Clinical trial NCT03311126
Conditions: Mantle Cell Lymphoma Non-hodgkin Lymphoma Non Hodgkin Lymphoma
Sponsor: University of Wisconsin, Madison
Start date: 2017-09-29; Completion date: 2023-07-31
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase II single-arm, open-label, multicenter study evaluating the efficacy and safety of the combination of induction chemoimmunotherapy with bendamustine and obinutuzumab (BO) followed by consolidation therapy and maintenance therapy with obinutuzumab in subjects who have not received prior cytotoxic chemotherapy for their Mantle Cell Lymphoma (MCL) (i.e., prior single agent rituximab is permitted, prior involved-field radiotherapy is permitted).

Detailed description:
This is a phase II single-arm, open-label, multicenter study evaluating the efficacy and safety of the combination of induction chemoimmunotherapy with bendamustine and obinutuzumab (BO) followed by consolidation therapy and maintenance therapy with obinutuzumab in subjects who have not received prior cytotoxic chemotherapy for their MCL (i.e., prior single-agent rituximab is permitted, prior involved-field radiotherapy is permitted). Therapy for individual subjects will be risk-adapted based on results of minimal residual disease (MRD) testing performed after the consolidation phase. The study will be carried out at the University of Wisconsin Carbone Cancer Center (UWCCC) and participating community and academic practice sites within the Wisconsin Oncology Network (WON). There will be 6-10 sites participating in this study.

The subject participation will include a screening period, treatment period, and a follow-up period. The induction chemoimmunotherapy regimen consists of bendamustine and obinutuzumab for 4-6 cycles, followed by consolidation and maintenance therapy with obinutuzumab in subjects achieving an objective response to induction therapy (i.e., complete or partial response; stable disease with objective evidence of tumor shrinkage. Subjects who are MRD-negative (determined by MRD testing on bone marrow and PB) after consolidation therapy will omit maintenance therapy.

Subjects will undergo disease reassessment after C4 of induction BO chemoimmunotherapy, after obinutuzumab consolidation therapy, and after C4 and C8 of maintenance obinutuzumab. MRD testing will be done after C2 of induction (PB only), after consolidation (BMA and PB), and post-maintenance or end of treatment (EOT) (PB only).

Arms: arm 1: Induction chemoimmunotherapy (28 day cycles):

Bendamustine 90 mg/m2 IV days 1 \& 2 every 28 days X 4-6 cycles

Obinutuzumab:

* Cycle 1: 100 mg IV day 1, 900 mg IV day 2, 1000 mg IV days 8 \& 15
* Cycles 2-6: 1000 mg IV day 1

Consolidation phase:

Obinutuzumab 1000 mg IV weekly X 4 doses

Maintenance phase (8 week cycles):

Obinutuzumab 1000 mg IV on day 1 of cycles 1-8
Interventions: intervention 1: Bendamustine intervention 2: Obinutuzumab
Intervention descriptions: intervention 1: Bendamustine is a chemotherapeutic agent that has dual functional properties of both an alkylating agent and a nitrogen mustard. Through these unique cytostatic properties, bendamustine is able to inhibit DNA transcription, replication, and repair. Bendamustine is approved in the U.S. for treatment of chronic lymphocytic leukemia (CLL) and for indolent B cell non-Hodgkin lymphomas (NHLs) progressing during or within 6 months of rituximab or a rituximab - containing regimen. intervention 2: Obinutuzumab is a glycoengineered, humanized, type II anti-CD20 monoclonal antibody (mAb).

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Bendamustine + obinutuzumab induction 
chemoimmunotherapy with risk-adapted obinutuzumab 
maintenance therapy in previously untreated mantle cell 
lymphoma 
NCT03311126 
4/13/2021 


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Bendamustine + obinutuzumab induction chemoimmunotherapy with 
risk-adapted obinutuzumab maintenance therapy in previously 
untreated mantle cell lymphoma 
 
 
 
 
 
 
 
SPONSOR: 
University of Wisconsin Carbone 
Cancer Center (UWCCC) 
Genentech, Inc. 
Adaptive Biotechnologies 
Sponsor Protocol #:          UW16086 
Genentech Tracking #: 
ML39383 
VERSION DATE: 
4/13/2021 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless law 
or regulations require such disclosure. Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them. 


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INVESTIGATOR SIGNATURE 
PAGE 
 
 
Bendamustine + obinutuzumab induction chemoimmunotherapy with risk- 
adapted obinutuzumab maintenance therapy in previously untreated mantle 
cell lymphoma 
 
 
The signature below confirms that I have read this protocol and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable US federal regulations and ICH guidelines. 
 
 
Site Name:   
 
 
 
Investigator Signature: 
Date:   
 


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STUDY PERSONNEL 
 
Industry 
Genentech, Inc 
collaborators/ 
1 DNA Way 
Supporters: 
South San Francisco, CA 94080-4990 
Adaptive Biotechnologies 
1551 Eastlake Ave E #200, Seattle, WA 98102 
Study Location: 
University of Wisconsin Carbone Cancer Center (UWCCC) 
Madison, Wisconsin 
Wisconsin Oncology Network 
Study Principal 
Julie E. Chang, MD 
Investigator: 
Phone: 608-262-3970 
Fax: 608-262-4598 
jc2@medicine.wisc.edu 
WON Co-Investigator 
Ryan J. Mattison, MD 
Phone: 608-262-5697 
rjmattison@medicine.wisc.edu 
Program Manager: 
 
Mitch Howard 
Phone: 608-265-4729 
Fax: 608-406-2034 
mvhoward@wisc.edu 
 
WON affiliate 
WON Affiliate Coordinator: 
coordinators: 
affiliatecoordinators@uwcarbone.wisc.edu 
Fax: 608-265-5676 
 
Phone: 608-265-2867 
Statistician: 
KyungMann Kim, Ph.D. 
Phone: 608-265-6380 
kmkim@biostat.wisc.edu 


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Table of Contents 
 
1 
Schema .................................................................................................................................................. 7 
2 
Protocol Synopsis .................................................................................................................................. 8 
3 
Schedule of Study Assessments ........................................................................................................... 12 
4 
Glossary of Abbreviations .................................................................................................................... 14 
5 
Background and Rationale .................................................................................................................. 17 
5.1 
Diagnosis and natural history of mantle cell lymphoma .......................................................... 17 
5.2 
Initial treatment of MCL .......................................................................................................... 17 
5.3 
Bendamustine in MCL.............................................................................................................. 18 
5.4 
Monoclonal antibody therapy in MCL ..................................................................................... 19 
5.5 
Obinutuzumab ........................................................................................................................ 20 
5.6 
MRD testing in lymphoma ....................................................................................................... 24 
5.7 
Study rationale ........................................................................................................................ 28 
6 
Study Objectives and Endpoints .......................................................................................................... 29 
6.1 
Primary objective ..................................................................................................................... 29 
6.2 
Secondary objectives ............................................................................................................... 29 
7 
Investigational Plan ............................................................................................................................. 29 
7.1 
MRD assessments .................................................................................................................... 29 
7.2 
Induction chemoimmunotherapy (28 day cycles) .................................................................... 32 
7.3 
Consolidation therapy ............................................................................................................. 32 
7.4 
Maintenance therapy (8 week cycles) ..................................................................................... 33 
7.5 
Follow-up phase ...................................................................................................................... 33 
7.6 
Discontinuation of Study Treatment ....................................................................................... 34 
7.7 
Screening and Eligibility ........................................................................................................... 34 
7.8 
Registration ............................................................................................................................. 36 
8 
Drug Administration, Formulation, and Procurement ........................................................................ 37 
8.1 
Drug administration................................................................................................................. 37 
8.2 
Record of administration and treatment compliance .............................................................. 40 
9 
Dose Modifications and Interruptions ................................................................................................. 40 
Dose modifications are only required and applicable for study drugs to which a toxicity is at least 
possibly attributed. ..................................................................................................................................... 40 
9.1 
Dose modification guidelines during induction chemotherapy ............................................... 40 


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9.2 
Dose modification guidelines for consolidation and maintenance therapy ............................ 42 
9.3 
Concomitant therapy .............................................................................................................. 43 
10 
Data Safety Monitoring Plan ........................................................................................................... 45 
10.1 
Oversight and Monitoring Plan ................................................................................................ 45 
10.2 
Safety Reconciliation ............................................................................................................... 47 
11 
Adverse Event Reporting Requirements ......................................................................................... 47 
11.1 
Adverse Event Reporting Period .............................................................................................. 47 
11.2 
Assessment of Adverse Events ................................................................................................. 47 
11.3 
Expedited Adverse Event Reporting ......................................................................................... 51 
11.4 
Study PI Adverse Event Reporting Requirements .................................................................... 59 
12 
Response Criteria ............................................................................................................................ 61 
13 
Protocol Amendments and Deviations ............................................................................................ 62 
13.1 
Protocol amendments ............................................................................................................. 62 
13.2 
Protocol deviations .................................................................................................................. 62 
14 
Statistical Considerations ................................................................................................................. 62 
14.1 
Overview ................................................................................................................................. 62 
14.2 
Study Endpoints ....................................................................................................................... 62 
14.3 
Sample Size Calculation ........................................................................................................... 62 
14.4 
Statistical Analysis Plan ............................................................................................................ 63 
14.5 
Early stopping rule for toxicity ................................................................................................. 64 
14.6 
Accrual Rate and Feasibility ..................................................................................................... 64 
15 
Regulatory Considerations .............................................................................................................. 64 
15.1 
Oversight and Monitoring Plan ................................................................................................ 64 
15.2 
Oversight of WON Sites ........................................................................................................... 65 
15.3 
Monitoring and Reporting Guidelines ..................................................................................... 65 
15.4 
Investigator responsibilities with study monitoring and auditing ........................................... 65 
15.5 
Study records requirements .................................................................................................... 66 
15.6 
Institutional Review Board/Ethics Committee approval .......................................................... 66 
15.7 
Informed consent .................................................................................................................... 66 
15.8 
Subject confidentiality ............................................................................................................. 67 
15.9 
Premature discontinuation of study ........................................................................................ 67 
16 
References ....................................................................................................................................... 68 
Appendix A: ECOG performance status ....................................................................................................... 72 
Appendix B: Body surface area calculation ................................................................................................. 73 
Appendix C: Cockcroft-Gault estimation of CrCl: ......................................................................................... 74 


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Appendix D: Mantle Cell Lymphoma International Prognostic Index (MIPI)20,63 score calculation ...... 75 
Appendix E: Assessment of response: Lugano Classification17 .................................................................. 76 
Appendix F: Obinutuzumab formulation and preparation .......................................................................... 79 
Appendix G: Bendamustine formulation, preparation, and adverse effects .............................................. 81 
Appendix H: Grading events of tumor lysis syndrome ................................................................................ 85 
 


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1 Schema 
 
 
 
*Subjects achieving an objective response to induction therapy but with toxicities that may 
limit ability to receive 6 cycles of bendamustine + obinutuzumab (BO) may proceed to 
consolidation therapy as early as after 4 cycles of induction BO. Subjects formally meeting 
criteria for stable disease (SD) and evidence of objective response may continue to 
consolidation and maintenance at investigator discretion. 
 
1 Minimal residual disease (MRD) assessment on peripheral blood will be performed after 
cycle 2 of induction BO. 
 
2Restaging and MRD assessments with marrow aspirates and peripheral blood will be 
performed after completion of consolidation therapy. In patients going on to maintenance 
therapy, an additional MRD assessment on peripheral blood only will be performed after 
completion of maintenance therapy or end of treatment (EOT). 


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2 Protocol Synopsis 
 
PROTOCOL TITLE: Bendamustine + obinutuzumab induction chemoimmunotherapy with risk-
adapted obinutuzumab consolidation and maintenance therapy in previously untreated mantle cell 
lymphoma 
UWCCC PROTOCOL NUMBER: 
UW16086 
DATE PROTOCOL FINAL: 
3/17/2017 
INDICATION: 
Mantle cell lymphoma, previously untreated with 
cytotoxic chemotherapy. 
STUDY PHASE: 
Phase II 
Background and rationale 
Non-intensive chemotherapy-based therapy remains the standard for older and less fit mantle cell 
lymphoma (MCL) patients unable to tolerate consolidative autologous stem cell transplant (ASCT). 
Bendamustine + rituximab (BR) was established as a reasonable induction standard by the German 
StiL trial,1 with MCL patients having 2-year progression-free survival (PFS) of approximately 60-70% 
(after 6 cycles of BR and no maintenance therapy).2 Various other induction regimens such as 
rituximab + modified hyper-CVAD and VcR-CVAD (bortezomib, rituximab and modified hyper-CVAD) 
followed by maintenance rituximab have shown 3-year PFS >60-70%.3,4 These cited trials involved 
previously untreated MCL patients conducted within the Wisconsin Oncology Network (WON). These 
data have been the basis for cooperative group trial E1411, which is investigating an induction 
regimen of BR versus BVR (BR + bortezomib) X 6 cycles and a 2nd randomization to rituximab versus 
rituximab + lenalidomide. This trial is scheduled to meet accrual by fall 2016. At present, there are no 
predecessor studies for non-intensive therapy of previously untreated MCL planned for roll-out from 
the U.S. cooperative groups (personal communication, Dr. Brad Kahl, Washington University, ECOG 
Lymphoma Committee Chair). In the interim, induction chemotherapy with BR with or without 
maintenance rituximab is the most common first-line non-intensive regimen used for older or less fit 
adults with MCL.  
There are emerging data in MCL showing a strong correlation between achieving minimal residual 
disease (MRD) after induction therapy and PFS. For example, the results of S1106 (BR versus 
rituximab + hyper-CVAD induction followed by ASCT) included MRD evaluation using next-
generation sequencing (NGS) in 10 patients treated with BR induction therapy.5 Eight patients 
achieved MRD-negative status post-induction, and 2-year PFS was 100% among these MRD-
negative patients post-induction. In another lymphoid malignancy, diffuse large B-cell lymphoma 
(DLBCL), there was a strong correlation between MRD status after 2 cycles of EPOCH ± rituximab 
and 5-year time-to-progression (TTP) with use of NGS on peripheral blood (PB) samples; patients 
who were MRD-negative after 2 cycles of chemotherapy had 5-year TTP of 80.2% compared with 
41.7% for MRD+ patients.6 
Prior to the availability of NGS technology, MRD evaluation with polymerase chain repeat (PCR)-
based techniques was explored in MCL, and confirmed to have prognostic value.7,8 A retrospective 
analysis of 27 patients evaluable for MRD after ASCT for consolidation of initial cytoreductive 
chemotherapy showed a significant association between MRD status in the first year post-ASCT and 
PFS and overall survival (OS).7 Another retrospective review of outcomes based on MRD status prior 
to ASCT in MCL (n=75) reported from the Fred Hutchison Cancer Center found that MRD-positive 
patients had significantly worse outcomes, with a median PFS of 2.38 years (median PFS not 
reached for MRD-negative patients and median OS of 3.01 years (median OS not reached for MRD-
negative patients; 5-year OS 82% for MRD-negative patients). 


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Pott et al described the relationship of MRD status to clinical outcomes in 2 large international phase 
III trials of the European MCL Network in which MRD was a secondary endpoint.8 The 2 trials included 
both younger patients treated with a more intensive induction and ASCT (MCL Younger) and older 
patients (MCL Elderly) treated with a less intensive induction (R-FC versus R-CHOP) followed by 
rituximab or interferon maintenance. Patients in clinical remission who achieved an MRD-negative 
status after induction had an 87% chance of ongoing remission at 2 years compared with 61% of 
patients with residual MRD-positivity despite clinical remission (p=.004).9 Sustained MRD negativity 
during maintenance therapy was also predictive of outcome. In the MCL Elderly trial, the response 
duration at 2 years was 76% in those with sustained MRD-negative status, compared with 36% of 
those with persistent residual disease by MRD analysis (p=.015).9 
In addition, MCL has a variable disease course, with up to one-third of patients experiencing a more 
indolent disease course.10-12 There are limited clinical or histologic markers that can prospectively 
identify patients with more favorable disease course. MRD status may prove to be a means of 
identifying patients with more favorable disease for which prolonged durations of remission may be 
achieved with less therapy.  
Obinutuzumab, a novel glycoengineered anti-CD20 monoclonal antibody, offers additional benefits 
when combined with bendamustine in induction and continued as consolidation and maintenance 
therapy. Although direct comparisons of obinutuzumab versus rituximab activity in previously 
untreated MCL are not available, inference from available data show an advantage in terms of higher 
rates of response, and could offer the possibility of higher rates of MRD negativity after a course of 
induction chemotherapy with bendamustine-based treatment. Obinutuzumab is a glycoengineered 
type II antibody, with increased affinity on the Fc-receptors of effector cells that confers greater 
antibody-dependent cell-mediated cytotoxicity compared with non-glycoengineered antibodies (i.e., 
rituximab). Obinutuzumab has demonstrated superiority to rituximab in preclinical studies using 
whole-blood depletion assays and human DLBCL and MCL xenograft models.13 The GAUGUIN study 
investigated differing dose levels of single-agent obinutuzumab in previously treated DLBCL and 
MCL. Overall response rates were 24% (for 400 mg treatment arms) and 37% (for 1600/800 mg 
treatment arms) in this pretreated population, including a 20% response rate in rituximab-refractory 
patients.14 The GADOLIN trial of bendamustine + obinutuzumab (BO) + versus bendamustine alone 
in relapsed and rituximab-refractory indolent NHL (not including MCL patients) showed significant 
improvement in PFS with the combination of BO. The study was closed after a pre-planned interim 
analysis determined a statistically significant improvement in the primary endpoint of PFS after a 
median follow-up of 21.0 months (BO arm) and 20.3 months (B-alone arm). PFS was not reached in 
the BO arm versus 14.9 months in the B-alone arm (hazard ratio 0.55, p=.0001).15  
The activity of obinutuzumab in up-front therapy of lymphoma may be superior to rituximab as 
suggested by results of the CLL11 trial.16  In CLL11, the activity of obinutuzumab + chlorambucil was 
compared with rituximab + chlorambucil and chlorambucil alone in older adults with previously 
untreated chronic lymphocytic leukemia (CLL). PFS was significantly improved with the combination 
of obinutuzumab + chlorambucil (26.7 months) compared with chlorambucil alone (11.1 months), and 
a trend toward improved PFS compared with rituximab + chlorambucil (16.3 months).16 It is of 
considerable interest as to whether this same benefit with use of obinutuzumab as front-line therapy 
can be extrapolated to other non-Hodgkin lymphoma (NHL) histologies, including MCL.  
This proposed study would build on the known activity of bendamustine, with the addition of 
obinutuzumab as a more potent anti-CD20 monoclonal antibody alternative agent to rituximab. This 
study will investigate the impact obinutuzumab will have on the depth and duration of remission in 
previously untreated MCL. The other novel aspect of this trial includes MRD evaluation after 2 cycles 
of induction BO (evaluating correlation with PFS at this time point as previously described in DLBCL6) 
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achieving MRD-negativity at the time of post-consolidation restaging. This approach will allow for 
minimizing treatment-related toxicity in an older and less fit population that has achieved a very high 
level of remission by MRD testing following induction and consolidation therapy.  
STUDY DESIGN: 
 
This is a phase II single-arm, open-label, multicenter study evaluating the efficacy and safety of the 
combination of induction chemoimmunotherapy with bendamustine and obinutuzumab (BO) 
followed by consolidation therapy and maintenance therapy with obinutuzumab in subjects who 
have not received prior cytotoxic chemotherapy for their MCL (i.e., prior single-agent rituximab is 
permitted, prior involved-field radiotherapy is permitted). Therapy for individual subjects will be risk-
adapted based on results of minimal residual disease (MRD) testing performed after the 
consolidation phase. The study will be carried out at the University of Wisconsin Carbone Cancer 
Center (UWCCC) and participating community and academic practice sites within the Wisconsin 
Oncology Network (WON).  There will be 6-10 sites participating in this study. 
 
The subject participation will include a screening period, treatment period, and a follow-up period. 
The induction chemoimmunotherapy regimen consists of bendamustine and obinutuzumab for 4-
6 cycles, followed by consolidation and maintenance therapy with obinutuzumab in subjects 
achieving an objective response to induction therapy (i.e., complete or partial response; stable 
disease with objective evidence of tumor shrinkage. Subjects who are MRD-negative (determined 
by MRD testing on bone marrow and PB) after consolidation therapy will omit maintenance 
therapy.  
 
Subjects will undergo disease reassessment after C4 of induction BO chemoimmunotherapy, after 
obinutuzumab consolidation therapy, and after C4 and C8 of maintenance obinutuzumab.  See 
schedule of assessments for details. MRD testing will be done after C2 of induction (PB only), after 
consolidation (BMA and PB), and post-maintenance or EOT (PB only). 
STUDY ENDPOINTS 
Primary Objective:  
• 
The primary objective is progression-free survival (PFS). 
Secondary Objectives:  
• 
To estimate the MRD status (MRD defined as reduction to ≥10-6 fold reduction in the IgVH 
unique clone of MCL by NGS).  
• 
To estimate the concordance rate between peripheral blood and bone marrow aspirates in 
predicting MRD-negative status. 
• 
To determine objective response rates (CR + PR) with induction BO in previously untreated 
MCL using the International Working Group Criteria17 for response in lymphoma. 
• 
To determine overall survival.  
To determine toxicities observed with induction BO and consolidation and maintenance 
obinutuzumab. 
STUDY DURATION: Anticipated accrual period 
of 30 months, with a follow-up period of at least 
2 years after completion of therapy or until death 
or profession, or until the last subject has been 
followed for at least 1 year following completion 
of therapy. 
 
 
TOTAL SAMPLE SIZE: Approximately 32 
subjects are planned for enrollment. 


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DOSING REGIMEN(S): 
Induction 
chemoimmunotherapy 
(28 
day 
cycles): 
• 
Bendamustine 90 mg/m2 IV days 1 & 2 
every 28 days X 4-6 cycles 
• 
Obinutuzumab: 
            Cycle 1: 100 mg IV day 1, 900 mg IV  
                 day 2, 1000 mg IV days 8 & 15 
            Cycles 2-6: 1000 mg IV day 1 
Consolidation phase: 
Obinutuzumab 1000 mg IV weekly X 4 
doses 
Maintenance phase (8 week cycles): 
Obinutuzumab 1000 mg IV on day 1 of cycles 1-
8 
STUDY DRUG SUPPLIES: 
 
Bendamustine is commercially available. 
 
For study participants, obinutuzumab will be 
provided by Genentech, Inc. at no charge.  
 
 
 


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3 Schedule of Study Assessments 
 
Baseline1 
C1-6 Induction 
chemotherapy 
Consolidation 
therapy19 
 
(±3 days) 
 
 
 
Post 
Consolidation 
therapy20 
Maintenance 
therapy 
(every 8 
weeks ±14 
days) 
EOT17 
Follow-up 
phase2 
Every 3 
months for 2 
years 
(±3 weeks) 
D1 (±7 days)1 
Informed consent 
X 
Medical history & 
medications 
X 
Physical exam, vital signs, 
weight, height3, ECOG 
performance status 
X 
X 
X4 
 
X 
X4 
X 
X 
MIPI score (Appendix D)1 
X 
Bone marrow aspirate 
(BMA) & biopsy and flow 
cytometry5 
X 
X7 
 
X7 
X 
MRD assessment 
X6 
X7 
X7 
X7 
X7 
X7 
P53 mutation analysis 
X22 
 
 
 
 
 
Hematology profile 
X 
X8 
X8 
X 
X8 
X 
X 
Chemistry profile 
X9 
X9,10 
X9 
X10 
X10 
X10 
X10 
Creatinine clearance18 
X 
Beta-2 microglobulin level 
X 
Immunoglobulin levels11 
X 
X 
X 
X 
X 
Hepatitis screening12 
X 
Pregnancy testing13 
X 
X 
X 
 
X 
CT of the chest & 
abdomen/pelvis14,23 
X 
X 
X 
X 
X 
X 
X 
PET imaging15,23 
X 
X 
X 
 
X 
X 
Formal Disease assessment 
(CT scans, palpated 
disease, and other 
assessable disease)16 
X 
X 
X 
 
X 
X 
X 
X 
Record adverse events 
X 
X 
X 
X 
X 
X 
X 
Bendamustine infusion 
X 
Obinutuzumab infusion 
X21 
X 
 
X 
 
 
1Baseline assessments to be done within 28 days of enrollment, unless otherwise noted.  If baseline assessments were done 
within 7 days of C1D1, they do not need to be repeated on C1D1. Baseline disease assessments (i.e. CT scans and 
bone marrow biopsy/aspirate) may be performed within 6 weeks of enrolment. The parameters used for calculating MIPI 
score (i.e., ECOG performance status, LDH, white blood cell count) must be collected from the baseline assessment 
values. 
2The follow-up phase of therapy will begin after confirmation of MRD-negative status, after treatment completion (last cycle 
of treatment completed), or after stopping treatment early for reasons other than PD. The follow-up phase will continue for 
up to 2 years or until: death, progression of disease, start of a new anti-cancer therapy, or withdrawal. After the follow-
up phase is completed, subjects will be followed annually for 5 years after treatment completion for survival and disease 
progression. See section 7.5. 
3Required as baseline only. 
4Required to be performed on D1 of consolidation, and on D1 of each maintenance dose. 


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5Bone marrow aspirate (BMA) and biopsy and flow cytometry to be done at baseline and after completion of consolidation 
therapy as part of restaging and MRD assessment of marrow. Subjects with possible CR during maintenance therapy 
will require a BMA and biopsy to confirm a CR as best treatment response at scheduled disease assessments. Refer to 
section 12.0. Response criteria for additional guidance of when BMA and biopsy are required. 
6Confirm that baseline MRD sample available on enrollment or pre-enrollment samples. Pre-enrollment samples must be from 
within 12 months of enrollment. Additional details, including sample types, outlined in section 7.1.1. 
7MRD assessments will include: PB only after C2 of induction (up to 7 days before C3D1); both (peripheral blood) PB and 
BMA post consolidation therapy; PB only after completion of maintenance (4-6 weeks after final dose of maintenance); PB 
only at EOT. Required at EOT visit in subjects discontinuing protocol therapy due to toxicity or patient preference. Not 
required at EOT in subjects stopping protocol treatment due to progression. Not required at EOT visit in subjects with MRD 
negative status in both marrow and blood after consolidation who proceed to clinical observation. 
8Hematology profile (CBC, differential) is required within 48 hours prior to D1 of: induction C2-6, consolidation, and each 
maintenance dose. 
9Chemistry profile during baseline, C1D1 of induction and D1 of consolidation: sodium, potassium, chloride, CO2 
(bicarbonate) calcium, magnesium, phosphorus, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, 
alkaline phosphatase, total bilirubin, AST/SGOT, ALT/SGPT, lactate dehydrogenase (LDH), and uric acid. To be 
obtained within 48 hours of: induction C1D1 and D1 of consolidation.  
10Chemistry profile during C2-6 of induction, post consolidation, maintenance, EOT and follow-up phase: sodium, 
potassium, chloride, CO2 (bicarbonate), BUN, creatinine, and LDH. To be obtained within 48 hours of visit. 
11Immunoglobulin levels (quantitative serum levels of IgA, IgG, IgM) should be evaluated at baseline, at the end of 
induction chemotherapy (at least 4 weeks after last induction dose and/or prior to C1D1 of consolidation), post 
consolidation therapy, at completion of maintenance therapy, and/or at the EOT. 
12Hepatitis screening to include hepatitis B surface antigen, hepatitis B core antibody, and hepatitis C antibody 
13Pregnancy tests for females of childbearing potential: A female of childbearing potential (FCBP) is a sexually mature 
female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal 
for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Pregnancy 
testing must be performed with a method of serum or urine testing with a sensitivity of at least 50 mIU/mL. Pregnancy 
testing in FCBP will occur at baseline and within 48 hours of each induction, consolidation, and maintenance therapy. 
14CT imaging of chest, abdomen, pelvis (and neck if clinically indicated) to be performed at baseline, after C4 of induction, 
post consolidation therapy, and after C4 and C8 of maintenance. The post C8 scans should be done at the same time as 
the EOT visit, approximately 30 (+/-5) days post last dose. CT imaging is required after treatment completion or at the EOT 
visit for all subjects, regardless of reason for treatment discontinuation. During the follow-up phase, CT imaging will occur 
approximately every 6 months for up to 2 years. Thereafter, follow-up imaging will be at physician discretion. See section 
7.5. CT imaging of the neck, abdomen, and pelvis should be performed with IV contrast; chest CT imaging may be performed 
without IV contrast. 
15PET imaging is required as part of disease assessments only for subjects who require re-assessment to determine CR status 
or if clinically indicated as part of disease assessment (i.e., disease sites not adequately visualized/assessed by CT 
imaging). 
16Formal disease assessments (palpable disease, imaging assessment, other clinically evaluable disease) to be performed 
at baseline, after C4 of induction, post consolidation therapy, and after C4 and C8 of maintenance. The post C8 disease 
evaluation should be done at the same time as the EOT visit, approximately 30 (+/-5) days post last dose. During the 
follow-up phase, disease assessment with clinical evaluation will occur every 3 months for up to 2 years. After 2 years 
of follow-up, subjects will be followed annually for up to 5 years for survival and disease progression. See section 7.5. 
17EOT visit will be performed at 30 days (±5 days) following the last dose of study drug, including post C8 of maintenance. 
18Creatinine clearance to be calculated using Cockcroft-Gault formula (Appendix C). Baseline creatinine clearance may be 
verified by 24-hour urine collection. 
19To be obtained pre-consolidation, unless otherwise noted. 
20Post consolidation therapy visit will be performed at 30 days (+5 days) following the final dose of consolidation therapy. 
21Obinutuzumab infusions C1D8 and C1D15 may be given in a treatment window of ±3 days.  
22Baseline p53 mutation analysis is strongly recommended, although not required for study enrollment. In subjects already enrolled, 
p53 mutation analysis can be performed retrospectively or prospectively on diagnostic specimens. For ALL UW subjects, additional, 
but separate p53 testing will be performed on existing tissue samples as part of Dr. Yang's research study, UW16068.Acceptable 
methods of p53 mutation testing include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and/or molecular 
sequencing.  
23Spleen craniocaudal dimension of 13 cm is the upper limits of normal for response assessment. 


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4 Glossary of Abbreviations 
Abbreviation 
Term 
5-HT3 
5-hydroxytryptamine (serotonin) 
ADCC 
Antibody-dependent cellular cytotoxicity 
ADCP 
Antibody-dependent cellular phagocytosis 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ANC 
Absolute neutrophil count 
ASCT 
Autologous stem cell transplant 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BM 
Bone marrow 
BMA 
Bone marrow aspirate 
BO 
Bendamustine + obinutuzumab 
BR 
Bendamustine + rituximab 
BSA 
Body surface area 
BVR 
Bendamustine, bortezomib, rituximab 
C 
Cycle 
CDC 
Complement-dependent cytotoxicity 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CLL 
Chronic lymphocytic leukemia 
CR 
Complete response 
CRC 
Clinical Research Committee 
CrCl 
Creatinine clearance 
CRF 
Case report form 
CRCO 
Central Research Coordinating Office 
Cri 
Complete response with incomplete count recovery 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
D 
Day 


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DLBCL 
Diffuse large B cell lymphoma 
DLT 
Dose-limiting toxicity 
DOT 
Disease Oriented Team 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics committee 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment 
FCBP 
Females of childbearing potential 
FDA 
United States Food and Drug Administration 
FISH 
Fluorescence in situ hybridization 
G-CSF 
Granulocyte colony stimulating factor 
GCP 
Good clinical practice 
IB 
Investigational Brochure 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRR 
Infusion related reactions 
IV 
Intravenous/intravenously 
IWCLL 
International Working Group on Chronic Lymphocytic Leukemia 
L O D 
Limit of Detection 
LOQ 
Limit of quantification 
MCL 
Mantle cell lymphoma 
mAb 
Monoclonal antibody 
MIPI 
Mantle cell lymphoma International Prognostic Index 
MRD 
Minimal residual disease 
NK 
Natural killer 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse 
Events NGS 
Next generation sequencing 
NHL 
Non-Hodgkin lymphoma 
ORR 
Overall response rate 


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OS 
Overall survival 
PB 
Peripheral blood 
PCR 
Polymerase chain reaction 
PFS 
Progression-free survival 
PD 
Progressive disease 
PET 
Positron-emission tomography 
PI 
Principal investigator 
PR 
Partial response 
PSR 
Protocol Summary Report 
R-CHOP 
 Rituximab, cyclophosphamide, doxorubicin, 
vincristine, prednisone 
R-FC 
Rituximab, fludarabine, cyclophosphamide 
SAE 
Serious adverse events 
SD 
Stable disease 
SPM 
Second primary malignancy 
TLS 
Tumor lysis syndrome 
TTP 
Time to progression 
ULN 
Upper limit of laboratory normal 
UWCCC 
University of Wisconsin Carbone Cancer Center 
VcR-CVAD 
Bortezomib, rituximab, cyclophosphamide, vincristine, 
doxorubin, dexamethasone 
WBC 
White blood cell count 
WON 
Wisconsin Oncology Network


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5 Background and Rationale 
5.1 Diagnosis and natural history of mantle cell lymphoma 
Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphoma (NHL) with a 
disease history and prognosis that tends to be intermediate between that of indolent and 
aggressive NHLs.18,19 Patients with MCL tend to present with advanced stage disease and 
extranodal sites of involvement.19 Therapy can result in disease remission, but ultimately 
any therapy administered is not curative. The median age of diagnosis is above the age of 
60 years, and many patients diagnosed in this typical age range have pre-existing 
medical co-morbidities.19 The natural history and prognosis of MCL can be quite variable, 
with up to one-third of MCL patients exhibiting a more indolent disease progression 
pattern.10-12 The variability in disease behavior and diversity in patients; ages and co-
morbidities can greatly affect the choice and tolerability of first-line therapy. 
 
Based on current prognostic indices, it remains difficult to predict patients who may 
experience more indolent disease behavior at the time of diagnosis. The MCL 
International Prognostic Index (MIPI) is based on the 4 independent prognostic factors 
of age, ECOG performance status, LDH, and WBC, and is of value for pretreatment risk-
assessment in patients with advanced stage MCL.20 However, additional indicators of longer-
term outcomes based on early response assessment and other means of individual risk 
assignment remain insufficient. Minimal residual disease (MRD) testing is proposed as a 
means of identifying patients who may experience durable remissions with initial non-
intensive therapy approaches, and offers the possibility of individually tailoring therapy 
based on early response, thereby minimizing treatment-related toxicities while preserving 
efficacy of therapy. 
 
 
5.2 Initial treatment of MCL 
In younger and fitter adults with MCL, more intensive induction therapy with consolidative 
ASCT is considered a standard therapy approach. This is based on compelling data from the 
NORDIC lymphoma group reporting impressive 6 year event-free and progression-free 
survivals of 56% and 66%, respectively, in patients younger than age 66 with newly 
diagnosed MCL treated with dose-intensive induction chemotherapy (R-maxi-CHOP 
alternating with R-cytarabine) followed by consolidative ASCT.21 Similarly, several studies 
using dose-intensive regimens in younger MCL patients have demonstrated excellent long 
term outcomes, with 5-year progression-free survival (PFS) rates of 50-60% and 5-year 
overall survival (OS) rates of 65-75%.21-24 As anticipated, toxicities (primary hematologic and 
infectious) are substantial with these intensive up-front treatment approaches, making 
them not feasible for older adults. However, it is still somewhat unclear as to whether 
intensive strategies improve OS in MCL relative to non- intensive strategies. One 
randomized clinical trial showed improved PFS using an intensive strategy, while one 
observational study reveals similar outcomes using non-intensive strategies.25,26 In addition, 
moderate intensity induction regimens with bortezomib combined with rituximab and a 
modified hyper-CVAD regimen have demonstrated 3-year PFS of 63% and 72%, with an 
enrolled population that included older and less fit adult patients.3,4 
 
However, a majority of patients with MCL will not be eligible for these high- or 
moderate- intensity regimens based on age and co-morbidities. In these patients, a 


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bendamustine + rituximab (BR) induction regimen has been a standard based on the 
data reported by the German StiL trial,1 with MCL patients having an overall response rate 
of 93% (CR rate of 40%) and 2-year PFS of approximately 60-70% after receiving 6 cycles 
of BR and no maintenance therapy).2 In the StiL trial, patients were randomized between 6 
cycles of BR or R-CHOP, and toxicity was more favorable with BR, with significantly less 
neutropenia with BR (rates of grade 3-4 neutropenia 29% versus 69%) and infections 
(37% versus 50%).1 Confirmation of these high rates of objective responses with an initial 
BR induction in MCL and other indolent NHLs was reported in the BRIGHT trial.27 These 
data have been the basis for cooperative group trial E1411, which is investigating an 
induction regimen of BR versus BVR (BR + bortezomib) X 6 cycles and a 2nd randomization 
to rituximab versus rituximab + lenalidomide. This trial is scheduled to meet accrual by fall 
2016. At present, there are no predecessor studies for non- intensive therapy of previously 
untreated MCL planned for roll-out from the U.S. cooperative groups (personal 
communication, Dr. Brad Kahl, Washington University, ECOG Lymphoma Committee 
Chair). In the interim, induction chemotherapy with BR with or without maintenance 
rituximab is the most common first-line non-intensive regimen used for older or less fit 
adults with MCL. 
 
 
5.3 Bendamustine in MCL 
Bendamustine is a chemotherapeutic agent that has dual functional properties of both an 
alkylating agent and a nitrogen mustard.28 Through these unique cytostatic properties, 
bendamustine is able to inhibit DNA transcription, replication, and repair. In addition, some 
data have suggested that bendamustine’s improved chemical stability compared with other 
nitrogen mustards may enable the compound to have more efficient DNA alkylating 
properties. These unique properties of bendamustine also enable it to exhibit only partial 
cross-resistance with other alkylating agents.28,29  Bendamustine is approved in the U.S. for 
treatment of CLL and for indolent B cell NHLs progressing during or within 6 months of 
rituximab or a rituximab - containing regimen. 
 
Bendamustine is frequently administered as a front-line chemotherapy agent in multiple 
subtypes of indolent NHL, including CLL and MCL, based on its known efficacy and 
acceptable  toxicity profile.1,30,31 Overall response rates of 75-92% and complete response 
(CR) rates of 33- 50% were reported in three separate phase II studies of BR in subgroup 
analyses of relapsed, indolent NHL populations with MCL.32-34 BR was established as a 
reasonable induction standard by the German StiL trial (R-CHOP versus BR in previously 
untreated indolent NHL and MCL), with MCL patients (n=94) having 2-year PFS of 
approximately 60-70% (after 6 cycles of BR and no maintenance therapy).1 The BRIGHT trial 
investigated the activity of R-CHOP/R-CVP versus BR as initial therapy for indolent NHL and 
MCL.27 In this international, randomized, non- inferiority study (n=447), BR was determined to 
be non-inferior to R-CHOP/R-CVP with overall response rate (ORR) 97% versus 91% and 
CR rate of 31% versus 25%. There was more GI toxicity (i.e., nausea and vomiting) and 
hypersensitivity reactions with bendamustine, but less neutropenia, alopecia, and 
neuropathy.27 Among the subgroup of patients with previously untreated MCL, ORR was 94% 
and CR was 50%, consistent with other reports.27 However, data regarding PFS with front-
line therapy with BR in MCL was not reported. 
 
Additional reports have shown activity of bendamustine in relapsed and previously untreated 
MCL. Rummel et al reported outcomes of a subgroup of patients with relapsed/refractory 
NHL treated with BR, including 16 patients with MCL (7 refractory to their last therapy). 


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Among these MCL patients, 12/16 (75%) responses were observed, including 50% with a 
CR.33   Robinson et al reported an ORR of 92% and complete or unconfirmed CR rate of 59% 
among a subgroup of NHL patients with MCL.32 PFS was 23 months in the entire cohort of 
relapsed indolent NHL treated with bendamustine.32 Toxicity was manageable in this report 
of patients with relapsed indolent NHL or MCL treated with BR (n=66). While 36% of patient 
experienced grade 3-4 neutropenia, only 10% of patients experienced grade 3-4 infections; 
only 9% of patients experienced grade 3-4 thrombocytopenia.32 Warsch et al reported a 
multicenter experience with bendamustine for treatment of MCL. The ORR of 83% and CR 
rate of 50% was consistent with objective response in other reports, and the observed time-
to-treatment failure was 16.2 months in this predominantly relapsed MCL population.35 
Grade 3-4 infections were observed in 10% of treated patients, and neutropenic fever 
occurred in only 7% of patients. Thrombocytopenia is common with bendamustine, and 20% 
of patients experienced grade 3-4 thrombocytopenia, although notably without significant 
bleeding complications observed.35 
 
Based on these data of efficacy and tolerability of bendamustine in MCL, the combination of 
bendamustine + monoclonal antibody therapy (primarily rituximab) is considered a standard 
induction therapy for previously untreated ML, particularly in older adults with co-morbidities 
and toxicity concerns with more intensive induction approaches. BR is a listed as a standard 
therapy option in elderly MCL in the NCCN guidelines: 
(https://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf). 
 
 
5.4 Monoclonal antibody therapy in MCL 
The majority of data with monoclonal antibody (mAb) therapy in treatment of MCL has been 
with the anti-CD20 mAb rituximab. Rituximab has limited durable benefit as a single-agent in 
MCL, but rituximab combinations with cytotoxic chemotherapy are standard induction 
therapy approaches in both newly diagnosed and relapsed MCL. In addition, there has been 
experience with maintenance rituximab in MCL, utilizing the same approach to improve PFS 
demonstrated with maintenance rituximab in follicular lymphoma and other indolent NHL 
histologies.36-40 
 
Two small, randomized controlled trials observed conflicting results about the benefit of 
maintenance rituximab following induction chemotherapy in MCL. The German Low Grade 
Lymphoma Study Group treated patients with relapsed NHL with induction rituximab + 
chemotherapy, then randomized patients to rituximab maintenance for 9 months or 
observation.38 Of the 47 patients analyzed in the MCL cohort, a statistically significant 
improvement in response duration was observed in favor of maintenance rituximab 
(remission beyond 2 years, 45% vs. 9%, p = 0.049).38   In comparison, the Swiss Group for 
Clinical Cancer Research (SAKK) randomized104 patients with a mixture of untreated and 
relapsed MCL to a single 4-week rituximab treatment or a prolonged rituximab schedule of 
a 4-week treatment followed by a single dose every 8 weeks for 4 doses. The extended 
schedule did not improve response rates, response duration, or event-free survival (EFS).41 
The reasons for these discrepant results are unclear, but the quality of the response to 
induction therapy may affect the likelihood of benefit from maintenance rituximab. 
 
A phase II study from the Wisconsin Oncology Network (WON) in 30 patients with previously 
untreated MCL observed a 3-year PFS of 63% and OS of 86% following treatment with an 
induction regimen of bortezomib, rituximab, and modified hyper-CVAD chemotherapy (VcR- 
CVAD) followed by maintenance rituximab as a single dose every 3 months for 5 years.42 


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E1405 further evaluated the efficacy of VcR-CVAD X 6 cycles in previously untreated MCL, 
followed by 2 years of maintenance rituximab or ASCT. Three-year PFS and OS were 77% 
and 88%, respectively, and did not differ between those patients who received maintenance 
rituximab (n=44) and ASCT (n=22).43 Similarly, a recent report by the European Mantle Cell 
Lymphoma Network reported an excellent 3- year overall survival of 86% among elderly 
patients with newly diagnosed MCL treated with 8 cycles of R-CHOP chemotherapy followed 
by rituximab maintenance administered until disease progression.44 The observed PFS and 
OS in these studies compares favorably with some reports of more intensive induction 
regimens with or without consolidative ASCT in front-line therapy of MCL.22,24 Incorporation 
of novel mAbs such as obinutuzumab may improve upon these established outcomes with 
rituximab maintenance without significantly altering the toxicity profile. 
 
 
5.5 Obinutuzumab 
 
5.5.1 
Structure and mechanism of action of obinutuzumab 
Obinutuzumab (GA101, RO5072759), is a glycoengineered, humanized, type II anti-CD20 
mAb. Obinutuzumab was derived by humanization of the parental B-Ly1 mouse antibody 
and subsequent glycoengineering leading to the following characteristics: high antibody-
dependent cellular cytotoxicity (ADCC); high affinity binding to the CD20 antigen; low 
complement- dependent cytotoxicity (CDC) activity; and antibody dependent cellular 
phagocytosis (ADCP) through recruitment of FcψRIII positive immune effector cells such as 
natural killer (NK) cells, macrophages and monocytes; and high direct cell death 
induction.13,45 Obinutuzumab has demonstrated superiority to rituximab in preclinical studies 
using whole-blood depletion assays and human diffuse DLBCL and MCL xenograft 
models.13 Given the direct cell death-inducing properties of obinutuzumab and the 
significantly enhanced ADCC in preclinical assays, it is possible that obinutuzumab may 
have greater efficacy than the widely used anti-CD20-mAb rituximab (Rituxan). 
 
 
5.5.2 
Clinical experience with obinutuzumab in CD20+ NHLs 
For the most up-to-date information on obinutuzumab, please refer to the current version of 
the Investigator’s Brochure. Summaries of the clinical experience in CD20+ NHLs are 
included in the following section. 
 
Study BO20999 (GAUGUIN; NCT00517530) (Phase I) 
 
BO20999 is an open-label, multicenter, phase I/II study to explore obinutuzumab safety 
and activity in relapsed/refractory NHL and CLL.46   Thirteen CLL patients have received 
obinutuzumab at doses with a range of 400−2000 mg (given as a flat dose) across four 
cohorts.47   There were no dose-limiting toxicities (DLTs) and no requirement for dose 
reductions.  Infusion-related reactions (IRRs) occurred in all CLL patients and were 
characterized predominantly by National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) grade 1−2 toxicities: chills, nausea, vomiting, fever, 
pyrexia, hypertension, hypotension, dyspnea, and dizziness. Two patients experienced 
four NCI- CTCAE grade 3 toxicities: sweats, flushing, asthenia, and hepatic cytolysis. 
Although the safety profile appears otherwise similar between NHL and CLL, there was an 
increase in NCI-CTCAE v3.0 grade 3/4 neutropenia noted in CLL patients, which were 
observed in 9 patients across the four dose levels administered.  Five patients experienced 
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neutropenia as the maximum severity. Of the 9 patients, 7 had one NCI-CTCAE grade 3/4 
event and 2 patients experienced more than one event. Granulocyte colony-stimulating 
factor (G-CSF) support was administered to 6 of the 9 patients, and these patients 
responded quickly to G-CSF support. For the 3 patients who did not receive G-CSF, 
neutrophil counts normalized spontaneously. 
 
Furthermore, it is important to note that these neutropenia events did not appear to be 
accompanied by a higher incidence of infections. No deaths were reported in Phase I of this 
study for CLL. 
 
As assessed by the International Working Group on CLL (IWCLL) criteria, the end-of-treatment 
response rate with obinutuzumab monotherapy was 62% (8 of 13 patients with partial response 
(PR)).47 
 
Study BO20999 (GAUGUIN; NCT00517530) (Phase II) 
 
Twenty patients with relapsed/refractory CLL have received 1000 mg of obinutuzumab. The 
most commonly reported adverse event (AE) during the treatment period was IRR, reported in 
19 (95%) of 20 patients.  Fifteen patients experienced grade 3/4 AEs, of whom 14 patients 
had treatment-related grade 3/4 AEs (investigator assessment). Treatment-related grade 3/4 
AEs were IRR (6 patients), neutropenia (4 patients), lymphopenia (2 patients), 
thrombocytopenia (2 patients), and anemia, pure red cell aplasia, pancytopenia, febrile 
neutropenia, herpes zoster, and interstitial lung disease (1 patient each).  Eleven serious 
adverse events (SAEs) in 9 patients were reported during treatment, 9 of which were 
assessed by the investigator as related to obinutuzumab: IRR (4 patients) and febrile 
neutropenia, pancytopenia, pure red cell aplasia, interstitial lung disease and pyrexia (1 
patient each). Three patients withdrew from further study treatment after the first infusion 
due to IRR.  One death has been reported during follow-up from colon cancer. The most 
common AE in follow-up was nasopharyngitis, reported in 2 patients.  End-of-treatment 
response assessment showed that four patients (20%) achieved a clinical response, with a 
best ORR of 25% in evaluable patients.48 
A separate randomized phase II portion of the GAUGUIN trial evaluated the efficacy and 
safety of two doses of obinutuzumab in patients with heavily pretreated diffuse large B-cell 
lymphoma (DBLCL) and MCL.14 The GAUGUIN study investigated differing dose levels of 
single-agent obinutuzumab in previously treated DLBCL and MCL. Patients were 
randomized to receive either 8 cycles of a 400 mg flat dose (n=21, 10 DLBCL, 11 MCL) or 8 
cycles of obinutuzumab at an initial dose of 1600 mg for cycle 1 followed by 800 mg dosing 
for cycles 2-8 (n=19, 15 DLBCL, 4 MCL). Overall response rates were 24% (for 400 mg 
treatment arm) and 37% (for 1600/800 mg treatment arm) in this pretreated population, 
including a 20% response rate in rituximab-refractory patients.14 Infusion-related reactions 
(IRR) were the most common treatment-related AEs, which were primarily grade 1-2 with 
the exception of 3 patients experiencing grade 3-4 IRRs. Hematologic toxicity was 
manageable, with only 1 patient experiencing grade 3-4 neutropenia.14 
 
Study BO21003 (GAUSS; NCT00576758) (Phase I) 
 
BO21003 is an open-label, dose-escalating, multicenter phase I/randomized phase II study 
in patients with relapsed/refractory CD20+ malignant disease. In study BO21003, 22 
patients have been administered obinutuzumab (10 follicular, 5 CLL, 2 small lymphocytic 
lymphoma, 3 DLBCL, 1 MCL, 1 transformed lymphoma). Patients were heavily pretreated 


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with a median of 4 prior therapies, and 50% of patients were rituximab-refractory. Infusion 
related events were the most common toxicity, with 16 events during the first infusion and 
only 8 events with all subsequent infusions. Most IRR were grade ≤2, although 4 grade 3 
IRR were observed and 1 grade 4 IRR (associated hypoxia which led to permanent 
discontinuation of study treatment in this patient). Five events of grade 3/4 neutropenia 
were observed, and 1 event of grade 3 thrombocytopenia was reported. Six minor infections 
and 1 event of febrile neutropenia were reported. The ORR was 25% (5 patients, all partial 
responses), with 13 additional patients demonstrating SD.49 
 
Study GAO4768g / GAGE / NCT01414205 (Phase II) 
 
GAO4768g is an open-label, randomized, multicenter, phase II study evaluating the efficacy 
and safety of obinutuzumab administered at 1000 mg versus 2000 mg doses in patients with 
previously untreated CLL.50 Eighty patients were randomized and stratified based on Rai 
stage and tumor mass. For patients who received the 1000-mg doses, obinutuzumab was 
administered with three 1000-mg doses in the first 21-day cycle (the first 1000-mg dose was 
administered over 2 days: 100 mg administered on day 1, 900 mg administered on day 2; 
1000 mg was administered on both days 8 and 15).  In the subsequent cycles (cycles 2 
− 8), 1000 mg of obinutuzumab was administered on the first day of each cycle. For 
patients who received the 2000-mg doses, obinutuzumab was administered as follows: 100 
mg on cycle 1, day 1; 900 mg on day 2; and 1000 mg on day 3. On days 8 and 15 of cycle 1, 
2000 mg was administered on each day. For cycles 2 − 8, 2000 mg of obinutuzumab was 
administered on day 1 of each cycle. ORR was assessed at 2 months post-therapy 
according to the IWCLL criteria.  The ORR for the 1000 mg and 2000 mg obinutuzumab 
treatment arms were 49% compared with 67%, respectively; 2-sided p = 0.0779.  Complete 
response/complete remission with incomplete blood count recovery (CR/CRi) was achieved 
by 5% of patients (2/41) in the 1000-mg arm compared with 21% of patients (8/39) in the 
2000-mg arm. 
 
The most common Grade 3/4 AEs were IRRs (23% vs. 11%) and neutropenia (3% vs. 5%) 
for the 1000-mg and 2000-mg arms, respectively.50 
 
Study GAO4779g (GALTON; NCT01300247) (Phase II) 
 
GAO4779g is an open-label, non-randomized, multicenter, phase II study.51 In the GALTON 
study, 41 patients with untreated CLL were treated with obinutuzumab 1000 mg (100 mg IV 
on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15 of cycle 1; 1000 mg on day 1 in 
cycles 2 − 8) and either fludarabine + cyclophosphamide (G-FC: 25/250 mg/m2 IV on days 
2 − 4 of cycle 1, then on days 1 − 3 of cycles 2 − 6) or bendamustine (G-B: 70 mg/m2 IV 
on days 2 – 3 of cycle 1, then on days 1 – 2 of cycles 2 – 6. Each cycle was 28 days. 
 
The most common AEs (any grade) occurring in the G-FC arm were obinutuzumab-related 
IRRs (91%), nausea (76%), fatigue (57%), constipation (48%), and neutropenia (43%); in the 
G-B arm, they were obinutuzumab-related IRRs (90%), nausea (65%), neutropenia (55%), 
diarrhea (50%), and pyrexia (45%). The most common Grade 3/4 AEs were obinutuzumab-
related IRRs (29%, 10%), neutropenia (43%, 55%), and infections (19%, 5%) for G-FC and 
G-B, respectively. Fourteen patients experienced SAEs (G-FC, n = 6; G-B, n = 8), with 
events including febrile neutropenia (5 events); infections (4 events); IRRs (3 events); 
nausea, vomiting, pyrexia (2 events each); and diarrhea, fatigue, tachycardia, tumor lysis 
syndrome, syncope, mental status changes, neutropenia, face swelling, and hypertension (1 


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event each).  Nine patients (G-FC, n = 7; G-B, n = 2) had AEs leading to treatment 
discontinuation, including grade 3/4 neutropenia (3 patients in G-FC [1 of these 3 patients 
also had grade 4 cellulitis] and 2 patients in G-B), grade 3 thrombocytopenia (2 patients in G-
FC), grade 4 pancytopenia (1 patient in G-FC), and grade 4 aspartate aminotransferase 
(AST)/grade 3 alanine aminotransferase (ALT) elevation (1 patient in G-FC). 
The ORR was 62% (CR, 2; CRi, 3; PR, 8) in patients who received G-FC and 90% (CR, 4; 
CRi, 5; PR, 9) in patients who received G-B, including 6 patients (G-FC, n = 4; G-B, n = 2) 
not evaluable due to inadequate response evaluation.  Four patients in the G-FC arm (0 in 
G-B) had SD during and after therapy.  No patient progressed during the study. 
 
Study BO21004 (CLL11; NCT01010061) (Phase III) 
 
CLL11/BO21004 is an open-label, multicenter, three-arm randomized, Phase III study to 
compare the efficacy and safety of obinutuzumab + chlorambucil (GClb), rituximab + GClb 
(RClb), or Clb alone in previously untreated CLL patients with comorbidities.16 The primary 
endpoint of the study is PFS. 
 
BO21004 enrolled 781 patients and an additional 6 patients during a safety run-in period 
before randomization. The median age of enrolled patients was 73, and the median 
Cumulative Illness Rating Score was 8 (score of >6 required for enrollment; range of rating 
score 0-56 with higher score indicating worse health). Toxicities that were more frequent in 
obinutuzumab-treated patients included infusion-related reactions (grade ≥3 IRR in 20% of 
obinutuzumab-treated patients compared with 4% of rituximab-treated patients) and 
neutropenia (35% of obinutuzumab-treated patients experiencing grade ≥3 neutropenia 
compared with 27% of rituximab-treated patients). However, risk of infection was not 
increased with obinutuzumab versus rituximab (grade ≥3 infections 14% versus 12%). In 
addition, rate of infection was not different compared with chlorambucil alone (rate of grade 
≥3 infection 14% with chlorambucil alone).16 
 
Overall response rates and CR rates were increased in obinutuzumab-treated patients. 
Patients treated with GClb had an ORR of 77.3% (22.3% CR’s) compared with RClb (ORR 
65.7%; CR 7.3%) and Clb alone (ORR 31.4%, all PRs). The response rate of GClb and 
RClb were statistically significantly improved when each were compared with Clb alone, and 
CR rates were significantly improved with GClb compared with RClb. 
 
Median PFS was significantly improved for both GClb and RClb compared with Chl alone. 
Median PFS was 26.7 months with GClb compared with 11.1 months with Chl alone (hazard 
ratio for progression or death, 0.18; 95% confidence interval [CI] 0.13-0.24; p<0.001). 
Patients treated with RClb experienced a median PFS of 16.3 months (compared with PFS 
of Chl alone, hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with GClb 
compared with RChl resulted in prolonged PFS (hazard ratio, 0.39; 95% CI, 0.31-0.49; 
P<0.001). In addition, there was an overall survival benefit with GClb compared with Chl 
alone (hazard ratio for death, 0.41; 95% CI, 0.23-0.74; p=0.002).16 
 
GAO4753g, GO01297 GADOLIN trial (NCT01059630) 
 
The GADOLIN trial evaluated the efficacy of obinutuzumab in the treatment of rituximab- 
refractory indolent non-Hodgkin lymphoma. GADOLIN was an open-label, randomized, 
multicenter/multinational phase III trial including adult patients with CD20+ rituximab-refractory 
NHL.15 Patient were randomized to receive either 6 cycles of induction chemotherapy with 


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bendamustine + obinutuzumab (BO) or 6 cycles of bendamustine alone (B-alone). Dosing for  
the BO arm was bendamustine 90 mg/m2 IV on days 1 & 2 of each 28-day treatment cycle 
(cycles 1-6), and obinutuzumab 1000 mg IV on days 1, 8 & 15 of cycle 1 and 1000 mg IV on 
day 1 of cycles 2-6. Dosing in the B-alone arm was bendamustine 120 mg/m2 IV on days 1 & 
2 of each 28-day cycles (cycles 1-6). Patients not progressing in the BO induction treatment 
were eligible to receive obinutuzumab maintenance therapy 1000 mg IV every 2 months for 
up to 2 years. 
 
The median age was 63 years in each treatment arm, and approximately 80% of enrolled 
patients have follicular lymphoma histology. This study did not include MCL patients. Over 
90% of patients were refractory to their last chemotherapy regimen (in addition to being 
rituximab-refractory as eligibility criteria) and >75% were refractory to both rituximab and an 
alkylating agent.15 
 
The study was closed after a pre-planned interim analysis determined a statistically 
significant improvement in the primary endpoint of PFS after a median follow-up of 21.0 
months (BO arm) and 20.3 months (B-alone arm). PFS was not reached in the BO arm 
versus 14.9 months in the B-alone arm (hazard ratio 0.55, p=.0001).15 
 
Obinutuzumab did not appear to significantly increase the risk of SAEs with treatment. As 
expected, IRRs were more common with BO versus B-alone (11% versus 16%). SAEs were 
observed in 38% of BO patients versus 33% of B-alone patients, with deaths due to AEs 
occurring in 12 patients in both treatment arms. Three of these deaths in the BO arm were 
treatment-related, and 5 deaths in the B-alone arm were treatment-related. Fatal AEs in the 
BO group during induction were (n=3): agranulocytosis, colorectal cancer, and vascular 
pseudoaneurysm. Fatal AEs in the BO group following induction were: Fatal AEs after 
induction were (n=9): acute myeloid leukemia (n=1), chronic renal failure (n=1), bacterial 
sepsis (n=2), fungal sepsis (n=1), sepsis unspecified (n=1), gastroenteritis (n=1), graft-
versus-host disease (n=1), and T-cell lymphoma (n=1). Fatal AEs in the B-alone group 
during induction were: adenocarcinoma, Pneumocystis jirovecii pneumonia, sepsis (n=2), 
and tumor lysis syndrome. 
 
Fatal AEs in the B-alone group after induction were (n=7): acute myeloid leukemia, ischemic 
stroke, leukemia, neutropenic sepsis, pneumonia, Pneumocystis jirovecii pneumonia, and 
sepsis.15 
 
Other common toxicities observed with BO versus B-alone treatment included: neutropenia (33% vs 
26%), thrombocytopenia (11% vs 16%), and anemia (8% vs 10%).15 
 
Additional Clinical Experience with Obinutuzumab 
 
For the most up-to-date information on obinutuzumab, please refer to the current version of 
the Investigator’s Brochure. 
 
5.6 MRD testing in lymphoma 
 
5.6.1 
Background on MRD testing with next-generation sequencing 
in MCL 
Therapy for MCL may result in sustained remissions for many patients, but disease relapse 
is inevitable. Residual lymphoma cells that are below the level or routine laboratory or 


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radiographic evaluation are the presumed source of relapse. Current standard strategies 
to determine the extent and depth of remission include radiographic imaging and bone 
marrow aspirate (BMA)/biopsy. The definition of bone marrow (BM) response is a 
morphologically normal marrow with <2% clonal B-cells detected by flow cytometry. Imaging 
assessment requires all lymph nodes to have been reduced to a maximum of <1-1.5 cm in 
size and/or be negative by PET imaging.52 However, the presence of a CR by imaging 
assessment does not preclude the possibility of a substantial burden of microscopic disease. 
For example, the diagnostic accuracy of PET imaging is quite limited with nodal disease <1 
cm in size. Further quantification of the burden of residual lymphoma post-treatment beyond 
what is assessed with standard imaging and biopsy practices may better predict depths and 
durations or remission. 
 
Clinically relevant MRD information can be evaluated through several different techniques, 
including flow cytometric immunophenotyping (using aberrant or lymphoma-associated 
immunophenotypes and immunoglobulin light chain restriction), polymerase chain reaction 
(PCR) targeting specific chromosomal aberrations or clonally rearranged immunoglobulin 
genes, and most recently, next-generation sequencing (NGS) to detect clonally rearranged 
immunoglobulin genes. In MCL, the immunoglobulin heavy chain gene rearrangement is the 
most broadly applicable marker for MRD studies, as a rearrangement is detectable in 
approximately 80-85% of cases.9 NGS is a high-throughput gene sequencing methodology 
that permits a tremendous depth of DNA sequencing. The modern NGS platform by 
Adaptive Biotechnologies (ClonoSEQ) is able to detect 1 in 10-6 lymphoma cells, which is 
superior to the level of MRD detectable by other methods (for example, 10-3 sensitivity 
achievable with four- color flow cytometry, and 10-4 to 10-5 achievable with PCR-based 
assays).9 
 
5.6.2 
Clinical experience with MRD testing in MCL 
Prior to the availability of NGS technology, MRD evaluation with PCR-based techniques was 
explored in MCL, and confirmed to have prognostic value.7,8 A retrospective analysis of 27 
patients evaluable for MRD after autologous stem cell transplant (ASCT) for consolidation of 
initial cytoreductive chemotherapy showed a significant association between MRD status in 
the first year post-ASCT and PFS and OS. Of the 14 patients with clinical remission and 
MRD- negative status (defined as ≥10-4), median PFS was 92 months and median OS was 
not reached, which was significantly improved compared with median PFS of 21 months 
(p<.001) and median OS of 44 months (p<.003) among the 13 patients with residual MRD 
demonstrated during the first year post-ASCT (MRD from blood or marrow collected every 3 
months for 12 months post-ASCT).7 Another retrospective review of outcomes based on 
MRD status prior to ASCT in MCL was reported from the Fred Hutchison Cancer Center. 
This report described outcomes for 75 patients with MCL in complete remission prior to 
ASCT for MCL, using PCR- based techniques (for IgH rearrangement and translocation 
11;14) as well was flow cytometry as part of the MRD assessment.53 Eleven percent of 
patients were MRD-positive post-induction and prior to ASCT. Compared with patients who 
were MRD-negative, these MRD-positive patients had significantly worse outcomes, with a 
median PFS of 2.38 years (median PFS not reached for MRD-negative patients; 5-year PFS 
75% for MRD-negative patients) and median OS of 3.01 years (median OS not reached for 
MRD-negative patients; 5-year OS 82% for MRD-negative patients).53 
 
In the Nordic Lymphoma Group MCL-2 trial, patients were treated with an induction 
chemotherapy regimen of R-maxi-CHOP/R-cytarabine followed by consolidative ASCT. PFS 
differed significantly between patients with residual MRD-positivity by PCR-based techniques 


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within the first year of follow-up (median PFS 1.5 years) compared with those developing 
MRD positive >1 year post-treatment (median PFS 5 years). .21 A subset of MCL patients 
treated with an intensive approach on CALGB 59909 had paired marrow and peripheral 
blood (PB) samples available for MRD assessment post-induction (2 cycles of rituximab, 
augmented CHOP, methotrexate), post-high-dose consolidation (rituximab, etoposide, 
cytarabine), and 3 months post-ASCT (following ASCT and 2 doses maintenance 
rituximab).54 Thirty-nine patients had paired samples available for prognostic correlations. 
Three-year PFS was 82% versus 48% among those who were MRD-negative versus MRD-
positive after induction chemotherapy. 
 
However, post-induction MRD evaluations at later time points were not significantly 
associated with either time-to-progression or survival.54 A report of CALGB 50403 
investigated prognostic implications of MRD status using PCR-based technique in 49 MCL 
patients treated with intensive consolidation and consolidative ASCT for whom sequential 
MRD samples were available.55 Patients with early eradication of MRD following 2 cycles of 
intensive induction therapy had significantly improved PFS (p=.017), and none of the 
patients who achieved MRD- negative status post-induction (n=15) have relapsed after a 
median of 3.3 years of follow-up.55 
 
Pott et al described clinical outcomes as it relates to MRD status in 2 large international 
phase III trials of the European MCL Network in which MRD was a secondary endpoint.8 
The 2 trials included both younger patients treated with a more intensive induction and 
ASCT (MCL Younger) and older patients (MCL Elderly) treated with a less intensive 
induction (R-FC versus R-CHOP) followed by rituximab or interferon maintenance. Notably, 
there was a 90% success rate in obtaining PCR-amplifiable tumor tissue for MRD testing, 
which affirms the feasibility of MRD testing in these diverse populations enrolled at multiple 
centers.8,56 PCR-based MRD testing evaluated clonal IgH VH-JH rearrangements as well as 
the translocation 11;14, with sensitivity to detect MRD to a level of at least 10-4. Time points 
for MRD assessment by PB and/or BM samples included mid-term staging (after 3 or 4 
cycles of induction), 4 weeks after completion of induction therapy, and every 2-3 months 
during maintenance or post-ASCT. A total of 156 patients had available MRD data and a 
documented clinical remission after induction. Patients in clinical remission who achieved an 
MRD-negative status after induction had an 87% chance of ongoing remission at 2 years 
compared with 61% of patients with residual MRD-positivity despite clinical remission 
(p=.004).9 Sustained MRD negativity during maintenance therapy was also predictive of 
outcome. In the MCL Elderly trial, the response duration at 2 years was 76% in those with 
sustained MRD-negative status, compared with 36% of those with persistent residual 
disease by MRD analysis (p=.015).9 
 
5.6.3 
Next-generation sequencing in MRD assessment in MCL 
More recently, MRD data have emerged using NGS technology. PCR-based assessments of 
MRD have multiple limitations which NGS may potentially overcome, including failure of 
amplification and/or identification of the clonal rearrangment in somatically hypermutated 
tumors and in cases of low-level lymphoma, residual disease below a feasible level of 
quantification by PCR-based assays.57 In addition, NGS avoids the need for preparation of 
clonotype-specific primers for each patient and has the potential to achieve a higher level of 
sensitivity to 10-6 (compared with 10-4 to 10-5 in most PCR-based assays). Additionally, as an 
unbiased technique, NGS permits analysis of the clonogenic heterogeneity which may 
contribute to a better understanding of disease biology.57 
 


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A recent publication evaluated the concordance between MRD testing with real-time 
quantitative PCR (RQ-PCR) and NGS in multiple subtypes of B-cell lymphoproliferative 
disorders, including MCL.57 Thirty patients with MCL were included in the analysis comparing 
RQ-PCR and NGS MRD assessments, which included 8 cases where an IgH marker by RQ-
PCR was not detectable. Twenty-six (86%) of the MCL cases could be monitored by NGS, 
including 4 cases in which RQ-PCR failed to evaluate MRD. Among the MCL patients, there 
were 156 follow-up samples available for analysis, and 128 of the 156 (82%) follow-up 
samples were concordant between RQ-PCR and MRD.57 Another report investigated 
concordance between MRD quantification in 22 patients with MCL treated on CALGB 10403 
and CALGB 59909.58 A high-frequency clonal rearrangement was observed in at least 2 
receptors in 95% of MCL patients. 
 
Good concordance was observed in the MCL patients with MRD assessed by PCR versus 
NGS, with NGS offering the improved ability to monitor multiple clonal sequences, having 
an improved turnaround time (about 1 week), and greater sensitivity (MRD detectable to 
10-6).58 
 
Clinical data are emerging with NGS used prospectively for MRD assessments. For example, 
the results of S1106 (BR versus hyper-CVAD induction followed by autologous transplant) 
included MRD evaluation using NGS (Adaptive Biotechnologies) in 10 patients treated with 
BR induction therapy.5 Eight patients achieved MRD-negative status post-induction, and 2-
year PFS was 100% among these MRD-negative patients post-induction.5 
 
A compelling retrospective analysis in diffuse large B-cell lymphoma using NGS 
demonstrated a strong correlation between 5-year time to progression and MRD status after 
only 2 cycles of chemotherapy.6 Interim monitoring of circulating tumor DNA was available in 
108 patients after 2 cycles of chemotherapy (EPOCH or rituximab + EPOCH chemotherapy). 
The 5-year time to progression was 80.2% for patients who were MRD-negative after 2 
cycles of treatment compared with 41.7% in those who remained MRD-positive after 2 
treatment cycles.6 These data are striking, and the basis for MRD testing of peripheral 
blood after 2 cycles of induction therapy in this protocol design. 
 
5.6.4 
Use of blood and marrow samples for MRD analysis 
 
The optimal tissue source of MRD assessment remains an important issue, and available 
data with PCR-based techniques suggest there may be disparity between PB and BM MRD 
assessments. Existing data supports about an 80-90% concordance between MRD 
assessments in the PB and marrow utilizing PCR-based techniques, while data regarding 
this concordance is yet to be definitively understood with NGS technology. For example, a 
German study with 40 paired BM and PB samples showed comparable results regarding 
MRD prediction in paired samples, although patients had not received rituximab + CHOP 
based induction regimens7,9. In a transplant population, 18 of 325 (5%) of BM samples after 
ASCT were discordant with PB.59 The European MCL study group reported that 21 of 108 
(19%) paired samples demonstrated MRD negativity in the PB while low-level MRD was 
detectable in the BM8.8,9  
 
In the MRD assessment by PCR techniques utilized in CALGB 59909, 39 MCL patients had 
paired marrow and PB samples available for assessment after induction chemotherapy.54 
Nineteen patients were MRD-positive in both the marrow and the blood, and 12 patients were 
MRD-negative in both. Therefore, there was a discordance between PB and marrow in 8 of 39 
patients (21%). Of these 8 patients, 6 were MRD-negative in the blood but positive in the 


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marrow, indicating that PB analysis underestimated MRD in approximately 15% of patients.54 
Two patients were MRD-positive in the PB and negative in the marrow, which was postulated 
to be related to focal presentation of lymphoma in the BM, or poor quality of BMA, or lack of 
marrow involvement by lymphoma.54 Potts et al reported that among 44 paired PB and BM 
samples evaluated for MRD by PCR-based testing, concordance was observed in 86% (18 
paired samples were MRD+ in marrow/blood and 20 samples were MRD-negative in 
marrow/blood).7 There were 3 patients who were MRD negative in PB, but low-level MRD 
detectable in BM; in 3 patients with MRD-negative BM, MRD was detectable in PB.7 The 
current ECOG protocol E1411 investigating and induction BR-based therapy is incorporating 
NGS (Adaptive Biotechnologies) as part of a prospective MRD analysis, including paired 
marrow and PB samples. Data from studies such as E1411 may help clarify if MRD testing 
using more easily attainable PB samples can yield consistent concordance with marrow 
samples. 
 
5.6.5 
Summary of rationale for NGS as MRD assessment tool 
The NGS technology utilizing the ClonoSEQ platform by Adaptive Biotechnologies offers the 
opportunity to reliably evaluate MRD status during therapy for MCL, with good feasibility and 
rapid turn-around of results. The ClonoSEQ NGS assay is commercially available for use with 
multiple lymphoproliferative diseases, including MCL, and is performed by a CLIA (Clinical 
Laboratory Improvement Amendments) certified laboratory.  Given the uncertainties that 
remain about concordance of MRD testing results from PB and marrow, MRD assessment 
used for decision-making after consolidation therapy will include both marrow and blood 
samples. MRD testing at other time points (after cycle 2 induction, post-maintenance or EOT) 
will be primarily correlative in nature and will include only MRD analysis on PB. 
 
5.7 Study rationale 
Therapy options for older adults with MCL can be diverse depending on a patient’s age 
and comorbidities as a primarily determinant of initial therapy intensity. In older adults, 
BR is a reasonable front-line regimen based on its efficacy and safety profile. In 
addition, multiple studies have suggested benefit of maintenance therapy with rituximab as a 
means of improving PFS with acceptable toxicity.  However, there remains the need for 
improving depths and duration of responses and minimizing toxicity in older and frailer MCL 
patients. 
 
Obinutuzumab is a more potent mAb compared with rituximab, which may improve the 
response rate and PFS when combined with bendamustine in this population of MCL patients. 
Although direct comparisons of obinutuzumab versus rituximab activity in previously untreated 
MCL are not available, inference from available data show an advantage in terms of higher 
rates of response and PFS in other histologies (i.e., CLL and indolent NHL), and could offer 
the possibility of higher rates of MRD negativity after a course of induction chemotherapy 
with bendamustine-based treatment.15,16 
 
Multiple studies support a correlation between MRD-negative status and improved PFS. 
Evaluation of MRD status during the course of therapy may allow for treatment duration to be 
tailored based on the quality of an individual patient’s response, thereby minimizing toxicity 
and offering the potential to preserve efficacy. In an older and frailer adult population, this 
focus on risk-adapted therapy to minimize toxicity is particularly relevant. In addition, up to 
one-third of mantle cell lymphomas will have a more indolent natural history of progression, 
which can be difficult to identify prospectively. Risk-adapting therapy offers the possibility of 
reducing over-treatment and minimizing toxicity in this heterogeneous population. 


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6 Study Objectives and Endpoints 
6.1 Primary objective 
The primary objective is PFS. 
 
 
6.2 Secondary objectives 
• 
To estimate the MRD status (MRD defined as reduction to ≥10-6 fold reduction in 
the IgVH unique clone of MCL by NGS). 
 
• 
To estimate the concordance rate between PB and bone marrow aspirates in 
predicting MRD status. To determine objective response rates (CR + PR) with 
induction BO in previously untreated MCL using the Lugano classification for 
response in lymphoma.17 
 
• 
To determine overall survival. 
 
• 
To determine toxicities observed with induction BO chemoimmunotherapy 
and obinutuzumab consolidation and maintenance. 
 
7 Investigational Plan 
Subjects meeting eligibility criteria will begin treatment as described below. All subjects 
will undergo BM biopsy, CT imaging, and/or PET imaging within 6 weeks prior to enrollment. 
 
 
7.1 P53 mutation testing 
 
Data on p53 mutation testing will be obtained from subject’s  baseline diagnostic tissue 
sample by either immunohistochemistry, fluorescence in situ hybridization, or molecular 
sequencing. P53 mutation testing can be obtained retrospectively in subjects already 
enrolled at the time that p53 mutation testing was added as a baseline characteristic, and 
have had prior p53 testing completed as standard of care. Subjects whom have not had 
prior p53 testing completed as standard of care on their baseline diagnostic tissue sample 
will be requested to have prospective p53 testing added to their baseline diagnostic tissue 
sample as research and will have this completed commercially. Although every effort will 
be made to obtain p53 mutation testing on enrolled patients, there may be cases where 
obtaining testing is not possible either retrospectively or prospectively due to 
circumstances such as cost issues (for non-UW sites obtaining p53 testing commercially) 
or lack of additional tissue. In those cases, p53 mutation testing is not a requirement for 
study enrollment. Commercial p53 testing results will be disclosed to subjects by their 
treating physician and be placed in their medical record. 
 
Subjects enrolled at UW will have archived diagnostic research samples sentfor 
additional p53 mutation testing. This will be performed through a separate research 
protocol UW16068, which is performing p53 testing in mantle cell lymphoma via IHC, 
FISH, and molecular sequencing to validate the best testing method for reliably 


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establishing p53 mutation status in MCL. Samples submitted for protocol UW16068 
(2017-0879) will be de-identified, glass slides assigned a separate subject ID. The 
investigator for protocol UW16068 will be blinded to the subject’s identification and clinical 
information. 4-6 unstained biopsy slides will be obtained for each UW16086 subject 
enrolled at UW, with a minimum of 4 unstained slides required for p53 mutation testing 
though protocol UW16068. De-identification of these samples will include removing all 
protected health information and labeling obtained samples with the UW16068 study 
number, a separate subject ID, date of collection and sample type. No subject samples 
outside of UW Hospital will be included in the biopsy specimens shared with research 
protocol UW16068. Data generated from protocol UW16068 will not be included in 
UW16086. The p53 status obtained from protocol UW16068 will not be viewable to 
subjects in their electronic medical record and will not be disclosed to subjects by the 
treating physician.   
 
Subjects may have commercial p53 testing done as part of their standard of care 
procedures and independent of this research protocol as this testing is available to all 
subjects. If commercial p53 testing is completed, these results will be made available 
outside of the research study and included in the subject’s medical record.  
 
 
7.2 MRD assessments 
 
7.1.1 
Baseline MRD samples 
A pre-treatment tissue sample must be identified and submitted to Adaptive Biotechnologies 
for identification of the unique clones of immunoglobulin heavy gene (IgVH) mutations 
present at baseline to use as comparison for subsequent MRD assessments. Preferably this 
sample would be from the dominant site of disease involvement (i.e., lymph nodes, BM, PB). 
 
Samples submitted for baseline MRD testing must be collected within 12 months from the 
date of enrollment, or between enrollment and C1D1 of treatment. For example, a BMA may 
be collected for MRD evaluation at the time a staging BM biopsy is performed to fulfill 
eligibility requirements per protocol. Subjects with baseline lymphocytosis at enrollment may 
have a PB sample drawn for baseline MRD analysis. MRD samples collected after 
enrollment should be submitted immediately to allow for identification of the unique 
immunoglobulin heavy gene clones, but must be submitted no later than concurrent with the 
first interim MRD assessment after C2 of induction chemotherapy (i.e., the baseline MRD 
sample and the first interim PB MRD assessment after C2 of induction chemotherapy may 
be submitted concurrently). 
 
It is anticipated that up to 8-10% of subjects with mantle cell lymphoma may not have a 
unique enough immunoglobulin heavy chain sequence to allow for MRD assessment 
(i.e., considered to be MRD-negative even in the situation of clinically evident 
disease). In this case, subjects may continue on protocol therapy to receive the full 
protocol therapy as if they are presumed to be MRD-positive at each MRD evaluation. 
The sample size has been adjusted to account for this situation of a non-unique heavy chain 
sequence for reliable MRD assessment (refer to section 14, Statistical Considerations). 
 
Tissue samples acceptable for assessment of immunoglobulin heavy chain sequencing for 
MRD analysis include: 


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• 
Formalin-fixed, paraffin-embedded (FFPE) tissue, 3-5 slides should be unstained and 
preferably 8-10 um thick 
• 
Fresh BMA (3 cc in EDTA tube) 
• 
Fresh PB (10 cc in EDTA tube) 
• 
Other acceptable specimens include frozen cells/cell pellet and purified DNA; refer 
to Adaptive Biotechnologies ClonoSEQ specimen requisition form for details. 
 
Adaptive Biotechnologies is providing the sample collection kits.  Refer to the WON 
Operations Manual for details. 
 
7.1.2 
MRD follow-up assessments 
MRD assessment will be obtained at the following time points: 
• 
After C2 of induction therapy ( up to 7 days before C3D1 of induction therapy) – PB only 
• 
After consolidation therapy (30 days (+ 5 days) following the final dose of 
consolidation therapy) – PB and BMA 
• 
After maintenance therapy (between 4-6 weeks after the final dose of 
maintenance obinutuzumab) – PB only 
• 
At the EOT visit (30 days (+/-5) post last dose) in subjects discontinuing protocol 
therapy early, in the absence of progression – PB only 
 
Investigators should be aware that the time period from sample submission to Adaptive 
Biotechnologies and reporting of results is 7 business days. The timing of samples being 
drawn and submitted should be performed to allow for adequate processing time to allow 
adherence with the treatment calendar. 
 
Tissue sample types acceptable for submission for MRD assessments are identical to the 
sample types listed in section 7.1.1. 
 
 
7.1.3 
Discordant MRD assessments 
Discordance between BMA and PB MRD assessments 
Based on the experience of Potts et al, it is anticipated that there may be 20% of patients 
with discordance between MRD assessments in the PB and BMA. Most commonly, this 
would be expected to occur with negative PB MRD assessments and persistently positive 
MRD assessments in the BM. The presence of MRD negativity in the BM but positive MRD 
assessments in the PB appears to be a relatively infrequent phenomenon, occurring in <5% 
of cases. Because MRD status is being utilized as a parameter for potentially omitting 
maintenance therapy, it is required that both PB and BM show MRD negativity for a patient 
to be considered MRD negative per the protocol therapy and be allowed to receive 
abbreviated therapy. 
 
Discordance between restaging imaging and MRD assessments 
Subjects do not need to meet criteria for CR by imaging to be considered MRD-negative. 
However, subjects who are felt to have clinical evidence of residual lymphoma by CT or PET 
imaging at restaging following consolidation obinutuzumab are allowed to continue receiving 
protocol therapy as if they are MRD positive regardless of the MRD status in the PB and 
BM. This discordance between imaging and MRD status is anticipated to be a rare event. 
 


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7.1.4 
Interpretation of MRD assessments 
Two distinct thresholds of disease detection are reported with the ClonoSEQ Assay: the 
Limit of Detection (LOD) and the Limit of Quantitation (LOQ). The LOD is the lowest level of 
residual disease that can be reliably detected with a 95% probability that the sequence(s) 
detected are true markers of the malignancy being tracked. LOQ refers to the lowest level 
of residual disease that can be reliably quantified. For the purposes of MRD 
interpretation, only results showing residual sequences below the level of detection 
are considered to be MRD-negative.  
 
Subjects must have MRD-negative status of both PB and BM to be considered MRD 
negative for purposes of protocol therapy. Subjects determined to be MRD negative in both 
BM and PB after consolidation therapy will omit maintenance therapy and proceed directly 
to the follow-up phase. A copy of the MRD testing results will be generated and scanned 
into the electronic medical record (EMR) of enrolled subjects. A printed copy of the MRD 
results will additionally by offered to subjects.   
 
7.2 Induction chemoimmunotherapy (28 day cycles) 
Cycle 1 induction: 
 
• 
Bendamustine 90 mg/m2/day IV days 1 and 2 
• 
Obinutuzumab 100 mg IV day 1, 900 mg IV day 2, 1000 mg IV days 8 & 15 
Cycles 2-6 induction: 
• 
Bendamustine 90 mg/m2/day IV days 1 and 2 every 28 days, C2-6 
• 
Obinutuzumab 1000 mg IV day 1 every 28 days, C2-6 
 
All subjects will undergo a PB MRD assessment after C2 of induction therapy.  Subjects will 
undergo repeat disease assessments after C4 of induction. Subjects with baseline marrow 
involvement who have achieved a possible CR based on imaging should be considered to 
have an unconfirmed CR until after the post-consolidation restaging BM biopsy. Subjects 
achieving an objective response to induction therapy, but with toxicities that may limit ability 
to receive 6 cycles of BO, may proceed to consolidation therapy as early as after 4 cycles of 
induction BO (following lymphoma restaging and MRD assessment). 
 
Subjects achieving an objective response (i.e., PR, CR, or stable disease with tumor 
shrinkage not meeting criteria for PR) to bendamustine and obinutuzumab induction 
chemotherapy are eligible to proceed to obinutuzumab consolidation therapy. Subjects who 
have findings on clinical or laboratory exam suggesting progressive disease (PD) must 
undergo CT imaging at the time of suspected progression to reassess their disease status. 
 
Subjects with possible CR with residual masses of undetermined significance at the time of 
disease assessments will undergo PET imaging to evaluate their remission status. 
Responses will be assessed according to the Lugano classification criteria.17 
 
 
7.3 Consolidation therapy 


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• 
Obinutuzumab 1000 mg IV weekly X 4 doses 
 
Consolidation therapy will begin no later than 12 weeks after the last dose of induction 
chemotherapy once there has been recovery of the neutrophils to ≥1000/µL. 
 
Subjects will undergo reassessment of disease 30 days (+/- 5 days) following the final dose 
of consolidation therapy. All subjects will undergo a PB draw and BMA for assessment of 
MRD status. Subjects will undergo a restaging BM assessment to confirm objective 
response, and additional marrow aspirates will be sent for standard of care morphology and 
flow cytometry (in addition to research sample for MRD assessment), and a core biopsy will 
be collected to evaluate for morphologic involvement by lymphoma (standard of care to 
restage lymphoma). 
 
Subjects achieving an objective response (i.e., PR, CR, or SD with tumor shrinkage not 
meeting criteria for PR) to obinutuzumab consolidation therapy and are MRD positive are 
eligible to proceed to obinutuzumab maintenance therapy. If subjects are MRD-negative 
and have clinical evidence of residual lymphoma by CT or PET, they are allowed to proceed 
to maintenance therapy, see section 7.1.3.  Subjects who have findings on clinical or 
laboratory exam suggesting progression of disease must undergo CT imaging at the time of 
suspected progression to reassess their disease status. 
 
Subjects with possible CR with residual masses of undetermined significance at the time of 
disease assessments will undergo PET imaging to evaluate their remission status. 
Responses will be assessed according to the International Working Group Criteria.52 
 
7.4 Maintenance therapy (8 week cycles) 
Obinutuzumab 1000 mg IV day 1 of each cycle X 8 cycles. Maintenance therapy will begin 
no later than 8 weeks after the last dose of consolidation chemotherapy once there has 
been recovery of neutrophils to ≥1000/uL. 
 
Subjects will undergo reassessment of disease after C4 and C8 of maintenance 
obinutuzumab. The post C8 disease evaluation should be done at the same time as the 
EOT visit, approximately 30 (+/-5) days post last dose. Subjects with CT and/or PET 
imaging consistent with possible CR will undergo BM evaluation to verify a CR. All subjects 
will undergo a PB draw for assessment of MRD status 4-6 weeks after the final dose of 
obinutuzumab maintenance therapy. 
 
7.5 Follow-up phase 
At the time of treatment discontinuation for any reason, all subjects will undergo EOT 
evaluations at 30 days (+/-5) post last dose of treatment. Whenever possible, restaging CT 
scans (with or without repeat PET imaging) and a clinical assessment of any other sites of 
evaluable disease should be performed at 30 days (+/- 5) of last dose. In addition, a safety 
assessment will be done approximately 30 days (+/-5) following the last dose of study drug. 
 
Subjects who are MRD-negative following consolidation, or who complete the full course of 
maintenance therapy, will continue in the follow-up phase of the protocol. During the follow-
up phase, subjects will be evaluated at 3 month intervals, from the time of MRD-negative 
status or treatment completion, for 2 years with a physical examination and repeat imaging 
every 6 months to evaluate for evidence of disease progression.  After 2 years of follow-up 


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in the absence of progression, the frequency of ongoing care and assessment will be at the 
discretion of the subject’s treating physician. However, it is recommended that 
reassessment of the subject’s disease status be performed by repeat imaging at least every 
6 months. Information on the subject’s survival and progression status will be updated 
annually for up to 5 years following the date of MRD-negative status or completion of 
therapy. 
 
For subjects who discontinue therapy due to progression, or those who progress or start 
non-protocol therapy while on follow up, information on the subject’s survival will be updated 
annually for up to 5 years following MRD-negative status or completion of therapy. 
 
Subjects who discontinue treatment early due to toxicity or the subject’s decision to 
discontinue treatment (but not to withdraw consent from the protocol), follow-up with clinical 
and/or radiographic reassessment approximately every 3 months will be continued until 
evidence of progression or up to 2 years.  After 2 years of follow-up, the frequency of 
ongoing care and assessment will be at the discretion of the subject’s treating physician, 
although it is recommended that reassessment of the subject’s disease status be performed 
by repeat imaging at least every 6 months. Information on the subject’s survival and 
progression status will be updated annually for up to 5 years after discontinuation of 
therapy. 
 
7.6 Discontinuation of Study Treatment 
Treatment will continue until completion of the protocol therapy or the occurrence of any of 
the following events: 
• 
Disease progression, defined as clinical, laboratory, or radiographic criteria 
for progression as defined in the response criteria. 
• 
Adverse event(s) that, in the judgment of the investigator, may cause severe 
or permanent harm or which rule out continuation of the treatment regimen. 
• 
Discontinuation of protocol treatment for any reason. 
• 
Initiation of alternative anti-cancer therapy, even in the absence of progression. 
• 
Major violation of the study protocol that in the opinion of the Study PI, 
warrants treatment discontinuation. 
• 
Withdrawal of consent. 
• 
Lost to follow up. 
• 
Death. 
 
7.7 Screening and Eligibility 
The investigator is responsible for keeping a record of all subjects who sign an Informed 
Consent Form for entry into the study. All subjects will be screened for eligibility.  Screening 
procedures are outlined in Section 3, Schedule of Study Assessments, and unless otherwise 
specified, must take place within 28 days prior to initiation of therapy. 
 
 
7.7.1 
Inclusion criteria 


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1. Age ≥18 years at the time of signing the informed consent document. 
2. Histologically confirmed mantle cell lymphoma (confirmation of cyclin D1 positivity 
on diagnostic biopsy). 
3. Subjects must have at least one bi-dimensionally measurable lesion; one of the 
measurements must be ≥1.5 cm in one dimension. 
4. No prior cytotoxic chemotherapy; prior therapy with single-agent rituximab is 
permitted. Prior involved-field radiotherapy to symptomatic nodal sites of 
involvement is also permitted. 
5. Prior therapy with rituximab is permitted, even in the setting of rituximab-
refractory disease. 
6. Must meet one of the following criteria: 
a. Not eligible for more intensive cytotoxic chemotherapy or 
consolidative autologous stem cell transplant based on one or more 
of the following: 
i. Clinically significant heart or lung comorbidities, as reflected by at 
least 1 of the following: 
1.  LVEF ≤ 50% 
2. Chronic stable angina or congestive heart failure controlled 
with medication 
3. NYHA class III or IV heart failure 
4. Symptomatic chronic pulmonary disease or requirement 
for intermittent or continuous oxygen therapy 
ii. Presence of other medical comorbidity or limitation in functional status 
which the investigator judges to be incompatible with an 
acceptable risk to the subject with the use of intensive 
chemotherapy. The associated comorbidity or functional 
limitation must be clearly documented in the medical record at 
the time of enrollment. 
OR 
b. Subject has been informed of the risks and benefits of intensive 
chemotherapy and autologous stem cell transplant for treatment of mantle 
cell lymphoma and has refused this option. This discussion must be clearly 
documented in the medical record at the time of enrollment. 
7. ECOG performance status of <2 at study entry. 
8. Laboratory test results within these ranges: 
• 
Absolute neutrophil count ≥1500/µL. 
• 
Platelet count ≥100,000/µL. 
• 
Subjects with neutrophils <1500/µL or platelets <100,000/µL with 
splenomegaly or extensive bone marrow involvement as the etiology for 
their cytopenias are eligible. 
• 
Subjects must have adequate renal function with a creatinine clearance of 
≥40 mL/min as determined by the Cockcroft-Gault calculation. 
• 
Total bilirubin ≤2X upper limit laboratory normal (ULN); subjects with 


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non- clinically significant elevations of bilirubin due to Gilbert’s 
disease are not required to meet these criteria. 
• 
Serum transaminases AST (SGOT) and ALT (SGPT) ≤5X ULN. 
• 
Serum alkaline phosphatase ≤5X ULN. 
9. Disease-free of prior malignancies for ≥2 years with the exception of basal or 
squamous cell skin carcinoma, carcinoma “in situ” of the breast or cervix, or localized 
prostate cancer (treated definitively with hormone therapy, radiotherapy, or surgery). 
10. Life expectancy of at least 3 months. 
11. Understand and voluntarily sign an informed consent document. 
 
7.7.2 
Exclusion criteria 
1. Subjects are not eligible if there is a prior history or current evidence of central 
nervous system or leptomeningeal involvement. 
2. Concurrent use of other anti-cancer agents or treatments. 
3. Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent document or complying 
with the protocol treatment. 
4. Prior malignancy, except for adequately treated basal cell or squamous cell skin 
cancer, in situ cervical or breast cancer, or other cancer from which the subject has 
been disease free for at least 2 years. 
5. Severe or life-threatening anaphylaxis or hypersensitivity reaction when 
previously exposed to rituximab or other mAb therapy. 
6. Known to be positive for HIV or infectious hepatitis (type B or C). 
7. Pregnant or breast-feeding females. 
8. Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study or confounds 
the ability to interpret data from the study. 
 
7.8 Registration 
Each subject enrolled in the study is to be registered with the UWCCC OnCore database at 
study entry. If a registering institution were to be unable to access the OnCore database for 
any reason, an alternative registration option would be to call the Study WON Affiliate 
Coordinator at 608-265-5676 or 608-265-2867 between 8:30 am and 4:30 pm CST, Monday 
through Friday. 
 
At the time of registration, the following will be verified in OnCore: 
• 
IRB approval at the registering institution 
• 
Subject eligibility 
• 
Existence of a signed informed consent form 
• 
Existence of a signed authorization for use and disclosure of protected 
health information 
• 
Accrual assessed for subject to enter study 
 


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Documentation of current approval by the investigator’s Institutional Review Board must be 
on file with the Central Research Coordinating Office (CRCO) affiliate coordinators at the 
University of Wisconsin before an investigator may register subjects. 
 
In addition to submitting initial IRB approval documents, ongoing continuing review approval 
documentation must be submitted (no less than annually) to the affiliate coordinators at the 
University of Wisconsin. If the necessary documentation is not submitted in advance of 
attempting subject registration, the registration will not be accepted and the subject may not 
be enrolled in the protocol until the documents are received. 
 
Treatment on this protocol must commence at an approved, participating center. Treatment 
cannot begin prior to registration and must begin ≤7 days following registration. Pre-
registration tests must be completed within the guidelines as outlined in Section 3, Schedule 
of Study Assessments. All required baseline symptoms must be documented and graded. 
 
Reference the WON Operations Manual for additional details. 
 
7.8.1 
WON Registration 
To register a patient onto the trial at a WON site: 
 
The following documents should be completed by the research nurse or data manager 
and faxed [608-265-5676] or e-mailed [affiliatecoordinators@uwcarbone.wisc.edu] to the 
Affiliate Coordinator for WON sites: 
• 
Copy of required laboratory tests 
• 
Signed patient consent form 
• 
HIPAA authorization form 
• 
Other appropriate forms (e.g., Eligibility Screening Worksheet, Registration Form) 
 
The research nurse or data manager at the participating site will then call [608-265-2867 or 
608-262-9654] or e-mail [affiliatecoordinators@uwcarbone.wisc.edu] the Affiliate Coordinator 
to verify eligibility.  To complete the registration process, the Coordinator will 
 
• 
assign a patient study number 
• 
register the patient on the study 
• 
fax or e-mail the patient study number to the participating site 
 
8 Drug Administration, Formulation, and Procurement 
8.1 Drug administration 
 
8.1.1 
Obinutuzumab 
Dosage and Administration 
 
Induction therapy (in combination with bendamustine) (28 day cycles): 
• 
Obinutuzumab 100 mg IV C1D1 
• 
Obinutuzumab 900 mg IV C1D2 
• 
Obinutuzumab 1000 mg IV C1D8 and C1D15 


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• 
Obinutuzumab 1000 mg IV C2-6 D1 
Consolidation therapy: 
• 
Obinutuzumab 1000 mg IV weekly X 4 doses 
Maintenance therapy (8 week cycles): 
• 
Obinutuzumab 1000 mg IV D1 of cycle X 8 cycles 
 
Obinutuzumab will be provided by Genentech for participants in this study. Obinutuzumab 
should be administered by IV infusion, per the package insert instructions. 
 
Obinutuzumab must be administered in a clinical setting (inpatient or outpatient) where full 
emergency resuscitation facilities are immediately available, and patients should be under 
close supervision at all times. Obinutuzumab should be given as a slow IV infusion through 
a dedicated line.  IV infusion pumps should be used to control the infusion rate of 
obinutuzumab, and should not be administered as an IV push or bolus.  After the end of the 
first infusion, the IV line should remain in place for at least 2 hours in order to be able 
to administer IV drugs if necessary. If no AEs occur after 2 hours, the IV line may be 
removed.  For subsequent infusions, the IV line should remain in place for at least 1 
hour from the end of infusion; if no AEs occur after 1 hour, the IV line may be 
removed. Monitoring during the interval from completion of drug infusion until the IV 
line is removed will consist of observation for clinical signs or symptoms of a delayed 
infusion-related reaction, and vital signs are not required. Monitoring during this 
period may be performed according to the local institutional standard of care. 
 
If obinutuzumab dosing cannot be completed in a single treatment day for any reason (with 
the exception of C1D1 dosing of 100 mg), the remainder of the dose may be completed the 
following calendar day.  
 
Subjects experiencing AEs may need study treatment modifications (See Section 9). 
 
Additional information on drug formulation and preparation is summarized in Appendix F. 
Complete information including adverse effects are available in the GA101 (Obinutuzumab) 
Investigator Brochure, version 11 (September 2016). 
 
Infusion-related reaction (IRR) prophylaxis and treatment 
IRR prophylaxis: 
Cycle 1, Days 1 and 2, all subjects require pre-medication with: 
• 
Steroid: Dexamethasone 20 mg IV or methylprednisolone 80 mg IV administered at 
least one hour prior to obinutuzumab infusion.  Hydrocortisone should not be used as 
it has not been effective in reducing rates of IRR. 
• 
Acetaminophen 1000 mg orally. 
• 
Antihistamine such as diphenhydramine (50 mg orally or IV) administered at least 
30 minutes before starting each obinutuzumab infusion. Hydroxyzine is an 
acceptable alternative in subjects who have allergies or intolerances to 
diphenhydramine. 
Cycle 1, Days 8 and 15 and Cycles 2-6, Day 1: 
• 
All subjects require pre-medication with oral acetaminophen (1000 mg) administered 


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at least 30 minutes before starting each obinutuzumab infusion. 
• 
Patients who experience an IRR (Grade 1 or more) with the previous infusion will 
require pre-medication with an antihistamine such as diphenhydramine (50 mg) or an 
acceptable alternative administered at least 30 minutes before starting each 
subsequent obinutuzumab infusion. 
• 
Patients who experience a Grade 3 IRR with the previous infusion or who have 
lymphocyte counts of ≥25 × 109/L prior to the next treatment will require pre 
medication with IV glucocorticoid: Dexamethasone (20 mg) or methylprednisolone 
(80 mg) administered at least one hour prior to obinutuzumab infusion.  
Hydrocortisone should not be used as it has not been effective in reducing rates of 
IRR. 
• 
Patients who experience recurrent Grade 3 IRRs despite maximum prophylaxis 
with anti-histamines and IV glucocorticoid must discontinue obinutuzumab and 
protocol therapy. 
 
Hypotension may be expected to occur during obinutuzumab infusions.  Withholding of 
antihypertensive treatments should be considered for 12 hours prior to and 
throughout each obinutuzumab infusion and for the first hour after administration. 
Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of 
withholding their hypertensive medication. 
 
 
8.1.2 
Bendamustine 
Dosage and Administration 
 
Induction therapy (in combination with obinutuzumab) (28 day cycles): 
• 
Bendamustine 90 mg/m2 IV C1 – 6, Days 1 and 2 
 
Bendamustine will be obtained commercially, and will not be supplied by the study 
supporters. Available bendamustine products for use include generic bendamustine, and 
Bendeka™. 
 
Bendamustine will be infused over approximately 30-60 minutes for generic bendamustine, 
and will be infused over approximately 10 minutes for the Bendeka™ product. 
 
The amount of drug to be administered will be based on body surface area (BSA). The 
preferred method for calculating body surface area is the Mosteller formula60 on C1D1. At 
some participating community sites, the Dubois formula61 is the primary BSA calculation used 
as part of an electronic medical record and drug ordering template. In such cases, calculations 
using the Dubois formula are permitted as long as there is no more than a 10% difference in 
dosing between the Mosteller and Dubois calculations. If a >10% difference in drug dosing is 
observed, then the Mosteller calculation must be used. The drug doses calculated on C1D1 of 
chemotherapy administration will be used at subsequent visits. However, if the subject 
experiences a >10% change in body weight from the baseline weight used for initial BSA 
calculation, then drug doses must be recalculated with the more recent body weight (Appendix 
B for BSA guidelines).  Per institutional standards, bendamustine doses may be rounded 
within 10% of the calculated dose based on the subject’s BSA to accommodate at least half 


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vial size increments (50 mg for bendamustine).  
 
 
On treatment days when both bendamustine and obinutuzumab are administered, 
bendamustine should be the agent administered first. 
 
Subjects experiencing AEs may need study treatment modifications (See Section 9). 
 
Complete information on drug formulation, preparation, and adverse effects of 
bendamustine is summarized in Appendix G and available in the Package Insert. 
 
 
8.2 Record of administration and treatment compliance 
Accurate records will be kept of all study drug administration (including prescribing and 
dosing) and maintained in the source documents.  Clear documentation will be recorded of 
dose modifications made based on observed toxicities. 
 
9 Dose Modifications and Interruptions 
 
9.1 General principles for dose modification 
 
Dose modifications are only required and applicable for study drugs to which a 
toxicity is at least possibly attributed.  
9.2 Dose modification guidelines during induction chemotherapy 
 
9.2.1 
Dose modification guidelines for obinutuzumab during 
induction therapy 
Obinutuzumab administration must follow labeling instructions and guidelines. Please refer 
to the approved product label for instructions. Subjects who develop severe IRR should 
have the obinutuzumab infusion discontinued and have supportive care measures instituted 
as medically indicated (e.g., IV fluids, vasopressors, oxygen, bronchodilators, 
diphenhydramine, and acetaminophen). In most cases, the infusion can be resumed at a 
50% reduced rate, after symptoms have completely resolved. Subjects requiring close 
monitoring during first and all subsequent infusions include those with pre-existing cardiac 
and pulmonary conditions, those with prior clinically significant cardiopulmonary events, and 
those with high numbers of circulating malignant cells (>25,000/mm3) with or without 
evidence of high tumor burden. 
 
On the first day of each new induction treatment cycle, on day 1 of consolidation therapy, 
and on day 1 of each maintenance cycle, the subject will be evaluated for possible 
toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed 
according to the NCI-CTCAE version 5.0, and attribution or non-attribution to 
obinutuzumab must be documented. 
 
The dose of obinutuzumab will not change based upon hematologic toxicity. Subjects who 
develop neutropenia with at least a possible attribution to obinutuzumab may receive growth 


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factor support as clinically indicated and may continue obinutuzumab administration per 
protocol. If obinutuzumab therapy must be held for >8 weeks due to neutropenia 
(neutrophil <1000/uL), then subjects must be withdrawn from protocol therapy. 
 
In subjects who develop viral hepatitis, obinutuzumab should be discontinued and 
appropriate treatment, including antiviral therapy, initiated. 
 
 
9.2.2 
Dose modification guidelines for bendamustine during 
induction therapy 
On the first day of each new induction treatment cycle (i.e., before each day 1 bendamustine 
dose), the subject will be evaluated for possible toxicities that may have occurred after the 
previous dose(s). Toxicities are to be assessed according to the NCI-CTCAE version 5.0, 
and attribution or non-attribution to bendamustine must be documented. 
 
The following dose-reduction rules for bendamustine should be followed (Tables 1 
and 2): 
If toxicities occurred at 90 mg/m2, reduce to 70 mg/m2; if toxicity occurred at 70 mg/m2, 
reduce to 50 mg/m2; if toxicity occurred at 50 mg/m2, reduce to 40 mg/m2, if toxicity occurred 
at 40 mg/m2, discontinue bendamustine and withdraw the subject from the study protocol. If 
the dose of bendamustine is reduced due to toxicity, it will not be re-escalated later in the 
study. 
 
Table 1. Bendamustine dose reduction steps† 
 
Bendamustine dose level 
Bendamustine dose reduction 
Starting dose 
90 mg/m2 
-1 
70 mg/m2 
-2 
50 mg/m2 
-3 
40 mg/m2 
-4 
Discontinue bendamustine and withdraw from 
study protocol. 
†If subjects have disease-related splenomegaly or significant BM involvement as the etiology of cytopenias at enrollment, 
treatment may be continued without meeting the hematologic criteria for subsequent cycles of induction chemotherapy. In such 
cases, the decision to continue dosing of bendamustine at the current dose is at the investigator’s discretion. 
 
 
Table 2. Dose modification guidelines for bendamustine 
 
NCI-CTCAE category 
Severity 
Dose modification 
Hematologic† 
Neutrophil <1000/µL on 
day 1 of cycles 2-6 
Initiation (day 1) of cycles 2-6 should be delayed until 
the neutrophil count is ≥1000/µL and the platelet count 
is ≥75,000/µL.†  If day 1 is delayed by more than 2 
weeks, then bendamustine should be resumed at the 
next lower dose level. 
Platelets <50,000/µL on 
day 1 of cycles 2-6 
Grade 4 neutropenia 
with fever/infection 
Initiation (day 1) of cycles 2-6 should be delayed until 
the neutrophil count is ≥1000/µL without evidence of 
fever or infection and the platelet count is ≥50,000/µL.† 
Bendamustine should then be resumed at the next 
lower dose level. 
Grade 4 neutropenia 
lasting ≥7 days 


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NCI-CTCAE category 
Severity 
Dose modification 
Grade 4 platelets for ≥7 
days or a platelet count 
<10,000/µL at any time 
Nausea, emesis, or 
diarrhea in the 
absence of maximal 
prophylaxis 
≥Grade 3 
Continue treatment, but with institution of maximum 
prophylactic therapy, including a 5-HT3 antagonist for 
nausea and emesis, and loperamide, or a comparable 
antidiarrheal agent, for diarrhea. Events of grade 4 
toxicity require holding treatment until resolution of 
toxicity to ≤grade 2 with use of maximum prophylaxis. 
Nausea, emesis, or 
diarrhea with maximal 
prophylaxis 
≥Grade 3 
Hold bendamustine for up to 2 weeks or until the toxicity 
returns to ≤grade 2, and restart at the next lower dose. If 
treatment is delayed by more than 2 weeks, treatment 
with bendamustine must be discontinued. 
All other non- 
hematologic toxicities 
≥Grade 3 
†If subjects have disease-related splenomegaly or significant BM involvement as the etiology of cytopenias at enrollment, 
treatment may be continued without meeting the hematologic criteria for subsequent cycles of induction chemotherapy. In such 
cases, the decision to continue dosing of bendamustine at the current dose is at the investigator’s discretion. 
 
9.2 Dose modification guidelines for consolidation and 
maintenance therapy 
Consolidation therapy with obinutuzumab will begin no later than 12 weeks after day 1 of the 
last induction chemotherapy cycle. Maintenance therapy will begin no later than 8 weeks 
after the final consolidation dose of obinutuzumab. 
 
On the first day of consolidation therapy and each new maintenance cycle, the subject will 
be evaluated for possible toxicities that may have occurred after the previous doses. 
Toxicities are to be assessed according to the CTCAE, version 5.0. 
 
The neutrophils count must be recovered to ≥ 1000/µLprior to the start of consolidation and 
maintenance obinutuzumab. 
 
 
Table 3. Dose modification of obinutuzumab for toxicities 
 
NCI-CTCAE Toxicity 
Dose modification 
Grade 1-2 infusion reaction 
and/or cytokine release 
syndrome 
Reduce infusion rate and treat symptoms. Upon resolution 
of symptoms, continue infusion and, if patient does not 
experience any infusion reaction symptoms, infusion rate 
escalation may resume at the increments and intervals as 
appropriate for the treatment dose. 


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NCI-CTCAE Toxicity 
Dose modification 
≥Grade 3 infusion reaction 
and/or cytokine release 
syndrome possibly or likely 
attributable to 
obinutuzumab 
Grade 3 infusion reaction: Upon resolution of symptoms, 
restart infusion at no more than half the previous rate (the 
rate being used at the time that the infusion reaction 
occurred) and, if patient does not experience any infusion 
reaction symptoms, infusion rate escalation may resume at 
the increments and intervals as appropriate for the treatment 
dose. 
If grade 3 infusion reactions and/or cytokine release 
syndrome occurs, increase steroid and anti-histamine 
prophylaxis with subsequent infusions as directed in section 
8.1.1. If grade 3 infusion reaction and/or cytokine release 
syndrome recurs despite this maximum prophylaxis, then 
discontinue obinutuzumab. 
If grade 4 infusion reaction and/or cytokine release 
syndrome occurs (e.g., anaphylactic shock, severe 
hypotension), obinutuzumab must be discontinued. 
≥Grade 3 toxicity likely 
attributable to 
obinutuzumab 
If recurrent ≥grade 3 toxicity is observed that, in the opinion 
of the investigator, is likely attributable to obinutuzumab, 
consideration should be made for discontinuation of 
obinutuzumab. 
Neutropenia, particularly in 
setting of severe and 
unexplained nadir in 
neutrophil count with 
relative stability in 
hemoglobin and platelet 
counts 
Consider possibility of delayed immune-mediated 
obinutuzumab -induced neutropenia, which may be 
observed at any time during an extended treatment course 
with obinutuzumab. 
Immune-mediated obinutuzumab -induced neutropenia is 
not a contra-indication to ongoing obinutuzumab therapy. 
However, administration of growth factor is recommended to 
increase ANC > 1000/μL prior to next obinutuzumab dose if 
this etiology for neutropenia is suspected. 
Hypogammaglobulinemia 
Levels of serum immune globulins below the lower limits of 
normal in the setting of clinically significant and recurrent 
infections (i.e., sinusitis, upper respiratory infections, 
pneumonia, cellulitis, colitis, etc.) may warrant 
discontinuation of obinutuzumab. 
 
 
9.3 Concomitant therapy 
Subjects should receive full supportive care, including transfusions of blood products, 
antibiotics, and anti-emetics when appropriate. Growth factor support is permissible 
during any phase of protocol therapy to prevent or treat neutropenia.  
 
9.3.1 
Tumor lysis syndrome (TLS) prophylaxis 
Tumor lysis syndrome (TLS) may be a risk in subjects with high tumor burden MCL initiating 
induction chemotherapy with bendamustine and obinutuzumab. 
 
Allopurinol prophylaxis is to be considered (but is not mandatory) for subjects during 
induction chemotherapy based on the risk for tumor lysis syndrome. The recommended 
allopurinol dosing is 300 mg orally once or twice daily for 7 days. Alternatively, subjects at 
high-risk for TLS with intolerance to allopurinol or judged to be at increased risk for TLS even 


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with allopurinol prophylaxis, should be considered for treatment with rasburicase for TLS 
prophylaxis. 
Allopurinol prophylaxis is not mandatory in any patient, but is to be considered at the 
discretion of the investigator. The following are guidelines for patients at higher risk for 
tumor lysis syndrome for which allopurinol prophylaxis should be considered: 
• 
Baseline uric acid ≥7.5 mg/dL 
• 
Bulky disease (one or more masses >10 cm, measuring >10 cm in at least one 
direction of a bi-dimensionally measurable lesion) 
• 
Elevated LDH (> 2X/ULN) 
• 
Serum creatinine >1.5X/ULN 
 
 
9.3.2 
Infections Prophylaxis 
Pneumocystis jirovecii pneumonia prophylaxis (160 mg trimethoprim/800 mg 
sulfamethoxazole orally twice daily or suitable alternative according to each site’s institutional 
standards) and anti- herpetic viral prophylaxis (acyclovir 400 mg orally twice daily or suitable 
alternative) are recommended during treatment and for up to 6 months following treatment 
as appropriate. 
 
 
9.3.3 
Hematopoietic Growth Factors 
Growth factor support is permissible during any phase of protocol therapy to prevent or treat 
neutropenia. Prophylactic G-CSF is permitted during cycle 1 of induction in subject judged to 
be at increased risk of treatment-related neutropenia. Growth factor support may include 
filgrastim, pegfilgrastim, or TBO-filgrastim (or other filgrastim biosimilar). 
 
 
9.3.4 
Hepatitis B reactivation 
Positive serology for Hepatitis B is defined as positivity for Hepatitis B surface antigen 
(HBsAg) or Hepatitis B core antibody (anti-HBc).  Patients who are positive for anti-HBc 
may be considered for inclusion in the study on a case-by-case basis if they are Hepatitis B 
viral DNA negative and are willing to undergo ongoing HBV DNA testing by real-time PCR.  
Patients with positive serology may be referred to a hepatologist or gastroenterologist for 
appropriate monitoring and management. 
 
For the subset of patients who are Hepatitis B viral DNA negative and anti-HBc positive and 
have undetectable Hepatitis B viral DNA levels at screening, Hepatitis B viral DNA levels 
must be followed approximately every 4 weeks. Guidelines for the management of hepatitis 
B reactivation are outlined in Table 4. 
 
 
Table 4 
Management of hepatitis B reactivation 
 
Hepatitis B Viral DNA 
Level by Real-Time PCR 
Guideline 


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> 100 IU/mL 
• Hold obinutuzumab. 
• Begin anti-viral medication and treat for at least 1 year after the 
last dose of obinutuzumab. 
• Immediately refer the patient to a gastroenterologist or 
hepatologist for management. 
• Resume obinutuzumab once Hepatitis B viral DNA levels 
decrease to undetectable levels. 
> 100 IU/mL while on 
anti-viral medication 
Discontinue obinutuzumab. 
29−100 IU/mL 
Retest within 2 weeks. 
If still hepatitis B viral DNA positive: 
• Hold obinutuzumab. 
• Begin anti-viral medication and treat for at least 1 year after the 
last dose of obinutuzumab. 
• Immediately refer the patient to a gastroenterologist or 
hepatologist for management. 
• Resume obinutuzumab once Hepatitis B viral DNA levels 
decrease to undetectable levels. 
 
 
9.3.5 
Prohibited concomitant therapy 
Concomitant use of other anti-cancer therapies, including radiation or other investigational 
agents is not permitted while subjects are receiving study drug during the treatment phase 
of the study. 
 
10 Data Safety Monitoring Plan 
10.1 Oversight and Monitoring Plan 
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for the regular 
review and monitoring of all ongoing clinical research in the UWCCC.  A summary of DSMC 
activities are as follows: 
• 
Reviews all clinical trials conducted at the UWCCC for subject safety, 
protocol compliance, and data integrity. 
• 
Reviews all SAE requiring expedited reporting, as defined in the protocol, for all 
clinical trials conducted at the UWCCC, and studies conducted at external sites for 
which UWCCC acts as an oversight body. 
• 
Reviews all reports generated through the UWCCC DSMS elements (Internal 
Audits, Quality Assurance Reviews, Response Reviews, Compliance Reviews, and 
Protocol Summary Reports). 
• 
Notifies the protocol Principal Investigator of DSMC decisions and, if applicable, 
any requirements for corrective action related to data or safety issues. 
• 
Notifies the CRC of DSMC decisions and any correspondence from the DSMC to 
the protocol Principal Investigator. 
• 
Works in conjunction with the UW Health Sciences IRB in the review of relevant 
safety information as well as protocol deviations, non-compliance, and unanticipated 
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• 
Ensures that notification is of SAEs requiring expedited reporting is provided to 
external sites participating in multi-institutional clinical trials coordinated by the 
UWCCC. 
 
10.1.1 
Monitoring and Reporting Guidelines 
UWCCC quality assurance and monitoring activities are determined by study sponsorship 
and risk level of the protocol as determined by the PRMC.  All protocols (including 
Intervention Trials, Non-Intervention Trials, Behavioral and Nutritional Studies, and trials 
conducted under a Training Grant) are evaluated by the PRMC at the time of committee 
review.  UWCC monitoring requirements for trials without an acceptable external DSMB are 
as follows: 
 
 
a) Intermediate Monitoring 
 
 
Protocols subject to intermediate monitoring generally include UW Institutional Phase 
I/II and Phase II Trials. These protocols undergo review of subject safety at regularly 
scheduled DOT meetings where the results of each subject’s treatment are discussed 
and the discussion is documented in the DOT meeting minutes. The discussion 
includes the number of subjects enrolled, significant toxicities, dose adjustments, and 
responses observed. Protocol Summary Reports are submitted on a semi-annual 
basis by the study team for review by the DSMC. Subjects being treated in this 
study protocol will be monitored according to this intermediate monitoring 
category. 
 
 
10.1.2 
Protocol Summary Reports 
Protocol Summary Reports (PSR) are required to be submitted to the DSMC semi-annually. 
The PSR provides a cumulative report of SAEs, as well as instances of non-compliance, 
protocol deviations, and unanticipated problems, toxicities and responses that have 
occurred on the protocol in the timeframe specified.  PSRs for those protocols scheduled 
for review are reviewed at each DSMC meeting. 
 
Protocol Summary Reports enable DSMC committee members to assess whether significant 
benefits or risks are occurring that would warrant study suspension or closure. This 
information is evaluated by the DSMC in conjunction with other reports of quality assurance 
activities (e.g., reports from Internal Audits, Quality Assurance Reviews, etc.) occurring since 
the prior review of the protocol by the DSMC.  Additionally, the DSMC requires the study 
team to submit external DSMB or DSMC reports, external monitoring findings for industry-
sponsored studies, and any other pertinent study-related information. 
 
In the event that there is significant risk warranting study suspension or closure, the DSMC 
will notify the PI of the DSMC findings and ensure the appropriate action is taken for the 
protocol (e.g., suspension or closure). The DSMC ensures that the PI reports any 
temporary or permanent suspension of a clinical trial to the sponsor (e.g., NCI Program 
Director, Industry Sponsor Medical Monitor, Cooperative Group Study Chair, etc.), WON 
sites, and other appropriate agencies. DSMC findings and requirements for follow-up action 
are submitted to the CRC. 
 


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10.2 Safety Reconciliation 
The Sponsor agrees to conduct reconciliation for obinutuzumab. Genentech and the 
Sponsor will agree to the reconciliation periodicity and format, but agree at minimum to 
exchange quarterly line listings of cases received by the other party. If discrepancies are 
identified, the Sponsor and Genentech will cooperate in resolving the discrepancies. The 
responsible individuals for each party shall handle the matter on a case-by-case basis until 
satisfactory resolution. 
 
11 Adverse Event Reporting Requirements 
11.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after the initiation 
of study treatment and ends 30 days following the last administration of study treatment or 
study discontinuation/termination (prior to completing all protocol-directed therapy), whichever 
is earlier. After this period, investigators should only report SAEs that are possibly, probably, 
or definitely attributed to prior study treatment. 
 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, are collected and reported to the FDA, appropriate IRB(s), and 
Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports). 
 
11.2 Assessment of Adverse Events 
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational medicinal product or other protocol- 
imposed intervention, regardless of attribution. 
 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with MCL that were  not 
present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations). 
• 
Preexisting medical conditions (other than the condition being studied) judged by 
the investigator to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period. 
• 
Changes in vital signs are considered to be adverse events only if they result in 
discontinuation from the study, necessitate therapeutic medical intervention or if 
the investigator considers them to be adverse events. 
• 
Clinically Significant Laboratory Abnormalities: The investigator must appraise and 
document all abnormal laboratory results for their clinical significance. If an 
abnormal laboratory result is considered clinically significant, the value must be 
recorded in the research chart on the Adverse Events Log. 
 
Attribution of Adverse Events 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply 
the following general guideline: 
 


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RELATIONSHIP 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
A clinical event in which a relationship to the study drug seems 
improbable because of factors such as inconsistency with known 
effects of the study drug; lack of a temporal association with study 
drug administration; lack of association of the event with study 
drug withdrawal or rechallenge; and/or presence of alternative 
explanations for the event.  Alternative explanations might include 
a known relationship of the adverse event to a concomitant drug, 
past medical history of a similar event, the patient’s disease state, 
intercurrent illness, or environmental factors. 
Unlikely 
The AE is doubtfully related to treatment. 
A clinical event with a temporal relationship to study drug 
administration that makes a causal relationship improbable and 
for which other factors suggesting an alternative etiology exist. 
Such factors might include a known relationship of the AE to a 
concomitant drug, past medical history of a similar event, the 
patient’s disease state, inter-current illness, or environmental 
factors. 
Possible 
The AE may be related to treatment. 
A clinical event with a reasonable temporal association with 
administration of the study drug, and that is not likely to be 
explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal may be lacking. 
Probable 
The AE is likely related to treatment. 
A clinical event in which a relationship to the study drug seems 
probable because of such factors as consistency with known 
effects of the drug; a reasonable temporal association with the 
use of the drug; lack of alternative explanations for the event; and 
improvement upon withdrawal of the drug (de-challenge). 
Definite 
The AE is clearly related to treatment. 
A clinical event in which a relationship to the use of the study drug 
seems definite because of such factors as consistency with known 
effects of the drug; a clear temporal association with the use of  
the drug; lack of alternative explanations for the event; 
improvement upon withdrawal of the drug (de-challenge); and 
recurrence upon resumption of the drug (rechallenge). 
 
Expectedness of Adverse Events 
 
Expected AEs are those AEs that are listed or characterized in the Package Insert or current 
Investigator Brochure (IB). 
 
Unexpected AEs are those not listed in the package insert or 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 IB only referred to elevated hepatic enzymes or 
hepatitis. 
 
 


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11.2.1 
Procedures for Eliciting, Recording, and Reporting Adverse Events 
Genentech and the UWCCC have specific language regarding adverse event assessment 
and reporting.  Participating investigators should review the following information carefully, 
and if an event meets criteria for reporting to any one of these entities, the event should be 
reported following the guidelines in section 11.3. 
 
11.2.1.1 Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should 
be adopted. Examples of non-directive questions include: 
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last here?” 
 
11.2.1.2 Protocol Specific Instructions for Recording Adverse Events 
Toxicities and adverse events will be scored using CTCAE, version 5.0. A copy of the CTCAE, 
version 5.0 can be downloaded from the CTEP homepage (https://ctep.cancer.gov/). All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. All 
adverse clinical experiences, whether observed by the investigator or reported by the subject, 
must be recorded, with details about the duration and intensity of each episode, the action taken 
with respect to the test drug, and the subject’s outcome. The investigator must evaluate each 
adverse experience for its relationship to the study drug(s) and for its seriousness. 
 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
 
a. Diagnosis vs. Signs and Symptoms 
 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, it is ok to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information.  
b. Deaths 
 
All deaths that occur during the protocol-specified AE reporting period (see Section 
11.1), regardless of attribution, will be reported to the appropriate parties. When 
recording a death, the event or condition that caused or contributed to the fatal 
outcome should be reported as the single medical concept. If the cause of death is 
unknown and cannot be ascertained at the time of reporting, report “Unexplained 
Death”. 
 
c. Pre-existing Medical Conditions 
 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE 
only if the frequency, severity, or character of the condition worsens during the study. 
When reporting such events, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more 


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frequent headaches”). 
 
d. Hospitalizations for Medical or Surgical Procedures 
 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a 
medical or surgical procedure as a result of an AE, the event responsible for the 
procedure, not the procedure itself, should be reported as the SAE. For example, if a 
subject is hospitalized to undergo coronary bypass surgery, record the heart 
condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions. 
• 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
 
e. Post-Study Adverse Events 
 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if possibly, probably, or definitely 
attributed to prior study drug exposure per section 11.3. If the investigator should 
become aware of the development of cancer or a congenital anomaly in a 
subsequently conceived offspring of a female subject who participated in the study, 
this should be reported as an SAE per section 11.3. 
 
11.2.1.3 Protocol Specific Instructions for Reporting Adverse Events 
 
a) General Adverse Event Reporting 
 
All AEs and SAEs will be recorded in the research chart on the Adverse Events 
Log, regardless of whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), seriousness criteria if applicable, suspected relationship (attribution) to 
the study drugs (see following guidance), and actions taken. A trained investigator 
should review each event. 
 
Only the worst grade toxicity for a specific AE should be reported on the electronic 
case report form (eCRF) within each reporting period. A reporting period is defined 
as each treatment cycle of maintenance and induction, and the interval between each 
follow-up visit after completion or discontinuation of therapy. 
 
Anticipated grade 1-2 toxicities that are excluded from reporting on the electronic case 
report form (must be recorded on the AE log if deemed clinical significant): 
• 
Leukopenia (WBC decreased) 
• 
Lymphopenia (Absolute lymphocyte count decreased) 


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• 
Neutropenia (Absolute neutrophil count decreased) 
• 
Anemia (Hemoglobin decreased) 
 
b) Expedited Adverse Event Reporting 
 
Serious Adverse Events: See section 11.3 for details. 
 
Pregnancy: See section 11.3.3 for details. 
 
Adverse Events of Special Interest (AESI): See section 11.3.3 for details. 
 
11.3 Expedited Adverse Event Reporting 
Reference the WON Operations Manual for additional information, cover sheets, and forms. 
 
11.3.1 SAE Reporting 
Depending on the nature, severity, and attribution of the serious adverse event an SAE 
report will be phoned in, submitted in writing, or both according to Table 5 below. All serious 
adverse events must also be reported to the UWCCC Data and Safety Monitoring 
Committee Chair.  All serious adverse events must also be reported to the UW IRB (if 
applicable), and any sponsor/funding agency not already included in the list. 
 
Refer to section 11.4.1 regarding additional reporting guidelines to sponsor (Genentech). 
 
Determine the reporting time line for the SAE in question by using Table 5. Then refer to 
sections A and B below if the SAE occurred at the UWCCC or sections C and D if the 
SAE occurred at 1 South Park or a WON Site. 
 
11.3.2 
SAE Definition 
A SAE is one that at any dose (including overdose): 
• Results in death. 
• Is life-threatening, meaning that the subject was at immediate risk of death at the 
time of the SAE; it does not refer to a SAE that hypothetically might have caused 
death if it were more severe. 
• Requires subject hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability or incapacity, which is defined as a 
substantial disruption of a subject’s ability to carry out normal life functions. 
• Is a congenital anomaly or birth defect. 
• Is an important (significant) medical event, with medical and scientific judgment 
exercised in deciding whether expedited reporting is appropriate in situations where 
none of the outcomes listed above has occurred. 
• Important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above should 
also usually be considered serious. 
o Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias 


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or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. A new diagnosis of 
cancer during the course of a treatment should be considered as 
medically important. 
• Suspected pregnancy. 
• A secondary primary malignancy. 


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Table 5. Reporting Requirements for Serious Adverse Events (UW Carbone 
Cancer Center requirements) 
 
NOTE: Investigators MUST immediately report to the UWCCC and any other parties outlined in the protocol 
ANY Serious Adverse Events, whether or not they are considered related to the investigational 
agent(s)/intervention (21 CFR 312.64). 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death. 
2) 
A life-threatening adverse event. 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours. 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition (FDA 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria* MUST be immediately reported to the 
UWCCC within the timeframes detailed in the table below: 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
hospitalization 
≥24 hrs 
10 Calendar Days 
24-Hour; 5 
Calendar Days 
Not resulting in 
Hospitalization ≥24 
hrs 
Not required 
10 Calendar Days 
NOTE: See section 11.3.3 for additional protocol-specific exceptions to and requirements of 
expedited reporting 
Expedited AE reporting timelines are defined as: 
• 
24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
• 
10 Calendar Days – A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4 and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
• 
Grade 3 events 
 
11.3.3 Additional Protocol-Specific Instructions, Requirements, and 
Exceptions to Expedited Reporting 
 
11.3.3.1 Protocol-Specific Expedited Reporting Requirements 
A. Pregnancy 
 


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If a female patient becomes pregnant while receiving obinutuzumab or within one 
year after the last dose of obinutuzumab, or the partner of a male patient becomes 
pregnant while receiving therapy or within three months of completing therapy, a 
report should be completed and expeditiously submitted to the Roche/Genentech, 
Inc by UWCCC staff per section 11.4.1.  Follow-up to obtain the outcome of the 
pregnancy should also occur. Abortion, whether accidental, therapeutic, or 
spontaneous, should always be classified as serious, and expeditiously reported as 
an SAE.  Similarly, any congenital anomaly/birth defect in a child born to a female 
patient exposed to obinutuzumab should be reported as an SAE. 
 
All Sites: Report to the UWCCC (saenotify@uwcarbone.wisc.edu): 
 
Complete the following for all reports as soon as possible after becoming aware of 
the event and within 27 calendar days of the awareness date: 
• 
FDA MedWatch Form 3500A 
• 
UW16086 Pregnancy Report Cover Sheet 
 
UWCCC: Report to Industry Collaborators: 
 
Complete the following and submit along with the FDA MedWatch Form 3500A to 
Genentech as soon as possible after becoming aware of the event and within 30 days 
of the initial awareness date: 
• 
Genentech Safety Reporting Fax Cover Sheet 
 
B. Adverse Events of Special Interest (AESIs) 
AESIs are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product. AESI in clinical trials are sent to Genentech by UWCCC 
staff per section 11.4.1.  The following AEs are considered of special interest 
and must be reported to the Sponsor expeditiously, irrespective of regulatory 
seriousness criteria: 
• 
Grade ≥2 clinical tumor lysis syndrome, (see appendix H for details on 
grading TLS). 
• 
Second malignancies. 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law and based on the following observations: - Treatment-emergent ALT or AST > 
3 x baseline value in combination with total bilirubin > 2 x ULN (of which > 35% is 
direct bilirubin) - Treatment-emergent ALT or AST > 3 x baseline value in 
combination with clinical jaundice 
• 
Suspected transmission of an infectious agent by the study treatment, as defined 
below - Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a patient exposed to a medicinal product. This term applies only when a 
contamination of study treatment is suspected 
 
 


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All Sites: Report to the UWCCC (saenotify@uwcarbone.wisc.edu): 
 
For events that meet the seriousness criteria in section 11.3.2: 
 
Follow the SAE reporting directions and time periods in section 11.3.4.  Submit the 
following in addition: 
• 
UW16086 AESI Report Cover Sheet 
 
For events that do NOT meet the seriousness criteria in section 11.3.2 and are 
considered possibly, probably, or definitely related to obinutuzumab therapy: 
 
Complete the following as soon as possible after becoming aware of the event and 
within 12 calendar days of the awareness date: 
• 
FDA MedWatch Form 3500A 
• 
UW16086 AESI Report Cover Sheet 
 
For events that do NOT meet the seriousness criteria in section 11.3.2 and are 
considered unrelated or unlikely related to obinutuzumab therapy: 
 
Complete the following as soon as possible after becoming aware of the event and 
within 27 calendar days of the awareness date: 
• 
FDA MedWatch Form 3500A 
• 
UW16086 AESI Report Cover Sheet 
 
UWCCC: Report to Industry Collaborators: 
 
For events that meet the seriousness criteria in section 11.3.2 or are considered 
possibly, probably, or definitely related obinutuzumab therapy: 
 
Complete the following and submit along with the FDA MedWatch Form 3500A to 
Genentech as soon as possible after becoming aware of the event and within 15 days 
of the initial awareness date: 
• 
Genentech Safety Reporting Fax Cover Sheet 
 
For events that do NOT meet the seriousness criteria in section 11.3.2: 
 
Complete the following and submit along with the FDA MedWatch Form 3500A to 
Genentech as soon as possible after becoming aware of the event and within 30 days 
of the initial awareness date: 
• 
Genentech Safety Reporting Fax Cover Sheet 
 
11.3.3.2 Protocol-Specific Exceptions to Expedited Reporting 
The following toxicities are anticipated and will NOT require expedited reporting: 
Induction 
• 
Grade 3 – 4 Lymphocyte count decreased 
• 
Grade 3 – 4 White blood cell decreased 
• 
Grade 3 – 4 Neutrophil count decreased 
• 
Grade 3 – 4 Platelet count decreased 
 


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Consolidation and Maintenance 
• 
Grade 3 – 4 Lymphocyte count decreased 
• 
Grade 3 White blood cell decreased 
 
 
11.3.4 
General procedures for SAE reporting 
Serious adverse event – reported within 24 hours 
 
Serious Adverse Events requiring reporting within 24 hours (as described in the protocol) 
must also be reported to the Data and Safety Monitoring Committee (DSMC) Chair via an 
email to saenotify@uwcarbone.wisc.edu within one business day. The OnCore SAE Details 
Report must be submitted along with other report materials as appropriate (Medwatch Form 
#3500A and/or any other documentation available at that time of initial reporting). The 
DSMC Chair will review the information and determine if immediate action is required. 
Within 5 calendar days a final initial report is required to be submitted, all available 
subsequent SAE documentation must be submitted electronically along with a completed 
UWCCC SAE Routing Form to  saenotify@uwcarbone.wisc.edu. Follow up reports should be 
submitted, as needed, when additional information becomes available. All information is 
entered and tracked in the UWCCC OnCore database. 
 
As applicable, the study PI notifies all investigators involved with the study at the UWCCC, 
the IRB, the sponsor, and the funding agency and provides documentation of these 
notifications to the DSMC. 
 
For  a  multiple-institutional  clinical  trial  the  study  PI  is  responsible  for  ensuring  SAEs  
are reported to all participating investigators. 
 
See Section 11.3.5 for detailed instructions on SAE reporting. 
Serious adverse event – reported within 10 days 
SAEs requiring reporting within 10 days (as described in the protocol) must also be reported 
to 
the Data and Safety Monitoring Committee (DSMC) Chair via an email to 
saenotify@uwcarbone.wisc.edu. The OnCore SAE Details Report must be submitted along 
with other report materials as appropriate (Medwatch Form #3500A and/or any other 
documentation available at that time of initial reporting). The DSMC Chair will review the 
information and determine if further action is required. Follow up reports should be submitted, 
as needed, when additional information becomes available. All information is entered and 
tracked in the UWCCC OnCore database. 
 
As applicable, the study PI notifies all investigators involved with the study at the UWCCC, 
the IRB, the industry collaborators, and the FDA (if applicable) and provides documentation of 
these notifications to the DSMC. 
 
For a multiple-institutional clinical trial the study PI is responsible for ensuring SAEs are 
reported to all participating investigators. 
 
See Section 11.3.5 for detailed instructions on SAE reporting. 


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11.3.5 
Expedited Reporting of Serious Adverse Events 
All sites: Complete the following for all reports, regardless of reporting period: 
• 
FDA MedWatch Form 3500A 
• 
OnCore SAE Details Report 
• 
Serious Adverse Event Routing Form 
 
UWCCC Only: Complete the following for all reports regardless of SAE location 
• 
Genentech Safety Reporting Fax Cover Sheet 
 
A. SAE Requiring 24 Hour Reporting Occurs at UWCCC: 
 
1. Report to the UWCCC: 
 
Reference the SAE SOP (Standard Operating Procedure) and the SAE 
Reporting Workflow for DOTs on the UWCCC website, Data and Safety 
Monitoring page, (https://kb.wisc.edu/uwccc/internal/41020) for specific 
instructions on how and what to report to the UWCCC for [24] hour initial and 
follow-up reports.  A final initial report is required to be submitted within 5 
calendar days of the initial 24 hour report. 
 
Submit the following items: 
• 
FDA MedWatch Form 3500A 
• 
SAE Routing Form 
• 
OnCore SAE details report 
• 
Source documentation as applicable 
 
For this protocol, the following UWCCC entities are required to be notified: 
a) saenotify@uwcarbone.wisc.edu 
b) Julie Chang, MD (Study PI) jc2@medicine.wisc.edu 
c) Any other appropriate parties listed on the SAE Routing Form 
 
2. Report to Industry Collaborators: 
 
Submit the following items to Genentech: 
• 
Genentech Safety Reporting Fax Cover Sheet 
• 
FDA MedWatch Form 3500A 
• 
Source documentation as applicable 
 
Genentech Drug Safety  
Fax- 650-238-6067  
Email: usds_aereporting-d@gene.com 
 
3. Report to the IRB: 
 
Consult the UW-IRB website (kb.wisc.edu/hsirbs) for reporting guidelines. 


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B. SAE Requiring [10] Day Reporting Occurs at UWCCC: 
 
1. Report to the UWCCC: 
 
Reference the SAE SOP and the SAE Reporting Workflow for DOTs on the 
UWCCC website, Data and Safety Monitoring page, 
(https://kb.wisc.edu/uwccc/internal/41020) for specific instructions on how and 
what to report to the UWCCC for 10 day reports. 
 
Submit the following items: 
• 
FDA MedWatch Form 3500A 
• 
SAE Routing Form 
• 
OnCore SAE details report 
• 
Source documentation as applicable 
 
For this protocol, the following UWCCC entities are required to be notified: 
a. saenotify@uwcarbone.wisc.edu 
b. Julie Chang, MD (Study Chair) jc2@medicine.wisc.edu 
c. Any other appropriate parties listed on the SAE Routing Form 
 
2. Report to Industry Collaborators: 
 
Submit the following items to Genentech: 
• 
Genentech Safety Reporting Fax Cover Sheet 
• 
FDA MedWatch Form 3500A 
• 
Source documentation as applicable 
 
Genentech Drug Safety   
Fax- 650-238-6067  
Email: usds_aereporting-d@gene.com 
3. 
Report to the IRB: 
 
Consult the UW-IRB website (kb.wisc.edu/hsirbs) for reporting guidelines. 
 
C. SAE Requiring 24 hour reporting Occurs at 1 South Park (1SP) or a WON 
Site: 
 
1. Affiliate Site: Report to the UWCCC: 
 
Reference the SAE SOP and the SAE Reporting Workflow for 1SP and WON 
Affiliates on the UWCCC website, Data and Safety Monitoring page 
(https://kb.wisc.edu/uwccc/internal/41020) for specific instructions on how and 
what to report to the UWCCC for 24 hour initial and follow-up reports.  A final 
initial report is required to be submitted within 5 working days of the initial 
24 hour report. 
 
Submit the following items to UWCCC at saenotify@uwcarbone.wisc.edu 


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• 
FDA MedWatch Form 3500A 
• 
SAE Routing Form 
• 
OnCore SAE details report 
• 
Source documentation as applicable 
 
NOTE:  After 1SP or a WON site has submitted the 24 hour SAE report, the 
report is triaged initially to the UW Principal Investigator or Study Chair, the DOT 
Program Manager, the Affiliate Coordinator, and the DSMC Chair for review.  
The Principal Investigator or Study Chair is then responsible for ensuring 
the SAE is reported to the global sponsor, the UW IRB, and any other entity 
requiring notification, in accordance each entities’ reporting requirements. 
 
2. UWCCC: Report to Industry Collaborators: 
 
Affiliate sites will not submit directly to the sponsor, but will submit SAEs to the 
UWCCC. The Study PI will report all SAEs to Genentech within the timelines 
described in section 11.4.1. 
 
Submit the following items to Genentech: 
• 
Genentech Safety Reporting Fax Cover Sheet 
• 
FDA MedWatch Form 3500A 
• 
Source documentation as applicable 
 
3. All Sites: Report to the IRB: 
 
WON sites should follow their local IRB reporting guidelines for SAE 
submission. The Study PI is responsible for the submission of the SAE to the 
UW IRB for any sites for which the UW IRB serves as the IRB of record. 
 
D. SAE Requiring 10 Day Reporting Occurs at 1 South Park (1SP) or a WON 
Site: 
 
1. Affiliate Sites: Report to the UWCCC: 
 
Reference the SAE SOP and the SAE Reporting Workflow for 1SP and WON 
Affiliates on the UWCCC website, Data and Safety Monitoring page, 
(https://kb.wisc.edu/uwccc/internal/41020) for specific instructions on how and 
what to report to the UWCCC for 10 day reports. 
 
Submit the following items to UWCCC at saenotify@uwcarbone.wisc.edu 
• 
FDA MedWatch Form 3500A 
• 
SAE Routing Form 
• 
OnCore SAE details report 
• 
Source documentation as applicable 
 
NOTE:  After 1SP or a WON site has submitted the 10 day SAE report, the 
report is triaged initially to the UW Principal Investigator or Study Chair, the DOT 
Program Manager, the Affiliate Coordinator, and the DSMC Chair for review.  
The Principal Investigator or Study Chair is then responsible for ensuring 
the SAE is reported to the global sponsor , the UW IRB, and any other 


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entity requiring notification, in accordance each entities’ reporting 
requirements. 
 
2. UWCCC: Report to Industry Collaborators: 
 
Affiliate sites will not submit directly to the sponsors, but will submit SAEs to the 
UWCCC. The Study PI will report all SAEs to Genentech within the timelines 
described in section 11.4.1. 
 
Submit the following items to Genentech: 
• 
Genentech Safety Reporting Fax Cover Sheet 
• 
FDA MedWatch Form 3500A 
• 
Source documentation as applicable 
 
3. All Sites: Report to the IRB: 
 
WON sites should follow their local IRB reporting guidelines for SAE 
submission. The Study PI is responsible for the submission of the SAE to the 
UW IRB for any sites for which the UW IRB serves as the IRB of record. 
 
 
11.4 Study PI Adverse Event Reporting Requirements 
 
11.4.1 
Adverse event reporting to Genentech 
The study PI will report all SAEs to Genentech within the timelines described below. WON 
sites will not submit directly to Genentech, but will submit SAEs to UWCCC, and the 
PI will review and submit to Genentech on behalf of the WON site. The completed FDA 
MedWatch Form 3500A should be faxed immediately upon completion to Genentech Drug 
Safety at: 
 
Fax- 650-238-6067  
Email: usds_aereporting-d@gene.com 
SAEs, pregnancy reports and AESIs, where the patient has been exposed to obinutuzumab, 
will be sent on a MedWatch form to Roche/Genentech. Transmission of these reports (initial 
and follow-up) will be either electronically or by fax and within the timelines specified below:] 
 
• 
Serious Adverse Drug Reactions (SADRs) 
Serious AE reports that are related to obinutuzumab shall be transmitted to 
Roche/Genentech within fifteen (15) calendar days of the awareness date. 
 
• 
Other SAEs 
Serious AE reports that are unrelated to obinutuzumab shall be transmitted to 
Roche/Genentech within thirty (30) calendar days of the awareness date. 
 
• 
Pregnancy reports 
While such reports are not serious AEs or ADRs per se, as defined herein, any reports 
of pregnancy, where the fetus may have been exposed to obinutuzumab, shall 
be transmitted to Roche/Genentech within thirty (30) calendar days of the awareness 
date. Pregnancies will be followed up until the outcome of the pregnancy is known, 


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whenever possible, based upon due diligence taken to obtain the follow-up information. 
 
• 
AESIs 
AESIs that meet criteria for seriousness OR are at least possibly related to 
obinutuzumab require expedited reporting and shall be forwarded to Roche/Genentech 
within fifteen (15) calendar days of the awareness date.  Others shall be sent within thirty 
(30) calendar days. 
 
 
FDA MedWatch Form 3500A (Mandatory Reporting) is available at:  
http://www.fda.gov/medwatch/getforms.html 
 
Special situation reports 
In addition to all AEs, pregnancy reports and AESIs, the following Special Situations Reports 
should be collected and transmitted to Roche/Genentech even in the absence of an Adverse 
Event within thirty (30) calendar days: 
• 
Data related to the Product usage during pregnancy or breastfeeding. 
• 
Data related to overdose, abuse, off-label use, misuse, inadvertent/erroneous 
administration, medication error or occupational exposure, with or without 
association with an AE/SAE unless otherwise specified in the protocol. 
• 
Data related to a suspected transmission of an infectious agent via a medicinal 
product (STIAMP). 
• 
Lack of therapeutic efficacy. 
 
In addition, reasonable attempts should made to obtain and submit the age or age group of 
the patient, in order to be able to identify potential safety signals specific to a particular 
population. 
 
Aggregate Reports 
A copy of the Final Study Report will be submitted to Roche/Genentech by the study principal 
investigator upon completion of the Study. Any publications of interim results will also be 
submitted to Roche/Genentech for review. The study principal investigator will forward a copy 
of the final publication to Roche/Genentech upon completion of the study. Copies of such 
reports should be mailed to the assigned Clinical Operations contact for the study: 
 
Email:  ga101-gsur@gene.com 
Fax:  866-706-3927 
 
The study PI will compile into a report all non-serious adverse events once all study 
subjects are off treatment.  
 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form 
Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e. D.O.B. initials, patient number), protocol description and number, if 


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assigned, brief adverse event description, and notation that additional or 
follow- up information is being submitted (The patient identifiers are important 
so that the new information is added to the correct initial report) 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom an adverse event was reported. For questions regarding 
SAE reporting, you may contact the Genentech Drug Safety representative or the MSL 
assigned to the study. Relevant follow-up information should be submitted to Genentech Drug 
Safety as soon as it becomes available and/or upon request. 
 
11.4.2  Product complaints to Genentech 
Recently the FDA announced an update to the Post Marketing Safety Reporting regulation 
which requires the Marketing Authorization Holder (i.e., Genentech/Roche) to report product 
complaints to the FDA. A product complaint is 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 an AE should be reported via e-mail to: 
usds_aereporting-d@gene.com OR 650-238-6067 
 
Product complaints without an AE should be reported via e-mail to  
Kaiseraust.global_impcomplaint_management@roche.com 
 
All complaints must be filed within 15 calendar days. Complaints can be reported using a 
Medwatch, CIOMS, or any Genentech-approved response reporting form. 
 
12 Response Criteria 
Baseline lesion assessments must occur within 6 weeks of enrollment, as indicated in Section 
3, Schedule of Study Assessments. Efficacy assessments are scheduled to occur at the end 
of cycle 4 of induction therapy, following consolidation therapy, and after cycles 4 and 8 of 
maintenance therapy. 
 
Response and progression will be evaluated using the Lugano classification criteria.17 The 
criteria are outlined in detail in Appendix E. PET/CT-based response criteria should be used if 
PET/CT is performed; otherwise CT-based response criteria will apply. For this study, a score 
of 1, 2, or 3 on a PET 5-point scale will be considered a complete metabolic response.62 
Radiological methodologies, techniques and/or physical examination, established at baseline 
for the assessment and measurement of each identified lesion will be used for all subsequent 
assessments. Spleen craniocaudal dimension of 13 cm is the upper limits of normal for 
response assessment. 
 
For patients who had a positive BM by BMA and/or biopsy at baseline but negative by FDG-
PET at baseline, a follow-up BMA and/or biopsy will be obtained to confirm CR. If the 
BMA and/or biopsy was negative at baseline, but FDG-PET was positive for marrow 
involvement, FDG-PET negativity will be sufficient to confirm CR. If both modalities were 
positive at baseline, either may be repeated to confirm CR. The follow-up bone marrow 


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biopsy sample must be negative for confirmation of a CR. If the follow-up morphology is 
indeterminate, the biopsy sample must be negative by immunohistochemistry or the patient 
will be assessed a response of PR. 
 
13 Protocol Amendments and Deviations 
13.1 Protocol amendments 
Any amendment to this protocol must be agreed to by the PI and reviewed by Genentech. 
Amendments should only be submitted to the local IRB after consideration of study 
supporters’ reviews. Written verification of IRB approval will be obtained before any 
amendment is implemented. 
 
13.2 Protocol deviations 
When an emergency occurs that requires a deviation from the protocol for a subject, a deviation 
will be made only for that subject. A decision will be made as soon as possible to determine 
whether or not the subject (for whom the deviation from protocol was effected) is to continue 
in the study. The subject’s medical records will completely describe the deviation from the 
protocol and state the reasons for such deviation. In addition, the investigator will notify the IRB 
in writing of such deviation from protocol according to local policy. In addition, the investigator 
will inform the DSMC of the event around the protocol deviation, to determine if the subject 
should be removed from protocol therapy. 
Non-emergency minor deviations from the protocol will be permitted with approval of the PI. 
 
14 Statistical Considerations 
14.1 Overview 
This single arm, open-label phase II study will be carried out at an academic medical center 
as well as community practice sites. Participating centers will include the UWCCC and 
participating community practice sites within the WON. The primary efficacy endpoint of this 
study is PFS. 
 
 
14.2 Study Endpoints 
The primary efficacy endpoint of the study will be 2-year PFS. Secondary endpoints include 
1.) MRD status after 2 cycles of induction chemoimmunotherapy with bendamustine and 
obinutuzumab, after 4 cycles of consolidation with obinutuzumab, and after an additional 
8 cycles of maintenance with obinutuzumab and 2.) Response status with induction 
chemoimmunotherapy, both as a dichotomous variable. Safety endpoints include toxicity 
graded using CTCAE. 
 
 
14.3 Sample Size Calculation 
According to the literature, 2-year PFS with standard of care is 50% (pc=0.50). We would be 
interested in the protocol regimen if it improves the 2-year PFS to at least 65% 
(pt≥0.65).Therefore, we will test the null hypothesis that H0:pt≤pc against the alternative 


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hypothesis H1:pt>pc. In order to test H0 at a one-tailed significance level a=0.10 with power 
1-1=0.85 to detect pt=0.65, 0.70 or 0.75, the study will require observing 24, 13 or 7 
progressions or deaths, respectively.  The table below shows the required number of 
subjects to be enrolled for different durations of accrual, with a minimum follow-up of 2 
years. 
 
Accrual duration (in years) 
pt 
2 
2.5 
3 
0.65 
51 
48 
46 
0.70 
30 
28 
27 
0.75 
20 
19 
18 
 
In order to detect an increase in 2-year PFS to 70% with the protocol therapy, we would need 
to enroll a total of 28 patients over 2.5 years for a total of 4.5 years of study, and the 
study will terminate when 13 progressions or deaths are observed. In addition, up to 
10% of subjects enrolled may not have a unique enough variation in heavy chain domain 
for MRD testing to be performed; therefore, the sample size is increased from 28 to 32 in 
order to account for this anticipated number of subjects who will not be evaluable for MRD 
testing. 
 
14.4 Statistical Analysis Plan 
 
14.4.1 
Primary endpoint 
The analysis will be undertaken when each patient has been potentially followed for a 
minimum of 24 months. For each patient, profession-free survival (PFS) will be defined as 
the number of days from C1D1 of induction chemoimmunotherapy to the day patient 
experiences an event of disease progression or death, whichever occurs first. If a patient 
has not experienced an event at the time of analysis, patient’s data will be censored at the 
date of the last available evaluation. The 2-year PFS probability will be estimated using the 
Kaplan-Meier method. The null hypothesis that the 2-year PFS probability is at most 0.5 will 
be tested versus that alternative hypothesis that it is greater than 0.7. PFS will be 
summarized using point estimate of the median PFS, and associated 95% confidence 
intervals. The confidence interval will be computed using the Brookmeyer-Crowley method. 
The data will be presented graphically using Kaplan-Meier plot. According to the design, 
we will reject the null hypothesis in favor of the alternative hypothesis that the 2-year PFS 
is 70% or greater if the observed 2-year PFS based on 13 PFS events is 61.5% or greater. 
 
 
14.4.2 
Secondary endpoints 
Secondary endpoints of MRD status after 2 cycles of induction therapy with bendamustine 
and obinutuzumab, after 4 cycles of consolidation therapy with obinutuzumab, and after 
an additional 8 cycles of maintenance therapy with obinutuzumab and response status 
will be summarized using frequency and proportion with 95% confidence intervals. 
 
Adverse events will be summarized with frequency and worst grade. Toxicities will be 
summarized in a similar way. Data from all subjects who receive any study drug will be 
included in the safety analyses. The severity of the toxicities will be graded according to the 
NCI CTCAE, version 5.0 whenever possible. Frequency tables (type of toxicity and grade) for 
all toxicities will be provided. 
 


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Concordance between PB and BMA in predicting MRD negative status will be summarized 
with frequency and proportion. 
 
For a given subject, OS will be defined as the number of days from C1D1 of the 
induction chemoimmunotherapy to the day the subject dies. Survival times of subjects who 
are still alive at the end of the follow-up period will be censored. OS will be summarized 
using point estimate of the median OS, along with the 95% confidence interval. Survival 
data will be presented graphically using Kaplan-Meier plot. 
 
14.5 Early stopping rule for toxicity 
An early stopping rule is in place for excessive toxicity. An AE will be considered excessive 
if it meets the following criteria: 
 
• 
Any grade 5 event attributed to treatment (i.e., treatment-related deaths) 
• 
Any grade 4 event excluding neutropenia and lymphopenia. Grade 4 
neutropenic fever is also excluded, as this is an expected event. Essentially 
all event of neutropenic fever require hospitalization and IV antibiotics, which 
requires classification as a grade 4 event even if patients are clinically stable 
without any additional complications. 
• 
Any patient that discontinues therapy due to grade ≥3 toxicities attributed to study 
treatment. 
 
Toxicities will be evaluated after each patient and the trial considered for early termination for 
excessive adverse events (AEs) listed above using a sequential probability ratio test (SPRT) 
of the null hypothesis H0: p≤ p0 against the alternative hypothesis H1: p≥ p1 with a one-tailed 
significance level a=0.05 and power 1-b=0.95 where p denotes the probability of the above 
AEs. The protocol stopping rule considers p1=0.25 to be unacceptable, and p0=0.05.  Early 
stopping will be considered only for excess toxicities (H1). According to the SPRT, early 
stopping will be considered if the number of patients (x) experiencing the above listed AEs 
out of the number of patients (n) treated with the protocol regimen exceeds 1.60 + 0.128n.  
For example, early stopping will be considered if 2 AEs are observed out of 2 to 3 patients, 3 
AEs out of 4 to 10 patients, 4 AEs out of 11 to 18 patients, 5 AEs out of 19 to 26 patients, 
and 6 AEs out of 27 to 32 patients. This early stopping rule has power 0.95 to detect 
excessive toxicities (H1: p≥0.25). 
 
14.6 Accrual Rate and Feasibility 
Based on our experience with studies involving MCL subjects at UWCCC and affiliated WON 
sites, we anticipate an accrual rate of approximately 10-12 subjects per year. Therefore, it 
is expected that accrual will be completed within 2.5 years. 
 
15 Regulatory Considerations 
15.1 Oversight and Monitoring Plan 
The UWCCC Data and Safety Monitoring Committee (DSMC), is responsible for monitoring 
data quality and subject safety for all UWCCC clinical studies. A summary of DSMC activities 
follows: 
 


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• 
Review of all clinical trials conducted at the UWCCC for data integrity and safety 
• 
Review of all serious adverse events requiring expedited reporting as defined in 
the protocol 
• 
Review of reports generated by the UWCCC data quality control review process 
• 
Submit  recommendations  for  corrective  action  to  the  Clinical  Research  
Committee (CRC) 
• 
Notify the Study Chair of the DSMC recommendation to the CRC 
• 
The committee ensures that notification is provided to external sites participating 
in multiple-institutional clinical trials coordinated by the UWCCC of adverse events 
requiring expedited reporting. 
 
15.2 Oversight of WON Sites 
The UWCCC Affiliate Office serves as the coordinating center for WON. For this 
protocol, coordinating center responsibilities are shared between the Affiliate Coordinator 
and UWCCC Lymphoma/Myeloma DOT. A detailed description of coordinating center 
responsibilities, as well as other WON processes and procedures, including periodic 
routine auditing procedures, is provided in the WON Manual available on the UWCCC 
website (https://kb.wisc.edu/uwccc/internal/page.php?id=42878). 
 
Regular communication between the UWCCC Affiliate Office and WON sites ensures that 
all participating parties are notified of protocol changes, informed consent document 
revisions, action letters, study status changes, reportable events/SAEs (as necessary), 
and any other applicable information. This communication is accomplished through regular 
email updates and conference calls. Reference the study specific WON Operations 
Manual for additional study- specific requirements. 
 
15.3 Monitoring and Reporting Guidelines 
Data related to these trials are discussed at regularly scheduled DOT meetings where the 
result of each subject’s treatment is discussed and the discussion is documented in the 
minutes. The discussion will include the number of subjects, significant toxicities as described 
in the protocol, dose adjustments, and responses observed.  
Twice yearly, summaries will be submitted to the DSMC for review.  Summaries will be 
provided to the supporters of the study (i.e., Genentech). 
 
15.4 Investigator responsibilities with study monitoring and auditing 
Investigator responsibilities are set out in the International Conference on Harmonization 
(ICH) guideline for Good Clinical Practice (GCP) and in the US Code of Federal Regulations. 
 
Investigators must enter study data onto CRFs or other data collection system. The 
investigator will permit study-related audits by Genentech or its representatives, IRB/EC 
review, and regulatory inspection(s) (e.g., FDA, EMEA and TPD), providing direct access to 
the facilities where the study took place, to source documents, to CRFs, and to all other 
study documents. 
 
The investigator, or a designated member of the investigator’s staff, must be available at 
some time during audit visits to review data and resolve any queries and to allow direct 
access to the subject’s records (e.g., medical records, office charts, hospital charts, and 
study related charts) for source data verification. The data collection must be completed 


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prior to each visit and be made available to the Genentech representative so that the 
accuracy and completeness may be checked. 
 
15.5 Study records requirements 
The case report forms will be completed. All documentation of adverse events and all IRB 
correspondence will be retained for at least 2 years after the investigation is completed. 
 
The investigator must ensure that the records and documents pertaining to the conduct of 
the study and the distribution of the study drug, be retained by the investigator for as long as  
needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval). These records and 
documents include copies of CRFs and source documents (original documents, data, and 
records [e.g., hospital records; clinical and office charts; laboratory notes; memoranda; 
subject’s diaries or evaluation checklists; SAE reports, pharmacy dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification 
as being accurate copies; microfiches; photographic negatives, microfilm, or magnetic 
media; x-rays; subject files; and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical study; documents regarding subject 
treatment and study drug accountability; original signed informed consents, etc.]). The 
investigator agrees to adhere to the document/records retention procedures by signing the 
protocol. 
 
15.6 Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki. The review of this protocol by the IRB/EC and 
the performance of all aspects of the study, including the methods used for obtaining 
informed consent, must also be in accordance with principles enunciated in the declaration, 
as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 
Protection of Human Subjects and Part 56 Institutional Review Boards. 
 
The investigator will be responsible for preparing documents for submission to the relevant 
IRB/EC and obtaining written approval for this study. The approval will be obtained prior to the 
initiation of the study. 
The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by 
the investigator to the IRB/EC for approval. The investigator is also responsible for notifying 
the IRB/EC of any serious deviations from the protocol, or anything else that may involve added 
risk to subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved 
by the IRB/EC prior to use. 
 
15.7 Informed consent 
The investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study and 
the informed consent process should be recorded in the subject’s source documents. The 


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original consent form signed and dated by the subject and by the person consenting the subject 
prior to the subject’s entry into the study, must be maintained in the investigator’s study files. 
 
15.8 Subject confidentiality 
Identifiable patient information will be maintained at the enrolling site. All source documentation 
will be maintained within the subject’s research chart which will be accessible only to authorized 
personnel. Study data will be collected in the UWCCC OnCore database. The enrolling site is 
responsible for completing eCRFs per WON standard operating procedures. Subject data will 
be coded, with the link to demographic information maintained within the OnCore database. 
The study PI, statistician, and research team at UWCCC will have access to this information 
and will manage the study data.  Data will be maintained per federal guidelines. 
Genentech will affirm the subject’s right to protection against invasion of privacy. In compliance 
with United States federal regulations, the study supporters (i.e., Genentech and Adaptive 
Biotechnologies) require the investigator to permit representatives of Genentech and Adaptive 
Biotechnologies, when necessary, representatives of the FDA or other regulatory authorities 
to review and/or copy any medical records relevant to the study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the investigator to obtain 
such permission in writing from the appropriate individual. 
 
15.9 Premature discontinuation of study 
The responsible local clinical investigator as well as Genentech have the right to discontinue 
this study at any time for reasonable medical or administrative reasons in any single center 
or all participating centers. Possible reasons for termination of the study could be but are 
not limited to: 
• 
Unsatisfactory enrollment with respect to quantity or quality. 
• 
Inaccurate or incomplete data collection. 
• 
Falsification of records. 
• 
Failure to adhere to the study protocol. 
 
 


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16 References 
1. 
Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP 
plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an 
open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013;381:1203-10. 
2. 
Campo E, Rule S. Mantle cell lymphoma: evolving management strategies. Blood 
2015;125:48- 55. 
3. 
Kahl BS, Longo WL, Eickhoff JC, et al. Maintenance rituximab following induction 
chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study 
from the Wisconsin Oncology Network. Ann Oncol 2006;17:1418-23. 
4. 
Chang JE, Li H, Smith MR, et al. Phase 2 study of VcR-CVAD with maintenance rituximab 
for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405). Blood 
2014;123:1665-73. 
5. 
Chen R, Li H, Bernstein SH, et al. Pre-Transplant R-Bendamustine Induces High Rates 
of Minimial Residual Disease in MCL Patients: Updated Results of S1106: US Intergroup Study 
of a Randomized Phase II Trial of R-HCVAD Vs. R-Bendamustine Followed By Autologous Stem 
Cell Transplants for Pat…. Blood 2015;126:518-. 
6. 
Roschewski M, Dunleavy K, Pittaluga S, et al. Circulating tumour DNA and CT monitoring 
in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet 
Oncol 2015;16:541-9. 
7. 
Pott C, Schrader C, Gesk S, et al. Quantitative assessment of molecular remission after 
high- dose therapy with autologous stem cell transplantation predicts long-term remission in 
mantle  cell lymphoma. Blood 2006;107:2271-8. 
8. 
Pott C, Hoster E, Delfau-Larue MH, et al. Molecular remission is an independent predictor 
of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a 
European MCL intergroup study. Blood 2010;115:3215-23. 
9. 
Pott C. Minimal residual disease detection in mantle cell lymphoma: technical aspects and 
clinical relevance. Semin Hematol 2011;48:172-84. 
10. 
Furtado M, Rule S. Indolent mantle cell lymphoma. Haematologica 2011;96:1086-8. 
11. 
Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-
cell lymphoma. J Clin Oncol 2009;27:1209-13. 
12. 
Eve HE, Furtado MV, Hamon MD, Rule SA. Time to treatment does not influence overall 
survival in newly diagnosed mantle-cell lymphoma. J Clin Oncol 2009;27:e189-90; author reply e91. 
13. 
Mossner E, Brunker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy 
through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune 
effector cell- mediated B-cell cytotoxicity. Blood 2010;115:4393-402. 
14. 
Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy 
in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the 
phase II GAUGUIN study. J Clin Oncol 2013;31:2912-9. 
15. 
Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus 
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Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with 
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Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell 
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Romaguera JE, Fayad L, Rodriguez MA, et al. High rate of durable remissions after treatment 
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Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative 
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Martin P, Chadburn A, Christos P, et al. Intensive treatment strategies may not provide 
superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard 
therapies. Ann Oncol 2008;19:1327-30. 
27. 
Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or 
R- CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 
2014;123:2944-52. 
28. 
Gandhi V. Metabolism and mechanisms of action of bendamustine: rationales for 
combination therapies. Semin Oncol 2002;29:4-11. 
29. 
Strumberg D, Harstrick A, Doll K, Hoffmann B, Seeber S. Bendamustine hydrochloride 
activity against doxorubicin-resistant human breast carcinoma cell lines. Anticancer Drugs 1996;7:415-
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30. 
Fischer K, Cramer P, Busch R, et al. Bendamustine in Combination With Rituximab for 
Previously Untreated Patients With Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial 
of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2012;30:3209-16. 
31. 
Rummel M, Kaiser U, Balser C, et al. Bendamustine plus rituximab versus fludarabine 
plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, 
randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol 2016;17:57-66. 
32. 
Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of 
bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's 
lymphoma. J Clin Oncol 2008;26:4473-9. 
33. 
Rummel MJ, Al-Batran SE, Kim SZ, et al. Bendamustine plus rituximab is effective and has 
a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. 
J Clin Oncol 2005;23:3383-9. 
34. 
Weide R, Pandorf A, Heymanns J, Koppler H. Bendamustine/Mitoxantrone/Rituximab (BMR): 
a very effective, well tolerated outpatient chemoimmunotherapy for relapsed and refractory CD20-
positive indolent malignancies. Final results of a pilot study. Leuk Lymphoma 2004;45:2445-9. 
35. 
Warsch S, Hosein PJ, Maeda LS, Alizadeh AA, Lossos IS. A retrospective study evaluating 
the efficacy and safety of bendamustine in the treatment of mantle cell lymphoma. Leuk Lymphoma 
2012;53:1299-305. 
36. 
Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after 
cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced 
indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol 2009;27:1607-
14. 
37. 
Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with 
high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a 
phase 3, randomised controlled trial. Lancet 2011;377:42-51. 
38. 
Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to 
a significant prolongation of response duration after salvage therapy with a combination of 
rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients  with recurring 
and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of 
the German Low Grade Lymphoma Study Group (GLSG). Blood 2006;108:4003-8. 
39. 
van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome 
of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab 
during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006;108:3295-


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301. 
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van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of 
relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase 
III randomized intergroup study. J Clin Oncol 2010;28:2853-8. 
41. 
Ghielmini M, Schmitz SF, Cogliatti S, et al. Effect of single-agent rituximab given at the 
standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the 
Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol 2005;23:705-11. 
42. 
Chang JE, Peterson C, Choi S, et al. VcR-CVAD induction chemotherapy followed by 
maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study. Br J 
Haematol 2011;155:190-7. 
43. 
Chang JE, Li H, Smith MR, et al. Phase 2 study of VcR-CVAD with maintenance rituximab 
for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405). Blood 
2014;123:1665-73. 
44. 
Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-
cell lymphoma. N Engl J Med 2012;367:520-31. 
45. 
Beers SA, French RR, Chan HT, et al. Antigenic modulation limits the efficacy of anti-
CD20 antibodies: implications for antibody selection. Blood 2010;115:5191-201. 
46. 
Salles G, Morschhauser F, Lamy T, et al. Phase I Study of RO5072759 (GA101) in Patients 
with Relapsed/Refractory CD20+ Non-Hodgkin Lymphoma (NHL). Blood 2009;114:1704-. 
47. 
Morschhauser F, Cartron G, Lamy T, et al. Phase I Study of RO5072759 (GA101) in 
Relapsed/Refractory Chronic Lymphocytic Leukemia. Blood 2009;114:884-. 
48. 
Salles GA, Morschhauser F, Thieblemont C, et al. Efficacy and Safety of Obinutuzumab 
(GA101) Monotherapy in Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma: Results From 
a Phase I/II Study (BO20999). ASH Annual Meeting Abstracts 2011;118:268-. 
49. 
Sehn LH, Assouline SE, Stewart DA, et al. A Phase I Study of GA101 (RO5072759) 
Monotherapy Followed by Maintenance in Patients with Multiply Relapsed/Refractory CD20+ 
Malignant Disease. Blood 2009;114:934-. 
50. 
Flynn JM, Byrd JC, Kipps TJ, et al. Obinutuzumab (GA101) 1,000 mg versus 2,000 mg in 
patients with chronic lymphocytic leukemia (CLL): Results of the phase II GAGE (GAO4768g) trial. 
ASCO Meeting Abstracts 2014;32:7083. 
51. 
Brown JR, O'Brien S, Kingsley CD, et al. Obinutuzumab plus fludarabine/cyclophosphamide 
or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood 
2015;125:2779-85. 
52. 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007;25:579-86. 
53. 
Cowan AJ, Stevenson PA, Cassaday RD, et al. Pretransplantation Minimal Residual 
Disease Predicts Survival in Patients with Mantle Cell Lymphoma Undergoing Autologous Stem Cell 
Transplantation in Complete Remission. Biol Blood Marrow Transplant 2016;22:380-5. 
54. 
Liu H, Johnson JL, Koval G, et al. Detection of minimal residual disease following 
induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final 
results of CALGB 59909. Haematologica 2012;97:579-85. 
55. 
Johnson J, Kaplan LD,  Koval G, et al. Minimal Residual  Disease (MRD) Status  Following 
Induction Chemo-Immunotherapy Predicts Progression-Free Survival In Mantle Cell Lymphoma 
(MCL): CALGB 50403 (Alliance). Blood 2013;122:3002-. 
56. 
Ladetto M. The adulthood of MRD detection in MCL. Blood 2010;115:3180-1. 
57. 
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-
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58. 
Malnassy G, Geyer S, Fulton N, et al. Comparison Of Deep Sequencing and Allele-
Specific Oligonucleotide PCR Methods For MRD Quantitation In Acute Lymphoblastic Leukemia and 
Mantle Cell Lymphoma: CALGB 10403 and CALGB 59909 (Alliance). Blood 2013;122:2547-. 
59. 
Andersen NS, Pedersen LB, Laurell A, et al. Pre-emptive treatment with rituximab of 
molecular relapse after autologous stem cell transplantation in mantle cell lymphoma. J Clin Oncol 
2009;27:4365- 70. 
60. 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098. 
61. 
DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight 


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be known. Arch Intern Medicine 1916;17:863-71. 
62. 
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;32:3048-58. 
63. 
Hoster E, Klapper W, Hermine O, et al. Confirmation of the mantle-cell lymphoma 
International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma 
Network. J Clin Oncol 2014;32:1338-46. 
64. 
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br 
J Haematol 2004;127:3-11. 


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Appendix A: ECOG performance status 
 
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light house work, 
office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 


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Appendix B: Body surface area calculation 
 
The preferred method for calculating body surface area is with the Mosteller formula:60 
BSA (m2)= [Height(cm) X Body weight (kg)/3600]1/2 
At some participating community sites, the Dubois formula is the primary BSA calculation 
used as part of an electronic medical record and drug ordering template. In such cases, 
calculations using the Dubois formula are permitted as long as there is no more than a 10% 
difference in dosing between the Mosteller and Dubois calculations. If a >10% difference in 
drug dosing is observed, then the Mosteller calculation must be used. 
 
Dubois formula:61 
 
BSA (m2) = 0.007184 X [Body weight (kg)]0.425 X [Height (cm)]0.725 
 
The same BSA will be used for each dose calculation of bendamustine and rituximab unless 
the subjects experiences a >10% change in body weight from the weight used for the most 
recent BSA calculation. 


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Appendix C: Cockcroft-Gault estimation of CrCl: 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl): (Cockcroft, 
1976; Luke 1990) 
 
CrCl (mL/min) = 
 
(140 – age) x (weight, kg) 
(Males) 
72 x (serum creatinine, mg/dL) 
 
CrCl (mL/min) = 
 
(140 – age) x (weight, kg)_    x 0.85 
(Females) 
72 x (serum creatinine, mg/dL) 


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Appendix D: Mantle Cell Lymphoma International Prognostic Index 
(MIPI)20,63 score calculation 
 
 
 
 
 
As described in section 3.0, Schedule of Study Assessments, baseline/screening values for 
age, ECOG performance status, LDH, and WBC (white blood cell count) must be used for 
calculation of baseline MIPI score. 
 
*LDH is reported in standard values of U/L. 
*WBC is reported in 109/L. For example, a lab result reported in standard US labs as 
10.5 K/uL is equivalent to 10.5 X 109/L. 
 
 
Determination of risk group 
MIPI score 
Risk group 
<5.7 
Low 
5.7-6.2 
Intermediate 
≥6.2 
High 


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Appendix E: Assessment of response: Lugano Classification17 
 
 
 


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Spleen craniocaudal dimension of 13 cm is the upper limits of normal for response assessment.  


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Time to Progression 
 
Time to progression will be measured as the time from when the subject started treatment to 
the time the subject is first recorded as having disease progression, or the date of death 
if the subject dies due to causes other than disease progression. 
 
Time to Treatment Failure 
 
Time to treatment failure will be measured as the time from when the subject started treatment 
to the time the subject is withdrawn due to: AEs, progressive disease/insufficient therapeutic 
response, death, failure to return, and refused treatment/did not cooperate/withdrew consent. 
The date of last dose of treatment will be used as the date of event in the case that PD was 
not recorded earlier. 
 
Survival 
 
Survival will be measured as the time from start of treatment to the date of death or the last 
date the subject was known to be alive. 
 
Time to Response 
 
For subjects who achieve a major objective response (CR or PR of measurable disease), 
the time to response will be assessed as the time from start of treatment to the date of 
response. 


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Appendix F: Obinutuzumab formulation and preparation 
 
Obinutuzumab is provided as a single-use vial.  Each vial contains a sterile liquid formulation 
in a 50-mL pharmaceutical-grade glass vial containing a nominal dose of 1000 mg of 
obinutuzumab (G3 material).  The formulated drug product consists of 25 mg/mL drug 
substance formulated in histidine/histidine-HCl, trehalose, and poloxamer 188. The vial 
contains 41 mL (with 2.5% overfill). 
 
Storage 
 
The recommended storage conditions for the obinutuzumab drug product are between 2°C 
and 8°C, protected from light.  Chemical and physical in-use stability for obinutuzumab 
dilutions in 0.9% sodium chloride (NaCl) at concentrations of 0.2 − 20 mg/mL have been 
demonstrated for 24 hours at 2°C − 8°C and an additional 24 hours at ambient temperature 
and ambient room lighting. The prepared diluted product should generally be used 
immediately.  If not used immediately, in-use storage times and conditions prior to use are 
the responsibility of the user and would normally not be longer than 24 hours at 2°C − 8°C 
unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.  
Obinutuzumab should not be frozen or shaken.  Mix gently.  All transfer procedures require 
strict adherence to aseptic techniques. Do not use an additional in line filter because of 
potential adsorption. 
 
Preparation 
 
Obinutuzumab drug product intended for IV infusion is prepared by dilution of the drug 
product into an infusion bag containing 0.9% NaCl. 
 
One vial may be used to prepare both the 100-mg dose (equals 4 mL) and 900-mg dose 
(equals 36 mL) following the directions below.  If both bags are prepared at the same time, 
the reconstitution/dilution has to take place in a controlled and validated aseptic conditions. 
Subsequently store the 900-mg bag for a maximum of 24 hours at 2°C − 8°C and 
administer the next day. 
 
To prepare a 100-mg dose: The final drug concentration of a 100-mg dose should be in the 
range of 0.4 mg/mL to 4.0 mg/mL.  Using a 100-mL infusion bag containing 0.9% NaCl, 
withdraw 4 mL of obinutuzumab from a single glass vial and inject it into the infusion bag 
(discard any unused portion of obinutuzumab left in the vial unless reconstitution/dilution has 
taken place in controlled and validated aseptic conditions). Gently invert the infusion bag to 
mix the solution.  Do not shake. 
 
To prepare a 900-mg dose: The final drug concentration of a 900-mg dose should be in the 


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range of 0.4 mg/mL to 4.0 mg/mL.  Using a 250-mL infusion bag containing 0.9% NaCl, 
withdraw 36 mL of obinutuzumab from a single glass vial and inject it into the infusion bag 
(discard any unused portion of obinutuzumab left in the vial unless reconstitution/dilution has 
taken place in controlled and validated aseptic conditions). Gently invert the infusion bag to 
mix the solution.  Do not shake. 
 
To prepare a 1000-mg dose: The final drug concentration of a 1000-mg dose should be 
0.4 mg/mL to 4 mg/mL.  Using a 250-mL infusion bag containing 0.9% NaCl, withdraw 40 
mL of obinutuzumab from a single glass vial and inject it into the infusion bag (discard any 
unused portion of obinutuzumab left in the vial).  Gently invert the infusion bag to mix the 
solution.  Do not shake. 
 
Administration sets with polyvinyl chloride, polyurethane, or polyethylene as product contact 
surface and IV bags with polyolefin, polypropylene, polyvinyl chloride, or polyethylene as 
product contact surface are compatible and may be used.  Use of a port or peripherally 
inserted central catheter line is acceptable. 
 
Do not use obinutuzumab beyond the expiration date stamped on the carton. 
 
References: Investigator’s Brochure, GA101 (Obinutuzumab for injection, version 11 
(September 2016). 


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Appendix G: Bendamustine formulation, preparation, and adverse 
effects 
 
I. 
Drug formulation and preparation 
I.A. 
Other names 
Treanda™, SDX-105, Bendeka™ 
Bendamustine is available in several formulations, including Treanda™ (available 
in liquid and powder formulations infused over 30-60 minutes), and Bendeka™ (a ready-
to- dilute formulation available to infuse over 10 minutes). Bendeka™ was introduced 
in the market in December 2015 by Teva Pharmaceuticals, with the simultaneous 
decision by Teva to stop manufacturing Treanda™ during roll-out of Bendeka™. 
Generic marketing and availability of bendamustine is anticipated to be unpredictable 
in the months following introduction of the Bendeka™ product. Bendeka™ and 
Treanda™ are nearly identical in action and toxicities, and can be used 
interchangeably for administration of induction chemotherapy per the study protocol 
depending on availability of the bendamustine product and institutional preference. 
 
1.B. 
Classification and mode of action: 
Bendamustine is a DNA alkylating agent with amphoteric properties due to the nitrogen 
mustard group and butyric acid side chain. Bendamustine has multiple mechanisms 
of action related to the alkylating activity of the 1-methyl-benzimidazole moiety and 
the nitrogen mustard group. 
Bendamustine acts as an alkylating agent causing intra-strand and inter-strand cross- 
links between DNA bases, thus directly inhibiting DNA replication, transcription, 
and repair. At equitoxic concentrations, bendamustine induces more DNA double-
strand breaks than other alkylating agents (i.e., melphalan, cyclophosphamide, and 
carmustine). In addition, these breaks also appear to be more durable and less easily 
repaired than those induced by other agents. Bendamustine has also demonstrated 
pro- apoptotic activity in combination with other anti-cancer agents in several in vitro 
tumor models, including in primary tumor cells from CLL and non-Hodgkin lymphoma 
subjects. Treatment with bendamustine HCl has also demonstrated down-regulation 
of several cell cycle mitotic checkpoint regulators, including polo-like kinase 1 
(PLK-1), aurora kinase A and cyclin B1. Bendamustine shows only partial cross-
resistance with other alkylating agents when investigated in a variety of cell lines, 
which may be related to the relatively slow repair rate associated with this agent. No 
evidence of in vitro drug resistance to bendamustine was observed when the drug 
was tested in paried tumor cells expressing various drug resistance mechanisms 
including the overexpression of P-glycoprotein, of multi-drug resistant-associated 


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protein (MRP), or dihydrofolate reductase (DHFR). 
I.C Storage and stability 
Bendamustine vials should be stored at refrigerated temperatures of 2o to 8oC (36o 
to 46oF) and protected from light. Bendamustine is stable for 5 hours when stored 
at normal room temperature conditions, 15oC to 30oC (59oF to 86oF). Bendamustine 
is a cytotoxic anticancer agent and should be handled according to the recommended 
procedures described in the current edition of the American Society of Health-System 
Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous 
Drugs. Procedures described in each institution’s pharmacy or hospital standard 
operating procedure manual should be followed when handling cytotoxic drugs. 
The Bendeka product is supplied in multi-dose vials. Although it does not contain 
any anti-microbial preservative, Bendeka is bacteriostatic. The partially used vials are 
stable for up to 28 days when stored in its original carton under refrigeration 2-8oC or 
36-46oF). Each vial is not recommended for more than a total of 6 dose withdrawals. 
1.D. 
Preparation 
Bendamustine is available in several formulations, including Treanda™ (available 
in liquid and powder formulations) infused over 30-60 minutes, and Bendeka™ 
(newer formulation available to infuse over 10 minutes). Preparation should be 
followed according to the package inserts for Treanda™and Bendeka™. 
1.E. 
Administration 
The bendamustine solution should be used promptly after reconstitution and dilution. 
The route of administration is by IV infusion over 30-60 minutes for Treanda™ and 
over 
10 minutes for Bendeka™The infusion line would be primed with drug solution.  If 
medical conditions necessitate, e.g., fluid management issues of infusion reactions, 
the infusion may be given over a longer period of time, though the infusion should be 
≤120 minutes. In-line filters are not required for administration. Refer to the Pharmacy 
Manual for more detailed instructions. 
 
1.F.     Availability 
Commercial: Bendamustine is a white to off-white, crystalline powder. Mannitol is 
contained in the finished product as an excipient to enhance solubility during 
reconstitution of the powder. Bendamustine is lyophilized due to long-term instability 
in aqueous medium. Bendamustine is available in 100 mg single use vials. Bendeka is 
a clear colorless-yellow 25 mg/mL solution supplied in multi-dose vials (100 mg/4 mL 
vials). 
1.G. 
Drug interactions 
No formal pharmacokinetic drug-drug interactions have been determined for 


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bendamustine. However, bendamustine’s active metabolites are formed via 
cytochrome P450 CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) 
have the potential to increase plasma concentrations of bendamustine and decrease 
plasma concentrations of active metabolites. Inducers of P450 CYP1A2 (e.g., 
omeprazole, smoking) have the potential to decrease plasma concentrations of 
bendamustine and increase plasma concentrations of its active metabolites. 
1.H. 
Side effects – Please refer to package insert 
Hematologic: neutropenia (grade 3 or 4 neutropenia in up to 25% of treated subjects), 
thrombocytopenia infrequently requiring transfusions, and anemia. 
Infections: increased risk of infections (e.g., pneumonia) and sepsis have been reported 
following treatment with bendamustine. 
Infusion reactions and anaphylaxis: have been reported commonly in clinical trials 
with symptoms including fever, chills, pruritis, and rash. Rare reports of anaphylactic 
or anaphylactoid reactions have occurred. 
Tumor lysis syndrome: reported in several subjects treated with bendamustine, 
primarily during the first cycle of therapy. 
Skin reactions: reported reactions include rash, toxic skin reactions, and bullous 
exanthema 
Elevated LFT’s: reported increase in total bilirubin and transaminases in up to 30% 
of subjects in some clinical trials. 
Gastrointestinal: frequent reporting of nausea, vomiting, and stomatitis. 
1.I. 
Frequency of adverse effects: 
Frequent adverse events: asthenia, fatigue, malaise, and weakness; dry mouth; 
somnolence; cough; constipation; headache; mucosal inflammation and stomatitis; 
nausea, vomiting, and diarrhea. Hematologic toxicity is very frequent including grade 
3 and 4 neutropenia and thrombocytopenia. Mild elevation of liver function tests 
(total bilirubin and transaminases). 
Less common adverse events: hypersensitivity reactions, skin eruptions, fevers, 
chills, hypertension, pyrexia, and neutropenic infection. 
1.J. 
Nursing/subject implications 
 
Subjects require close monitoring during the first infusion for evidence of 
hypersensitivity 
reaction, which is an uncommon but serious side effect with 
bendamustine. 
Hematologic toxicity is the primary dose-limiting toxicity, and hematologic nadirs 
should be expected in the third week of therapy. 
Infection, including pneumonia and sepsis, have been reported following treatment 


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with bendamustine, usually in combination with myelosuppression. Subjects with 
myelosuppression need education regarding monitoring for signs of fever or infection. 
Prophylaxis for tumor lysis syndrome should be considered in subjects with high tumor 
burden, or elevated uric acid and/or LDH. 
Subjects should be educated on supportive measures for management of nausea, 
vomiting, diarrhea, constipation, and stomatitis. 
1.K. 
References 
Bendamustine package insert. 


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Appendix H: Grading events of tumor lysis syndrome 
 
Adverse of events of tumor lysis syndrome must be reported according to the Cairo-
Bishop definition of tumor lysis syndrome (TLS).64 Only clinical TLS is to be reported as 
an adverse event. The table describing criteria for laboratory evidence of TLS is only to 
be used for calculation of the clinical grade score for TLS. Grade ≥2 TLS requires 
reporting as AESI. 
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (LTLS) 
 
Uric Acid 
≥ 476 µmol/l (≥8.0 mg/dl) or 25% increase from baseline 
Potassium 
≥ 6.0 mmol/l (≥ 6.0 mEq/l) or 25% increase from baseline 
Phosphorous 
≥1.45 mmol/l (≥ 4.5 mg/dl) or 25 % increase from baseline 
Calcium 
≤1.75 mmol/l (≤ 7.0 mg/dl) or 25% decrease from baseline 
Laboratory tumor lysis syndrome (LTLS) is defined as either a 25% change or level above or below 
normal, as defined above, for any two or more serum values of uric acid, potassium, phosphate, and 
calcium within 3 days before or 7 days after the initiation of chemotherapy. This assessment assumes 
that a subject has or will receive adequate hydration (± alkalinization) and a hypouricaemic agent(s). 
Cairo-Bishop Grading System for Clinical TLS 
 
Grade 
LTLS 
Creatinine 
Cardiac Arrhythmia 
Seizure 
0 
- 
≤ 1.5 x ULN 
None 
None 
1 
+ 
1.5 x ULN 
Intervention not 
indicated 
None 
2 
+ 
> 1.5 – 3.0 x 
ULN 
Non-urgent medical 
intervention indicated 
One brief generalized seizure; 
seizure(s) well controlled or infrequent; 
focal motor seizures not interfering with 
ADL 
3 
+ 
> 3.0 – 6.0 x 
ULN 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device 
Seizure in which consciousness is 
altered; poorly controlled seizure 
disorder; breakthrough generalized 
seizures despite medical intervention 
4 
+ 
> 6.0 x ULN 
Life-Threatening 
Seizures of any kind that are prolonged, 
repetitive, or difficult to control 
5 
+ 
Death* 
Death* 
Death* 
LTLS, laboratory tumor lysis syndrome; ULN, upper limit of normal; ADL, activities of daily living 
*Probably or definitely attributable to clinical TLS