs 
 
 
X 
 
 
 
Routine Clinical 
Laboratory Assessment1 
 
X 
X 
 
X 
X 
Quantitative 
Immunoglobulins 
 
X 
 
 
 
 
HIV, HCV, HBV testing 
 
X 
 
 
 
 
DLBCL Confirmation 
Biopsy 
X2 
 
 
 
 
 
FDG PET/CT 
X2 
X2 
 
X 
X 
X5 
CT with IV contrast of 
neck – pelvis3 
X2 
X2 
 
 
X 
X5 
Chest X-ray 
X2 
X2 
 
 
 
 
Echo or MUGA 
X2 
X2 
 
 
 
 
Correlative Blood Draw 
 
X 
X6 
 
X 
X4 
Bone Marrow Biopsy 
 
X 
 
 
X4 
 
Lumbar Puncture 
 
X4 
 
 
 
 
1: Routine clinical laboratory assessment will include: CBC with differential, Serum chemistries – sodium (Na), potassium (K), chloride (Cl), glucose, bicarbonate 
(CO2), blood urea nitrogen (BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), phosphorus, total protein, albumin, alkaline phosphatase, aspartate transaminase 
(AST), alanine transaminase (ALT), total bilirubin, uric acid, and lactate dehydrogenase (LDH), and other testing at the discretion of the treating physician. 
2: These tests are standard of care tests required of all patients treated by the M.D. Anderson Department of Lymphoma for newly diagnosed DLBCL. As these 
tests are not protocol specific, they may be obtained at the discretion of the treating physician during the screening period (i.e., they will be allowed for protocol 
analysis if they are obtain as routine standard of care testing prior to the patient undergoing screening for the protocol). DLBCL Confirmation (lymph node biopsy 
and bone marrow) will be within 42 days of Day 1. 
3: CT with IV contrast may be obtained simultaneously with FDG PET/CT scans as per MD Anderson Diagnostic Imaging protocols. 
4: This test is not required by the protocol and will be obtained at the discretion of the treating physician if deemed necessary for initial disease workup. 
5. At follow up time points, either FDG PET/CT or CT with IV and oral contrast are acceptable 
6. Per Section 7.3 An additional purple top tube (10ml) will be obtained prior to the start of each additional cycle of therapy 
 


 
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N.B.: All time points mentioned in the Study Flowchart are detailed in Section 7, and are included in this table format for easy visualization. The time points in 
section 7 include +/- time windows to account for scheduling issues/delays. Any discrepancies between Section 7 and the Study Flowchart will be resolved in favor 
of Section 7. 


 
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Appendix 2 Calculation of Creatinine Clearance Using the Cockcroft-Gault Formula 
 
Creatinine Clearance (men) = (140-Age)  Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL)  72 
 
Creatinine Clearance (women) = 0.85  (140-Age)  Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL)  72 
Reference: 
Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted serum creatinine (editorial). 
Nephron 1992;62:249. 
 


 
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Appendix 3 Safety Reporting Fax Cover Sheet 
 
GENENTECH SUPPORTED RESEARCH 
AE/SAE FAX No:  (650) 225-4682 
Alternate Fax No:  (650) 225-5288 
 
Page 1 of ___ 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
Initial Report Date 
 
 
/ 
/ 
 
 
dd / mmm / yyyy 
Follow-up Report Date 
 
 
/ 
/ 
 
 
dd / mmm / yyyy 
Patient Initials 
(Please enter a dash if the 
patient has no middle name) 
____ - ____ -____ 
 
SAE or Safety Reporting questions, contact Genentech Safety:  (888) 835-2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS 
COVER SHEET 
 


 
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Appendix 4 FDA MedWatch 3500 Form 
This form is included in the study start-up zip file to be sent to sites via email. 
 


 
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Appendix 5 Current NCI Common Terminology Criteria for Adverse Events 
(CTCAE) 
 
Please use the following link to the NCI CTCAE website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
12. 
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