Clinical trial NCT03834688
Conditions: Mantle Cell Lymphoma
Keywords: Venetoclax Bendamustine Rituximab Bcl-2 Family Protein Inhibitor
Sponsor: PrECOG, LLC.
Start date: 2020-01-13; Completion date: 2024-07-26
Enrollment: 33 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Eligible untreated patients will receive single arm venetoclax, bendamustine and rituximab as induction therapy. After 6 cycles, maintenance rituximab may be administered per physician discretion.

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 mantle cell lymphoma. Venetoclax may make the cancer cells sensitive to chemotherapy. This may help to slow down the growth of cancer or may cause cancer cells to die.

The purpose of this study is to see if venetoclax in combination with bendamustine and rituximab chemotherapy is effective in treating people who have mantle cell lymphoma and to examine the side effects, good and bad, associated with this combination.

Detailed description:
Mantle cell lymphoma (MCL) is a subtype of Non-Hodgkin Lymphoma (NHL) which is considered incurable with conventional therapy. With an incidence of approximately 70,000 cases diagnosed in the United States (US) per year, the disease is rare.

This is an open-label phase II study of venetoclax in combination with bendamustine and rituximab. Patients will receive induction therapy with venetoclax, bendamustine and rituximab for six cycles (1 cycle = 28 days). There will be an interim analysis after 19 patients are enrolled to evaluate for tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells which can lead to electrolyte and kidney problems.

Tumor assessments will be performed after Cycle 3-4 and at end of induction therapy.

Mandatory pre-treatment tumor tissue sample (i.e., obtained in the course of standard biopsy or surgery) will be required for research (if sufficient tissue is available).

Mandatory bone marrow aspirate (obtained in the course of standard biopsy) and peripheral blood sample will be collected at the end of treatment for Minimal Residual Disease (MRD). MRD measures the disease remaining after treatment. Optional peripheral blood samples will also be collected for future research.

10/11/2021: Due to slower than anticipated enrollment, the study was redesigned to reflect the current historical complete response rate and with a lowered sample size for prompt primary endpoint readout.

Arms: arm 1: Venetoclax, bendamustine and rituximab as induction therapy for 6 cycles of 28 days.
Interventions: intervention 1: Venetoclax intervention 2: Bendamustine intervention 3: Rituximab
Intervention descriptions: intervention 1: Cycle 1: Venetoclax by mouth daily. The dose will gradually increase during Cycle 1. (Day 1-7: 20 mg; Day 8-14: 50 mg; Day 15-21: 100 mg; Day 22-28: 200 mg.)

Cycles 2-6: Venetoclax 400 mg by mouth daily on Days 1-10 (1 cycle = 28 days). intervention 2: Cycle 1-6: Bendamustine 90 mg/m² intravenous (IV) on Days 1 and 2 of each cycle. Bendamustine may be started at 70 mg/m² in patients over the age of 75 years with comorbid conditions or patients over the age of 80 years without comorbid conditions. intervention 3: Cycle 1-6: Rituximab 375 mg/m² IV on Day 1 of each cycle. After 2 consecutive cycles of Rituximab IV are well tolerated, Rituximab may be given subcutaneously.

Protocol documents:
Prot_000.pdf: 
PrECOG Protocol Number: PrE0405 
Date: 10/11/2021 
 
 
 
PrECOG Protocol Number: PrE0405 
Phase II Study of Bendamustine and Rituximab plus 
Venetoclax in Untreated Mantle Cell Lymphoma over 60 Years 
of Age 
 
NCT#: 
NCT03834688 
IND #: 
143290 
Protocol Version Number: 
5.0 
Version Date: 
10/11/2021 
 


PrECOG Protocol Number: PrE0405 
IND Number: 143290 
Confidential 
Date: 10/11/2021 
 
 
 
PrECOG Protocol Number: PrE0405 
Phase II Study of Bendamustine and Rituximab plus 
Venetoclax in Untreated Mantle Cell Lymphoma over 60 Years 
of Age 
STUDY CHAIR: Craig A. Portell, MD 
STUDY CO-CHAIR: 
 
: 
 
STATISTICIAN: 
 
PRECOG STUDY SITE CONTACT: 
 
MEDICAL MONITOR: 
 
(Internal Use Only) Genentech US Ref. ID Number: ML40551 
 
 
IND #: 
143290 
Version Number: 
5.0 
Version Date: 
October 11, 2021 
 
 
Release/Revision History 
Version 1.0: 4/9/2019 
Released to Sites 
Version 2.0: 8/30/2019 
Released to Sites 
Version 3.0: 1/29/2020 
Released to Sites 
Version 4.0: 11/9/2020 
Released to Sites 
Version 5.0: 10/11/2021 
Released to Sites 
 
This protocol contains information that is confidential and proprietary 


PrECOG Protocol Number: PrE0405 
IND Number: 143290 
Confidential 
Date: 10/11/2021 
 
2 
Table of Contents 
List of Abbreviations ....................................................................................................................................6 
1. 
Introduction- Background and Rationale ...........................................................................................9 
1.1 
Mantle Cell Lymphoma – Disease Overview ................................................................................9 
1.2 
Induction Therapy in MCL .............................................................................................................9 
1.3 
Pending Studies with Bendamustine and Rituximab in MCL ..................................................... 10 
1.4 
Venetoclax (ABT-199, GDC-0199) ............................................................................................ 10 
1.5 
MRD Monitoring in MCL ............................................................................................................. 11 
1.6 
Summary of Rationale for Proposed Study ............................................................................... 11 
2. 
Study Objectives ................................................................................................................................ 13 
2.1 
Primary Objective ....................................................................................................................... 13 
2.2 
Secondary Objectives ................................................................................................................ 13 
2.3 
Exploratory Objectives ............................................................................................................... 13 
3. 
Selection of Patients .......................................................................................................................... 14 
4. 
Registration Procedures .................................................................................................................... 17 
4.1 
Ethics ......................................................................................................................................... 17 
4.2 
Regulatory Requirements .......................................................................................................... 17 
4.3 
Patient Registration .................................................................................................................... 17 
4.4 
Research Tissue, Bone Marrow and Blood Samples ................................................................ 17 
5. 
Treatment Plan ................................................................................................................................... 19 
5.1 
Overview .................................................................................................................................... 19 
5.2 
Treatment and Administration Schedule .................................................................................... 20 
5.3 
Tumor Lysis Prophylaxis ............................................................................................................ 21 
5.4 
Tumor Lysis Monitoring .............................................................................................................. 22 
5.5 
Neutropenic Sepsis Prophylaxis ................................................................................................ 23 
5.6 
Infection Prophylaxis .................................................................................................................. 23 
5.7 
Monitoring for Cytomegalovirus (CMV) ...................................................................................... 23 
6. 
Dose Delays & Modifications ............................................................................................................ 25 
6.1 
Dose Modifications ..................................................................................................................... 25 
6.2 
Concurrent Therapies ................................................................................................................ 28 
7. 
Study Duration and Discontinuation of Therapy ............................................................................ 31 
7.1 
Study Duration ........................................................................................................................... 31 
7.2 
Duration of Follow-Up ................................................................................................................ 31 
7.3 
Criteria for Removal from Study Treatment ............................................................................... 31 
8. 
Adverse Event Reporting .................................................................................................................. 33 
8.1 
Collection of Safety Information ................................................................................................. 33 
8.2 
Serious Adverse Events ............................................................................................................. 34 
8.3 
Adverse Events of Special Interest (AESI) ................................................................................ 35 
8.4 
Special Situation Reports........................................................................................................... 36 
8.5 
SAE Reporting Requirements .................................................................................................... 36 
8.6 
Product Complaints .................................................................................................................... 37 
8.7 
Reporting of Other Second Primary Cancers ............................................................................ 38 
8.8 
Procedures in Case of Pregnancy ............................................................................................. 38 
9. 
Measurement of Effect ....................................................................................................................... 39 
9.1 
Response Assessments ............................................................................................................ 39 


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9.2 
Lymphoma Response Criteria (Lugano Classification)32 ........................................................... 39 
9.3 
Minimum Residual Disease (MRD) Measurements ................................................................... 40 
10. Study Treatments, Parameters, and Assessments ........................................................................ 41 
11. Drug Formulation and Procurement ................................................................................................ 46 
11.1 Venetoclax21,22 ........................................................................................................................... 46 
11.2 Bendamustine38 ......................................................................................................................... 49 
11.3 Rituximab39,40 ............................................................................................................................. 51 
12. Statistical Considerations ................................................................................................................. 54 
12.1 Study Design, Sample Size Considerations & Statistical Analyses .......................................... 54 
12.2 Planned Analyses ...................................................................................................................... 54 
13. Laboratory and Pathology Correlative Studies ............................................................................... 57 
13.1 Correlative Studies: Mandatory Tumor Samples (if sufficient tissue available) ......................... 57 
13.2 Correlative Studies: Mandatory Bone Marrow Samples ............................................................ 58 
13.3 Correlative Studies: Mandatory and Optional Peripheral Blood Samples ................................. 59 
13.4 Assay Methodology .................................................................................................................... 61 
14. Administrative .................................................................................................................................... 62 
14.1 Protocol Compliance .................................................................................................................. 62 
14.2 Institutional Review Board ......................................................................................................... 62 
14.3 Informed Consent Procedures ................................................................................................... 62 
14.4 Safety Communication ............................................................................................................... 63 
14.5 Monitoring 63 
14.6 Study Records ........................................................................................................................... 63 
14.7 Electronic Case Report Form (eCRF) Information .................................................................... 64 
14.8 Records Retention ..................................................................................................................... 64 
15. References .......................................................................................................................................... 65 
Appendix I: 
ECOG Performance Status ................................................................................. 68 
Appendix II: 
Calculation of Creatinine Clearance Using the Cockcroft-Gault Formula ..... 69 
Appendix III: 
Additional Excluded and Cautionary Medications ........................................... 70 
Appendix IV: 
Definitions for Tumor Lysis Syndrome31 ........................................................... 72 
Appendix V: 
Revised Criteria for Response Assessment32 ................................................... 73 
Appendix VI: 
Investigator’s Statement ..................................................................................... 76 
 
 
 


PrECOG Protocol Number: PrE0405 
IND Number: 143290 
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Date: 10/11/2021 
 
4 
PrECOG STUDY SITE CONTACT 
MEDICAL MONITOR 
 
Project Manager 
PrECOG, LLC 
1818 Market Street 
Suite 3000 
Philadelphia, PA 19103 
Phone: 215-789-7001 
Email: PrE0405@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: PrE0405SAE@qdservices.com 
 


PrECOG Protocol Number: PrE0405 
IND Number: 143290 
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Date: 10/11/2021 
 
5 
Brief Protocol Synopsis 
See Protocol Document Sections for complete details 
Study Schema 
 
Mantle Cell Lymphoma (MCL) 
 
 
 
INDUCTION1 
 
 
 
 
MAINTENANCE5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accrual goal: 33 patients 
Cycle length: 28 days (4 weeks) 
1 Interim safety analysis planned after 19 patients are enrolled for review of tumor lysis syndrome (TLS) events. Section 
12.2.1 for details. 
2 If the first two cycles of intravenous (IV) rituximab (or two consecutive cycles) are well tolerated, IV rituximab may be 
replaced with 1400 mg/23,400 units subcutaneous (SQ) rituximab/hyaluronic acid on Day 1 of Cycles 3-6 (or after 2 
consecutive cycles are well tolerated). See Section 5.2.3 for details. 
3 Per investigator discretion, bendamustine may be started at 70 mg/m2 in patients over the age of 75 years with 
comorbid conditions or patients over the age of 80 years without comorbid conditions. See Section 5.2.2 for details. 
4 Cycle 1: Goal venetoclax dose will be 400 mg but careful titration and escalation of dose will need to be done during 
Cycle 1 to mitigate the risk of TLS. See Section 5.3 and Section 5.4 for details. 
5 After 6 cycles of venetoclax, bendamustine and rituximab, subjects responding to therapy may receive maintenance 
rituximab (one dose every 8 ± 2 weeks for 12 doses or 24 months whichever comes first) per physician and patient 
preference. 
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 
Rituximab 375 mg/m2 IV day 1 
every 28 days x 6 cycles2 
Bendamustine 90 mg/m2 IV days 
1, 2 every 28 days x 6 cycles3 
Cycle 1: Venetoclax titration to 
200 mg PO daily days 1-284 
Cycle 2-6: Venetoclax 400 mg PO 
daily days 1-10 of each 28 day 
cycle 
Per Investigator 
Discretion 
Rituximab 375 mg/m2 IV or 
SQ every 8 weeks x 12 
doses or 24 months2 
(whichever comes first) 
Progression 
Off Study 


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List of Abbreviations 
5-HT3 
5-Hydroxytryptamine 3 Serotonin Receptor 
5PS 
5 Point Scale 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
anti-HBc or HBcAB 
Hepatitis B Core Antibody 
AST 
Aspartate Aminotransferase 
BCL1 
B-Cell Lymphoma 1 
BCL2 
B-Cell Lymphoma 2 
BR 
Bendamustine Rituximab 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CBC 
Complete Blood Count 
CBPF 
Central Biorepository Pathology Facility 
CLL 
Chronic Lymphocytic Leukemia 
cm 
Centimeter 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CI 
Confidence Interval 
CR 
Complete Response or Complete Remission 
CrCl 
Creatinine Clearance 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapeutic Evaluation Program 
dL 
Deciliter 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
ECOG-ACRIN 
Eastern Cooperative Oncology Group-American College of Radiology 
Imaging Network 
eCRF 
electronic Case Report Form 
eDC 
Electronic Data Capture 
EDTA 
Ethylenediamine Tetraacetic Acid 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FFPE 
Formalin-Fixed Paraffin-Embedded 


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FISH 
Fluorescence In Situ Hybridization 
FR 
Fludarabine and Rituximab 
g 
gram 
GCP 
Good Clinical Practice 
GCSF 
Granulocyte Colony-Stimulating Factor 
GI 
Gastrointestinal 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCO3 
Bicarbonate 
Hct 
Hematocrit 
HCV 
Hepatitis C Virus 
Hgb 
Hemoglobin 
HIPPA 
Health Information Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
hr 
Hour 
HR 
Hazard Ratio 
HSV 
Herpes Simplex Virus 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
LDH 
Lactate Dehydrogenase 
LDi 
Longest Transverse Diameter of a Lesion 
m 
Meter 
m2 
Meter Squared 
mcg 
Microgram 
MCL 
Mantle Cell Lymphoma 
mg 
Milligram 
min 
Minute 
MIPI 
MCL International Prognostic Index 
mL 
Milliliter 
mm 
Millimeter 
mm3 
Cubic Millimeter 
mmol 
Millimole 
MRD 
Minimal Residual Disease 
MRI 
Magnetic Resonance Imaging 
n 
number 


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NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NGS 
Next Generation Sequencing 
NHL 
Non-Hodgkin Lymphoma 
OBI 
On Body Injector 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PCR 
Polymerase-Chain Reaction 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PJP 
Pneumocystis Jiroveci Pneumonia 
PO 
per os; By Mouth (orally) 
PPD 
Cross Product of the LDi and Perpendicular Diameter 
PR 
Partial Response or Partial Remission 
PS 
Performance Status 
R-BAC 
Rituximab-Bendamustine Cytarabine 
RCHOP 
Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone  
RPM 
Revolutions Per Minute 
R/R 
Relapsed/Refractory 
SAE 
Serious Adverse Event 
SCT 
Stem Cell Transplant 
SD 
Stable Disease 
SDi 
Shortest Axis Perpendicular to the LDi 
SPD 
Sum of the Product of the Perpendicular Diameters of Multiple Lesions 
SQ 
Subcutaneous 
SRM 
Study Reference Manual 
TLS 
Tumor Lysis Syndrome 
ULN 
Upper Limit of Normal 
μmol 
Micromole 
US 
United States 
vs 
versus 
WBC 
White Blood Cell 
WOCBP 
Women of Childbearing Potential 
wt 
Weight 


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1. 
Introduction- Background and Rationale 
1.1 
Mantle Cell Lymphoma – Disease Overview 
Mantle cell lymphoma (MCL) is a subtype of Non-Hodgkin Lymphoma (NHL) which is 
considered incurable with conventional therapy. With an incidence of approximately 70,000 
cases diagnosed in the United States (US) per year, the disease is rare. It typically occurs 
in patients over the age of 60 and 2/3rd of the cases are male.1 
There are three variants of MCL that have different clinical and treatment implications. First 
is considered the typical form of MCL, occurring in 60-75% of cases. This form typically 
presents with symptomatic disease with lymphadenopathy and occasionally cytopenias. 
The second is an indolent form typically presenting with an elevated white blood cell (WBC) 
count and circulating lymphoma cells as well as splenomegaly. This indolent form is 
characterized by an often-slow course and observation alone is recommended if 
asymptomatic.2 The final form is a blastic variety which is typically quite aggressive, often 
presenting with marked lymphadenopathy and B-symptoms including fevers, chills, sweats, 
and/or weight loss. Other than observation in the indolent variety, there is no treatment 
differences between the variants of MCL. 
1.2 
Induction Therapy in MCL 
Initial treatment in MCL includes a combination of chemotherapy and immunotherapy. For 
patients who can tolerate such an approach, an aggressive chemo-immunotherapy regimen 
is utilized to achieve remission. This typically is followed by high dose chemotherapy with 
autologous stem cell rescue. This approach is too toxic for the majority of patients 
presenting with MCL given the advanced age at diagnosis. Other approaches have been 
studied with bendamustine and rituximab (BR) currently considered a standard induction 
regimen for patients unwilling or ineligible for aggressive therapy. 
BR was first studied by the German cooperative group study evaluating RCHOP (rituximab, 
cyclophosphamide, doxorubicin, vincristine and prednisone) vs. BR in indolent NHL. The 
MCL cohort included 94 patients and BR had an improved median progression-free survival 
(PFS) over RCHOP (35.4 vs 22.1 months, Hazard Ratio (HR) 0.49, p=0.0044).3 Superiority 
of BR over RCHOP was also confirmed in the US through the BRIGHT study.4 Another 
study through the German cooperative group compared FR (fludarabine and rituximab) to 
BR in indolent NHL. The MCL cohort in this study was 47 patients and again showed 
improved median PFS to BR over FR (17.6 vs. 4.7 months, p=0.01).5 These studies support 
BR as the standard of care for MCL patients unable to be treated with aggressive measures. 
Bendamustine and rituximab is generally well tolerated in this patient population. The only 
elderly MCL study assessing BR showed a Serious Adverse Event (SAE) rate of 2/63 during 
induction; however, there were deaths during the maintenance phase of this study (3 of 
62).6 Other studies, which include other NHL histologies, show a similar rate of SAE or 
Grade 3/4 non-hematologic toxicities that occasionally prompts withdrawal prior to 
completion of recommended 6 cycles.3,4,5 Deaths during induction are rare. However, in a 
retrospective study of CLL patients, dose reductions to 70 mg/m2 occurred in half of patients 
over the age of 65, mostly due to neutropenia and infections.7 Of those over the age of 75, 
69% of patients required dose reduction to 70 mg/m2. 7 This has prompted some providers 
to start all patients of very advanced age (over 80) and others with comorbid conditions at 
70 mg/m2 instead of 90 mg/m2 day 1 and 2. 
Maintenance rituximab is more controversial in MCL. Most providers extend maintenance 
rituximab after chemo-immunotherapy induction to MCL patients as it has been shown to 
be superior to observation alone in other histologies of NHL.8 However, the German group 
evaluated maintenance rituximab vs. observation after BR induction in MCL. They found no 
statistical benefit to maintenance rituximab and a suggestion of increased toxicity.9 
However, this study was small and the report was early and only presented in abstract form. 


PrECOG Protocol Number: PrE0405 
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In a conflicting study, a meta-analysis showed superiority of maintenance rituximab in 
MCL.10 At this time, a consensus on this has not been reached. 
1.3 
Pending Studies with Bendamustine and Rituximab in MCL 
Many groups have added agents active in relapsed MCL to BR with the goal of inducing 
deeper remissions and prolonging the interval of treatments. The E1411 intergroup study, 
which recently finished accrual, evaluated BR with or without bortezomib.11 The industry-
sponsored SHINE study, which also recently finished accrual, evaluated BR with or without 
ibrutinib.12 The Nordic LENA-BERIT study evaluated BR with the addition of lenalidomide,13 
and the Italian R-BAC studies have evaluated BR with different doses of cytarabine.14 The 
results of the induction portion of these studies, which are expected within 2 years, will set 
the stage for a Phase III study comparing the most promising BR based regimens. However, 
there are other promising therapies, including venetoclax that will likely be important in MCL 
within this two year time frame. This study evaluates venetoclax in combination with 
bendamustine and rituximab. If there is promise in this study, this combination will be 
considered in a larger Phase III study for induction therapy in MCL planned through the US 
cooperative groups. 
Safety in the reported combination studies with BR indicate increased toxicity with additional 
drugs. The LENA-BERIT (BR+ Lenalidomide) study mentioned previously had a Grade 3-5 
infection rate of 42% (21 of 51) with a death rate during induction of 3 of 51. This was 
considered overly toxic, though the efficacy was high in this study.13 The addition of 
bortezomib and dexamethasone to BR (RiBVD) in 76 older MCL patients showed 4 deaths 
during induction; 1 infection, 1 progressive multifocal leukoencephalopathy (PML) and 2 
cardiac arrests.14 The rate of febrile neutropenia on this study was 11% (11 of 74) and 24 
episodes of infection were identified as SAEs.14 Therefore, there is a suggestion that studies 
combining novel agents with BR show more toxicity than BR alone and should be evaluated 
closely for toxicity including deaths and infection. It is known that bendamustine can cause 
delayed lymphocyte recovery and thus atypical infections, such as Pneumocystis Jiroveci 
Pneumonia (PJP), Cytomegalovirus (CMV) and Herpes Simplex Virus (HSV) are possible 
and have been reported and seen by investigators.15,16,17 
1.4 
Venetoclax (ABT-199, GDC-0199) 
Venetoclax is a novel, oral, highly selective BCL2 inhibitor which is currently Food and Drug 
Administration (FDA) approved in relapsed chronic lymphocytic leukemia (CLL).18 Inhibition 
of BCL2, an anti-apoptotic protein that is overexpressed in many NHL’s, allows for apoptosis 
to proceed and induces rapid cell kill.19 Venetoclax has been studied in various NHL 
histologies as a single agent and in combination with chemotherapy and other targeted 
agents. 
1.4.1 
Clinical Efficacy and Safety in MCL and NHL 
Response to single-agent venetoclax has been documented in 28 relapsed MCL 
patients in a Phase I study evaluating all histologies of NHL. The MCL cohort had 
an overall response rate (ORR) of 75% (n=21) with few complete responses (CRs) 
(n=6, 21%).20 Given the risk of TLS, the dose of venetoclax was increased from 20 
mg to the target dose over several weeks. The ending dose was 200 mg (n=1), 400 
mg (n=9), 600 mg (n=4), 800 mg (n=7), 900 mg (n=1) and 1200 mg (n=6). There 
was no difference in efficacy between these doses and the target dose going 
forward for MCL is 400 mg orally (PO) daily. Additional studies evaluating 
combinations of venetoclax with chemotherapy and other targeted agents are on-
going. 
Venetoclax is generally safe though the majority of patients will experience a 
treatment emergent adverse event. Common side effects in NHL are mostly 
hematologic including neutropenia (Grade 3 or 4: 14.8%), febrile neutropenia 


PrECOG Protocol Number: PrE0405 
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(Grade 3 or 4: 2.2%), thrombocytopenia (Grade 3 or 4: 9.6%), and anemia (Grade 
3 or 4: 14.8%). Gastrointestinal (GI) toxicities including nausea and diarrhea are 
also common but tend to be low grade (all grade 47%, Grade 3 or 4 <1%). 
Infections, mostly being upper respiratory can also be seen with venetoclax. Please 
see the Investigator Brochure (IB) and prescribing information for more detail.21,22 
1.4.2 
Venetoclax Clinical Pharmacology21 
Venetoclax is dosed daily with good bioavailability. In NHL, plasma concentrations 
peaked at approximately 4-8 hours after doses between 50 and 400 mg daily and 
had a half-life of 14.1 to 18.2 hours. Absorption is improved with a meal or snack. 
Venetoclax and its metabolites are metabolized by CYP34A and is excreted through 
the bile duct and feces. There is minimal renal excretion. A Phase I study evaluating 
venetoclax with bendamustine did not suggest a change in pharmacokinetics with 
bendamustine administration. 
1.4.3 
Dose Rationale 
Preclinical studies have evaluated venetoclax as a chemotherapy sensitizer, 
suggesting that venetoclax can sensitize cancer cells to chemotherapy.23,24,25 An 
interim analysis of a clinical trial in follicular lymphoma has demonstrated that BR 
plus venetoclax is tolerable and active, though more Grade 3-4 events occurred in 
the venetoclax containing arm.26 The activity of venetoclax in MCL combined with 
the preclinical rationale and the safety data in follicular lymphoma suggest that a 
Phase II study of BR + venetoclax is warranted in MCL. Dosing with chemotherapy 
has not been optimized. The follicular lymphoma study utilized continuous dosing 
of venetoclax with BR and demonstrated a Grade 3-4 Adverse Event (AE) rate of 
78% compared to 46% without venetoclax.24 We hypothesize that intermittent 
dosing of venetoclax will still improve efficacy over BR alone but will be better 
tolerated. 
Venetoclax can induce clinically significant TLS in CLL with the first dose of drug.19 
The risk of TLS necessitates careful dose titration of the drug and sometimes 
admission for hydration and TLS monitoring. Tumor lysis has also been seen in 
MCL, but to a lesser degree and usually in the setting of high tumor burden (verbal 
communication, unpublished data). Thus, in MCL, careful upward dose titration is 
still needed. In this study, we will start with 20 mg of venetoclax and increase the 
dose weekly to a maximum dose of 400 mg by Cycle 2, Day 1. 
1.5 
MRD Monitoring in MCL 
The absence of Minimal Residual Disease (MRD) is a powerful predictor of outcome after 
induction in MCL. MRD can be measured in many ways but the most sensitive is a 
polymerase-chain reaction (PCR) based test quantifying the presence of a clonal 
immunoglobulin heavy chain re-arrangement or t(11;14).27,28 A combined analysis of 
transplant eligible and ineligible patients (MCL Younger and MCL Elderly studies) showed 
MRD positive patients consistently had an adverse PFS after all induction treatment 
(chemotherapy in MCL Elderly and chemotherapy followed by autologous stem cell 
transplant (SCT) in MCL Younger).29 Patients in clinical remission after induction also have 
a survival advantage if there is no MRD detected at that time.29 Thus, MRD is a quick, 
meaningful surrogate of PFS and overall survival (OS) after induction therapy in MCL 
patients. 
1.6 
Summary of Rationale for Proposed Study 
To summarize, there are several pending studies combining various agents with what is 
considered a standard therapy, bendamustine and rituximab, in MCL patients ineligible for 
aggressive therapy. This study seeks to add venetoclax, a promising single agent in MCL, 
to BR with plans to add this regimen, if promising, to a larger Phase III study of various BR 


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12 
combinations in MCL. 
Given the risk of TLS in MCL, venetoclax dose will be escalated through Cycle 1 with close 
monitoring of TLS. The monotherapy dose of venetoclax moving forward in MCL is 400 mg 
daily and there is no suggestion that combination with BR will change the pharmacokinetics 
of venetoclax. Thus, the maximum dose of 400 mg PO daily will be used from Cycle 2 
onward. Given toxicity seen in the follicular lymphoma study combining BR with continuous 
venetoclax, we will utilize venetoclax as a chemosensitizer and only treat for 10 days with 
each cycle. Maintenance rituximab will be allowed per investigator discretion given the 
complexity of the issue in MCL after BR therapy. 
We plan to utilize a CR rate of 70% as a historical control based on early evaluation of the 
induction therapy of E1411.29 To be considered promising, we hope to improve this by 15% 
to 85%. CR is our primary outcome to allow for a quick readout and allow for potential 
inclusion in a future randomized study. We will also monitor MRD via PCR based methods 
throughout the study as an exploratory objective. 
1.6.1 
October 11, 2021: Revised Summary of Rationale 
Preliminary data from a similar cohort of patients as that enrolled in this study 
indicates that post-induction CR rate is 60%, not 70% as initially assumed. In 
addition, the observed study accrual rate (1.1 patients/month) is significantly lower 
than the planned/expected study accrual rate of 2.3 patients/month. For both 
reasons, the study was redesigned to reflect the current historical CR rate and with 
a lowered sample size for prompt primary endpoint readout. Accrual before this 
redesign is 25 patients. 
A 17% increase in CR rate from 60% (null) to 77% (alternate) is of interest. 


PrECOG Protocol Number: PrE0405 
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2. 
Study Objectives 
2.1 
Primary Objective 
To determine the CR rate of BR + venetoclax in untreated MCL patients over the age of 60 
years. 
2.2 
Secondary Objectives 
● 
Evaluate the safety of the combination, with particular attention to TLS incidence with 
Cycle 1. 
● 
To determine the overall response rate (complete response [CR] + partial response 
[PR]) of BR + venetoclax in untreated MCL patients over the age of 60 years. 
● 
To determine the survival (progression-free survival [PFS] and overall survival [OS]) of 
MCL patients treated with BR + venetoclax induction. 
2.3 
Exploratory Objectives 
• 
Bone marrow aspirate and peripheral blood assessed minimal residual disease (MRD) 
negative rate of BR + venetoclax in untreated MCL patients over the age of 60 years. 
• 
Evaluate the utility of morphologic assessment of bone marrow biopsy and aspiration 
when combined with peripheral blood MRD and PET assessments on CR rate at end 
of treatment. 


PrECOG Protocol Number: PrE0405 
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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: PrECOG does not allow waivers to any protocol specified criteria. All eligibility criteria listed 
in Section 3 must be met, without exception. All questions regarding clarification of eligibility 
criteria must be directed to the Medical Monitor or PrECOG Study 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 
Patients must have histologically confirmed (biopsy-proven) diagnosis of mantle cell 
lymphoma (MCL), with documented cyclin D1 (BCL1) expression by immunohistochemical 
stains and/or t(11;14) by cytogenetics or FISH.30 
Date of Diagnosis: _____________ 
3.2 
Patients must have measurable or evaluable disease as defined as a lymph node measuring 
>1.5 cm in any dimension or splenomegaly with spleen >15 cm in craniocaudal dimension. 
3.3 
Age ≥ 60 years. 
3.4 
No intention to undergo consolidation with high dose chemotherapy and autologous stem 
cell rescue (Autologous Stem Cell Transplant) in first remission. 
3.5 
ECOG performance status of 0-2 (Appendix I). 
Performance Status: Please circle 
0 
1 
2 
Date: ___________ 
3.6 
Ability to understand and willingness to sign IRB-approved informed consent. 
3.7 
Willing to provide mandatory tissue samples (if sufficient tissue available), bone marrow and 
blood samples for research purposes (Section 13). 
3.8 
Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to 
registration: 
• 
Absolute Neutrophil Count (ANC) ≥ 1000/mm3 unless there is bone marrow involvement 
or splenomegaly 
ANC: __________________ 
Date of Test: ____________ 
• 
Hemoglobin ˃8.0 g/dL 
Hemoglobin: ____________ 
Date of Test: ____________ 
• 
Platelets ˃75,000/mm3 or ˃50,000/mm3 if there is bone marrow involvement or 
splenomegaly 
Platelets: _______________ 
Date of Test: ____________ 
 
_____
_____
_____
_____
_____
_____
_____
_____ 


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• 
Creatinine Clearance ≥ 40 mL/min 
Creatinine Clearance: ______ 
Date of Test: ____________ 
NOTE: Acceptable Measures of Creatinine Clearance: Cockcroft-Gault formula 
(Appendix II or direct measured creatinine clearance [by 24 hour urine 
collection or other methods]). 
• 
Total Bilirubin ≤ 1.5x upper limit of normal (ULN) or ≤ 3x ULN for patients with 
documented Gilbert’s syndrome 
Total Bilirubin: ___________ 
ULN: ________ 
Date of Test: ___________ 
• 
Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤ 2.5x ULN 
AST: ______________ 
ULN: _______ 
Date of Test: ___________ 
ALT: ______________ 
ULN: _______ 
Date of Test: ___________ 
3.9 
All females of childbearing potential (not surgically sterilized and between menarche and 1 
year post menopause) must have a blood 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: ____________________________ 
3.10 
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 12 months 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. 
3.11 
Patients should not have prior chemotherapy, radiotherapy or immunotherapy for 
lymphoma. 
• 
Corticosteroids used for other non-lymphomatous conditions will be allowed. 
• 
Corticosteroids no greater than 1 mg/kg prednisone (or equivalent) given for ≤ 14 days 
will be allowed for treatment of lymphoma related symptoms. 
3.12 
Patients must have no recent (<1 year) history of malignancy except for the following: 
• 
adequately treated non-melanoma skin cancer 
• 
adequately treated Stage I melanoma of the skin 
• 
in situ cervical cancer 
• 
low grade prostate adenocarcinoma (Gleason grade ≤ 6) managed with observation 
and stable for 6 months. 
NOTE: Any malignancy treated with curative intent and disease free without treatment for 
≥ 1 year prior to enrollment may be included. 
3.13 
Patients should not have known evidence of central nervous system (CNS) lymphoma. 
3.14 
Patients must not have received a prior allogeneic stem cell transplant or solid organ 
transplant (except for cornea) for any indication. 
3.15 
Patients must have no active, uncontrolled infections. 
 
_____
_____ 
_____ 
_____ 
_____
_____ 
_____ 


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3.16 
Patients must not have active hepatitis B or be chronic carriers of hepatitis B. This is defined 
as patients with hepatitis B surface antigen (HBsAg) positive. Patients with prior exposure 
to hepatitis B (hepatitis B core antibody (anti-HBc) positive AND HBsAg negative) are 
allowed with a protective level hepatitis B surface antibody AND a negative hepatitis B viral 
load by polymerase-chain reaction (PCR). 
3.17 
Patients must not have active hepatitis C (HCV) as defined by a hepatitis C viral load 
detectable by PCR. Patients with a negative HCV antibody are assumed to have a negative 
HCV viral load. Patients with a positive HCV antibody must have a negative hepatitis C viral 
load by PCR. Prior treatment for an active HCV infection will be allowed as long as the 
hepatitis C viral load by PCR is negative. 
3.18 
Patients must not have known active Human Immunodeficiency Virus (HIV). Testing not 
required in absence of clinical suspicion. 
3.19 
Patients must not have evidence of significant, uncontrolled concomitant diseases, including 
psychiatric diseases, that could affect compliance with the protocol or interpretation of 
results or that could increase risk to the patient. 
3.20 
Patients must not have conditions that preclude oral administration or absorption of 
medications through the GI tract, including but not limited to the inability to swallow pills or 
malabsorption syndromes. 
3.21 
Patients must not have known allergies to both xanthine oxidase inhibitors and rasburicase. 
3.22 
Patients must not require the use of warfarin. Blood thinners of other classes are permitted. 
3.23 
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 
• 
Strong and moderate P-gp inhibitors 
NOTE: Continuous use of strong and moderate CYP3A inhibitors, CYP3A inducers or P-
gp inhibitors is not allowed. If a subject requires continuous use of these drugs they 
will need to be excluded. Please refer to Section 6.2.2 and Appendix III “Additional 
Excluded and Cautionary Medications” for further details. 
3.24 
Patients must not have consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of 
venetoclax. 
_____
_____
_____
_____
_____
_____ 
_____
_____
_____


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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 enroll 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. Once PrECOG activates a site, enrollment may occur. No patients will begin 
protocol therapy without formal registration as per the process below. 
4.3 
Patient Registration 
After written informed consent has been obtained, protocol-required assessments will be 
performed. 
Patients must meet all of the eligibility requirements listed in Section 3 prior to registration. 
Patients must not start protocol treatment 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. 
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 
Research Tissue, Bone Marrow and Blood Samples 
Pre-treatment, diagnostic pathology specimens (organ or lymph node biopsy or excision) 
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. 
 


PrECOG Protocol Number: PrE0405 
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NOTE: If blocks and/or slides are unavailable and bone marrow is involved with mantle cell 
lymphoma, obtain two 2 mL EDTA tubes of bone marrow aspirate (one for baseline 
MRD analysis and one for future research). If blocks/slides and bone marrow are 
unavailable and peripheral blood is involved with mantle cell lymphoma obtain one 
4 mL and one 6 mL EDTA tubes of peripheral blood (one for baseline MRD analysis 
and one for future research). If baseline samples (blocks/slides, bone marrow, 
and/or peripheral blood) are not submitted at baseline for MRD (i.e., not involved 
with mantle cell lymphoma), then patients will be allowed to remain on study but 
MRD samples will not be collected during the study. 
If bone marrow procedure is completed per standard of care, mandatory bone marrow 
aspirate sample for MRD analysis will be collected at the end of treatment. Please note, if 
bone marrow is positive for mantle cell lymphoma at baseline, an end of treatment bone 
marrow must be collected to confirm response. 
Mandatory peripheral blood samples for MRD analysis will be collected at the end of 
treatment. 
Optional peripheral blood samples will also be collected for future research. 
Optional: At time of progression, biopsy and peripheral blood samples are requested to 
be sent for correlative studies and banked for future research. 
NOTE: No bone marrow biopsy/aspirate or tissue biopsy should be performed solely for the 
purposes of obtaining research samples. 
Time points for tissue, bone marrow and blood 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 PrE0405 lab manual. 


PrECOG Protocol Number: PrE0405 
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5. 
Treatment Plan 
5.1 
Overview 
Eligible patients will be treated in a single arm with venetoclax, bendamustine and rituximab 
as induction therapy for 6 cycles of 28 ± 3 day length as outlined in Table 5-1. After 6 cycles, 
maintenance rituximab may be administered per physician discretion. The recommended 
schedule for maintenance rituximab is every 8 ± 2 weeks for 12 doses or 24 months 
(whichever comes first). 
Table 5-1: Treatment Overview 
Agent 
Route 
Dose 
Days 
Venetoclax 
Oral 
20 mg 
50 mg 
100 mg 
200 mg 
400 mg 
Day 1-7 (Cycle 1 only) 
Day 8-14 (Cycle 1 only) 
Day 15-21 (Cycle 1 only) 
Day 22-28 (Cycle 1 only) 
Day 1-10 (Cycle 2-6) 
Bendamustine 
IV 
90 mg/m2a 
Day 1 and 2 (Cycle 1-6) 
Rituximabb 
IV 
SQ (optional) 
375 mg/m2 
1400 mg (optional) 
Day 1 (Cycle 1-6b) 
Day 1 (Cycle 3-6) (optional) 
a Per investigator discretion, bendamustine may be started at 70 mg/m2 in patients over 
the age of 75 years with comorbid conditions or patients over the age of 80 years without 
comorbid conditions. 
b Rituximab should be administered as 375 mg/m2 IV on day 1 of each cycle. If the first 
two cycles of rituximab (or two consecutive cycles) are well tolerated, IV rituximab may 
be replaced with 1400 mg/23,400 units subcutaneous (SQ) rituximab/hyaluronic acid on 
Day 1 of Cycles 3-6 (or after 2 consecutive cycles are well tolerated), per 
rituximab/hyaluronic acid package insert. Biosimilars for rituximab are permitted. 
All doses are based on actual body weight. 
Prophylactic filgrastim, pegfilgrastim or pegfilgrastim on body injector (OBI) or biosimilars 
will be administered for all patients on study per Section 5.5. 
Pneumocystis Jiroveci Pneumonia (PJP) and antiviral prophylaxis will be initiated in all 
patients (Section 5.6). 
Section 5.7 for Monitoring of Cytomegalovirus (CMV). 
Premedication: Acetaminophen and diphenhydramine should be administered prior to 
each infusion or injection of rituximab, per institution guidelines. Other prophylactic 
medications may be administered per institution guidelines. 
Antiemetic Therapy: Standard anti-emetic therapy may be given to patients prior to 
administration of bendamustine per institutional guidelines. However, 5-HT3 serotonin 
receptor agonist and steroids are strongly recommended. 
Tumor lysis syndrome (TLS) is an event of interest and will be monitored closely during 
therapy. TLS will be assessed by the Data Safety and Monitoring Board (DSMB) among the 
first 19 patients accrued to this study who received venetoclax treatment for at least 3 cycles 
with no hold to accrual. 


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5.2 
Treatment and Administration Schedule 
Venetoclax must be administered before bendamustine and/or rituximab. Bendamustine 
and rituximab may be given in any order (venetoclax, bendamustine, rituximab or 
venetoclax, rituximab, bendamustine). One cycle=28 days. 
5.2.1 
Venetoclax Administration 
Venetoclax will be administered once daily and, given risk of tumor lysis syndrome 
in MCL, will be dose escalated with Cycle 1, as per Table 5-1 and Table 5-2. In 
Cycles 2-6, venetoclax will be given at 400 mg oral daily for 10 days starting on day 
1. Venetoclax should be given prior to administering bendamustine or rituximab on 
day 1 of each cycle. Venetoclax will be supplied in 10 mg, 50 mg and 100 mg tablets 
and administration instructions are listed in Table 5-2. 
Table 5-2: Venetoclax Dosing 
Days 
Total Daily Dose 
Administration Instructions 
Cycle 1 
Day 1-7 
20 mg PO daily 
Take two 10 mg tablets PO daily 
Day 8-14 
50 mg PO daily 
Take one 50 mg tablet PO daily 
Day 15-21 
100 mg PO daily 
Take one 100 mg tablet PO daily 
Day 22-28 
200 mg PO daily 
Take two 100 mg tablets PO daily 
Cycle 2-6 
Day 1-10 
400 mg PO daily 
Take four 100 mg tablets PO daily  
Day 11-28 
No venetoclax administered. 
Venetoclax should be administered with a meal and swallowed whole with an 8-
ounce glass of water. 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. 
If patient misses a dose of venetoclax within 8 hours of when it is usually taken, the 
patient should take the dose as soon as possible and resume normal daily dosing 
schedule. Should the dose be missed by greater than 8 hours, the dose should be 
skipped and patient should resume normal daily dosing the following day. This dose 
should not be made up. 
Patient compliance in taking assigned daily dose of venetoclax will be assessed by 
pill counts and IRB reviewed medication diary (provided to sites). Bottles containing 
venetoclax tablets will be given to patients at regularly scheduled visits. Previously 
distributed bottles will be returned to the clinic. A medication diary will be given to 
document compliance. 
5.2.1.1 
Adherence 
Medication diaries will be maintained on all patients taking venetoclax. 
Diaries will be completed by patients and subsequently reviewed by the 
research staff with the patient at the following visits (Cycle 1 Day 8, Cycle 
1 Day 15, Cycle 1 Day 22, Cycle 2-6 Day 1). Pill counts of venetoclax will 
also be performed and recorded at Cycle 1 Day 8, Cycle 1 Day 15, Cycle 
1 Day 22, Cycle 2-6 Day 1 by the research staff and documented on the 


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drug accountability record. If the pill count is discrepant with the drug 
diary, the pill count will be used to determine adherence status. Patients 
may be counseled by the study doctor regarding adherence issues. 
5.2.2 
Bendamustine Dosing 
Bendamustine will be administered as 90 mg/m2 as IV infusion on days 1 and 2 of 
each 28 day cycle per institution guidelines. Subjects with advanced age or other 
comorbid conditions are known to have more side effects with bendamustine at 
90 mg/m2.7 Per investigator discretion, bendamustine may be administered as 
70 mg/m2 is IV infusion on days 1 and 2 in patients over 75 years with comorbid 
conditions or over 80 years without comorbid conditions. 
Bendamustine must be given after venetoclax but may be given before or after 
rituximab. 
5.2.3 
Rituximab Administration 
Rituximab should be administered on day 1 of each 28 day cycle after 
administration of venetoclax. Rituximab should be given as a “standard” IV infusion 
at 375 mg/m2 for Cycle 1 per institution guidelines and package insert. For patients 
that do not have a Grade 3-4 infusion related adverse event, Cycle 2-6 may be 
given as a “rapid” IV infusion at 375 mg/m2 per institution guidelines and package 
insert. Patients that do have a Grade 3-4 infusion related adverse event should 
receive the “standard” infusion rate for the subsequent cycle. Patients may receive 
the “rapid” infusion schedule if the prior infusion was not associated with a Grade 
3-4 infusion related adverse event. Biosimilars for rituximab are permitted. 
Patients who did not have a Grade 3-4 infusion related adverse event with the first 
2 cycles of IV rituximab (or two consecutive cycles), may be switched to SQ 
rituximab/hyaluronic acid at a dose of 1400 mg/23,400 units on Day 1 of Cycles 3-
6 (or after 2 consecutive cycles are well tolerated) according to package insert and 
institution guidelines. This is per patient and institution preference. Patients may be 
switched back to IV rituximab at any time and switching to SQ rituximab is not 
required. 
All doses of rituximab should be administered with acetaminophen and 
diphenhydramine (or another anti-histamine) pre-medication per institution 
guidelines. Other pre-medications may be utilized per institution guidelines. 
Rituximab must be given after venetoclax but may be given before or after 
bendamustine. 
After 6 cycles of venetoclax, bendamustine and rituximab, subjects responding to 
therapy may receive maintenance rituximab IV or SQ (one dose every 8 ± 2 weeks 
for 12 doses or 24 months whichever comes first) per physician and patient 
preference. 
5.3 
Tumor Lysis Prophylaxis 
TLS is a risk for MCL patients treated with venetoclax. The highest risk for TLS occurs within 
the first 24 hours of a dose escalation. Ramp up dosing helps to mitigate this risk however, 
careful prophylaxis of TLS is required, including the following: 
• 
Allopurinol 300 mg PO daily 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 
hours prior to Cycle 1, Day 1 and continue through at least Cycle 2, Day 10. Allopurinol 
can continue longer per treating physician discretion. 
• 
One liter of IV fluids on Day 1 of Cycle 1 and Cycle 2 of chemotherapy. 


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• 
Encourage oral hydration of at least 2 liters of any form of fluid per day starting 24 hours 
prior to Cycle 1, Day 1 and continuing until Cycle 2, Day 10. 
• 
Rasburicase is allowed per institutional guidelines. 
• 
Additional IV fluids and monitoring for TLS is allowed per treating physician discretion. 
• 
What is listed in the protocol are minimum standards. 
o 
Admission to the hospital is allowed for advanced treatment and monitoring of TLS 
per treating physician discretion/institutional standards. 
NOTE: Defined risks for TLS are not clear in MCL but some higher risk situations include: 
 
Bulky disease (any lymph node mass >10 cm) 
 
Circulating mantle cell lymphoma with Absolute Lymphocyte Count (ALC) >25 
x 109/L 
 
Borderline renal function 
 
Rapidly progressing disease. 
5.4 
Tumor Lysis Monitoring 
Tumor lysis syndrome (TLS) has been documented in patients treated with single agent 
venetoclax in other studies. Tumor lysis is most common within the first 24 hours of a dose 
increase of venetoclax. It is an outcome of interest in the current study and will be monitored 
closely in patients with Cycle 1 and Cycle 2. 
Tumor lysis laboratory studies include the following: Basic Metabolic Panel (Sodium, 
Potassium, Chloride, Bicarbonate (HCO3), BUN, Creatinine, Calcium), Albumin, Uric Acid, 
and Phosphorus. Monitoring for TLS is listed in Table 5-3. 
Table 5-3: Tumor Lysis Monitoring 
Days 
Dose of Venetoclax 
TLS Lab Timing 
Cycle 1 
Day 1 
20 mg PO 
- Prior to dosing Venetoclax 
- 6-8 hours after dosing Venetoclax 
Day 2 
20 mg PO 
Prior to dosing Venetoclax and Bendamustine 
Day 8 
50 mg PO 
- Prior to dosing Venetoclax 
- 6-8 hours after dosing Venetoclax 
Day 9 
50 mg PO 
Prior to dosing Venetoclax a 
Day 15 
100 mg PO 
- Prior to dosing Venetoclax 
- 6-8 hours after dosing Venetoclax 
Day 16 
100 mg PO 
Prior to dosing Venetoclax a 
Day 22 
200 mg PO 
Prior to dosing Venetoclax 
Day 23 
200 mg PO 
Prior to dosing Venetoclax a 
Cycle 2 
Day 1 
400 mg PO 
- Prior to dosing Venetoclax 
- 6-8 hours after dosing Venetoclax 
Day 2 
400 mg PO 
Prior to dosing Venetoclax and Bendamustine 


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Cycle 3-6 
Day 1 
400 mg PO 
Prior to dosing Venetoclax 
a Can be performed locally. 
Venetoclax dose may be given prior to results returning on Cycle 1: Days 9, 16, 23; and 
Cycle 4-6: Day 1. 
Venetoclax should not be administered prior to results returning on Cycle 1: Days 1, 2, 8, 
15, 22; Cycle 2: Days 1 and 2; and Cycle 3: Day 1. 
5.5 
Neutropenic Sepsis Prophylaxis 
Bendamustine and venetoclax can cause neutropenia. Prophylaxis for neutropenic sepsis 
and febrile neutropenia is required with one of the following (Growth Colony Stimulating 
Factors [GCSFs]) to be administered 24-72 hours after the last dose of bendamustine for 
each cycle. 
• 
Pegfilgrastim SQ 6 mg once 
• 
Pegfilgrastim SQ 6 mg via on-body injector (OBI) once 
• 
Filgrastim or filgrastim-sndz SQ 300 or 480 mcg for 5 days 
• 
Biosimilars are also allowed for prophylaxis for neutropenic sepsis and febrile 
neutropenia 
5.6 
Infection Prophylaxis 
All patients must be initiated on prophylaxis for PJP at the time of Cycle 2 of venetoclax, 
bendamustine and rituximab. However, PJP prophylaxis may be administered with Cycle 1 
if the treating physician feels the risk of PJP is higher than the risks during the venetoclax 
dose ramp up. Trimethoprim-sulfamethoxazole (Bactrim) is the preferred treatment of 
choice for PJP prophylaxis. PJP prophylaxis should continue until 6-8 weeks from Day 1 of 
last completed induction cycle. 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 Herpes 
Simplex and Varicella Zoster 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. 
NOTE: The above mentioned prophylactic medications have no known interactions with the 
study drugs. 
5.7 
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 and at the end of 
induction. 
Maintenance Phase: Treating physician discretion or per institutional standards; however, 
if the CMV level at the end of induction is detectable, it is recommended to continue 
monitoring CMV PCR per institutional standards. 


PrECOG Protocol Number: PrE0405 
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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 without dose reduction 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. 
 


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6. 
Dose Delays & Modifications 
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). 
A 3 day window is allowed for scheduled therapy, tests and/or results except as noted for TLS 
monitoring. Delays due to holidays, weekends, bad weather or other unforeseen circumstances will 
be permitted. 
If administration of venetoclax, bendamustine or rituximab 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 rituximab should also be delayed so that 
they are given together beginning on Day 1 of the same cycle (Cycle 1 cannot be more than 49 
days). 
NOTE: For CMV reactivation and infection management, please refer to Section 5.7 
If any of the study drugs are permanently discontinued (i.e., Grade 4 infusion-related reaction with 
rituximab), the patient will be removed from study and followed per Section 7.2. 
NOTE: TLS will be considered as laboratory or clinical TLS per Appendix IV. 
6.1 
Dose Modifications 
6.1.1 
Hematologic Toxicities 
Table 6-1: Dose Modifications and Delay for Hematologic Toxicity 
 GCSF will be administered to all patients per Section 5.5. 
 If a cycle is delayed by >28 days, then patient will discontinue study treatment. 
 Best supportive care should be offered to all patients per Section 6.2. 
 Refer to Table 6-4 for Dose Modifications. 
Event 
Dose Delays or Modifications 
During Cycle 1: 
• 
Febrile neutropenia 
• 
Grade 4 thrombocytopenia 
• 
Grade 3 thrombocytopenia 
with bleeding 
- 
Hold venetoclax until febrile neutropenia resolves, ANC recovers to >1000/mm3 
and/or platelets recover to >50,000/mm3. Resume venetoclax dosing. 
- 
There may be a prolongation of Cycle 1 by up to 28 days. In general, after 
resuming venetoclax, please allow for 7 (+/- 1) days with each dose increase. 
Cycle 1 cannot be more than 49 days. 
At Start of Cycle 2-6: 
• 
Grade 3 or 4 neutropenia or 
thrombocytopenia 
- 
Hold all protocol therapy and delay cycle for at least 7 days and up to 28 days. 
- 
Once ANC resolves to >1000/mm3 and/or platelets resolve >75,000/mm3, resume 
cycle as below: 
o 
For first occurrence: 
 
If hold was ≤ 10 days, resume cycle at Dose Level 0. 
 
If hold was >10 days, resume cycle at Dose Level -1. 
o 
For second occurrence of any length: 
 
Resume cycle at Dose Level -1. 
o 
For any occurrence after a cycle at Dose Level -1. 
 
Resume cycle at Dose Level -2. 
o 
For any occurrence after a cycle at Dose Level -2. 
 
Subject will discontinue study treatment. 
During Cycle 2-6: 
• 
Febrile neutropenia 
• 
Thrombocytopenia with 
bleeding 
- 
If taking venetoclax (Days 2-10), hold venetoclax until next cycle AND 
- 
For subsequent cycles, resume at Dose Level -1. 
- 
If recurrence, dose subsequent cycles at Dose Level -2. 
- 
For third recurrence, subject will discontinue study treatment. 


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6.1.2 
Non-Hematologic Toxicities 
Table 6-2: Dose Modifications and Delay for Non-Hematologic Toxicity 
 Dose modifications should occur only for treatment emergent and related toxicities. 
 Dose reductions should be made to the attributed drug. No dose reductions in rituximab are 
permitted. If both venetoclax and bendamustine are attributed to the AE of interest, venetoclax 
must be dose reduced; however, bendamustine may also be dose reduced per investigator 
discretion. 
 If a cycle is delayed by >28 days, then patient will discontinue study treatment. 
 Best supportive care should be given to all patients according to Section 6.2. 
 Refer to Table 6-5 and Table 6-6 for Dose Modifications. 
Event 
Dose Delays and Modifications 
Grade 3 to 4 Non-Hematologic 
Toxicity 
(not otherwise described) 
• 
excluding alopecia 
- 
During Cycle 1, hold all study treatment and resume once Grade ≤ 1. 
o 
Resume venetoclax treatment and dose escalation at the dose the toxicity 
occurred. 
o 
There may be a prolongation of Cycle 1 by up to 28 days. In general, after 
resuming venetoclax, please allow for 7 (+/- 1) days with each dose increase. 
Cycle 1 cannot be more than 49 days. 
o 
Re-challenge may occur twice during Cycle 1, a third occurrence will require 
subject discontinue study treatment. 
- 
During Cycle 2-6, hold all study treatment and delay subsequent cycle until resolves 
to Grade ≤ 1. 
o 
If delay in cycle is required but ≤ 10 days, no dose modification is required. 
 
However, dose reduction of venetoclax or bendamustine is allowed per 
investigator discretion depending on attribution. 
o 
If delay in cycle is >10 days, then reduce to Dose Level -1 (or Dose Level -2 if 
toxicity occurred after Dose Level -1) of attributed drug. 
o 
If toxicity occurs at Dose Level -2 of attributed drug, subject may dose reduce 
the other drug. 
o 
If toxicity occurs with venetoclax at 200 mg PO for 5 days and bendamustine 
50 mg/m2 IV day 1 and 2, subject must discontinue study treatment. 
Grade 2 Non-Hematologic 
Toxicity 
• 
excluding alopecia, 
nausea/vomiting, diarrhea, 
and fatigue 
- 
During Cycle 1, hold all study treatment and resume once Grade ≤ 1. 
o 
Resume venetoclax treatment and dose escalation at the dose the toxicity 
occurred. 
o 
There may be a prolongation of Cycle 1 by up to 28 days. In general, after 
resuming venetoclax, please allow for 7 (+/- 1) days with each dose increase. 
Cycle 1 cannot be more than 49 days. 
o 
Re-challenge may occur twice during Cycle 1, a third occurrence will require 
subject discontinue study treatment. 
- 
During Cycle 2-6, if occurs at the start of a cycle, delay cycle for at least 7 days and 
up to 28 days. Resume at same dose level when toxicity resolves to Grade ≤ 1. 
o 
If toxicity recurs and causes a delay in a cycle, subsequent cycles should be 
dose reduced to Dose Level -1 of the attributed drug. 
o 
If toxicity occurs at Dose Level -1, modify subsequent cycles to Dose Level –2 
of the attributed drug. 
o 
If toxicity occurs at Dose Level -2 of the attributed drug, subject may dose reduce 
the other drug. 
o 
If toxicity occurs with venetoclax at 200 mg PO for 5 days and bendamustine 
50 mg/m2 IV day 1 and 2, subject must discontinue study treatment. 
 


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- 
If taking venetoclax when toxicity occurs and toxicity is attributed to venetoclax, hold 
dose until next cycle and administer without dose modification. 
o 
If toxicity recurs during venetoclax treatment (Days 2-10) and is attributed to 
venetoclax, hold venetoclax dose and reduce venetoclax next cycle to Dose 
Level -1. 
o 
If toxicity occurs at Dose Level -1, modify subsequent cycles to Dose Level –2 
of venetoclax if attributed to venetoclax. 
o 
If toxicity occurs at Dose Level -2 of venetoclax, consider dose reduction of 
bendamustine. 
 
6.1.3 
Tumor Lysis Syndrome Management 
Table 6-3: Tumor Lysis Syndrome Management 
Dose Patient 
Taking When TLS 
Occurs 
If Tumor Lysis Is Suspecteda 
Restart Instructionsd 
Venetoclax 20 mg 
-Hold venetoclax 
-Strongly consider admission for IV fluids and 
monitoring 
-Give supportive careb 
-Recheck TLS labs every 6 hours until resolvedc 
If TLS is absent and investigator feels safe: 
-Resume venetoclax at 20 mg. 
-Dose escalate on schedule if no signs of TLS 
24 hours after re-dosing per protocol. 
Venetoclax 50 mg 
-Hold venetoclax 
-Strongly consider admission for IV fluids and 
monitoring 
-Give supportive careb 
-Re-check TLS labs every 6 hours until resolvedc 
If TLS is absent and investigator feels safe: 
-Resume venetoclax at 20 mg. 
-Dose escalate on schedule if no signs of TLS 
24 hours after re-dosing per protocol. 
Venetoclax 100 mg 
-Hold venetoclax 
-Strongly consider admission for IV fluids and 
monitoring 
-Give supportive careb 
-Recheck TLS labs at least daily until resolvedc 
If TLS is absent and investigator feels safe:  
-Resume venetoclax at 50 mg. 
-Dose escalate per protocol if no signs of TLS. 
Venetoclax 200 mg 
-Hold venetoclax 
-Give supportive careb 
-Recheck TLS labs every 2-3 days until resolvedc 
If TLS is absent and investigator feels safe: 
-Resume venetoclax at 100 mg. 
-Re-check TLS labs after 2 days. 
-Dose escalate per protocol if no signs of TLS. 
Venetoclax 400 mg 
-Hold venetoclax for rest of cycle 
-Give supportive careb 
-Recheck TLS labs every 2-3 days until resolvedc 
If TLS absent and patient is not clinically 
progressing and investigator feels safe: 
-Give venetoclax at 400 mg for subsequent 
cycle. 
-Re-check TLS labs after 2 days. 
a See Appendix IV for Definitions of Tumor Lysis Syndrome.31 
b Recommend aggressive IV and oral hydration, electrolyte management, and depending on severity, rasburicase per 
institutional standards. Depending on severity, consider hospital admission. 
c If TLS does not improve after 14 days, with good supportive care, patient must discontinue study treatment. 
d After a TLS event, there may be a prolongation of Cycle 1 by up to 28 days. In general, after resuming venetoclax, please 
allow for 7 (+/- 1) days with each dose increase. Cycle 1 cannot be more than 49 days. 
 


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6.1.4 
Dose Level Reductions 
Table 6-4: Dose Modifications for Hematologic Toxicity 
 Note that dose escalations after a dose reduction are not allowed. 
Dose Level 
Venetoclax 
Bendamustine 
Rituximab 
0 
400 mg PO daily x 10 days 
90 mg/m2 IV days 1 and 2 
(70 mg/m2 if starting dose is 
such per Section 5.2.2) 
No dose modifications  
-1 
400 mg PO daily x 5 days 
90 mg/m2 IV days 1 and 2 
(70 mg/m2 if starting dose is 
such per Section 5.2.2) 
No dose modifications 
-2 
400 mg PO daily x 5 days 
70 mg/m2 IV days 1 and 2 
(50 mg/m2 if starting dose is 
such per Section 5.2.2) 
No dose modifications 
 
Table 6-5: Dose Modifications for Non-Hematologic Toxicity—Venetoclax 
 Note that dose escalations after a dose reduction are not allowed. 
Dose Level 
Venetoclax 
Rituximab 
0 
400 mg PO daily x 10 days 
No dose modifications 
-1 
400 mg PO daily x 5 days 
No dose modifications 
-2 
200 mg PO daily x 5 days 
No dose modifications 
 
Table 6-6: Dose Modifications for Non-Hematologic Toxicity—Bendamustine 
 Note that dose escalations after a dose reduction are not allowed. 
Dose Level 
Bendamustine 
Rituximab 
0 
90 mg/m2 IV day 1 and 2 
No dose modifications  
-1 
70 mg/m2 IV day 1 and 2 a 
No dose modifications 
-2 
50 mg/m2 IV day 1 and 2 
No dose modifications 
a 70 mg/m2 maybe the initial dose for some subjects per Section 5.2.2. 
 
6.2 
Concurrent Therapies 
6.2.1 
Permitted Concurrent Therapies 
Concurrent therapy includes any prescription or over-the-counter medication used 
by a patient between the 7 days preceding the study entry evaluation and the end 
of treatment/study termination visit. 
All supportive measures consistent with optimal patient care will be given 
throughout the study. Transfusion of blood products per institutional guidelines is 
permitted. 
Prior to Cycle 1, Day 1, systemic (IV or PO) corticosteroids no greater than 1 mg/kg 
prednisone (or equivalent) given for less than or equal to 14 days will be allowed 
for treatment of lymphoma related symptoms. While on study, systemic (IV, IM, or 
PO) corticosteroids used for non-lymphomatous conditions will be allowed; 


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however, systemic (IV, IM, or PO) corticosteroids will not be allowed to control 
lymphoma related symptoms after Cycle 1 Day 5. Inhaled and topical 
corticosteroids are allowed. 
Prevention and treatment of reactions to rituximab and bendamustine are allowed 
per intuitional standards. 
6.2.2 
Not Permitted 
The use of live viral vaccines during study treatment is not allowed. Use of live viral 
vaccines within 28 days prior to the initiation of study treatment or within 30 days of 
the last treatment is not allowed. 
Effectiveness of inactivated vaccines, recombinant vaccines, and cell-wall vaccines 
are unreliable in NHL patients but are allowed on this protocol per treating physician 
discretion. 
The following treatments are prohibited from 7 days prior to initiation of treatment, 
during the study treatment, and within 30 days of the last study treatment: 
• 
Immunotherapy other than prescribed in the treatment plan. 
• 
Any FDA-approved or experimental therapy intended for the treatment of 
lymphoma including systemic corticosteroids, unless otherwise listed. 
• 
Warfarin (novel anticoagulants are allowed so long as there are no other drug-
drug interactions). 
• 
Strong to moderate inhibitors or inducers of CYP3A per Appendix III. 
o 
Weak inhibitors and inducers are allowed 
o 
Please contact PrECOG for more guidance if needed 
• 
Strong to moderate P-gp inhibitors such as amiodarone, azithromycin, 
captopril, carvedilol, cyclosporine, felodipine, quercetin, quinidine, ranolazine, 
ticagrelor (Appendix III). 
• 
Grapefruit and grapefruit juice, Seville oranges (including marmalade/jam) and 
star fruit are known inhibitors of CYP3A and should be avoided. 
• 
In cycles 2-6 when venetoclax will not be administered (i.e., Days 11-28), avoid 
the use of strong or moderate CYP3A inhibitors or P-gp inhibitors 2 to 3 days 
prior to the next cycle of venetoclax treatment. 
• 
In cycles 2-6 when venetoclax will not be administered (i.e., Days 11-28), avoid 
the use of strong or moderate CYP3A inducers at least 7 days prior to the next 
cycle of venetoclax treatment. 
NOTE: Continuous use of strong and moderate CYP3A inhibitors, CYP3A inducers 
or P-gp inhibitors is not allowed. If a patient requires continuous use of 
these drugs they will need to be excluded. 
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: 
o 
P-gp substrates such as digoxin, everolimus, and sirolimus due to inhibition 
potential at therapeutic dose levels. 


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– 
P-gp substrate should be avoided. If a concomitant use is unavoidable, 
separate dosing of the P-gp substrate at least 6 hours before venetoclax. 
o 
CYP2C8 substrates such as thiazolidinediones (glitazones) and select statins 
(because of expected inhibition of the metabolism of CYP2C8 substrates) by 
venetoclax. 
o 
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. 
Additionally, caution should be exercised, or alternative treatments considered, 
when co-administering bendamustine with a CYP1A2 inhibitor or CYP1A2 inducer. 
Refer to Appendix III: “Additional Excluded and Cautionary Medications” for 
additional information. 


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7. 
Study Duration and Discontinuation of Therapy 
7.1 
Study Duration 
Patients will receive protocol therapy until: 
1. Any of the study drugs are permanently discontinued (i.e., Grade 4 infusion-related 
reaction with rituximab), the patient will be removed from study. 
2. Subject completes 6 cycles of treatment per Section 5. 
3. Disease progression per Lugano staging26 or clinical parameters. 
4. Toxicities considered unacceptable by either the patient or the investigator, despite 
optimal supportive care and dose modifications. 
5. Development of an inter-current illness that prevents further administration of study 
treatment. 
6. Extraordinary Medical Circumstances: If at any time the constraints of this protocol are 
detrimental to the patient's health, protocol treatment should be discontinued. 
7. Patient withdraws consent or is unable to comply with study procedures. 
7.2 
Duration of Follow-Up 
Patients will be followed for adverse events for 30 days after their last dose of study 
medication. Patients should be followed every 3-6 months or per institutional guidelines for 
up to 5 years from treatment discontinuation or study closure for progression and survival. 
Initiation of first anti-cancer therapy will 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 
with the exception of allowed maintenance rituximab. 
For patients who are registered but do not receive any protocol therapy, baseline and follow-
up information per Section 10 will be collected. 
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. 
2. Intercurrent illness that prevents further administration of treatment per investigator 
discretion. 
3. Unacceptable adverse events. 
4. Treatment interruption of more than 4 weeks (28 days). 
5. Investigator and/or patient decision to discontinue treatment. 
6. Pregnancy. 
7. Develops a second malignancy (except for non-melanoma skin cancer or cervical 
carcinoma in-situ) that requires treatment, which would interfere with this study. 
8. The patient may choose to withdraw from the study at any time for any reason. 


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9. General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in the judgment of the investigator. 
10. Severe non-compliance to protocol as judged by the investigator. 
11. Lost to follow-up. 
12. Death. 
13. Closure of study by PrECOG. 
Any patient who receives at least one dose of study drug (bendamustine, rituximab or 
venetoclax) 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 (bendamustine, rituximab or 
venetoclax), only AEs/SAEs caused by a protocol-mandated intervention not considered 
standard of care 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; 
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. 


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• Unlikely: There is doubtful causal relationship between the study drug and the event. 
• 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 Investigator’s Brochure (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 bendamustine, rituximab or venetoclax, disease, 
etc. 
AEs related to bendamustine, rituximab or venetoclax 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 
Serious Adverse Events 
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. 


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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. 
8.3 
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. 
Non Drug Specific AESIs (applicable to Venetoclax and Rituximab) 
• 
Drug-Induced Liver Toxicity 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law 
and based on the following observations: 
o 
Treatment-emergent ALT or AST >3x baseline value in combination with total 
bilirubin >2x ULN (of which >35% is direct bilirubin) 
o 
Treatment-emergent ALT or AST >3x baseline value in combination with clinical 
jaundice 
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 treatment, as defined below: 
o 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a patient exposed to a medicinal product. This term applies only when a 
contamination of study treatment is suspected. 
Venetoclax Events of Special Interest 
• 
Any grade tumor lysis syndrome (TLS) 
o 
Definitions for TLS is described in Appendix IV: “Definition of Tumor Lysis 
Syndrome”31. Please note that, if the clinical scenario fits for TLS, use these criteria 
for evaluating renal and electrolyte imbalances occurring at the same time. 
- 
Laboratory TLS (2 or more metabolic abnormalities present) = Grade 3 
- 
Clinical TLS (laboratory TLS must also be present) = Grade 4 
- 
Fatal = Grade 5 
Rituximab Events of Special Interest 
• 
None 


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8.4 
Special Situation Reports 
8.4.1 
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 8.2 
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. 
8.4.2 
Other 
In addition, the following Special Situation Reports should be collected and reported 
to PrECOG on a PrE0405 SAE Form even in the absence of an AE and PrECOG 
will transmit to Genentech within thirty (30) calendar days: 
● 
Data related to the product usage during pregnancy or breastfeeding (Section 
8.7). 
● 
Data related to overdose, abuse, misuse, error (including potentially exposed 
or intercepted medication errors). 
- 
For any symptomatic overdose, even if not fulfilling a seriousness 
criterion, a SAE form should be completed and reported to PrECOG 
within 24 hours of the investigator’s knowledge of the overdose. 
● 
Data related to a “suspected transmission of an infectious agent via a medicinal 
product. 
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 


PrECOG Protocol Number: PrE0405 
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37 
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 PrE0405SAE@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 
Email:
 
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 
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 bendamustine, 
rituximab or venetoclax 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 originating from the Study will be 
collected and reported to PrECOG on a PrE0405 Product Complaint Reporting Form even 
in the absence of an AE (if product complaint is an SAE, the PrE0405 SAE form will also be 
completed). PrECOG will transmit product complaints to Genentech for venetoclax within 
fifteen (15) calendar days. Product complaints for bendamustine and rituximab will be 
reported per each sites standard procedures. 


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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 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 12 months 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. 


PrECOG Protocol Number: PrE0405 
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39 
9. 
Measurement of Effect 
9.1 
Response Assessments 
Patients should have a baseline PET/CT. Repeat imaging in the form of CT or PET/CT 
before Cycle 3 or 4 should be done per institution guidelines. End of treatment PET/CT 
should be performed 6-8 weeks after the final cycle of therapy (6-8 weeks after Cycle 6 Day 
1) and is the primary endpoint for this study. Bone marrow biopsy and aspiration will be 
performed at the end of treatment when it is standard of care. 
Any progression on therapy should be confirmed with PET/CT. 
After the End of treatment PET/CT, all other imaging will be per institution standards. 
Patients will be followed until progression or for up to 5 years from treatment discontinuation 
or study closure. 
9.2 
Lymphoma Response Criteria (Lugano Classification)32 
Response and progression will be evaluated in this study using international criterial 
proposed by the 11th International Conference on Malignant Lymphoma in Lugano 
Switzerland (Lugano Classification).32 
The criteria use Complete Response (CR), Partial Response (PR), Stable disease (SD) or 
Progressive Disease (PD) to evaluate response. PET/CT is the primary modality to measure 
response and will be utilized for the primary outcomes; however, CT without PET 
component may be adequate at other measurements. 
Tumor measurements will be recorded at baseline for at least 6 dominant nodes or 
extranodal masses. If there are less than 6 measurable lesions, all lesions must be 
measured and followed. Selection of masses to follow should maintain that they are clearly 
measurable in 2 perpendicular directions, and should be from different regions of the body 
whenever possible. Measurements should be in centimeters to the nearest one tenth and 
in two planes, one being the longest diameter and the other its perpendicular counterpart. 
Measurements of lesions will be done at baseline and at each disease assessment. 
Non-target lesions can be utilized also. These may be dominant lesions over 6 nodes 
identified or lesions which are seen but difficult to measure (i.e., a bone lesion with FDG 
activity but no clearly defined borders). Non-target lesions will be recorded as present or 
absent. 
Spleen size, in cranio-caudal cross sectional measurement, should be recorded at each 
disease assessment. 
Full criteria can be found in Appendix V: Revised Criteria for Response Assessment.32 
End of treatment PET/CT is the primary response assessment. A 5-point scale, also known 
as the Deauville criteria, (Table 9-1) should be utilized to measure FDG uptake and 
treatment response via PET. Each target lesion should have a Deauville score at the end of 
treatment.33 
 
 
 
 
 
 
 


PrECOG Protocol Number: PrE0405 
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40 
 
 
 
 
 
 
 
 
 
 
9.2.1 
Complete Response Definition 
CR rate per Lugano criteria, utilizing the PET/CT criteria listed in Appendix V, is the 
primary outcome for this study. It is defined as a complete metabolic response via 
PET/CT as well as a morphologically negative bone marrow biopsy and aspiration. 
Bone marrow flow cytometry should not be utilized in CR assessments. If bone 
marrow biopsy and aspiration was not involved by MCL at screening, a repeat bone 
marrow biopsy and aspiration is not required to assess CR status (PET/CT imaging 
alone will suffice). 
All other responses, including PR, SD, PD and CT based criteria are indicated 
in the Lugano Criteria, listed in Appendix V Revised Criteria for Response 
Assessment.32 
9.3 
Minimum Residual Disease (MRD) Measurements 
MRD negative rate at the end of treatment assessment are exploratory endpoints in this 
study. MRD will be measured using PCR based markers through Adaptive Biotechnologies 
(clonoSEQ) on tumor tissue (baseline only), liquid marrow aspirate and peripheral blood 
samples. 
Baseline tumor tissue sample will be obtained. If tumor tissue is not available, bone marrow 
aspirate or peripheral blood may be substituted, if involved with mantle cell lymphoma, for 
baseline comparison sample. If baseline samples (blocks/slides, bone marrow, and/or 
peripheral blood) are not submitted at baseline for MRD (i.e., not involved with mantle cell 
lymphoma), then patients will be allowed to remain on study but MRD samples will not be 
collected during the study. 
Bone marrow aspirate for MRD testing will be collected at the end of treatment per standard 
of care. Please note, if bone marrow is positive for mantle cell lymphoma at baseline, an 
end of treatment bone marrow must be collected to confirm response. 
Peripheral blood for MRD assessments will be collected at the end of treatment. 
 
Table 9-1: Deauville Criteria for Target and Non-Target Lesions 
Score 
Criteria 
1 
No uptake 
2 
Uptake less than or equal to the mediastinal blood pool 
3 
Uptake greater than the mediastinal blood pool but less than the liver 
4 
Uptake moderately higher than the liver 
5 
Uptake markedly higher than the liver and/or new lesions 
X 
Areas of uptake unlikely to be related to lymphoma 


PrECOG Protocol Number: PrE0405 
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41 
10. 
Study Treatments, Parameters, and Assessments 
1. All pre-study scans and biopsies should be done ≤ 6 weeks prior to registration. 
2. All other pre-study assessments should be done ≤ 2 weeks prior to registration, unless otherwise noted. 
Procedures 
Screening 
Cycle 1* 
(1 cycle=28 Days) 
Cycle 2 and Subsequent 
Cycles* 
Prior to 
Cycle 3 
or 4 
End of  
Treatment 
Visit25 
Follow-Up27 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
2 
Day 
10 
Day 
11-28 
Windows (+/- days): 
-28 to -1 
 
1 
1 
1 
1 
3 
1 
 
 
7 
14 
 
Administrative Procedures 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Characteristics1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Baseline Signs 
& Symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Clinical Procedures/Assessments 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam including Weight 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Vital Signs 
(Temperature, Pulse, Blood 
Pressure) 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
Body Surface Area (BSA) 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Review Adverse Events 
 
X 
 
X 
X 
X 
X 
 
 
 
 
X26 
 
Laboratory Assessments 
CBC/Differential/Platelets2 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
X 
 
Chemistry3 
X 
X 
X 
X 
X 
X 
X 
X4 
 
 
 
X 
 
Liver Function5 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
LDH 
X 
 
 
 
 
 
 
 
 
 
 
X 
 


PrECOG Protocol Number: PrE0405 
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42 
Procedures 
Screening 
Cycle 1* 
(1 cycle=28 Days) 
Cycle 2 and Subsequent 
Cycles* 
Prior to 
Cycle 3 
or 4 
End of  
Treatment 
Visit25 
Follow-Up27 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
2 
Day 
10 
Day 
11-28 
Windows (+/- days): 
-28 to -1 
 
1 
1 
1 
1 
3 
1 
 
 
7 
14 
 
Tumor Lysis Labs6 
 
X 
X 
X 
X 
X 
X 
X4 
 
 
 
 
 
Beta-2 Microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Hepatitis B and C Testing7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CMV Monitoring9 
X 
 
 
 
 
 
X 
 
 
 
 
X9 
 
Treatments10 
Oral Hydration11 
 
X 
X 
X 
X 
X 
X11 
 
 
 
 
 
 
Intravenous Hydration12 
 
X 
 
 
 
 
X12 
 
 
 
 
 
 
Venetoclax (dose in mg)13 
 
20 
20 
50 
100 
200 
400 
400 
400 
0 
 
 
 
Bendamustine14 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
Rituximab15 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Growth Factor Support16 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
PJP & Antiviral Prophylaxis17 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
 
Subject Calendars 
Venetoclax Medication Diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Disease Assessments/Measurements 
PET/CT 
X 
 
 
 
 
 
 
 
 
 
 
X18 
 
Bone Marrow Biopsy & Aspirate 
X 
 
 
 
 
 
 
 
 
 
 
X19 
 
CT Chest/Abdomen/Pelvis 
 
 
 
 
 
 
 
 
 
 
X20 
 
 
Disease and Survival Status 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Correlative Study Samples 
Archived Tissue Procurement 
(Mandatory)21 
X 
 
 
 
 
 
 
 
 
 
 
X22 
X22 
Research Blood Specimens 
(Optional)23 
 
X 
 
 
 
 
X23 
 
 
 
 
X 
 
MRD testing24 
(Mandatory) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 


PrECOG Protocol Number: PrE0405 
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43 
* 
Scheduled Visits: In general +/- 3 day window for therapy/tests/visits during therapy except as noted for TLS monitoring. Delay due to holidays, weekends, 
bad weather or other unforeseen circumstances will be permitted. 
1 
Record date of diagnosis, primary tumor type, histology, stage, and MCL international prognostic index (MIPI). MIPI calculator can be accessed using the 
website 
at 
https://qxmd.com/calculate/calculator_149/mipi-mantle-cell-lymphoma-prognosis34 
or 
https://www.mdcalc.com/mantle-cell-lymphoma-
international-prognostic-index-mipi35.36,37 
2 
CBC with differential and platelet count which includes WBC, ANC, Platelets, Hgb, and Hct. Required prior to each dose of treatment, and results known prior 
to treatment administration. 
3 
BUN/creatinine, sodium, potassium, chloride, bicarbonate (HCO3), glucose, and calcium. Refer to Section 5.4, Table 5-3 “Tumor Lysis Monitoring” for 
additional time points and days not captured on Study Calendar. 
4 
Cycle 2, Day 2 only. 
5 
Albumin, total protein, alkaline phosphatase, AST, ALT, and total bilirubin. 
6 
Basic Metabolic Panel (Sodium, Potassium, Chloride, Bicarbonate (HCO3), BUN, Creatinine, Calcium), Albumin, Uric Acid, and Phosphorus. Refer to Section 
5.4, Table 5-3 “Tumor Lysis Monitoring” for additional time points and days not captured on Study Calendar. See Appendix IV for “Definitions of Tumor Lysis 
Syndrome31”. 
7 
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) are allowed with protective hepatitis B surface antibody AND a negative hepatitis B viral load by PCR. If enrolled, 
patients must be willing to undergo monthly HBV DNA testing. 
Patients with positive HCV antibody must be negative for HCV by PCR to be eligible for study participation. Prior treatment for an active hepatitis C infection 
will be allowed so long as the hepatitis C viral load by PCR is negative. 
8 
Required for females of child-bearing potential. 
9 
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 5.7: Monitoring for Cytomegalovirus (CMV) for additional monitoring parameters and guidelines. 
Induction: Once a month and end of induction. 
Maintenance: Treating physician discretion or per institutional standards; however, if detectable, recommend continued monitoring per institutional standards. 
10 Standard pre-medications and antiemetic therapy per institutional guidelines are allowed per Section 5.1. Also, refer to Section 5.3 for details on prophylaxis 
for TLS. 
11 Encourage at least 2 liters of oral fluids per day starting 24 hours prior to Cycle 1, Day 1 and continuing until Cycle 2, Day 10. Refer to Section 5.3 for details. 
12 At least 1 liter of IV hydration should be given on Day 1 of Cycle 1 and Cycle 2. Additional IV fluids and monitoring for TLS is allowed per treating physician 
discretion. Refer to Section 5.3 for details. 
13 Venetoclax will be administered orally. Cycle 1: 20 mg on Day 1-7; 50 mg on Day 8-14; 100 mg on Day 15-21; and 200 mg on Day 22-28. Cycle 2-6: 400 mg 
on Day 1-10. One cycle = 28 days. On days when venetoclax is given with additional anti-lymphoma agents, venetoclax should be given first. See Section 5 
for dosing instructions and tumor lysis prophylaxis/monitoring and Section 6 for dose delays/modifications. 


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14 Bendamustine is given as 90 mg/m2 IV day 1 and 2 before or after rituximab. See Section 5 for dosing instructions and Section 6 for dose delays/modifications. 
NOTE: Per investigator discretion, bendamustine may be started at 70 mg/m2 in patients over the age of 75 years with comorbid conditions or patients over 
the age of 80 years without comorbid conditions. 
15 Rituximab 375 mg/m2 is given on Day 1 of each cycle before or after bendamustine. If the first two cycles (or two consecutive cycles) of rituximab are well 
tolerated, IV rituximab may be replaced with 1400 mg/23,400 units SQ rituximab/hyaluronic acid on Day 1 of Cycles 3-6 (or after 2 consecutive cycles are 
well tolerated), per investigator and patient preference. Biosimilars for rituximab are permitted. See Section 5 for dosing instructions and Section 6 for dose 
delays/modifications. 
NOTE: After 6 cycles of venetoclax, bendamustine and rituximab, subjects responding to therapy may receive maintenance rituximab (one dose every 8 ± 
2 weeks for 12 doses or 24 months whichever comes first) per physician and patient preference. 
16 Growth factor support should be given 24-72 hours after the last dose of bendamustine for each cycle per Section 5.5. 
17 All patients must be initiated on prophylaxis at the start of Cycle 2 of venetoclax, bendamustine and rituximab. 
PJP Prophylaxis: Trimethoprim-sulfamethoxazole (Bactrim) for PJP prophylaxis and should continue until 6-8 weeks from Day 1 of last completed induction 
cycle. 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 5.6: Infection Prophylaxis for additional parameters and guidelines. 
18 PET/CT 6-8 weeks after Day 1 of last completed cycle. Each target lesion should have Deauville score at end of treatment. Refer to Section 9.2, Table 9-1 
and Appendix V for details. 
19 Bone marrow biopsy and aspirate per standard of care but must be performed if PET/CT shows CR and bone marrow biopsy was positive at screening to 
confirm CR. Mandatory sample submission for research when collected per standard of care. 
20 Repeat imaging before Cycle 3 or 4 per institutional guidelines. CT scans or PET/CT scans may be used at this time point per institution standards. Any 
progression should be confirmed by PET/CT. 
21 Pre-treatment, diagnostic pathology specimens (organ or lymph node biopsy or excision) obtained in the course of standard biopsy or surgery (if sufficient 
tissue is available, submission is mandatory). Formalin-Fixed Paraffin-Embedded (FFPE) blocks and 5 FFPE slides or up to 15 FFPE slides plus H&E slide 
(if tissue is limited, then minimum of 10 slides) will be required. Procurement of tissue will be mandatory for enrollment, but if additional tissue from initial 
biopsy is not available, repeat biopsy will not be required. Optional: Any leftover tissue banked for future research. See Section 13.1 and PrE0405 Lab Manual 
for details. 
NOTE: If blocks and/or slides are unavailable and bone marrow is involved with mantle cell lymphoma, obtain two 2 mL EDTA tubes of bone marrow aspirate 
(one for baseline MRD analysis and one for future research). If blocks/slides and bone marrow are unavailable and peripheral blood is involved with 
mantle cell lymphoma obtain one 4 mL and one 6 mL EDTA tubes of peripheral blood (one for baseline MRD analysis and one for future research). 
If baseline samples (blocks/slides, bone marrow, and/or peripheral blood) are not submitted at baseline for MRD (i.e., not involved with mantle cell 
lymphoma), then patients will be allowed to remain on study but MRD samples will not be collected during the study. 
22 Optional: At time of progression, biopsy samples are requested to be sent for correlative studies and banked for future research. See Section 13.1 and 
PrE0405 Lab Manual for details. 


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23 Optional Research Bloods: See Section 13.3 and PrE0405 Lab Manual for details. 
Cycle 1, Day 1 (prior to treatment) 
Peripheral Blood: One 10 mL red top tube and one 6 mL in EDTA tube 
Cycle 2, Day 1 (prior to treatment) 
Peripheral Blood: One 10 mL red top tube and one 6 mL in EDTA tube 
Cycle 4, Day 1 (prior to treatment) 
Peripheral Blood: One 10 mL red top tube and one 6 mL in EDTA tube 
End of Treatment Visit 
Peripheral Blood: One 10 mL red top tube and one 6 mL in EDTA tube 
At Time of Progression 
Peripheral Blood: One 10 mL red top tube, one 4 mL and one 6 mL in EDTA tube 
24 Mandatory MRD Samples: See Section 13.1, 13.2, 13.3 and PrE0405 Lab Manual for details. 
Screening/Study Entry 
FFPE: 3-5 FFPE slides from lymph node (preferred) 
NOTE: If FFPE unavailable, either bone marrow aspirate (2 mL EDTA tube) or peripheral blood (4 mL EDTA tube) are acceptable as long as they are 
involved with mantle cell lymphoma. If baseline samples (blocks/slides, bone marrow, and/or peripheral blood) are not submitted at baseline for MRD 
(i.e., not involved with mantle cell lymphoma), then patients will be allowed to remain on study but MRD samples will not be collected during the 
study. 
End of Treatment Visit 
Peripheral Blood: One 4 mL in EDTA tube 
Bone Marrow Aspirate (per standard of care)*: One 2 mL in EDTA tube 
*Bone Marrow Aspirate: Submission is mandatory when collected per standard of care. Please note, if bone marrow is positive for mantle cell lymphoma at 
baseline, an end of treatment bone marrow must be collected to confirm response. 
25 6-8 weeks after Day 1 of last completed cycle. 
26 Patients will be followed for adverse events for 30 days after their last dose of study medication. 
27 Every 3-6 months or per institutional guidelines for up to 5 years from treatment discontinuation for progression and survival. Imaging to be done per institution 
standards and/or physician discretion. Maintenance rituximab is allowed and will be documented but will not constitute additional therapy. 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 with the exception of allowed maintenance rituximab for up to 5 years or study closure. 


PrECOG Protocol Number: PrE0405 
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46 
11. 
Drug Formulation and Procurement 
11.1 
Venetoclax21,22 
11.1.1 Other Names 
GDC-0199, ABT-199, RO5537382. 
11.1.2 Classification 
Oral Bcl-2 family protein inhibitor. 
11.1.3 Storage and Stability 
Venetoclax will be supplied in bottles with 10 mg, 50 mg, and 100 mg tablets. 
The 10 mg film-coated tablets are round, biconvex shaped, pale yellow debossed with 
“V” on one side and “10” on the other side. 
The 50 mg film-coated tablets are oblong, biconvex shaped, beige debossed with “V” 
on one side and “50” on the other side. 
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). 
11.1.4 Dose Specifics 
In Cycle 1, venetoclax is dispensed in a 1-week supply. There will be a gradual dose 
escalation in Cycle 1 (Table 5-2). 
In Cycle 2-6, venetoclax is dispensed in a 4-week supply. Cycle 2-6, patients will take 
four tablets (400 mg) daily on days 1-10 for each 28 day cycle. Tablets should not be 
chewed, crushed or broken. 
On days when venetoclax is given with bendamustine and rituximab, 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. 
If patient misses a dose of venetoclax within 8 hours of when it is usually taken, the 
patient should take the dose as soon as possible and resume normal daily dosing 
schedule. Should the dose be missed by greater than 8 hours, the dose should be 
skipped and patient should resume normal daily dosing the following day. This dose 
should not be made up. 
Refer to Section 5.2 for details. 
11.1.5 Drug Interactions 
Drug-drug interactions may occur with venetoclax. Co-administration of venetoclax 
with strong to moderate inhibitors or inducers of CYP3A or P-gp inhibitors is prohibited. 
Co-administration with weak CYP3A inhibitors and inducers is allowed. P-gp substrate 
should be avoided. If a concomitant use is unavoidable, separate dosing of the P-gp 
substrate at least 6 hours before venetoclax. 
In cycles 2-6 when venetoclax will not be administered (i.e., Days 11-28), avoid the 
use of strong or moderate CYP3A inhibitors or P-gp inhibitors 2 to 3 days prior to the 
next cycle of venetoclax treatment. Also avoid the use of strong or moderate CYP3A 
inducers at least 7 days prior to the next cycle of venetoclax treatment. 


PrECOG Protocol Number: PrE0405 
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47 
See Section 6.2.2 and Appendix III: Additional Excluded and Cautionary Medications 
for a list of medications that are to be excluded or used with caution in patients 
receiving venetoclax. 
11.1.6 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. 
11.1.7 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. 
11.1.8 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. 
11.1.9 Side Effects 
11.1.9.1 Tumor Lysis Syndrome 
TLS is a risk for patients with MCL who are treated with high cell-killing 
agents, including venetoclax. The highest risk for TLS occurs within the first 
24 hours of a dose escalation caused by rapid reduction of the tumor. Refer 
to Section 5.3 for Tumor Lysis Prophylaxis and Section 5.4 for Tumor Lysis 
Monitoring. 
NOTE: Defined risks for TLS are not clear in MCL but some higher risk 
situations include: 
 
Bulky disease (any lymph node mass >10 cm) 
 
Circulating mantle cell lymphoma with ALC >25 x 109/L 
 
Borderline renal function 
 
Rapidly progressing disease. 
11.1.9.2 Neutropenia 
Neutropenia is an important identified risk for venetoclax, specifically in CLL. 
Clinical data from the oncology studies suggest that the neutropenia 
adverse events 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. Serious adverse 
events of neutropenia or neutropenia events that lead to discontinuations 
are few across the entire venetoclax oncology program. 
11.1.9.3 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 


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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] for oncology subjects). 
11.1.9.4 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. 
11.1.9.5 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. 
11.1.9.6 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 jiroveci pneumonia infections. 
11.1.9.7 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. 
11.1.9.8 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 relapsed/refractory (R/R) disease who had 
previously been treated with various cytotoxic agents, second primary 
malignancies should be closely monitored. 
11.1.9.9 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. 
 
 


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11.1.9.10 Drug-Drug Interaction 
Co-administration of venetoclax with strong to moderate inhibitors or 
inducers of CYP3A or P-gp inhibitors is prohibited. Co-administration with 
weak CYP3A inhibitors and inducers is allowed. P-gp substrate should be 
avoided. If a concomitant use is unavoidable, separate dosing of the P-gp 
substrate at least 6 hours before venetoclax. 
In cycles 2-6 when venetoclax will not be administered (i.e., Days 11-28), 
avoid the use of strong or moderate CYP3A inhibitors or P-gp inhibitors 2 to 
3 days prior to the next cycle of venetoclax treatment. Also avoid the use of 
strong or moderate CYP3A inducers at least 7 days prior to the next cycle 
of venetoclax treatment. (Section 6.2.2 and Appendix III: Additional 
Excluded and Cautionary Medications). 
Live attenuated vaccines should not be administered prior to, during, or 
after treatment with venetoclax until B-cell recovery occurs. 
11.1.9.11 Overdose 
There is no specific antidote for venetoclax. For patients who experience 
overdose, closely monitor and provide appropriate supportive treatment; 
during ramp-up phase interrupt venetoclax and monitor carefully for signs 
and symptoms of TLS along with other toxicities. 
11.1.10 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 
Bendamustine38 
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. 
11.2.1 Other Names 
Bendamustine hydrochloride, Treanda, Bendeka. 
11.2.2 Classification 
Alkylating neoplastic agent. 
11.2.3 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. 
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% 


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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. 
11.2.4 Dose Specifics 
Induction: Bendamustine will be administered at 90 mg/m² intravenously on Day 1 and 
Day 2 of every 28 day cycle for 6 cycles. 
NOTE: Per investigator discretion, bendamustine may be started at 70 mg/m2 in 
patients over the age of 75 years with comorbid conditions or patients over 
the age of 80 years without comorbid conditions. 
11.2.5 Preparation 
Refer to commercial package insert or institutional guidelines for preparation of 
bendamustine. 
11.2.6 Route of Administration  
Bendamustine will be administered as an IV infusion per institutional guidelines and 
package insert at a dose of 90 mg/m2 on days 1 and 2 of each 28-day cycle. 
NOTE: Per investigator discretion, bendamustine may be started at 70 mg/m2 in 
patients over the age of 75 years with comorbid conditions or patients over 
the age of 80 years without comorbid conditions. 
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. 
11.2.7 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. 
11.2.8 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 


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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. 
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. 
11.2.9 Incompatibilities 
No incompatibilities are known (no data is available). 
11.2.10 Side Effects 
Please refer to Package Insert. 
11.2.11 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. 
11.3 
Rituximab39,40 
Rituximab 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. 
Biosimilars for rituximab are permitted. 
11.3.1 Other Names 
IDEC-C2B8, Chimeric anti-CD20 monoclonal antibody, Rituxan. 
11.3.2 Classification 
Antibody 
 
 


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11.3.3 Storage and Stability 
Rituximab IV: Store vials in the refrigerator at 2ºC–8ºC (36ºF–46ºF). Protect vials from 
direct sunlight. Once diluted to a concentration of 1 to 4 mg/mL in polyvinylchloride or 
polyolefin IV bags containing normal saline or 5% dextrose, the product is stable for up 
to 24 hours at 2ºC–8ºC (36ºF–46ºF), and at room temperature for an additional 12 
hours after refrigeration (for a maximum period of 36 hours) if protected from light. 
Rituximab SQ: Store vials in the refrigerator at 2ºC–8ºC (36ºF–46ºF) in the original 
carton to protect from light. Do not freeze. 
Biosimilars for rituximab are permitted. Refer to package insert for storage and stability 
parameters. 
11.3.4 Dose Specifics 
Induction: Rituximab will be administered at 375 mg/m² intravenously every 28 days for 
6 cycles. 
NOTE: For patients that do not have a Grade 3-4 infusion related adverse event, 
Cycle 2-6 may be given as a “rapid” IV infusion at 375 mg/m2 per package 
insert. 
Additionally, if the first two cycles (or two consecutive cycles) of rituximab are 
well tolerated, IV rituximab may be replaced with 1400 mg/23,400 units SQ 
rituximab/hyaluronic acid on Day 1 of Cycle 3-6 (or after 2 consecutive cycles 
are well tolerated), per rituximab/hyaluronic acid package insert. 
Maintenance: After 6 cycles of venetoclax, bendamustine and rituximab, subjects 
responding to therapy may receive maintenance rituximab IV or SQ (one dose every 
8 ± 2 weeks for 12 doses or 24 months whichever comes first) per physician and 
patient preference. 
Biosimilars for rituximab are permitted. Refer to package insert for dose specifics. 
11.3.5 Preparation 
Rituximab IV: Withdraw the necessary amount of rituximab and dilute to a final 
concentration of 1 to 4 mg/mL into an infusion bag containing either 0.9% Sodium 
Chloride or 5% Dextrose in Water. Gently invert the bag to mix the solution. Caution 
should be taken during the preparation of the drug, as shaking can cause aggregation 
and precipitation of the antibody. 
Rituximab preparation may also be done per institutional standards. 
Rituximab SQ: Subcutaneous injection is supplied as a sterile preservative-free liquid 
solution in a single-dose vial. 
Biosimilars for rituximab are permitted. Refer to package insert for preparation 
instructions. 
11.3.6 Route of Administration 
Rituximab IV: Rituximab should be given as a “standard” IV infusion at 375 mg/m2 
for Cycle 1 per institution guidelines and package insert. For patients that do not 
have a Grade 3-4 infusion related adverse event, Cycle 2-6 may be given as a “rapid” 
IV infusion at 375 mg/m2 per institution guidelines and package insert. Patients that 
do have a Grade 3-4 infusion related adverse event should receive the “standard” 
infusion rate for the subsequent cycle. Patients may receive the “rapid” infusion 
schedule if the prior infusion was not associated with a Grade 3-4 infusion related 
adverse event. 


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Rituximab SQ: 1400 mg/23,400 units SQ rituximab/hyaluronic acid on Day 1 of Cycle 
3-6 (or after two consecutive cycles are well tolerated), per rituximab/hyaluronic acid 
package insert. 
Biosimilars for rituximab are permitted. Refer to package insert for route of 
administration instructions. 
11.3.7 Incompatibilities 
Rituximab IV: Do not mix or dilute rituximab with other drugs. No incompatibilities 
between rituximab and polyvinylchloride or polyethylene bags have been observed. 
Rituximab Biosimilars: Refer to package insert for incompatibilities. 
11.3.8 Side Effects 
Please refer to Package Insert. 
11.3.9 Nursing/Patient Implications 
1. Monitor blood pressure, pulse, respiration, and temperature every 15 minutes x 
4 or until stable and then hourly until the infusion is discontinued or per standard 
of care. 
2. Have epinephrine for subcutaneous injections, diphenhydramine for intravenous 
injection, and resuscitation equipment for 
emergency management of 
anaphylactoid reactions available. 
3. Monitor and alter infusion rates in the presence of toxicities. 


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12. 
Statistical Considerations 
12.1 
Study Design, Sample Size Considerations & Statistical Analyses 
12.1.1 Primary Endpoint 
The primary endpoint of this single arm Phase II study is CR rate after 6 cycles of BR 
+ venetoclax. A 15% improvement in the historical post-induction CR rate of 70% to 
85% is of interest. A total of 56 patients will be enrolled, 53 of whom are expected to 
be eligible and treated. There will be 90% power to detect the 15% improvement in 
CR rate from 70% using one-sided exact binomial test with 10% Type I error. This 
treatment combination will be considered worthy of further investigation if 42 or more 
eligible and treated patients achieve CR. The efficacy population consists of all eligible 
and treated patients. 
12.1.1.1 Revised Study Design 
Preliminary data from a similar cohort of patients as that enrolled in this 
study indicates that post-induction CR rate is 60%, not 70% as initially 
assumed. In addition, the observed study accrual rate (1.1 patients/month) 
is significantly lower than the planned/expected study accrual rate of 2.3 
patients/month. For both reasons, the study was redesigned to reflect the 
current historical CR rate and with a lowered sample size for prompt primary 
endpoint readout. Accrual before this redesign is 25 patients as of 
10/11/2021. 
With a revised accrual goal of 33 patients, 32 patients expected to be eligible 
and treated, there is 81.8% power and 11.6% alpha using exact binomial 
test to detect a 17% difference in CR rate from 60% to 77%. The null 
hypothesis will be rejected, and treatment combination declared positive if 
≥ 23 (71.9%) CRs are observed among 32 eligible and treated patients. 
12.1.2 Secondary Endpoints 
Secondary endpoints include progression free survival (PFS) and overall survival 
(OS). PFS is defined as time from registration to disease progression or death from 
any cause, whichever occurs first. Patients that are alive and progression free at the 
time of analysis will be censored at the date of last disease assessment. OS is defined 
as time from registration to death; patients will be censored at the time of last study 
contact. PFS and OS will be estimated using Kaplan-Meier methodology and 90% 
confidence interval (CI) around estimates will be presented. Appropriate descriptive 
measures will be used to describe clinical and demographic variables. 
12.2 
Planned Analyses 
12.2.1 Toxicity Monitoring Plan 
12.2.1.1 Tumor Lysis Syndrome 
Tumor Lysis Syndrome (TLS) is an event of interest in this study. TLS risk 
factors are listed in Section 5.3, TLS monitoring plan is detailed in Section 
5.4 and “Definitions for Tumor Lysis Syndrome” noted in Appendix IV. The 
risk for TLS will be assessed among the first 19 patients accrued to this 
study who received venetoclax treatment for at least 3 cycles with no hold 
to accrual. Given the expected clinical TLS rate of 5%, the probability of 
observing at least one clinical TLS among 19 patients is 62%, and 82% 
among 33 patients. 
 
 


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A TLS incidence rate of no more than 15% (≤ 3 out of 19 patients) is 
permissible on this study. If the observed TLS is ≥ 21% (≥ 4 out of 19 
patients) then a detailed review of TLS cases will be conducted by the Data 
Safety Monitoring Board (DSMB). This is the boundary and the DSMB could 
recommend closing the study due to high incidence of TLS. If the true 
incidence of TLS is 30% or higher, there is at least 87% probability of 
crossing the boundary. Whereas, if the true incidence of TLS is 10% there 
is only 11% chance of crossing the boundary. 
12.2.1.2 Non-Disease Related Death on Treatment 
Deaths during induction have been reported in prior studies with BR and 
novel combinations, particularly bortezomib and lenalidomide.13,14 The 
combined rate of non-disease related death in these studies is 
approximately 5.5%, which is considered unacceptable. Non-disease 
related death, defined as death from any cause not due to mantle cell 
lymphoma and occurring at any time from Cycle 1, Day 1 to end of 
treatment, will be monitored during the study and each event will be reported 
to the DSMB. In addition to reporting each non-disease related death event 
to the DSMB for review, the cumulative observed number of events will be 
assessed, based on the presented operating characteristics, at specific 
accrual stages specified in the table below. These accrual stages include 
after 19, 28, and 33 patients enrollment. If at any of the accrual stages the 
specified boundary for that stage is crossed, the study will pause enrollment 
and await DSMB review and recommendations. During the review, the 
DSMB may decide that a death event is not related to treatment and may 
exclude the event from further calculations (i.e. accident or suicide). 
From the table, at the 19 patient enrollment and treatment milestone, the 
expected number of non-disease related death is 1 (based on the 5.5% rate 
reported from referenced studies). If ≥ 2 such death events occur (i.e. 
boundary is crossed) among 19 patients then the DSMB will review all non-
disease related death cases. There is 8.1%, 28.1%, 45.6%, 58.0%, 68.3%, 
and 80.2% probability of crossing the boundary if the true underlying non-
disease related death rate is 2.5%, 5.5%, 8%, 10%, 12%, and 15% 
respectively. 
If at any time there are greater than 5 non-disease related deaths during 
induction, the study may close for safety. If the true non-disease related 
death rate is 5.5% then the probability of observing >5 events among 33 
patients is only 0.8%. Whereas the probability of observing >5 events is 
10.6% if the true non-disease related death rate is 10%, and 67.1% if the 
true underlying death rate is 20%. 
 
 
 
 
 
 
 
 


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Table12-1: Operating Characteristics of Non-Disease Related Death on Treatment 
 
Accrual Stage 
(Number of Expected Eligible and Treated 
Patients 
Total Accrual (N=33) 
19 
28 
33 
 
*Expected # of deaths based on 5.5% estimate 
1 
2 
2 
 
Boundary (defined as expected # of deaths + 1) 
2 
3 
3 
 
Probability of crossing boundary given true 
death rate of 
 
 
 
 
 
a) 2.5% 
 
 
 
 
 
b) 5.5% 
 
 
 
 
 
c) 8% 
 
 
 
 
 
d) 10% 
 
 
 
 
 
e) 12% 
 
 
 
 
 
f) 15% 
 
 
8.1% 
28.1% 
45.6% 
58.0% 
68.3% 
80.2% 
 
 
3.2% 
19.8% 
39.1% 
54.1% 
67.0% 
81.3% 
 
 
4.9% 
27.2% 
49.8% 
65.4% 
77.5% 
89.1% 
 
*Rounded to the nearest whole number 
12.2.1.3 Other Toxicity 
Toxicity and adverse events for all enrolled patients will be monitored 
throughout the conduct of the study. Toxicity rates, with 90% exact binomial 
CIs, will be estimated for all enrolled patients who received at least one cycle 
of treatment, irrespective of eligibility. These rates will be estimated for 
Grade 3 or higher treatment-related toxicities using CTCAE Version 5.0. If 
all 33 patients are treated, the maximum width of a 90% exact CI on the rate 
of Grade 3 or higher treatment-related toxicities will be no wider than 31%. 
The probability of observing at least one rare toxicity event (given a true rate 
of 5%) is 81.6%. The DSMB will review safety data and may halt the study 
for safety if any grade 4 or higher specific toxicity occurs with an incidence 
rate of >30%. 
12.2.1.4 Study and Safety Monitoring Plan 
This study will be monitored by the PrECOG DSMB. The DSMB meets twice 
each year, or as frequently as deemed necessary by the DSMB. For each 
meeting, all monitored studies are reviewed for toxicity and progress toward 
completion. If a safety concern is identified, the DSMB may recommend 
halting or permanently stopping the trial at any time. 
12.2.2 Analyses of Correlative Studies 
Minimum Residual Disease (MRD) will be analyzed as a binary endpoint and 90% 
exact CI around the estimated MRD negative rate will be reported. This estimate will 
also be reported within levels of response to BR + venetoclax treatment. 


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13. 
Laboratory and Pathology Correlative Studies 
13.1 
Correlative Studies: Mandatory Tumor Samples (if sufficient tissue available) 
13.1.1 Research Tumor Sample Collection 
Pre-treatment, diagnostic pathology specimens (organ or lymph node biopsy or 
excision) obtained in the course of standard biopsy or surgery (if sufficient tissue is 
available, submission is mandatory). 
Formalin-fixed paraffin-embedded (FFPE) blocks and 5 FFPE tissue on unstained (5 
um) slides or if blocks are not available, up to 15 FFPE tissue on unstained (5 um) 
slides plus H&E slide (if tissue is limited, then minimum of 10 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). 
Five slides per patient will be sent to Adaptive Biotechnologies for baseline calibration 
(obtained from a patient at the time of diagnosis and before treatment has begun) 
measurement for MRD. 
If blocks and/or slides are unavailable and bone marrow is involved with mantle cell 
lymphoma, obtain two 2 mL EDTA tubes of bone marrow aspirate (one for baseline 
MRD analysis and one for future research). If blocks/slides and bone marrow are 
unavailable and peripheral blood is involved with mantle cell lymphoma obtain one 4 
mL and one 6 mL EDTA tubes of peripheral blood (one for baseline MRD analysis and 
one for future research). If baseline samples (blocks/slides, bone marrow, and/or 
peripheral blood) are not submitted at baseline for MRD (i.e., not involved with mantle 
cell lymphoma), then patients will be allowed to remain on study but MRD samples will 
not be collected during the study. 
Optional: Any tumor biopsy samples obtained during treatment or post-treatment 
(FFPE blocks or up to 15 FFPE tissue on unstained (5 um) slides plus H&E 
slide) will be requested for research if conducted due to concerns for 
progressive disease and banked for future research. 
Blocks or remaining slide samples will be sent to the ECOG-ACRIN Central 
Biorepository Pathology Facility (CBPF) for storage. 
13.1.2 Pathology Sample Processing and Shipment 
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. Refer to the 
PrE0405 Lab Manual for details. 
13.1.2.1 MRD Pathology Samples to Adaptive Biotechnologies 
Sites should submit 5 FFPE slides (minimum of 3 slides) from a tumor tissue 
block. Thickness of the sections should be at 5 micron. 
Samples should be shipped Monday-Thursday. Samples will be shipped 
ambient via overnight courier approximately every 6 months on a set 
schedule. For all patients the initial shipment should include Baseline (tissue 
sample) and End of Treatment (bone marrow, if collected and peripheral 
blood) samples. 


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13.1.2.2 Remaining Pathology Samples to Central Lab 
Sites should submit FFPE diagnosis tumor tissue blocks or up to 10 FFPE 
slides plus H&E slide from a tumor tissue block within 6 months of patient 
registration. Thickness of the sections should be at 5 micron. 
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 (5 microns) on unstained slides plus H&E slide) within 3 
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 to the CBPF approximately every 6 months. 
13.2 
Correlative Studies: Mandatory Bone Marrow Samples 
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. Refer to the PrE0405 
Lab Manual for details. 
13.2.1 Research Bone Marrow Sample Collection 
• 
Screening (only if FFPE tumor samples are not available and bone marrow 
involved with mantle cell lymphoma) 
- 
One 2 mL EDTA tube for MRD calibration sample 
- 
One 2 mL EDTA tube for future research 
• 
End of Treatment (submission is mandatory if collected) 
- 
One 2 mL EDTA tube for MRD analysis 
Please note, if bone marrow is positive for mantle cell lymphoma at baseline, an end 
of treatment bone marrow must be collected to confirm response. 
13.2.2 Research Bone Marrow Processing and Shipment 
13.2.2.1 MRD Bone Marrow Aspirate Samples to Adaptive Biotechnologies 
Store 2 mL EDTA tube in the freezer at ≤ -80°C or colder until shipped to 
Adaptive Biotechnologies. 
Samples should be shipped Monday-Thursday. Samples must be shipped 
on dry ice via overnight courier approximately every 6 months on a set 
schedule. For all patients the initial shipment should include Baseline (tissue 
sample) and End of Treatment (bone marrow aspirate, if collected and 
peripheral blood) samples. 
13.2.2.2 Remaining Bone Marrow Aspirate Samples to Central Lab, if applicable 
Store 2 mL EDTA tube in the freezer at ≤ -80°C or colder until shipped to 
ECOG-ACRIN CBPF. 
Bone marrow aspirate samples should be submitted approximately every 6 
months, as applicable. A copy of the BM report should be sent when the 
sample is shipped. Samples should be shipped Monday-Thursday. 
Samples must be shipped on dry ice via overnight courier to the CBPF. 
 


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13.3 
Correlative Studies: Mandatory and Optional Peripheral Blood Samples 
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. Refer to the PrE0405 
Lab Manual for details. 
MRD Samples are mandatory. Samples for future research are optional except screening 
sample is mandatory, as applicable. 
13.3.1 Research Blood Sample Collection 
• 
Screening (only if FFPE tumor and BM samples are not available and 
peripheral blood involved with mantle cell lymphoma) 
- 
One 4 mL EDTA tube for MRD calibration sample 
- 
One 6 mL EDTA tube for future research 
• 
Cycle 1, Day 1 
- 
One 10 mL red top tube for future research 
- 
One 6 mL EDTA tube for future research 
• 
Cycle 2, Day 1 (If sample drawn and cycle delayed, this sample may be used, 
do not need to repeat) 
- 
One 10 mL red top tube for future research 
- 
One 6 mL EDTA tube for future research 
• 
Cycle 4, Day 1 (If sample drawn and cycle delayed, this sample may be used, 
do not need to repeat) 
- 
One 10 mL red top tube for future research 
- 
One 6 mL EDTA tube for future research 
• 
End of Treatment 
- 
One 4 mL EDTA tube for MRD analysis 
- 
One 10 mL red top tube for future research 
- 
One 6 mL EDTA tube for future research 
• 
At Time of Progression 
- 
One 4 mL EDTA tube for future research 
- 
One 10 mL red top tube for future research 
- 
One 6 mL EDTA tube for future research 
13.3.2 Research Blood Sample Processing and Shipment 
13.3.2.1 MRD Peripheral Blood Samples to Adaptive Biotechnologies 
Store 4 mL EDTA tube in the freezer at ≤ -80°C or colder until shipped to 
Adaptive Biotechnologies. 
Samples should be shipped Monday-Thursday. Baseline and End of 
Treatment samples must be shipped on dry ice via overnight courier 
approximately every 6 months on a set schedule. For all patients the initial 
shipment should include Baseline (tissue sample) and End of Treatment 
(bone marrow aspirate, if collected and peripheral blood) samples. 
NOTE:  4 mL EDTA tube sample collected at time of progression for future 
research will be stored at site. PrECOG will instruct sites when to 
ship these samples to the CBPF (approximately every 6 months). 
 


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13.3.2.2 Remaining Peripheral Blood Samples to Central Lab 
Red Top Tube (10 mL) Processing for Serum 
Gently mix the blood sample by inversion 5 times (do not shake). Allow the 
sample to sit at room temperature for 30-60 minutes in vertical positon until 
a clot has formed. If the blood is not centrifuged immediately after the 
clotting time (30-60 minutes at room temperature), the tubes should be 
refrigerated (4°C) for no longer than 4 hours. 
Once the clot has formed, the sample is ready for centrifugation. Centrifuge 
for 15 minutes at room temperature at 1200 RPM or per institutional 
practices. Immediately aliquot and store the resulting serum into two (2) 
properly labeled polypropylene tubes. Be careful to not disturb the clot. 
Store the samples in the freezer at -80°C until they are shipped to the CBPF. 
EDTA Tube (6 mL) Processing for Plasma and Buffy Coat 
**Samples should be processed within 4 hours, but at limit of 
processing being same day** 
• 
Gently mix blood sample by inversion 10 times (do not shake). 
• 
Place tube immediately on wet ice for 5 minutes. 
• 
Centrifuge at 1200 RPM for 15 minutes at 4°C. If a refrigerated 
centrifuge is not available, spin sample at room temperature (1200 RPM 
for 15 minutes) or per institutional practices. Immediately place the tube 
on wet ice after centrifugation. 
After centrifugation, the plasma layer will be at the top half of the tube. The 
nucleated cells (WBC) will be in a whitish layer, called the “buffy coat”, just 
under the plasma and above the red blood cells. 
Plasma Preparation: 
• 
Using a transfer pipette take the top two-thirds of the plasma and 
transfer plasma into a 15 mL conical centrifuge tube, be careful not to 
disturb the buffy coat layer in the EDTA tube (NOTE: see below for buffy 
coat processing instructions). Centrifuge the 15 mL conical tube at 1200 
RPM for 15 minutes at 4°C. If a refrigerated centrifuge is not available, 
spin sample at room temperature (1200 RPM for 15 minutes). 
Immediately place the conical tube on wet ice after centrifugation. 
• 
Transfer equal amounts of plasma into two (2) properly labeled 
polypropylene tubes for cryopreservation being careful not to disturb the 
small PBMC/pellet. 
• 
Store the two aliquots of plasma samples in the freezer at ≤ -80°C or 
colder until they are shipped to the CBPF. 
Buffy Coat Preparation: 
• 
From the EDTA tube remove and aliquot the “buffy coat”; be careful not 
to disturb the layer of red blood cells. 
• 
Store the aliquot of cells in one (1) properly labeled polypropylene tube 
for cryopreservation. 
• 
Store the sample in the freezer at ≤ -80°C or colder until it is shipped to 
the CBPF. 


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Plasma and buffy coat samples should be batched together and shipped 
approximately every 6 months. Individual patients should only be included 
in the shipment if all of their samples have been completed through the End 
of Treatment sample. Samples should be shipped Monday-Thursday. 
Samples must be shipped on dry ice via overnight courier to the CBPF. 
13.4 
Assay Methodology 
13.4.1 MRD Analysis 
Adaptive’s NGS MRD Assay is a process for measuring minimal residual disease 
(MRD) and will be used to analyze calibration samples and end of treatment samples 
from patients. Exploratory analyses of B-cell receptor repertoire loci will be performed 
to (i) determine disease-correlated clonotypes from each of the calibration samples 
and (ii) assess the levels of Index Clonotypes (and therefore levels of MRD) in end of 
treatment samples. 
13.4.2 Planned Analysis for Future Research Samples 
Analysis may be performed depending on resources, sample quality and availability 
for possible future molecular and genomic testing. 


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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 


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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 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. 


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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. 
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. 
 


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15. 
References 
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14. Gressin R, Daguindau N, Tempescul A, et al. A phase 2 study of rituximab, bendamustine, 
bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma. 
Haematologica. 2019 Jan; 104(1):138-146. 


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15. Grigg A, Dyer M, González Díaz M, et al. Safety and efficacy of obinutuzumab with CHOP or 
bendamustine in previously untreated follicular lymphoma. Haematologica. 2017 102:765-772, 
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16. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine 
monotherapy in patients with rituximab-refractory indolent non-hodgkin lymphoma (GADOLIN): a 
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17. Hiddemann W, Barbui AM, Canales MA, et al. Immunochemotherapy with obinutuzumab or 
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18. Visco, C, Chiappella A, Nassi L, et al. Rituximab, bendamustine, and low-dose cytarabine as 
induction therapy in elderly patients with mantle cell lymphoma: a multicenter, phase 2 trial from 
Fondazione Italiana Linfomi. Lancet Haematol. 2017; 4(1); epub e15-23. 
19. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic 
lymphocytic leukemia. N Engl J Med. 2016; 374(4): 311-22. 
20. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients 
with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017, Mar 10; 35(8):826-833. 
21. Abbvie. Venetoclax/ABT-199 Investigator's Brochure, Version 8; Date: 15 February 2017. 
22. VENCLEXTA™ (venetoclax) tablets, for oral use; Initial U.S. Approval: 2016; Highlights of 
Prescribing Information; Revised 12/2017. 
23. Anderson NM, Harrold I, Mansour MR, et al. BCL2-specific inhibitor ABT-199 synergizes strongly 
with cytarabine against the early immature LOUCY cell line but not more-differentiated T-ALL cell 
lines. Leukemia. 2014; 28(5): 1145-1148. 
24. Boegenberger JM, Kornblau SM, Pierceall WE, et al. BCL-2 family proteins as 5-Azacytidine-
sensitizing targets and determinants of response in myeloid malignancies. Leukemia. 2014; 28(8): 
1657-1665. 
25. Johnson-Farley N, Veliz J, Bhagavathi S, and Bertino JR. ABT-199, a BH3 mimetic that specifically 
targets BCL-2, enhances the antitumor activity of chemotherapy, bortezomib and JQ1 in “double 
hit” lymphoma cells. Leuk Lymphoma. 2015; 56(7):  2146-2152. 
26. 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 [abstract]. Blood. 2016; 128(22): Abstract 617. 
27. Ladetto M, Bruggemann M, Monitillo L, et al.  Next-generation sequencing and real-time 
quantitative PCR for minimal residual disease detection in B-cell disorders.  Leukemia. 2014; 28: 
1299-1307. 
28. Hoster E, and Pott, C. Minimal residual disease in mantle cell lymphoma: insights into biology and 
impact on treatment. Hematology Am Soc Hematol Educ Program. 2016; 1: 437-445. 
29. Pott C, Macintyre E, Delfau-Larue MH, et al. MRD eradiation should be the therapeutic goal in 
mantle cell lymphoma and may enable tailored treatment approaches: results of the intergroup 
trials of the European MCL Network [abstract] Blood. 2014; 124(21): Abstract 147. 
30. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization 
classification of lymphoid neoplasms. Blood 2016; 127:2375-2390. 
31. Howard SC, Jones, DP and Pui CH. The Tumor Lysis Syndrome. N Engl J Med 2011; 364: 1844-
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32. Cheson BD, Fisher RI, Barrington SF, Cavalli F, et al. Recommendations for Initial Evaluation, 
Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: the Lugano 
Classification. J Clin Oncol. 2014 Sep 20; 32(27):3059-3068. 
33. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response 
assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas 
Imaging Working Group. J Clin Oncol. 2014 Sep 20; 32(27):3048-58. 
34. Calculate by QxMD; MIPI: Mantle Cell Lymphoma Prognosis; 2020 QxMD Software, Inc.; 
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1/27/2020. 
35. MD+Calculate; Mantle Cell Lymphoma International Prognostic Index (MIPI); MDCalc 2005-2020; 
https://www.mdcalc.com/mantle-cell-lymphoma-international-prognostic-index-mipi; last accessed 
1/27/2020. 
36. Hoster E, Dreyling M, Klapper W et al. A new prognostic index (MIPI) for patients with advanced 
stage mantle cell lymphoma. Blood. 2007; 111:558-565. 
37. American Society of Hematology, 2008. Correction to Hoster, et al. 111 (7): 558. Erratum in Hoster 
et al. A new prognostic index (MIPI) for patients with advanced stage mantle cell lymphoma. Blood. 
2008; 111: 558-565. 
38. Treanda ® (bendamustine hydrochloride) for injection, for intravenous use; Initial U.S. Approval: 
2008; Highlights of Prescribing Information; Revised 12/2017. 
39. Rituxan® (rituximab) injection, for intravenous use; Initial U.S. Approval: 1997; Highlights of 
Prescribing Information; Revised 4/2016. 
40. Rituxan Hycela™ (rituximab and hyaluronidase human) injection, for subcutaneous use; Initial U.S. 
Approval: 2017; Highlights of Prescribing Information; Revised 6/2017. 
 


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Appendix I: 
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 
house work, 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 II: 
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 


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Appendix III: 
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 and P-gp 
Inhibitors 
Continuous use of strong and moderate CYP3A inhibitors, CYP3A inducers or P-gp Inhibitors is not allowed. 
If a subject requires continuous use of these drugs they will be excluded. Consider alternative medications. 
NOTE: In cycles 2-6 when venetoclax will not be administered (i.e., Days 11-28), avoid the use of strong or 
moderate CYP3A inhibitors or P-gp inhibitors 2 to 3 days prior to the next cycle of venetoclax treatment. Also 
avoid the use of strong or moderate CYP3A inducers at least 7 days prior to the next cycle of venetoclax 
treatment. 
Co-administration with the use of weak CYP3A inducers and inhibitors is allowed. P-gp substrate should be 
avoided. If a concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before 
venetoclax. 
CYP3A INHIBITORS 
STRONG INHIBITORS 
boceprevir, clarithromycin, cobicistat, conivaptan, grapefruit juice, idelalisib, indinavir, itraconazole, lopinavir, 
ketoconazole, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, teleprevir, telithromycin, 
troleandamycin, voriconazole 
MODERATE INHIBITORS 
amprenavir, aprepitant, atazanavir, cimetidine, ciprofloxacin, clotrimazole, crizotinib, darunovir, diltiazem, dronedarone, 
erythromycin, fluconazole, fosamprenavir, imatinib, isavuconazole, nifedipine, seville oranges, star fruit, tofisopam, 
verapamil 
CYP3A INDUCERS 
STRONG INDUCERS 
avasimibe, carbamazepine, enzalutamine, mitotane, phenobarbital, phenytoin, rifampin, St. John’s Wort 
MODERATE INDUCERS 
bosentan, efavirenz, etravirine, modafinil, nafcillin, oxcarbazepine 
P-gp INHIBITORS (STRONG & MODERATE) 
STRONG & MODERATE INHIBITORS 
amiodarone, azithromycin, captopril, carvedilol, cyclosporine, dronedarone, elacridar, felodipine, ginkgo (ginkgo biloba), 
mibefradil, milk thistle (silybum marianum), nitrendipine, quercetin, quinidine, ranolzine, schisandra chinensis, 
telmisartan, ticagrelor, tipranavir, valspodar 
 
 
 


PrECOG Protocol Number: PrE0405 
IND Number: 143290 
Confidential 
Date: 10/11/2021 
 
71 
Cautionary Use 
CYP3A 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 
CYP3A INDUCERS 
WEAK INDUCERS 
armodafinil, clobazamechinacea, pioglitazone, prednisone, rufinamide, vemurafenib 
P-gp 
P-gp SUBSTRATES 
aliskiren, ambrisentan, colchicines, dabigatran etexilate, digoxin, everolimus, fexofenadine, indinavir, lapatinib, 
loperamide, maraviroc, nilotinib, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan 
 


PrECOG Protocol Number: PrE0405 
IND Number: 143290 
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Date: 10/11/2021 
 
72 
Appendix IV: 
Definitions for Tumor Lysis Syndrome31 
 
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 
 
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). 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. 
Copyright © 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical 
Society. 


PrECOG Protocol Number: PrE0405 
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73 
Appendix V: Revised Criteria for Response Assessment32 
Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Complete Metabolic Response 
Complete Radiologic Response 
(all of the following) 
 
Score 1, 2, or 3*- with or without a residual mass on 
5PS† 
Target nodes/nodal masses must regress 
to ≤ 1.5 cm in LDi 
Lymph Nodes and 
Extralymphatic Sites 
It is recognized that in Waldeyer's ring or extranodal 
sites with high physiologic uptake or with activation 
within spleen or marrow (e.g., with chemotherapy or 
myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the 
tissue has high physiologic uptake. 
No extralymphatic sites of disease 
Nonmeasured Lesion 
Not applicable 
Absent 
Organ Enlargement 
Not applicable 
Regress to normal 
New Lesions 
None 
None 
Bone Marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if indeterminate, 
IHC negative 
Partial 
Partial Metabolic Response 
Partial Remission 
(all of the following) 
Lymph Nodes and 
Extralymphatic Sites 
Score 4 or 5† with reduced uptake compared with 
baseline and residual mass(es) of any size 
≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites 
 
At interim, these findings suggest responding 
disease 
When a lesion is too small to measure on 
CT, assign 5 mm × 5 mm as the default 
value 
 
At end of treatment, these findings indicate residual 
disease 
When no longer visible, 0 × 0 mm 
 
For a node > 5mm × 5 mm, but smaller than 
normal, use actual measurement for 
calculation 
Nonmeasured 
Lesions 
Not applicable 
Absent/normal, regressed, but no increase 
Organ Enlargement 
Not applicable 
Spleen must have regressed by >50% in 
length beyond normal 
New Lesions 
None 
None 
Bone Marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline (diffuse 
uptake compatible with reactive changes from 
chemotherapy allowed). If there are persistent focal 
changes in the marrow in the context of a nodal 
response, consideration should be given to further 
evaluation with MRI or biopsy or an interval scan. 
Not applicable 


PrECOG Protocol Number: PrE0405 
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74 
Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
No Response or 
Stable Disease 
No Metabolic Response 
Stable Disease 
Target Nodes/ Nodal 
Masses, Extranodal 
Lesions 
Score 4 or 5 with no significant change in FDG 
uptake from baseline at interim or end of treatment 
<50% decrease from baseline in SPD of up 
to 6 dominant, measurable nodes and 
extranodal sites; no criteria for progressive 
disease are met 
Nonmeasured 
Lesions 
Not applicable 
No increase consistent with progression 
Organ Enlargement 
Not applicable 
No increase consistent with progression 
New Lesions 
None 
None 
Bone Marrow 
No change from baseline 
Not applicable 
Progressive Disease 
Progressive Metabolic Disease 
Progressive Disease 
requires at least 1 of the following 
Individual Target 
Nodes/Nodal Masses 
Score 4 or 5 with an increase in intensity of uptake 
from baseline and/or 
PPD progression: 
Extranodal Lesions 
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment 
An individual node/lesion must be abnormal 
with:  
- 
LDi >1.5 cm and 
- 
Increase by ≥ 50% from PPD nadir 
and 
- 
An increase in LDi or SDi from nadir 
o 
0.5 cm for lesions ≤ 2 cm 
o 
1.0 cm for lesions >2 cm 
- 
In the setting of splenomegaly, the 
splenic length must increase by >50% 
of the extent of its prior increase 
beyond baseline (e.g., a 15-cm spleen 
must increase to >16 cm). If no prior 
splenomegaly, must increase by at 
least 2 cm from baseline 
- 
New or recurrent splenomegaly 
Nonmeasured 
Lesions 
None 
New or clear progression of preexisting 
nonmeasured lesions 
New Lesions 
New FDG-avid foci consistent with lymphoma rather 
than another etiology (e.g., infection, inflammation). 
If uncertain regarding etiology of new lesions, biopsy 
or interval scan may be considered. 
- 
Regrowth 
of previously 
resolved 
lesions 
- 
A new node >1.5 cm in any axis 
- 
A new extranodal site >1.0 cm in any 
axis; if <1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
- 
Assessable disease of any size 
unequivocally 
attributable 
to 
lymphoma 
Bone Marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 


PrECOG Protocol Number: PrE0405 
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Date: 10/11/2021 
 
75 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; 
LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, 
cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product 
of the perpendicular diameters for multiple lesions. 
* 
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time 
of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid undertreatment). 
- 
Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal 
lesions selected to be clearly measurable in two diameters. Nodes should preferably be from disparate 
regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-
nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, 
cutaneous lesions, or those noted on palpation. 
- 
Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable 
disease should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site 
of suspected disease that would be difficult to follow quantitatively with measurement, including pleural 
effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that 
cannot be confirmed and followed by imaging. 
- 
In Waldeyer's ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater 
than in the mediastinum with complete metabolic response, but should be no higher than surrounding 
normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid growth 
factors). 
† 
PET 5PS: 
1. No uptake above background 
2. Uptake ≤ mediastinum 
3. Uptake >mediastinum but ≤ liver 
4. Uptake moderately >liver 
5. Uptake markedly higher than liver and/or new lesions 
6. X: new areas of uptake unlikely to be related to lymphoma. 
 
Source: Reprinted with permission. © 2014 American Society of Clinical Oncology. All right reserved. Cheson 
BD, Fisher RI, Barrington SF, Cavalli F, et al. Recommendations for Initial Evaluation, Staging and Response 
Assessment of Hodgkin and Non-Hodgkin Lymphoma: the Lugano Classification. Table 3. JCO. 2014 Sep 20; 
32(27):3059-3068. 


PrECOG Protocol Number: PrE0405 
IND Number: 143290 
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Date: 10/11/2021 
 
76 
Appendix VI: Investigator’s Statement 
1. 
I have carefully read this protocol entitled “Phase II Study of Bendamustine and 
Rituximab plus Venetoclax in Untreated Mantle Cell Lymphoma over 60 Years of 
Age”, Version 5.0 dated 10/11/2021 (Protocol Number PrE0405) 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: 
PrECOG Protocol Number: PrE0405 
Date: 02/05/2020 
 
 
 
PrE0405: Statistical Analysis Plan 
Phase II Study of Bendamustine and Rituximab plus 
Venetoclax in Untreated Mantle Cell Lymphoma over 60 Years 
of Age 
 
NCT#: 
NCT03834688 
Protocol Version Number: 
1 
Version Date: 
02/05/2020 
 


Statistical Analysis Plan  
PrECOG, LLC 
Protocol: PrE0405 
Version: 1 / 05-Feb-2020 
1 
 
 
 
Statistical Analysis Plan 
Study Number 
PrE0405 
Version 
1 
Date 
05-February-2020 
Phase II Study of Bendamustine and Rituximab plus Venetoclax in Untreated Mantle Cell 
Lymphoma over 60 Years of Age 


Statistical Analysis Plan  
PrECOG, LLC 
Protocol: PrE0405 
Version: 1 / 05-Feb-2020 
2 
 
 
DOCUMENT: 
 Statistical Analysis Plan 
 
PROTOCOL 
  
 
Number: 
 PrE0405 
 
Title: 
 Phase II Study of Bendamustine and Rituximab plus 
Venetoclax in Untreated Mantle Cell Lymphoma over 60 
Years of Age 
 
Date: 
 Version 1.0:  
09 April 2019 
 
 Version 2.0:  
30 August 2019 
 
  
SAP STATUS 
 Final 
SAP VERSION AND 
DATE 
 Version: 1   Date: 05 February 2020 
 
SPONSOR: 
 PrECOG, LLC 
1818 Market Street 
Suite 3000 
Philadelphia, PA 19103 
 
 
PREPARED BY: 
 Andrew Ricchezza 
Biostatistician 
Quality Data Services, Inc. 
 
 
  
 




Statistical Analysis Plan  
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Protocol: PrE0405 
Version: 1 / 05-Feb-2020 
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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 ................................................. 13 
4.1. Determination of Sample Size.............................................................................. 13 
4.2. Methodology ....................................................................................................... 13 
4.3. Handling of Dropouts or Missing Data ................................................................ 13 
4.4. Interim Analyses and Data Monitoring ............................................................... 13 


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4.5. Multi-center Studies ............................................................................................ 14 
4.6. Multiple Comparisons / Multiplicity .................................................................... 14 
4.7. Analysis Populations ........................................................................................... 14 
4.7.1. Safety Population ............................................................................................... 14 
4.7.2. 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 
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 .................................................................................................... 18 
APPENDIX 1.  STUDY PROCEDURES AND ASSESSMENTS................................. 20 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation/Acronym 
Definition 
AE 
Adverse event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BR 
Bendamustine + Rituximab 
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 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
Ethylenediamine Tetraacetic Acid 
FFPE 
Formalin-Fixed Paraffin-Embedded 
GCSF 
Granulocyte Colony-Stimulating Factor 
H&E 
Hematoxylin & Eosin 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
IRB 
Investigational Review Board 
IV 
Intravenous 
mcg 
microgram 
MCL 
Mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mg/m2 
Milligrams per square meter of body surface area 
MIPI 
MCL International Prognostic Index 


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mITT 
Modified Intent-to-Treat Population 
mL 
milliliter 
MRD 
Minimum Residual Disease 
OBI 
On-Body Injector 
ORR 
Overall 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 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation OR Stable disease 
SPD 
Sum of the product of (the two largest perpendicular) diameters 
SQ 
Subcutaneous 
TEAE 
Treatment-emergent adverse event 
TLFs 
Tables, listings, and figures 
TLS 
Tumor lysis syndrome 
Un 
Unevaluable 
WBC 
White Blood Cells 
 
 


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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 analysis 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 determine the CR rate of BR + venetoclax in untreated MCL patients over the age of 60 years 
2.2.   Secondary Objectives 
• 
To evaluate the safety of the combination, with particular attention to TLS incidence with Cycle 1 
• 
To determine the overall response rate (complete response [CR] + partial response [PR]) of BR + 
venetoclax in untreated MCL patients over the age of 60 years 
• 
To determine the survival (progression-free survival [PFS] and overall survival [OS]) of MCL 
patients treated with BR + venetoclax induction 
2.3.   Exploratory Objectives (Outside of scope of this analysis plan) 
• 
To evaluate the bone marrow aspirate and peripheral blood assessed minimal residual disease 
(MRD) negative rate of BR + venetoclax in untreated MCL patients over the age of 60 years  
• 
To evaluate the utility of morphologic assessment of bone marrow biopsy and aspiration when 
combined with peripheral blood MRD and PET assessments on CR rate at end of treatment 


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2.4.   Study Endpoints 
2.4.1.   Efficacy Endpoints 
• 
Incidence of complete response (CR) by the end of induction 
• 
Overall response rate (complete response [CR] + partial response [PR]), through the end of 
induction 
• 
Overall response rate (complete response [CR] + partial response [PR]), through the end of 
treatment (including both induction and, where relevant, maintenance) 
• 
Progression-free survival (PFS)  
• 
Overall survival (OS) 
• 
Duration of response (either partial or complete) 
2.4.2.   Safety Endpoints  
• 
Adverse events, including 
o Incidence rate of treatment-related events of CTCAE grade 3 or higher 
o Incidence rate of tumor lysis syndrome 
o Incidence rate of non-disease-related death events 
o Incidence rate of serious adverse events (SAEs) 
• 
Exposure to study treatments 
3.   STUDY DESIGN 
3.1.   Study Design 
This is a single-arm phase II clinical trial in treatment-naïve adult male and female subjects over 60 years 
of age with a histologically confirmed (biopsy-proven) diagnosis of mantle cell lymphoma (MCL) and 
measurable or evaluable disease as defined as a lymph node measuring >1.5 cm in any dimension or 
splenomegaly with spleen >15 cm in craniocaudal dimension.  Eligible patients will receive venetoclax, 
bendamustine, and rituximab as induction therapy for 6 cycles of 28 ± 3 days in length.  Upon completing 
six cycles of induction therapy, subjects may be administered maintenance rituximab per physician 
discretion.  The recommended schedule for maintenance rituximab is every 8 ± 2 weeks for 12 doses or 
24 months (whichever comes first).  More details on the treatment schedule can be found in the following 
schema: 
 
 
 
 
 
 


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Figure 1  Study Schema  
 
Tumor assessments will be performed in the form of CT or PET/CT before Cycle 3 or 4 and PET/CT after 
Cycle 6 (6-8 weeks after Cycle 6 Day 1).  After the PET/CT at the end of induction, all other imaging will 
be per institution standards.  Subjects will be followed until progression or for up to 5 years from 
induction treatment discontinuation or study closure.  Response and progression will be evaluated using 
the international criteria proposed by the 11th International Conference on Malignant Lymphoma in 
Lugano Switzerland (Lugano Classification).  


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3.2.   Study Duration 
The study will consist of 2 periods: an Induction Treatment Period (6 cycles of 28 days each), followed 
by a Follow-up Period (5 years from induction treatment discontinuation or study closure) during which 
to monitor survival status, disease progression, and initiation of new cancer therapies.  Maintenance 
therapy (maximum of 24 months) may be administered during the Follow-up Period according to 
investigator discretion.  The total duration of the study for each subject will be a maximum of 5.5 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, investigator determination that protocol requirements are 
detrimental to subject health, or completion of 6 cycles of induction treatment (and 12 doses or 24 months 
of maintenance rituximab, if recommended by the investigator).   
3.3.   Study Population 
A total of 56 subjects will be enrolled, 53 of whom are expected to be eligible and treated.  Subjects who 
discontinue from the study will not be replaced. 
The study population will consist of treatment-naïve adult male and female subjects over 60 years of age 
with a histologically confirmed (biopsy-proven) diagnosis of mantle cell lymphoma (MCL) and 
measurable or evaluable disease as defined as a lymph node measuring >1.5 cm in any dimension or 
splenomegaly with spleen >15 cm in craniocaudal dimension.     
3.4.   Randomization and Blinding 
All subjects will follow the same open-label treatment regimen.   
3.5.   Treatment Administration 
Eligible subjects will be treated in a single arm with venetoclax, bendamustine, and rituximab as 
induction therapy for 6 cycles of 28 ± 3 days in length as outlined in the table below: 
Agent  
Route  
Dose  
Days  
Venetoclax  
Oral  
20 mg  
50 mg  
100 mg  
200 mg  
400 mg  
Day 1-7 (Cycle 1 only)  
Day 8-14 (Cycle 1 only)  
Day 15-21 (Cycle 1 only)  
Day 22-28 (Cycle 1 only)  
Day 1-10 (Cycle 2-6)  
Bendamustine  
IV  
90 mg/m2 
Day 1 and 2 (Cycle 1-6)  
Rituximaba 
IV  
SQ (optional)  
375 mg/m2  
1400 mg (optional)  
Day 1 (Cycle 1-6a)  
Day 1 (Cycle 3-6) (optional)  
a Rituximab should be administered as 375 mg/m2 IV on day 1 of each cycle.  If the first two cycles of 
rituximab are well-tolerated, IV rituximab may be replaced with 1400 mg/23,400 units subcutaneous (SQ) 
rituximab/hyaluronic acid on Day 1 of Cycles 3-6, per rituximab/hyaluronic acid package insert.  
 


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Due to risk of tumor lysis syndrome, the daily dose of venetoclax is titrated from 20 mg to 200 mg by the 
end of cycle 1.  Venetoclax is then dosed at 400 mg per day, days 1-10 only, for each of the remaining 5 
cycles of induction.  Dose compliance for venetoclax will be monitored via pill counts and an IRB 
reviewed medication diary. 
Upon completion of 6 cycles of induction therapy, maintenance rituximab may be administered per 
physician discretion to subjects responding to therapy.  The recommended schedule for maintenance 
rituximab is every 8 ± 2 weeks for 12 doses or 24 months (whichever comes first).  The maintenance 
administration may be either the 375 mg/m2 intravenous dose or the 1400 mg/23,400 unit subcutaneous 
dose of rituximab/hyaluronic acid in accordance with physician and patient preference. 
If toxicities occur during cycle 1, the Venetoclax dose will be held until resolution and then rechallenge 
will occur at the same dose.  If tumor lysis syndrome is suspected during cycle 1, venetoclax will be held 
until resolution and then restarted at same dose level if the subject was taking 20 mg daily and one 
titration dose level lower otherwise (i.e., at 20 mg, 50 mg, or 100 mg if the subject was receiving 50 mg, 
100 mg, or 200 mg daily, respectively).   
Dose reductions resulting from on-treatment toxicities during induction cycles 2-6 will follow the table 
below: 
Dose Level  
Venetoclax  
Bendamustine  
Rituximab  
0 (starting dose) 
400 mg PO daily x 10 days  
90 mg/m2 IV days 1 and 2  
No dose modifications  
-1 (first reduction) 
400 mg PO daily x 5 days  
90 mg/m2 IV days 1 and 2  
No dose modifications  
-2 (second reduction) 
400 mg PO daily x 5 days  
70 mg/m2 IV days 1 and 2  
No dose modifications 
 
Toxicities warranting a dose reduction while the subject is being dosed at level -2 will result in the subject 
being discontinued from all study treatments.  If tumor lysis syndrome is suspected during cycles 2-6, 
venetoclax will be held for the rest of the cycle and upon resolution will be restarted at the same dose 
level at the start of the next cycle.   
Acetaminophen and diphenhydramine (or another anti-histamine) will be administered prior to each 
infusion or injection of rituximab, per institution guidelines. Standard anti-emetic therapy may be given to 
patients prior to administration of bendamustine per institutional guidelines. However, 5-HT3 serotonin 
receptor agonist and steroids are strongly recommended. 
To mitigate the risk of neutropenic sepsis and febrile neutropenia due to bendamustine or venetoclax, 
prophylaxis will be required for all subjects with one of the following growth colony stimulating factors 
(GCSFs) to be administered 24-72 hours after the last dose of bendamustine for each cycle: 
• 
Pegfilgrastim SQ 6 mcg once 
• 
Pegfilgrastim SQ 6 mcg via on-body injector (OBI) once 
• 
Filgrastim or filgrastim-sndz SQ 300 or 480 mcg for 5 days 
3.6.   Study Procedures and Assessments 
All study procedures and assessments are listed in the table in Appendix 1. 


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4.   GENERAL STATISTICAL CONSIDERATIONS 
4.1.   Determination of Sample Size 
The primary endpoint of this single arm Phase II study is CR rate after 6 cycles of BR + venetoclax. A 
15% improvement in the historical post-induction CR rate of 70% to 85% is of interest. A total of 56 
subjects will be enrolled, 53 of whom are expected to be eligible and treated. In order to have 90% power 
to detect the 15% improvement in CR rate from 70% using a one-sided exact binomial test with 10% 
Type I error, 53 subjects will be needed for the analysis.  A total of 56 subjects will be enrolled with the 
expectation that 53 will be eligible and treated.  
4.2.   Methodology 
In general, listings will be sorted by site, subject number, visit, and date and time of assessment or event.  
All listings will include flags to indicate subject-level inclusion/exclusion for each of the analysis 
populations. 
Post-dose safety and efficacy parameters will be summarized for all subjects in aggregate.  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.   
4.3.   Handling of Dropouts or Missing Data 
Subjects who withdraw from the study will not be replaced. 
 
 
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 
A review of tumor lysis syndrome (TLS) events will be conducted at interim once 19 subjects (> 1/3 of 
enrollment goal) have been enrolled in the study and either completed cycle 1 of induction treatment or 
discontinued treatment.  A TLS incidence rate of no more than 15% (≤ 3 out of 19 subjects) is permissible 
on this study.  If the observed TLS incidence rate is ≥ 21% (≥ 4 out of 19 subjects) then a detailed review 
of TLS cases will be conducted by the Data Safety Monitoring Board (DSMB) to decide whether to 
recommend closing the study due to unacceptable TLS risk.  If the true incidence rate of TLS is 30% or 
higher, there is at least 87% probability of crossing the boundary; whereas, if the true incidence of TLS is 
10%, there is only 11% chance of crossing the boundary. 


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4.5.   Multi-center Studies 
This study will be conducted at 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 evaluated via a single confidence interval.  TLS incidence rate will be evaluated for a 
decision rule at interim at 1/3 of the accrual goal; however, TLS incidence will not be evaluated at the end 
of the study via a decision rule or hypothesis test.  Thus, there are no multiplicity considerations related to 
the interim analysis.  
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 either the Safety Population or Modified Intent-to-Treat (mITT) Population. 
4.7.1.   Safety Population 
The Safety Population is defined as all subjects who received at least one dose of any study treatment – 
bendamustine, rituximab, or venetoclax.  All summaries and analyses of safety data, including treatment 
exposure and toxicity, will be completed on the Safety Population.   
4.7.2.   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, continuing to maintenance 
therapy, and completing the study versus discontinuing the study will be tabulated (Table 14.1.1).  
Subjects discontinuing treatment will be categorized by reason for discontinuation separately for each 
treatment phase (induction versus maintenance).  All treated subjects also will be tabulated by site. 
5.2.   Demographics and Baseline Characteristics 
Demographic data (age, sex, race, and ethnicity) and screening characteristics (weight; spleen size; MIPI 
score; ECOG performance status; tumor, lymph node, and metastasis staging; and Ann Arbor staging – 
including presence/absence of B symptoms) will be summarized for the Safety Population and mITT 
Population (Table 14.1.2).  Descriptive statistics (mean, standard deviation, median, minimum, and 
maximum for numeric variables, count and percentage for categorical variables) will be presented as 
applicable. 


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6.   SAFETY ANALYSIS 
The post-baseline safety assessments in this study include adverse event assessments and study treatment 
exposure.  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.   
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 will be assumed to be treatment-related for inclusion in 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 count of subjects experiencing 
TEAEs will be subdivided in the same table by seriousness, CTCAE v5.0 toxicity grade, outcome, 
relation to each of the three study medications, whether 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), 
whether the event resulted in study discontinuation, and various combinations of these criteria.  To 
support the safety endpoints of tumor lysis syndrome and non-disease-related deaths during induction, the 
number of subjects experiencing these events will also be tabulated with tumor lysis syndrome events 
subdivided between events during induction cycle 1 and those after cycle 1 (Table 14.3.1.1).  The set of 
all non-disease-related death events during induction also will be listed by subject (Listing 16.2.7).  The 
listing will include the MedDRA (version 22.0) system organ class and preferred term, the date and time 
and study day relative to the first study treatment administration 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, 
and all criteria met for classification as a serious adverse event.  Study day will be calculated for the 
listing as (adverse event start/end date – first study treatment dosing date + 1) since all events in the 
listing will start and end on or after the first day of induction treatment. 
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 22.0 (Table 14.3.1.2).  An event will be 
considered to be treatment-related if its relationship to any of the three study treatments is assessed by the 
investigator as definite, probable, or possible.  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.   
A separate table will count by system organ class and preferred term subjects who experience treatment-
emergent SAEs, regardless of relationship to the study treatments (Table 14.3.1.3).  This table, too, will 
order the system organ classes, and preferred terms within each system organ class, by descending 
incidence rate. 


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6.2.   Study Drug Administration and Dose Compliance 
The number of cycles in which any of the three study treatments were administered will be tabulated 
separately for induction and maintenance 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 (i.e., 
bendamustine anytime during induction, venetoclax during titration [cycle 1], and venetoclax during 
cycles 2-6) with counts and percentages based on the number of subjects who received at least one dose 
of the given treatment during the given cycle(s).  The reasons for dose reductions in bendamustine and 
any cycle of venetoclax will be summarized similarly by counts and percentages.  To describe the actual 
exposure to bendamustine, considering dose reductions and any non-compliance, the mean dose per 
administration will be summarized with descriptive statistics (n, mean, standard deviation, median, 
minimum, maximum).  The actual venetoclax exposure will be summarized as dose intensity per 6 weeks 
for induction cycle 1 and separately for cycles 2-6.  Dose intensity is defined as [cumulative dose / 
treatment duration], normalized to a six-week treatment duration.  Since the cumulative venetoclax 
exposure during cycle 1 will depend on whether toxicities occur that delay the titration schedule, the cycle 
1 venetoclax exposure will be summarized also via descriptive statistics of the number of days of 
venetoclax dosing during cycle 1.  As the rituximab dose is dependent on the formulation (IV vs. SQ), 
with the subcutaneous dose expected to be delivered in full at all relevant administrations, the exposure to 
rituximab during induction and during maintenance each will be summarized with descriptive statistics of 
the mean rituximab dose per IV administration.  Also to be summarized with descriptive statistics is the 
duration of rituximab maintenance therapy in months.  
7.   EFFICACY ANALYSIS 
The efficacy analyses are designed to evaluate the CR rate according to the Lugano criteria through the 
end of induction treatment, the overall response rate (complete response [CR] or partial response [PR]) 
through the end of induction treatment and through the end of all study treatment, including maintenance, 
where relevant, and survival and progression-free survival through the end of the five-year follow-up 
period after induction.  All efficacy endpoints are evaluated on the Modified Intent-to-Treat (mITT) 
Population. 
7.1.   Primary and Secondary Efficacy Endpoint Analyses 
The primary endpoint in this study is the proportion of eligible and treated subjects who achieve a 
complete response (CR) at any disease response assessment through the end of induction treatment.  This 
proportion will be computed for the mITT Population and presented along with the Clopper-Pearson exact 
90% lower confidence bound on the proportion, expressed as a percent (Table 14.2.1).  The treatment 
combination of BR + venetoclax will be considered worthy of further investigation if the one-sided 90% 
lower confidence bound is greater than 70%.  For the desired size of 53 subjects for the mITT Population, 
this equates to 42 or more subjects achieving CR.  The hypothesis test implied by the lower confidence 
bound and defined formally as H0: CR rate = 70%, HA: CR rate > 70% has 90% power assuming a true 
CR rate of 85%.   
The same table (Table 14.2.1) will show the proportion of subjects in the mITT Population whose best 
overall disease response during induction treatment was a partial response (PR), stable disease (SD), 
progressive disease (PD), or 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 induction for any reason, including termination of study treatment prior to a 
subject’s first on-treatment disease response assessment during induction.  The table also will display the 


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overall response rate (ORR) through the end of induction treatment and summarize subjects’ Deauville 
scores from the assessment at the end of induction with counts and percentages for each potential score.  
The overall response rate is defined as the proportion of subjects whose best overall disease response was 
either a complete response (CR) or a partial response (PR).   
One of the secondary endpoints of the study is the Overall Response Rate across both induction and 
maintenance treatment phases.  The Overall Response Rate will be computed for the mITT Population 
and the count of subjects with a response will be subdivided by the time of eventual death or disease 
progression – during induction, during maintenance therapy, during the post-treatment follow-up period, 
or absence of such an event prior to study discontinuation (Table 14.2.2).  The table will also summarize 
the best overall disease response, i.e., CR, PR, SD, PD, or Un, across all induction and maintenance 
assessments and present the Kaplan-Meier estimate of the median duration in months of overall response 
among subjects who attained a PR or CR during either induction or maintenance therapy.  A 90% 
confidence interval of the median response duration estimate will be computed using Brookmeyer and 
Crowley’s method1 and presented. 
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 Kaplan-Meier 
survival curves for progression-free survival and overall survival will be presented on the mITT 
Population in Figures 14.2.3 and 14.2.4, respectively.  Each figure will plot a two-sided 90% confidence 
band on the survival function, the median estimate for survival time, and a two-sided 90% confidence 
interval of the estimate of median survival time.  The 90% confidence band on the survival function will 
use Greenwood’s formula2 to estimate the variance of the survival function.  The 90% confidence interval 
of the median survival time will be computed using Brookmeyer and Crowley’s method1.  Each figure 
also will include the number of subjects in the risk set and the number of censored subjects computed at 
3-month intervals.   
8.   SUMMARY OF CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
There are no changes to the planned analyses described in version 2.0 of the clinical trial protocol dated 
August 30, 2019. 
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 
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). 


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• 
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. 
10.   REFERENCES 
1. Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
2. Greenwood M. The natural duration of cancer. Reports on Public Health and Medical Subjects. 
London: Her Majesty's Stationery Office 1926;33:1-26. 
3. SAS Institute, Inc., SAS® Version 9.2 software, Cary, NC. 


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4. ICH Guidance for Industry: E9 Statistical Principles for Clinical Trials, 1998. 
5. 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: In general +/- 3 day window for therapy/tests/visits during therapy except as noted for TLS monitoring. Delay due to holidays, weekends, 
bad weather or other unforeseen circumstances will be permitted.  
1. 
Record date of diagnosis, primary tumor type, histology, stage, and MCL international prognostic index (MIPI). MIPI calculator can be accessed using the 
European MCL Network website at http://www.european-mcl.net/en/clinical_mipi.php. 
2. 
CBC with differential and platelet count which includes WBC, ANC, Platelets, Hgb, and Hct. Required prior to each dose of treatment, and results known prior 
to treatment administration.  
3. 
BUN/creatinine, sodium, potassium, chloride, bicarbonate (HCO3), glucose, and calcium. Refer to Section 5.4, Table 5-3 “Tumor Lysis Monitoring” in the 
clinical study protocol for additional time points and days not captured on Study Calendar.  
4. 
Cycle 2, Day 2 only.  
5. 
Albumin, total protein, alkaline phosphatase, AST, ALT, and total bilirubin.  
6. 
Basic Metabolic Panel (Sodium, Potassium, Chloride, Bicarbonate (HCO3), BUN, Creatinine, Calcium), Albumin, Uric Acid, and Phosphorus. Refer to Section 
5.4, Table 5-3 “Tumor Lysis Monitoring” in the clinical study protocol for additional time points and days not captured on Study Calendar. See Appendix IV in 
the clinical study protocol for “Definitions of Tumor Lysis Syndrome”.  
7. 
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) are allowed with protective hepatitis B surface antibody AND a negative hepatitis B viral load by PCR. If enrolled, 
patients must be willing to undergo monthly HBV DNA testing. 
Patients with positive HCV antibody must be negative for HCV by PCR to be eligible for study participation. Prior treatment for an active hepatitis C infection 
will be allowed so long as the hepatitis C viral load by PCR is negative.  
8. 
Required for females of child-bearing potential.  
9. 
Standard pre-medications and antiemetic therapy per institutional guidelines are allowed per Section 5.1 of the clinical study protocol. Also, refer to Section 
5.3 in the clinical study protocol for details on prophylaxis for TLS.  
10. Encourage at least 2 liters of oral fluids per day starting 24 hours prior to Cycle 1, Day 1 and continuing until Cycle 2, Day 10. Refer to Section 5.3 in the 
clinical study protocol for details.  
11. At least 1 liter of IV hydration should be given on Day 1 of Cycle 1 and Cycle 2. Additional IV fluids and monitoring for TLS is allowed per treating physician 
discretion. Refer to Section 5.3 in the clinical study protocol for details.  
12. Venetoclax will be administered orally. Cycle 1: 20 mg on Day 1-7; 50 mg on Day 8-14; 100 mg on Day 15-21; and 200 mg on Day 22-28. Cycle 2-6: 400 mg 
on Day 1-10. One cycle = 28 days. On days when venetoclax is given with additional anti-lymphoma agents, venetoclax should be given first. See Section 5 of 
the clinical study protocol for dosing instructions and tumor lysis prophylaxis/monitoring and Section 6 of the clinical study protocol for dose 
delays/modifications.  
13. Bendamustine is given as 90 mg/m2 IV day 1 and 2 before or after rituximab. See Section 5 of the clinical study protocol for dosing instructions and Section 6 
of the clinical study protocol for dose delays/modifications.  
14. Rituximab 375 mg/m2 is given on Day 1 of each cycle before or after bendamustine. If the first two cycles of rituximab are well tolerated, IV rituximab may be 
replaced with 1400 mg/23,400 units SQ rituximab/hyaluronic acid on Day 1 of Cycles 3-6, per investigator and patient preference. See Section 5 of the clinical 
study protocol for dosing instructions and Section 6 of the clinical study protocol for dose delays/modifications.  


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NOTE: After 6 cycles of venetoclax, bendamustine and rituximab, subjects responding to therapy may receive maintenance rituximab (one dose every 8 ± 2 
weeks for 12 doses or 24 months whichever comes first) per physician and patient preference. 
15. Growth factor support should be given 24-72 hours after the last dose of bendamustine for each cycle per Section 5.5 of the clinical study protocol.  
16. PET/CT 6-8 weeks after Day 1 of last completed cycle. Each target lesion should have Deauville score at end of treatment. Refer to Section 9.2, Table 9-1 
and Appendix V in the clinical study protocol for details.  
17. Bone marrow biopsy and aspirate per standard of care. Mandatory sample submission for research when collected per standard of care. 
18. Repeat imaging before Cycle 3 or 4 per institutional guidelines. CT scans or PET/CT scans may be used at this time point per institution standards. Any 
progression should be confirmed by PET/CT.  
19. Pre-treatment, diagnostic pathology specimens (organ or lymph node biopsy or excision) obtained in the course of standard biopsy or surgery (if sufficient 
tissue is available, submission is mandatory). Formalin-Fixed Paraffin-Embedded (FFPE) blocks and 5 FFPE slides or up to 15 FFPE slides plus H&E slide (if 
tissue is limited, then minimum of 10 slides) will be required. Procurement of tissue will be mandatory for enrollment, but if additional tissue from initial biopsy 
is not available, repeat biopsy will not be required. Optional: Any leftover tissue banked for future research. See Section 13.1 of the clinical study protocol and 
the PrE0405 Lab Manual for details.  
NOTE: If blocks and/or slides are unavailable and bone marrow is involved with mantle cell lymphoma, obtain two 2 mL EDTA tubes of bone marrow aspirate 
(one for baseline MRD analysis and one for future research). If blocks/slides and bone marrow are unavailable and peripheral blood is involved with 
mantle cell lymphoma obtain one 4 mL and one 6 mL EDTA tubes of peripheral blood (one for baseline MRD analysis and one for future research).  If 
baseline samples (blocks/slides, bone marrow, and/or peripheral blood) are not submitted at baseline for MRD (i.e., not involved with mantle cell 
lymphoma), then patients will be allowed to remain on study but MRD samples will not be collected during the study. 
20. Optional: At time of progression, biopsy and peripheral blood samples are requested to be sent for correlative studies and banked for future research. See 
Section 13.1 of the clinical study protocol and the PrE0405 Lab Manual for details.  
21. Optional Research Bloods: See Section 13.3 in the clinical study protocol and the PrE0405 Lab Manual for details.  
Cycle 1, Day 1 (prior to treatment)  
Peripheral Blood: One 10 mL red top tube and one 6 mL in EDTA tube  
Cycle 2, Day 1 (prior to treatment)  
Peripheral Blood: One 10 mL red top tube and one 6 mL in EDTA tube  
Cycle 4, Day 1 (prior to treatment)  
Peripheral Blood: One 10 mL red top tube and one 6 mL in EDTA tube  
End of Treatment Visit  
Peripheral Blood: One 10 mL red top tube and one 6 mL in EDTA tube  
At Time of Progression 
Peripheral Blood: One 10 mL red top tube, one 4 mL and one 6 mL in EDTA tube 
22. Mandatory MRD Samples: See Sections 13.1, 13.2, and 13.3 of the clinical study protocol and the PrE0405 Lab Manual for details.  
Screening/Study Entry  
FFPE: 3-5 FFPE slides from lymph node (preferred)  
NOTE: If FFPE unavailable, either bone marrow aspirate (2 mL EDTA tube) or peripheral blood (4 mL EDTA tube) are acceptable as long as they are 
involved with mantle cell lymphoma. If baseline samples (blocks/slides, bone marrow, and/or peripheral blood) are not submitted at baseline for MRD 
(i.e., not involved with mantle cell lymphoma), then patients will be allowed to remain on study but MRD samples will not be collected during the study. 


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End of Treatment Visit  
Peripheral Blood: One 4 mL in EDTA tube  
Bone Marrow Aspirate (per standard of care)*: One 2 mL in EDTA tube  
*Bone Marrow Aspirate: Submission is mandatory when collected per standard of care. 
23. 6-8 weeks after Day 1 of last completed cycle.  
24. Patients will be followed for adverse events for 30 days after their last dose of study medication.  
25. Every 3-6 months or per institutional guidelines for up to 5 years from treatment discontinuation for progression and survival. Imaging to be done per institution 
standards and/or physician discretion. Maintenance rituximab is allowed and will be documented but will not constitute additional therapy. 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 with the exception of allowed maintenance rituximab for up to 5 years or study closure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
PrECOG, LLC 
Protocol: PrE0405 
Version: 1 / 05-Feb-2020 
 
DOCUMENT HISTORY 
 
Version Date 
Modified By 
Summary of Changes