Clinical trial NCT03113422
Conditions: Follicular Lymphoma Non-Hodgkin's Lymphoma Follicular Non-Hodgkin's Lymphoma, Adult High Grade
Keywords: High Tumor Burden Follicular Lymphoma Venetoclax Obinutuzumab Bendamustine Bcl-2 Family Protein Inhibitor Monoclonal Antibody
Sponsor: PrECOG, LLC.
Start date: 2017-12-27; Completion date: 2023-01-06
Enrollment: 56 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients with high tumor burden, low grade follicular lymphoma that has never been treated, will receive venetoclax in combination with obinutuzumab and bendamustine.

Venetoclax is an oral Bcl-2 family protein inhibitor. It targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth and is overexpressed in many patients with follicular lymphoma. Venetoclax may help to slow down the growth of cancer or may cause cancer cells to die.

The purpose of this study is to see whether adding venetoclax to obinutuzumab and bendamustine improves the response (the tumor shrinks or disappears) in patients with follicular lymphoma.

As of 9/5/2018, a higher than expected incidence of tumor lysis syndrome (TLS) was experienced among patients receiving venetoclax, obinutuzumab and bendamustine on Cycle 1, Day 1 of treatment. TLS is caused by the fast breakdown of cancer cells. These patients developed an increase in some of their blood tests (uric acid, phosphorus, potassium and/or creatinine). They received a medication called rasburicase and continued with treatment. It is unclear if the TLS was due to the venetoclax or the standard treatment of obinutuzumab and bendamustine. For the remaining patients, venetoclax will start on Cycle 2, Day 1 (previously Cycle 1, Day 1).

As of 9/16/2021, additional maintenance therapy has been suspended for those patients who remain on study. These patients will not receive any further treatment and will move on to the two year survival follow-up.

Detailed description:
Follicular lymphoma (FL) is the most common low grade lymphoma comprising 70% of low-grade non-Hodgkin's lymphoma (NHL) and 22% of all cases of NHL. The survival rates for patients with indolent NHL remained unchanged from the 1950s through the early 1990s, but recent evidence suggests that outcomes continue to improve. High-risk patients with FL, defined as having advanced stage and high tumor burden have significantly shorter progression free survival despite significant advances.

This is an open-label phase II study of venetoclax in combination with obinutuzumab and bendamustine. Patients will receive induction therapy with obinutuzumab and bendamustine for six cycles (1 cycle = 28 days). Venetoclax will start with 2nd cycle of induction therapy (previously started with cycle 1). There will be a formal, detailed toxicity evaluation after 21 patients complete 3 cycles of treatment.

Patients who achieve partial response or stable disease will receive therapy with obinutuzumab every 2 months for 12 cycles and venetoclax every month for 24 cycles. Patients who achieve a complete response will receive obinutuzumab every 2 months for 12 cycles. Patients with progressive disease will not continue onto the maintenance arm.

Tumor assessments will be performed approximately every 12 weeks during induction and every 6 months during maintenance therapy.

Mandatory pre-treatment tumor tissue sample (i.e., obtained during a previous procedure or biopsy) will be required for research (if sufficient tissue is available). Optional tumor biopsy samples obtained during treatment or post-treatment will also be requested for research.

Arms: arm 1: Cycle 1-6: Obinutuzumab intravenously (IV) and bendamustine IV. Cycle 2-6: Venetoclax (oral) arm 2: Patients with stable or improved disease will receive venetoclax by mouth daily for 24 cycles (1 cycle=1 month) and obinutuzumab IV every 2 months for 12 cycles. Patients with no evidence of disease will receive obinutuzumab IV every 2 months for 12 cycles.
Interventions: intervention 1: Induction Venetoclax intervention 2: Maintenance Venetoclax
Intervention descriptions: intervention 1: 1 cycle = 28 days.

* Cycle 1-6: Obinutuzumab IV. Cycle 1, Day 1 obinutuzumab 100 mg and Cycle 1, Day 2 obinutuzumab 900 mg for total dose of 1000 mg. On Cycle 1, Day 8 and Day 15 obinutuzumab 1000 mg. Starting with Cycle 2, obinutuzumab 1000 mg on Day 1 only of each cycle.
* Cycle 1-6: Bendamustine 90 mg/m² IV on Days 1 and 2 of each cycle over 15 minutes after obinutuzumab.
* Cycle 2-6: Venetoclax 800 mg by mouth daily on Days 1-10 administered before obinutuzumab and/or bendamustine. intervention 2: Patients whose disease is the same or improved will receive venetoclax 800 mg by mouth daily for 24 cycles (1 cycle=1 month) and obinutuzumab 1000 mg IV every 2 months for 12 cycles. Patients with no evidence of disease will receive obinutuzumab 1000 mg IV every 2 months for 12 cycles.

Protocol documents:
Prot_000.pdf: 
PrECOG Protocol Number: PrE0403 
Date: 10/15/2021 
 
1 
 
 
PrECOG Protocol Number: PrE0403 
Phase II Study of Venetoclax (ABT-199/GDC-0199) in 
Combination with Obinutuzumab and Bendamustine in 
Patients with High Tumor Burden Follicular Lymphoma as 
Front Line Therapy 
 
NCT#: 
NCT03113422 
IND #: 
134855 
Protocol Version Number: 
8.0 
Version Date: 
10/15/2021 
 


PrECOG Protocol Number: PrE0403 
IND Number: 134855 
Confidential 
Date: 10/15/2021 
PrECOG Protocol Number: PrE0403
Phase II Study of Venetoclax (ABT-199/GDC-0199) in 
Combination with Obinutuzumab and Bendamustine in 
Patients with High Tumor Burden Follicular Lymphoma as 
Front Line Therapy 
STUDY CHAIR: 
Craig A. Portell, MD 
STUDY CO-CHAIR: 
: 
: 
STATISTICIAN: 
PRECOG STUDY SITE CONTACT: 
Carolyn Andrews, RN 
MEDICAL MONITOR: 
(Internal Use Only) Genentech US Ref. ID Number: ML39161 
IND #: 
134855 
Version Number: 
8.0 
Version Date: 
October 15, 2021 
Release/Revision History 
Version 1.0: 5/25/2017 
Released to Sites 
Version 2.0: 11/7/2017 
Released to Sites 
Version 3.0: 11/16/2017 
Released to Sites 
Version 4.0: 1/23/2018 
Released to Sites 
Version 5.0: 9/25/2018 
Released to Sites 
Version 6.0: 8//28/2019 
Released to Sites 
Version 7.0: 2/5/2020 
Released to Sites 
Version 8.0: 10/15/2021 
Released to Sites 
This protocol contains information that is confidential and proprietary 


PrECOG Protocol Number: PrE0403 
IND Number: 134855 
Confidential 
Date: 10/15/2021 
 
2 
Table of Contents 
List of Abbreviations .......................................................................................................................6 
1. 
Introduction- Background and Rationale ........................................................................... 10 
1.1 
Follicular Lymphoma (FL) – Disease Overview ....................................................... 10 
1.2 
Treatment of High Risk Follicular Lymphoma ......................................................... 10 
1.3 
Overview of Obinutuzumab9 .................................................................................... 11 
1.4 
Venetoclax Background13 ........................................................................................ 12 
1.5 
Nonclinical Studies of Venetoclax and Obinutuzumab in Combination ................... 14 
1.6 
Rationale for the Dosing, Study Design and Treatment Plan .................................. 16 
2. 
Study Objectives ................................................................................................................... 20 
2.1 
Primary Objective .................................................................................................... 20 
2.2 
Secondary Objectives .............................................................................................. 20 
2.3 
Exploratory Objectives ............................................................................................. 20 
3. 
Selection of Patients ............................................................................................................. 21 
4. 
Registration Procedures....................................................................................................... 25 
4.1 
Ethics ....................................................................................................................... 25 
4.2 
Regulatory Requirements ........................................................................................ 25 
4.3 
Patient Registration ................................................................................................. 25 
4.4 
Mandatory Research Tissue Samples (if sufficient tissue available) ...................... 25 
5. 
Treatment Plan ...................................................................................................................... 26 
5.1 
Overview .................................................................................................................. 26 
5.2 
Induction Administration Schedule .......................................................................... 28 
5.3 
Maintenance Administration Schedule .................................................................... 30 
6. 
Dose Modification ................................................................................................................. 32 
6.1 
Dose Modifications & Toxicity Management – Induction Phase ............................. 32 
6.2 
Dose Modifications & Toxicity Management – Maintenance Phase ....................... 37 
6.3 
Concurrent Therapies .............................................................................................. 39 
6.4 
Supportive Care ....................................................................................................... 40 
7. 
Study Duration and Discontinuation of Therapy ............................................................... 41 
7.1 
Study Duration ......................................................................................................... 41 
7.2 
Duration of Follow-Up .............................................................................................. 41 
7.3 
Criteria for Removal from Study Treatment ............................................................. 41 
8. 
Adverse Event Reporting ..................................................................................................... 43 
8.1 
Collection of Safety Information ............................................................................... 43 
8.2 
Definition of Adverse Events of Special Interest (AESI) .......................................... 44 
8.3 
Special Situation Reports ........................................................................................ 45 
8.4 
Handling of Serious Adverse Events (SAEs) .......................................................... 46 
8.5 
SAE Reporting Requirements ................................................................................. 46 
8.6 
Product Complaints ................................................................................................. 47 
8.7 
Reporting of Other Second Primary Cancers .......................................................... 47 
8.8 
Procedures in Case of Pregnancy ........................................................................... 47 
8.9 
Reporting Guidelines in the Case of Overdose ....................................................... 48 
9. 
Measurement of Effect .......................................................................................................... 49 


PrECOG Protocol Number: PrE0403 
IND Number: 134855 
Confidential 
Date: 10/15/2021 
 
3 
9.1 
Lymphoma Response Cheson Criteria.................................................................... 49 
9.2 
Response ................................................................................................................. 51 
10. Study Parameters .................................................................................................................. 53 
11. Drug Formulation and Procurement ................................................................................... 57 
11.1 
Venetoclax13 ............................................................................................................ 57 
11.2 
Obinutuzumab9 ........................................................................................................ 59 
11.3 
Bendamustine20 ....................................................................................................... 65 
12. Statistical Considerations .................................................................................................... 69 
12.1 
Primary Endpoint ..................................................................................................... 69 
12.2 
Secondary Endpoints............................................................................................... 70 
12.3 
Exploratory Endpoints.............................................................................................. 71 
13. Laboratory and Pathology Correlative Studies .................................................................. 72 
13.1 
Correlative Studies: Mandatory Tumor Samples (f sufficient tissue available) ....... 72 
14. Administrative ....................................................................................................................... 75 
14.1 
Protocol Compliance................................................................................................ 75 
14.2 
Institutional Review Board ....................................................................................... 75 
14.3 
Informed Consent Procedures ................................................................................. 75 
14.4 
Safety Communication............................................................................................. 76 
14.5 
Monitoring ................................................................................................................ 76 
14.6 
Study Records ......................................................................................................... 76 
14.7 
Electronic Case Report Form (eCRF) Information .................................................. 76 
14.8 
Records Retention ................................................................................................... 77 
15. References ............................................................................................................................. 78 
Appendix I: 
Modified Ann Arbor Staging System ................................................................. 80 
Appendix II: 
ECOG Performance Status ................................................................................. 81 
Appendix III: 
Calculation of Creatinine Clearance Using the Cockcroft-Gault Formula .... 82 
Appendix IV: 
Definitions of Tumor Lysis Syndrome18 ........................................................... 83 
Appendix V: 
Venetoclax Medication Diary .............................................................................. 84 
Appendix VI: 
Additional Excluded and Cautionary Medications .......................................... 87 
Appendix VII: 
Follicular Lymphoma International Prognostic Index (FLIPI)-1 .................... 88 
Appendix VIII: 
Follicular Lymphoma International Prognostic Index (FLIPI)-2 ................... 89 
Appendix IX: 
Investigator’s Statement .................................................................................... 90 
 
 
 


PrECOG Protocol Number: PrE0403 
IND Number: 134855 
Confidential 
Date: 10/15/2021 
 
4 
PrECOG STUDY SITE CONTACT 
MEDICAL MONITOR 
Carolyn Andrews, RN 
Project Manager 
PrECOG, LLC 
1818 Market Street 
Suite 3000 
Philadelphia, PA 19103 
Phone: 215-789-7001 
Email: PrE0403@precogllc.org 
 
985 Old Eagle School Road 
Suite 510 
Wayne, PA 19087 
During normal business hours 
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Phone: 484-574-2367 
Email: 
 
SAE Email: PrE0403SAE@qdservices.com 
 


PrECOG Protocol Number: PrE0403 
IND Number: 134855 
Confidential 
Date: 10/15/2021 
 
5 
Brief Protocol Synopsis 
See Protocol Document Sections for complete details 
Study Schema 
 
High Risk Follicular Lymphoma: GELF (High Tumor Burden) OR FLIPI (Score 3-5) 
 
 
 
INDUCTION1 
 
 
 
 
MAINTENANCE3,4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accrual goal: 56 patients 
Cycle length: 28 days (4 weeks) 
1 There will be a formal, detailed toxicity evaluation after 21 patients complete 3 cycles of treatment (including patients 
that come off treatment for any reason). Section 12.1 for details. 
2 Cycle 1 only obinutuzumab: 100 mg IV will be given on day 1 and 900 mg will be given on day 2. Cycle 1, day 8 and 
day 15, 1000 mg IV will be given. Starting with cycle 2 obinutuzumab 1000 mg will be given on Day 1 only. 
3 Patients will move on to the maintenance phase no earlier than 8 weeks and no later than 12 weeks post completion 
of cycle #6, day 28 of induction therapy. 
4 Further maintenance therapy was suspended on 9/16/2021. Refer to Section 1.6.3 for details. 
* Patients with venetoclax dose reduction to 400 mg during induction phase will continue with 400 mg dosing during 
maintenance therapy for the 28 day cycle. 
NOTE: At the time of restaging (or if a scan is done earlier for another reason) and disease progression is noted, 
patients will come off study. 
R 
E 
G 
I 
S 
T 
R 
A 
T 
I 
O 
N 
Cycle 1-6: Obinutuzumab 1000 mg IV2 
Cycle 1-6: Bendamustine 90 mg/m2 IV 
days 1, 2 every 28 days 
Cycle 2-6: Venetoclax 800 mg PO 
daily days 1-10 of each 28 day cycle 
Partial Response 
or Stable Disease 
Complete Response 
Obinutuzumab 1000 mg IV every 
2 months x 12 cycles 
+ 
*Venetoclax 800 mg PO, daily 
days 1-28 every 28 days x 24 
cycles 
Obinutuzumab 1000 mg IV 
every 2 months x 12 cycles 
Progression 
Off Study 


PrECOG Protocol Number: PrE0403 
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List of Abbreviations 
ADCC 
Antibody-Dependent Cellular Cytotoxicity 
ADCP 
Antibody Dependent Cellular Phagocytosis 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AIDS 
Acquired Immunodeficiency Syndrome 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
anti-HBc or HBcAB 
Hepatitis B Core Antibody 
AST 
Aspartate Aminotransferase 
Bcl-2 
B-Cell Lymphoma 2 
BID 
Twice a Day 
BR 
Bendamustine Rituximab 
BSA 
Body Surface Area 
C 
Celsius 
CBC 
Complete Blood Count 
CDC 
Complement-Dependent Cytotoxicity 
CHOP 
Cyclophosphamide, Doxorubicin, Vincristine, Prednisone 
CI 
Confidence Interval 
Clb 
Chlorambucil 
CLL 
Chronic Lymphocytic Leukemia 
cm 
Centimeter 
CMV 
Cytomegalovirus 
CR 
Complete Response or Complete Remission 
CrCl 
Creatinine Clearance 
Cru 
Unconfirmed Complete Response 
CT 
Computerized Tomography 
CTEP 
Cancer Therapeutic Evaluation Program 
dL 
Deciliter 
DLBCL 
Diffuse Large B-Cell Lymphoma 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
eDC 
Electronic Data Capture 
EFS 
Event-Free Survival 
F 
Fahrenheit 


PrECOG Protocol Number: PrE0403 
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FC 
Fludarabine Cyclophosphamide 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FISH 
Fluorescence In Situ Hybridization 
FL 
Follicular Lymphoma 
FLIPI 
Follicular Lymphoma International Prognostic Index 
G 
Obinutuzumab (GA101) 
G-benda 
Obinutuzumab-bendamustine 
G-CHOP 
Obinutuzumab in combination with Cyclophosphamide, Doxorubicin, 
Vincristine, Prednisone 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GELF 
Groupe D’Etude des Lymphomes Follicularies 
GI 
Gastrointestinal 
gm 
Gram 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
Hct 
Hematocrit 
HCV 
Hepatitis C Virus 
Hgb 
Hemoglobin 
HIPPA 
Health Information Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
hr 
Hour 
HR 
Hazard Ratio 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
IgE 
Immunoglobulin E 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
iNHL 
Indolent Non-Hodgkin’s Lymphoma 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
Infusion-Related Reactions 
ITT 
Intent To Treat 
IV 
Intravenous 
IWWM 
International Workshop-Waldenstrom's Macroglobulinemia (Criteria) 


PrECOG Protocol Number: PrE0403 
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JC Virus 
John Cunningham Virus 
Kg 
Kilogram 
L 
Liter 
LDH 
Lactate Dehydrogenase 
M 
Meter 
m2 
Meter Squared 
MCL 
Mantle Cell Lymphoma 
Mcl-1 
Myeloid Cell Leukemia-1 
mg 
Milligram 
mL 
Milliliter 
mm3 
Cubic Millimeter 
mmol 
Millimole 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
MTD 
Maximum Tolerated Dose 
N 
Number 
NaCl 
Sodium Chloride 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NHL 
Non-Hodgkin’s Lymphoma 
NK 
Natural Killer 
OBI 
On Body Injector 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PCP 
Pneumocystis Jiroveci Pneumonia 
PCR 
Polymerase-Chain Reaction 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PJP 
Pneumocystis Jiroveci Pneumonia 
PML 
Progressive Multifocal Leukoencephalopathy 
PO 
per os; By Mouth (orally) 
PR 
Partial Response or Partial Remission 
PS 
Performance Status 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
R 
Rituximab 


PrECOG Protocol Number: PrE0403 
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9 
R-CHOP 
Rituximab in Combination with Cyclophosphamide, Doxorubicin, 
Vincristine, Prednisone 
RNA 
Ribonucleic Acid 
R/R 
Relapsed/Refractory 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SPD 
Sum of Products of the Diameter 
SRM 
Study Reference Manual 
STiL 
Study Group Indolent Lymphomas 
TEN 
Toxic Epidermal Necrolysis 
TLS 
Tumor Lysis Syndrome 
TMA 
Tissue Microarray 
TTF 
Time to Treatment Failure 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
μmol 
Micromole 
USA 
United States of America 
USPI 
United States Product Insert 
WBC 
White Blood Cell 
V+BR 
Venetoclax + Bendamustine Rituximab 
WHO 
World Health Organization 
WM 
Waldenstrom's Macroglobulinemia 
WNL 
Within Normal Limits 
WOCBP 
Women of Childbearing Potential 
 
 


PrECOG Protocol Number: PrE0403 
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10 
1. 
Introduction- Background and Rationale 
1.1 
Follicular Lymphoma (FL) – Disease Overview 
It is estimated that approximately 71,850 individuals were diagnosed with non-Hodgkin’s 
lymphoma (NHL) and over 19,000 men and women died of the disease in 2015. Follicular 
lymphoma (FL) is the most common low-grade lymphoma comprising 70% of low-grade NHL 
and 22% of all cases of NHL.1 The survival rates for patients with indolent NHL remained 
unchanged from the 1950s through the early 1990s, but recent evidence suggests that 
outcomes continue to improve. High-risk patients with FL, defined as having advanced stage 
and high tumor burden have significantly shorter progression free survival despite significant 
advances.2,3,4 
The hallmark of FL is abnormal co-expression of Bcl-2 protein by germinal center-type (CD10+ 
and/or Bcl-6+) B cells, which implies the presence of the anti-apoptotic driver t(14;18) IgH/Bcl-
2 rearrangement. Up to 90% of FL express Bcl-2 by immunohistochemistry with standard 
antibodies, more commonly in grade 1-2 (85-90%) compared to grade 3A tumors (50%).5 
Absence of bcl-2 protein expression can be a consequence of mutations in the BCL2 gene 
preventing antibody recognition of the protein; true absence of t(14;18) is uncommon.6 
1.2 
Treatment of High Risk Follicular Lymphoma 
1.2.1 
Current Standard Approach to Frontline Therapy 
Bendamustine is an alkylating agent that contains a bifunctional mechlorethamine derivative, a 
benzimidazole heterocyclic ring, and a butyric acid substituent. Bendamustine received approval 
in the United States of America (USA) in 2008 by the Food and Drug Administration (FDA) for 
the first-line treatment of patients with chronic lymphocytic leukemia (CLL), and for the treatment 
of patients with advanced indolent B-cell NHL that progressed during or within 6 months of 
treatment with rituximab or a rituximab-containing regimen. 
The pivotal, multicenter, randomized Phase 3 study, conducted by the Study Group Indolent 
Lymphomas, Germany (StiL), enrolled 549 patients with advanced indolent NHL or mantle cell 
lymphoma (MCL) to treatment with either bendamustine in combination with rituximab (BR) or 
standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in 
the first-line setting. The primary objective was to prove non-inferiority of the BR regimen 
compared with the R-CHOP regimen, defined as a difference of less than 10% in progression-
free survival (PFS) after 3 years but with an improved safety profile. The overall response rate 
(ORR) was 92.7% for BR and 91.3% for R-CHOP; however, complete response (CR) rate was 
improved for BR (40%) compared with R-CHOP (31%). Among all patients, BR was associated 
with a superior PFS compared with R-CHOP (BR: 54.9 vs. R-CHOP: 34.8 months (median), 
Hazard Ratio (HR)=0.57 (95% Confidence Interval (CI): 0.43-0.76; p=0.00012) as was the time 
to next treatment (BR: not reached vs. R-CHOP: 37.5 months (median), HR=0.52 (95% CI: 0.38-
0.70), p=0.00002). No differences in overall survival (OS) were noted.7 In terms of toxicity, 
significant differences in hematologic toxicities were observed for neutropenia grade 3/4 
occurring in 46.5% of patients receiving R-CHOP vs. 10.7% with BR (p<0.0001). Other toxicities 
that were significantly increased with R-CHOP compared with BR included: Alopecia (all vs. 
<2% patients, p<0.0001), paresthesia (73 vs. 18, <0.0001), stomatitis (47 vs. 16, <0.0001), 
infectious complications (127 vs. 96, p=0.0025), sepsis (8 vs. 1 patient, p=0.0190). The only 
side effects more frequent with BR compared with R-CHOP were skin/erythema (42 vs. 23 
p=0.0122) and allergic reaction (skin) (40 vs. 15, p=0.0003). In this final analysis, the 
combination of BR improved PFS and CR rates, while showing a better tolerability profile. These 
results established BR as a standard first-line treatment for patients with high tumor burden FL. 
1.2.2 
Maintenance Therapy with Monoclonal Antibody 
To improve the response rate, duration of response, and potentially prolong OS, additional 
doses of rituximab have been administered as post-remission or maintenance therapy. 


PrECOG Protocol Number: PrE0403 
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11 
A randomized open label study (PRIMA) was undertaken in 1217 patients with previously 
untreated FL needing systemic therapy and were assigned to one of the three induction arms 
containing immunochemotherapy. 1019 patients achieved a complete or partial response and 
were randomized to receive a 2-year maintenance treatment with rituximab or observation. In 
the intention to treat analysis, the PFS was 74.9% in the rituximab maintenance arm compared 
with 57.6% in the group that were observed at a median follow up of 36 months (p<0.0001).8 
1.3 
Overview of Obinutuzumab9 
Obinutuzumab (GA101, RO5072759, Gazyva, Gazyvaro) is a humanized glycoengineered 
type II anti-CD20 monoclonal antibody. It is characterized by high-affinity binding to a CD20 
epitope that is different from the epitope targeted by rituximab, which is currently the widely used 
anti-CD20 monoclonal antibody.10,11 Obinutuzumab was derived by humanization of the parental 
B-Ly1 mouse antibody and subsequent glycoengineering leading to the following 
characteristics: high-affinity binding to the CD20 antigen, high antibody-dependent cellular 
cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP); low complement-
dependent cytotoxicity (CDC) activity; and high direct cell death induction. Nonclinical studies 
with obinutuzumab in comparison with rituximab show significantly greater ADCC and ADCP, 
increased direct cell-death induction, and low CDC. Superior efficacy to rituximab has been 
demonstrated in various human lymphoma xenograft models.10,12 
1.3.1 
Clinical Experience with Obinutuzumab in NHL 
As of 2 July 2015, obinutuzumab has been administered to 2105 patients with NHL in 
4 monotherapy studies and 6 combination therapy studies. The combination therapy studies 
include the following: 
• 
Study BO21000 (GAUDI): A Phase Ib, open-label study of obinutuzumab in combination 
with CHOP (G-CHOP), fludarabine/cyclophosphamide (FC), or bendamustine in patients 
with CD20+ B-cell FL. A total of 137 patients were enrolled, including 56 with 
relapsed/refractory (R/R) disease (obinutuzumab + FC: n=28; obinutuzumab + CHOP: 
n=28) 
and 
80 
first-line 
patients 
(obinutuzumab + bendamustine: 
n=41; 
obinutuzumab + CHOP: n=40). 
• 
Study GAO4915g (GATHER): A Phase II, open-label study of obinutuzumab + CHOP in 
previously untreated advanced Diffuse Large B-Cell Lymphoma (DLBCL). A total of 100 
patients were enrolled. 
• 
Study GAO4753g (GADOLIN): A Phase III study of obinutuzumab + bendamustine (G-
benda) vs. bendamustine alone in patients with rituximab-refractory CD20+ indolent NHL 
(iNHL). A total of 194 patients were randomized to the G-benda arm and 202 to 
bendamustine arm. 
• 
Study BO21223 (GALLIUM): A Phase III study of G-chemo vs. R-chemo in patients with 
advanced iNHL. Enrollment to the study has completed with 1401 enrolled patients; the 
study is ongoing. 
• 
Study BO21005 (GOYA): A Phase III study of G-CHOP vs. R-CHOP in patients with 
previously untreated CD20+ DLBCL. Enrollment to the study has completed with 1418 
enrolled patients; the study is ongoing. 
• 
Study JO29737 (GATS): A Phase II, open-label study of obinutuzumab (shorter duration of 
infusion) in patients with CD20+ NHL. Enrollment is ongoing, with 14 patients enrolled 
(planned enrollment of 36). 
Details regarding all obinutuzumab studies, including the obinutuzumab monotherapy studies in 
NHL and studies in other indications are provided in the Obinutuzumab Investigator’s Brochure 
(IB). 


PrECOG Protocol Number: PrE0403 
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12 
1.3.2 
Clinical Efficacy of Obinutuzumab in NHL 
In the monotherapy setting (studies BO20999, BO21003, YP25623, and JO21900), the 
proportion of patients who had a response (CR or partial response [PR]) at the end of treatment 
ranged from 28% (11/40 patients) to 58% (7/12 patients). Although patients had 
treatment-refractory (including rituximab-refractory) or relapsed disease, some patients in 
studies BO20999, BO21003 (Phase II), and JO21900 achieved a CR by the end of treatment 
assessment. 
In the chemotherapy combination studies BO21000 and GAO4915g, the proportion of patients 
achieving a response exceeded 90% among FL patients and was 82% among DLBCL patients. 
The CR rate was also higher (35%−50% of patients with FL and 55% of patients with DLBCL) 
than in the monotherapy studies. 
Data from the pivotal chemotherapy combination Phase III study (GAO4753g) in patients with 
FL showed that treatment with G-benda for 6 cycles (28 days per cycle) followed by 2-year 
monotherapy with obinutuzumab resulted in a clinically meaningful and statistically significant 
increase in PFS compared with bendamustine alone. The median Independent Review 
Committee (IRC)-assessed PFS in the bendamustine arm was 13.8 months. Median IRC-
assessed PFS was not reached in the G-benda arm (PFS HR=0.48, 95% CI: 0.34−0.68; 
stratified log-rank test p-value <0.0001). An analysis conducted with 24.1 months of median 
observation time revealed that the median OS was not yet reached in either arm. 
1.3.3 
Clinical Safety of Obinutuzumab 
As of 2 July 2015 (the safety data cutoff date for all studies except MO28543), obinutuzumab 
has been administered to a total of 3386 patients, including 1281 patients with CLL and 2105 
patients with NHL, from doses of 50 mg to 2000 mg in monotherapy or in combination with 
CHOP, FC, bendamustine, or chlorambucil (Clb). Overall, the safety of monotherapy 
obinutuzumab, or obinutuzumab combination therapy with CHOP, FC, bendamustine, or Clb, 
was manageable. 
The most frequent causes of death were disease progression and adverse events (AEs) of 
infectious diseases. This is consistent with the study population and the disease being treated. 
Of particular interest, infusion related reactions (IRRs) were observed consistently in all 
obinutuzumab trials. In patients with CLL (study BO21004), the highest incidence of IRR was at 
the first infusion with the incidence decreasing rapidly with subsequent infusions. The incidence 
of IRR observed with combination therapy (FC, CHOP, or bendamustine) appears similar to that 
observed with monotherapy. 
Adverse events of special interest include IRRs, tumor lysis syndrome (TLS), thrombocytopenia 
(including acute thrombocytopenia), neutropenia (including late-onset and prolonged 
neutropenia), prolonged B-cell depletion, infections including progressive multifocal 
leukoencephalopathy (PML) and hepatitis B virus (HBV) reactivation, worsening of pre-existing 
cardiac conditions, gastrointestinal (GI) perforation, and second malignancies. 
1.3.4 
Risks Associated with Obinutuzumab 
Please see Section 11.2.11 for Risks Associated with Obinutuzumab and the current IB for more 
information. 
1.4 
Venetoclax Background13 
1.4.1 
Structure and Mechanism of Action 
Venetoclax (GDC-0199, ABT-199, A-1195425.0, or RO5537382) is a selective, orally 
bioavailable, small-molecule Bcl-2 family protein inhibitor. Overexpression of Bcl-2 has been 
demonstrated in various hematologic and solid tumor malignancies and has been implicated as 
a resistance factor for certain therapeutic agents. Venetoclax helps restore the process of 


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apoptosis by binding directly to the Bcl-2 protein, displacing pro-apoptotic proteins like Bcl-2-
like protein 11 (commonly called BIM), and triggering mitochondrial outer membrane 
permeabilization and the activation of caspases. In nonclinical studies, venetoclax has 
demonstrated cytotoxic activity in a variety of B cell and other hematologic malignancies.14,15 
1.4.2 
Clinical Experience with Venetoclax in NHL 
As of 28 November 2015, six Phase I/II studies with venetoclax are ongoing in NHL, including 
three monotherapy and three combination studies. 
• 
Study M12-175 (Arm B): A Phase I, first-in-human, open-label, dose-escalation study of 
venetoclax in patients with R/R CLL (Arm A) and NHL (Arm B). A total of 106 patients with 
R/R NHL received at least 1 dose of venetoclax in Arm B. Of these patients, 70 patients 
were enrolled during the dose-escalation portion of the study. 
• 
Study M13-834: A Phase I study of venetoclax in Japanese subjects with hematological 
malignancies. As of 28 November 2015, 11 patients with NHL have received at least 1 dose 
of venetoclax and had available safety data in Arm A. 
• 
Study M13-835: An extension study of venetoclax in patients with advanced NHL. As of 28 
November 2015, 11 patients have been rolled over from Study M13-364 (drug-drug 
interaction study of ketoconazole) and had available safety data. 
• 
Study M12-630: A Phase I study of venetoclax + bendamustine/rituximab (BR) in in patients 
with R/R NHL. A total of 58 patients received at least 1 dose of venetoclax and had available 
data. 
• 
Study GO27878/CAVALLI: A Phase Ib/II study of venetoclax + R-CHOP or venetoclax + G-
CHOP in patients with B-cell NHL and DLBCL. As of 28 November 2015, 54 patients have 
been enrolled (Section 1.5.2.1). 
• 
Study BO29337 (CONTRALTO): A Phase II study of venetoclax + BR, BR alone, or 
venetoclax + R in patients with R/R follicular NHL. As of 28 November 2015, 103 patients 
have safety data available, including 9 patients in the run-in phase, 52 patients in Arm A 
(venetoclax + R), 21 patients in Arm B (venetoclax + BR), and 21 patients in Arm C (BR). 
Details regarding all venetoclax studies, including the venetoclax monotherapy studies in NHL 
and studies in other indications are provided in the Venetoclax IB. 
1.4.3 
Clinical Efficacy of Venetoclax in NHL 
As of 15 September 2015, efficacy data for Arm B of Study M12-175 are available for a total of 
106 patients with R/R NHL enrolled in Arm B (70 in the dose-escalation cohorts and 36 in the 
safety expansion cohort). Patients were evaluated for objective response following the 
International Working Group criteria (patients with Waldenstrom's macroglobulinemia [WM] 
were evaluated using the International Workshop [IWWM] criteria). The investigator-assessed 
ORR for all FL patients and DLBCL patients, excluding DLBCL-Richter's transformation patients 
(across dose escalation and safety expansion), was 37.9% and 17.6%, respectively; CR was 
achieved by 4 patients in each group (13.8% and 11.8%, respectively). 
Preliminary efficacy data are available for 48 patients with R/R NHL for Study M12-630 as of 17 
September 2015. Median time on study was 5.3 months (range: 0.1 to 38.1 months). The ORR 
was 67.4% (31 of 48 evaluable patients), with CR in 13 patients (28.3%) and PR in 18 patients 
(39.1%). Three additional patients (6.5%) experienced stable disease (SD). 
1.4.4 
Clinical Safety Summary for Combination Studies M12-630 and BO29337 
Safety data are available for 58 patients in Study M12-630 and 108 patients in Study BO29337. 
An overview of adverse events reported in these two venetoclax combination NHL studies is 
provided below. See the current Venetoclax IB for additional safety information. 


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Most patients receiving venetoclax in combination with BR in Study M12-630 (57/58, 98.3%) 
reported at least 1 adverse event. The most common adverse events were nausea (63.8%), 
neutropenia (55.2%), and diarrhea (50.0%). In this study, 46 patients (79.3%) had Grade ≥ 3 
adverse events, 21 patients (36.2%) had serious adverse events, 9 patients (15.5%) had 
adverse events leading to discontinuation of study drug, and 4 patients (6.9%) had fatal adverse 
events (2 events of malignant neoplasm progression and 1 event each of disease progression 
and respiratory failure). None of the fatal events were considered to be related to venetoclax. 
Most patients in Study BO29337 (90/108, 83.3%) reported at least 1 adverse event. The most 
common adverse events were nausea (28.7%), diarrhea (26.9%), and neutropenia (21.3%). The 
types of adverse events were similar across cohorts; however, patients in Arm C (BR) 
experienced fewer adverse events than patients in Arm A or Arm B. Grade ≥ 3 adverse events 
were reported in 45 patients (41.7%). Serious adverse events were reported in 18 patients 
(16.7%), including 3 patients in the run-in phase, 12 patients in Arm A, and 3 patients in Arm B 
(but no patients in Arm C). Serious adverse events occurring in 2 patients each were blood 
lactate dehydrogenase increased and TLS. All other events occurred in 1 patient each. Six 
patients (5.6%) experienced adverse events that led to study drug discontinuation. Nausea 
occurred in 2 patients each; all other events occurred in 1 patient each. Fatal events were 
reported in 2 patients in Arm A: 1 event of pulmonary hemorrhage and 1 event of colitis. Neither 
of the fatal events was considered related to venetoclax. 
1.4.5 
Overall Safety Summary for Venetoclax in NHL 
As of 28 November 2015, a total of 346 patients with NHL have been treated in the venetoclax 
oncology clinical program: 131 patients received venetoclax as a single agent and 215 patients 
received venetoclax in combination with other agents, including rituximab, obinutuzumab, and 
bendamustine; R-CHOP; or G-CHOP. 
Overall, most patients with NHL experience at least one adverse event when treated with 
venetoclax as a single agent or in combination with other therapies, with the most common 
events being nausea or diarrhea; whereas neutropenia and IRRs commonly occur in 
combination studies. Approximately half of patients in NHL clinical trials experienced Grade ≥ 3 
adverse events, with most common being neutropenia, anemia, and thrombocytopenia. The 
frequency of thrombocytopenia and anemia are slightly higher in NHL combination trials; 
however, the numbers are small. 
The incidence of TLS in NHL studies is low, with reported 2 cases (1.9%) of TLS in monotherapy 
Study M12-175 (Arm B), 3 cases of TLS (2.8%) in combination Study BO29337 
(venetoclax + BR), and 3 cases of TLS (6.1%) in combination Study GO27878 (venetoclax + R-
CHOP or G-CHOP). TLS remains an important identified risk for the NHL program. 
Neutropenia has a similar frequency in the NHL clinical program as in the CLL population, with 
higher frequency in NHL combination studies. Serious adverse events of neutropenia and febrile 
neutropenia, although relatively rare, occurred with higher frequency in the combination studies 
and remain important identified risks. Infections, including serious infections, were observed in 
the NHL clinical program, with similar incidence in monotherapy and combination studies. There 
were no deaths due to infections in the NHL program. Infection remains a potential risk for the 
NHL clinical program. 
1.4.6 
Risks Associated with Venetoclax 
See Section 11.1.8 for Risks Associated with Venetoclax and the current IB for more information. 
1.5 
Nonclinical Studies of Venetoclax and Obinutuzumab in Combination 
Nonclinical pharmacology and pharmacokinetics, and product metabolism studies have been 
conducted with the combination of venetoclax and obinutuzumab. 
 
 
 When combined at optimal doses, 


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an additive effect of the two drugs was observed.
 
 
 
 
 For 
details regarding nonclinical studies for each individual agent, refer to current version of the IB. 
1.5.1 
Clinical Studies of Venetoclax and Obinutuzumab 
The combination of venetoclax and obinutuzumab is being evaluated in three clinical studies: 
• 
Study GP28331: A Phase Ib study of venetoclax + obinutuzumab in patients with 
relapsed/refractory (R/R) CLL or previously untreated CLL 
• 
Study BO25323 (CLL14): A Phase III randomized study of venetoclax + obinutuzumab vs. 
obinutuzumab + chlorambucil in patients with previously untreated CLL with coexisting 
medical conditions 
• 
Study GO27878/CAVALLI: A Phase Ib/II, study of venetoclax + rituximab (R) or 
obinutuzumab (G) plus cyclophosphamide, doxorubicin, vincristine, and prednisone 
(CHOP) in patients with B-cell NHL and DLBCL 
As of 28 November 2015, 51 patients with R/R CLL or previously untreated CLL have been 
treated in Study GP28331, 110 patients (both arms) with previously untreated CLL have been 
treated in Study BO25323, and 46 patients with untreated or R/R B-cell NHL (Phase I) and 8 
patients with previously untreated DLBCL (Phase II) have been treated in Study 
GO27878/CAVALLI. 
Data from Study GO27878/CAVALLI in patients with NHL are summarized below. Details 
regarding Study GP28331 and Study BO25323 in patients with CLL are provided in the 
Venetoclax and Obinutuzumab IBs. 
1.5.2 
Clinical Studies with Venetoclax and Obinutuzumab in Combination in NHL 
1.5.2.1 
Study GO27878 (CAVALLI) 
Study GO27878 is a Phase Ib/II, open-label study evaluating the safety and pharmacokinetics 
of venetoclax in combination with rituximab (R) or obinutuzumab (G) plus CHOP in patients with 
B-cell NHL and DLBCL. 
In the dose-finding Phase I portion of the study, two parallel treatment arms of up to 4 cohorts 
each explored venetoclax at doses ranging from 200 to 800 mg in combination with R-CHOP 
and G-CHOP. The maximum tolerated dose was not reached in Phase I, and a recommended 
Phase II dose of 800 mg for Arm A is being used in Phase II. Patients are treated for a total of 
8 cycles (6 to 8 cycles of CHOP and 8 cycles of venetoclax + R or venetoclax + G). Each cycle 
is 21 days. 
In order to mitigate the risk for TLS, CHOP was initiated before venetoclax and all patients 
receive TLS prophylaxis before the first dose of venetoclax, with those at higher risk of TLS 
hospitalized for the initial dose. 
The planned enrollment for the study is 24−48 patients in Phase I and 180−200 patients in Phase 
II. As of 28 November 2015, 46 and 8 patients have been enrolled in the Phase I and Phase II 
portions of the study, respectively. 
Two patients in Arm A experienced dose-limiting toxicity (DLT); one case of DLT occurred at the 
200 mg dose in Cohort 1 (Grade 3 neutropenia) and the other case of DLT occurred at the 600 
mg dose in Cohort 3 (Grade 4 TLS). For the latter case of DLT, the severity Grade of 4 was 
assigned by the investigator although the patient had laboratory abnormalities only, was not 
symptomatic, and had stable cardiac and renal function and vital signs. Three patients in Arm B 
experienced DLT; 2 cases of DLTs occurred at the 200 mg dose in Cohort 1 (Grade 3 


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pneumonia and Grade 3 infection). The third case of DLT occurred at the 600 mg dose in Cohort 
3 (Grade 4 sepsis). 
Preliminary Safety Summary: 
As of 28 November 2015, 54 subjects have been enrolled in Study GO27878 and 49 subjects 
had available data. Most subjects (95.9%) across all cohorts in Study GO27878 experienced at 
least 1 treatment-emergent adverse event. The most common adverse events across cohorts 
in Study GO27878 were nausea (44.9%), diarrhea (38.8%), fatigue and neutropenia (36.7%), 
constipation (34.7%), vomiting (28.6%), and thrombocytopenia (26.5%). Serious adverse events 
have been reported for 26 patients (53.1%) in the study. The most common serious adverse 
event was febrile neutropenia in 10 patients (20.4%). Eleven patients (22.4%) experienced 
adverse events that led to withdrawal from any treatment. The most common events leading to 
study drug discontinuation were thrombocytopenia and peripheral neuropathy in 2 patients 
each; all other events leading to study drug discontinuation occurred in 1 patient each. No events 
resulted in death. 
One case of drug-induced liver injury (Preferred Term) was reported in Study GO27878. Patient 
 had a slight elevation in liver function test (2x upper limit of 
normal [ULN]) on Cycle 3, Day 7. On Cycle 4, Day 1, liver function tests were 7 to 8x ULN with 
normal bilirubin. Venetoclax and other NHL treatments were discontinued because of this event. 
All viral studies were normal; however, the patient was taking concomitant 
 for 
. A liver biopsy demonstrated relatively nonspecific features consistent with drug-
induced hepatitis. 
 liver function tests continued to be abnormal during the subsequent 8 
months following discontinuation of all cancer treatments. 
 was then discontinued, 
and 
 liver function tests as of 
 remained mildly elevated. The investigator 
considered this event to be related to venetoclax, G, and CHOP. In the investigator’s opinion, 
other etiological factors for the event included concomitant medication. 
1.6 
Rationale for the Dosing, Study Design and Treatment Plan 
1.6.1 
Dosing Regimen Rationale 
Bendamustine is an alkylating agent indicated for the treatment of FL. Dosing is based on the 
approved package insert. 
Obinutuzumab dosing regimen is based on the dosing regimen currently being used in Phase 
III clinical trials. 
Information from the ongoing Venetoclax development program in NHL has suggested that an 
intermittent administration of Venetoclax, when combined with chemotherapy, is better tolerated 
than continuous dosing. This has been demonstrated in trials M12-630 (Ven + BR, 
NCT01594229) and CAVALLI (Ven + R-CHOP, NCT02055820). 
Venetoclax dosing is based on the CAVALLI (Section 1.5.2.1) and the M12-630 and 
CONTRALTO clinical trials (see below). The M12-630 trial included dosing up to 1200 mg. No 
maximum tolerated dose has been reached. 
1.6.1.1 
M12-630 and CONTRALTO Trial Overview 
A phase 1 dose escalation trial (M12-630) combined Venetoclax with Bendamustine (90 mg/m2) 
and Rituximab (375 mg/m2) in patients with FL, DLBCL and MCL. Venetoclax doses were 
escalated from 50 mg (intermittent) to 1200 mg (continuous daily). No dose limiting toxicities 
have been identified. 
In the 800 mg cohort (n=5) the following grade 3/4 AEs were noted: neutropenia (2), lymphocyte 
count decrease (1), leukopenia (1), anemia (1). One SAE (respiratory failure) occurred. 
 


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Thus, combination therapy with venetoclax and BR (V + BR) demonstrated a tolerable safety 
profile. A protocol amendment was implemented after cohort 5 to strongly encourage 
granulocyte-colony stimulating factor (G-CSF) prophylaxis during venetoclax administration, 
particularly in heavily pretreated patients. 
The combination of venetoclax, bendamustine and rituximab and in patients with R/R follicular 
lymphoma is currently explored in a Phase Ib/2 study (Study BO29337, CONTRALTO). The 
recommended phase 2 dose of venetoclax is 800 mg given once daily continuously, in 
combination with bendamustine 90 mg/m2 given on days 1 and 2 and Rituximab 375 mg/m2 
(V+BR) given on day 1. 
In the randomized portion of that trial, per data cut Sept 27, 2016, 49 patients were evaluable 
for safety in the treatment arm (V+BR) and 50 in the control arm (BR). Three deaths occurred, 
1 due to pneumonia in the V+BR arm and 1 each due to PD and hypoxia in the BR arm. In the 
V+BR arm laboratory tumor lysis syndrome was seen in 3 patients and was manageable. In the 
V+BR arm 16 pts (33%) discontinued at least one drug to adverse events. In the control arm 
one patient stopped BR due to an AE.16 
Most frequent AEs (all grades) were neutropenia (73%), nausea (65%), thrombocytopenia 
(59%) and diarrhea (49%) in the V+BR arm and nausea (44%), neutropenia (38%), constipation 
(34%) and fatigue (28%) in the BR arm. 
Grade 3/4 AEs occurring in more than 10% of patients were neutropenia (61% with V+BR, 30% 
with BR), thrombocytopenia (45%, 6%), anemia (14%, 2%) and febrile neutropenia (12%, 6%). 
Based on the higher rate of grade 3/4 AEs and the more frequent drug discontinuations in V+BR 
compared to BR in the CONTRALTO Trial, a pulsatile administration of venetoclax given for 14 
days per 28 day cycle is planned and is expected to improve the safety profile of V+BR. A similar 
approach has been followed in DLBCL, where venetoclax was given in combination with R-
CHOP for 10 days per 21 day cycle, resulting in a promising CR rate including for patients with 
double-expressor DLBCL.17 
1.6.2 
Study Design and Treatment Plan 
Bendamustine plus rituximab induction followed by rituximab maintenance therapy has been the 
most commonly used frontline approach for FL in the United States for several years. Genentech 
has sponsored an international study (GALLIUM trial) comparing R-chemotherapy 
(bendamustine most commonly used chemotherapy) with rituximab maintenance therapy to 
obinutuzumab-chemotherapy followed by obinutuzumab maintenance therapy. A press release 
in May of 2016 indicates the trial met its primary endpoint and shows superiority for the 
obinutuzumab-chemotherapy arm. This trial is highly likely to define a new standard of care in 
FL of obinutuzumab-bendamustine followed by obinutuzumab maintenance. The question now 
is can those outcomes be further improved? Given the central role of BCL2 overexpression in 
the biology of FL, targeting BCL2 with the addition of venetoclax to the new standard therapy 
(bendamustine-obinutuzumab) is logical. 
Our hypothesis is that enhanced induction therapy and/or improved continuation treatment 
(post-induction) will improve CR rates and PFS for patients with high tumor burden low-grade 
lymphoma. Furthermore, these new novel therapeutic combinations will be safe and well 
tolerated among this patient population. Since venetoclax has not previously been combined 
with obinutuzumab and bendamustine in the front line setting, there will be a formal, detailed 
toxicity evaluation after 21 patients complete 3 cycles of treatment (including patients that come 
off treatment for any reason). Toxicity evaluation after 21 patients completed 3 cycles of 
treatment was reviewed on March 28, 2019, see Section 12.1.1 for details. Enrollment will not 
stop for safety analysis. 
 
 


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Our hypothesis will be tested in a single-arm phase II  clinical trial with venetoclax, 
obinutuzumab and bendamustine induction followed by obinutuzumab continuation in patients 
achieving a CR. In patients achieving a PR or SD after induction therapy, both venetoclax and 
obinutuzumab will be continued. 
NOTE: 
We observed a high incidence of tumor lysis syndrome (TLS) among the cases 
currently enrolled and treated with this agent combination. Currently, it is not clear if 
the TLS events are attributable to venetoclax therapy. The study and its treatment 
combination (including treatment dates, relevant labs, criteria that was met for TLS 
definition, clinical course and management of TLS event, patients' baseline disease 
stage) regarding the TLS events that have happened to date have been reviewed. 
An updated definition of TLS (see Appendix IV), distinguishing between laboratory 
and clinical TLS event, is being implemented in this updated protocol. To mitigate the 
risk of clinical and/or of laboratory TLS, venetoclax will be withheld from cycle 1 and 
will be initiated in cycle 2, day 1 for all patients. Also, laboratory assessment will be 
conducted and reviewed for potential TLS events on day 2, day 8 and day 15 (if 
required) of cycle 1 and also on day 2 of cycle 2. 
The synergistic effect of chemoimmunotherapy and venetoclax will be maintained 
through cycle 2-6. 
On January 9, 2020 enrollment was suspended due to a report of an unexpected event of Grade 
5 Cytomegalovirus (CMV) related Encephalitis infection probably related to the combination of 
the study drug regimen (venetoclax, obinutuzumab, and bendamustine). There have been no 
other adverse event reports to date for CMV and/or Encephalitis infection for this study. 
As a safety measure, monitoring for CMV will now be performed. In addition, all patients will be 
initiated on Pneumocystis Jiroveci Pneumonia (PJP) and antiviral prophylaxis. 
1.6.3 
Maintenance Therapy Suspension as of 9/16/2021 
Due to a recent Grade 5 event of myocarditis in a patient on maintenance therapy, the study 
investigators are concerned about atypical infections that have been seen after induction 
therapy on study. There have been four events of atypical infections as listed below: 
• 
Treatment related death due to cytomegalovirus encephalitis as well as Pneumocystis 
jiroveci Pneumonia (PJP) occurring after cycle 6 of induction but before maintenance 
therapy. 
• 
BK virus nephropathy leading to end stage renal disease and chronic hemodialysis in a 
patient following 6 doses of maintenance obinutuzumab. 
• 
Respiratory syncytial virus pneumonia 30 days after cycle 6 of induction and later, after 2 
cycles of maintenance obinutuzumab, developed PJP. 
• 
The recent fatal myocarditis which is suspected, but not proven, to be viral in etiology. 
Given these adverse events we are suspending any additional maintenance therapy for those 
patients on study. These patients will not receive any further treatment and move on to the two 
year survival follow-up portion of the study. All study-required follow-up activities remain 
unchanged. 
Patients with follicular lymphoma are not thought to be cured with initial therapy and several 
other treatments are available. Maintenance therapy has never been shown to improve overall 
survival in follicular lymphoma, only progression free survival and thus, we feel comfortable 
stopping maintenance therapy at this time. 
 
 


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There are currently 7 patients on maintenance therapy. The site investigators with patients were 
contacted via e-mail and agree with the recommendation to stop additional maintenance 
therapy. Several patients have already been taken off of study during maintenance due to the 
COVID-19 pandemic and either developing COVID-19 or having cytopenias related to 
maintenance therapy. 
The PrECOG Data Safety and Monitoring Board has also reviewed and agree with the 
recommendation to stop additional maintenance therapy. 


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2. 
Study Objectives 
2.1 
Primary Objective 
To estimate the proportion of patients achieving a complete remission (CR) at the end of 
induction with the combination of venetoclax, obinutuzumab and bendamustine. 
2.2 
Secondary Objectives 
• 
To determine the ORR of patients treated. 
• 
To determine the proportion of patients who achieve a PR with induction therapy and later 
convert to CR with maintenance therapy. 
• 
To evaluate PFS and OS in the intent to treat (ITT) population. 
• 
To evaluate the compliance and toxicities of patients receiving induction and maintenance 
therapy. 
2.3 
Exploratory Objectives 
• 
To compare Bcl-2 protein expression by immunohistochemistry (IHC) in pretreatment 
biopsies with response, PFS, and OS. 
• 
To assess Bcl-2 family expression by mRNA expression including ratios of Bcl-2/BIM, Bcl-
2/Mcl-1 and others with response, PFS and OS. 
• 
To compare BCL2 rearrangement status by fluorescence in situ hybridization (FISH) in 
pretreatment biopsies and correlate with response, PFS, and OS. 
• 
To compare Mcl-1 and Bcl-XL protein expression by IHC in pretreatment biopsies with 
response, PFS, and OS. 
• 
To compare histologic features of pretreatment biopsies with response, PFS, and OS. 


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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be considered 
eligible for this study. Use the checklist to confirm a patient’s eligibility. For each patient, this 
checklist must be photocopied, completed and maintained in the patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later 
would be considered Day 28. 
PrECOG Patient No. 
 
 
Patient’s Initials ( F, M, L) 
 
 
Physician Signature and Date 
 
NOTE: All questions regarding eligibility should be directed to the Medical Monitor or Study Site 
Contact. 
NOTE: Institutions may use the eligibility checklist as source documentation if it has been reviewed, 
signed, and dated prior to registration by the treating physician. 
3.1 
Patient must have a histologically confirmed (biopsy-proven) diagnosis of follicular B-cell 
non-Hodgkin lymphoma (WHO classification: follicular center grades 1, 2, and 3a [3b 
patients are not eligible]), with no evidence of transformation to large cell histology. 
Date of Diagnosis: 
_____________ 
WHO Classification Grade: 
_______ 
3.2 
Patient must meet criteria for High Tumor Burden (higher risk) as defined by either the 
Groupe D’Etude des Lymphomes Follicularies (GELF) criteria OR the follicular lymphoma 
international prognostic index (FLIPI): 
• 
To meet GELF criteria, a patient must have at least one criterion (please answer yes or 
no for each criterion): 
Nodal or extranodal mass >7 cm 
Record largest/longest single nodal/extranodal mass diameter: _____ 
 Yes  No 
At least 3 nodal masses: all >3.0 cm in diameter 
 Yes  No 
Systemic symptoms due to lymphoma or B symptoms 
 Yes  No 
Splenomegaly with spleen >16 cm by CT scan 
 Yes  No 
Evidence 
of 
compression 
syndrome 
(e.g., 
ureteral, 
orbital, 
gastrointestinal) or pleural or peritoneal serous effusion due to 
lymphoma (irrespective of cell content). 
 Yes  No 
Leukemic presentation (>5.0 x 109/L malignant circulating follicular 
cells) 
 Yes  No 
Cytopenias (polymorphonuclear leukocytes <1.0 x 109/L, hemoglobin 
<10 gm/dL, and/or platelets <100 x 109/L) 
 Yes  No 
 
 
_____
_____


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• 
FLIPI criteria: a patient must have a score of 3, 4, or 5 (per FLIPI-1, one point each for 
below criterion; please answer yes or no for each criterion): 
Age >60 years 
 Yes  No 
Ann Arbor stage III-IV 
 Yes  No 
Hemoglobin level <12 mg/dL 
 Yes  No 
>4 nodal areas 
 Yes  No 
Serum LDH level above normal 
 Yes  No 
FLIPI Score: Please circle 
3 
4 
5 
 
3.3 
Patient must have Stage II, III or IV disease (Appendix I: Modified Ann Arbor Staging). 
 Stage II 
OR 
 Stage III 
OR 
 Stage IV 
3.4 
Baseline measurements and evaluations (PET/CT) must be obtained within 10 weeks of 
randomization to the study. Patient must have at least one objective measurable disease 
parameter. Measurable disease in the liver is required if the liver is the only site of 
lymphoma. Please see Section 9.1 for definition of measurable disease. 
3.5 
Age ≥ 18 years. 
3.6 
ECOG performance status of 0-2 (Appendix II). 
Performance Status: Please circle 
0 
1 
2 
Date: ____________ 
3.7 
Ability to understand and willingness to sign IRB-approved informed consent. 
3.8 
Willing to provide mandatory tissue samples (if sufficient tissue available) for research 
purposes (Section 13). 
3.9 
Adequate organ function as measured by the following criteria: 
• 
Absolute Neutrophil Count (ANC) ≥ 1000/mm3 
ANC: __________________ 
Date of Test: ____________ 
• 
Hemoglobin ≥ 8 g/dL 
Hemoglobin: _______________ 
Date of Test: ____________ 
• 
Platelets ˃75,000/mm3 
Platelets: _______________ 
Date of Test: ____________ 
NOTE: Patients with documented marrow involvement (with lymphoma) or 
hypersplenism secondary to involvement of the spleen by lymphoma at the time 
of randomization are not required to meet the above hematologic parameters. 
• 
Creatinine clearance ≥ 50 mL/min, calculated with the use of 24-hour creatinine 
clearance or by Cockcroft-Gault formula (Appendix III). 
Creatinine: ________ 
ULN: ________ 
Date of Test: ___________ 
• 
Total Bilirubin ≤ 1.5x ULN or ≤ 3x ULN for patients with documented Gilbert’s syndrome 
Total Bilirubin: ___________ 
ULN: ________ 
Date of Test: ___________ 
 
 
_____
_____
_____
_____
_____
_____
_____


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• 
Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤ 2.5x ULN 
AST: ________________ 
ULN: _______ 
Date of Test: ___________ 
ALT: ________________ 
ULN: _______ 
Date of Test: ___________ 
• 
Alkaline Phosphatase <5x ULN 
Alkaline Phosphatase: __________ ULN: _______ Date of Test: ___________ 
3.10 
All females of childbearing potential (not surgically sterilized and between menarche and 1 
year post menopause) must have a blood or urine test to rule out pregnancy within 2 weeks 
prior to registration. 
Is the patient a woman of childbearing potential? _____________________ (yes/no) 
If yes, Date of Test: _______________ Results: ____________________________ 
3.11 
Women must not be pregnant or breastfeeding. Females of childbearing potential who are 
sexually active with a non-sterilized male partner and sexually active men must agree to 
use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) prior to 
study entry, for the duration of study participation, and for 18 months for females and 6 
months for males after last dose of therapy. Method of contraception must be documented. 
NOTE: Should a woman become pregnant or suspect she is pregnant while participating in 
this study, she should inform her treating physician immediately. 
3.12 
Patient must have had no prior chemotherapy, radiotherapy or immunotherapy for 
lymphoma. For purposes of this trial, prednisone or other corticosteroids used for non-
lymphomatous conditions will not be considered as prior chemotherapy. In addition, a 
prior/recent short course (<2 weeks) of steroids for symptom relief of lymphoma-related 
symptoms will not make a patient ineligible. 
3.13 
Patient must have no recent history of malignancy except for adequately treated basal cell 
or squamous cell skin cancer, Stage I melanoma of the skin, or in situ cervical cancer. 
Individuals in documented remission without treatment for ≥ 1 year prior to enrollment may 
be included at the discretion of the investigator. 
3.14 
Patient must have no active, uncontrolled infections. 
3.15 
Patients must be tested for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg+) 
and hepatitis C (HCV) antibody within 6 weeks of registration. Patients who are chronic 
carriers of HBV with positive HBsAg+ and positive HCV serology are excluded, as 
chemotherapy and B-cell depleting therapy have been associated with virus reactivation 
and fulminant hepatitis. 
Hepatitis B: Results: ____________________ 
Date of Test: ____________ 
Hepatitis C: Results: ____________________ 
Date of Test: ____________ 
NOTE: Patients with a past or resolved HBV infection (defined as the presence of hepatitis 
B core antibody [anti-HBc] and absence of HBsAg) may be included if HBV DNA is 
undetectable. If enrolled, patients must be willing to undergo monthly HBV DNA 
testing. 
Patients with positive HCV antibody must be negative for HCV by polymerase chain 
reaction (PCR) to be eligible for study participation. 
 
 
 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 


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3.16 
HIV positive patients are not excluded, but to enroll, must meet all of the below criteria: 
• 
HIV is sensitive to antiretroviral therapy. 
• 
Must be willing to take effective antiretroviral therapy if indicated. 
• 
No history of CD4 prior to or at the time of lymphoma diagnosis <300 cells/mm3. 
• 
No history of AIDS-defining conditions. 
• 
If on antiretroviral therapy, must not be taking zidovudine or stavudine. 
• 
Must be willing to take prophylaxis for Pneumocystis jiroveci pneumonia (PCP) during 
therapy and until at least 2 months following the completion of therapy or until the CD4 
cells recover to over 250 cells/mm3, whichever occurs later. 
3.17 
Evidence of significant, uncontrolled concomitant diseases that could affect compliance with 
the protocol or interpretation of results or that could increase risk to the patient. 
3.18 
No major surgery within 2 weeks prior to cycle 1, other than for diagnosis. 
3.19 
A condition that precludes oral route of administration (venetoclax). 
3.20 
No known allergies to both xanthine oxidase inhibitors and rasburicase. 
3.21 
Patient must not require the use of warfarin (because of potential drug-drug interactions that 
may potentially increase the exposure of warfarin). Blood thinners of other classes are 
permitted. 
3.22 
Patient may not receive the following agents within 7 days prior to the first dose of 
venetoclax: 
• 
Strong and moderate CYP3A inhibitors 
• 
Strong and moderate CYP3A inducers 
• 
Consumed grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax. 
NOTE: 
Please refer to Section 6.3.2 and Appendix VI “Additional Excluded and 
Cautionary Medications” for further information. 
3.23 
Patient must not have serious medical or psychiatric illness likely to interfere with 
participation in this clinical study. 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 


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4. 
Registration Procedures 
4.1 
Ethics 
This study will be conducted in accordance with the ethical principles that have their origin in 
the current Declaration of Helsinki and will be consistent with applicable US regulatory 
requirements and International Conference on Harmonization/Good Clinical Practice 
(ICH/GCP). 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the patient informed consent will receive Institutional Review Board (IRB) approval prior to 
initiation of the study. 
Freely given written informed consent must be obtained from every patient or their legally 
acceptable representative prior to clinical trial participation, including informed consent for any 
screening procedures conducted to establish patient eligibility for the trial. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of investigators 
or study personnel where sanctions have been invoked or where there has been scientific 
misconduct or fraud (e.g., loss of medical licensure, debarment). Investigators are responsible 
for the conduct of the study at their study site. 
4.2 
Regulatory Requirements 
Before a site may enter patients, protocol-specific regulatory and other documents must be 
submitted to PrECOG as noted in study materials. Detailed information regarding document 
submission and control is provided to each site in separate study materials. 
Once required documents are received, reviewed, and approved by PrECOG or their 
representative, a Study Reference Manual (SRM) will be forwarded to the site. Any changes to 
site regulatory documents must be submitted by the investigator to the responsible party in a 
timely manner. Initial study drug shipment will not occur until the regulatory packet is complete. 
No patients will begin protocol therapy without formal registration as per the process below. 
4.3 
Patient Registration 
Patients must not start protocol treatment prior to registration. 
Patients must meet all of the eligibility requirements listed in Section 3 prior to registration. 
Treatment should begin ≤ 10 working days from study entry (date of registration). 
An eligibility checklist is included in Section 3. A confirmation of eligibility assessment by the 
investigator and/or site will be performed during the registration process. 
Upon determination that a subject meets eligibility criteria, the subject will be registered in the 
study by site personnel via an electronic data capture (eDC) system. Confirmation of registration 
will be displayed in the eDC system. 
Full information regarding registration procedures and guidelines can be found in the SRM 
provided. Correspondence regarding patient registration must be kept in the study records. 
4.4 
Mandatory Research Tissue Samples (if sufficient tissue available) 
Pre-treatment, diagnostic pathology specimens obtained in the course of standard biopsy or 
surgery are required for enrollment (if sufficient tissue is available, submission is mandatory). 
However, if there is insufficient tissue available for sample submission (i.e. <10 slides) patients 
may still be enrolled to the trial. Optional: Any tumor biopsy samples during treatment or post-
treatment will be requested and leftover tissue (pre-treatment, during treatment or post-
treatment) banked for future research. 
Time points for tissue samples are outlined in the study parameters (Section 10) and specific 
requirements are outlined in the correlative section of this protocol (Section 13) and the lab 
manual. 


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5. 
Treatment Plan 
5.1 
Overview 
Eligible patients will receive induction therapy with obinutuzumab and bendamustine for cycle 
1-6 with the addition of venetoclax for cycle 2-6. There will be a formal, detailed toxicity 
evaluation after 21 patients complete 3 cycles of treatment (including patients that come off 
treatment for any reason). Toxicity evaluation after 21 patients completed 3 cycles of treatment 
was reviewed on March 28, 2019, see Section 12.1.1 for details. 
Patients with progressive disease will not continue on the maintenance arm. Patients who 
achieve a CR will receive obinutuzumab every 2 months for a total of 12 cycles. Patients who 
achieve partial response or stable disease will receive therapy with obinutuzumab (12 cycles) 
and venetoclax (24 cycles). 
Table 5-1: 
Induction Phase 
Cycle 
Agent 
Dose 
Route 
Day(s) 
Cycle Length 
Cycle 1-6 
Obinutuzumab 
100 mg 
900 mg 
1000 mg 
1000 mg 
IV 
1 (Cycle 1) 
2 (Cycle 1) 
8, 15 (Cycle 1) 
1 (starting Cycle 2) 
28 days 
Cycle 1-6 
Bendamustine 
90 mg/m2 
IV 
Days 1,2 
28 days 
Cycle 2-6 
Venetoclax 
800 mg 
Oral 
Days 1-10 
28 days 
All doses are based on actual body weight. In general +/- 3 day window for therapy/tests/visits 
during therapy except as noted for TLS monitoring. Alterations due to holidays, weekends, bad 
weather or other unforeseen circumstances will be permitted. 
Prophylactic filgrastim, pegfilgrastim or pegfilgrastim on body injector (OBI) will be administered 
in all patients. 
Pneumocystis Jiroveci Pneumonia (PJP) and antiviral prophylaxis will be initiated in all patients 
(Section 5.1.2). 
Section 5.1.3 for Monitoring of Cytomegalovirus (CMV). 
Premedication: Acetaminophen (650 or 1000 mg orally) and diphenhydramine (25 or 50 mg 
oral or intravenous) is to be administered prior to starting each infusion of obinutuzumab or per 
institutional guidelines. In addition, cycle 1, days 1 and 2 should receive dexamethasone (20 
mg) or methylprednisolone (80 mg) prior to obinutuzumab or per institutional guidelines. Since 
transient hypotension may occur during obinutuzumab infusion, consideration should be given 
to withholding anti-hypertensive medications 12 hours prior to obinutuzumab infusion. 
Antiemetic Therapy: Standard anti-emetic therapy may be given to patients prior to 
administration of each chemotherapy cycle per institutional guidelines: 5-HT3 serotonin receptor 
antagonists (e.g., ondansetron 8-16 mg) +/- steroids (e.g., dexamethasone) are recommended. 
5.1.1 
Tumor Lysis Prophylaxis 
TLS is a risk for patients with NHL who are treated with high cell-killing agents. Changes in blood 
chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 
hours following the first dose of treatment. The risk of TLS is a continuum based on multiple 
factors, including tumor burden and comorbidities. Patient characteristics that may suggest an 
increased risk of TLS include, but are not limited to, the following: 
• 
Any lymph mass ≥ 10 cm on the screening imaging 
• 
ALC >25 x 109/L 


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• 
Overall disease burden (e.g., several enlarged lymph nodes, even if none reaching 10 cm) 
• 
Elevated LDH levels 
• 
Creatinine clearance <60 mL/min 
• 
Extensive bone marrow involvement/skeletal involvement 
• 
Dehydration 
TLS Considerations: 
• 
Allopurinol (300 mg daily or bid [twice a day]) MAY be given if the risk of TLS is thought to 
be higher than the risk of Steven-Johnson syndrome. If Allopurinol is given, we recommend 
starting 24-48 hours prior to cycle 1, day 1 and continue through cycle 1, day 10 or per 
treating physician discretion. 
• 
Additional IV fluids are allowed per treating physician discretion. 
• 
Patients should be encouraged to consume oral hydration of 1.5-2 L/day beginning 48 hours 
prior to treatment and to continue for 24 hours post treatment. 
• 
Rasburicase is allowed per institutional guidelines. 
• 
Chemistry and hematology will be obtained and reviewed by a health care provider: 
o 
Cycle 1 
 
Day 1 approximately 6 hours after treatment initiation 
 
Day 2 prior to initiating day 2 treatment 
 
Day 8 prior to initiating day 8 treatment 
 
Day 15 prior to initiating day 15 treatment, only if day 8 labs indicate continued 
testing is needed 
o 
Cycle 2 
 
Day 1 approximately 6 hours after treatment initiation 
 
Day 2 prior to initiating day 2 treatment 
• 
Additional monitoring for TLS is allowed per treating physician discretion. 
If clinically significant TLS is identified during treatment, manage patients according to 
institutional guidelines. Refer to Appendix IV for “Definitions of Tumor Lysis Syndrome”18. 
5.1.2 
Infection Prophylaxis 
All patients must be initiated on prophylaxis for Pneumocystis Jiroveci Pneumonia (PJP) within 
2 weeks of initiating therapy with bendamustine and obinutuzumab. Trimethoprim-
sulfamethoxazole (Bactrim) is the preferred treatment of choice for PJP prophylaxis. PJP 
prophylaxis should continue until first restaging visit after completion of induction. PJP 
prophylaxis may be discontinued at that time, or continued at the discretion of the treating 
physician. If the patient will not be able to take trimethoprim-sulfamethoxazole then alternatives 
include: Dapsone, Pentamidine (aerosol) or Atovaquone. (The myelosuppressive effects of 
trimethoprim-sulfamethoxazole when administered in prophylactic doses is minimal.) 
Patients must also be initiated on acyclovir or valcyclovir as prophylaxis against simple viral 
infections. Antiviral prophylaxis should continue for a minimum of 6 months after completion of 
induction, and may be discontinued at that time, or continued at the discretion of the treating 
physician. 
If lymphopenia is documented (absolute lymphocyte count <500), then the investigator may 
choose to continue prophylactic medications for a longer duration. 


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NOTE: The above mentioned prophylactic medications have no known interactions with the 
study drugs. 
5.1.3 
Monitoring for Cytomegalovirus (CMV) 
Patients will be monitored for CMV reactivation using Quantitative PCR assay for CMV DNA. 
Induction Phase: Quantitative PCR will be checked once a month. 
Maintenance Phase: Quantitative PCR will be checked once every 2 months. 
There are four possible results: 
● 
Not detected 
● 
CMV DNA detected <137 IU/mL 
● 
CMV DNA detected between 137 and 9,100,000 IU/mL 
● 
CMV DNA detected >9,100,000 IU/mL 
If CMV PCR is reported as >137 IU/mL, then the frequency of testing for the PCR needs to be 
changed to weekly monitoring. 
If CMV PCR is >500 IU/ml and the trend is rising, on subsequent weekly measurements then: 
● 
The study treatment will be held 
● 
Preemptive CMV therapy will be initiated as per institutional guidelines in conjunction with 
Infectious disease specialists 
NOTE: CMV testing will likely be reported in ~ 48-72 hours and the patient may have received 
all the study drugs and may or may not be receiving venetoclax. 
Study drugs may be restarted after resolution of asymptomatic CMV reactivation if all the 
following conditions are met: 
● 
CMV reactivation is resolved as determined by the investigator 
● 
The CMV reactivation was NOT associated with any known end organ disease (for example: 
pneumonitis, hepatitis, gastroenteritis, retinitis, encephalitis) 
● 
Patient is deemed clinically appropriate to restart therapy 
Once treatment is restarted, secondary prophylaxis must be maintained per institutional 
guidelines. 
If there is associated end organ damage, patient will be removed from study. 
5.2 
Induction Administration Schedule 
Venetoclax (cycle 2-6) must be administered before obinutuzumab and/or bendamustine. 
Obinutuzumab and bendamustine may be given in any order (venetoclax, obinutuzumab, 
bendamustine or venetoclax, bendamustine, obinutuzumab). One cycle=28 days. 
5.2.1 
Obinutuzumab 
Cycle 1-6: Obinutuzumab 100 mg will be administered on cycle 1, day 1. The remaining 900 mg 
is to be administered on cycle 1, day 2. A fixed dose of 1000 mg is to be administered on cycle 
1, day 8 and 15, and on day 1 of cycles 2-6. For rate of infusion see Table 5-2 on next page and 
for management of infusion reactions please refer to Section 6.1.2.1 and Section 11.2.6.1. 
Obinutuzumab must be given after venetoclax but may be given before or after bendamustine. 
 
 
 


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Table 5-2: 
Obinutuzumab Rate of Infusion 
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 
100 mg 
Administer at 25 mg/hour over 4 hours. Do not increase the 
infusion rate. 
Day 2 
900 mg 
Administer at 50 mg/hour. The rate of the infusion can be 
escalated in increments of 50 mg/hour every 30 minutes to a 
maximum rate of 400 mg/hour. 
Day 8 
1000 mg 
Infusions can be started at a rate of 100 mg/hour and 
increased by 100 mg/hour increments every 30 minutes to a 
maximum of 400 mg/hour. 
Day 15 
1000 mg 
Cycles 2-6 
Day 1 
1000 mg 
5.2.2 
Bendamustine 
Cycle 1-6: Bendamustine 90 mg/m2 will be administered to patients by IV infusion on days 1, 2 
of each 28 day cycle. The infusions are administered over a 15-30 minute period or per 
institutional guidelines. Bendamustine must be given after venetoclax but may be given before 
or after obinutuzumab. 
5.2.3 
Venetoclax 
Cycle 2-6: Venetoclax 800 mg will be dispensed on day 1 of each 28 day cycle. On days when 
venetoclax is given with additional anti-lymphoma agents, venetoclax should be given first. A 
pill diary will be given to document compliance (Appendix V). 
Venetoclax will be taken once daily on days 1-10 and should be administered with a meal. If 
vomiting occurs within 15 minutes after taking venetoclax and all expelled tablets are still intact, 
another dose may be given. Otherwise, no replacement dose is to be given. In cases where a 
dose of venetoclax is missed or forgotten, the patient should take the dose as soon as possible 
and ensure that the minimal interval between the current dose and the next dose is at least 16 
hours in order to avoid excessive drug accumulation after the next dose. 
Patient compliance in taking the assigned daily dose of venetoclax will be assessed by standard 
pill counts. Bottles containing venetoclax tablets will be given to patients at regular scheduled 
visits. Previously distributed bottles will be returned to the clinic and tablets counted. Any 
discrepancy will be resolved with the patient at each clinic visit and documented in the patient 
record. 
5.2.4 
Restaging and Length of Therapy 
Repeat cycles every 28 days for a total of six cycles. Patients may be evaluated more frequently 
if needed at physician discretion. 
Patients will be restaged after 3 cycles of therapy. Patients who are in at least stable disease 
(SD, PR or CR) after 3 cycles will receive 3 additional cycles. Patients who have improved 
response or no interval change in their tumor measurements with restaging between cycles 3 
and 6 will proceed to the maintenance phase. Patients who achieve a complete remission 
following six cycles of therapy, will receive therapy with obinutuzumab and patients who are 
declared to be in a partial remission or stable disease following six cycles of therapy, based on 
PET/CT imaging, will receive therapy with venetoclax and obinutuzumab during maintenance. 
Patients with progressive disease will discontinue study protocol. 
 
 


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Table 5-3: 
Patients with Complete Response 
Agent 
Dose 
Route 
Day 
Cycle Length 
Obinutuzumab 
1000 mg 
IV 
1 
Every 2 months x 12 
cycles 
 
Table 5-4: 
Patients with Partial Response or Stable Disease 
Agent 
Dose 
Route 
Day 
Cycle Length 
Venetoclax 
800 mg 
Oral 
1-28 
Every month x 24 cycles 
Obinutuzumab 
1000 mg 
IV 
1 
Every 2 months x 12 
cycles 
The first dose of maintenance obinutuzumab should be given 8-12 weeks after completion of 
cycle 6, day 28 of induction therapy. Patients who do not start maintenance therapy by week 12 
will be removed from study. 
For patients with partial response or stable disease, a 28 day supply of venetoclax will be 
dispensed. Therefore, for patients receiving both venetoclax and obinutuzumab, patients will be 
seen every 28 days. If venetoclax was dose reduced to 400 mg during the induction phase, the 
same dose of 400 mg will continue during the maintenance phase for the 28 day cycle. (Patients 
on both venetoclax and obinutuzumab who convert to CR, will remain on both venetoclax and 
obinutuzumab for a total of 24 cycles and 12 cycles, respectively.) 
Section 5.1.3 for Monitoring of Cytomegalovirus (CMV). 
Premedication: Acetaminophen (650 or 1000 mg orally) and diphenhydramine (25 or 50 mg 
oral or intravenous) is to be administered prior to starting each infusion of obinutuzumab or per 
institutional guidelines. Since transient hypotension may occur during obinutuzumab infusion, 
consideration should be given to withholding anti-hypertensive medications 12 hours prior to 
obinutuzumab infusion. 
5.3 
Maintenance Administration Schedule 
The following are to be administered during the maintenance phase. 
Obinutuzumab: A fixed dose of 1000 mg is to be administered on day 1 every 2 months for a 
total of 12 cycles. Management of infusion reactions please refer to Section 6.1.2.1 and Section 
11.2.6.1. 
Venetoclax: Venetoclax 800 mg will be dispensed on day 1 every 28 days and taken once daily 
on days 1-28. A pill dairy will be given to document compliance (Appendix V). Venetoclax will 
only be administered for patients with a partial response or stable disease. On days when 
venetoclax is given with obinutuzumab, venetoclax should be given first. (Patients on both 
venetoclax and obinutuzumab who convert to CR, will remain on both venetoclax and 
obinutuzumab for a total of 24 and 12 cycles, respectively.) 
NOTE: 
If venetoclax was dose reduced during the induction phase, the same dose reduction 
will continue during the maintenance phase for the 28 day cycle. 
5.3.1 
Maintenance Therapy Suspension as of 9/16/2021 
Due to a recent Grade 5 event of myocarditis in a patient on maintenance therapy, the study 
investigators are concerned about atypical infections that have been seen after induction 
therapy on study. There have been four other events of atypical infections (Section 1.6.3 for 
details). 


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Given these adverse events we are suspending any additional maintenance therapy for those 
patients on study. These patients will not receive any further treatment and move on to the two 
year survival follow-up portion of the study. All study-required follow-up activities remain 
unchanged. 
There are currently 7 patients on maintenance therapy. The site investigators with patients were 
contacted via e-mail and agree with the recommendation to stop additional maintenance 
therapy. Several patients have already been taken off of study during maintenance due to the 
COVID-19 pandemic and either developing COVID-19 or having cytopenias related to 
maintenance therapy. 
 


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6. 
Dose Modification 
6.1 
Dose Modifications & Toxicity Management – Induction Phase 
All toxicities should be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events Version 5.0 (CTCAE V5.0). A copy of the CTCAE 
V5.0 can be downloaded from the CTEP website (http://www.ctep.cancer.gov). 
In general +/- 3 day window for therapy/tests/visits during therapy except as noted for TLS 
monitoring. Alterations due to holidays, weekends, bad weather or other unforeseen 
circumstances will be permitted. 
If administration of venetoclax, obinutuzumab or bendamustine is delayed on day 1 of a cycle, 
the administration of all the agents should be delayed for the same timeframe. For example, if 
bendamustine is delayed, administration of venetoclax and obinutuzumab should also be 
delayed so that they are given together beginning on Day 1 of the same cycle. 
NOTE: If any of the study drugs are permanently discontinued (i.e., Grade 4 IRR with 
obinutuzumab), the patient will be removed from study.


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6.1.1 
Venetoclax 
6.1.1.1 
Hematologic Toxicities for Venetoclax, Obinutuzumab and Bendamustine during Induction 
Table 6-1: 
Venetoclax, Obinutuzumab, and Bendamustine Dose Delay or Modifications for Hematologic Toxicity (G-CSF will be 
administered in all patients) 
 
G-CSF will be used in all patients starting with cycle 1 of treatment and will be continued unless contraindicated. 
 
If a cycle is delayed by >28 days then patients will discontinue further treatment on protocol. 
 
Table 6-3 for Venetoclax Dose Reductions and Table 6-4 for Bendamustine Dose Reductions. 
Event(s) 
Dose Delay or Modification 
Grade 3 or 4 neutropenia on Cycle 2 Day 1 with 
or without infection or fever a OR First episode 
• Delay doses of all study treatment by 7 days (+/-4 days) 
• If ANC recovers to ≥ 1000/mm3 by Day 7 of the scheduled date for the next cycle, proceed with the 
previous dose levels 
• If ANC recovers to ≥ 1000/mm3 on or after Day 8 of the scheduled date for the next cycle, change the 
dose of venetoclax to dose level -1. Bendamustine and obinutuzumab will be restarted at full dose. 
• If the primary cause of neutropenia is thought to be lymphoma infiltration into the bone marrow, the 
investigator may elect not to reduce the dose of venetoclax. Decisions must be made in consultation 
with and with approval of PrECOG. 
Recurrent Grade 3 or 4 neutropenia on Cycle 3 
onwards 
• Delay doses of all study treatment by 7 days (+/-4 days) 
• If ANC recovers to ≥ 1000/ mm3 by Day 7 of the scheduled date for the next cycle, and the previous 
venetoclax dose change has been made (Dose Level -1) then, continue with bendamustine at 90 mg/m2 
(days 1,2). Obinutuzumab will be restarted at full dose. 
• If ANC is <1000/mm3 on or after Day 7, postpone therapy by 7 days (+/-4 days) of the scheduled date 
for the next cycle and the previous venetoclax dose change was made (Dose Level -1), change the 
dose of venetoclax to dose level -2 and decrease bendamustine to 70 mg/m2. Obinutuzumab will be 
restarted at full dose. 
• If recurrent grade 3 or 4 neutropenia requiring dose delays of >7 days with venetoclax dosing at Dose 
Level -2 and decreased bendamustine dose, patient will discontinue study treatment. 
Recurrent Grade 4 neutropenia on Cycle Day 1 • If patient develops persistent Grade 4 neutropenia requiring dose delay despite growth factor support 
and following venetoclax dosing schedule changes and bendamustine dose reduction, and treatment 
is delayed by 28 days discontinue all study treatment permanently. 
 


PrECOG Protocol Number: PrE0403 
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Event(s) 
Dose Delay or Modification 
Grade 3 or 4 neutropenia or cytopenias without 
infection or fever (between cycles)  
• Continue dosing with venetoclax. Venetoclax need not be held if cytopenias are documented in between 
cycles. 
Grade 3 or 4 neutropenia with infection 
• Hold all study treatments until infection resolves following adequate treatment with antibiotics. 
Grade 3 or 4 thrombocytopenia on Cycle Day 
1a OR First Episode 
• Delay doses of all study treatment. 
• If platelet count recovers to ≥ 75,000/mm3 by Day 7 of the scheduled date of the next cycle, administer 
full dose of study treatment. 
• If platelet count recovers to ≥ 75,000/mm3 on or after Day 8 of the scheduled date for the next cycle, 
change the dose of venetoclax to dose level -1. Bendamustine and obinutuzumab will be restarted at 
full dose. 
• If the patient had baseline thrombocytopenia and the primary cause of thrombocytopenia is thought to 
be lymphoma infiltration into the bone marrow, the investigator may elect not to reduce the dose of 
venetoclax. 
Recurrent Grade 3 or 4 thrombocytopenia 
• Delay doses of all study treatment. 
• If platelet count recovers to ≥ 75,000/mm3 by Day 7 of the scheduled date for the next cycle, and the 
previous venetoclax dose change has been made (Dose Level -1) then, continue with bendamustine 
90 mg/m2 (days 1,2). Obinutuzumab will be restarted at full dose. 
• If platelet count recovers to ≥ 75,000/mm3 on or after Day 8, postpone therapy by 7 days (+/-4 days) of 
the scheduled date for the next cycle and the previous venetoclax dose change has been made (Dose 
Level -1), change the dose of venetoclax to dose level -2 and decrease bendamustine to 70 mg/m2. 
Obinutuzumab will be restarted at full dose. 
• If recurrent grade 3 or 4 thrombocytopenia requiring dose delays of >7 days with venetoclax dosing at 
Dose Level -2 and decreased bendamustine dose, the patient will discontinue study treatment. 
Grade 1 or 2 neutropenia and/or 
thrombocytopenia 
• No dose reduction or delay. 
a 
All based on laboratory results obtained within 72 hours prior to infusion of Day 1 of that cycle. 


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6.1.1.2 
Non-Hematologic Toxicities for Venetoclax, Obinutuzumab and Bendamustine during Induction 
Table 6-2: 
Venetoclax, Obinutuzumab and Bendamustine: Dose Delays and Modifications for Non-Hematologic Toxicity 
Event(s) 
Dose Delay or Modification 
Grade 3 or 4 TLS (first episode and 
subsequent episodes) 
• Refer to Appendix IV for “Definitions of Tumor Lysis Syndrome”18. 
• Hold all study treatments until TLS resolves. Resume treatment once TLS resolves. Missed doses may be 
administered to complete the intended treatment for that cycle. 
• Following complete resolution of TLS, if venetoclax was held for 14 days or less, venetoclax may be restarted 
at the same dose or changed to dose level -1 as determined by the investigator based on a risk assessment 
(including tumor burden status) in conjunction with prophylactic hydration and uricosuric agent; 
hospitalization for restarting the venetoclax dose may be considered at the discretion of the investigator. 
Dose escalation to the standard venetoclax should be considered in the following cycle. Obinutuzumab will 
be restarted at full dose and bendamustine will be resumed at the previous dose (dose before the delay) for 
the next infusion. 
• If clinically significant TLS is identified, manage patients according to institutional guidelines. 
Grade 
3 
or 
4 
treatment-related 
non-hematologic toxicity not specifically 
described above 
(excludes alopecia) 
• Delay attributable treatment until resolution for a maximum of 28 days. 
• First episode: If improvement to Grade ≤ 1 or baseline, resume previous doses of venetoclax, obinutuzumab 
and bendamustine. 
• Missed doses of venetoclax will NOT be made up. 
• For subsequent episodes: If improvement to Grade ≤ 1 or baseline, restart attributable treatment with 
appropriate dose reduction. Venetoclax at dose level -1 (or dose level -2, if patient already at dose level -1) 
and/or bendamustine at 70 mg/m2 (Table 6-3 and Table 6-4). Obinutuzumab will be restarted at full dose. 
Grade 
2 
treatment-related 
non-hematologic 
toxicity 
except 
nausea/vomiting (see below) 
(excludes alopecia and fatigue) 
• Delay treatment with venetoclax, obinutuzumab and bendamustine until resolution to Grade ≤ 1 (or baseline 
status) for a maximum of 28 days. After resolution, resume the full dose of venetoclax or dose before the 
delay. Obinutuzumab will be restarted at full dose and bendamustine will be resumed at the previous dose 
(dose before the delay) for the next infusion. 
• NOTE: Bendamustine should not be used in patients with AST or ALT ≥ 3.0x ULN and total bilirubin ≥ 1.5x 
ULN. 
Grade 2 treatment-related nausea and 
vomiting despite antiemetic treatment 
• Delay attributable treatment for a maximum of 28 days. 
• First episode: If improvement to Grade ≤ 1 or baseline, resume previous doses of venetoclax, obinutuzumab 
and bendamustine. 
• For subsequent episodes: If improvement to Grade ≤ 1 or baseline, restart attributable treatment with 
appropriate dose reduction. Venetoclax at dose level -1 (or dose level -2, if patient already at dose level -1) 
and/or bendamustine at 70 mg/m2 (Table 6-3 and Table 6-4). Obinutuzumab will be restarted at full dose. 
TLS=Tumor Lysis Syndrome 
Refer to Section 6.2 for Dose Modifications & Toxicity Management- Maintenance Phase.


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6.1.1.3 
Induction Phase Venetoclax Dose Reductions 
Table 6-3: 
Induction Phase Venetoclax Dose Modifications 
Starting Dose Level 
800 mg days 1-10 
Dose Level -1 
800 mg days 1-5 
Dose Level -2 
400 mg days 1-5 
Patients who cannot tolerate dose level -2 dosing will be discontinued from study treatment. 
6.1.2 
Obinutuzumab 
Dose delays as a result of adverse events should proceed on the basis of the principle of 
maintaining the dose intensity of immunochemotherapy. The determination of all schedule 
modifications will be made on the basis of the investigator’s assessment of ongoing clinical 
benefit with continuing study treatment. There will be no dose reductions for obinutuzumab. 
Please refer to Table 6-1: Venetoclax, Obinutuzumab, and Bendamustine Dose Delay or 
Modifications for Hematologic Toxicity and Table 6-2: Venetoclax, Obinutuzumab and 
Bendamustine: Dose Modifications for Non-Hematologic Toxicity. Refer to Section 6.2 for Dose 
Modifications & Toxicity Management- Maintenance Phase. In addition, refer to below for other 
adverse events and dose delays for obinutuzumab. 
6.1.2.1 
Infusion Related Toxicities 
If a patient experiences an infusion-related reaction (IRR) of any grade during infusion, adjust 
the infusion as follows: 
• 
Grade 4 (life-threatening): Stop infusion immediately and permanently discontinue 
obinutuzumab therapy. 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. Patients who 
experience any of these reactions should receive aggressive treatment of symptoms and 
will be discontinued from study treatment. 
• 
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 per institutional 
guidelines. 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 per 
institutional guidelines. 
Section 11.2.6.1 premedication requirements for patients who experience IRRs. 
6.1.2.2 
Hepatitis B Virus Reactivation 
Patients who are both HBsAg negative and hepatitis B core antibody (anti-HBc) positive may be 
included in studies with obinutuzumab. These patients should have HBV DNA levels obtained 
monthly for at least 12 months after the last cycle of therapy by means of real-time PCR with 
the use of an assay that has a sensitivity of at least 10 IU/mL. 
 


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If the HBV DNA assay becomes positive and is above the World Health Organization’s (WHO) 
cutoff of 100 IU/mL, treatment with immunochemotherapy should be held and the patient should 
be treated (for at least 1 year after the last dose of obinutuzumab) with an appropriate nucleoside 
analogue and immediately referred to a gastroenterologist or hepatologist for management.  
Patients may resume immunochemotherapy once HBV DNA levels decrease to undetectable 
levels. 
If the HBV DNA assay becomes positive and is ≤ 100 IU/mL, the patient should be retested 
within 2 weeks. If the assay is still positive, treatment with immunochemotherapy must be held 
and the patient should be treated with an appropriate nucleoside analogue (for at least 1 year 
after the last dose of obinutuzumab) and immediately referred to a gastroenterologist or 
hepatologist for management. Patients may resume immunochemotherapy once the HBV DNA 
levels decrease to undetectable levels. 
If a patients HBV DNA level exceeds 100 IU/mL while the patient is receiving antiviral 
medication, treatment with immunochemotherapy must be permanently discontinued. 
If prophylactic antiviral medications for hepatitis B reactivation is the standard of care, patients 
may be treated prophylactically. 
6.1.3 
Bendamustine 
Guidelines and dose modifications for bendamustine are below. Dose modifications will be 
made according to Table 6-1 Venetoclax, Obinutuzumab, and Bendamustine Dose Delay or 
Modifications for Hematologic Toxicity and Table 6-2: Venetoclax, Obinutuzumab and 
Bendamustine: Dose Modifications for Non-Hematologic Toxicity. 
6.1.3.1 
Hematologic and Non-Hematologic Toxicity 
At the start of each cycle, ANC must be at least 1000/mm3 and platelet count must be at least 
75,000/mm3 to proceed with treatment (unless the patient has documented marrow involvement 
with lymphoma suppressing blood counts). Granulocyte-colony stimulating factor (G-CSF) 
support is required. 
NOTE: Bendamustine should not be used in patients with AST or ALT ≥ 3.0x ULN and total 
bilirubin ≥ 1.5x ULN. 
Table 6-4: 
Bendamustine Dose Modification 
Bendamustine Starting Dose 
Bendamustine Dose Reduction (Dose Level -1) 
90 mg/m2 
Reduce dose to 70 mg/m2 
Patients will be removed from study treatment if they require a dose reduction of bendamustine 
below 70 mg/m2. 
6.2 
Dose Modifications & Toxicity Management – Maintenance Phase 
All toxicities should be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events Version 5.0 (CTCAE V5.0). A copy of the CTCAE 
V5.0 can be downloaded from the CTEP website (http://www.ctep.cancer.gov). 
In general +/- 3 day window for therapy/tests/visits during therapy except as noted for TLS 
monitoring. Alterations due to holidays, weekends, bad weather or other unforeseen 
circumstances will be permitted. 
 


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6.2.1 
Obinutuzumab Maintenance for Patients Achieving a Complete Remission 
Table 6-5: 
Obinutuzumab Dose Modification 
Event 
Dose Delay or Modification 
Grade 3 or 4 Neutropenia 
• 
First Episode: Delay treatment by minimum of 7 days 
for a maximum of 28 days. GCSF support may be 
offered per investigator discretion. If ANC recovers to 
Grade 2 or less, resume maintenance with 
obinutuzumab. 
• 
If ANC does not improve to Grade 2 or less, 
discontinue maintenance therapy with obinutuzumab. 
• 
For subsequent episodes: Discontinue maintenance 
with obinutuzumab. 
∗Hypogammaglobulinemia 
(asymptomatic) 
• 
IgG <300mg/dl, discontinue obinutuzumab 
maintenance. 
∗Hypogammaglobulinemia 
(symptomatic) 
Defined as 2 or more ≥ grade 2 infections 
in a six month period after obinutuzumab 
treatment in the absence of neutropenia. 
• 
IgG <500mg/dl, discontinue obinutuzumab 
maintenance, and consider IVIG replacement therapy. 
Grade 3 or 4 infections with or without 
neutropenia 
• 
Discontinue obinutuzumab maintenance. 
6.2.2 
Venetoclax and Obinutuzumab Maintenance for Patients Achieving a Partial Response 
or Stable Disease 
Table 6-6: 
Venetoclax and Obinutuzumab Dose Modification 
Event 
Dose Delay or Modifications 
Grade 3 or 4 Neutropenia 
• 
First Episode: Delay treatment by minimum of 7 days 
for a maximum of 28 days. GCSF support may be 
offered per investigator discretion. If ANC recovers to 
Grade 2 or less, resume maintenance with venetoclax 
and obinutuzumab. 
• 
If ANC does not improve to Grade 2 or less, 
discontinue maintenance therapy. 
• 
For subsequent episodes: Discontinue maintenance 
therapy. 
∗Hypogammaglobulinemia 
(asymptomatic) 
• 
IgG <300mg/dl, discontinue obinutuzumab 
maintenance. Continue venetoclax. 
∗Hypogammaglobulinemia 
(symptomatic) 
Defined as 2 or more ≥ grade 2 infections 
in a six month period after obinutuzumab 
treatment in the absence of neutropenia. 
• 
IgG <500mg/dl, discontinue obinutuzumab 
maintenance, replace with monthly (IVIG 400 mg/kg) 
until IgG improves to >500-550mg/dl). Further therapy 
based on investigator discretion. Continue venetoclax. 
Grade 3 or 4 infections with or without 
neutropenia 
• 
Discontinue maintenance therapy. 
Grade 2 or higher nausea/vomiting 
• 
Reduce venetoclax to 400 mg daily. If 400 mg not 
tolerated, discontinue venetoclax. 
∗Hypogammaglobulinemia are not graded in the CTCAE Version 5.0. The current recommendations are 
modified from the American Academy of Allergy, Asthma and Immunology guidelines. 


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6.3 Concurrent Therapies 
6.3.1 
Permitted 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient between the 7 days preceding the study entry evaluation and the early study 
treatment termination visit/study treatment completion visit. 
Patients who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use. Effective contraception is required while receiving 
obinutuzumab. For women, effective contraception is required to continue for ≥ 18 months after 
the last dose of obinutuzumab. For men, effective contraception is required to continue for ≥ 6 
months after the last dose of obinutuzumab. 
Systemic steroid therapy other than the prednisone component of chemotherapy regimens 
will not be allowed during study treatment with the exception of inhaled corticosteroids for the 
treatment of asthma or chronic obstructive pulmonary disease, infusions of steroids prior to 
obinutuzumab infusions or for IRRs, topical steroids, or replacement corticosteroid therapy for 
an inherited or acquired deficiency. 
For infusion related reactions and anaphylaxis, medications (including subcutaneous 
epinephrine, corticosteroids, and intravenous diphenhydramine) and resuscitation equipment 
should be available for immediate use. 
6.3.2 
Not Permitted 
The use of live viral vaccines is contraindicated. Responses to inactivated vaccines, 
recombinant vaccines, and cell-wall vaccines are unreliable and suboptimal in NHL patients. 
Receipt of live viral vaccines within 28 days prior to the initiation of study treatment, at any time 
during study treatment, or in the 30 days following last dose of study treatment. 
Use of the following therapies are prohibited during the study: 
- 
Immunotherapy 
- 
Hormone therapy (other than contraceptives, hormone replacement therapy, or megestrol 
acetate) 
- 
Any therapies intended for the treatment of lymphoma whether FDA approved or 
experimental (outside of this study) 
Use of the following concomitant medications is prohibited from 7 days prior to initiation of drug 
treatment and during the study: 
– 
Steroid therapy for anti-neoplastic intent with the exception of inhaled steroids for asthma 
or chronic obstructive pulmonary disease, prior to obinutuzumab infusions or for IRRs, 
topical steroids, or replacement/stress corticosteroids 
– 
Warfarin or warfarin derivatives (Factor Xa is allowed) 
– 
Co-administration with strong and moderate CYP3A inhibitors is not recommended. Consider 
alternative medications if necessary. If subject requires the use of these medications, use 
with caution and reduce the venetoclax dose by 2-fold for moderate inhibitors and 4-fold for 
strong inhibitors during co-administration. If subject requires use of strong or moderate 
CYP3A inducers, use with caution and contact PrECOG for guidance. Co-administration with 
the use of weak CYP3A inducers and weak CYP3A4 inhibitors should be undertaken with 
caution. 
– 
Avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain 
inhibitors of CYP3A. 
 


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Concomitant medications that fall into the categories below could potentially lead to adverse 
reactions and should be considered cautionary (except where noted). If a potential study patient 
is taking any of the medications in the categories described below, the investigator must assess 
and document the use of medications known or suspected to fall in the following medication 
categories: 
– 
P-gp inhibitors such as amiodarone, azithromycin, captopril, carvedilol, cyclosporine, 
felodipine, quercetin, quinidine, ranolazine, ticagrelor 
– 
P-gp substrates such as digoxin, everolimus, and sirolimus due to inhibition potential at 
therapeutic dose levels 
– 
CYP2C8 substrates such as thiazolidinediones (glitazones) and select statins (because of 
expected inhibition of the metabolism of CYP2C8 substrates) by venetoclax 
– 
CYP2C9 substrates such as tolbutamide (because of expected inhibition of the metabolism 
of CYP2C9 substrates by venetoclax). It is recommended to exclude CYP2C9 substrates 
with a narrow therapeutic index such as phenytoin. 
See Appendix VI “Additional Excluded and Cautionary Medications” for additional information. 
6.4 
Supportive Care 
All supportive measures consistent with optimal patient care will be given throughout the study. 


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7. 
Study Duration and Discontinuation of Therapy 
7.1 
Study Duration 
Patients will receive protocol therapy unless: 
1. Disease progression per Lymphoma Response Criteria (Cheson Criteria) guidelines or 
clinical progression. 
2. Toxicities considered unacceptable by either the patient or the investigator, despite optimal 
supportive care and dose modifications. 
3. Development of an inter-current illness that prevents further administration of study 
treatment. 
4. Extraordinary Medical Circumstances: If at any time the constraints of this protocol are 
detrimental to the patient's health, protocol treatment should be discontinued. 
5. Patient withdraws consent or is unable to comply with study procedures. 
7.2 
Duration of Follow-Up 
Adverse events will be captured for 30 days after the last dose of study medication. Patients will 
be followed every 6 months for up to 2 years from treatment discontinuation or study closure. 
Initiation of first anti-cancer therapy will also be documented. 
If a patient is removed from treatment for reason(s) other than progression, follow with regular 
tumor assessments per standard of care until progression or start of new treatment. 
For patients who are registered but do not receive any protocol therapy, baseline and follow-up 
information per Section 10 will be collected. 
NOTE: 
Further maintenance therapy was suspended on 9/16/2021. Follow-up will continue 
as noted above. 
7.3 
Criteria for Removal from Study Treatment 
A genuine effort will be made to determine the reason(s) why a patient fails to return for the 
necessary visits or is discontinued from the trial, should this occur. It will be documented whether 
or not each patient completed the clinical study. If for any patient study treatment or observations 
were discontinued, the reason will be recorded on the appropriate electronic case report form. 
Reasons that a patient may discontinue treatment in a clinical study are considered to constitute 
one of the following: 
1. Recurrence of disease or documented progression of disease, including disease 
transformation. 
2. Intercurrent illness that prevents further administration of treatment per investigator 
discretion. 
3. Severe or life-threatening anaphylaxis or hypersensitivity reaction. 
4. Unacceptable adverse events. 
5. Treatment interruption of more than 28 days. 
6. Investigator and/or patient discontinue chemotherapy. 
7. Pregnancy. 
8. Develops a second malignancy (except for non-melanoma skin cancer or cervical 
carcinoma in-situ) that requires treatment, which would interfere with this study. 
9. The patient may choose to withdraw from the study at any time for any reason. 


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10. General or specific changes in the patient's condition that render the patient unacceptable 
for further treatment in the judgment of the investigator. 
11. Severe non-compliance to protocol as judged by the investigator. 
12. Lost to follow-up. 
13. Death. 
14. Closure of study by PrECOG. 
Any patient who receives at least one dose of study drug (venetoclax, obinutuzumab, and/or 
bendamustine) will be included in the safety analysis. Patients who discontinue study treatment 
early should be followed for response assessments, if possible. Follow-up will continue per 
Section 10, as applicable. 
 


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8. 
Adverse Event Reporting 
8.1 
Collection of Safety Information 
Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-
existing medical condition in a patient administered a medicinal product in a clinical investigation 
and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (e.g., including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a product (investigational 
or marketed), whether or not considered related to the product (investigational or marketed). 
After informed consent, but prior to initiation of study treatment (venetoclax, obinutuzumab, 
and/or bendamustine), only AEs/SAEs caused by a protocol-mandated intervention will be 
collected (e.g., SAEs related to invasive procedures such as biopsies). After the initiation of 
study treatment, all identified AEs and SAEs must be recorded and described on the appropriate 
page of the electronic Case Report Form (eCRF). If known, the diagnosis of the underlying 
illness or disorder should be recorded, rather than individual symptoms. The following 
information should be documented for all AEs: date of onset and resolution, severity of the event; 
the investigator’s opinion of the relationship to investigational product (see definitions below); 
treatment required for the AE treatment required for the AE; cause of the event (if known); and 
information regarding resolution/outcome. 
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the eCRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more-frequent follow-up assessments, further 
diagnostic investigation, etc.). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5x the ULN associated with cholecystitis), only the diagnosis (e.g., 
cholecystitis) needs to be recorded on the Adverse Event eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF. If the laboratory 
abnormality can be characterized by a precise clinical term, the clinical term should be recorded 
as the AE or SAE. For example, an elevated serum potassium level of 7.0 mEq/L should be 
recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the eCRF unless their severity, seriousness, or 
etiology changes. 
Severity 
The categories and definitions of severity used for clinical trials AEs are defined in the NCI’s 
Common Terminology Criteria (CTCAE) V5.0 (http://www.ctep.cancer.gov). 
Attribution 
The following categories and definitions of causal relationship or attribution to study drug should 
be used to assess Adverse Events: 
• 
Definite: There is a reasonable causal relationship between the study drug and the event. 
The event response to withdrawal of study drug (dechallenge) and recurs with rechallenge, 
if clinically feasible. 
• 
Probable: There is a reasonable causal relationship between the study drug and the event. 
The event responds to dechallenge. Rechallenge is not required. 
• 
Possible: There is a reasonable causal relationship between the study drug and the event. 
Dechallenge information is lacking or unclear. 
• 
Unlikely: There is doubtful causal relationship between the study drug and the event. 


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• 
Unrelated: There is clearly not a causal relationship between the study drug and the event 
or there is a causal relationship between another drug, concurrent disease, or 
circumstances and the event. 
Categories ‘definite’, ‘probable’ and ‘possible’ are considered study drug related. Categories 
‘unlikely’ and ‘unrelated’ are considered not study drug-related. 
The development of a new cancer should be regarded as an AE. New cancers are those that 
are not the primary reason for administration of study treatment and have been identified after 
inclusion of the patient into the clinical study. 
Expected/Unexpected: Expected AEs are those AEs that are listed or characterized in the 
Package Insert or current IB. 
Unexpected AEs are those not listed in the Package Insert or current IB or not identified. This 
includes AEs for which the specificity or severity is not consistent with the description in the 
Package Insert or IB. For example, under this definition, hepatic necrosis would be unexpected 
if the Package Insert or Investigator’s Brochure only referred to elevated hepatic enzymes or 
hepatitis. 
Attribution and expected/unexpected should be assessed against the study drug(s). The 
investigator will determine if event is due to venetoclax, obinutuzumab, bendamustine, disease, 
etc. 
AEs related to venetoclax, obinutuzumab, and/or bendamustine should be followed for 
30 days after last dose of study therapy until ≤ grade 1 or stabilization, and reported as 
SAEs if they become serious. 
Any AE’s (serious or not) that occur after the above time periods but are deemed to be at 
least possibly related to study therapy shall be reported. 
8.2 
Definition of Adverse Events of Special Interest (AESI) 
The following adverse events are considered of special interest and must be reported to 
PrECOG as serious adverse events (Section 8.5 for reporting instructions), irrespective of 
regulatory seriousness criteria. 
Obinutuzumab and Venetoclax Combination Therapy Events of Special Interest: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law. 
Criteria for Hy’s Law (FDA Guidance 2009) 
 The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold 
or greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control 
drug or placebo. 
 Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3x ULN, one or more also show elevation of 
serum total bilirubin to >2x ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase). 
 No other reason can be found to explain the combination of increased 
aminotransferases and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or 
acute liver disease; or another drug capable of causing the observed injury. 
• 
Suspected transmission of an infectious agent by the study drug, as defined below: 
o 
Any organism, virus, or infectious particle (e.g., prior protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent. A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product. This term applies only when contamination of the study drug is suspected. 


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Venetoclax Events of Special Interest: 
• 
Refer to Appendix IV “Definitions for Tumor Lysis Syndrome”18 
Obinutuzumab Events of Special Interest: 
• 
All Tumour Lysis Syndrome (irrespective of seriousness, causality or severity) 
o 
Refer to Appendix IV “Definitions for Tumor Lysis Syndrome”18 
• 
Second Malignancies 
Selected events (events for which additional data collection or analyses will be performed; no 
special case handling or follow-up is required) include the following: 
• 
IRRs 
• 
Infections (including PML) 
• 
Neutropenia (including late-onset neutropenia, defined as neutrophil count <1000 
cells/mm3, occurring 28 days or more after obinutuzumab treatment has been completed or 
stopped; prolonged neutropenia, defined as neutrophil count <1000 cells/mm3, that does 
not resolve after 28 days (without obinutuzumab treatment) 
• 
Thrombocytopenia (including acute thrombocytopenia occurring during and within 24 hours 
post obinutuzumab infusion) 
• 
Hepatitis B reactivation 
• 
Cardiac events (cardiomyopathy, arrhythmias, myocardial infarction, etc.) 
• 
Second malignancies (any malignancy other than basal cell carcinoma of skin, squamous 
cell carcinoma of skin, carcinoma -in -situ of the cervix) 
• 
Gastrointestinal (GI) perforation 
8.3 
Special Situation Reports 
8.3.1 
COVID-19 Reporting 
All positive COVID-19 test results must be reported with the type of test performed recorded. 
Coding for COVID-19 adverse events will be as follows. 
• 
Infections and infestations - Other, specify 
• 
Specify = COVID-19 
The categories and definitions of severity used for COVID-19 AEs are defined in NCI’s CTCAE 
V5.0 (http://www.ctep.cancer.gov). 
COVID-19 adverse events that qualify as Serious Adverse Events per Section 8.4 must be 
reported as such, per Section 8.5. The following information will be captured: 
• 
Narrative: Identify all pertinent facts related to the COVID-19 infection including, but not 
limited to the following: Presumptive vs confirmed diagnosis. If presumptive, please update 
narrative if/when diagnosis is confirmed, including timelines. 
- 
Treatment information 
- 
Recovery information, including timelines 
- 
Outcome information/status 
All deviations or withdrawals due to COVID-19 will documented as such in the eCRF. 
 


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8.4 
Handling of Serious Adverse Events (SAEs) 
8.4.1 
SAE Definitions 
A serious AE is any untoward medical occurrence occurring after initiation of study treatment 
or that at any dose: 
• 
results in death (i.e., the adverse event actually causes or leads to death) 
• 
is life-threatening (defined as an event in which the study patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity (i.e., the adverse event results in 
substantial disruption of the subject’s ability to conduct normal life functions) 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the patient or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above). 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result 
in hospitalization. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
NOTE: Patients admitted for monitoring of tumor lysis is NOT considered an SAE. 
8.5 
SAE Reporting Requirements 
Serious adverse events (SAE) are defined above. The investigator should inform PrECOG of 
any SAE within 24 hours of being aware of the event. The date of awareness should be noted 
on the report. This must be documented on the PrECOG SAE form. This form must be 
completed and supplied to PrECOG within 24 hours/1 business day at the latest on the following 
working day. The initial report must be as complete as possible, including details of the current 
illness and (serious) adverse event, and 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 PrECOG SAE report form. A final report to document resolution of 
the SAE is required. The investigator is responsible for following all SAEs until resolution, until 
the subject returns to baseline status, or until the condition has stabilized with the expectation 
that it will remain chronic, even if this extends beyond study participation. A copy of the email of 
the SAE report to PrECOG should be attached to the SAE and retained with the patient records. 
SAEs should be scanned and emailed to PrE0403SAE@qdservices.com as per the 
instructions found in study materials provided to the investigator site. 
 
Medical Monitor 
During normal business hours  
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Phone: 484-574-2367 
 
Manager, Clinical Safety 
During normal business hours  
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Cell: 484-574-2367 


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PrECOG will notify Genentech of any SAE’s and AEs of Special Interest (regardless of causality) 
within 1 business day of the Awareness Date. All non-serious adverse events will be provided 
to Genentech quarterly. Relevant follow-up information will be provided to Genentech as soon 
as it becomes available. 
Investigators should also report event(s) to their IRB as required. 
Collection of complete information concerning SAEs is extremely important. Full descriptions of 
each event will be followed. Thus, follow-up information which becomes available as the SAE 
evolves, as well as supporting documentation (e.g., hospital discharge summaries and autopsy 
reports), should be collected subsequently, if not available at the time of the initial report, and 
immediately sent using the same procedure as the initial SAE report. 
All SAEs, regardless of causality, must be collected which occur within 30 days of last dose of 
study treatment. This includes all deaths within 30 days of last dose of venetoclax, 
obinutuzumab, and/or bendamustine, regardless of attribution. In addition, the Investigator 
should notify PrECOG or designee of any SAE that may occur after this time period which they 
believe to be definitely, probably or possibly related to investigational product. 
NOTE: 
After study closure, study-drug related SAEs should be reported voluntarily by the 
treating physician to the manufacturer. 
Serious adverse event reporting to regulatory authorities and all participating investigators will 
be conducted by PrECOG (or designee) in accordance with 21CFR312.32, local requirements 
and international regulations, as appropriate. FDA reporting requirement timelines will be 
followed. PrECOG will also concurrently forward any such reports to Genentech. 
8.6 
Product Complaints 
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial. 
Product Complaints (with or without an AE) for venetoclax and obinutuzumab originating from 
the Study will be collected and reported to PrECOG on a PrE0403 Product Complaint Reporting 
Form even in the absence of an AE (if product complaint is an SAE, the PrE0403 SAE form will 
also be completed). PrECOG will transmit product complaints to Genentech for venetoclax and 
obinutuzumab within fifteen (15) calendar days. Product complaints for bendamustine will be 
reported per each sites standard procedures. 
8.7 
Reporting of Other Second Primary Cancers 
New cancers are those that are not the primary reason for administration of study treatment and 
have been identified after inclusion of the patient into the clinical study. 
All cases of new primary cancers that occur during or after protocol treatment must be reported 
to PrECOG on a Second Primary Cancer form within 30 days of diagnosis, regardless of 
relationship to protocol treatment. Secondary primary malignancies should also be reported as 
a SAE. The SAE form is not for use for reporting recurrence or development of metastatic 
disease. A copy of the pathology report, if applicable, should be sent, if available. 
NOTE: Once data regarding survival and remission status are no longer required by the protocol, 
no follow-up data should be submitted. 
8.8 
Procedures in Case of Pregnancy 
Prior to study enrollment, women of childbearing potential (WOCBP) and male patients with a 
female partner of childbearing potential must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional pregnancy, 
documented in the informed consent. In addition, all WOCBP should be instructed to contact 


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the Investigator immediately if they suspect they might be pregnant (e.g., missed or late 
menstrual period) at any time during study participation. 
Pregnancy of a female patient or the female partner of a male patient occurring while the patient 
is receiving study drug or within 18 months for a female patient or 6 months for the female 
partner of a male patient after the patient’s last dose of study drug will be reported to PrECOG 
on a Pregnancy Form within 24 hours of the investigator’s knowledge of the pregnancy. 
All reports of congenital abnormalities/birth defects and spontaneous miscarriages should also 
be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth 
including health of the newborn or congenital abnormality) must be followed and documented 
on the Pregnancy Form even if the subject was discontinued from the study treatment. Should 
pregnancy occur during a subject’s participation, the subject will immediately be discontinued 
from the treatment and followed per protocol. 
The study-specific Pregnancy Form can be found in the Study Reference Manual. 
PrECOG will notify Genentech of any pregnancy within 1 business day of the Awareness Date. 
8.9 
Reporting Guidelines in the Case of Overdose 
In the event of an overdose with any of the study drugs (venetoclax, obinutuzumab and/or 
bendamustine), defined as any dose higher than the patient allocated dose in the study, this 
should be captured as an adverse event. Both symptomatic and non-symptomatic overdose 
must be reported. For any accidental or intentional overdose with the study treatment that is 
symptomatic, even if not fulfilling a seriousness criterion, a SAE form should also be 
completed and reported to PrECOG within 24 hours of the investigator’s knowledge of the 
overdose. 


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9. 
Measurement of Effect 
Lymphoma Response Criteria (Cheson Criteria) 
NOTE: These criteria are based upon the criteria from the Revised Response Criteria for 
Malignant Lymphoma.19 
9.1 
Lymphoma Response Cheson Criteria 
The criteria use the following categories of response: Complete Response (CR), Partial 
Response (PR), Stable Disease (SD), Relapse and Progression (PD). In the case of stable 
disease, follow-up assessments must have met the SD criteria at least once after study entry at 
a minimum interval of six weeks. 
The following guidelines are to be used for establishing tumor measurements at baseline and 
for subsequent comparison: 
• 
The six largest dominant nodes or extranodal masses must be identified at baseline. 
• 
If there are 6 or fewer nodes and extranodal masses, all must be listed as dominant. 
• 
If there are more than 6 involved nodes or extranodal masses, the 6 largest dominant nodes 
or extranodal masses should be selected according to the following features: a) they should 
be clearly measurable in at least two perpendicular measurements; b) they should be from 
as disparate regions of the body as possible; and c) they should include mediastinal and 
retroperitoneal areas of disease whenever these sites are involved. 
• 
Measurements for all dominant nodes and extranodal masses will be reported at baseline. 
Measurements on non-dominant nodes are not required. 
• 
The lymph nodes or extranodal masses selected for measurement should be measured in 
two perpendicular diameters, one of which is the longest perpendicular diameter. The lymph 
nodes should be measured in centimeters to the nearest one tenth of a centimeter (e.g. 
2.0 cm, 2.1 cm, 2.2 cm, etc.) 
• 
The two measured diameters of each lymph node site or extranodal mass should be 
multiplied giving a product for each nodal site or extranodal mass. The product of each nodal 
site should be added, yielding the sum of products of the diameters (SPD). The SPD will be 
used in determining the definition of response for those who have less than a complete 
response. 
9.1.1 
Complete Response 
Complete disappearance of all detectable clinical evidence of disease, and disease-related 
symptoms if present prior to therapy. 
For lymphomas for which the PET scan was positive prior to therapy: a post-treatment residual 
mass of any size is permitted as long as it is PET-negative. 
If the pretreatment PET scan was negative: all lymph nodes and extranodal masses must have 
regressed on CT to normal size (<1.5  cm in their greatest transverse diameter for nodes 
>1.5 cm prior to therapy). Previously involved nodes that were 1.1-1.5 cm in their long axis and 
>1.0 cm in their short axis prior to treatment must have decreased to <1 cm in their short axis 
after treatment. 
The spleen and/or liver, if considered enlarged prior to therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination, and nodules related 
to lymphoma should disappear. However, no normal size can be specified because of the 
difficulties in accurately evaluating splenic and hepatic size and involvement. For instance, a 
spleen considered normal size may contain lymphoma, whereas an enlarged spleen may not 
necessarily reflect the presence of lymphoma, but variations in anatomy, blood volume, the use 
of hematopoietic growth factors, or other causes. 


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If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared 
on repeat bone marrow biopsy. The biopsy sample on which this determination is made must 
be adequate (with a goal of >20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by IHC. A sample that is negative by IHC but demonstrating 
a small population of clonal lymphocytes by flow cytometry will be considered a CR until data 
become available demonstrating a clear difference in patient outcome. 
NOTE: Complete Remission/unconfirmed (CRu): Using the above definition for CR and that 
below for PR eliminates the category of CRu. 
9.1.2 
Partial Response 
The designation of PR requires all of the following: 
A >50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant 
nodes or extranodal masses. These nodes or masses should be selected according to the 
following: (a) they should be clearly measurable in at least 2 perpendicular dimensions; if 
possible, they should be from disparate regions of the body; (b) they should include mediastinal 
and retroperitoneal areas of disease whenever these sites are involved. 
No increase in the size of other nodes, liver or spleen. 
Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior 
to treatment. However, if positive, the cell type should be specified, e.g. large-cell lymphoma or 
small cleaved cell lymphoma. No new sites of disease. 
9.1.3 
Stable Disease 
Failing to attain the criteria needed for a PR or CR, but not fulfilling those for progressive 
disease. 
Typically FGD-avid lymphomas: The PET should be positive at prior sites of disease with no 
new areas of involvement on the post- treatment CT or PET. 
For variably FDG-avid lymphomas/FDG-avidity unknown: For patients without a pretreatment 
PET scan or if the pre-treatment PET was negative, there must be no change in the size of the 
previous lesions on the post-treatment CT scan. 
9.1.4 
Progression Disease/Relapse 
For determination of relapsed and progressive disease, lymph nodes should be considered 
abnormal if the long axis is more than 1.5 cm, regardless of the short axis. If a lymph node has 
a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if the short axis is more than 
1 cm. Lymph nodes <1 x <1 cm will not be considered as abnormal for relapse or progressive 
disease. 
Treatment decisions in patients with presumed refractory, relapsed or progressive disease 
should not be made solely on the basis of a single PET scan without histologic confirmation. 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size. Increased FDG uptake in a previously unaffected 
site should only be considered relapsed or progressive disease after confirmation with other 
modalities. In patients with no prior history of pulmonary lymphoma, new lung nodules identified 
by CT are mostly benign. Thus, a therapeutic decision should not be made solely on the basis 
of the PET without histologic confirmation. 
At least a 50% increase from nadir in the SPD of any previously involved nodes or extranodal 
masses, or in a single involved node or extranodal mass, or the size of other lesions (e.g. splenic 
or hepatic nodules). To be considered progressive disease, a lymph node or extranodal mass 
with a diameter of the short axis of less than 1.0 cm must increase by >50% and to a size of 1.5 
cm x 1.5 cm or more than 1.5 cm in the long axis. 


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At least a 50% increase in the longest diameter of any single previously identified node or 
extranodal mass more than 1 cm in its short axis. 
Lesions should be PET positive if the lesion was PET positive before therapy unless the lesion 
is too small to be detected with current PET systems (<1.5 cm in its long axis by CT).  
Measurable extranodal disease should be assessed in a manner similar to that for nodal 
disease. For these response criteria, the spleen is considered nodal disease. Disease that is 
only assessable (e.g., pleural effusions, bone lesions) will be recorded as present or absent 
only, unless, while an abnormality is still noted by imaging studies or physical examination, it is 
found to be histologically negative. 
9.2 
Response 
9.2.1 
Duration of Response 
This is measured from the documented beginning of response (CR or PR) to the time of relapse. 
This is measured in responders. 
9.2.2 
Survival 
Survival is defined as the date of study entry to the date of death. 
9.2.3 
Progression-Free Survival 
Progression-free Survival (PFS) is defined as the time from entry onto study until lymphoma 
progression or death from any cause. PFS is often considered the preferable endpoint in 
lymphoma clinical trials, especially those involving incurable histologic subtypes (e.g., follicular 
and low grade, MCL). PFS reflects tumor growth and, therefore, occurs prior to the endpoint of 
overall survival. In addition, PFS is not confounded by the administration of subsequent therapy. 
Whether a prolongation of PFS represents direct clinical benefit or a surrogate for clinical benefit 
depends on the magnitude of the effect and the risk-benefit ratio of the therapy under 
investigation. Unlike survival, the precise date of progression is generally unknown. It may be 
defined as the first date of documentation of a new lesion or enlargement of a previous lesion, 
or the date of the scheduled clinic visit immediately after radiologic assessment has been 
completed. Where there is missing information, censoring of the data may be defined as the last 
date at which progression status was adequately assessed or the first date of unscheduled new 
anti-lymphoma treatment. 
9.2.4 
Time to Progression 
Time to progression (TTP) is defined as the time from study entry until lymphoma progression 
or death due to lymphoma. In TTP, deaths from other causes are censored either at the time of 
death or at an earlier time of assessment, representing a random pattern of loss from the study. 
TTP is not as useful as PFS unless the majority of deaths on a study are unrelated to the 
lymphoma due to the efficacy of the treatment and/or prolonged follow-up. 
9.2.5 
Time to Treatment Failure 
Time to treatment failure [TTF] (event-free survival [EFS]) is measured from the time from study 
entry to any treatment failure including discontinuation of treatment for any reason, such as 
disease progression, toxicity, patient preference, initiation of new treatment without documented 
progression, or death. This composite endpoint is generally not encouraged by regulatory 
agencies because it combines efficacy, toxicity and patient withdrawal. 
9.2.6 
Disease-Free Survival 
Disease-free survival is measured from the time of occurrence of disease-free state (e.g., the 
adjuvant setting following surgery or radiation therapy or attainment of a complete remission) to 
disease recurrence or death from lymphoma or acute toxicity of treatment. This definition may 
be complicated by deaths that occur during the follow-up period that are unrelated to the 


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lymphoma and there is controversy as to whether such deaths should be considered as events 
or censored at the time of occurrence. Whereas it is often possible to  identify those deaths 
related to the lymphoma, there is the potential for bias in the attribution of deaths. 
9.2.7 
Disease-Specific Survival 
Disease-specific survival (e.g., lymphoma-specific survival, cause-specific survival) is 
potentially subject to bias because the exact cause of death is not always easy to ascertain. To 
minimize the risk of bias, the event should be recorded as death from lymphoma, or from toxicity 
from the drug. Death from unknown causes should be attributed to the drug. For certain trials, 
time to next lymphoma treatment may be of interest, defined as time from the end of primary 
treatment until the initiation of the next therapy. 
 


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10. 
Study Parameters 
1. All pre-study scans and bone marrow biopsy should be done ≤ 10 weeks prior to registration. 
2. All other pre-study assessments should be done ≤ 4 weeks prior to registration, unless otherwise noted. 
Procedures 
Screening 
Cycle 1* 
(1 cycle=28 Days) 
Cycles 2-6* 
Every 3 Cycles 
(every 12 weeks) 
Maintenance19* 
Follow-Up20 
Day 1 
Day 2 
Day 8 
Day 15 
Day 21 
Break 
Day 1 
Day 2 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Documentation of GELF, 
FLIPI and FLIP2 criteria1 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
Assessment of Baseline 
Signs & Symptoms 
X 
 
 
 
 
 
 
 
 
 
 
Height in cm 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
Weight in kg 
X 
X 
 
 
 
 
X 
 
 
X 
 
Vital Signs 
(Temperature, Pulse, 
Blood Pressure) 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
Body Surface Area (BSA) 
X 
X 
 
 
 
 
X 
 
 
X 
 
Performance Status 
X 
X 
 
 
 
 
X 
 
 
X 
 
CBC/Differential/Platelets2 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
Chemistry3 
X 
X 
 
X 
 
 
X 
 
 
X 
 
Hepatitis B & C Testing4 
X 
 
 
 
 
 
 
 
 
 
 
Beta-2 Microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
Immunoglobulin (IgG)5 
X 
 
 
 
 
 
 
 
X5 
X5 
 


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Procedures 
Screening 
Cycle 1* 
(1 cycle=28 Days) 
Cycles 2-6* 
Every 3 Cycles 
(every 12 weeks) 
Maintenance19* 
Follow-Up20 
Day 1 
Day 2 
Day 8 
Day 15 
Day 21 
Break 
Day 1 
Day 2 
 
 
 
Serum or Urine 
Pregnancy Test6 
X 
 
 
 
 
 
 
 
 
 
 
CMV Monitoring7 
X 
 
 
 
 
 
X 
 
 
X 
 
Tumor Lysis Labs8 
 
X 
X 
X 
X8 
 
X8 
X8 
 
 
 
PET CT9 
X 
 
 
 
 
 
 
 
X10 
X11 
 
Chest, Abdomen, and 
Pelvic CT9 
 
 
 
 
 
 
 
 
X 
X11 
 
Bone Marrow Biopsy 
X 
 
 
 
 
 
 
 
X12 
 
 
Archived Tissue 
Procurement 
(Mandatory)13 
X 
 
 
 
 
 
X14 
 
 
X14 
X14 
Induction Treatment 
Administration15 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
Maintenance Treatment 
Administration16 
 
 
 
 
 
 
 
 
 
X16 
 
PJP & Antiviral 
Prophylaxis17 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
Adverse Events 
Assessment 
 
X 
X 
X 
X 
 
X 
X 
 
X18 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
X 
 


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* 
Scheduled Visits: In general +/- 3 day window for therapy/tests/visits during therapy except as noted for TLS monitoring. Alterations due to holidays, 
weekends, bad weather or other unforeseen circumstances will be permitted. 
1 
Record the GELF, FLIPI-1 (Appendix VII) and FLIPI-2 criteria (Appendix VIII). 
2 
CBC with differential and platelet count which includes WBC, ANC, Platelets, Hgb, and Hct. Required prior to each dose of chemotherapy (days 1, 2, 8 and 
15 of cycle 1 and day 1 of cycle 2 and subsequent cycles), and results known prior to treatment administration. 
3 
Albumin, BUN/creatinine, uric acid, sodium, potassium, chloride, glucose, calcium, alkaline phosphatase, AST, ALT, total bilirubin, LDH and total protein. 
4 
Hepatitis B (HBV), Hepatitis B surface antigen (HBsAg), and Hepatitis C (HCV) testing within 6 weeks of registration. Patients who are chronic carriers of HBV 
with positive HBsAg+ and positive HCV serology are excluded. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core 
antibody [anti-HBc] and absence of HBsAg) may be included if HBV DNA is undetectable. If enrolled, patients must be willing to undergo monthly HBV DNA 
testing. Patients with positive HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation. 
5 
Obtain quantitative immunoglobulins at end of induction and every 6 months during maintenance therapy. 
6 
Required for females of childbearing potential within 2 weeks of registration. 
7 
Patients will be monitored for CMV reactivation using Quantitative PCR Assay for CMV DNA. If CMV PCR is reported as >137 IU/mL increase frequency of 
testing to weekly. See Section 5.1.3: Monitoring for Cytomegalovirus (CMV) for additional monitoring parameters and guidelines. 
Induction: Once a month. 
Maintenance: Once every 2 months. 
8 
Labs for tumor lysis monitoring include uric acid, calcium, albumin, phosphorus, potassium, and serum creatinine. Information on prophylaxis for TLS and 
definitions for tumor lysis syndrome refer to Section 5.1.1 and Appendix IV. 
• 
Cycle 1 
o 
Day 1 approximately 6 hours after treatment initiation 
o 
Day 2 prior to initiating day 2 treatment 
o 
Day 8 prior to initiating day 8 treatment 
o 
Day 15 prior to initiating day 15 treatment, only if day 8 labs indicate continued testing is needed 
• 
Cycle 2 
o 
Day 1 approximately 6 hours after treatment initiation 
o 
Day 2 prior to initiating day 2 treatment 
9 
PET/CTs are the preferred imaging modality. Notably however, once a patient enters complete remission, then only CT’s (chest/abdomen/pelvis) should be 
obtained (not both PET/CT and dedicated CTs) except as noted in footnote #9 below. MRI exams of the chest/abdomen/pelvis may be performed, if CTs of 
the chest/abdomen/pelvis cannot be obtained. 
10 PET/CT to be obtained after cycle 6 (not required after cycle 3). CT of the chest/abdomen/pelvis will suffice at interim restaging i.e., after cycle 3. 
11 Performed every 6 months or as per standard of care. 
12 Performed after cycle 6. Bone marrow biopsy at the end of induction treatment needs to be obtained only if it was positive prior to initiation of therapy. 
 


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13 Pre-treatment, diagnostic pathology specimens obtained in the course of standard biopsy or surgery (if sufficient tissue is available, submission is mandatory): 
Formalin-Fixed Paraffin-Embedded (FFPE) blocks and 7-10 FFPE slides or if blocks are not available, up to 25 FFPE slides plus H&E slide (if tissue is limited, 
then minimum of 13 slides) will be required. Procurement of tissue will be mandatory for enrollment (submission of tissue is not required prior to registration), 
but if additional tissue from initial biopsy is not available, repeat biopsy will not be required (no biopsy should be performed solely for the purposes of obtaining 
research samples). 
14 Optional: Any tumor biopsy samples obtained during treatment or post-treatment (Formalin-Fixed Paraffin-Embedded (FFPE) blocks or up to 15 FFPE slides 
plus H&E slide) will be requested for research and any leftover tissue (pre-treatment, during treatment or post-treatment) will be banked for future research. 
See Section 13.1 for details. 
15 Cycle 1-6: Patients will receive obinutuzumab by IV infusion on Cycle 1, days 1, 2, 8, and 15 of 28 day cycle and Cycles 2-6 on day 1 of each 28 day cycle 
(1 cycle=28 days). 
Cycle 1-6: Bendamustine will be administered on days 1, 2 of each cycle. 
Cycle 2-6: Venetoclax will be administered orally as continuous dosing days 1-10 of each 28 day cycle. On days when venetoclax is given with additional 
anti-lymphoma agents, venetoclax should be given first. 
See Section 5 for dosing instructions and Section 6 for dose delays/modifications. 
16 The maintenance phase will start no earlier than 8 weeks and no later than 12 weeks following completion of cycle 6, day 28 of induction therapy (patients 
who do not start maintenance therapy by week 12 will be removed from study). During the maintenance phase, patients who are in a complete remission will 
receive obinutuzumab every 2 months for a total of 12 cycles. Patients who are in a PR or stable disease will receive venetoclax and obinutuzumab for a total 
of 24 cycles and 12 cycles, respectively. Patients who receive venetoclax (orally as continuous dosing days 1-28) and obinutuzumab (obinutuzumab will be 
given every 8 weeks) will be seen every month (to dispense venetoclax). On days when venetoclax is given with additional anti-lymphoma agents, venetoclax 
should be given first. (Patients on both venetoclax and obinutuzumab who convert to CR, will remain on both venetoclax and obinutuzumab for a total of 24 
cycles and 12 cycles respectively.) 
NOTE: 
If venetoclax was dose reduced during the induction phase, the same dose reduction will continue during the maintenance phase for the 28 day 
cycle. 
**Further maintenance therapy was suspended on 9/16/2021. Refer to Section 1.6.3 for details. Follow-up will continue as noted in footnote 20. 
17 All patients must be initiated on prophylaxis within 2 weeks of initiating therapy with bendamustine and obinutuzumab. 
PJP Prophylaxis: Trimethoprim-sulfamethoxazole (Bactrim) for PJP prophylaxis and should continue until patients first restaging visit, after completion of 
induction. PJP prophylaxis may be discontinued at that time, or continued at the discretion of the treating physician. 
Antiviral Prophylaxis: Acyclovir or valcyclovir for antiviral prophylaxis. Antiviral prophylaxis should continue for a minimum of 6 months after completion of 
induction, and may be discontinued at that time, or continued at the discretion of the treating physician. 
See Section 5.1.2: Infection Prophylaxis for additional parameters and guidelines. 
18 Adverse events will be captured for 30 days after their last dose of study medication. 
19 Patients who receive obinutuzumab only will be seen every 2 months with indicated exams/testing performed. Patients who receive obinutuzumab and 
venetoclax will be seen every month with indicated exams/testing performed. 
20 Every 6 months for up to 2 years from treatment discontinuation or until study closure. Initiation of first anti-cancer therapy will also be documented. 
NOTE: 
If patient is removed from treatment for reason(s) other than progression, follow with regular tumor assessments per standard of care until 
progression or start of new treatment. 


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11. 
Drug Formulation and Procurement 
11.1 
Venetoclax13 
For complete information, please refer to the current IB. 
11.1.1 
Other Names 
GDC-0199, ABT-199, RO5537382. 
11.1.2 
Storage and Stability 
Venetoclax will be supplied in bottles with 100 mg tablets. The 100 mg film-coated tablets are 
oblong, biconvex shaped, pale yellow debossed with “V” on one side and “100” on the other side. 
The tablets must be stored at 15°C−25°C (59°F−77°F). 
11.1.3 
Dose Specifics 
The recommended venetoclax dose for NHL is 800 mg daily orally. Venetoclax is dispensed in a 4-
week supply. Patients will take eight tablets (800 mg) daily on days 1-10 for each 28 day cycle 
during Induction and days 1-28 during Maintenance. Tablets should not be chewed, crushed or 
broken. 
On days when venetoclax is given with obinutuzumab and bendamustine, venetoclax should be 
given first. 
If vomiting occurs within 15 minutes after taking venetoclax and all expelled tablets are still intact, 
another dose may be given. Otherwise, no replacement dose is to be given. In cases where a dose 
of venetoclax is missed or forgotten, the patient should take the dose as soon as possible and 
ensure that the minimal interval between the current dose and the next dose is at least 16 hours in 
order to avoid excessive drug accumulation after the next dose. 
Refer to Section 6.1 and Table 6-1, Table 6-2 and Table 6-3 for Dose Delays and Modifications 
details during Induction. Refer to Section 6.2 for Dose Modifications & Toxicity Management- 
Maintenance Phase. 
11.1.4 
Drug Interactions 
Drug-drug interactions may occur with venetoclax. Co-administration of venetoclax with CYP3A4 
inhibitors and strong inducers is prohibited. Co-administration with moderate/weak CYP3A4 
inducers, CYP2C8 substrates, and CYP2C9 substrates should be undertaken with caution. See 
Section 6.3.2 and Appendix VI: Additional Excluded and Cautionary Medications for a list of 
medications that are to be excluded or used with caution in patients receiving venetoclax. 
11.1.5 
Availability 
Venetoclax will be supplied by Genentech. 
The initial supply of venetoclax will be sent directly to the site upon site activation. As needed, 
venetoclax may be requested by the Principal Investigator (or their authorized designees) at each 
participating institution. The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the receipt, disposition, and return/destruction (site’s drug 
destruction policy must be reviewed and approved by PrECOG before any study drug can be 
destroyed at a site) of venetoclax. 
11.1.6 
Agent Ordering 
PrECOG will be responsible for ordering drug for re-supply to the site. Requests for shipments of 
venetoclax will be coordinated between PrECOG and Genentech. 
 
 


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11.1.7 
Agent Accountability 
Venetoclax will be stored in a secure location. Only authorized pharmacy and study staff will have 
access to this agent. Drug accountability will be performed by PrECOG. 
Please refer to the current Investigator’s Brochure for additional information. 
11.1.8 
Risks Associated with Venetoclax 
11.1.8.1 
Tumor Lysis Syndrome 
TLS is a risk for patients with NHL who are treated with high cell-killing agents. The risk of TLS is 
a continuum based on multiple factors, including tumor burden and comorbidities. Risk is highest 
for those with bulky disease, elevated leukocyte count, elevated pretreatment LDH levels, 
compromised renal function, and dehydration. Perform tumor burden assessment with CT scan 
and CBC with WBC differential, assess blood chemistry (potassium, uric acid, phosphorus, 
calcium, and creatinine) in all patients and correct pre-existing chemistry abnormalities prior to 
initiation of treatment. 
Refer to Section 5.1.1 for “Tumor Lysis Prophylaxis” guidelines and Appendix IV for “Definitions of 
Tumor Lysis Syndrome”18. 
11.1.8.2 
Neutropenia 
Neutropenia is an important identified risk for venetoclax, specifically in CLL. Clinical data from 
oncology studies suggest the neutropenia AEs are observed among subjects who receive 
venetoclax as a single agent or in combination with other therapeutic agents, with slightly higher 
frequency observed in some combination studies. SAEs of neutropenia or neutropenia events that 
lead to discontinuations are few across the entire venetoclax oncology program. 
11.1.8.3 
Infections 
Infections have been reported in the oncology clinical studies; however, these events are 
confounded by the underlying disease, comorbidities, and other immunosuppressive medications. 
To date, no clear relationship has been noted between serious infectious events and neutropenia. 
The types of infectious events observed generally have been consistent with those anticipated in 
the elderly population of heavily pretreated subjects with hematologic malignancies and are similar 
across all indications. 
Infections should be closely monitored in this study. Recommendations for anti-infective 
prophylaxis are per standard of care (e.g., National Comprehensive Cancer Network guidelines 
[NCCN 2016] for oncology subjects). 
Serious infections, including cytomegalovirus (CMV) reactivations, have been reported in patients 
treated with venetoclax in combination with other agents, including obinutuzumab. 
11.1.8.4 
Anemia 
Anemia has been reported in the oncology studies with slightly higher frequency in some studies 
in which venetoclax is combined with other chemotherapeutic agents; however, most of the events 
were nonserious and confounded by disease factors and prior therapies. The dataset in non-CLL 
indications is small. 
11.1.8.5 
Thrombocytopenia 
Thrombocytopenia adverse events have been reported in the oncology studies, with slightly higher 
frequency in studies in which venetoclax is combined with other chemotherapeutic agents. 
However, most of the events were nonserious and assessment of these events is confounded by 
the patients’ underlying disease states, prior therapies, and preexisting thrombocytopenia, 
including autoimmune thrombocytopenia, in several patients. The dataset in non-CLL indications 
is small. 


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11.1.8.6 
Lymphopenia 
Lymphopenia has been observed in nonclinical studies with venetoclax. While opportunistic 
infections have been reported in the clinical program, data are confounded by patients’ underlying 
disease and prior therapies. 
If clinically indicated, anti-infective prophylaxis should be implemented, including appropriate 
prophylaxis for viral, fungal, bacterial, or Pneumocystis carinii pneumonia infections. 
11.1.8.7 
Reproductive System Effects 
Based on nonclinical studies, there is a potential for decreased spermatogenesis. Male patients 
considering preservation of fertility should bank sperm before treatment with venetoclax. Long-
term effects of venetoclax on female reproductive potential are unknown. 
11.1.8.8 
Treatment-Emergent Malignancies (Second Primary Malignancies) 
Events of second primary malignancies have been reported across the oncology program. No 
pattern has been was observed. As venetoclax is being evaluated in patients with R/R disease 
who had previously been treated with various cytotoxic agents, second primary malignancies 
should be closely monitored. 
11.1.8.9 
Food Effect 
Administration with a low-fat meal increased venetoclax exposure by approximately 3.4-fold and 
administration with a high-fat meal increased venetoclax exposure by 5.1- to 5.3-fold compared to 
fasting conditions. Venetoclax should be administered with a meal. 
11.1.8.10 
Drug-Drug Interaction 
Co-administration of venetoclax with inhibitors or strong inducers of CYP3A4 are not 
recommended. Co-administration with moderate/weak CYP3A4 inducers, CYP2C8 substrates, 
and CYP2C9 substrates should be undertaken with caution (Section 6.3.2 and Appendix VI: 
Additional Excluded and Cautionary Medications). 
11.1.9 
Nursing/Patient Implications 
1. TLS: Inform patient to immediately report any signs and symptoms associated with TLS 
(fever, chills, nausea, vomiting, confusion, shortness of breath, seizure, irregular heartbeat, 
dark or cloudy urine, unusual tiredness, muscle pain, and/or joint discomfort) to their doctor. 
2. Neutropenia: Monitor blood counts and for signs of infection; manage as medically 
appropriate. 
3. Advise patients to avoid consuming grapefruit products, Seville oranges, or starfruit during 
treatment with venetoclax. Advise patients to inform their doctor of the use of any prescription 
medication, over-the-counter drugs, vitamins and herbal products. 
11.2 
Obinutuzumab9 
For complete information, please refer to the current IB. 
11.2.1 
Other Names 
Gazyva™; GA101; RO5072759. 
11.2.2 
Formulation 
Obinutuzumab is provided as a single-use vial. Each vial contains a sterile liquid formulation in a 
40 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. 


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11.2.3 
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 per institutional standards. 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. 
11.2.4 
Preparation 
Obinutuzumab drug product intended for IV infusion is prepared by dilution of the drug product into 
an infusion bag containing 0.9% NaCl. 
One vial may be used to prepare both the 100 mg dose (equals 4 mL) and 900 mg dose (equals 
36 mL) following the directions below. If both bags are prepared at the same time, the 
reconstitution/dilution has to take place in a controlled and validated aseptic conditions. 
Subsequently store the 900 mg bag for a maximum of 24 hours at 2°C−8°C. After allowing the 
diluted bag to come to room temperature, use immediately per institutional standards. 
To prepare a 100 mg dose: The final drug concentration of a 100 mg dose should be in the range 
of 0.4 mg/mL to 4.0 mg/mL. Using a 250 mL infusion bag containing 0.9% NaCl, withdraw and 
discard 4 mL of the sodium chloride. Withdraw 4 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 unless 
reconstitution/dilution has taken place in controlled and validated aseptic conditions). Gently invert 
the infusion bag to mix the solution. Do not shake. 
To prepare a 900 mg dose: The final drug concentration of a 900 mg dose should be in the range 
of 0.4 mg/mL to 4.0 mg/mL. Using a 250 mL infusion bag containing 0.9% NaCl, withdraw and 
discard 36 mL of the sodium chloride. Withdraw 36 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 unless 
reconstitution/dilution has taken place in controlled and validated aseptic conditions). Gently invert 
the infusion bag to mix the solution. Do not shake. 
To prepare a 1000 mg dose: The final drug concentration of a 1000 mg dose 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. 
11.2.5 
Dosage and Administration 
Obinutuzumab administered by IV infusion for up to 6 cycles (28-day cycles): 
• 
On Cycle 1, Day 1, 100 mg obinutuzumab will be administered 
• 
On Cycle 1, Day 2, 900 mg of obinutuzumab will be administered 
• 
On Cycle 1, Days 8 and 15, 1000 mg of obinutuzumab will be administered. 
• 
On Cycles 2−6, Day 1, 1000 mg of obinutuzumab will be administered. 
• 
Maintenance: Every 2 months x 12 cycles, 1000 mg of obinutuzumab will be administered. 


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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 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 30 minutes from the end of 
infusion; if no AEs occur after 30 minutes, the IV line may be removed. During the maintenance 
phase, the IV access may be removed at the end of the infusion if no adverse events occurred 
during the infusion. 
11.2.6 
Premedication Requirements 
11.2.6.1 
Infusion Related Reactions 
Since some patients may develop hypersensitivity or other IRRs to obinutuzumab, pre-medication 
is recommended to reduce the risk of infusion reactions as outlined below or per institutional 
guidelines: 
• 
Cycle 1, Days 1 and 2, all patients require pre-medication with: 
– 
IV glucocorticoid: dexamethasone (20 mg) or methylprednisolone (80 mg) administered 
prior to obinutuzumab infusion. Hydrocortisone should not be used as it has not been 
effective in reducing rates of IRR. 
– 
An oral acetaminophen (650-1000 mg) and an antihistamine such as diphenhydramine 
(25-50 mg) administered before starting each obinutuzumab infusion. 
• 
Cycle 1, Days 8 and 15; Cycles 2-6, Day 1; and Maintenance: 
– 
An oral acetaminophen (650-1000 mg) and an antihistamine such as diphenhydramine 
(25-50 mg) administered before starting each obinutuzumab infusion. 
– 
Patients who experience a Grade 3 IRR with the previous infusion or who have lymphocyte 
counts of ≥ 25 x 109/L prior to the next treatment will require pre medication with IV 
glucocorticoid: dexamethasone (20 mg) or methylprednisolone (80 mg) administered prior 
to obinutuzumab infusion. Hydrocortisone should not be used as it has not been effective 
in reducing rates of IRR. 
11.2.6.2 
Hypotension 
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. 
11.2.7 
Obinutuzumab Dosing 
The first 1000 mg of obinutuzumab will be administered over 2 days. During Cycle 1, Day 1, 100 mg 
will be administered. On the following day (Cycle 1, Day 2), 900 mg will be administered (Table 
11-1). 
 
 
 
 


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Table 11-1: 
Obinutuzumab Rate of Infusion 
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 
100 mg 
Administer at 25 mg/hour over 4 hours. Do not increase the 
infusion rate. 
Day 2 
900 mg 
Administer at 50 mg/hour. The rate of the infusion can be 
escalated in increments of 50 mg/hour every 30 minutes to 
a maximum rate of 400 mg/hour. 
Day 8 
1000 mg 
Infusions can be started at a rate of 100 mg/hour and 
increased by 100 mg/hour increments every 30 minutes to 
a maximum of 400 mg/hour. 
Day 15 
1000 mg 
Cycles 2−6 
Day 1 
1000 mg 
NOTE: Rates above are listed in mg/hr. Please remember to take into consideration the final 
concentration of the prepared dose if the rate will be converted into mL/hour for the infusion 
pump. 
If a patient experiences any grade infusion reaction during infusion, adjust the infusion as below: 
• 
Grade 4 (life-threatening): Stop infusion immediately and permanently discontinue 
obinutuzumab therapy. 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. Patients who experience any of these 
reactions should receive aggressive treatment of symptoms and will be discontinued from 
study treatment. 
• 
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 per institutional guidelines. 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 per institutional 
guidelines. 
Refer to Section 6.1 and Table 6-1 and Table 6-2 for Dose Delays and Modifications details during 
Induction. Refer to Section 6.2 for Dose Modifications & Toxicity Management- Maintenance 
Phase. 
11.2.8 
Availability 
Obinutuzumab will be supplied by Genentech. 
The initial supply of obinutuzumab will be sent directly to the site upon site activation. As needed, 
obinutuzumab may be requested by the Principal Investigator (or their authorized designees) at 
each participating institution. The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the receipt, disposition, and return/destruction (site’s drug 
destruction policy must be reviewed and approved by PrECOG before any study drug can be 
destroyed at a site) of obinutuzumab. 


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11.2.9 
Agent Ordering 
PrECOG will be responsible for ordering drug for re-supply to the site. Requests for shipments of 
obinutuzumab will be coordinated between PrECOG and Genentech. 
11.2.10 
Agent Accountability 
Obinutuzumab will be stored in a secure location. Only authorized pharmacy and study staff will 
have access to this agent. Drug accountability will be performed by PrECOG. 
11.2.11 
Risks Associated with Obinutuzumab 
Important risks identified in clinical investigations with obinutuzumab were: IRRs, TLS, 
thrombocytopenia (including acute thrombocytopenia), neutropenia (including prolonged and late 
onset neutropenia), prolonged B-cell depletion, infections (including hepatitis B reactivation and 
PML), worsening of pre-existing cardiac conditions and GI perforation. 
Please refer to the current IB for additional information. 
11.2.11.1 
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. 
Screen all patients for HBV infection before initiating treatment with obinutuzumab. For patients 
who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or 
HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B 
regarding monitoring, and consider HBV antiviral therapy. 
Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of 
hepatitis or HBV reactivation during and for several months following treatment with obinutuzumab.  
HBV reactivation has been reported for other CD20-directed cytolytic antibodies following 
completion of therapy. 
In patients who develop reactivation of HBV while receiving obinutuzumab, immediately 
discontinue obinutuzumab and any concomitant chemotherapy, and institute appropriate 
treatment. Resumption of obinutuzumab in patients whose HBV reactivation resolves should be 
discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding 
the safety of resuming obinutuzumab in patients who develop HBV reactivation. 
11.2.11.2 
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. 


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11.2.11.3 
Infusion-Related Reactions 
Obinutuzumab can cause severe and life-threatening IRRs; 65% of patients with CLL experienced 
a reaction to the first 1000 mg infused of obinutuzumab, and 38% of iNHL patients experienced a 
reaction on Day 1 of obinutuzumab infusion. IRRs within 24 hours of receiving obinutuzumab have 
occurred. 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 fatigue, dizziness, 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. 
• 
For patients with any Grade 4 IRRs, including but not limited to anaphylaxis, acute life-
threatening respiratory symptoms, or other life-threatening infusion reaction, stop the 
obinutuzumab infusion. Permanently discontinue obinutuzumab therapy. 
• 
For patients with Grade 1, 2, or 3 IRRs, interrupt obinutuzumab for Grade 3 reactions until 
resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions 
and manage symptoms. 
• 
For patients with pre-existing cardiac or pulmonary conditions, monitor more frequently 
throughout the infusion and the post-infusion period because these patients may be at greater 
risk of experiencing more severe reactions. Hypotension may occur as part of the 
obinutuzumab IRR. Consider withholding antihypertensive treatments for 12 hours prior to, 
during, and for the first hour after administration of each obinutuzumab infusion until blood 
pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits 
versus the risks of withholding their hypertensive medication. 
11.2.11.4 
Tumor Lysis Syndrome 
TLS, including fatal cases, has been reported in patients receiving obinutuzumab. Patients with 
high tumor burden, high circulating lymphocyte count (>25 x 109/L) or renal impairment are at 
greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-
hyperuricemics (e.g., allopurinol or rasburicase) and hydration prior to the infusion of 
obinutuzumab. Continue prophylaxis prior to each subsequent obinutuzumab infusion, as needed. 
During the initial days of obinutuzumab treatment, monitor the laboratory parameters of patients 
considered at risk for TLS. For treatment of TLS, correct electrolyte abnormalities, monitor renal 
function and fluid balance, and administer supportive care, including dialysis as indicated. 
11.2.11.5 
Infection 
Serious bacterial, fungal, and new or reactivated viral infections can occur during and following 
obinutuzumab therapy. Fatal infections have been reported. 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. 
11.2.11.6 
Neutropenia 
Severe and life threatening neutropenia, including febrile neutropenia, has been reported during 
treatment with obinutuzumab. 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 severe or long-lasting (>1 week) neutropenia are strongly recommended to receive 
antimicrobial prophylaxis until resolution of neutropenia to Grade 1 or 2. Antiviral and antifungal 
prophylaxis should be considered. 


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11.2.11.7 
Thrombocytopenia 
Severe and life threatening thrombocytopenia has been reported during treatment with 
obinutuzumab in combination with chlorambucil or bendamustine. Fatal hemorrhagic events during 
Cycle 1 have also been reported in patients with CLL treated with obinutuzumab. 
Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the 
first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently 
until resolution and consider subsequent dose delays of obinutuzumab and chemotherapy or dose 
reductions of chemotherapy. Transfusion of blood products (i.e., platelet transfusion) may be 
necessary. Consider withholding concomitant medications which may increase bleeding risk 
(platelet inhibitors, anticoagulants), especially during the first cycle. 
11.2.11.8 
Immunization 
The safety and efficacy of immunization with live or attenuated viral vaccines during or following 
obinutuzumab therapy have not been studied. Immunization with live-virus vaccines is not 
recommended during treatment and until B-cell recovery. 
11.2.12 
Nursing/Patient Implications 
1. Monitor blood pressure, pulse, respiration, and temperature per institutional guidelines. 
2. Medications (including oxygen, epinephrine for subcutaneous injections, corticosteroids, 
diphenhydramine for IV injection, and meperidine) and resuscitation equipment should be 
available for all infusions for immediate use in the event of an anaphylactic reaction or moderate 
to severe IRR. 
3. Monitor and alter infusion rates in the presence of toxicities. 
4. Cases of TLS have been reported in patients treated with obinutuzumab. Patients with a high 
tumor burden including those patients with a lymphocyte count ≥ 25 x 109/L (in particular 
patients with B-CLL and MCL) are at increased risk of TLS and severe IRRs. Aggressive 
intravenous hydration is the cornerstone of prevention of TLS and is recommended prior to 
therapy in all patients at intermediate or high risk for TLS. Prior to initiation of IV hydration, 
reversible forms of renal insufficiency (e.g., volume contraction, hypercalcemia, urinary tract 
obstruction) should be corrected. In addition, all patients considered to be at risk of TLS, should 
be premedicated with an agent to reduce uric acid (e.g., allopurinol or rasburicase). In addition, 
care should be taken to ensure that patients have adequate fluid intake. For subsequent 
infusions, patients at risk for TLS should receive TLS prophylaxis with anti-hyperuricemics and 
adequate hydration prior to each infusion. 
5. Patients who experience Grade 3/4 neutropenia or thrombocytopenia should be monitored until 
neutrophil and platelet values return to at least Grade 2. The administration of transfusion of 
blood products according to institutional practice is at the discretion of the investigators. Use 
of G-CSF has been found to result in a rapid normalization of neutrophils similar to what has 
been observed in patients treated with rituximab. Obinutuzumab should not be administered in 
the presence of active severe infections. Physicians should exercise caution when considering 
the use of obinutuzumab in patients with a history of recurring or chronic infections or with 
underlying conditions that may predispose patients to infections. 
11.3 
Bendamustine20 
Bendamustine will be obtained by the individual study sites as standard of care treatments from 
commercial stock. Refer to commercial package inserts for full prescribing information. 
11.3.1 
Storage and Stability 
Bendamustine for injection, is supplied in multiple-dose vials containing 100 mg of bendamustine 
hydrochloride as a clear, and colorless to yellow ready-to-dilute solution. Store intact vials in 
refrigerator, 2°-8°C (36°- 46°F). Vials should be retained in the original package until time of use 
to protect from light. 


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Admixture Stability: Bendamustine contains no antimicrobial preservative. The admixture should 
be prepared as close as possible to the time of patient administration.  Once diluted with either 
0.9% Sodium Chloride Injection, USP, or  2.5% Dextrose/0.45% Sodium Chloride Injection, USP, 
the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 6 hours 
when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of 
bendamustine must be completed within this period. 
11.3.2 
Preparation 
Refer to commercial package insert or institutional guidelines for preparation of bendamustine. 
11.3.3 
Route of Administration 
Bendamustine will be administered as a 10 minute or per institutional guidelines IV infusion at a 
dose of 90 mg/m2 on days 1 and 2 of each 28-day cycle. 
If medical conditions necessitate, e.g., fluid management issues or infusion reactions, the infusion 
may be given over a longer period of time. In–line filters are not required for administration. Unless 
there are extenuating circumstances, all of the drug should be administered to the patient with the 
exception of what remains in the line. Be sure to document any problems you may encounter with 
the infusion. If for any reason the drug cannot be entirely administered, please measure the 
remaining volume in the infusion bag and record on your source documentation. 
Refer to Section 6.1 and Table 6-1, Table 6-2 and Table 6-4 for Dose Delays and Modifications 
details during Induction. 
11.3.3.1 
Dosage in Renal or Hepatic Failure 
In a population pharmacokinetic analysis of bendamustine in patients receiving 120 mg/m2 there 
was no meaningful effect of renal impairment (CrCL 40-80 mL/min, N=31) on the pharmacokinetics 
of bendamustine. Bendamustine has not been studied in patients with CrCL <40 mL/min. These 
results are however limited, and therefore bendamustine should be used with caution in patients 
with mild or moderate renal impairment. Bendamustine should not be used in patients with CrCL 
<40 mL/min. 
In a population pharmacokinetic analysis of bendamustine in patients receiving 120 mg/m2 there 
was no meaningful effect of mild (total bilirubin ≤ ULN, AST ≥ ULN to 2.5x ULN, and/or ALP ≥ ULN 
to 5.0x ULN, N=26) hepatic impairment on the pharmacokinetics of bendamustine. Bendamustine 
has not been studied in patients with moderate or severe hepatic impairment. These results are 
however limited, and therefore bendamustine should be used with caution in patients with mild 
hepatic impairment. Bendamustine should not be used in patients with AST or ALT ≥ 3.0x ULN 
and total bilirubin ≥ 1.5x ULN. 
11.3.4 
Drug Interactions 
Bendamustine is a substrate for the cytochrome P450(CYP) 1A2 isoenzyme. 
Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent 
administration of a CYP1A2 inhibitor such as atazanavir, cimetidine, ciprofloxacin, fluvoxamine, 
mexiletine, tacrine, thiabendazole, zileuton, norfloxacin, and/or ethinyl estradiol may increase 
bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments 
considered, when co-administering bendamustine with a CYP1A2 inhibitor. 
Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent 
administration of a CYP1A2 inducer such as barbiturates, carbamazepine, and/or rifampin may 
cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. 
The parent compounds are believed to be primarily responsible for the cytotoxicity of this agent. 
Caution should be exercised, or alternative treatments considered, when co-administering 
bendamustine with a CYP1A2 inducer. 
 


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Bendamustine is metabolized to minimally active metabolites by CYP1A2. Smoking tobacco has 
been shown to induce CYP1A2, and may cause a decrease in bendamustine plasma 
concentrations and a potential decrease in cytotoxicity. The parent compound is believed to be 
primarily responsible for the cytotoxicity of this agent. Caution should be exercised, or smoking 
cessation considered, when co-administering bendamustine with a CYP1A2 inducer. 
11.3.5 
Incompatibilities 
No incompatibilities are known (no data is available). 
11.3.6 
Side Effects 
The adverse events specified below are also likely to be of clinical importance and may result in 
bendamustine dose delays or dose reductions. 
11.3.6.1 
Infection and Pneumonia 
Infection, including pneumonia and sepsis, has been reported and, in rare cases, infection has 
been associated with hospitalization, septic shock, and death. Patients with myelosuppression 
following bendamustine treatment are susceptible to infections and should be advised to contact a 
physician if they have symptoms or signs of infection, including fever or respiratory symptoms. 
11.3.6.2 
Infusion Reactions and Anaphylaxis 
Infusion reactions with bendamustine have occurred commonly in clinical studies with symptoms 
that are generally mild and include fever, chills, pruritus, and rash. In rare instances, severe 
infusion reactions, described as anaphylactic and anaphylactoid reactions, have occurred, 
particularly in the second and subsequent cycles of therapy. Patients should be asked about 
symptoms suggestive of infusion reactions after their first cycle of therapy. Measures to prevent 
severe reactions, including antihistamines, antipyretics, and corticosteroids should be considered 
in subsequent cycles in patients who have previously experienced infusion reactions. 
11.3.6.3 
Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported with bendamustine, with onset typically within the first 
treatment cycle. Tumor lysis syndrome may lead to acute renal failure and death without 
appropriate medical intervention. Preventive measures include maintaining adequate volume 
status, close monitoring of blood chemistry (particularly potassium and uric acid levels), and the 
use of allopurinol during the first 1 to 2 weeks of bendamustine treatment. 
11.3.6.4 
Skin Reactions 
Skin reactions have been reported with the use of bendamustine, including non-specific rash, toxic 
skin reactions, and bullous exanthema. The relationship of skin reactions to bendamustine 
administration is often unclear as bendamustine is frequently administered with other anti-cancer 
therapies. A case of fatal toxic epidermal necrolysis (TEN) has been reported in 1 patient treated 
with a combination of bendamustine and rituximab. 
TEN was considered possibly related to either agent. The relationship of this adverse event to 
bendamustine remains uncertain as TEN has also been reported with single-agent rituximab. 
When skin reactions occur, they may be progressive and increase in severity with further treatment. 
If skin reactions are severe or progressive, bendamustine should be withheld or discontinued. 
NOTE: There is the potential for overlapping skin reaction toxicity with concomitant administration 
of bendamustine with allopurinol. Allopurinol may be temporarily disrupted if safe from a 
tumor lysis standpoint. 
11.3.6.5 
Other Malignancies 
Development of premalignant and malignant disorders following treatment with bendamustine has 
been reported. The reports are limited and included development of myelodysplastic syndromes, 
myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. Because of 


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confounding effects of other previous chemotherapy in these patients, the relationship to 
bendamustine could not be determined. 
11.3.7 
Nursing/Patient Implications 
1. Monitor CBC, platelet count. Advise patients of increased risk of infection with absolute 
neutrophil count less than 500 cells/mm3 and increased risk of bleeding with platelet counts 
less than 20,000 cells/mm3. Advise patients to call the clinic if they develop a fever above 
101oF or notice any easy bruising, petechiae (pinpoint red spots on skin), or prolonged 
bleeding. 
2. Advise patient of possible alopecia, although this is very uncommon with bendamustine 
therapy. 
3. Assess hydration and fluid balance. Patients should be encouraged to have at least 1 liter of 
fluids per day for 72 hours after administration. 
4. Consider premedication with antiemetics. 
5. Observe for possible phlebitis at injection site. 
6. Administer antiemetics as indicated. 


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12. 
Statistical Considerations 
12.1 
Primary Endpoint 
The study is a single arm phase II study combining venetoclax, obinutuzumab and bendamustine. 
Patients with a high tumor burden based on FLIPI or GELF criteria will be enrolled. 
The primary objective of this study is CR after induction. We anticipate a 50% CR rate after 
induction treatment with obinutuzumab and bendamustine. With the addition of venetoclax (given 
concurrently), a CR rate of 65% (15% improvement from 50%) would be considered promising for 
the addition of venetoclax to the induction regimen. A total of 56 patients will be enrolled into the 
study, 51 of which are expected to be eligible and treated. Among 51 eligible, treated patients, this 
study will have 85% power to detect a 15% improvement in CR using a one-sided exact binomial 
test with 15% Type I error. This regimen combination of venetoclax + obinutuzumab and 
bendamustine will be considered worthy of further investigation if 30 or more patients achieve CR. 
CR rate will be estimated among all eligible, treated patients. 
Given the study treatment combination, there will be a formal, detailed, toxicity evaluation. To 
maintain homogeneity, this toxicity evaluation will be performed after the first 21 enrolled patients 
(~38% of total accrual), treated on the same venetoclax schedule, have been on study and 
received 3 full treatment cycles. This includes patients who come off treatment for any reason. For 
all treatment-related Grade 3 or higher AEs, the formal evaluation will be done within each AE 
category and also for the overall AE rate. All treatment-related AEs information will be collected 
and tabulated by toxicity grade. 
• 
It is expected that the proportion of any Grade 3 or higher, treatment-related, AEs will be no 
higher than 35% within each AE category. This includes expected, treatment-related, Grade 3 
or higher toxicities including any cytopenias (neutropenia, anemia, thrombocytopenia, 
lymphopenia), infections, electrolyte changes, skin rash, hyper/hypotension, transient 
diarrhea, vascular disorders. 
If any event’s observed Grade 3 or higher, treatment-related, AE proportion is higher than 45% 
(≥ 10 out of 21 patients), a detailed review of all treatment-related AE will be conducted and 
the study review team may decide if treatment modification is necessary. If the true proportion 
of any AE is 55% or higher there is at least 82% probability of exceeding the observed AE 
boundary. Whereas, if the true proportion of any AE is 35% there is 16% probability of crossing 
the toxicity boundary. The above decision boundary (45% or more observed events) will be 
followed for all treatment-related Grade 3 or higher events within each AE category. 
• 
The expected overall toxicity rate for all Grade 3 or higher, treatment-related, AEs is 
approximately 40%. If the observed overall Grade 3 or higher, treatment-related, AEs 
proportion is higher than 50% (≥ 11 out of 21 patients), a detailed review of all treatment-
related AE will be conducted and the study review team may decide if treatment modification 
is necessary. If the true proportion of overall AE is 60% or higher, there is at least 83% 
probability of exceeding the observed boundary. Whereas, if the true proportion is 40% there 
is 17% chance of crossing the toxicity boundary. This decision boundary will be followed for 
the overall treatment-related Grade 3 or higher AEs. 
A detailed review of AEs could be triggered by the within-category or overall AEs based on the 
rules specified above. 
12.1.1 
Data Safety Monitoring Board (DSMB) Monitoring and Interim Safety Analysis 
As at the time of this amendment #6, there have been 3 DSMB reviews for this study: June 2018, 
December 2018, and most recently in June 2019. 
In addition, the DSMB convened an ad hoc web teleconference meeting March 28, 2019 to review 
the findings from the planned interim safety analyses which took place after the first 21 enrolled 
patients were treated on the same venetoclax schedule for 3 full treatment cycles (all patients 


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started venetoclax with Cycle 1). At the time of analyses, 19 of 21 patients experienced treatment-
related worst toxicity Grade of 3 or higher for an adverse event proportion (Exact 90% CI) of 90.5% 
(72.9, 98.3). Twelve (12) unique patients experienced treatment-related Grade 3 or higher 
cytopenias for an adverse event proportion (Exact 90% CI) of 57.1% (37.2, 75.5). The proportion 
(Exact 90% CI) of TLS events was 38.1% (20.6, 58.3). 
The observed proportion of overall and cytopenia AE exceeded the pre-specified thresholds in 
Section 12.1. Based on the data, the high proportion of overall AEs were found to be a result of 
high cytopenias which is common for this disease and treatment. 
At the end of the meeting, the DSMB made three recommendations: continue a) close monitoring 
for TLS, b) to receive SAE Reports for TLS events in real time, and c) monitor neutropenia and 
sequelae. 
NOTE: 
In Version 5.0 of the protocol, venetoclax was changed to start with Cycle 2. 
12.2 
Secondary Endpoints 
The secondary objectives of this study include evaluation of ORR among treated patients; 
proportion of patients who achieve PR in induction and then CR with maintenance therapy; 
evaluation of PFS and OS among treated patients (ITT); and evaluation of compliance to therapy 
and toxicities of all patients. 
Descriptive statistics will be used to compute proportion of ORR and the proportion of patients that 
achieve CR in maintenance therapy. A 90% exact binomial confidence interval (CI) around 
response rates will also be computed for descriptive purposes. Kaplan Meier method will be used 
to estimate the PFS and OS among all treated patients; the 90% CI will be provided for these 
estimates. 
All enrolled patients who received treatment, irrespective of eligibility, will be evaluated for toxicities 
attributable to treatment during induction and maintenance therapy. Toxicity rates will be described 
using proportions and 90% exact binomial CI will be provided. If a total of 56 patients are treated, 
the maximum width of 90% CI on the proportion of treatment-related Grade 3 or higher toxicity will 
be no wider than 23%. The probability of observing at least one rare toxicity (true toxicity rate if 
5%) is approximately 94.3%. We will also describe all toxicities, regardless of treatment attribution. 
Descriptive statistics using mean and proportions will be used to describe compliance to induction 
and maintenance therapy. 
12.2.1 
Maintenance Therapy Suspension as of 9/16/2021 
Due to a recent Grade 5 event of myocarditis in a patient on maintenance therapy, the study 
investigators are concerned about atypical infections that have been seen after induction therapy 
on study. There have been four events of atypical infections as listed below: 
• 
Treatment related death due to cytomegalovirus encephalitis as well as Pneumocystis jiroveci 
Pneumonia (PJP) occurring after cycle 6 of induction but before maintenance therapy. 
• 
BK virus nephropathy leading to end stage renal disease and chronic hemodialysis in a patient 
following 6 doses of maintenance obinutuzumab. 
• 
Respiratory syncytial virus pneumonia 30 days after cycle 6 of induction and later, after 2 cycles 
of maintenance obinutuzumab, developed PJP. 
• 
The recent fatal myocarditis which is suspected, but not proven, to be viral in etiology. 
Given these adverse events we are suspending any additional maintenance therapy for those 
patients on study. These patients will not receive any further treatment and move on to the two year 
survival follow-up portion of the study. All study-required follow-up activities remain unchanged. 
The PrECOG Data Safety and Monitoring Board has also reviewed and agree with the 
recommendation to stop additional maintenance therapy. 


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12.3 
Exploratory Endpoints 
As part of exploratory analyses, treatment outcome measures (ORR, PFS, and OS) will be 
correlated with potential prognostic factors and correlative measures. Fisher’s exact or Chi-square 
test will be used to assess relationship between binary factors and outcome measures; logistic 
regression will be used for a combination of multiple factors with binary treatment outcome. 
Independent and paired t-tests (or Wilcoxon rank-sum and Signed Rank tests respectively) will be 
used to assess association between continuous correlative measures accordingly. For time-to-
event treatment outcome measures, Kaplan-Meier and the logrank test, as well as Cox proportional 
hazards models, will be used to assess relationship with one or multiple factors. 


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13. 
Laboratory and Pathology Correlative Studies 
13.1 
Correlative Studies: Mandatory Tumor Samples (f sufficient tissue available) 
13.1.1 
Overview 
Pre-treatment, diagnostic pathology specimens obtained in the course of standard biopsy or 
surgery (if sufficient tissue is available, submission is mandatory): Formalin-fixed paraffin-
embedded (FFPE) blocks and 7-10 FFPE tissue on unstained (4-5 um) slides or if blocks are not 
available, up to 25 FFPE tissue on unstained (4-5 um) slides plus H&E slide (if tissue is limited, 
then minimum of 13 slides). NOTE: If additional tissue from initial biopsy is not available, repeat 
biopsy will not be required (no biopsy should be performed solely for the purposes of obtaining 
research samples). 
Analyses to be performed may include the following: 
• 
Bcl-2 protein expression by immunohistochemistry (IHC) in pretreatment biopsies. Analysis 
will include assessment of Bcl-2 by IHC using the Ventana validated reagents, being 
developed as potential companion diagnostic for the venetoclax development program. 
• 
Bcl-2 family expression by mRNA expression including ratios of Bcl-2/BIM, Bcl-2/Mcl-1 with 
response, PFS and OS and/or other analysis. Additional hypothesis from biomarker analysis 
from the CONTRALTO study, such as Bcl-2 alterations at the tumor DNA level, may be tested. 
• 
BCL2 rearrangement status by fluorescence in situ hybridization (FISH) in pretreatment 
biopsies. 
• 
Mcl-1 and Bcl-XL protein expression by IHC in pretreatment biopsies. 
• 
Histologic features of pretreatment biopsies. 
Seven to ten slides per patient will be sent to Ventana Medical Systems, Inc. within 4 months of 
slides being cut for Bcl-2, Mcl-1 and Bcl-XL analysis. 
Optional: Any tumor biopsy samples obtained during treatment or post-treatment (formalin-fixed 
paraffin-embedded (FFPE) blocks or up to 15 FFPE tissue on unstained (4-5 um) slides plus H&E 
slide) will be requested for research. Any leftover tissue (pre-treatment, during treatment or post-
treatment) will be banked for future research. 
All other samples will be sent to a central lab for storage. This will include up to 4 slides for 
mRNA/DNA analysis to test biomarker hypothesis from the CONTRALTO study. These samples 
will be stored at central lab until triggered at a testing lab. Additional testing will be batch-performed 
following receipt of all accrued samples by Vanderbilt University Medical Center. 
13.1.2 
Assay Methodology 
13.1.2.1 
To Compare Bcl-2 Protein Expression by IHC in Pretreatment Biopsies with Response, PFS, 
and OS. 
In the rituximab era, the absence or presence of Bcl-2 protein expression and the intensity of 
expression are not significant prognostic indicators of PFS and OS in FL. We hypothesize that with 
the addition of the Bcl-2 inhibitor venetoclax to obinutuzumab and bendamustine therapy in FL, the 
presence of Bcl-2 protein expression and strong intensity of expression will be associated with 
favorable outcome compared to cases with lower or no Bcl-2 expression. 
IHC for Bcl-2 protein will be performed on all pretreatment FFPE biopsy samples by Ventana 
Medical Systems. All samples with sufficiently abundant material will be included in triplicate on a 
tissue microarray (TMA) on which Bcl-2 IHC will be performed. Excisional lymph node or extranodal 
tissue biopsies are preferred over core needle biopsies. On any sample too small for inclusion on 
the TMA, Bcl-2 IHC will be performed on an unstained slide section in parallel with the TMA 
staining. If Bcl-2 IHC was performed on the case at the originating institution, these slides will also 
be reviewed and Bcl-2 expression and intensity assessed. 


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Additionally IHC assessment using the validated Ventana IHC test or rescoring of stained slides 
using the Ventana algorithm may be performed. Analysis will be performed within 4 months of 
slides being cut, to adhere to the IHC assay stability window. 
The results will be compared with IGH/BCL2 FISH status, treatment response, PFS, and OS. 
13.1.2.2 
To Compare BCL2 Rearrangement Status by FISH in Pretreatment Biopsies and Correlate 
with Response, PFS, and OS. 
A majority of, but not all, FL harbor an isolated t(14;18) IgH/Bcl-2 translocation. Similarly, to Bcl-2 
protein expression, we hypothesize that the presence of BCL2 rearrangement may correlate with 
more favorable outcome compared to cases lacking a rearrangement. 
Use of BCL2 break-apart FISH probes is the most accurate qualitative method of capturing variant 
translocations21 and cases with BCL2 mutations and/or extensive somatic hypermutation22 that 
may prevent PCR primer binding. IGH and BCL2 break-apart FISH probes will be applied to 
unstained slides of each pretreatment FFPE biopsy. Testing will be batch-performed following 
receipt of all accrued samples. 
The reviewing molecular pathologist(s) will be blinded to the clinical outcome data and Bcl-2 
expression status. The number of positive signals will be expressed as a percent of the total cells 
examined by clinically validated methods. The results will be compared with Bcl-2 protein 
expression status by IHC, treatment response, PFS, and OS. 
13.1.2.3 
To Compare Mcl-1 and Bcl-XL Protein Expression by IHC in Pretreatment Biopsies with 
Response, PFS, and OS 
Myeloid leukemia sequence 1 (Mcl-1) and B-cell lymphoma XL (Bcl-XL) are additional anti-apoptotic 
proteins closely related to Bcl-2. In pre-clinical studies, pharmacologic loss of Mcl-1 function is 
reported to sensitize B-cell lymphoma cell lines to Bcl-2 inhibition by ABT-199 and other agents.23 
Similarly, selective inhibition in vivo of BCL-XL sensitizes zenograft models of carcinoma to 
standard cytotoxic chemotherapy.24 We hypothesize that low expression levels of Mcl-1 and Bcl-
XL may correlate with more robust treatment response and longer PFS and OS compared with 
cases showing high Bcl-1 and Bcl-XL expression. 
IHC for Mcl-1 and Bcl-XL protein expression will be performed and reviewed on all pretreatment 
FFPE biopsy samples on TMAs in the same manner as Bcl-2 IHC. Appropriate positive and 
negative control samples will be included from archival clinical tissue blocks, first assessed 
separately. As with Bcl-2 IHC, the reviewing pathologist(s) will be blinded to the clinical outcome 
data. Scoring of staining intensity for each antibody will be defined following initial stain review. 
Additional proteins in the Bcl-2 and related pathway may also be interrogated by IHC based on 
emerging literature. The results will be compared to Bcl-2 expression and intensity, histopathologic 
features, and treatment response, PFS, and OS. 
13.1.2.4 
To Compare Histologic Features of Pretreatment Biopsies with Response, PFS, and OS. 
High histologic grade in FL, i.e. grade 3A, and diffuse architecture have been associated with 
relatively aggressive behavior and a greater likelihood of progression to DLBCL.25 Similarly, tumor 
proliferative rate as estimated by Ki67 IHC in low-grade (grade 1-2) cases has been suggested as 
an adverse prognostic feature.26 We hypothesize that in the setting of pharmacologic Bcl-2 
inhibition, histologic grade, diffuse architecture, and Ki67 proliferation fraction may not be 
significantly associated with outcome. 
All diagnostic pretreatment biopsies will be reviewed by the study pathologist(s). Histologic grade 
(grade 1-2 or grade 3A) will be assigned in a manner blinded to the original pathology report. 
Similarly, architectural pattern will be assigned in the following proportions as recommended by 
the WHO: follicular pattern=>75% follicular architecture, follicular and diffuse patterns=25-75% 
follicular architecture, focally follicular pattern=<25% follicular architecture, and diffuse=0% 


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follicular architecture. The Ki67 proliferation fraction will be estimated from Ki67 IHC on the TMA 
as follows: <10%, 10-20%, 20-30%, and >30% of tumor cells. 
Each feature (grade, architecture, and Ki67 proliferation fraction) will be compared to treatment 
response, PFS, and OS. Statistical methods and inferences will be informed by relative sample 
sizes. 
NOTE: Any tissue biopsies obtained during treatment or post-treatment (Formalin-Fixed Paraffin-
Embedded (FFPE) blocks or up to 15 FFPE slides plus H&E slide), whether or not involved 
by lymphoma (persistent/recurrent/transformed), will also be centrally reviewed by the 
study pathologist(s). If deemed appropriate, additional immunohistochemistry (including 
but not limited to Bcl-2 and Mcl-1), BCL2 FISH, and IGH/BCL2 PCR may be performed for 
assessment of additional pathology objectives and/or for generation of additional 
histopathologic hypothesis generation. 
13.1.3 
Pathology Sample Processing and Shipment 
13.1.3.1 
Bcl-2 Samples to Ventana 
Sites will submit 7-10 FFPE tissue slides per patient within 4 months of slides being cut to Ventana 
Medical Systems, Inc. Shipping kits, supplies and instructions will be provided. 
13.1.3.2 
Remaining Pathology Samples to Central Lab 
Sites should submit FFPE diagnosis tumor tissue blocks or up to 15 FFPE (if tissue is limited, then 
minimum of 6 slides are required) unstained slides plus H&E slide from relevant tumor tissue 
block(s) within 12 months of patient registration. Thickness of the sections should be at 4-5 
microns. 
Sites should submit any optional tumor samples obtained during treatment or post-treatment 
(formalin-fixed paraffin-embedded (FFPE) blocks or up to 15 FFPE tissue (4-5 microns) on 
unstained slides plus H&E slide) within 4 months of procedure. 
A copy of the pathology report from initial diagnosis and/or subsequent tumor sampling should be 
sent when the sample is shipped. Samples should be shipped Monday-Thursday. Samples will 
be shipped ambient via overnight courier. 
All samples collected will be labeled with a unique numeric identifier that will be coded for patient 
privacy protection. 
Kits will be supplied. Instructions and shipping address will be provided. 
 


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14. 
Administrative 
14.1 
Protocol Compliance 
The study shall be conducted as described in this protocol. All revisions to the protocol must be 
discussed with, and be prepared by PrECOG and/or representatives. The Investigator should not 
implement any deviation or change to the protocol or consent without prior review and documented 
approval from PrECOG and/or representatives and the Institutional Review Board (IRB) of an 
amendment, except where necessary to eliminate an immediate hazard(s) to study patients. 
If a deviation or change to the approved protocol is implemented to eliminate an immediate 
hazard(s) prior to obtaining IRB approval, notification will be submitted to the IRB for review and 
approval as soon as possible afterward. Documentation of approval signed by the chairperson or 
designee of the IRB(s) should be in the study records. If PrECOG and/or representatives provides 
an amendment that substantially alters the study design or increases the potential risk to the 
patient; the consent form must be revised and submitted to the IRB(s) for review and approval; the 
revised form must be used to obtain consent from patients currently enrolled in the study if they 
are affected by the Amendment; and the new form must be used to obtain consent from new 
patients prior to study entry. Information as to who investigators should send correspondence will 
be provided in additional study documents. 
14.2 
Institutional Review Board 
Before study initiation, the Investigator must have written and dated approval from their respective 
IRB for the protocol, consent form, patient recruitment materials/process and any other written 
information to be provided to patients. The Investigator should also provide the IRB with a copy of 
the Investigator Brochure or product labeling, and any updates. 
The Investigator should provide the IRB with reports, updates, and other information (e.g., Safety 
Updates, amendments, and administrative letters) according to regulatory requirements, IRB or 
study site procedures. 
14.3 
Informed Consent Procedures 
Investigators must ensure that patients who volunteer for clinical trials or their legally acceptable 
representative are clearly and fully informed about the purpose, potential risks and other 
information. 
A protocol specific informed consent form (ICF) template will be provided to sites. Preparation of 
the site-specific consent form is the responsibility of the site Investigator and must include all 
applicable regulatory and IRB requirements, and must adhere to Good Clinical Practices (GCP) 
and to the ethical principles that have their origin in the Declaration of Helsinki. All changes to the 
ICF template will be approved by PrECOG and/or their representatives prior to implementation. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the consent 
process will also include written authorization by patients to release medical information to allow 
PrECOG and/or its agents, regulatory authorities, and the IRB of record at the study site for access 
to patient records and medical information relevant to the study, including the medical history. This 
will be documented in the informed consent form or other approved form obtained at the time of 
informed consent per institutional policies. This form should also be submitted to PrECOG and/or 
its agents for review prior to its implementation. 
The Investigator must provide the patient or legally acceptable representative with a copy of the 
consent form and written information about the study in the language in which the patient is most 
proficient. The language must be non-technical and easily understood. The Investigator should 
allow time necessary for patient or patient's legally acceptable representative to inquire about the 
details of the study, then informed consent must be signed and personally dated by the patient or 
the patient's legally acceptable representative and by the person who conducted the informed 
consent discussion. The patient or legally acceptable representative should receive a copy of the 


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signed informed consent and any other written information provided to study patients prior to 
patient's participation in the trial. The investigator is responsible for assuring adequate 
documentation of this process and for storage and maintenance of the original signed consent form 
for each patient/subject. 
The informed consent and any other information provided to patients or the patient's legally 
acceptable representative, should be revised whenever important new information becomes 
available that is relevant to the patient's consent, and should receive IRB approval prior to use. 
The Investigator, or a person designated by the Investigator should inform the patient or the 
patient's legally acceptable representative of all pertinent aspects of the study and of any new 
information relevant to the patient's willingness to continue participation in the study. This 
communication should be documented in the patient record. During a patient's participation in the 
trial, any updates to the consent form and any updates to the written information will be provided 
to the patient. 
14.4 
Safety Communication 
Investigators will be notified of all AEs that are serious, unexpected, and definitely, probably, or 
possibly related to the investigational product. Upon receiving such notices, the Investigator must 
review and retain the notice with the Investigator Brochure and submit a copy of this information 
to the IRB according to local regulations. The Investigator and IRB will determine if the informed 
consent requires revision. The Investigator should also comply with the IRB procedures for 
reporting any other safety information. All revisions should be submitted to PrECOG and/or agents 
for review. 
14.5 
Monitoring 
Representatives and agents of PrECOG and, as applicable to the study, the manufacturer of 
investigational product must be allowed to visit all study site locations periodically to assess the 
data, quality and study integrity. The purpose of this visit is to review study records and directly 
compare them with source documents and discuss the conduct of the study with the Investigator, 
and verify that the facilities remain acceptable. Monitoring of drug accountability will also occur. 
The study may be evaluated by other auditors and government inspectors who must be allowed 
access to electronic Case Report Forms (eCRFs), source documents and other study files. The 
Investigator must notify PrECOG of any scheduled visits by regulatory authorities, and submit 
copies of all reports. Information as to who investigators should notify of an audit or where to 
address questions will be provided in additional study materials. 
14.6 
Study Records 
An Investigator is required to maintain adequate regulatory files with corresponding communication 
and approvals, accurate histories, observations and other data on each individual treated. Full 
details of required regulatory documents will be provided in additional study materials. Data 
reported on the eCRFs must be consistent with the source documents as part of the patient record. 
The confidentiality of records that could identify patients must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s). 
A study specific signature record will be maintained to document signatures and initials of all 
persons at a study site who are authorized to make entries and/or corrections on eCRFs as well 
as document other study-specific roles. 
14.7 
Electronic Case Report Form (eCRF) Information 
Additional information regarding eCRF instructions, timelines for data entry/ submission and query 
completion can be found in supplemental materials provided to the site. Sites will be expected to 
complete eCRFs as per the schedule provided and submit all relevant data as per the specified 
timelines. All items recorded on eCRFs must be found in source documents. 


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77 
The completed eCRF must be promptly reviewed, electronically signed, and dated by the Principal 
Investigator. 
Instructions for management of patients who do not receive any protocol therapy: 
If a patient is registered and does not receive any assigned protocol treatment, baseline, Serious 
Adverse Event and follow-up data will still be entered and must be submitted according to the 
eCRF instructions. Document the reason for not starting protocol treatment on the appropriate 
electronic off treatment form. 
14.8 
Records Retention 
FDA Regulations (21CFR 312.62) require clinical investigators to retain all trial-related 
documentation, including source documents for the periods described below for studies performed 
under a US Investigational New Drug (IND): 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of trials and that an 
application will not be submitted. 
The Investigator must retain investigational product disposition records, copies of eCRFs (or 
electronic files), and source documents for the maximum period required by applicable regulations 
and guidelines, or Institution procedures, whichever is longer. The Investigator must contact 
PrECOG and/or representatives prior to destroying any records associated with the study. 
Information as to who investigators should contact for questions will be provided in additional study 
documents. PrECOG and/or representatives will notify the Investigator when the trial records for 
this study are no longer needed. 
 


PrECOG Protocol Number: PrE0403 
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78 
15. 
References 
1. Siegel RL, Miller KD, Jemal A. Cancer Statistics 2015, CA Cancer J Clin. 2015; 65:5-29. 
2. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence 
patterns by WHO subtype in the United States, 1992-2001. Blood. 2006; 107:265-276. 
3. Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin's 
lymphomas. N Engl J Med. 1984; 311:1471-1475. 
4. Swenson WT, Wooldridge JE, Lynch CF, Forman-Hoffman VL, Chrischilles E, Link BK. Improved 
survival of follicular lymphoma patients in the United States. J Clin Oncol. 2005; 23:5019-5026. 
5. Lai R, Arber DA, Chang KL, Wilson CS, Weiss LM. Frequency of bcl-2 expression in non-Hodgkin’s 
lymphoma: a study of 7788 cases with comparison of marginal zone lymphoma and monocytoid 
B-cell hyperplasia. Mod Pathol 1998; 11:864-869. 
6. Schraders M, de Jong D, Kluin P, Groenen P, van Krieken H. Lack of Bcl-2 expression in follicular 
lymphoma may be caused by mutations in the BCL2 gene of by absence of the t(14;18) 
translocation. J Pathol 2005; 205:329-335. 
7. Rummel MJ, Niederle N, Maschmeyer G, Banat GA et al., Bendamustine plus rituximab versus 
CHOP plus rituximab as first line treatment for patients with indolent and mantle cell lymphomas: 
an open-label, multicenter, randomised, phase 3 non-inferiority trial. Lancet 2013; 381:1203-10. 
8. Salles G, Seymour J, Offner F, et al. Rituximab maintenance for 2 years in patients with high 
tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a Phase 
3, randomised controlled trial. Lancet 2011; 377:42−51. 
9. F. Hoffman-La Roche, LTD. Obinutuzumab/GAZYVA Investigator's Brochure, Version 11; Date: 
September 2016. 
10. Mössner E, Brünker B, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through 
the engineering of a new Type II anti-CD20 antibody with enhanced direct and immune effector 
cell–mediated B-cell cytotoxicity. Blood 2010; 115:4393−402. 
11. Niederfellner G,Lammens A, Mundigl O. et al. Epitope characterization and crystal structure of 
GA101 provide insights into the molecular basis for type I/II distinction of CD20 antibodies. Blood 
2011 Jul 14; 118(2):358-67. 
12. Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 
(obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol 
Cancer Ther. 2013 Oct; 12(10):2031-4. 
13. Abbvie. Venetoclax/ABT-199 Investigator's Brochure, Version 8; Date: 15 February 2017. 
14. Davids MS, Letai A. Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 2012 
Sep 1; 30(25):3127-35. 
15. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, 
achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb; 19(2):202-8. 
16. Zinzani PL, Topp MS, Yuen SLS, et al. Phase 2 Study of Venetoclax Plus Rituximab or 
Randomized Ven Plus Bendamustine+Rituximab (BR) Versus BR in Patients with 
Relapsed/Refractory Follicular Lymphoma: Interim Data. Oral presentation at ASH 2016; Session: 
623- Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma-Clinical Studies: 
Chemoimmunotherapy in Follicular Lymphoma; 05 December 2016. 
17. Zelenetz AD, Gilles AS, Mason KD, et al. Results of a Phase Ib Study of Venetoclax Plus R- or G-
CHOP in Patients with B-Cell Non-Hodgkin Lymphoma. Blood 2016: 128:3032. 
18. Howard SC, Jones, DP and Pui CH. The Tumor Lysis Syndrome. N Engl J Med 2011; 364: 1844-
54. 


PrECOG Protocol Number: PrE0403 
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79 
19. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister AT. 
Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-
Hodgkin Lymphoma: the Lugano Classification JCO. 2014: 32’ 3057-3067. 
20. Bendamustine Package Insert. August 2008-2017. 
21. Baro C, Espinet B, Salido M, et al. Cryptic IGH/BCL2 rearrangements with variant FISH patterns 
in follicular lymphoma. Leukemia Research 2011; 35(2):256-259. 
22. Burkhard R, Bhagat G, Cogliatti SB, et al. BCL2 mutation spectrum in B-cell non-Hodgkin 
lymphomas and patterns associated with evolution of follicular lymphoma. Hematol Oncol 2015; 
33(1):23-30. 
23. Phillips DC, Xiao Y, Lam LT, et al. Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell 
lines to the BCL-2-selective inhibitor venetoclax (ABT-199). Blood Cancer Journal 2015; 5:e368. 
24. van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins 
and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006; 10:389-99. 
25. Martin AR, Weisenburger DD, Chan WC, et al. Prognostic value of cellular proliferation and 
histologic grade in follicular lymphoma. Blood 1995; 85:3671-3678. 
26. Wang SA, Wang L, Hochberg EP, Muzikansky A, Harris NL, Hasserjian RP. Low histologic grade 
follicular lymphoma with high proliferation index: morphologic and clinical features. Am J Surg 
Pathol 2005; 29(11):1490-6. 
27. Buske C, Hoster E, Dreyling M, Hasford J, Unterhalt M, Hiddemann W. The Follicular Lymphoma 
International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients 
with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of 
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment 
outcome. Blood. 2006; 108:1504-1508. 
28. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. 
Blood. 2004; 104:1258-1265. 
29. Federico M, Bellei M, Marcheselli L, et al. Follicular Lymphoma International Prognostic Index 2: 
A New Prognostic Index for Follicular Lymphoma Developed by the International Follicular 
Lymphoma Prognostic Factor Project. J Clin Oncol 2009 Sep 20; 27(27):4555-62. 
 


PrECOG Protocol Number: PrE0403 
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80 
Appendix I: 
Modified Ann Arbor Staging System 
 
Stage I 
Involvement of a single lymph node region. 
Stage II 
Involvement of 2 or more lymph node regions on the same side 
of the diaphragm. 
Stage III1 
Involvement of lymph node regions on both sides of the 
diaphragm. Abdominal disease is limited to the upper 
abdomen: spleen, splenic hilar node, celiac node, porta 
hepatitis node. 
Stage III2 
Involvement of lymph node regions on both sides of the 
diaphragm. 
Abdominal 
disease 
includes 
para-aortic, 
mesenteric, iliac, or inguinal involvement with or without 
disease in the upper abdomen. 
Stage IV 
Diffuse or disseminated involvement of one or more extra 
lymphatic organs or tissues, with or without associated lymph 
node involvement. 
In Stage III1, the subscript S may be used to denote splenic involvement. The 
subscript E (e.g., IE or IIE) is used to denote involvement of an extra lymphatic site 
primarily or by direct extension, rather than hematogenous spread, as in the case of 
a mediastinal mass extending to involve the lung. 
The presence of (B) or absence of (A) fever, night sweats, and/or unexplained loss of 
10% or more body weight in the 6 months prior to admission are denoted by the 
corresponding suffix letters B and A. 
 


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Appendix II: 
ECOG Performance Status 
 
PS 0 
Fully active, able to carry on all pre-disease performance without 
restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature e.g. light 
housework, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities. Up and about more than 50% of waking 
hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
Source: Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 


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Appendix III: 
Calculation of Creatinine Clearance Using the Cockcroft-Gault Formula 
 
 
(140 - age [years]) (body wt [kg]) 
Creatinine clearance for males =  
————————————————— 
(72) (serum creatinine [mg/dL]) 
 
 
(140 - age [years]) (body wt [kg]) 
Creatinine clearance for females =  ————————————————— 
x 0.85 
(72) (serum creatinine [mg/dL]) 
 
NOTE: Actual body weight in kg. 
 
Source: Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted serum 
creatinine (editorial). Nephron 1992; 62:249 
 


PrECOG Protocol Number: PrE0403 
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83 
Appendix IV: 
Definitions of Tumor Lysis Syndrome18 
All tumor lysis syndrome events should be graded per the NCI CTCAE, Version 5.0 criteria. 
Definitions of Tumor Lysis Syndrome 
Metabolic Abnormality 
Criteria for Classification of 
Laboratory Tumor Lysis Syndrome* 
Criteria for Classification of Clinical Tumor 
Lysis Syndrome* 
Hyperuricemia 
Uric acid >8.0 mg/dl (475.8 μmol/liter) 
in adults. 
 
Hyperphosphatemia 
Phosphorus >4.5 mg/dl (1.5 mmol/liter) 
in adults. 
 
Hyperkalemia 
Potassium >6.0 mEq/L (6.0 mmol/liter) 
in adults. 
Cardiac dysrhythmia or sudden death probably 
or definitely caused by hyperkalemia. 
Hypocalcemia 
Corrected calcium <7.0 mg/dl (1.75 
mmol/liter) or ionized calcium <1.12 
(0.3 mmol/liter)† 
Cardiac dysrhythmia, sudden death, seizure, 
neuromuscular irritability (tetany, paresthesias, 
muscle 
twitching, 
carpopedal 
spasm, 
Trousseau’s 
sign, 
Chvostek’s 
sign, 
laryngospasm, or bronchospasm), hypotension, 
or heart failure probably or definitely caused by 
hypocalcemia. 
Acute Kidney Injury‡ 
N/A 
Increase in the serum creatinine level of 0.3 
mg/dl (26.5 μmol/liter) (or a single value >1.5x 
the upper limit of the age appropriate normal 
range if no baseline creatinine measurement is 
available) or the presence of oliguria, defined as 
an average urine output of <0.5 mL/kg/hr for 6 hr. 
* 
In laboratory tumor lysis syndrome, two or more metabolic abnormalities must be present during the same 24-hour 
period within 3 days before the start of therapy or up to 7 days afterward (Grade 3). This window applies to initiation 
of any study therapy. Clinical tumor lysis syndrome requires the presence of laboratory tumor lysis syndrome plus 
an increased creatinine level, seizures, cardiac dysrhythmia, or death (Grade 4 or Grade 5[death]). 
† The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 × 
(4 – albumin in grams per deciliter). 
‡ Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 μmol per 
liter) or a period of oliguria lasting 6 hours or more. By definition, if acute kidney injury is present, the patient has 
clinical tumor lysis syndrome if no other cause can be found. 
Source: Howard SC, Jones, DP and Pui CH. The Tumor Lysis Syndrome. N Engl J Med 2011; 364: 1844-54. 
(reused with permission) 


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Appendix V: 
Venetoclax Medication Diary 
 
Patient Instructions: 
1. Complete each form as instructed by your physician or study nurse. Please complete in ink. 
2. Please complete this diary every day. Write the date of each dose of venetoclax you take. 
3. Venetoclax should be administered with a meal and swallowed whole with an 8-ounce glass of 
water. Tablets should not be chewed, crushed or broken. You should take the tablets at 
approximately the same time each day. 
4. If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day 
with food. There must be a minimum of 16 hours between the current dose and the next dose. 
Return to the normal schedule the following day. 
5. Extra tablets should not be taken to make up for the missed dose. If you vomit within 15 minutes 
of taking venetoclax and all tablets are intact, you may take another dose otherwise, do not repeat 
the dose but resume dosing at the time of the next scheduled dose. Please mark dates of any 
missed tablet on your record. 
6. You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in 
marmalades) or starfruit while you are taking venetoclax. These products may increase the amount 
of venetoclax in your blood. 
7. Store venetoclax at or below 86°F. 
8. If you have any side effects or comments, please note in the comment section or on the back of 
the page. If you have questions or concerns, please call 
______________________________________ at: (_____) _____ - _________. 
Please bring your venetoclax bottle(s) (unused medication and empty bottles) and this form to 
every appointment with your study doctor. 
 
 
 


PrECOG Protocol Number: PrE0403 
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INDUCTION Cycle 2-6 Venetoclax Medication Diary 
Site #:___________ 
Subject #:___________ 
Subject Initials:____________ 
Cycle:___________ 
Dose:_______________ 
Number of Tablets: _____ mg: #________ 
 
DAY 
DATE 
DOSE 
Aspirin (or any other blood 
thinning medication) 
COMMENTS 
1 
____/____/____ 
______mg 
 
 
2 
____/____/____ 
______mg 
 
 
3 
____/____/____ 
______mg 
 
 
4 
____/____/____ 
______mg 
 
 
5 
____/____/____ 
______mg 
 
 
6 
____/____/____ 
______mg 
 
 
7 
____/____/____ 
______mg 
 
 
8 
____/____/____ 
______mg 
 
 
9 
____/____/____ 
______mg 
 
 
10 
____/____/____ 
______mg 
 
 
Patient Signature: _______________________________________________ Patient Initials: _________ 
 
 


PrECOG Protocol Number: PrE0403 
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86 
MAINTENANCE Venetoclax Medication Diary 
Patient Signature: ________________________________________________ Patient Initials: _________ 
Site #:___________ 
Subject #:___________ 
Subject Initials:____________ 
Cycle:___________ 
Dose:_______________ 
Number of Tablets: _____ mg: 
#________ 
DAY 
DATE 
DOSE 
Aspirin (or any other blood 
thinning medication) 
COMMENTS 
1 
____/____/____ 
______mg 
 
 
2 
____/____/____ 
______mg 
 
 
3 
____/____/____ 
______mg 
 
 
4 
____/____/____ 
______mg 
 
 
5 
____/____/____ 
______mg 
 
 
6 
____/____/____ 
______mg 
 
 
7 
____/____/____ 
______mg 
 
 
8 
____/____/____ 
______mg 
 
 
9 
____/____/____ 
______mg 
 
 
10 
____/____/____ 
______mg 
 
 
11 
____/____/____ 
______mg 
 
 
12 
____/____/____ 
______mg 
 
 
13 
____/____/____ 
______mg 
 
 
14 
____/____/____ 
______mg 
 
 
15 
____/____/____ 
______mg 
 
 
16 
____/____/____ 
______mg 
 
 
17 
____/____/____ 
______mg 
 
 
18 
____/____/____ 
______mg 
 
 
19 
____/____/____ 
______mg 
 
 
20 
____/____/____ 
______mg 
 
 
21 
____/____/____ 
______mg 
 
 
22 
____/____/____ 
______mg 
 
 
23 
____/____/____ 
______mg 
 
 
24 
____/____/____ 
______mg 
 
 
25 
____/____/____ 
______mg 
 
 
26 
____/____/____ 
______mg 
 
 
27 
____/____/____ 
______mg 
 
 
28 
____/____/____ 
______mg 
 
 


PrECOG Protocol Number: PrE0403 
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Appendix VI: 
Additional Excluded and Cautionary Medications 
The following is NOT a complete list of medications that are potentially incompatible with treatment on this 
protocol. As the list of these agents are constantly changing, it is important to regularly consult a frequently 
updated medical reference. Please refer to the following website for more information: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeli
ng/ucm093664.htm 
Clinically Relevant Drug Interactions: Inhibitors and Inducers of Isoenzyme CYP3A 
Co-administration with strong and moderate CYP3A inhibitors is not recommended. Consider alternative 
medications if necessary. If subject requires the use of these medications, use with caution and reduce the 
venetoclax dose by 2-fold for moderate inhibitors and 4-fold for strong inhibitors during co-administration. If 
subject requires use of strong or moderate CYP3A inducers, use with caution and contact PrECOG for guidance. 
Co-administration with the use of weak CYP3A inducers and weak CYP3A4 inhibitors should be undertaken 
with caution. 
INHIBITORS 
STRONG INHIBITORS 
boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, lopinavir, ketoconazole, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, teleprevir, telithromycin, troleandamycin, voriconazole 
MODERATE INHIBITORS 
amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunovir, diltiazem, dronedarone, erythromycin, 
fluconazole, fosamprenavir, imatinib, nifedipine, seville oranges, star fruit, verapamil 
INDUCERS 
STRONG INDUCERS 
avasimibe, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s Wort 
MODERATE INDUCERS 
bosentan, efavirenz, etravirine, modafinil, nafcillin, oxcarbazepine 
Cautionary Use 
INHIBITORS 
WEAK INHIBITORS 
alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, 
fluvoxamine, ginkgo, goldenseed, isoniazid, nilotinib, oral contraceptives, pazopanib, ranitidine, ranolazine, ticagrelor, 
tipranavir, zileuton 
INDUCERS 
WEAK INDUCERS 
armodafinil, clobazamechinacea, pioglitazone, prednisone, rufinamide, vemurafenib 
PgP 
PgP SUBSTRATES 
aliskiren, ambrisentan, colchicines, dabigatran etexilate, digoxin, everolimus, fexofenadine, indinavir, lapatinib, 
loperamide, maraviroc, nilotinib, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan 
PgP INHIBITORS 
amiodarone, azithromycin, captopril, carvedilol, cyclosporine, elacridar, felodipine, ginkgo (ginkgo biloba), mibefradil, milk 
thistle (silybum marianum), nitrendipine, quercetin, quinidine, ronalzine, schisandra chinensis, telmisartan, ticagrelor, 
tipranavir, valspodar 
 


PrECOG Protocol Number: PrE0403 
IND Number: 134855 
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Date: 10/15/2021 
 
88 
Appendix VII: Follicular Lymphoma International Prognostic Index (FLIPI)-1 
FLIPI-127,28 
Each patient should be assessed for the presence or absence of the following 5 adverse prognostic factors 
(adverse factor in italics): FLIPI 1  
1) Age (>60 years vs. ≤ 60 years) 
2) Ann Arbor stage (III-IV vs. I-II) 
3) Hemoglobin level (<120 g/L vs. 120 g/L or higher) 
4) Number of nodal areas (>4 vs. 4 or less; see figure below) 
5) Serum LDH level (above normal vs. normal or below) 
Each patient should then be assigned into one of the following 3 risk groups: 
 
Low risk (0-1 adverse factor) 
 
Intermediate risk (2 factors) (Bilateral involvement = 2) 
 
High risk (3 or more adverse factors) 
Figure. Nodal map according to FLIPI model. 
 
 
 


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Appendix VIII: Follicular Lymphoma International Prognostic Index (FLIPI)-2 
FLIPI-229 
An updated analysis of the FLIPI was reported (FLIPI-2). This analysis was completed on 832 follicular 
lymphoma patients treated from 2003 through 2005, of who the majority received rituximab-based therapy. 
Five clinical factors were identified as being correlated with survival. Three of the parameters were different 
than the original FLIPI (FLIPI-1), while two were similar (i.e., anemia and older age). 
Each patient treated should be further assessed for the presence or absence of the following 5 adverse 
prognostic factors (adverse factor in italics): 
1) 
Age (>60 years vs. 60 years or less) 
2) 
Hemoglobin level (<120 g/L vs. 120 g/L or higher) 
3) 
β2-microglobulin (above normal vs. normal or below) 
4) 
Largest involved lymph node (>6 cm vs. 6 cm or lower) 
5) 
Bone marrow (involved vs. not involved) 


PrECOG Protocol Number: PrE0403 
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Appendix IX: 
Investigator’s Statement 
1. 
I have carefully read this protocol entitled “Phase II Study of Venetoclax (ABT-
199/GDC-0199) in Combination with Obinutuzumab and Bendamustine in 
Patients with High Tumor Burden Follicular Lymphoma as Front Line Therapy”, 
Version 8.0 dated 10/15/2021 (PrE0403) and agree that it contains all the necessary 
information required to conduct the study. I agree to conduct the study as outlined in 
the protocol. 
2. 
I agree to conduct this study according to the moral, ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki, the principles of 
Good Clinical Practice (GCP) as described in 21 Code of Federal Regulations (CFR) 
and any applicable local requirements. 
3. 
I understand that this trial and any subsequent changes to the trial will not be initiated 
without approval of the appropriate Institutional Review Board, and that all 
administrative requirements of the governing body of the institution will be complied 
with fully. 
4. 
Informed written consent will be obtained from all participating patients in accordance 
with institutional and Food and Drug Administration (FDA) requirements as specified in 
Title 21, CFR, Part 50. 
5. 
I understand that my signature on the electronic Case Report Form (eCRF) indicates 
that I have carefully reviewed each page and accept full responsibility for the contents 
thereof. 
6. 
I understand that the information presented in this study protocol is confidential, and I 
hereby assure that no information based on the conduct of the study will be released 
without prior consent from PrECOG, LLC unless this requirement is superseded by the 
FDA. 
Principal Investigator (PI): 
PI Name: 
 
 
 
 
 
 
 
 
 
 
Site Name: 
 
 
 
 
 
 
 
 
 
 
Signature of PI: 
 
 
 
 
 
 
 
 
 
Date of Signature: 
 
 
\ 
 
\ 
 
 
 
 
 
 
 
MM 
 
DD 
 
YYYY 
 

SAP_001.pdf: 
Statistical Analysis Plan  
PrECOG, LLC 
Protocol: PrE0403 
Version: 1 / 13-Aug-2018 
1 
 
 
 
Statistical Analysis Plan 
Study Number 
PrE0403 
Version 
1 
Date 
13-August-2018 
Phase II Study of Venetoclax (ABT-199/GDC-0199) in Combination with Obinutuzumab and 
Bendamustine in Patients with High Tumor Burden Follicular Lymphoma as Front Line 
Therapy 


Statistical Analysis Plan  
PrECOG, LLC 
Protocol: PrE0403 
Version: 1 / 13-Aug-2018 
2 
 
 
DOCUMENT: 
 Statistical Analysis Plan 
 
PROTOCOL 
  
 
Number: 
 PrE0403 
 
Title: 
 Phase II Study of Venetoclax (ABT-199/GDC-0199) in 
Combination with Obinutuzumab and Bendamustine in 
Patients with High Tumor Burden Follicular Lymphoma as 
Front Line Therapy 
 
Date: 
 Version 1.0:  
25 May 2017 
 
 Version 2.0:  
07 November 2017 
 
 Version 3.0:  
16 November 2017 
 
 Version 4.0:  
23 January 2018 
 
  
SAP STATUS 
 Final 
SAP VERSION AND 
DATE 
 Version: 1   Date: 13 August 2018 
 
SPONSOR: 
 PrECOG, LLC 
1818 Market Street 
Suite 3000 
Philadelphia, PA 19103 
 
 
PREPARED BY: 
 
 
Biostatistician 
Quality Data Services, Inc. 
 
 
  
 




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TABLE OF CONTENTS 
 
SIGNATURES / APPROVAL PAGE .......................................................................... 3 
LIST OF ABBREVIATIONS ...................................................................................... 6 
INTRODUCTION....................................................................................................... 8 
1.1. Objective of the Statistical Analysis Plan ............................................................... 8 
2. STUDY OBJECTIVES ............................................................................................ 8 
2.1. Primary Objective ................................................................................................ 8 
2.2. Secondary Objectives ............................................................................................ 8 
2.3. Exploratory Objectives (Outside of scope of this analysis plan) .............................. 8 
2.4. Study Endpoints ................................................................................................... 9 
2.4.1. Efficacy Endpoints ............................................................................................... 9 
2.4.2. Safety Endpoints .................................................................................................. 9 
3. STUDY DESIGN ..................................................................................................... 9 
3.1. Study Design ......................................................................................................... 9 
3.2. Study Duration ................................................................................................... 11 
3.3. Study Population ................................................................................................ 11 
3.4. Randomization and Blinding ............................................................................... 11 
3.5. Treatment Administration .................................................................................. 11 
3.6. Study Procedures and Assessments ..................................................................... 12 
4. GENERAL STATISTICAL CONSIDERATIONS ................................................. 12 
4.1. Determination of Sample Size.............................................................................. 12 
4.2. Methodology ....................................................................................................... 12 
4.3. Handling of Dropouts or Missing Data ................................................................ 12 
4.4. Interim Analyses and Data Monitoring ............................................................... 13 


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4.5. Multi-center Studies ............................................................................................ 13 
4.6. Multiple Comparisons / Multiplicity .................................................................... 13 
4.7. Analysis Populations ........................................................................................... 14 
4.7.1. Intent-to-Treat Population ................................................................................... 14 
4.7.2. Safety Population ............................................................................................... 14 
4.7.3. Modified Intent-to-Treat (mITT) Population ......................................................... 14 
5. STUDY POPULATION CHARACTERISTICS ..................................................... 14 
5.1. Subject Accountability and Subject Disposition ................................................... 14 
5.2. Demographics and Baseline Characteristics ........................................................ 14 
6. SAFETY ANALYSIS ............................................................................................ 15 
6.1. Adverse Events ................................................................................................... 15 
6.2. Study Drug Administration and Dose Compliance ............................................... 16 
6.3. Clinical Laboratory Data .................................................................................... 16 
7. EFFICACY ANALYSIS ........................................................................................ 16 
7.1. Primary and Secondary Efficacy Endpoint Analyses ........................................... 16 
8. SUMMARY OF CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ......... 17 
9. REPORTING CONVENTIONS ............................................................................ 17 
10. REFERENCES .................................................................................................... 19 
APPENDIX 1.  STUDY PROCEDURES AND ASSESSMENTS................................. 20 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation/Acronym 
Definition 
AE 
Adverse event 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
Bcl-2 
B-cell lymphoma 2 
BSA 
Body surface area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete blood count 
cm 
Centimeters 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FISH 
Fluorescence in Situ Hybridization 
FLIPI 
Follicular Lymphoma International Prognostic Index 
GELF 
Groupe D’Etude des Lymphomes Follicularies 
H&E 
Hematoxylin & Eosin 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
ITT 
Intent-to-Treat Population 
IV 
Intravenous 
kg 
kilograms 
LDH 
Lactate Dehydrogenase 
Mcl-1 
Myeloid cell lymphoma-1 


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MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
mg/m2 
Milligrams per square meter of body surface area 
mITT 
Modified Intent-to-Treat Population 
mRNA 
Messenger ribonucleic acid 
msec 
Milliseconds 
ORR 
Objective Response Rate 
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PET 
Positron Emission Tomography 
PFS 
Progression-free survival 
PO 
Per os; By mouth (orally) 
PR 
Partial response 
QDS 
Quality Data Services 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation OR Stable disease 
SPD 
Sum of the product of (the two largest perpendicular) diameters 
TEAE 
Treatment-emergent adverse event 
TLF 
Tables, listings, and figures 
TLS 
Tumor lysis syndrome 
Un 
Unevaluable 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 
 


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INTRODUCTION 
1.1.   Objective of the Statistical Analysis Plan 
This statistical analysis plan (SAP) describes the planned analysis of the safety and efficacy data from this 
study. A detailed description of the associated planned tables, listings, and figures (TLFs) to be presented 
in any reporting of the results of the study, including manuscripts for consideration in academic journals, 
will be included in the accompanying mock TLFs document. 
The intent of this document is to provide guidance for the analysis of safety and efficacy data and to 
describe any applicable statistical procedures. In general, the analyses come directly from the protocol, 
unless they have been modified by agreement between PrECOG, LLC and Quality Data Services, Inc. 
(QDS). A limited amount of information concerning this study (e.g., objectives, study design) is 
summarized to help the reader interpret the accompanying TLF templates. Attached signatures indicate 
approval of the statistical analyses sections of the SAP and the accompanying TLF templates. These 
sections must be agreed upon prior to database lock. When the SAP and TLF templates are agreed upon 
and finalized, they will serve as the template for generation of the TLFs that will be the basis of the safety 
and efficacy results described in any reporting of the results of the study. 
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
different, they will be so identified and a rationale for the change provided. Any substantial deviations 
from this SAP will be agreed upon between PrECOG, LLC and QDS and documented in an Amendment 
to the SAP.   
2.   STUDY OBJECTIVES 
2.1.   Primary Objective 
• 
To estimate the proportion of patients achieving a complete remission (CR) at the end of 
induction with the combination of venetoclax, obinutuzumab, and bendamustine 
2.2.   Secondary Objectives 
• 
To determine the ORR of patients treated 
• 
To determine the proportion of patients who achieve a PR with induction therapy and later 
convert to CR with maintenance therapy 
• 
To evaluate PFS and OS in the intent to treat (ITT) population 
• 
To evaluate the compliance and toxicities of patients receiving induction and maintenance 
therapy 
2.3.   Exploratory Objectives (Outside of scope of this analysis plan) 
• 
To compare Bcl-2 protein expression by immunohistochemistry (IHC) in pre-treatment biopsies 
with response, PFS, and OS  
• 
To assess Bcl-2 family expression by mRNA expression including ratios of Bcl-2/BIM, Bcl-
2/Mcl-1 and others with response, PFS, and OS 


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• 
To compare BCL2 rearrangement status by fluorescence in situ hybridization (FISH) in 
pretreatment biopsies and correlate with response, PFS, and OS 
• 
To compare Mcl-1 and Bcl-XL protein expression by IHC in pretreatment biopsies with response, 
PFS, and OS 
• 
To compare histologic features of pretreatment biopsies with response, PFS, and OS 
 
2.4.   Study Endpoints 
2.4.1.   Efficacy Endpoints 
• 
Incidence of Complete Response (CR) during the induction phase 
• 
Objective Response Rate, over both induction and maintenance phases 
• 
Overall Survival (OS) 
• 
Progression-Free Survival (PFS)  
2.4.2.   Safety Endpoints  
• 
Adverse events, including 
o Percentage of subjects with treatment-related events of CTCAE grade 3 or higher 
o Percentage of subjects with events of special interest 
o Percentage of subjects withdrawn due to AEs 
• 
Dose compliance 
• 
Hematology and Chemistry Laboratory Assessments 
3.   STUDY DESIGN 
3.1.   Study Design 
This is a single-arm phase II clinical trial in adult male and female subjects with a histologically 
confirmed (biopsy-proven) diagnosis of follicular B-cell non-Hodgkin lymphoma and a high tumor 
burden (higher risk) as defined by either the GELF (Groupe D’Etude des Lymphomes Follicularies) or 
FLIPI (follicular lymphoma international prognostic index) criteria.  Eligible patients will receive 
induction therapy with venetoclax, obinutuzumab, and bendamustine for six cycles.  For patients without 
progressive disease, the induction phase will be followed by a maintenance phase in which patients who 
achieve a complete response (CR) will receive obinutuzumab every 2 months for a total of 12 cycles and 
patients who achieve partial response (PR) or stable disease (SD) will likewise receive obinutuzumab 
every 2 months for a total of 12 cycles, but accompanied by venetoclax therapy for the 12 cycles.  More 
details on the treatment schedule can be found in the schema below: 
 
 
 
 


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Figure 1  Study Schema  
 
Tumor assessments will be performed every 3 cycles (12 weeks) during the induction phase and every 6 
months during the maintenance phase. Tumor response will be assessed by the investigator in accordance 
with Cheson criteria.  Subjects who discontinue treatment in the absence of progression will continue to 
have tumor assessments until documented progression or initiation of alternate anti-cancer therapies.  


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3.2.   Study Duration 
The study will consist of 3 periods: an Induction Treatment Period (6 cycles of 28 days each), followed 
by a Maintenance Treatment Period (Patients with CR = every 2 months for 12 cycles; patients with SD 
or PR = every 28 days for 24 cycles), and a Follow-up Period (2 years from date of last study treatment or 
study closure) to monitor survival status, disease progression, and initiation of new cancer therapies.  
Maintenance therapy will start between 8 and 12 weeks following the end of the last induction therapy 
cycle.  Therefore, the total duration of the study for each subject will be a maximum of 4.75 years.  
 
Subjects will receive study therapy until disease progression, unacceptable toxicity, development of an 
inter-current illness that prohibits continuation of treatment, voluntary withdrawal of subject consent, 
inability to comply with study procedures, or investigator determination that protocol requirements are 
detrimental to subject health. 
3.3.   Study Population 
A total of 56 patients will be enrolled into the study, 51 of which are expected to be eligible and treated.  
Patients will be recruited from multiple US clinical sites.  Patients who discontinue from the study will 
not be replaced. 
The study population will consist of adult males and females with a histologically confirmed (biopsy-
proven) diagnosis of follicular B-cell non-Hodgkin lymphoma.  The stage of the disease at Screening 
must be II, III, or IV according to Modified Ann Arbor staging.  Patients must meet criteria for High 
Tumor Burden (higher risk) as defined by either the GELF or FLIPI criteria, have adequate organ 
function, and no prior chemotherapy, radiology, or immunotherapy for lymphoma.   
3.4.   Randomization and Blinding 
All subjects will follow the same open-label treatment regimen.   
3.5.   Treatment Administration 
Eligible patients will receive induction therapy with venetoclax, obinutuzumab, and bendamustine for six 
cycles of twenty-eight days each.  An 800 mg oral dose of venetoclax will be dispensed on Days 1-10 of 
each 28 day induction cycle.  In the first induction cycle, patients at high risk of tumor lysis syndrome 
(TLS) venetoclax will be administered on Days 8-14 instead.  Dose compliance will be monitored via a 
pill diary. In the first induction cycle, obinutuzumab will be administered as 100 mg on day 1, 900 mg on 
day 2, and 1000 mg on each of days 8 and 15.  In all subsequent induction cycles, obinutuzumab dosing 
will consist of a single 1000 mg IV administration on day 1 only.  Bendamustine will be administered to 
patients as a 90 mg/m2 IV infusion on days 1 and 2 of each 28-day induction cycle.   
Maintenance treatment will begin 8-12 weeks after the end of the last induction cycle.  Patients with 
progressive disease will not continue on the maintenance arm.  Patients who achieve a complete response 
(CR) at the end of the induction phase will receive a 1000 mg IV of obinutuzumab every 2 months for a 
total of 12 cycles.  Patients who achieve partial response (PR) or stable disease (SD) at the end of the 
induction phase will receive a 1000 mg IV of obinutuzumab every 2 months for a total of 12 cycles and 
will take a daily 800 mg oral tablet of venetoclax for 24 cycles of 28 days each.  If the dose of venetoclax 
as reduced during the induction phase, the same reduced dose will continue to be taken during the 
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In the event that venetoclax is not well-tolerated in the induction phase, the dose will be reduced from 800 
mg on days 1-10 to 800 mg on days 1-5 (Dose Level -1).  If dose level -1 is not well-tolerated either, the 
dose will be reduced to 400 mg on days 1-5 (Dose Level -2).  Patients who do not tolerate dose level -2 
will be discontinued from all study treatment.  In the event that bendamustine is not well-tolerated in the 
induction phase, the dose will be reduced to 70 mg/m2.  Patients will be removed from all study treatment 
if they require a dose reduction of bendamustine below 70 mg/m2.  
Acetaminophen (650 or 1000 mg orally) and diphenhydramine (25 or 50 mg oral or intravenous) will be 
administered 30 to 60 minutes prior to starting each infusion of obinutuzumab or per institutional 
guidelines. Since transient hypotension may occur during obinutuzumab infusion, consideration is to be 
given to withholding anti-hypertensive medications 12 hours prior to obinutuzumab infusion. 
3.6.   Study Procedures and Assessments 
All study procedures and assessments are listed in the table in Appendix 1. 
4.   GENERAL STATISTICAL CONSIDERATIONS 
4.1.   Determination of Sample Size 
The primary objective of this study is complete response (CR) after induction.  We anticipate a 50% CR 
rate after induction treatment with obinutuzumab and bendamustine.  With the addition of venetoclax 
(given concurrently), a CR rate of 65% (15% improvement from 50%) would be considered promising for 
the addition of venetoclax to the induction regimen.  A total of 56 patients will be enrolled into the study, 
51 of which are expected to be eligible and treated. Among 51 eligible, treated patients, this study will 
have the desired 85% power to detect a 15% improvement in CR using a one-sided exact binomial test.  
4.2.   Methodology 
In general, listings will be sorted by site, subject number, visit, and date and time of assessment.  All 
listings will include flags to indicate subject-level inclusion/exclusion for each of the analysis 
populations. 
Post-dose safety parameters will be summarized in aggregate for all subjects.  Induction phase data will 
not be presented in separate tables from maintenance phase data.  For tables summarizing change from 
baseline for laboratory data, baseline will be defined as the last non-missing result prior to the subject’s 
first study dosing of venetoclax, bendamustine, or obinutuzumab.  All tables will use only data pertaining 
to the specific population being analyzed.   
Continuous data will be summarized with the following descriptive statistics: number of observations (n), 
mean, standard deviation (SD), median, minimum, and maximum. Categorical data will be summarized 
with frequencies of subjects and associated percentages based on the number of subjects in the given 
analysis population.  Percentages will be computed using the number of subjects in the relevant analysis 
population as the denominator unless stated otherwise. 
4.3.   Handling of Dropouts or Missing Data 
Subjects who withdraw from the study will not be replaced. 
 
 


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If the start date of an adverse event is missing or ambiguous, the event will be assumed to be treatment-
emergent, that is, to have started after the first study treatment administration.  Similarly, if the 
relationship of an adverse event to a certain study treatment is not collected, then the adverse event will 
be assumed to be related to that treatment for inclusion in listings and tables of treatment-related events. 
The start and end dates of all adverse events and their relationships to study treatments will still be listed 
as collected.   
All other cases of missing or invalid data will be treated as missing and will not be imputed.   
4.4.   Interim Analyses and Data Monitoring 
There will be a formal, detailed, toxicity evaluation after 28 patients (50% of accrual target), including 
patients who terminate treatment for any reason, have been enrolled and have been on the study for the 
period of 3 cycles.  For all treatment-related Grade 3 or higher AEs, the formal evaluation will be done 
within each AE category and also for the overall AE rate.  
It is expected that the proportion of any CTCAE v5.0 toxicity grade 3 or higher, treatment-related adverse 
event will be no greater than 35% for each MedDRA system organ class or preferred term.  If the 
proportion of patients who experienced a Grade 3 or higher, treatment-related, adverse event for a given 
preferred term or system organ class is greater than 45% (~13 or more of 28 patients), a detailed review of 
all treatment-related adverse events will be conducted, and the study review team may decide if treatment 
modification is necessary. If the true proportion of patients with an adverse event within a given system 
organ class or preferred term is 55% or greater, then there is at least 93% probability of exceeding the 
observed adverse event boundary at interim. Conversely, if the true proportion of patients with an adverse 
event within a given system organ class or preferred term is 35% or less, then there is only 25% 
probability of crossing the toxicity boundary at interim. The above decision boundary (45% or more 
observed events) will be followed for all Grade 3 or higher, treatment-related events within each system 
organ class and preferred term. 
The expected overall toxicity rate, considering all Grade 3 or higher, treatment-related adverse events 
across all MedDRA system organ classes and preferred terms, is approximately 40%. If proportion of 
patients who experienced any Grade 3 or higher, treatment-related adverse event is higher than 50% (14 
or more out of 28 patients), a detailed review of all treatment-related adverse events will be conducted, 
and the study review team may decide if treatment modification is necessary.  If the true proportion of 
patients with any such event is 60% or higher, then there is at least 90% probability of exceeding the 
observed boundary at interim.  Conversely, if the true proportion is 40%, then there is only a 19% chance 
of crossing the toxicity boundary at interim.  This decision boundary will be followed for the overall 
incidence of any Grade 3 or higher, treatment-related adverse event. 
4.5.   Multi-center Studies 
This study will be conducted at a multiple study sites; however, no statistical adjustments or stratification 
is deemed necessary for site effects. 
4.6.   Multiple Comparisons / Multiplicity 
No statistical adjustments will be made for multiplicity considerations.  This study has a single primary 
objective which is tested via a single hypothesis test.  The formal, detailed toxicity evaluation at interim 
will consist of applying decision rules to three categories of adverse events.  No adjustment for 


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multiplicity will be made; the evaluation is intentionally conservative.  The three categories of adverse 
events being evaluated are subsets of one another, which reduces the need for multiplicity adjustments.  
4.7.   Analysis Populations 
This section is designed to identify the characteristics that are necessary for inclusion in particular 
populations defined for the purpose of analysis.  All analyses described in this document will be executed 
on the Intent-to-Treat Population, Safety Population, or Modified Intent-to-Treat (mITT) Population. 
4.7.1.   Intent-to-Treat Population 
The ITT Population will consist of all enrolled subjects.  Kaplan-Meier curves for the secondary enpoints 
of progression-free survival and overall survival will be created on the ITT population.  
4.7.2.   Safety Population 
The Safety Population is defined as all subjects who received at least one dose of any study treatment – 
venetoclax, bendamustine, or obinutuzumab.  All summaries and analyses of safety data, including dose 
compliance and toxicity, will be completed using the Safety Population.   
4.7.3.   Modified Intent-to-Treat (mITT) Population 
The mITT Population will consist of all subjects in the Safety Population who met all study eligibility 
criteria.  All efficacy endpoints (primary and secondary) will be evaluated on the mITT population. 
5.   STUDY POPULATION CHARACTERISTICS 
5.1.   Subject Accountability and Subject Disposition 
The number of subjects registered, included in each analysis population, completing the study, and 
discontinuing treatment will be tabulated (Table 14.1.1).  Subjects discontinuing treatment will be 
categorized by reason for discontinuation.   
5.2.   Demographics and Baseline Characteristics 
Demographic data (age, sex, and race) and screening characteristics (WHO tumor grade, FLIPI-1 and 
FLIPI-2 scores, number of GELF criteria met, ECOG performance status, presence/absence of bone 
marrow involvement, lymph node and metastasis staging, and Ann Arbor staging – including 
presence/absence of B symptoms) for all subjects will be listed (Listing 16.2.4).  These data, in addition 
to ethnicity, height, weight, body surface area, and the proportion of subjects meeting each individual 
FLIPI-1, FLIPI-2 and GELF criterion at screening, will be summarized for the ITT Population, Safety 
Population, and mITT Population (Table 14.1.2).  Descriptive statistics (mean, standard deviation, 
median, minimum, and maximum for numerical variables, count and percentage for categorical variables) 
will be presented where applicable. 


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6.   SAFETY ANALYSIS 
The post-baseline safety assessments in this study include adverse event assessments, dose compliance, 
and hematology and chemistry laboratory testing.  All safety data listings will be sorted by site and 
subject number.   
All summary statistics for safety data will be subset to the Safety Population.  If any pre-baseline safety 
data are repeated for a given visit time point, the measurement taken closest to the first study treatment 
dosing will be used in the analysis.  Baseline will be defined as the last non-missing result, including 
results from repeated measurements, before the first study dosing.  If there are repeated measurements at a 
time point after the first study treatment dosing, the earliest assessment at that time point will be used in 
the summary tables.  
6.1.   Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as events which were not present at baseline or 
worsened in severity following the subject’s first dosing with study treatment.  Where the start date of an 
adverse event is missing or ambiguous, the event will be assumed to be treatment-emergent.  Similarly, 
treatment-emergent adverse events for which the relationship to any one of the study treatments was not 
collected, the event will be assumed to be treatment-related for inclusion in listings and tables of 
treatment-related adverse events.  Nevertheless, the start and end dates of adverse events and their 
relationships to study treatments will still be listed as collected.    
The number of subjects who experience TEAEs will be summarized.  This summary will also be 
subdivided in the same table by seriousness, CTCAE v5.0 toxicity grade, outcome, relation to each of the 
three study medications, and whether or not the event necessitated a dose modification (i.e., a reduction in 
dose, delay or interruption in dosing, or withdrawal of one or more study treatments), study 
discontinuation, or fits the “special interest” category defined in the study protocol (Table 14.3.1.1). 
Treatment-related AEs with CTCAE v5.0 toxicity grade of three or greater will be summarized by system 
organ class and preferred term using MedDRA version 20.1 (Table 14.3.1.2).  An event will be 
considered to be treatment-related if it is assessed by the investigator as related, probably related, or 
possibly related to any of the three study treatments.  The table will summarize the number of subjects 
who experience such events, ordering the system organ classes, and preferred terms within each system 
organ class, by descending incidence rate.  A subject will be counted at most once for each preferred term 
and once for each system organ class, regardless of the number of relevant TEAEs experienced for a 
given category.  The table will also include a 90% Clopper-Pearson exact binomial confidence interval for 
the observed incidence rate of each system organ class and preferred term, and also for the overall total 
incidence rate across all system organ classes and preferred terms.  The set of all treatment-related AEs 
with toxicity grade of three or greater also will be listed by subject (Listing 16.2.7).  The listing will all 
include MedDRA (version 20.1) system organ class and preferred term, the date and time of the start and 
end of the event, the AE duration in days, relationship to and action taken with each of the three study 
treatments, event outcome, toxicity grade, any criteria met for classification as a serious adverse event, 
and whether or not the event meets the “special interest” criteria defined in the protocol.  This table and 
listing are designed to be used at the interim toxicity evaluation after 28 subjects have been enrolled and 
each either have completed three cycles of induction therapy or discontinued study treatment.   
Separate tables will be used to count by system organ class and preferred term subjects who experience 
treatment-emergent AEs with toxicity grade of three or greater, regardless of relationship to the study 


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treatments (Table 14.3.1.3), and treatment-emergent adverse events of special interest (Table 14.3.1.4).  
These tables, too, will summarize the number of subjects who experience such events, ordering the 
system organ classes, and preferred terms within each system organ class, by descending incidence rate.   
6.2.   Study Drug Administration and Dose Compliance 
The number of induction cycles in which any of the three study treatments were administered will be 
tabulated by counts of subjects and associated percentages (Table 14.3.5).  The number of subjects who 
experienced dose reductions will also be summarized by treatment and phase (induction vs. maintenance) 
with counts and percentages based on the number of subjects who received at least one dose of the given 
treatment during the given phase.  The number of scheduled venetoclax dosings missed per cycle will be 
summarized with descriptive statistics (n, mean, standard deviation, median, minimum, maximum) by 
study phase.  Also to be summarized with descriptive statistics is the cumulative dose of obinutuzumab 
and bendamustine by study phase and the duration of all-treatment exposure in the maintenance phase. 
6.3.   Clinical Laboratory Data 
Shift tables presenting toxicity grade changes from baseline for hematology (Table 14.3.6.1) and 
chemistry (Table 14.3.6.2) laboratory results will be created.  For each laboratory test, the shift tables will 
tabulate subjects by their toxicity grade, or lack thereof, at baseline, and their worst toxicity grade 
observed at any post-baseline assessment during either treatment phase.  Baseline is defined as the latest 
non-missing result prior to the first study dosing with venetoclax, obinutuzumab, or bendamustine. 
7.   EFFICACY ANALYSIS 
The efficacy analyses are designed to evaluate CR rates according to the Cheson criteria during both 
treatment phases of this study and to evaluate survival and progression of disease during both this study 
and the subsequent two-year follow-up period.  All efficacy endpoints are evaluated for either the Intent-
to-Treat (ITT) or Modified Intent-to-Treat (mITT) Population.   
7.1.   Primary and Secondary Efficacy Endpoint Analyses 
The primary endpoint in this study is the proportion of treated subjects who achieve a complete 
response (CR) at any disease response assessment during the induction phase.  This proportion will be 
computed for the mITT Population and presented along with the Clopper-Pearson exact 90% confidence 
interval of the proportion, expressed as a percent (Table 14.2.1).  The same table will show the proportion 
of subjects in the mITT Population whose best overall disease response during induction treatment phase 
is a partial response (PR), stable disease (SD), and progressive disease (PD), and unevaluable (Un).  The 
disease response option of ‘unevaluable (Un)’ is not a collected value on the CRF, but will be used in 
analysis for subjects who do not have a valid disease response assessment during the induction phase for 
any reason, including termination of study treatment prior to a subject’s first on-treatment disease 
response assessment during the induction phase.  One of the secondary endpoints of the study is the 
proportion of treated subjects whose best overall response during induction phase was a partial response 
and who then later achieved a complete response at any re-staging assessment after the start of the 
maintenance phase.  This proportion will be computed for the mITT Population along with the 90% 
Clopper-Pearson exact confidence interval for the proportion, expressed as a percent, and will be included 
in Table 14.2.1.  A listing of the best overall response during induction and the best overall response 
during maintenance by subject also will be generated for the mITT Population to support evaluation of 
this secondary endpoint (Table 14.2.2). 


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Another secondary endpoint of the study is the Objective Response Rate across both induction and 
maintenance treatment phases.  Objective Response Rate is defined as the proportion of treated subjects 
who achieved a partial response (PR) or complete response (CR) at any disease response assessment over 
the course of the study – both treatment phases considered together.  The Objective Response Rate will be 
computed for the mITT Population and will be presented along with the 90% Clopper-Pearson exact 
confidence interval of the proportion expressed as a percent (Table 14.2.3).  The table will also present 
the best overall disease response, i.e., CR, PR, SD, PD, or Un, across all induction and maintenance phase 
assessments and a summary of the duration of objective response in months among the subjects who 
attained a PR or CR in either treatment phase.  The summary of objective response duration will use 
descriptive statistics (n, mean, standard deviation, median, minimum, and maximum). 
The secondary endpoints of progression-free survival (PFS) and overall survival (OS) will be modeled 
using the Kaplan-Meier product-limit method.  Progression-free survival represents the time from the 
subject’s enrollment in the study until either death or disease progression, whichever occurs first.  
Censoring for progression-free survival occurs at the date that disease response was last adequately 
assessed as a part of study procedures.  Overall survival represents the time from the subject’s enrollment 
in the study until death from any cause.  Censoring for overall survival occurs at the date of last contact 
with the subject as a part of on-treatment procedures or follow-up assessments.  The number and percent 
of subjects who experience the corresponding events for PFS and OS and the number of subjects censored 
for each endpoint will be summarized along with the Kaplan-Meier median survival times and 
corresponding 90% confidence intervals (Table 14.2.4).  The 90% confidence intervals will be computed 
using Greenwood’s formula.  The Kaplan-Meier survival curves for progression-free survival and overall 
survival will be presented on the mITT Population in Figures 14.2.7 and 14.2.9, respectively, and on the 
ITT Population in Figure 14.2.8 and Figure 14.2.10, respectively. 
The assessment results for disease response (Listing 16.2.6.1) and target lesion size (Listing 16.2.6.2) will 
be listed by site, subject, visit, time point, and date of assessment.  The listing of target lesion assessments 
will have one row per target lesion and will indicate the length of the tumor in its two longest 
perpendicular dimensions and also the product of these two perpendicular measurements.   
The target lesion, non-target lesion, and overall disease responses (CR, PR, SD, PD, or Unevaluable) will 
be summarized on the mITT Population in Table 14.2.5 for each induction phase assessment along with 
the best target, non-target, and overall response observed during induction, maintenance, and induction 
and maintenance considered in aggregate.  The best target lesion response is also shown graphically in 
Figure 14.2.6.  The figure represents each subject’s maximum percent decrease in the sum over all target 
lesions of the product of each lesion’s two largest perpendicular diameters (SPD) as a vertical bar in a 
waterfall plot.  The bars will be colored according to the subject’s best overall disease response over both 
treatment phases.  Three colors will be used to distinguish complete responses (CR) from partial 
responses (PR) and stable or progressive disease (SD/PD). 
8.   SUMMARY OF CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
There are no changes to the planned primary and secondary endpoint analyses described in version 4.0 of 
the clinical trial protocol dated January 23, 2018.   
9.   REPORTING CONVENTIONS  
The mean and median will be displayed to one decimal place greater than the original value, and the 
standard deviation will be displayed to two decimal places greater than the original value. All statistical 


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programming and analyses will be performed using SAS® Release 9.2 or later (SAS Institute Inc., Cary, 
North Carolina, USA). 
The following standards will be used in the data presentation: 
• 
The filenames for each individual listing, table, or figure will include both the unique number 
assigned to the particular listing, table or figure in the accompanying mock TLF document and a brief 
description of the contents of the output (i.e., a shortened form of the title). 
• 
Percentages presented in in-text tables should be rounded to one decimal using the SAS rounding 
function. If “%” is part of the column heading, do not repeat the “%” sign in the body of the table. 
Unless specified otherwise, “%” should reflect the total population of the treatment group groups. 
Any deviation from that should be part of the footnote. For 0 counts, the corresponding percentage 
should be left blank, as should 0/0. 
• 
SD should be the default for representing scale, unless standard error has been specified. Standard 
deviation should be abbreviated as “SD”, and presented below the mean value. The SD should have 
one additional decimal place beyond that of the mean (e.g., mean has one decimal place, SD should 
have two). 
• 
If the table or listing is too long to display on one page, the additional (treatment group) columns will 
be continued on the following pages. 
• 
“N” will represent the entire treatment group for the population being analyzed, while “n” will 
represent a subset of “N”. For tables with population designated as a row heading, “N” should be used 
(i.e., tables where all participant data is not available for every variable within a treatment/memory 
status group). As a guideline, if the number is used in a denominator, it should be presented as “N”. If 
the number is used in the numerator, it should be presented as an “n”. 
• 
The heading should consist of four lines. Line 1: Sponsor identifier. Line 2: Protocol identifier. Line 
3: blank line. Line 4: Table/Appendix number Table Title – Population. The title for in-text tables 
should begin with the Table/Appendix number. The footer will include a line noting whether the 
table, listing, or figure is draft or final and blinded or unblinded (i.e., ‘Unblinded Draft’, ‘Blinded 
Final’, etc.).  
• 
All data listings will be sorted by site, subject number, visit, and date/time (as applicable). 
• 
All tables will be summarized for all subjects in aggregate and by phase and cycle where relevant. 
• 
The date format for all dates is DDMMMYYYY.  
• 
If no data are collected for use in the tables and listings, then a table and/or listing will be created 
stating that no data are available. 
• 
A solid line should appear both above and below the column headings of a table. A solid line should 
appear at the end of the table or at the bottom of each page if the table extends to more than one page. 
Footnotes should start after the bottom solid line. 
 


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10.   REFERENCES 
1. SAS Institute, Inc., SAS® Version 9.2 software, Cary, NC. 
2. ICH Guidance for Industry: E9 Statistical Principles for Clinical Trials, 1998. 
3. ICH Guidance for Industry: E3 Structure and Contents for Clinical Study Report, 1996.


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APPENDIX 1.  STUDY PROCEDURES AND ASSESSMENTS 
 
 


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* Scheduled Visits: The cycle length may be altered to -2 days or to +3 days for holidays or other extenuating scheduling situations.  
 
1. 
Record the GELF, FLIPI-1 (Appendix VII) and FLIPI-2 criteria (Appendix VIII).  
2. 
CBC with differential and platelet count which includes WBC, ANC, Platelets, Hgb, and Hct. Required prior to each dose of chemotherapy (days 1, 2, 8 
and 15 of cycle 1 and day 1 of cycle 2 and subsequent cycles), and results known prior to treatment administration.  
3. 
Albumin, BUN/creatinine, uric acid, sodium, potassium, chloride, glucose, calcium, alkaline phosphatase, AST, ALT, total bilirubin, LDH and total protein.  
4. 
Hepatitis B (HBV), Hepatitis B surface antigen (HBsAg), and Hepatitis C (HCV) testing within 6 weeks of registration. Patients who are chronic carriers of 
HBV with positive HBsAg+ and positive HCV serology are excluded. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B 
core antibody [anti-HBc] and absence of HBsAg) may be included if HBV DNA is undetectable. If enrolled, patients must be willing to undergo monthly 
HBV DNA testing. Patients with positive HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study 
participation.  
5. 
Obtain quantitative immunoglobulins at end of induction and every 6 months during maintenance therapy.  
6. 
Required for females of childbearing potential within 2 weeks of registration.  
7. 
Labs for tumor lysis: Cycle 1, day 1- add phosphorus to above chemistries. Cycle 1, day 2- BUN/creatinine, uric acid, sodium, potassium, chloride, 
glucose, calcium, phosphorus and LDH need to be obtained on all patients. Patients who are at high risk of tumor lysis (e.g., any lymph mass ≥ 10 cm on 
the screening CT scan, Absolute Lymphocyte Count (ALC) >25 x 109; Section 6.3.2 Prophylaxis and Guidelines for Hospitalization due to TLS Risk for 
additional details) or as determined by the treating physician may be admitted to the hospital to be monitored for tumor lysis. Patients at high-risk for TLS 
will start venetoclax on Cycle 1, day 8 (daily for 7 days total). Information on prophylaxis for TLS and/or if patients experiences tumor lysis refer to Section 
6.3.2 and Appendix V.  
NOTE: On Cycle 1, Day 8 for high risk TLS patients, vital signs will be measured and serum chemistry and hematology samples will be drawn before 
venetoclax dosing, and at 8, 12 and 24 hours post dose (8, 12 and 24 hour blood samples are mandated only if patient is hospitalized). These 
samples are to be sent immediately to the laboratory and the investigator or designee must review the results promptly. Laboratory values 
obtained before the dose of venetoclax are to be used to determine whether a patient developed a change related to TLS. Laboratory results of 
the 24-hour post dose must be reviewed before receiving the dose of venetoclax for that day  
8. 
PET/CTs are the preferred imaging modality. Notably however, once a patient enters complete remission, then only CT’s (chest/abdomen/pelvis) should 
be obtained (not both PET/CT and dedicated CTs) except as noted in footnote #9 below. MRI exams of the chest/abdomen/pelvis may be performed, if 
CTs of the chest/abdomen/pelvis cannot be obtained.  
9. 
PET/CT to be obtained after cycle 6 (not required after cycle 3). CT of the chest/abdomen/pelvis will suffice at interim restaging i.e., after cycle 3.  
10. Performed every 6 months or as per standard of care.  
11. Performed after cycle 6. Bone marrow biopsy at the end of induction treatment needs to be obtained only if it was positive prior to initiation of therapy.  
12. Pre-treatment, diagnostic pathology specimens obtained in the course of standard biopsy or surgery (if sufficient tissue is available, submission is 
mandatory): Formalin-Fixed Paraffin-Embedded (FFPE) blocks and 7-10 FFPE slides or if blocks are not available, up to 25 FFPE slides plus H&E slide 
(if tissue is limited, then minimum of 13 slides) will be required. Procurement of tissue will be mandatory for enrollment (submission of tissue is not 
required prior to registration), but if additional tissue from initial biopsy is not available, repeat biopsy will not be required (no biopsy should be performed 
solely for the purposes of obtaining research samples).  
13. Optional: Any tumor biopsy samples obtained during treatment or post-treatment (Formalin-Fixed Paraffin-Embedded (FFPE) blocks or up to 15 FFPE 
slides plus H&E slide) will be requested for research and any leftover tissue (pre-treatment, during treatment or post-treatment) will be banked for future 
research. See Section 13.1 for details. 


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14. Venetoclax will be administered orally as continuous dosing days 1-10 of each 28 day cycle (except for patients with high risk of developing TLS, will start 
venetoclax on day 8 of cycle 1 of therapy for a total of 7 days). On days when venetoclax is given with additional anti-lymphoma agents, venetoclax 
should be given first. Patients will receive obinutuzumab by IV infusion on Cycle 1, days 1, 2, 8, and 15 of 28 day cycle and Cycles 2-6 on day 1 of each 
28 day cycle (1 cycle=28 days). Bendamustine will be administered on days 1, 2 of each cycle. See Section 5 for dosing instructions and Section 6 for 
dose delays/modifications.  
15. The maintenance phase will start no earlier than 8 weeks and no later than 12 weeks following completion of cycle 6, day 28 of induction therapy (patients 
who do not start maintenance therapy by week 12 will be removed from study). During the maintenance phase, patients who are in a complete remission 
will receive obinutuzumab every 2 months for a total of 12 cycles. Patients who are in a PR or stable disease will receive venetoclax and obinutuzumab 
for a total of 24 cycles and 12 cycles, respectively. Patients who receive venetoclax (orally as continuous dosing days 1-28) and obinutuzumab 
(obinutuzumab will be given every 8 weeks) will be seen every month (to dispense venetoclax). On days when venetoclax is given with additional anti-
lymphoma agents, venetoclax should be given first. (Patients on both venetoclax and obinutuzumab who convert to CR, will remain on both venetoclax 
and obinutuzumab for a total of 24 cycles and 12 cycles respectively.)  
NOTE: If venetoclax was dose reduced during the induction phase, the same dose reduction will continue during the maintenance phase.  
16. Adverse events will be captured for 30 days after their last dose of study medication.  
17. Patients who receive obinutuzumab only will be seen every 2 months with indicated exams/testing performed. Patients who receive obinutuzumab and 
venetoclax will be seen every month with indicated exams/testing performed.  
18. Every 6 months for up to 2 years from treatment discontinuation or until study closure. Initiation of first anti-cancer therapy will also be documented. 
NOTE: If patient is removed from treatment for reason(s) other than progression, follow with regular tumor assessments per standard of care until 
progression or start of new treatment.


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DOCUMENT HISTORY 
 
Version Date 
Modified By 
Summary of Changes