Conditions: Non-Hodgkin's Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 133
Healthy volunteers: no

Brief summary:
This study will evaluate the safety, efficacy, and pharmacokinetics of induction treatment with obinutuzumab, polatuzumab vedotin, and venetoclax in participants with relapsed or refractory FL, and with rituximab, polatuzumab vedotin, and venetoclax in participants with DLBCL. Participants with FL who achieve complete response (CR), partial response (PR), or stable disease (SD) at the end of induction therapy will receive post-induction treatment with obinutuzumab and venetoclax, and participants with DLBCL who achieve CR or PR at the end of induction (EOI) will receive post-induction treatment with rituximab and venetoclax.

Detailed description:

Arms:
arm 1: Participants with relapsed or refractory FL will receive 18 weeks of induction treatment with polatuzumab vedotin and venetoclax at escalating doses to identify the recommended Phase 2 dose (RP2D) for polatuzumab vedotin and venetoclax when combined with a fixed dose of obinutuzumab. Those who achieve CR, PR, or SD at the EOI will be eligible to receive a 24-month maintenance regimen consisting of 8 months of venetoclax and 24 months of obinutuzumab. arm 2: Participants with relapsed or refractory DLBCL will receive 18 weeks of induction treatment. Venetoclax will be administered at escalating doses to identify the RP2D of venetoclax when combined with fixed doses of polatuzumab vedotin and rituximab. Those who achieve CR or PR at the EOI will be eligible to receive an 8-month consolidation regimen consisting of venetoclax and rituximab. arm 3: Participants with relapsed or refractory FL will receive 18 weeks of induction treatment with polatuzumab vedotin and venetoclax at the RP2D identified during the dose-escalation phase, in addition to obinutuzumab. Those who achieve CR, PR, or SD at the EOI will be eligible to receive a 24-month maintenance regimen consisting of 8 months of venetoclax and 24 months of obinutuzumab. arm 4: Participants with relapsed or refractory DLBCL will receive 18 weeks of induction treatment. Venetoclax will be administered at the RP2D identified during the dose-escalation phase, in addition to polatuzumab vedotin and rituximab. Those who achieve CR or PR at the EOI will be eligible to receive an 8-month consolidation regimen consisting of venetoclax and rituximab.

Interventions: intervention 1: Obinutuzumab intervention 2: Rituximab intervention 3: Polatuzumab Vedotin intervention 4: Venetoclax
Intervention descriptions: intervention 1: Participants will receive a fixed dose of obinutuzumab, 1000 milligrams (mg) via intravenous (IV) infusion to be given on Days 1, 8 and 15 of Cycle 1 and on Day 1 of Cycles 2 to 6. Cycle length will be 21 days. For eligible participants, post-induction treatment may be given at a dose of 1000 mg via IV infusion on Day 1 of every other month (starting from Month 2) for up to 24 months, until disease progression or unacceptable toxicity. intervention 2: Participants will receive a fixed dose of rituximab, 375 milligrams per square meter (mg/m\^2) via IV infusion to be given on Day 1 of Cycles 1 to 6. Cycle length will be 21 days. For eligible participants, post-induction treatment may be given at a dose of 375 mg/m\^2 via IV infusion on Day 1 of every other month (starting from Month 2) for up to 8 months, until disease progression or unacceptable toxicity. intervention 3: Participants will receive polatuzumab vedotin via IV infusion at doses of 1.4 or 1.8 milligrams per kilogram (mg/kg) (for FL), and 1.8 mg/kg (for DLBCL) on Day 1 of each 21-day cycle for up to 18 weeks during induction treatment. Polatuzumab vedotin will not be given during the post-induction period. intervention 4: Participants will receive venetoclax film-coated tablets at doses of 200, 400, 600, or 800 mg (for FL), and 400, 600, or 800 mg (for DLBCL) on Days 1 to 21 of each 21-day cycle. Post-induction venetoclax may continue for up to 8 months, until disease progression or unacceptable toxicity.

Protocol document:
Prot_SAP_000.pdf: 


 
Title
17-Jan-2017 20:07:21
Date and Time (UTC)
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4 
 
PROTOCOL 
TITLE: 
A PHASE Ib/II STUDY EVALUATING THE SAFETY AND 
EFFICACY OF OBINUTUZUMAB IN COMBINATION WITH 
POLATUZUMAB VEDOTIN AND VENETOCLAX IN 
PATIENTS WITH RELAPSED OR REFRACTORY 
FOLLICULAR LYMPHOMA AND RITUXIMAB IN 
COMBINATION WITH POLATUZUMAB VEDOTIN 
AND VENETOCLAX IN PATIENTS WITH RELAPSED 
OR REFRACTORY DIFFUSE LARGE B-CELL 
LYMPHOMA 
PROTOCOL NUMBER: GO29833 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2015-001998-40 
IND NUMBER: 
115045 
TEST PRODUCTS: 
Obinutuzumab (RO5072759) 
Rituximab (RO0452294) 
Polatuzumab vedotin (DCDS4501A; RO5541077)  
Venetoclax (GDC-0199; ABT-199; RO5537382) 
MEDICAL MONITOR: 
, Pharm.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  15 July 2015 
DATE AMENDED: 
Version 2:  26 August 2015 
Version 3:  1 August 2016 
Version 4:  See electronic date stamp below. 
 


Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
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PROTOCOL AMENDMENT, VERSION 4 
RATIONALE 
Changes to the protocol, along with a rationale for each change, are summarized as 
follows: 
• 
Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) 
will receive polatuzumab vedotin and venetoclax in combination with rituximab 
instead of obinutuzumab (see Section 3.3.1).  The rationale for this change is 
based on the results from the Phase III GOYA study (BO21005) showing that the 
addition of obinutuzumab to cyclophosphamide, doxorubicin, vincristine, 
and prednisone (CHOP) chemotherapy in patients with previously untreated 
DLBCL did not improve the primary endpoint of progression-free survival (PFS) 
compared with the standard regimen of rituximab + CHOP chemotherapy. 
The background (Section 1.2), rationale (Sections 1.5 and 3.3), study objectives 
(Section 2), study design (Section 3), eligibility criteria (Section 4.1) and 
statistical plan (Section 6) have been updated accordingly.   
The updated study design includes a dose-escalation phase in R/R DLBCL 
patients to assess the maximum tolerated dose of venetoclax when combined 
with rituximab and polatuzumab at the 1.8 mg/kg dose level.  Only venetoclax 
dosing will be escalated (Sections 3.1.2 and 3.1.3). 
• 
Rituximab will be provided by the Sponsor as an investigational medicinal product.  
This addition of rituximab has been reflected throughout the protocol in 
corresponding sections.  Rituximab risks have been added (see Section 5.1.2), and 
the risks of overlapping toxicities (Section 5.1.5) have been updated accordingly.   
• 
Obinutuzumab exposure data (Section 1.2) have been updated to reflect the most 
up-to-date information on clinical studies based on the latest Obinutuzumab 
Investigator’s Brochure, Version 11 (September 2016). 
• 
Text regarding polatuzumab vedotin (Section 1.3) has been updated to reflect the 
most up-to-date information on clinical studies, based on the Polatuzumab Vedotin 
Investigator’s Brochure, Version 7 (July 2016). 
• 
The adverse event reporting period for Grade 3 and 4 infections has been clarified:  
up to 2 years after last dose of study treatment only for patients receiving 
obinutuzumab (Section 5.3.1).   
• 
The classification of second malignancies has been changed from a selected 
adverse event to an adverse event of special interest in order to monitor this 
adverse event more closely (Section 5.2.3). 
• 
Guidelines for the second and subsequent infusion of obinutuzumab have been 
clarified (i.e., patients with no infusion-related reaction during prior infusion will 
receive only an analgesic/antipyretic as premedication).  Figure 7 and Table 13 
have been updated accordingly.  
• 
The defined primary populations to be analyzed have been changed to include 
patients who received at least one dose of any component of the combination 
(Section 6.3) 


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• 
The interim analysis was clarified to state that enrollment would not be stopped in 
the case of higher than expected efficacy (Section 6.10). 
 
Clarifications to the protocol are summarized as follows: 
• 
The exploratory efficacy objective was clarified:  If a patient with DLBCL has a 
positive PET-CT at end of induction, then they should have PET-CT repeated at 
end of consolidation (Section 2.2.3, Section 6.6.3, and footnote “cc“ in Appendix 2) 
• 
Duplicate sentence in Section 3.1.2.1.2 was removed as this sentence occurs later 
in the section on hospitalization for TLS (Section 5.1.6.2): “Patients determined by 
the investigator to be at particularly high risk for TLS may, in addition to 
hospitalization, delay the start of venetoclax to Day 8 in Cycle 1 following 
discussion with the Medical Monitor.”  
• 
The exclusion criteria for monoclonal antibodies and antibody–drug conjugate 
therapy have been clarified to consider half-lives in washout period (Section 4.1.2). 
• 
The safety of immunization was clarified to include both live and attenuated viral 
vaccines following obinutuzumab therapy (Section 5.1.1.6). 
• 
The number of patients in the study has been updated (Sections 3.1.1, 3.1.2, 
and 6.1). 
• 
The immunogenicity analysis was updated to clarify that human anti-human 
antibodies will be collected for patients receiving obinutuzumab (Section 6.8). 
• 
The time window for drawing β2 microglobulin and quantitative IgA, IgG, and IgM as 
predose collections on C1D1 was included (footnote “o“ in Appendix 1; 
footnote “o“ in Appendix 2). 
• 
The pharmacokinetic and immunogenicity sampling schedule time windows were 
clarified (Appendix 3 and Appendix 4). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
 


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PROTOCOL AMENDMENT, VERSION 4: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.2:  BACKGROUND ON OBINUTUZUMAB 
Obinutuzumab is approved for use in combination with chlorambucil for the treatment of 
patients with previously untreated chronic lymphocytic leukemia (CLL).  Obinutuzumab 
is currently under investigation in a large clinical program, including multiple Phase III 
studies versus rituximab in indolent NHL and DLBCLObinutuzumab is also approved for 
use in combination with bendamustine followed by obinutuzumab monotherapy for the 
treatment of patients with FL who did not respond to or who progressed during or after 
treatment with rituximab or a rituximab-containing regimen.   
SECTION 1.2.2:  Clinical Studies with Obinutuzumab 
As of 31 October 2014 4 July 2016, clinical data from Roche-sponsored studies on 
obinutuzumab are available from 13 clinical studies, 8 Phase I or II studies (BO20999, 
BO21003, JO21900, BO21000, GAO4915g, GAO4779g, YP25623, and GAO4768g), 
and 5 Phase III/IIIb studies (BO21004, GAO4753g, BO21005, BO21223, and MO28543) 
in patients with NHL or CLL.  Available safety results from all patients and efficacy 
results from the NHL cohorts in these studies are summarized in Sections 1.2.2.1 
and 1.2.2.2, respectively.  Efficacy data from a Phase III study of obinutuzumab 
(GAO4753g) are also presented. 
SECTION 1.2.2.1:  Clinical Safety of Obinutuzumab 
As of the safety data cutoff date of 31 October 2014 4 July 2016, an estimated 
3636 3484 patients with NHL (including DLBCL, indolent B-cell lymphoma, and CLL) had 
been treated with obinutuzumab given as monotherapy or in combination with CHOP, 
bendamustine, fludarabine plus cyclophosphamide, or chlorambucil, at doses ranging 
from 50 mg to 2000 mg.  The overall safety and toxicity profile of obinutuzumab as 
monotherapy and as combination therapy was manageable. 
[…] 
Other important risks associated or potentially associated with obinutuzumab are tumor 
lysis syndrome (TLS), thrombocytopenia (including acute thrombocytopenia), 
neutropenia (including prolonged and late onset neutropenia), prolonged 
B-cell depletion, infections (including progressive multifocal leukoencephalopathy [PML] 
and hepatitis B virus [HBV] reactivation), worsening of preexisting cardiac conditions, 
impaired immunization response, immunogenicity, gastrointestinal perforation, and 
second malignancies.  The important identified risks associated with obinutuzumab are 
presented in detail in Section 5.1.1 of this protocol and in the Obinutuzumab 
Investigator's Brochure. 


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SECTION 1.2.2.2:  Clinical Efficacy of Obinutuzumab in Patients with 
Non-Hodgkin's Lymphoma 
In early studies of obinutuzumab in combination with chemotherapy (i.e., CHOP or 
bendamustine) in patients with previously untreated or R/R NHL (Studies BO21000, 
GAO4915g, and GAO4753g), the proportion of patients with a CR or PR at the end of 
induction treatment ranged from 69% to 96%.  The CR rate was higher with combination 
therapy (35%−39% in previously untreated FL, 39%−50% in R/R FL, and 55% in 
previously untreated DLBCL) than with monotherapy. 
A Phase III study, GAO4753g, investigated obinutuzumab plus bendamustine (GB) 
compared with bendamustine alone in patients with rituximab-refractory indolent NHL 
(n = 396).  Patients in the GB group who had not experienced disease progression at the 
end of induction received obinutuzumab monotherapy every 2 months for up to 2 years.  
On the basis of positive results from this study, demonstrating significant improvement in 
PFS in the GB arm, with a median PFS of 29 versus 14 months (hazard ratio [HR]: 0.52; 
95% CI: 0.39, 0.70; p > 0.0001) (Sehn et al. 2015), obinutuzumab was granted approval 
for use in patients with FL who did not respond to or who progressed during or after 
treatment with rituximab or a rituximab-containing regimen (see Section 1.2).  
A Phase III study, BO21223, investigated obinutuzumab plus chemotherapy (G-benda, 
G-CVP, G-CHOP) compared with rituximab plus chemotherapy, followed by 
obinutuzumab or rituximab maintenance in patients with previously untreated indolent 
non-Hodgkin's lymphoma (iNHL; FL cohort, n = 1202).  On the basis of positive results 
that demonstrated significant improvement in PFS in the obinutuzumab chemotherapy 
arm, the Independent Data Monitoring Committee recommended that the study be 
unblinded to the Sponsor at a pre-planned interim analysis (Marcus et al. 2016). 
A Phase III study, BO21005, investigated obinutuzumab plus CHOP (G-CHOP) 
compared with rituximab plus CHOP (R-CHOP) in patients with previously untreated 
DLBCL.  The study did not meet its primary endpoint of PFS at final analysis.  Based 
upon the BO21005 efficacy results, this study protocol is amended to cease evaluating 
obinutuzumab in patients with R/R DLBCL; these patients will receive instead 
rituximab in combination with polatuzumab vedotin and venetoclax (Vitolo et al. 2016).   
SECTION 1.3.2:  Clinical Studies with Polatuzumab Vedotin 
Clinical data on polatuzumab vedotin in patients with NHL or CLL are available as of 
February 2014 from one completed Phase I/Ib study (DCS4968g) and onethe ongoing 
Phase Ib/II studystudies (GO27834, ) and as of June 2014 from one ongoing Phase Ib/II 
study (, GO29044), GO29834, BO29561, and GO29365) in patients with B-cell 
lymphoma.   
DCS4968g evaluated polatuzumab vedotin as a single agent and in combination with 
rituximab in patients with R/R B-cell lymphoma.   


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GO27834 is evaluating polatuzumab vedotin in combination with either obinutuzumab 
or rituximab in patients with R/R FL or DLBCL. 
GO29044 is evaluating polatuzumab vedotin in combination with R-CHP or G-CHP in 
patients with newly diagnosed or R/R B-cell lymphoma.   
GO29365 is evaluating polatuzumab vedotin in combination with bendamustine plus 
rituximab or obinutuzumab in patients with R/R FL or DLBCL.   
GO29834 is evaluating polatuzumab vedotin in combination with lenalidomide and 
either obinutuzumab or rituximab in patients with R/R FL or DLBCL. 
BO29561 is evaluating polatuzumab vedotin in combination with atezolizumab and 
either obinutuzumab or rituximab in patients with R/R FL or DLBCL.   
Available safety results and efficacy results from these studies are summarized in 
Section 1.3.2.1 and Section 1.3.2.2, respectively.  Data have been generated in these 
studies for patients treated at the 2.4 mg/kg dose; however, further investigation focused 
on the 1.8 mg/kg dose is ongoing. 
For more detailed clinical information on polatuzumab vedotin, including clinical 
pharmacology data, refer to the Polatuzumab Vedotin Investigator’s Brochure. 
SECTION 1.3.2.1:  Clinical Safety of Polatuzumab Vedotin 
Clinical safety data are available from 180327 patients with NHL or CLL who received 
polatuzumab vedotin as a single agent (DCS4968g), in combination with rituximab 
(DCS4968g and GO27834), in combination with obinutuzumab (GO27834), in 
combination with obinutuzumab or rituximab plus CHP (GO29044), and in 
combination with obinutuzumab or rituximab plus bendamustine (GO29365). 
:  86 patients treated with single agent polatuzumab vedotin (doses ranging from 0.1 to 
2.4 mg/kg) in Study DCS4968g, 88 patients treated with polatuzumab vedotin (1.8 mg/kg 
and 2.4 mg/kg) in combination with rituximab (375 mg/m2) in Studies DCS4968g and 
GO27834, and 6 patients treated with polatuzumab vedotin (1.0 mg/kg and 1.4 mg/kg) in 
combination with R CHP in Study GO29044.  Data from Study GO29044 are not yet 
available. 
[…] 
In the dose-escalation phase of Study DCS4968g, dose-limiting toxicities (DLTs) of 
Grade 4 neutropenia occurred in 1 of 10 DLT-evaluable patients treated with 2.4 mg/kg 
polatuzumab vedotin and 1 of 9 DLT-evaluable patients treated with 2.4 mg/kg 
polatuzumab vedotin in combination with rituximab.  Polatuzumab vedotin at a dose of 
2.4 mg/kg given every 3 weeks (q3w) was chosen as the recommended Phase II dose 
(RP2D) when administered as a single agent and in combination with rituximab.  Due to 
additional information about the benefit-risk profile of polatuzumab vedotin at the 


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2.4 mg/kg dose, the Sponsor is no longer pursuing the clinical development of the 
2.4 mg/kg dose of polatuzumab vedotin. 
[…] 
In Study GO29044, Grade ≥ 3 adverse events were reported in 19 of 40 patients (48%) 
with B-cell lymphoma who received polatuzumab vedotin (1.8 mg/kg) in combination 
with obinutuzumab or rituximab plus CHP.  The most frequent events (≥ 10% of 
patients) were fatigue (33%), diarrhea (33%), and nausea (30%).  Serious adverse 
events were reported for 33% of patients in this treatment group.     
In Study GO29365, Grade ≥ 3 adverse events were reported in 11 of 21 patients (52%) 
with B-cell lymphoma who received polatuzumab vedotin in combination with 
rituximab plus bendamustine and in 17 of 28 patients (61%) who received polatuzumab 
vedotin in combination with obinutuzumab plus bendamustine.  The most frequent 
events (≥ 10% of patients) were nausea (43%), diarrhea (41%), and fatigue (35%).  
Serious adverse events were reported for 33% of patients receiving polatuzumab 
vedotin in combination with rituxumab plus bendamustine and 39% of patients 
receiving polatuzumab vedotin in combination with obinutuzumab plus bendamustine.   
A total of 44 deaths have been reported:  11 deaths in patients treated with single-agent 
polatuzumab vedotin and 33 in patients treated with polatuzumab vedotin combined 
with rituximab or obinutuzumab.  The majority of deaths were judged as related to 
disease progression. 
SECTION 1.3.2.2:  Clinical Efficacy of Polatuzumab Vedotin in Patients with 
Non-Hodgkin’s Lymphoma 
Polatuzumab vedotin demonstrated clinical activity as a single agent.  
In Study DCS4968g, at the 2.4-mg/kg dose, objective responses (CR or PR) were 
observed in 7 of 16 patients (44%) with R/R indolent B−cell lymphoma (FL, marginal 
zone lymphoma [MZL], or small lymphocytic lymphoma [SLL]) and 14 of 27 patients 
(52%) with R/R DLBCL.  At a dose of 1.8 mg/kg, a PR was observed in 2 of 4 patients 
with DLBCL and in 2 of 2 patients with MCL, and no objective responses were observed 
in the 5 patients with CLL.  The median duration of response was 6.2 months (95% CI: 
3.3, 19.3) for the 2.4 mg/kg dose and 6.6 months (95% CI: 2.3, 11.4) for the 1.8 mg/kg 
dose.  At the 2.4-mg/kg dose, median PFS was 7.9 months (95% CI: 3.0, 11.6) for 
patients with indolent B-cell lymphoma and 5.0 months (95% CI: 2.3, 6.8) for patients 
with DLBCL.  Median PFS was 4.6 months (95% CI: 1.4, 13.9) for patients with 
DLBCL treated at the 1.8-mg/kg dose. 
No objective responses were observed in patients with CLL at doses of up to 1.8 mg/kg.  
Median PFS at doses of  ≥ 1.8 mg/kg was 7.9 months (95% CI: 3 months, not evaluable 
[NE]) for patients with R/R indolent NHL (FL, MZL, or SLL) and 4.9 months (95% CI: 2.5, 
6.7 months) for patients with R/R DLBCL. 


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Polatuzumab vedotin also demonstrated clinical activity when administered in 
combination with rituximab.  In Study DCS4968g, at a dose of 2.4 mg/kg, objective 
responses were observed in 7 of 9 patients with indolent B-cell lymphoma, DLBCL, or 
MCL (78%); 2 of the 7 patients had CRs.  Median duration of response among these 
patients was 12.3 months (95% CI: 4.3, not estimable [NE]).  Median PFS was 
12.5 months (95% CI: 6.9, 17.4). 
ForPreliminary data for patients in Study GO27834 who received polatuzumab vedotin 
(2.4 mg/kg) in combination with rituximab, objective responses were observed in 14 of 
20 patients with R/R FL (70%; 89 patients with CRs) and 2221 of 39 patients with R/R 
DLBCL (5654%; 68 patients with CRs).  For patients who received polatuzumab vedotin 
(1.8 mg/kg) in combination with rituximab, objective responses were observed in 15 of 
20 patients with FL (75%; 6 patients with CRs).   
For patients in Study DCS4968g who received polatuzumab vedotin (2.4 mg/kg) in 
combination with rituximab (all histologies), median PFS was 12.5 months 
(95% CI: 6.9, 17.3 months). 
Median duration of response was 12.9 months (95% CI: 6.7, NE) and 13.2 months 
(95% CI:  7.2, 21.2) for patients who received polatuzumab vedotin 1.8 mg/kg (FL) or 
2.4 mg/kg (FL or DLBCL), respectively.  At the 2.4 mg/kg dose, median PFS was 
15.1 months (95% CI:  11.8, NE) among the 20 patients with FL and 5.6 months 
(95% CI:  4.2, 12.7) among the 39 patients with DLBCL.  Among the 20 patients with 
R/R FL treated with 1.8 mg/kg polatuzumab vedotin in combination with rituximab, 
median PFS was 18.1 months (95% CI:  9.9, NE).   
For patients in Study GO27834 who received polatuzumab vedotin (1.8 mg/kg) in 
combination with obinutuzumab, overall responses were observed in 8 of 12 patients 
with R/R FL (67%; 1 patient with CR) and 3 of 15 patients with R/R DLBCL (20%; 0 
patients with CR).   
Preliminary data from Study GO29044 in patients treated with polatuzumab vedotin 
(1.0−1.8 mg/kg) in combination with R-CHP showed overall responses in 29 of 
31 patients (94%; 24 patients with CRs).  When polatuzumab vedotin (1.4 or 
1.8 mg/kg) was combined with G-CHP, overall responses were seen in 10 of 12 patients 
(83%; 10 patients with CRs).   
Preliminary data from GO29365 in FL patients treated with polatuzumab vedotin 
(1.8 mg/kg) in combination with bendamustine showed overall responses in 
7 of 7 patients (100%; 2 patients with CRs) when combined with rituximab and in 
3 of 4 patients (75%; 1 patient with CR) when combined with obinutuzumab.  Patients 
with DLBCL treated with polatuzumab vedotin (1.8 mg/kg) in combination with 
bendamustine showed overall responses in 3 of 7 patients (43%; 2 patients with CRs) 


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when combined with rituximab and in 6 of 8 patients (75%; 2 patients with CR) when 
combined with obinutuzumab. 
SECTION 1.5:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Progress has been made in the treatment of FL and DLBCL; however, a significant 
number of patients will not be cured of their disease.  Instead, they will experience 
relapse or die of progression or treatment-related toxicity.  Patients who relapsed after 
receiving several prior treatments may not be able to tolerate more bone marrow toxicity, 
which limits their treatment options.  There is a need for the continued development of 
safe and effective therapies for patients with disease that relapses or for those who 
develop refractory disease during or after first-line therapy.  This study will evaluate the 
activity of a novel triplet combination of obinutuzumab or rituximab plus, polatuzumab 
vedotin, and venetoclax.   
[…] 
Obinutuzumab has shown superiority over rituximab in a Phase III trial in first-line CLL 
(Goede et al. 2014).  Obinutuzumab was also shown to be superior compared to 
rituximab when combined with chemotherapy in a Phase III trial (BO21223) in 
previously untreated FL patients (Marcus et al. 2016). Obinutuzumab is being 
compared with rituximab in two large Phase III studies, one study (BO21005) in patients 
with previously untreated DLBCL and one study (BO21223) in patients with previously 
untreated iNHL, including FL.  Assuming that these studies demonstrate greater clinical 
benefit with obinutuzumab  versus rituximab containing regimens, potentially altering the 
standard of care in NHL, it will be important to also assess the safety and efficacy of 
incorporating obinutuzumab into treatment regimens.  A fourthThe Phase III study, 
GAO4753g investigated obinutuzumab combined with bendamustine followed by 
obinutuzumab maintenance compared with bendamustine alone in patients with 
rituximab-refractory iNHL, including FL, and showed improvement in PFS in the GB arm 
(Sehn et al. 2015).  Obinutuzumab will be included as the anti-CD20 backbone for 
patients with R/R FL in this study.   
Obinutuzumab did not show superiority compared to rituximab in the Phase III trial 
comparing R-CHOP to G-CHOP in patients with previously untreated DLBLC 
(BO21005; Vitolo et al. 2016).  Based upon the BO21005 efficacy results, this study 
protocol is amended and patients with R/R DLBCL will receive rituximab as the anti-
CD20 backbone in combination with polatuzumab vedotin and venetoclax.   
[…] 
Obinutuzumab, rituximab, polatuzumab vedotin, and venetoclax are known to deplete 
circulating B cells and tumor burden, which may potentially impact the target-mediated 
clearance of obinutuzumab, rituximab, and polatuzumab vedotin.  In R/R FL and 
DLBCL, the baseline B-cell count is very low; therefore, the likelihood of 


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pharmacodynamics (B-cell) mediated drug-drug interaction (DDI) is relatively low.  This 
was confirmed by the observation that no interaction was observed between 
polatuzumab and rituximab in R/R FL and DLBCL. 
[…] 
Available nonclinical and clinical data suggest that there is a strong rationale to expect 
an improved benefit-risk profile with the triplet combination of obinutuzumab or 
rituximab, polatuzumab vedotin, and venetoclax.  This novel triplet regimen may have 
the potential to extend treatment-free remissions and decrease toxicity by improving 
upon individual agents used as part of current standard of care.  Patients with 
overlapping toxicities will be closely monitored; such events are expected to be 
manageable in the clinical setting (see Section 5.1.5).   
SECTION 2:  OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety, efficacy, and pharmacokinetics of induction treatment 
consisting of obinutuzumab in combination with polatuzumab vedotin and venetoclax 
(G + Pola + V) in patients with R/R FL or DLBCL and rituximab in combination with 
polatuzumab vedotin and venetoclax (R + Pola + V) in patients with R/R DLBCL,.  
Induction will be followed by post-induction treatment with G + V (referred to as 
maintenance) in patients with FL who achieve a CR, PR, or stable disease at end of 
induction (EOI) and post-induction treatment with R + V (referred to as consolidation) 
in patients with DLBCL who achieve a CR or PR at EOI.  Specific objectives and 
corresponding endpoints for the study are outlined in Sections 2.1−2.5. 
In this study, "study treatment" refers to the protocol-mandated treatments under study 
(i.e., obinutuzumab, rituximab, polatuzumab vedotin, and venetoclax). 
SECTION 2.1:  SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To determine the RP2D for polatuzumab vedotin and venetoclax when given in 
combination with a fixed dose of obinutuzumab and the RP2D of venetoclax when 
given in combination with a fixed dose of polatuzumab vedotin on the basis of the 
following endpoint: 
– 
Incidence of DLTs during the first cycle of study treatment 
• 
To evaluate the safety and tolerability of G + Pola + V and R + Pola + V on the basis 
of the following outcome measures in the respective combinations: 
– 
Nature, frequency, severity, and timing of adverse events, including DLTs 
– 
Changes in vital signs, ECGs, and clinical laboratory results during and 
following study treatment administration 


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SECTION 2.2.1:  Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of G + Pola + V in 
patients with R/R FL and R + Pola + V in patients with R/R DLBCL on the basis of the 
following endpoint: 
• 
CR at EOI, as determined by the IRC on the basis of PET-CT scans  
 
SECTION 2.2.2:  Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of G + Pola + V 
and maintenance treatment with G + V in patients with R/R FL and R + Pola + V and 
consolidation treatment with R + V in patients with R/R DLBCL on the basis of the 
following endpoints: 
• 
CR at EOI, as determined by the investigator on the basis of PET-CT scans 
• 
CR at EOI, as determined by the IRC and by the investigator on the basis of CT 
scans alone 
• 
Objective response (defined as a CR or PR) at EOI, as determined by the IRC and 
by the investigator on the basis of PET-CT scans 
• 
Objective response (defined as a CR or PR) at EOI, as determined by the IRC and 
by the investigator on the basis of CT scans alone 
• 
Best response of CR or PR during the study, as determined by the investigator on 
the basis of CT scans alone 
 
SECTION 2.2.3:  Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
G + Pola + V and R + Pola + V on the basis of the following endpoints: 
• 
For patients who have positive PET scans at EOI:   
– 
 CR at 12 months, as determined by the IRC and by the investigator on the 
basis of PET-CT scans in FL patients 
– 
CR at EOC as determined by the IRC and by the investigator on the basis 
of PET-CT scans in DLBCL patients 
• 
PFS, defined as the time from initiation of study treatment to first occurrence of 
disease progression or relapse, as determined by investigator on the basis of 
CT scans alone, or death from any cause 
• 
EFS, defined as the time from initiation of study treatment to any treatment failure, 
including disease progression or relapse, as determined by investigator on the basis 
of CT scans alone, initiation of new anti-lymphoma therapy, or death from any cause, 
whichever occurs first 
• 
Disease-free survival (DFS), defined, among patients who achieve a CR, as the time 
from the first occurrence of a documented CR to relapse, as determined by the 
investigator on the basis of CT scans alone, or death from any cause, whichever 
occurs first 
• 
OS, defined as the time from initiation of study treatment to death from any cause 
 


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SECTION 2.3:  PHARMACOKINETIC OBJECTIVE 
The PK objective for this study is to characterize the PK profiles of obinutuzumab, 
rituximab, polatuzumab vedotin, and venetoclax when given in combination, on the 
basis of the following endpoints: 
• 
Observed serum concentration of obinutuzumab at specified timepoints 
• 
Observed serum concentration of rituximab at specified timepoints 
• 
Observed serum and plasma concentrations of polatuzumab vedotin and relevant 
analytes (total antibody, antibody-conjugated MMAE [acMMAE] and unconjugated 
MMAE) at specified timepoints 
• 
Observed plasma concentration of venetoclax at specified timepoints 
 
SECTION 3.1.1:  Overview of Study 
This is a Phase Ib/II, open-label, multicenter, non-randomized study that will evaluate the 
safety, efficacy, and pharmacokinetics of G + Pola + V in patients with R/R FL and 
R + Pola + V in patients with R/R DLBCL.  or DLBCL.  The study will include an initial 
dose escalation phase designed to determine the RP2D for polatuzumab vedotin and 
the RP2D for venetoclax in this treatment combination, followed by an expansion phase 
during which polatuzumab vedotin and venetoclax will be given at their RP2Ds (see 
Section 3.1.2.2).  Patients will receive induction treatment with obinutuzumab, 
polatuzumab vedotin, and venetoclax as outlined in Section 3.1.2.  Patients with FL who 
achieve a CR, PR, or SD at EOI and patients with DLBCL who achieve a CR or PR at 
EOI will receive post induction treatment with obinutuzumab and venetoclax (see 
Section 3.1.2 for details).   
The study will include an initial dose-escalation phase followed by an expansion phase 
during which polatuzumab vedotin and venetoclax will be given at their RP2Ds (see 
Sections 3.1.2 and 3.1.2.2).  Patients will receive induction treatment with 
obinutuzumab or rituximab, polatuzumab vedotin, and venetoclax as outlined in 
Sections 3.1.2 and 3.1.3.  Patients with FL who achieve a CR, PR, or SD at EOI will 
receive post-induction treatment with obinutuzumab and venetoclax, and patients with 
DLBCL who achieve a CR or PR at EOI will receive post-induction treatment with 
rituximab and venetoclax (see Sections 3.1.2 and 3.1.3 for details).  A study schema is 
provided in Figure 2. 
Approximately 104 119113−134 patients are expected to be enrolled in this study at 
approximately 20−25 investigative sites worldwide.   
[…] 
To characterize the PK properties of obinutuzumab, rituximab, polatuzumab vedotin, 
and venetoclax, blood samples will be obtained at various timepoints before and during 
study treatment administration (see Appendix 3 and Appendix 4). 


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FIGURE 2:  Study Schema 
Figure 2 has been revised to include rituximab. 
SECTION 3.1.2:  Obinutuzumab Plus Polatuzumab Vedotin Plus 
Venetoclax Treatment Group (Patients with Follicular 
Lymphoma) 
This is a new section heading to highlight the distinct patient groups. 
SECTION 3.1.2.1:  Follicular Lymphoma Dose-Escalation Phase 
The purpose of the FL dose-escalation phase is to identify the RP2D for polatuzumab 
vedotin and the RP2D for venetoclax when combined with a fixed dose of obinutuzumab 
as induction treatment.  TheThis dose-escalation phase will include FL patients only; 
these patients may receive post-induction treatment if eligible.  The RP2D will be based 
on the maximum tolerated doses (MTDs) and the totality of data for polatuzumab vedotin 
and venetoclax.  
Approximately 2421−39 patients will be enrolled in the FL dose-escalation phase.  
Initially, the study enrolled 3 patients starting in Cohort 1 at a dose level of 400 mg 
venetoclax and 1.4mg/kg polatuzumab vedotin.  With Amendment 3, Cohort 1a has 
beenwas added to the dose-escalation phase with a starting dose level of 200 mg 
venetoclax and 1.4mg/kg polatuzumab vedotin.  The original Cohort 1 dose level 
combination will be repeated to gather additional safety data in this dose level.  Dosing 
cohorts of 3−6 patients each will be treated in accordance with the treatment regimen 
and dose-escalation rules described in Sections 3.1.2.1.2 and 3.1.2.1.3, respectively. 
Patients will be closely monitored for adverse events during a DLT assessment window, 
which will be defined as the first treatment cycle (from Day 1 of Cycle 1 to Day 1 of 
Cycle 2).  Adverse events that meet the criteria for DLT, as defined in Section 3.1.2.1.1, 
will be reported to the Sponsor within 24 hours (see Section 5.4.2). 
Patients who discontinue from the study prior to completion of the DLT assessment 
window for reasons other than a DLT will be considered non-evaluable for 
dose-escalation decisions and MTD assessments and will be replaced by an additional 
patient at that same dose level.  Patients who miss one or more doses of polatuzumab 
vedotin or obinutuzumab or five consecutive daily doses of venetoclax during the DLT 
assessment window for reasons other than a DLT will also be replaced and considered 
non-evaluable for dose-escalation decisions.  Patients who receive supportive care 
during the DLT assessment window that may confound the evaluation of DLTs may be 
replaced at the discretion of the Medical Monitor. 
SECTION 3.1.2.1.2:  Treatment Regimens for the Follicular Lymphoma 
Dose-Escalation Phase 
Patients determined by the investigator to be at particularly high risk for TLS may, in 
addition to hospitalization, delay the start of venetoclax to Day 8 in Cycle 1 following 
discussion with the Medical Monitor.   


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TABLE 1:  Induction Treatment for the Follicular Lymphoma 
Dose-Escalation Phase 
The Table 1 title has been revised to specify the FL group. 
TABLE 2:  Maintenance Treatment for the Follicular Lymphoma 
Dose-Escalation Phase 
The Table 2 title has been revised to specify the FL group. 
SECTION 3.1.2.1.3:  Dose-Escalation Rules 
Intrapatient dose escalation will be allowed only for the Cohort 1a patients receiving 
200 mg of venetoclax.  In this cohort, the venetoclax dose may be escalated from 200 
mg to 400 mg once Cohorts 2 and 3 open after approval by the Medical Monitor.  
Intrapatient dose escalation is not allowed in other cohorts.  The overallFL 
dose-escalation plan is depicted in Figure 3, and the doses for each cohort are 
summarized in Table 3.   
[…] 
Relevant demographic, adverse event, laboratory, dosing administration/intensity, and 
PK (if available) data will be reviewed throughout the study by the Clinical Study Team 
and prior to dose-escalation decisions, which will be made by the Medical Monitor in 
consultation with the Principal Investigator and participating investigators. 
Although the DLT-assessment window is defined as the first treatment cycle (from Day 1 
of Cycle 1 to Day 1 of Cycle 2), cumulative or late toxicities that occur beyond the first 
cycle may be considered in determination of the RP2Ds.  Prior to opening the R/R FL 
expansion phase, the Clinical Study Team and the Medical Monitor will review the 
cumulative data, recommend the RP2D, and review this with the IMC for approval.   
FIGURE 3:  Overall Follicular Lymphoma Dose-Escalation Plan 
The Figure 3 title has been revised to specify the FL group. 
TABLE 3:  Follicular Lymphoma Dose-Escalation Cohorts  
The Table 3 title has been revised to specify the FL group. 
SECTION 3.1.2.2:  Follicular Lymphoma Expansion Phase 
The expansion phase is designed to further assess the safety and efficacy of 
polatuzumab vedotin and venetoclax at their respective RP2Ds when combined with a 
fixed dose of obinutuzumab in FL patients.   
Approximately 80 patients (40 patients with FL and 40 patients with DLBCL) will be 
enrolled during the expansion phase and treated as described below. 
All patients enrolled in the expansion phase will receive induction treatment, 
administered in 21-day cycles as outlined in Table 4.  When study treatments are given 


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on the same day, they will be administered sequentially in the following order:  
venetoclax, obinutuzumab, and polatuzumab vedotin. 
After completion of induction treatment, patients will continue to receive daily venetoclax 
treatment (during Month 1) until response is assessed at EOI.  Venetoclax will be 
discontinued if response assessments at EOI indicate that a patient is not eligible for 
post-induction treatment.  Patients with DLBCL who achieve a CR or PR at EOI will 
receive post induction treatment (referred to as consolidation) with obinutuzumab and 
venetoclax, and patientsPatients with FL who achieve a CR, PR, or SD at EOI will 
receive post-induction treatment (referred to as maintenance) with obinutuzumab and 
venetoclax, as outlined in Table 5.  Polatuzumab vedotin will not be given as post-
induction treatment.  Post-induction treatment will continue until disease progression or 
unacceptable toxicity for up to 8 months for consolidation treatment or 24 months for 
maintenance treatment.  When study treatments are given on the same day, venetoclax 
will be administered prior to obinutuzumab.   
The schedules of assessments are provided in Appendix 1 (FL). and Appendix 2 
(DLBCL).  
TABLE 4:  Induction Treatment for the Follicular Lymphoma Expansion 
Phase 
The Table 4 title has been revised to specify that the treatment is relevant to the FL 
group. 
TABLE 5:  Post-Induction Treatment for the Follicular Lymphoma 
Expansion Phase 
The Table 5 title has been revised to specify that the treatment is relevant to the FL 
group.  In addition, the treatment information about the consolidation treatment for 
patients with DLBCL has been removed. 
SECTION 3.1.3:  Rituximab Plus Polatuzumab Vedotin Plus Venetoclax 
Treatment Group (Patients with DLBCL) (NEW SECTION) 
Based on the safety and efficacy results from the Phase III study (BO21005) in patients 
with DLBCL, the protocol has been amended to explore dose-finding of venetoclax in 
combination with fixed doses of polatuzumab vedotin and rituximab instead of 
obinutuzumab for patients with R/R DLBCL.   
SECTION 3.1.3.1:  Dose-Escalation Phase in Relapsed or Refractory 
DLBCL Patients (NEW SECTION) 
The DLBCL dose-escalation phase will open with the purpose of identifying the RP2D 
for venetoclax when combined with polatuzumab vedotin at 1.8 mg/kg and rituximab at 
375 mg/m2 as induction treatment in patients with R/R DLBCL.  The dose escalation 
will initiate at the venetoclax 400-mg dose level and increase through Cohorts A, B, 
and C (see Figure 4).   


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Approximately 12−18 patients will be enrolled in the DLBCL dose-escalation phase.  
Cohorts of 3−6 patients each will be treated in accordance with the treatment regimens 
and dose-escalation rules described in Section 3.1.3.1.2. 
Patients will be closely monitored for adverse events during the DLT assessment 
window, defined as the first treatment cycle (from Day 1 of Cycle 1 to Day 1 of Cycle 2).  
Adverse events meeting the criteria for DLT, as defined above (see Section 3.1.2.1.1), 
will be reported to the Sponsor within 24 hours (see Section 5.4.2).  
Patients who discontinue from the study prior to completing the DLT assessment 
window for reasons other than a DLT will be considered non-evaluable for 
dose-escalation decisions and RP2D assessments and will be replaced by an additional 
patient at that same dose level.  Patients who miss one dose of polatuzumab vedotin or 
rituximab or five consecutive daily doses of venetoclax during the DLT assessment 
window for reasons other than a DLT will also be replaced and considered 
non-evaluable for dose-escalation decisions.  Patients who receive supportive care 
during the DLT assessment window that may confound the evaluation of DLTs may be 
replaced at the discretion of the Medical Monitor. 
Patients will receive induction treatment with R + Pola + V for a total of six cycles.  
Patients achieving a CR or PR at EOI will be eligible to receive consolidation treatment 
with R + V.  A study schema is provided in Figure 2.   
SECTION 3.1.3.1.1:  Treatment Regimens for DLBCL Dose-Escalation 
Phase (NEW SECTION) 
Patients enrolled in the DLBCL dose-escalation phase will receive induction treatment, 
administered in 21-day cycles as shown in Table 6.  When study treatments are given 
on the same day, they will be administered sequentially in the following order:  
venetoclax, rituximab, and polatuzumab vedotin.   
After completion of induction treatment, patients will continue to receive daily 
venetoclax treatment (during Month 1) until response is assessed at EOI.  Venetoclax 
will be discontinued if response assessments at EOI indicate that a patient is not 
eligible for post-induction treatment (referred to as consolidation).  Patients who 
achieve a CR or PR at EOI will receive consolidation treatment with rituximab and 
venetoclax, as outlined in Table 7.  Polatuzumab vedotin will not be given as 
consolidation treatment.  Consolidation treatment will continue until disease 
progression or unacceptable toxicity for up to 8 months.  When study treatments are 
given on the same day, venetoclax will be administered prior to rituximab.   
TABLE 6:  Induction Treatment for the DLBCL Dose-Escalation Phase 
Table 6 has been added.  Subsequent tables have been renumbered accordingly. 


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TABLE 7:  Consolidation Treatment for the DLBCL Dose-Escalation 
Phase 
Table 7 has been added.  Subsequent tables have been renumbered accordingly. 
SECTION 3.1.3.1.2:  Dose-Escalation Phase Rules (NEW SECTION) 
A standard 3 + 3 dose-escalation schema will be used.  The rituximab and polatuzumab 
dose levels will remain fixed during the dose-escalation phase and only the venetoclax 
will be dose escalated.  The polatuzumab dose of 1.8 mg/kg is based on ongoing Phase II 
trials (see Sections 1.3.2 and 3.3.3.3).  Intrapatient dose escalation is not allowed.  The 
overall DLBCL dose-escalation plan is depicted in Figure 4 and Table 8. 
Dose escalation will occur in accordance with the rules listed below. 
• 
A minimum of 3 patients will initially be enrolled in each cohort.  The first 
3 patients in each cohort will be sequentially enrolled and dosed at least 48 hours 
apart.   
• 
If none of the first 3 DLT-evaluable patients experiences a DLT, the doses in that 
cohort will be deemed safe and tolerable and escalation may continue per the 
dose-escalation plan described above. 
• 
If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will 
be expanded to 6 patients.  If there are no further DLTs in the first 
6 DLT-evaluable patients, the doses in that cohort will be deemed safe and tolerable 
and escalation may continue per the dose-escalation plan described above. 
• 
If a DLT is observed in ≥ 33% of patients (e.g., 2 or more of up to 6 DLT-evaluable 
patients), the dose combination at which this occurs will be considered intolerable 
and the MTD will have been exceeded for venetoclax in the R + Pola + V treatment 
combination.   
• 
If the MTD is exceeded in any cohort, the highest dose combination at which < 33% 
of patients (e.g., 2 of 6 DLT-evaluable patients) experience a DLT will be declared 
the combination MTD (i.e., the MTD venetoclax in the R + Pola + V treatment 
combination). 
• 
If the MTD is not exceeded at any dose level, the highest dose combination 
administered in this study will be declared the maximum administered dose for 
polatuzumab vedotin and venetoclax in the R + Pola + V treatment combination. 
 
If the MTD is exceeded in any cohort, de-escalation of the venetoclax dose and/or 
polatuzumab vedotin dose, and/or adjustment of treatment schedules (e.g., venetoclax 
treatment on Days 1−10) may occur.  Additional patients may be enrolled in a given 
cohort in the absence of DLTs to acquire additional safety data for the appropriate dose 
levels in the expansion phase of the study. 
On the basis of a review of real-time safety data and available preliminary PK data, 
dose escalation may be halted or modified by the Sponsor as deemed appropriate. 


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Relevant demographic, adverse event, laboratory, dosing administration/intensity, and 
PK (if available) data will be reviewed prior to dose-escalation decisions, which will be 
made by the Medical Monitor in consultation with the Principal Investigator and 
participating investigators. 
Although the DLT assessment window is defined as the first treatment cycle (from 
Day 1 of Cycle 1 to Day 1 of Cycle 2), cumulative or late toxicities that occur beyond 
the first cycle may be considered in determination of the RP2Ds.  Prior to opening the 
R/R DLBCL expansion phase, the Clinical Study Team and the Medical Monitor will 
review the cumulative data, determine the RP2D, and review this information with the 
IMC for approval.   
FIGURE 4:  DLBCL Dose-Escalation Plans 
Figure 4 has been added.  Subsequent figures have been renumbered accordingly. 
TABLE 8:  DLBCL Dose-Escalation Cohorts 
Table 8 has been added.  Subsequent tables have been renumbered accordingly. 
SECTION 3.1.3.2:  DLBCL Expansion Phase (NEW SECTION) 
The expansion phase is designed to further assess the safety and efficacy of venetoclax 
when combined with a fixed dose of rituximab and polatuzumab vedotin in DLBCL 
patients.  
Approximately 40 patients with DLBCL will be enrolled during the expansion phase 
and treated as described below. 
All patients enrolled in the expansion phase will receive induction treatment as 
outlined in Table 9.  When study treatments are given on the same day, they will be 
administered sequentially in the following order:  venetoclax, rituximab, and 
polatuzumab vedotin. 
After completion of induction treatment, patients will continue to receive daily 
venetoclax treatment (during Month 1) until response is assessed at EOI.  Venetoclax 
will be discontinued if response assessments at EOI indicate that a patient is not 
eligible for post-induction treatment.  Patients with DLBCL who achieve a CR or PR at 
EOI will receive post-induction treatment (referred to as consolidation) with rituximab 
and venetoclax, as outlined in Table 10.  Polatuzumab vedotin will not be given as post-
induction treatment.  Post-induction treatment will continue until disease progression 
or unacceptable toxicity for up to 8 months for consolidation treatment.  When study 
treatments are given on the same day, venetoclax will be administered prior to 
rituximab.   
TABLE 9:  Induction Treatment for the DLBCL Expansion Phase 
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TABLE 10:  Consolidation Treatment for the DLBCL Expansion Phase 
Table 10 has been added.  Subsequent tables have been renumbered accordingly. 
SECTION 3.2:  END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the time when both of the following criteria are met:  
• 
All enrolled FL patients have been followed for at least 90 days after they have 
completed or discontinued study treatment (including induction treatment and 
maintenance treatment as applicable).    
• 
All enrolled DLBCL patients have been followed for at least 1 year after they have 
completed or discontinued study treatment (including induction treatment and 
consolidation treatment as applicable).   
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4.5 years. 
SECTION 3.3.1:  Rationale for Patient Population 
As discussed in Section 1.1.1, despite significant therapeutic progress with the use of 
chemoimmunotherapy as first-line treatment, FL remains essentially an incurable 
disease.  Patients invariably relapse, and active and well-tolerated agents are needed 
following relapse.  DLBCL can be cured in > 50% of cases; however, up to one-third of 
patients have refractory disease of relapse after treatment.  Success rates with salvage 
therapy and autologous transplantation are poor, which highlights the urgent need for 
novel therapeutic approaches for these patients. 
On the basis of a compelling biologic and clinical rationale, as presented in Section 1.5 
the addition of polatuzumab vedotin to obinutuzumab or rituximab and venetoclax is a 
promising approach to expand the number of patients with R/R FL and DLBCL who 
achieve remission and to prolong the duration of response in these patients. 
The study will include an initial dose-escalation phase followed by an expansion phase.  
The objective of the dose-escalation phase is to define the RP2D for venetoclax and the 
RP2D for polatuzumab vedotin when given with obinutuzumab in patients with R/R FL 
and the RP2D for venetoclax when given in combination with polatuzumab at 
1.8 mg/kg and rituximab at 375 mg/m2 in patients with R/R DLBCL.  Although the DLT 
assessment window is the first cycle of treatment, long-term or cumulative toxicities will 
also be assessed and considered for the dose definition.  As relapsed or refractory 
DLBCL has a more aggressive course, with an expected higher risk of early progression 
than FL, patients with DLBCL will not be enrolled in the dose escalation phase, in an 
attempt to minimize the number of patients not evaluable for DLTs and increase the 
chances for assessing toxicities with later onset during treatment.  
SECTION 3.3.2:  Rationale for the Triplet Combination 
This study combines treatments with different mechanisms of action that have 
demonstrated clinical activity against B-cell lymphoma.  Refer to Appendix 12 for 
descriptions of clinical studies that use the study drugs as single or doublet treatment.  


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As mentioned in Section 1.5, there is a strong rationale to expect an improved 
benefit-risk profile with the triplet combination of obinutuzumab, or rituximab combined 
with polatuzumab vedotin, and venetoclax.  This novel triplet regimen may have the 
potential to extend treatment-free remissions and decrease toxicity by improving upon 
individual agents in the current standard of care.  Overlapping toxicities are anticipated 
and expected to be manageable in the clinical setting (see Section 5.1.6). 
Rituximab is established as a standard of care to treat B-cell lymphomas.  As discussed 
in Section 1.4, the development of obinutuzumab in B-cell malignancies is based on the 
hypothesis that obinutuzumab will be a superior anti-CD20 agent compared to 
rituximab in patients with FL.  This has been demonstrated in CLL (Goede et al. 2014) 
and has been studied in two additional Phase III studies in DLBCL (Study BO21005) 
and FL (Study BO21223).   
Study BO21223 investigated obinutuzumab plus chemotherapy (G-benda, G-CVP, 
G-CHOP) compared with rituximab plus chemotherapy, followed by obinutuzumab or 
rituximab maintenance in patients with previously untreated iNHL (FL cohort, 
n = 1202) and demonstrated positive results, showing a significant improvement in PFS 
in the obinutuzumab chemotherapy arm.   
Study BO21005 investigated obinutuzumab plus CHOP (G-CHOP) compared with 
rituximab plus CHOP (R-CHOP) in patients with previously untreated DLBCL, and 
this study did not meet its primary endpoint of PFS at final analysis.   
On the basis of the results of these Phase III studies evaluating obinutuzumab in 
combination with chemotherapy in both FL and DLBCL, current protocol amendment 
patients with R/R FL will continue to receive obinutuzumab in combination with 
polatuzumab vedotin and venetoclax, while patients with R/R DLBCL will instead 
receive rituximab in combination with polatuzumab vedotin and venetoclax.   
SECTION 3.3.3.1:  Rationale for Obinutuzumab Dosing Regimen in 
Follicular Lymphoma Patients 
The dose and schedule of obinutuzumab in the induction regimen for FL patients will be 
1000 mg intravenously (IV) on Days 1, 8, and 15 of Cycle 1 and Day 1 of each 
subsequent 21-day cycle (Cycles 2−6).  This is based on the recommended dose and 
schedule (6−8 cycles depending on the trial) of obinutuzumab in the ongoing Phase III 
program in patients with NHL.  For this protocol, patients will be treated for 6 cycles 
during the induction phase.   
The dose and schedule of obinutuzumab in the maintenance regimen (FL) will be 
1000 mg IV administered every 2 months for 2 years.  This dosing administration is 
based on the obinutuzumab maintenance regimen that was administered in the Phase III 
GAO4753g study (Sehn et al. 2015).  The dose and schedule of obinutuzumab in the 
consolidation regimen (DLBCL) will be 1000 mg IV administered every 2 months for up 


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to 6 months.  The consolidation regimen was modeled after the FL maintenance therapy.  
The GAO4753g study showed that bendamustine and obinutuzumab followed by 
obinutuzumab maintenance was associated with superior PFS compared with 
bendamustine alone (median PFS had not been reached in the obinutuzumab plus 
bendamustine followed by obinutuzumab maintenance arm vs. 14.9 months in the 
bendamustine arm; stratified HR = 0.55; 95% CI: 0.40, 0.74; p = 0.0001, by log-rank test). 
SECTION 3.3.3.2.1:  Rationale for Polatuzumab Vedotin Dose in Follicular 
Lymphoma Patients 
For this study, dose escalation of polatuzumab vedotin for R/R FL patients will begin at 
a dose level of 1.4 mg/kg (one dose level below the highest polatuzumab vedotin dose 
currently under development) and will escalate to a final dose of 1.8 mg/kg, if tolerated.  
The polatuzumab vedotin dosing for this studythe FL dose escalation phase is based on 
the experience from the Phase I study (DCS4968g) with single−agent polatuzumab 
vedotin and the Phase II study (GO27834) with polatuzumab vedotin in combination with 
rituximab in patients with R/R NHL, the majority of whom had R/R FL or DLBCL.  Most 
evidence of anti-tumor activity was observed at doses ≥ 1.8 mg/kg alone or in 
combination with rituximab (Advani et al. 2015; Palanca-Wessels et al. 2015).   
The combination of obinutuzumab with polatuzumab vedotin is being evaluated in 
several ongoing studies (see Table 11) including two Phase Ib/II trials in patients with 
R/R FL and R/R DLBCL and in R/R NHL and previously untreated DLBCL.   
In Study GO29044, the starting dose of polatuzumab vedotin is was 1.4 mg/kg and will 
be was escalated to 1.8 mg/kg, if tolerated, when combined in combination with G-CHP.  
In study GO29365, the starting dose of polatuzumab vedotin is 1.8 mg/kg when 
combined with G-bendamustine.  Since polatuzumab vedotin is being combined with 
obinutuzumab and chemotherapy (CHP or bendamustine) at 1.4 mg/kg or 1.8 mg/kg, 
dose escalation of polatuzumab vedotin for the patients with R/R FL in this study will 
begin at a dose level of 1.4 mg/kg (1 dose level below the highest allowed polatuzumab 
vedotin dose) and will escalate to a final dose of 1.8 mg/kg, if tolerated.  This novel triplet, 
G + Pola + V, substitutes out the standard chemotherapy components with venetoclax, 
which in this combination may have the potential to extend treatment-free remissions 
and decrease toxicity, compared to combinations with standard chemotherapy 
components. 
TABLE 11:  Polatuzumab Vedotin plus Obinutuzumab-Containing 
Regimens for the Treatment of Follicular Lymphoma 
Table 11 has been revised to include follicular lymphoma and delete the R/R DLBCL 
population treatment information.   


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SECTION 3.3.3.2.2:  Rationale for Polatuzumab Vedotin Dose in DLBCL 
Patients 
On the basis of the preliminary data from the DLBCL patients treated in Studies 
GO29044 and GO29365 at the dose level of polatuzumab vedotin at 1.8 mg/kg, this 
dose has been shown to be safe and tolerable in combination with rituximab and 
chemotherapy.   
Due to the aggressive nature of DLBCL and the evidence that anti-tumor activity was 
observed at doses ≥ 1.8 mg/kg alone or in combination with rituximab, the higher dose 
level of polatuzumab vedotin is preferredto maximize clinical benefit for the 
R/R DLBCL population, which has no standard of care.   
The safety profile of rituximab differs slightly in comparison with obinutuzumab and is 
expected to be tolerated when combined with polatuzumab vedotin and venetoclax.  In 
this amdendment, the R/R DLBCL dose-escalation phase will start at the dose level of 
1.8 mg/kg and only the venetoclax dose will be escalated to determine an RP2D in this 
population.    
SECTION 3.3.3.2.3:  Rationale for Polatuzumab Vedotin Dosing Schedule 
in Follicular Lymphoma and DLBCL Patients 
The number of induction cycles (six 21-day cycles) of this regimen (G + Pola + V) that will 
be evaluated in this study is similar to is in line with other anti-CD20 plus polatuzumab 
vedotin regimens studied in R/R NHL.   
SECTION 3.3.3.3:  Rationale for Venetoclax Dosing Regimen 
In patients with R/R FL, the starting dose of venetoclax in this study will be 200 mg.  
Because a case of laboratory TLS in a FL patient treated in this trial at a dose level of 
400 mg venetoclax and 1.4 mg/kg polatuzumab has been observed, the lower venetoclax 
dose level cohort of 200 mg was added in order to collect additional safety information 
for this novel triplet combination.  Given that venetoclax will be given in conjunction with 
obinutuzumab and polatuzumab vedotin, potentially resulting in synergistic toxicities, 
doses of venetoclax up to the MTD achieved when given as monotherapy may not be 
tolerable in this combination.  Following the 200 mg Cohort 1a clearing, subsequent 
dose cohorts will explore progressively higher starting and target doses up to a final daily 
dose of 800 mg if tolerated.  The number of cycles of dosing (six 21-day cycles) is 
designed to provide a treatment duration consistent with other therapies for NHL that 
have been shown to be sufficient to provide durable responses. 
In patients with R/R DLBCL, the starting dose of venetoclax in the dose-escalation 
phase will be 400 mg (Figure 4).  Ongoing studies in the DLBCL population have 
confirmed that the TLS risk with doses up to 800 mg is low.  No cases of TLS occurred 
in DLBCL patients in a trial with 800 mg venetoclax given intermittently at 
Days 4−10 of Cycle 1 and Days 1−10 of Cycles 2−8 in combination with R-CHOP 
(Zelenetz et al. 2016).   The duration of venetoclax dosing is designed to provide 


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overlapping exposure with obinutuzumab or rituximab.  Extended dosing of venetoclax 
up to 1 year with obinutuzumab or rituximab will allow exploration of whether additional 
activity is observed during the extended (post-induction) dosing period. 
SECTION 3.3.3.4:  Rationale for Treatment Duration 
Patients with R/R DLBCL who are not suitable for or do not benefit from consolidative 
autologous transplantation exhibit a poor prognosis.  Responses obtained with different 
rituximab treatment regimens tested in clinical trials (e.g., rituximab in combination with 
bendamustine, with gemcitabine plus oxaliplatin, or with lenalidomide) have been of 
short duration, with the longest reported median PFS of approximately 7 months 
observed in one study of BR (Ohmachi et al. 2013).  Thus, 86 months of consolidation 
treatment, for a total treatment duration of approximately 12 months, is considered to be 
a reasonable exploratory therapeutic approach in patients with R/R DLBCL with an 
anticipated positive benefit-risk ratio.  On the basis of the complementary mechanism of 
action between all 3 study drugs and considering the aggressiveness of R/R DLBCL, the 
study was designed to investigate the safety and efficacy of the triple combination in the 
consolidation setting. 
SECTION 4.1.1:  Inclusion Criteria 
• 
For patients enrolled in the dose escalation phaseFor G + Pola + V treatment group:  
R/R FL after treatment with at least 1 prior chemoimmunotherapy regimen that 
included an anti-CD20 monoclonal antibody and for which no other more 
appropriate treatment option exists, as determined by the investigator 
• 
For patients enrolled in the expansion phase:  B cell lymphoma classified as 
either of the following: 
 
R/R FL after treatment with at least 1 prior chemoimmunotherapy regimen 
that included an anti CD20 monoclonal antibody and for which no other more 
appropriate treatment option exists, as determined by the investigator 
• 
ForR + Pola + V treatment group:  R/R DLBCL after treatment with at least 1 prior 
chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody, 
with no curative option as determined by the investigator 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and for at least 12 months after the 
last dose of polatuzumab vedotin, 30 days after the last dose of venetoclax, and 
12 months after last dose of rituximab, or at least 18 months after the last dose of 
obinutuzumab. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 


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contraceptives that inhibit ovulation, hormone-releasing intrauterine devices 
(IUDs), and copper IUDs. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• 
For men:  Agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures and agreement to refrain from donating sperm, as 
defined below: 
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of < 1% per year during the treatment period and for at least 
5 months after the last dose of polatuzumab vedotin, 30 days after the last dose 
of venetoclax, and 3 months after the last dose of obinutuzumab or rituximab.  
Men must refrain from donating sperm for the same period. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 5 months after the last dose of 
polatuzumab vedotin, 30 days after the last dose of venetoclax, and 3 months 
after the last dose of obinutuzumab or rituximab.   
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
SECTION 4.1.2:  Exclusion Criteria 
• 
Prior standard or investigational anti-cancer therapy as specified below: 
– 
Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1 
– 
Monoclonal antibody or ADC therapy within 5 half-lives or 4 weeks prior to 
Day 1 of Cycle 1, whichever is longer 
– 
Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule 
therapy within 2 weeks prior to Day 1 of Cycle 1 
• 
Known sensitivity or allergy to murine products or any component of the 
obinutuzumab, rituximab, polatuzumab vedotin, or venetoclax formulations 
• 
Active bacterial, viral, fungal, or other infection  
Caution should be exercised when considering the use of obinutuzumab and 
rituximab in patients with a history of recurring or chronic infections. 
 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT 
This is a Phase Ib/II, open-label, multicenter, non-randomized study of G + Pola + V in 
patients with R/R FL or and R + Pola + V in patiens with R/R DLBCL.  During the 
dose-escalation phase, patients will be assigned to cohorts with varying polatuzumab 
vedotin (R/R FL dose-finding only) and venetoclax dose combinations, through use of 


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an interactive voice or Web-based response system (IxRS).  During the FL expansion 
phase, all patients will be treated at RP2Ds for polatuzumab vedotin and venetoclax.  If 
more than one combination of RP2Ds is identified, patients will be enrolled into multiple 
cohorts to allow for those combinations to be evaluated during the expansion phase.  
Post-induction treatment (for eligible patients only) will depend on lymphoma histology.  
Patients with FL will receive maintenance treatment with obinutuzumab and venetoclax 
for 24 months, and patients with DLBCL will receive consolidation treatment with 
obinutuzumabrituximab and venetoclax for 8 months (see Section 3.1 for details).  
Patients enrolled in the dose-escalation phase and expansion phase will receive fixed 
doses of obinutuzumab or rituximab. 
SECTION 4.3:  STUDY TREATMENTS  
The investigational medicinal products (IMPs) for this study are obinutuzumab, 
rituximab, polatuzumab vedotin, and venetoclax. 
SECTION 4.3.1.2:  Rituximab (NEW SECTION) 
Rituximab will be supplied by the Sponsor as an IMP.  Rituximab is packaged in 10-mL 
(100-mg) and 50-mL (500-mg) single-dose, pharmaceutical-grade glass vials at a 
concentration of 10 mg/mL of protein.  The antibody is formulated for IV injection as a 
sterile product in a solution of sodium chloride (pH 6.5) containing polysorbate 80 and 
sodium citrate.  For information on the formulation and handling of rituximab, see the 
pharmacy manual and the Rituximab Investigator's Brochure. 
SECTION 4.3.2:  Dosage, Administration, and Compliance 
Patients enrolled in the dose-escalation phase or the expansion phase will receive six 
21-day cycles of induction treatment with obinutuzumab or rituximab, polatuzumab 
vedotin, and venetoclax.  When study treatments are given on the same day, they will be 
administered sequentially in the following order:  venetoclax, obinutuzumab or rituximab, 
and polatuzumab vedotin.  
After completion of induction treatment, patients in both phases will continue to receive 
daily venetoclax treatment (during Month 1) until response is assessed at EOI.  However, 
venetoclax will be discontinued if response assessments at EOI indicate that a patient is 
not eligible for post-induction treatment.   
During both phases, patients with DLBCL who achieve a CR or PR at EOI will receive 
post-induction treatment (referred to as consolidation) with venetoclax and 
obinutuzumabrituximab for 8 months, and patients with FL who achieve a CR, PR, or 
SD at EOI will receive post-induction treatment (referred to as maintenance) with 
venetoclax for 8 months and obinutuzumab for 24 months.  When study treatments are 
given on the same day, venetoclax will be administered prior to obinutuzumab or 
rituximab. 


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FIGURE 5:  Induction and Post-Induction Treatment Regimens 
Figure 5 has been revised to more fully distinguish between the FL and DLBCL 
treatment groups. 
SECTION 4.3.2.1:  Obinutuzumab 
Obinutuzumab will be administered by IV infusion at an absolute (flat) dose of 1000 mg 
on Days 1, 8, and 15 of the first cycle and on Day 1 of each subsequent cycle during 
induction treatment, and on Day 1 of every other month (i.e., every 2 months) during 
consolidation (eligible patients with DLBCL only) or maintenance treatment (eligible 
patients with FL only).  A month is defined as 28 days. 
FIGURE 7:  Guidelines for Obinutuzumab Infusions:   Second and 
Subsequent Infusions  
Figure 7 has been revised to differentiate between the levels of IRR. 
SECTION 4.3.2.2:  Rituxumab (NEW SECTION) 
Rituximab will be administered by IV infusion at the dose of 375 mg/m2 on Day 1 of 
Cycles 1−6 during induction treatment and on Day 1 of every other month (i.e., every 
2 months) during consolidation treatment for patients with R/R DLBCL.   
Body surface area (BSA) will be determined at screening and should be used to 
calculate the dose of rituximab throughout the study unless the patient’s weight 
increases or decreases by > 10% from screening, in which case BSA should be 
recalculated and used for subsequent dosing.  In obese patients (defined as body mass 
index ≥ 30 kg/m2), there is no BSA cap and actual body weight, not adjusted weight, is 
recommended.  Empiric dose adjustment for obese patients may be implemented per 
institutional guidelines. 
The infusion of rituximab may be split over 2 days if the patient is at increased risk for 
an IRR (high tumor burden or high peripheral lymphocyte count).  Administration of 
rituximab may be continued on the following day, if needed, for patients who experience 
an adverse event during the rituximab infusion.  
If a dose of rituximab is split over 2 days, both infusions must occur with appropriate 
premedication (see Section 4.3.2.5) and at the first infusion rate (see Table 12). 
Rituximab infusions will be administered according to the instructions in Table 12.  
If a patient tolerates the first cycle of study treatment without significant infusion 
reactions, rituximab may be administered as a rapid infusion (over 60−90 minutes) in 
accordance with local institutional guidelines. 
During the treatment period, rituximab must be administered to patients in a setting 
where full emergency resuscitation facilities are immediately available.  Patients should 
be under close supervision of the investigator at all times.  


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Rituximab should be administered as a slow IV infusion through a dedicated line.  After 
the end of the first infusion, the IV line or central venous catheter should remain in 
place for ≥ 2 hours in order to administer IV drugs, if necessary.  If no adverse events 
occur after 2 hours, the IV line may be removed or the central venous catheter may be 
de-accessed.  For subsequent infusions, the IV line or central venous catheter should 
remain in place for at least 1 hour after the end of the infusion.  If no adverse events 
occur after 1 hour, the IV line may be removed or the central venous catheter may be 
de-accessed. 
No dose modification for rituximab is allowed.  Guidelines for treatment delays or 
discontinuation are provided in Section 5.1.7. 
Premedication with a corticosteroid, analgesic/antipyretic, and antihistamine, as 
outlined in Section 4.3.2.5, is required to reduce the incidence and severity of IRRs.  
For anaphylaxis precautions, see Appendix 9. 
TABLE 12:  Administration of First and Subsequent Infusions of 
Rituximab  
Table 12 has been added.  Subsequent tables have been renumbered accordingly. 
SECTION 4.3.2.3:  Polatuzumab Vedotin 
DuringFor R/R FL, during the dose-escalation phase, the dose of polatuzumab vedotin 
for each patient will depend on dose assignment (1.4 or 1.8 mg/kg).  During the 
expansion phase, the dose of polatuzumab vedotin for each patient will depend on the 
RP2D established during the dose-escalation phase.  For R/R DLBCL, during the 
dose-escalation phase and the expansion phase, the dose of polatuzumab vedotin will be 
fixed at 1.8 mg/kg.  Polatuzumab vedotin will be administered by IV infusion on Day 1 of 
each cycle, during induction treatment only. 
SECTION 4.3.2.4:  Venetoclax 
All patients who receive venetoclax must receive prophylaxis for TLS (see Section 5.1.6) 
before the initiation of venetoclax in the G + Pola + V and R + Pola + V combination 
treatment.  Patients who receive venetoclax who are at high risk for TLS or with 
compromised renal function must be hospitalized on the first day of Cycle 1 (see 
Section 5.1.6.2). 
TABLE 13:  Premedication  
Table 13 has been revised to detail premedication and administration on Cycle 1 
(Days 8 and 15) and Cycle 2 and beyond (Day 1). 
SECTION 4.3.3:  Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (obinutuzumab, rituximab, polatuzumab 
vedotin, and venetoclax) will be provided by the Sponsor.  The study site will 
acknowledge receipt of IMPs using the IxRS to confirm the shipment condition and 
content.  Any damaged shipments will be replaced. 


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SECTION 4.3.4:  Post-Trial Access to Obinutuzumab, Rituximab, 
Polatuzumab Vedotin, and Venetoclax 
Currently, the Sponsor does not have any plans to provide obinutuzumab, rituximab, 
polatuzumab vedotin, venetoclax, or any other study treatments or interventions to 
patients who have completed the study.  The Sponsor will evaluate whether to continue 
to provide obinutuzumab, rituximab, polatuzumab vedotin, and venetoclax in 
accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, available at the following Web site: 
SECTION 4.4.2:  Prohibited and Cautionary Therapy for Concomitant 
Medications 
Use of the following therapies (excluding protocol-specified treatments) is prohibited 
during the study: 
• 
Any anti-cancer therapy, approved or investigational, other than intrathecal CNS 
prophylaxis 
• 
Hormonal therapy other than contraceptives, stable hormone-replacement therapy, 
or megestrol acetate 
• 
Biologic agents other than hematopoietic growth factors (as described in 
Section 4.4.1) 
• 
Vaccination with live vaccines is not recommended during treatment with 
obinutuzumab or rituximab and until B-cell recovery 
 
SECTION 4.5.6:  Laboratory, Biomarker, and Other Biological Samples 
 
[…] 
Central Laboratory Assessments 
The following samples will be sent to one or several Sponsor-designated central 
laboratories or to the Sponsor for analysis: 
• 
Serum samples for rituximab PK analysis using a validated assay 
 
[…] 
Samples collected for PK and immunogenicity analyses may be used for PK assay 
development purposes and additional safety and immunogenicity assessments, as 
appropriate. 
Biological samples will be destroyed when the final clinical study report (CSR) has been 
completed, Unless the patient gives specific consent for thehis or her leftover samples to 
be stored for optional exploratory research, biological samples will be destroyed when 
the final Clinical Study Report has been completed, with the following exception(s): 
Serum (or plasma) samples collected for PK and immunogenicity (ATA) analysis may 
be needed for additional PK and ATA assay development and validation, and additional 


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immunogenicity characterization; therefore, these samples will be destroyed no later 
than 5 years after the final Clinical Study Report has been completed (see Section 4.5.8). 
SECTION 4.5.8.3:  Sample Collection 
The following samples and derivatives thereof (e.g., DNA, RNA, proteins, peptides) will 
be collected for research purposes, including but not limited to research on dynamic 
(non-inherited) and genetic (inherited) biomarkers related to obinutuzumab, rituximab, 
polatuzumab vedotin, venetoclax, or other types of cancer: 
• 
Peripheral blood (i.e., whole blood) 
• 
Remaining tumor tissue from lymph node biopsy (archival and/or fresh biopsy) 
• 
Remaining peripheral blood (e.g. whole blood, PBMCs, plasma, and serum) 
 
SECTION 4.6.2:  Study Treatment Discontinuation 
Patients who discontinue study treatment will not be replaced, except as outlined below: 
• 
During the dose-escalation phase, patients who discontinue study treatment prior to 
completion of the DLT assessment window for reasons other than a DLT will be 
replaced by an additional patient at that same dose level. 
• 
During the expansion phase, patients who discontinue study treatment prior to 
receiving at least one dose of each component of the combination will be replaced. 
• 
Patients who discontinue before having received at least one dose of each 
component of the combination will be replaced. 
 
SECTION 5.1:  SAFETY PLAN 
Venetoclax and pPolatuzumab vedotin are is not a marketed products, and 
venetoclaxobinutuzumab is not approved for R/R FL or DLBCL.  Obinutuzumab is only 
approved in combination with bendamustine for the treatment of R/R FL and rituximab 
is not approved for the treatment of R/R DLBCL.  Clinical development is ongoing.  The 
safety plan for patients in this study is based on clinical experience with obinutuzumab, 
rituximab, polatuzumab vedotin, and venetoclax in completed and ongoing studies.  The 
anticipated important safety risks of obinutuzumab, rituximab, polatuzumab vedotin, and 
venetoclax are outlined below.  Please refer to the Obinutuzumab, Rituximab, 
Polatuzumab Vedotin, and Venetoclax Investigator's Brochures for a complete summary 
of safety information.  
SECTION 5.1.1:  Risks Associated with Obinutuzumab 
As of the safety cutoff date of October 2014To date, the following adverse events are 
considered to be important identified risks associated with obinutuzumab:  IRRs, TLS, 
thrombocytopenia (including acute thrombocytopenia), neutropenia (including prolonged 
and late-onset neutropenia), infections (including PML and HBV reactivation), prolonged 
B-cell depletion, impaired immunization response, worsening of preexisting cardiac 
conditions, and gastrointestinal perforation. 


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SECTION 5.1.1.6:  Impaired Immunizations Response 
The safety of immunization with live virus or attenuated viral vaccines following 
obinutuzumab therapy has not been studied, and.  Thus, vaccination with live virus 
vaccines is not recommended during treatment and until B-cell recovery. 
SECTION 5.1.2:  Risks Associated with Rituximab (NEW SECTION) 
The following adverse events are considered to be important risks associated or 
potentially associated with rituximab:  IRRs, infections (including severe infections), 
progressive multifocal leukoencephalopathy (PML), Hepatitis B reactivation, 
neutropenia (including prolonged neutropenia), TLS, impaired immunization response, 
severe skin reactions (Stevens-Johnson syndrome/toxic epidermal necrolysis), and GI 
perforation.  Details for these risks are provided below; refer to the rituximab 
Investigator’s Brochure for full information. 
SECTION 5.1.2.1:  Infusion-Related Reactions (NEW SECTION) 
Acute IRRs are very common in patients receiving rituximab (occurring in ≥ 10% of 
patients) based on clinical trial experience.  However, serious IRRs are uncommonly 
reported (occurring in ≥ 1 of 1,000 and < 1 of 100 patients) and are rarely fatal 
(occurring in ≥ 1 of 10,000 and <  1 of 1,000 patients).  Most IRRs occur with the first 
administration of rituximab.  Most IRRs are mild to moderate in severity (Grade 1 or 2) 
and can be managed by slowing or stopping the rituximab infusion.  IRRs can be severe 
and, in rare cases, can result in death.  Rituximab-induced IRRs consist of a cluster of 
symptoms and signs occurring during or within 24 hours of a rituximab infusion, 
which may be related to cytokine release and/or other chemical mediators, and these 
acute IRRs overlap with “cytokine release syndrome.”  Anaphylactic and other 
hypersensitivity reactions have been reported following rituximab administration, and 
clinical manifestations of these reactions are similar to cytokine release syndrome.  In 
contrast to cytokine release syndrome, true hypersensitivity reactions typically occur 
within minutes of starting the rituximab infusion. 
SECTION 5.1.2.2:  Infections (Including Serious Infections) (NEW SECTION) 
Serious infections, including fatal bacterial, fungal, and new or reactivated viral 
infections, can occur during and up to 1 year following completion of rituximab-based 
therapy.   
SECTION 5.1.2.3:  Hepatitis B Reactivation (NEW SECTION) 
Reactivation of hepatitis B ranges from asymptomatic reactivations (detected by 
changes in laboratory parameters only) to fulminant liver failure and death.  Patients 
with chronic hepatitis B (HBsAg positive) viral infection are at risk for reactivation 
and will be excluded from the study.  Patients with evidence of prior hepatitis B 
exposure or who are carriers (defined as HBsAg negative and anti-HBcAb positive) are 
at a lower risk for reactivation.  Patients who demonstrate evidence of reactivation 
while receiving an appropriate anti-viral therapy will be discontinued from study 
treatment. 


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SECTION 5.1.2.4:  Progressive Multifocal Leukoencephalopathy 
(NEW SECTION) 
Rare cases of PML have also been reported in patients treated with rituximab alone or 
in combination with other immunosuppressive medications (Goldberg et al. 2002; 
Calabrese et al. 2007; Carson and Bennett 2009).  In a review of 57 patients who 
developed PML after rituximab administration, all patients had received prior therapies 
with alkylating agents, corticosteroids, purine analogs, or drugs to prevent allogeneic 
stem cell or solid-organ graft rejection.  The diagnosis of PML in any patient treated 
with rituximab is rare, but it should be suspected in any patient who develops 
new-onset neurologic manifestations.  The majority of patients with hematologic 
malignancies diagnosed with PML received rituximab in combination with 
chemotherapy or as part of a hematopoietic SCT.  Most cases of PML were diagnosed 
within 12 months of the patients’ last infusion of rituximab. 
SECTION 5.1.2.5:  Neutropenia (Including Prolonged Neutropenia) 
(NEW SECTION) 
Neutropenia is very common in patients receiving rituximab (occurring in ≥ 10% of 
patients) based on clinical trial experience.  However, delayed onset neutropenia is very 
rare (occurring in < 1 of 10,000 patients), and the incidence of prolonged neutropenia is 
unknown.  Neutropenia may lead to serious or overwhelming infection, especially if 
profound (Grade 3−4), prolonged, associated with breaches in natural mucosal barriers 
(e.g., diarrhea and/or mucositis), and/or other immunological defects (e.g., lymphopenia, 
hypogammaglobulinemia, and acquired immunodeficiency syndrome).  Despite an 
increase in incidence of neutropenia and Grade 3−4 neutropenia associated with 
rituximab, most studies have not reported a significant increase in serious neutropenic 
infections. 
SECTION 5.1.2.6:  Tumor Lysis Syndrome (NEW SECTION) 
Patients treated with rituximab may be at risk for TLS.  Severe TLS is very rare in 
patients receiving rituximab (occurring in < 1 of 10,000 patients), based on 
postmarketing experience.  Signs and symptoms (e.g., hyperuricemia, hyperkalemia, 
hypocalcemia, hyperphosphatemia, acute renal failure, and elevated LDH) that are 
consistent with TLS have been reported to occur after the first rituximab IV infusion in 
patients with high numbers of circulating malignant lymphocytes.  A high number of 
circulating malignant cells (≥ 25,000/mm3) or high tumor burden confers a greater risk 
of TLS.  For patients with evidence of TLS, rituximab should be discontinued, and the 
patient should be treated as clinically indicated. 
SECTION 5.1.2.7:  Impaired Immunization Response (NEW SECTION) 
B-cell depletion is expected (and desired) during rituximab therapy and is directly 
related to its mechanism of action.  In theory, peripheral B-cell depletion may reduce 
the effectiveness of immunization, since patients may not be able to mount an effective 
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SECTION 5.1.2.8:  Severe Skin Reactions: Stevens-Johnson Syndrome and Toxic 
Epidermal Necrolysis (NEW SECTION) 
Severe reactions, including fatal mucocutaneous reactions, can occur in patients 
receiving rituximab.  The onset of these reactions in patients treated with rituximab has 
varied from 1 to 13 weeks following rituximab exposure.  The majority of the 
Stevens-Johnson syndrome and toxic epidermal necrolysis cases reported with 
rituximab were associated with additional risk factors.  Fatal outcome also appeared to 
increase in patients who were exposed to multiple risk factors for Stevens-Johnson 
syndrome and toxic epidermal necrolysis. 
SECTION 5.1.2.9:  Gastrointestinal Perforation (NEW SECTION) 
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, can 
occur in patients receiving rituximab in combination with chemotherapy.  In 
postmarketing reports of rituximab, the mean time to documented GI perforation was 
6 days (range:  1−77 days) in patients with NHL. 
SECTION 5.1.3:  Risks Associated with Polatuzumab Vedotin  
The title of this section was revised. 
SECTION 5.1.3.1:  Identified Risks Known Risks:  Neutropenia and 
Peripheral Neuropathy  
The title of this section was revised. 
SECTION 5.1.3.2:  Potential Risks Associated with Polatuzumab Vedotin 
 
[…] 
Progressive Multifocal Leukoencephalopathy  
One case of PML was reported in an 
-year-old female with R/R FL after receiving 
one cycle of polatuzumab vedotin in combination with obinutuzumab and bendamustine.  
MRI showed changes suggestive of PML.  Cerebrospinal fluid test for JCV by 
polymerase chain reaction was negative.  Confounders included previous lines of 
anti-CD20 therapies and concurrent use of obinutuzumab.  Additional details of the 
case can be found in the Polatuzumab Vedotin Investigator’s Brochure.    
Infusion-Related Events 
Because of the potential for infusion reactions, administration of polatuzumab vedotin 
will be performed in a setting with access to emergency equipment and staff who are 
trained to monitor and respond to medical emergencies.  All patients will be monitored 
for infusion reactions during the infusion and immediately afterward (for additional 
instructions on the monitoring and management of infusion reactions, 
see Section 4.3.2.1).  Precautions for suspected anaphylactic reaction during study drug 
infusions are provided in Section 4.3.2.5.  The initial dose of polatuzumab vedotin may 
be administered with premedication with acetaminophen, antihistamines, or 
corticosteroids per institutional standard practice at the discretion of the Investigator.  


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Premedication should be instituted for subsequent doses if IRRs are observed in 
patients who receive their first dose of polatuzumab vedotin without premedications 
(see Section 4.3.2.5).  Significant issues with polatuzumab vedotin IRRs have not been 
observed. 
Similar considerations regarding infusion reactions are applicable for obinutuzumab.  
Refer to Section 4.3.2.5 for additional information.   
Tumor Lysis Syndrome  
There is a potential risk of TLS if treatment with polatuzumab vedotin results in the rapid 
destruction of a large number of tumor cells.  Patients will receive tumor lysis prophylaxis 
(e.g., allopurinol ≥ 300 mg/day orally or a suitable alternative treatment [according to 
institutional practice] starting prior to study treatment) and must be well hydrated before 
the initiation of study treatment at Cycle 1 Day 1.  Patients should continue to receive 
repeated prophylaxis with allopurinol and adequate hydration before each subsequent 
infusion, as deemed appropriate by the investigator.   
One case of Grade 3 laboratory TLS was reported in this ongoing study.  The patient 
was at high risk for TLS due to bulky disease and decreased renal function.  Potassium 
and phosphorous levels were elevated, while serum creatinine levels remained normal 
and patient was asymptomatic.  The TLS event was considered related to all 3 study 
treatments and resolved in 4 days with supportive care.  One case of TLS attributed to 
polatuzumab vedotin has been reported (GO27834); however, the laboratory elevations 
did not meet the Howard criteria for TLS (see Appendix 13).  The suspected TLS event 
resolved after 3 days of supportive care (see polatuzumab vedotin IB for case details).   
SECTION 5.1.5:  Risks of Overlapping Toxicities 
The overlapping toxicities from the combined administration of obinutuzumab or 
rituximab, polatuzumab vedotin, and venetoclax are anticipated in this clinical trial and 
will be closely monitored and managed throughout the study.  
Rituximab was safely combined with polatuzumab vedotin in patients with R/R FL or 
DLBCL.  Grade 3 or 4 neutropenia (21%) appeared to be the most important 
hematologic adverse event associated with this combination.  When given as 
monotherapy for the treatment of patients with R/R NHL, obinutuzumab was associated 
with a 5% incidence of Grade 3−4 neutropenia.  Because obinutuzumab is expected to 
have an incidence of neutropenia that is higher than that with rituximab monotherapy, 
there is a risk of increase incidence of neutropenia.  Obinutuzumab and polatuzumab 
vedotin for the treatment of patients with R/R FL or DLBCL is currently being assessed 
in Study GO27834.  Any applicable findings from this study that affect patient safety will 
be applied to this study.  
Venetoclax has also been associated with hematologic adverse events, including 
neutropenia.  Therefore, the combination of obinutuzumab or rituximab, polatuzumab 


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vedotin, and venetoclax is anticipated to have overlapping hematologic toxicity and will 
be closely monitored. Guidelines for management of patients who develop hematologic 
toxicities are provided in Section 5.1.6.  In addition to the standard hematologic 
monitoring, patients enrolled in this study will be closely monitored for evidence of 
infections.  
There is the identified risk of TLS if treatment with obinutuzumab or rituximab or 
venetoclax and a theoretical risk for polatuzumab vedotin since these agents can result 
in the rapid destruction of a large number of tumor cells.  Therefore, overlapping toxicity 
in regard to TLS cannot be excluded.  Guidelines for management of patients who 
develop TLS are provided in Section 5.1.6. 
SECTION 5.1.7:  Management of Specific Adverse Events 
Patients should be assessed clinically before each study treatment administration.  
Guidelines for management of toxicities are based on laboratory values obtained within 
72 hours prior to Day 1 of each cycle during induction or each month during 
maintenance (FL) or consolidation (DLBCL) or within 24 hours prior to Days 8 and 15 of 
Cycle 1 for patients receiving obinutuzumab.  Dosing will occur only if a patient’s clinical 
assessment and laboratory test values are acceptable.   
There will be no dose reductions of obinutuzumab or rituximab.  There will be no dose 
reductions of polatuzumab vedotin for any toxicity except neurotoxicity (see 
Section 5.1.7.2).  For patients receiving obinutuzumab, if toxicity occurs before Cycle 1 
Day 8 or Cycle 1 Day 15, these doses of obinutuzumab will not be skipped but given 
after resolution of toxicity.  Study treatment may be delayed for toxicity for a maximum 
amount of time (e.g., 21 days), as specified in the tables below.  If study treatment is 
delayed for longer than the specified maximum, study treatment will be permanently 
discontinued.  When a treatment cycle is delayed because of toxicity resulting from any 
component of the regimen, all study treatments should be held and resumed together to 
remain synchronized.  If one drug is discontinued, treatment with the other two drugs 
may be continued for patients experiencing clinical benefit as determined by the 
investigator after discussing with the Medical Monitor. 
TABLE 18:  Guidelines for Management of Hematologic Toxicities That 
Occur during Induction Treatment (Except Days 8 and 15 of Cycle 1 for 
Patients Receiving Obinutuzumab) 
Table 18 has been revised to not apply to patients receiving obinutuzumab on Days 8 
and 15 of Cycle 1. 
TABLE 19:  Guidelines for Management of Hematologic Toxicities That 
Occur on Days 8 and 15 of Cycle 1 for Patients Receiving Obinutuzumab 
Table 19 has been revised to specify only patients receiving obinutuzumab on Days 8 
and 15 and to clarify when venetoclax should be held. 


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TABLE 20:  Guidelines for Management of Non-Hematologic Toxicities That 
Occur During Induction 
Table 20 has been revised to include rituximab. 
TABLE 21:  Guidelines for Management of Toxicities That Occur during 
Consolidation or Maintenance Treatment 
Table 21 has been revised to include rituximab. 
SECTION 5.2.3:  Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following: 
• 
Second malignancies 
 
SECTION 5.2.5:  Selected Adverse Events 
The following adverse events are considered selected adverse events: 
• 
Secondary malignancies 
 
Events for which additional data collection will be required are PML and hepatitis B 
reactivation, and secondary malignancies. 
SECTION 5.3.1:  Adverse Event Reporting Period 
After initiation of study treatment, all adverse events will be reported until 90 days 
after the last dose of study treatment.  After this period, the investigator should report 
any serious adverse events that are believed to be related to prior study treatment and 
events of second malignancies for patients who received obinutuzumab 
(see Section 5.6). 
An exception is for FL patients receiving obinutuzumab, where Grade 3 and 4 infections 
(both related and unrelated), which should be reported until up to 2 years after the last 
dose of study treatmentobinutuzumab.  
SECTION 5.3.5.8:  Deaths 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an abrupt 
and unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 


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replaced by the established cause of death.  The term "sudden death" should not be used 
unless combined with the presumed cause of death (e.g., "sudden cardiac death").  Deaths that 
occur after the adverse event reporting period should be reported as described in 
Section 5.6.   
SECTION 5.3.5.11:  Hospitalization or Prolonged Hospitalization 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:The following hospitalization 
scenarios are not considered to be adverse events:  
[…] 
An event that leads to hospitalization under the following circumstance is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:The following hospitalization scenario is not considered to be a serious adverse 
event, but should be reported as an adverse event instead: 
 
SECTION 5.4:  Immediate Reporting Requirements from Investigator to 
Sponsor 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to any of the study treatments: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Dose-limiting toxicities (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
SECTION 5.4.2.2:  Events That Occur after Study Treatment Initiation 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment.  After this 
period, the investigator should report any serious adverse events that are believed to be 
related to prior study treatment (see Section 5.6).  An exception is for FL patients 
receiving obinutuzumab, where Grade 3 and 4 infections (both related and unrelated), 
which should be reported until up to 2 years after the last dose of study 
treatmentobinutuzumab.  DLTs will be reported during the DLT assessment window.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system. 


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In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting events after the post study adverse events reporting period are 
provided in Section 5.6. 
SECTION 5.4.3.2:  Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose for obinutuzumab and or rituximab, 30 days after the last 
dose of venetoclax and 5 months after last dose of polatuzumab vedotin.  A Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Attempts should be made to collect and report details 
of the course and outcome of any pregnancy in the partner of a male patient exposed to 
study treatment.  The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
After the authorization has been signed, the investigator will submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician. 
SECTION 5.6:  ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
90 days after the last dose of study treatment), if the event is believed to be related to 
prior study treatment.  The sponsor should also be notified of events of second 
malignancies after the end of the adverse event reporting period for patients who 
received obinutuzumab.   
An exception is for FL patients receiving obinutuzumab, where Grade 3–4 infections 
(both related and unrelated), which should be reported until up to 2 years after the last 
dose of study treatment obinutuzumab.  


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SECTION 5.7:  EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
Obinutuzumab Investigator's Brochure 
• 
Rituximab Investigator’s Brochure 
• 
Polatuzumab Vedotin Investigator's Brochure 
• 
Venetoclax in combination with Obinutuzumab Investigator's Brochure  
 
SECTION 6:  STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This is a Phase Ib/II, open-label, multicenter, non-randomized study of obinutuzumab in 
combination with polatuzumab vedotin and venetoclax (G + Pola + V) in patients with 
R/R FL orand rituximab in combination with polatuzumab vedotin and venetoclax 
(R + Pola + V) in patients with R/R DLBCL. 
The dose-escalation phase in patients with FL is designed to determine the RP2D for 
both polatuzumab vedotin and RP2D for venetoclax when combined with fixed doses of 
obinutuzumab (1000 mg).  The dose-escalation phase will include patients with FL only 
in patients with DLBCL is designed to determine the RP2D of venetoclax when 
combined with fixed doses of polatuzumab vedotin (1.8 mg/kg) and rituximab 
(375 mg/m2).  The expansion phase is designed to assess the safety and efficacy of 
polatuzumab vedotin and venetoclax at their respective RP2Ds in combination with 
obinutuzumab or rituximab.  
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE 
Limited dose finding will be conducted during the dose-escalation phase of this study.  
The estimated sample size follows from the dose-escalation rules for a standard 3 + 3 
algorithm, as outlined in Section 3.1.  It is anticipated that enrollment of 6 cohorts of 
3−6 patients each, for a total of 21−3624−39 patients, will be required to establish the 
RP2D during the dose-escalation phase for patients with R/R FL.  There are 3 possible 
cohorts of 3−6 patients each, for a total of 12−18 patients with replapsed or refractory 
DLBCL. 
Approximately 80 patients (40 patients with FL and 40 patients with DLBCL) will be 
enrolled during the expansion phase.  Overall, approximately 113−134104−119 patients 
will be enrolled in this study. 
[…] 
Table 23 provides 90% Clopper-Pearson exact CIs for the probability of achieving an 
EOI PET-CT−defined CR for a range of observed proportions based on a sample of 
40 patients.  A sample size of 40 patients is deemed sufficient to provide adequate 
precision for the point estimate and for the lower bound of the two-sided 90% CI to rule 


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out a clinically uninteresting probability of response of < 55%, assuming an observed 
PET-CT−defined CR rate of 65%−70%. 
SECTION 6.3:  DEFINITION OF ANALYSIS POPULATIONS 
The primary safety and efficacy The following populations are defined: 
• 
The primary safety and efficacy populations will include patients who receive at 
least one dose of each any component of the combination.   
• 
The safety and efficacy analyses will also be performed on the ITT intent-to-treat 
population, which will include all patients enrolled in the study. 
SECTION 6.5:  SAFETY ANALYSES 
The safety analyses will include all treated patients (i.e., patients who received any 
amount of study treatment).  Patients in the dose-escalation phase will be summarized 
by cohort and histology type, and patients in the dose expansion phase will be 
summarized by histology type (FL or DLBCL).  
[…] 
Relevant laboratory and vital sign (temperature, heart rate, respiratory rate, and blood 
pressure) data results will be displayed by time, with Grade 3 and 4 values identified as 
appropriate. 
SECTION 6.6:  EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include the primary efficacy 
population and the intent-to-treat population for patients enrolled in the expansion 
phase, with patients grouped according to histologic subtype, and will be performed by 
treatment group.  In addition, patients with FL and DLBCL who received polatuzumab 
vedotin and venetoclax at the RP2D during the dose-escalation phases will be pooled for 
analysis by histology with patients treated in the expansion phase at the same dose 
levels. 
SECTION 6.6.3:  Exploratory Efficacy Endpoints 
• 
For patients who have positive PET scans at EOI:   
– 
CR at 12 months, as determined by the IRC and by the investigator on the 
basis of PET-CT scans, in FL patients 
– 
CR at EOC, as determined by the IRC and by the investigator on the basis 
of PET-CT scans, in DLBCL patients 
 
SECTION 6.7:  PHARMACOKINETIC ANALYSES 
Serum or plasma concentrations of obinutuzumab, rituximab, polatuzumab vedotin and 
relevant analytes, and venetoclax will be tabulated and plotted over time after 
appropriate grouping.  Summary statistics of concentration data will be computed for 
each scheduled sampling time for each analyte after appropriate grouping.  Interpatient 


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variability and drug accumulation after multiple doses will be evaluated as appropriate.  
Compartmental, non-compartmental, and/or population approaches will be considered 
as appropriate.  Potential correlations between PK variability and pharmacodynamic, 
efficacy, and safety endpoints may be explored by exploratory graphical analysis and 
PK-pharmacodynamic modeling.  The exploratory analyses may be reported separately 
from the CSR.   
SECTION 6.8:  IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with at least one predose and 
one postdose HAHA or ATA assessment, with patients grouped according to histology. 
The numbers and proportions of HAHA- or ATA-positive patients and HAHA- or 
ATA-negative patients during both the treatment and follow-up periods will be 
summarized by histology group.  Patients are considered to be HAHA- or ATA-positive 
if they are HAHA- or ATA-negative at baseline but develop an HAHA or ATA response 
following study drug administration (treatment-induced HAHA or ATA response), or if 
they are HAHA- or ATA-positive at baseline and the titer of 1 or more post-baseline 
samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline 
sample (treatment-enhanced HAHA or ATA response).  Patients are considered to be 
HAHA- or ATA-negative if they are HAHA- or ATA-negative at baseline and all 
post-baseline samples are negative, or if they are HAHA- or ATA-positive at baseline 
but do not have any post-baseline samples with a titer that is at least 4-fold greater than 
the titer of the baseline sample (treatment unaffected). 
The relationship between HAHA or ATA status and safety, efficacy, PK, and biomarker 
endpoints will be analyzed and reported descriptively via subgroup analyses.  
Considering the historically low immunogenicity rate of rituximab in NHL patients, 
human anti-chimeric antibodies against rituximab will not be monitored in this study. 
SECTION 6.10:  INTERIM ANALYSES 
It is anticipated that at least one interim analysis will be conducted during the expansion 
phase of the study, when at least 15 patients in each treatment group have been 
evaluated for PET-CT−defined CR at the EOI.  Additional analyses may be conducted to 
guide early stopping of enrollment for safety on the basis of observed toxicities and the 
ability to maintain chemotherapy dose intensity. 
During the expansion phase, a modified version of the predictive probability design 
(Lee and LiuLui 2008) may be used to guide early stopping for futility by comparing the 
observed proportion of patients who achieve a PET-CT−defined CR at EOI in each 
expansion cohort with that in historical controls.  The earliest interim analysis would 
occur after at least 15 patients have been evaluated for PET CT−defined CR at EOI. The 
design is based on Lee and Lui 2008 with the modification that the uncertainty in the 
historical control data is fully taken into account by utilizing a beta posterior on the 
control response rate.  Interim analysis decision rules will be based on the predicative 


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probability that the trial will have a positive outcome if carried out to completion and 
will use the historical control data available at the time of analysis.   
If, at any time, an interim analysis suggests that the proportion of patients achieving a 
PET-CT−defined CR for one of the expansion cohorts is lower than expected, the IMC 
will review the data and decide whether to recommend an early decision to stop 
enrollment in that cohort because of futility.  Interim analysis decision rules will be based 
on the predictive probability that the trial will have a positive outcome if carried out to 
completion and will use the most current historical control data available at the time of 
analysis. 
Additional review of safety and/or efficacy data by the IMC may be requested by and 
carried out at the discretion of the Medical Monitor.  Further details regarding the rules 
and guidelines of data review will be provided to the IMC in an IMC charter. 
SECTION 9.2.:  PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
SECTION 9.5:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
 
APPENDIX 1:  Schedule of Assessments for Patients with Follicular 
Lymphoma  
The schedule of assessments for patients with follicular lymphoma has been revised to 
reflect the changes to the protocol. 
APPENDIX 2:  Schedule of Assessments for Patients with DLBCL 
The schedule of assessments for patients with DLBCL has been revised to reflect the 
changes to the protocol. 


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APPENDIX 3:  Pharmacokinetic and Immunogenicity Sampling Schedule 
for Obinutuzumab, Polatuzumab Vedotin, and Venetoclax in Relapsed or 
Refractory Follicular Lymphoma Patients 
Appendix 3 has been clarified to include patients with R/R FL, removing information 
about patients with DLBCL. 
APPENDIX 4:  Pharmacokinetic and Immunogenicity Sampling Schedule 
for Rituximab, Polatuzumab Vedotin, and Venetoclax in Relapsed or 
Refractory DLBCL Patients 
Appendix 4 has been added.  Subsequent appendices have been renumbered 
accordingly. 
APPENDIX 10:  Sample List of Excluded and Cautionary Medications 
The list of excluded and cautionary medications has been updated in Appendix 10. 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 53 
PROTOCOL SYNOPSIS .................................................................................... 54 
1. 
BACKGROUND .......................................................................................... 73 
1.1 
Background on Non-Hodgkin's Lymphoma ........................... 73 
1.1.1 
Follicular Lymphoma ............................................................. 73 
1.1.2 
Diffuse Large B-Cell Lymphoma............................................ 73 
1.2 
Background on Obinutuzumab .............................................. 74 
1.2.1 
Nonclinical Studies with Obinutuzumab................................. 75 
1.2.2 
Clinical Studies with Obinutuzumab ...................................... 75 
1.2.2.1 
Clinical Safety of Obinutuzumab............................................ 75 
1.2.2.2 
Clinical Efficacy of Obinutuzumab in Patients with 
Non-Hodgkin's Lymphoma .................................................... 76 
1.3 
Background on Polatuzumab Vedotin ................................... 77 
1.3.1 
Nonclinical Studies with Polatuzumab Vedotin...................... 78 
1.3.2 
Clinical Studies with Polatuzumab Vedotin............................ 78 
1.3.2.1 
Clinical Safety of Polatuzumab Vedotin................................. 79 
1.3.2.2 
Clinical Efficacy of Polatuzumab Vedotin in 
Patients with Non-Hodgkin’s Lymphoma ............................... 80 
1.4 
Background on Venetoclax.................................................... 82 
1.4.1 
Nonclinical Studies with Venetoclax ...................................... 82 
1.4.2 
Clinical Studies with Venetoclax............................................ 83 
1.4.2.1 
Clinical Results in Non-Hodgkin’s Lymphoma ....................... 83 
1.4.2.2 
Clinical Pharmacokinetics and 
Pharmacodynamics ............................................................... 84 
1.5 
Study Rationale and Benefit-Risk Assessment...................... 84 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 88 
2.1 
Safety Objectives................................................................... 88 
2.2 
Efficacy Objectives ................................................................ 88 
2.2.1 
Primary Efficacy Objective..................................................... 88 
2.2.2 
Secondary Efficacy Objective................................................ 89 
2.2.3 
Exploratory Efficacy Objective............................................... 89 
2.3 
Pharmacokinetic Objective .................................................... 89 


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2.4 
Immunogenicity Objectives.................................................... 90 
2.5 
Biomarker Objective .............................................................. 90 
3. 
STUDY DESIGN ......................................................................................... 90 
3.1 
Description of Study .............................................................. 90 
3.1.1 
Overview of Study ................................................................. 90 
3.1.2 
Obinutuzumab Plus Polatuzumab Vedotin 
Plus Venetoclax Treatment Group (Patients with 
Follicular Lymphoma) ............................................................ 93 
3.1.2.1 
Follicular Lymphoma Dose-Escalation Phase ....................... 93 
3.1.2.2 
Follicular Lymphoma Expansion Phase................................. 99 
3.1.3 
Rituximab Plus Polatuzumab Vedotin Plus 
Venetoclax Treatment Group (Patients with 
DLBCL)................................................................................ 100 
3.1.3.1 
Dose-Escalation Phase in Relapsed or 
Refractory DLBCL Patients.................................................. 101 
3.1.3.2 
DLBCL Expansion Phase .................................................... 104 
3.1.4 
Internal Monitoring Committee............................................. 106 
3.1.5 
Independent Review Committee.......................................... 106 
3.1.6 
Post-Treatment and Survival Follow-Up .............................. 106 
3.2 
End of Study and Length of Study....................................... 106 
3.3 
Rationale for Study Design.................................................. 107 
3.3.1 
Rationale for Patient Population .......................................... 107 
3.3.2 
Rationale for the Triplet Combination .................................. 107 
3.3.3 
Rationale for Dose and Schedule........................................ 108 
3.3.3.1 
Rationale for Obinutuzumab Dosing Regimen in 
Follicular Lymphoma Patients.............................................. 108 
3.3.3.2 
Rationale for Polatuzumab Vedotin Dosing 
Regimen .............................................................................. 108 
3.3.3.3 
Rationale for Venetoclax Dosing Regimen .......................... 110 
3.3.3.4 
Rationale for Treatment Duration ........................................ 111 
3.3.4 
Rationale for Positron Emission 
Tomography-Computed Tomography-Defined 
Complete Response as the Primary Efficacy 
Endpoint .............................................................................. 112 
3.3.5 
Rationale for Biomarker Assessments................................. 113 


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3.3.5.1 
Rationale for Analysis of Diffuse Large B-Cell 
Lymphoma Subtype, BCL2, and MYC................................. 113 
3.3.5.2 
Rationale for Assessment of Therapeutic Target 
Expression........................................................................... 113 
3.3.5.3 
Rationale for Assessment of Minimum Residual 
Disease................................................................................ 114 
3.3.5.4 
Rationale for Assessment of Lymphoma-Related 
Genetic Changes and Gene Expression.............................. 114 
4. 
MATERIALS AND METHODS .................................................................. 114 
4.1 
Patients................................................................................ 114 
4.1.1 
Inclusion Criteria.................................................................. 114 
4.1.2 
Exclusion Criteria................................................................. 116 
4.2 
Method of Treatment Assignment........................................ 118 
4.3 
Study Treatments ................................................................ 119 
4.3.1 
Formulation, Packaging, and Handling................................ 119 
4.3.1.1 
Obinutuzumab ..................................................................... 119 
4.3.1.2 
Rituximab............................................................................. 119 
4.3.1.3 
Polatuzumab Vedotin .......................................................... 119 
4.3.1.4 
Venetoclax........................................................................... 119 
4.3.2 
Dosage, Administration, and Compliance............................ 119 
4.3.2.1 
Obinutuzumab ..................................................................... 122 
4.3.2.2 
Rituximab............................................................................. 125 
4.3.2.3 
Polatuzumab Vedotin .......................................................... 126 
4.3.2.4 
Venetoclax........................................................................... 127 
4.3.2.5 
Premedication...................................................................... 128 
4.3.3 
Investigational Medicinal Product Accountability ................. 131 
4.3.4 
Post-Trial Access to Obinutuzumab, Rituximab, 
Polatuzumab Vedotin, and Venetoclax................................ 131 
4.4 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ......................................................... 131 
4.4.1 
Permitted Therapy ............................................................... 131 
4.4.2 
Prohibited and Cautionary Therapy for 
Concomitant Medications .................................................... 132 
4.4.3 
Prohibited Food ................................................................... 133 
4.5 
Study Assessments ............................................................. 133 


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4.5.1 
Informed Consent Forms and Screening Log...................... 133 
4.5.2 
Medical History and Demographic Data .............................. 134 
4.5.3 
Physical Examinations......................................................... 134 
4.5.4 
Vital Signs............................................................................ 135 
4.5.5 
Tumor and Response Evaluations....................................... 135 
4.5.5.1 
Radiographic Assessments ................................................. 135 
4.5.5.2 
Bone Marrow Assessments................................................. 136 
4.5.6 
Laboratory, Biomarker, and Other Biological 
Samples............................................................................... 136 
4.5.7 
Electrocardiograms.............................................................. 139 
4.5.7.1 
Multigated Acquisition Scan/Echocardiogram...................... 139 
4.5.8 
Samples for Roche Clinical Repository................................ 139 
4.5.8.1 
Overview of the Roche Clinical Repository.......................... 139 
4.5.8.2 
Approval by the Institutional Review Board or 
Ethics Committee ................................................................ 140 
4.5.8.3 
Sample Collection................................................................ 140 
4.5.8.4 
Confidentiality...................................................................... 140 
4.5.8.5 
Consent to Participate in the Roche Clinical 
Repository ........................................................................... 141 
4.5.8.6 
Withdrawal from the Roche Clinical Repository................... 141 
4.5.8.7 
Monitoring and Oversight..................................................... 142 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation.................................................................... 142 
4.6.1 
Patient Discontinuation........................................................ 142 
4.6.2 
Study Treatment Discontinuation......................................... 142 
4.6.3 
Study and Site Discontinuation............................................ 143 
5. 
ASSESSMENT OF SAFETY..................................................................... 143 
5.1 
Safety Plan .......................................................................... 143 
5.1.1 
Risks Associated with Obinutuzumab.................................. 144 
5.1.1.1 
Infusion-Related Reactions.................................................. 144 
5.1.1.2 
Tumor Lysis Syndrome........................................................ 145 
5.1.1.3 
Neutropenia......................................................................... 145 
5.1.1.4 
Thrombocytopenia............................................................... 145 
5.1.1.5 
Infections ............................................................................. 145 


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5.1.1.6 
Impaired Immunization Response ....................................... 146 
5.1.1.7 
Worsening of Preexisting Cardiac Condition ....................... 146 
5.1.1.8 
Gastrointestinal Perforation ................................................. 146 
5.1.2 
Risks Associated with Rituximab ......................................... 147 
5.1.2.1 
Infusion-Related Reactions.................................................. 147 
5.1.2.2 
Infections (Including Serious Infections) .............................. 147 
5.1.2.3 
Hepatitis B Reactivation....................................................... 147 
5.1.2.4 
Progressive Multifocal Leukoencephalopathy...................... 147 
5.1.2.5 
Neutropenia (Including Prolonged Neutropenia).................. 148 
5.1.2.6 
Tumor Lysis Syndrome........................................................ 148 
5.1.2.7 
Impaired Immunization Response ....................................... 148 
5.1.2.8 
Severe Skin Reactions: Stevens-Johnson 
Syndrome and Toxic Epidermal Necrolysis ......................... 148 
5.1.2.9 
Gastrointestinal Perforation ................................................. 149 
5.1.3 
Risks Associated with Polatuzumab Vedotin....................... 149 
5.1.3.1 
Identified Risks .................................................................... 149 
5.1.3.2 
Potential Risks..................................................................... 150 
5.1.4 
Risks Associated with Venetoclax ....................................... 152 
5.1.4.1 
Tumor Lysis Syndrome........................................................ 152 
5.1.4.2 
Cytopenia ............................................................................ 152 
5.1.4.3 
Infectious Complications...................................................... 153 
5.1.4.4 
Effects on Cardiac Function................................................. 153 
5.1.4.5 
Effects on Fertility ................................................................ 153 
5.1.4.6 
Drug Interactions ................................................................. 153 
5.1.5 
Risks of Overlapping Toxicities............................................ 153 
5.1.6 
Prophylaxis and Monitoring for Tumor Lysis 
Syndrome ............................................................................ 154 
5.1.6.1 
Prophylaxis and Monitoring for All Patients ......................... 154 
5.1.6.2 
Hospitalization for Patients at Higher Risk for 
Tumor Lysis Syndrome........................................................ 156 
5.1.7 
Management of Specific Adverse Events ............................ 157 
5.1.7.1 
Venetoclax Dose Reduction and Re-Escalation 
Steps ................................................................................... 158 
5.1.7.2 
Toxicities during Induction Treatment.................................. 158 


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5.1.7.3 
Toxicities during Consolidation or Maintenance 
Treatment ............................................................................ 163 
5.2 
Safety Parameters and Definitions ...................................... 163 
5.2.1 
Adverse Events ................................................................... 163 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 164 
5.2.3 
Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ............................ 165 
5.2.4 
Dose-Limiting Toxicities (Immediately Reportable 
to the Sponsor).................................................................... 165 
5.2.5 
Selected Adverse Events..................................................... 165 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 166 
5.3.1 
Adverse Event Reporting Period ......................................... 166 
5.3.2 
Eliciting Adverse Event Information ..................................... 167 
5.3.3 
Assessment of Severity of Adverse Events ......................... 167 
5.3.4 
Assessment of Causality of Adverse Events ....................... 168 
5.3.5 
Procedures for Recording Adverse Events.......................... 168 
5.3.5.1 
Infusion-Related Reactions.................................................. 168 
5.3.5.2 
Diagnosis versus Signs and Symptoms............................... 168 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................. 169 
5.3.5.4 
Persistent or Recurrent Adverse Events.............................. 169 
5.3.5.5 
Abnormal Laboratory Values ............................................... 170 
5.3.5.6 
Abnormal Vital Sign Values ................................................. 170 
5.3.5.7 
Abnormal Liver Function Tests............................................ 171 
5.3.5.8 
Deaths ................................................................................. 171 
5.3.5.9 
Preexisting Medical Conditions............................................ 172 
5.3.5.10 
Lack of Efficacy or Worsening of Lymphoma....................... 172 
5.3.5.11 
Hospitalization or Prolonged Hospitalization........................ 172 
5.3.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 173 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 174 
5.4.1 
Emergency Medical Contacts.............................................. 174 


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5.4.2 
Reporting Requirements for Serious Adverse 
Events, Adverse Events of Special Interest, and 
Dose-Limiting Toxicities....................................................... 175 
5.4.2.1 
Events That Occur prior to Study Treatment 
Initiation ............................................................................... 175 
5.4.2.2 
Events That Occur after Study Treatment 
Initiation ............................................................................... 175 
5.4.3 
Reporting Requirements for Pregnancies............................ 175 
5.4.3.1 
Pregnancies in Female Patients.......................................... 175 
5.4.3.2 
Pregnancies in Female Partners of Male Patients............... 176 
5.4.3.3 
Abortions ............................................................................. 176 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 176 
5.5 
Follow-Up of Patients after Adverse Events ........................ 177 
5.5.1 
Investigator Follow-Up......................................................... 177 
5.5.2 
Sponsor Follow-Up .............................................................. 177 
5.6 
Adverse Events that Occur after the Adverse 
Event Reporting Period........................................................ 177 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 178 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 178 
6.1 
Determination of Sample Size ............................................. 179 
6.2 
Summaries of Patient Characteristics.................................. 180 
6.3 
Definition of Analysis Populations........................................ 180 
6.4 
Summaries of Demographic and Baseline 
Characteristics..................................................................... 180 
6.5 
Safety Analyses................................................................... 180 
6.6 
Efficacy Analyses ................................................................ 181 
6.6.1 
Primary Efficacy Endpoint.................................................... 181 
6.6.2 
Secondary Efficacy Endpoints............................................. 181 
6.6.3 
Exploratory Efficacy Endpoints............................................ 181 
6.7 
Pharmacokinetic Analyses................................................... 182 
6.8 
Immunogenicity Analyses.................................................... 183 
6.9 
Biomarker Analyses............................................................. 183 
6.10 
Interim Analyses .................................................................. 183 


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7. 
DATA COLLECTION AND MANAGEMENT ............................................. 184 
7.1 
Data Quality Assurance....................................................... 184 
7.2 
Electronic Case Report Forms............................................. 185 
7.3 
Source Data Documentation................................................ 185 
7.4 
Use of Computerized Systems ............................................ 185 
7.5 
Retention of Records........................................................... 186 
8. 
ETHICAL CONSIDERATIONS.................................................................. 186 
8.1 
Compliance with Laws and Regulations .............................. 186 
8.2 
Informed Consent ................................................................ 186 
8.3 
Institutional Review Board or Ethics Committee.................. 187 
8.4 
Confidentiality...................................................................... 188 
8.5 
Financial Disclosure ............................................................ 188 
9. 
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION........................................................................... 188 
9.1 
Study Documentation .......................................................... 188 
9.2 
Protocol Deviations.............................................................. 189 
9.3 
Site Inspections ................................................................... 189 
9.4 
Administrative Structure....................................................... 189 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 189 
9.6 
Protocol Amendments ......................................................... 190 
10. REFERENCES ......................................................................................... 191 
 
 
LIST OF TABLES 
Table 1 
Induction Treatment for the Follicular Lymphoma 
Dose-Escalation Phase............................................................... 95 
Table 2 
Maintenance Treatment for the Follicular Lymphoma 
Dose-Escalation Phase............................................................... 96 
Table 3 
Follicular Lymphoma Dose-Escalation Cohorts .......................... 98 
Table 4 
Induction Treatment for the Follicular Lymphoma Expansion 
Phase........................................................................................ 100 
Table 5 
Post-Induction Treatment for the Follicular Lymphoma 
Expansion Phase...................................................................... 100 
Table 6 
Induction Treatment for the DLBCL Dose-Escalation Phase .... 102 


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Table 7 
Consolidation Treatment for the DLBCL Dose-Escalation 
Phase........................................................................................ 102 
Table 8 
DLBCL Dose-Escalation Cohorts.............................................. 103 
Table 9 
Induction Treatment for the DLBCL Expansion Phase.............. 105 
Table 10 
Consolidation Treatment for the DLBCL Expansion Phase ...... 105 
Table 11 
Polatuzumab Vedotin plus Obinutuzumab-Containing 
Regimens for the Treatment of Follicular Lymphoma ............... 109 
Table 12 
Administration of First and Subsequent Infusions of 
Rituximab.................................................................................. 126 
Table 13 
Premedication........................................................................... 129 
Table 14 
Proposed Non-Inherited Biomarkers......................................... 138 
Table 15 
Prophylaxis and Assessments for Tumor Lysis Syndrome ....... 155 
Table 16 
Venetoclax Dose Reduction Steps during Induction ................. 158 
Table 17 
Venetoclax Dose Reduction Steps during Maintenance ........... 158 
Table 18 
Guidelines for Management of Hematologic Toxicities That 
Occur during Induction Treatment (Except Days 8 and 15 of 
Cycle 1 for Patients Receiving Obinutuzumab)......................... 159 
Table 19 
Guidelines for Management of Hematologic Toxicities That 
Occur on Days 8 and 15 of Cycle 1 for Patients Receiving 
Obinutuzumab........................................................................... 160 
Table 20 
Guidelines for Management of Non-Hematologic Toxicities 
That Occur During Induction ..................................................... 161 
Table 21 
Guidelines for Management of Toxicities That Occur during 
Consolidation or Maintenance Treatment ................................. 163 
Table 22 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 167 
Table 23 
Potential 90% CI Estimates for the True Probability of 
Achieving a PET-CT−Defined Complete Response at End of 
Induction ................................................................................... 179 
 
 
LIST OF FIGURES 
Figure 1 
Anti-Tumor Activity with Obinutuzumab, Polatuzumab 
Vedotin, and Venetoclax in WSU-DLCL2 Model in CB17 
SCID Mice................................................................................... 86 
Figure 2 
Study Schema............................................................................. 92 
Figure 3 
Follicular Lymphoma Dose-Escalation Plan................................ 97 
Figure 4 
DLBCL Dose-Escalation Plan ................................................... 103 
Figure 5 
Induction and Post-Induction Treatment Regimens .................. 121 
Figure 6 
Guidelines for Obinutuzumab Infusions: First Infusion.............. 123 
Figure 7 
Guidelines for Obinutuzumab Infusions: Second and 
Subsequent Infusions ............................................................... 124 
 


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LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments for Patients with Follicular 
Lymphoma ................................................................................ 199 
Appendix 2 
Schedule of Assessments for Patients with DLBCL.................. 205 
Appendix 3 
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Obinutuzumab Polatuzumab Vedotin, and Venetoclax in 
Relapsed or Refractory Follicular Lymphoma Patients ............. 211 
Appendix 4 
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Rituximab, Polatuzumab Vedotin, and Venetoclax in 
Relapsed or Refractory DLBCL Patients................................... 215 
Appendix 5 
Modified Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) ................................................................. 219 
Appendix 6 
ECOG Performance Status Scale............................................. 224 
Appendix 7 
Ann Arbor Staging..................................................................... 225 
Appendix 8 
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index................................................... 226 
Appendix 9 
Anaphylaxis Precautions........................................................... 229 
Appendix 10 Sample List of Excluded and Cautionary Medications .............. 230 
Appendix 11 Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome............. 232 
Appendix 12 Clinical Studies of Study Drugs as Single Treatments and 
Part of Doublet Treatment Regimens........................................ 236 
Appendix 13 Diagnostic Criteria for Tumor Lysis Syndrome.......................... 240 


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE Ib/II STUDY EVALUATING THE SAFETY 
AND EFFICACY OF OBINUTUZUMAB IN 
COMBINATION WITH POLATUZUMAB VEDOTIN 
AND VENETOCLAX IN PATIENTS WITH 
RELAPSED OR REFRACTORY FOLLICULAR 
LYMPHOMA AND RITUXIMAB IN 
COMBINATION WITH POLATUZUMAB 
VEDOTIN AND VENETOCLAX IN PATIENTS 
WITH RELAPSED OR REFRACTORY DIFFUSE 
LARGE B-CELL LYMPHOMA 
PROTOCOL NUMBER: GO29833 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2015-001998-40 
IND NUMBER: 
115045 
TEST PRODUCT: 
Obinutuzumab (RO5072759) 
Rituximab (RO0452294) 
Polatuzumab vedotin (DCDS4501A; RO5541077)  
Venetoclax (GDC-0199; ABT-199; RO5537382) 
MEDICAL MONITOR: 
, Pharm.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor. 


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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE Ib/II STUDY EVALUATING THE SAFETY AND 
EFFICACY OF OBINUTUZUMAB IN COMBINATION WITH 
POLATUZUMAB VEDOTIN AND VENETOCLAX IN PATIENTS 
WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA 
AND RITUXIMAB IN COMBINATION WITH 
POLATUZUMAB VEDOTIN AND VENETOCLAX IN 
PATIENST WITH RELAPSED OR REFRACTORY DIFFUSE 
LARGE B-CELL LYMPHOMA 
PROTOCOL NUMBER: 
GO29833 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2015-001998-40 
IND NUMBER: 
115045 
TEST PRODUCTS: 
Obinutuzumab (RO5072759) 
Rituximab (RO0452294) 
Polatuzumab vedotin (DCDS4501A; RO5541077) 
Venetoclax (GDC-0199; ABT-199; RO5537382) 
PHASE: 
Phase Ib/II 
INDICATION: 
Follicular or diffuse large B-cell lymphoma 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Outcome Measures 
This study will evaluate the safety, efficacy, and pharmacokinetics of induction treatment 
consisting of obinutuzumab in combination with polatuzumab vedotin and venetoclax 
(G + Pola + V) in patients with relapse or refractory (R/R) follicular lymphoma (FL) and rituximab 
in combination with polatuzumab vedotin and venetoclax (R + Pola + V) in patients with R/R 
diffuse large B-cell lymphoma (DLBCL).  Induction will be followed by post-induction treatment 
with obinutuzumab incombination with venetoclax (G + V; referred to as maintenance) in 
patients with FL who achieve a complete response (CR), partial response (PR), or stable 
disease at end of induction (EOI) and nd post-induction treatment with R + V (referred to as 
consolidation) in patients with DLBCL who achieve a CR or PR at EOI.  Specific objectives and 
corresponding outcome measures for the study are outlined below. 
Safety Objectives 
The safety objectives for this study are as follows: 
• 
To determine the recommended Phase II dose (RP2D) for polatuzumab vedotin and 
venetoclax when given in combination with a fixed dose of obinutuzumab and the RP2D of 
venetoclax when given in combination with a fixed dose of polatuzumab vedotin on the 
basis of the following endpoint: 
– 
Incidence of dose-limiting toxicities (DLTs) during the first cycle of study treatment 


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• 
To evaluate the safety and tolerability of G + Pola + V and R + Pola + V on the basis of the 
following outcome measures in the respective combinations: 
– 
Nature, frequency, severity, and timing of adverse events, including DLTs 
– 
Changes in vital signs, ECGs, and clinical laboratory results during and following 
study treatment administration 
 
Efficacy Objectives 
Response will be determined on the basis of positron emission tomography and computed 
tomography (PET-CT) scans or CT scans alone, using Revised Lugano Response Criteria for 
Malignant Lymphoma, hereinafter referred to as Lugano 2014 criteria.  Response will be 
determined by an Independent Review Committee (IRC) and by the investigator. 
The primary efficacy objective for this study is to evaluate the efficacy of G + Pola + V in patients 
with R/R FL and R + Pola + V in patients with R/R DLBCL on the basis of the following 
endpoint: 
• 
CR at EOI, as determined by the IRC on the basis of PET-CT scans 
 
The secondary efficacy objective for this study is to evaluate the efficacy of G + Pola + V and 
maintenance treatment with G + V in patients with R/R FL and R + Pola + V and 
consolidation treatment with R + V in patients with R/R DLBCL on the basis of the following 
endpoints: 
• 
CR at EOI, as determined by the investigator on the basis of PET-CT scans 
• 
CR at EOI, as determined by the IRC and by the investigator on the basis of CT scans 
alone 
• 
Objective response (defined as a CR or PR) at EOI, as determined by the IRC and by the 
investigator on the basis of PET-CT scans 
• 
Objective response (defined as a CR or PR) at EOI, as determined by the IRC and by the 
investigator on the basis of CT scans alone 
• 
Best response of CR or PR during the study, as determined by the investigator on the basis 
of CT scans alone 
 
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
G + Pola + V and R + Pola + V on the basis of the following endpoints: 
• 
For patients who have positive PET scans at EOI:  CR at 12 months, as determined by the 
IRC and by the investigator on the basis of PET-CT scans in FL patients; CR at EOC as 
determined by the IRC and by the investigator on the basis of PET-CT scans in DLBCL 
patients 
• 
Progression-free survival, defined as the time from initiation of study treatment to first 
occurrence of disease progression or relapse, as determined by investigator, or death from 
any cause 
• 
Event-free survival, defined as the time from initiation of study treatment to any treatment 
failure, including disease progression or relapse, as determined by investigator, initiation of 
new anti-lymphoma therapy, or death from any cause, whichever occurs first 
• 
Disease-free survival, defined, among patients who achieve a CR, as the time from the first 
occurrence of a documented CR to relapse, as determined by the investigator, or death 
from any cause, whichever occurs first 
• 
Overall survival, defined as the time from initiation of study treatment to death from any 
cause 
 


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Pharmacokinetic Objective  
The pharmacokinetic (PK) objective for this study is to characterize the PK profiles of 
obinutuzumab, rituximab, polatuzumab vedotin, and venetoclax when given in combination, on 
the basis of the following endpoints: 
• 
Observed serum concentration of obinutuzumab at specified timepoints 
• 
Observed serum concentration of rituximab at specified timepoints 
• 
Observed serum and plasma concentrations of polatuzumab vedotin and relevant analytes 
(total antibody, antibody-conjugated mono-methyl auristatin E and unconjugated 
mono-methyl auristatin at specified timepoints 
• 
Observed plasma concentration of venetoclax at specified timepoints 
 
Immunogenicity Objective  
The immunogenicity objective for this study is to evaluate the immune response to 
obinutuzumab and to polatuzumab vedotin on the basis of the following endpoints: 
• 
Incidence of human anti-human antibodies (HAHAs) to obinutuzumab during the study 
relative to the prevalence of HAHAs at baseline 
• 
Incidence of anti-therapeutic antibody (ATAs) to polatuzumab vedotin during the study 
relative to the prevalence of ATAs at baseline 
 
The exploratory immunogenicity objective for this study is to evaluate potential relationships 
between HAHAs or ATAs and other endpoints on the basis of the following endpoint: 
• 
Correlation between HAHA or ATA status and efficacy, safety, or PK endpoints 
 
Biomarker Objective 
The exploratory biomarker objective for this study is to identify non-inherited biomarkers that are 
predictive of response to study treatment (i.e., predictive biomarkers), are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
acquired resistance to study treatment, are associated with susceptibility to developing adverse 
events, can provide evidence of study treatment activity, can increase the knowledge and 
understanding of lymphoma biology or study treatment mechanism of action, or can contribute 
to improvement of diagnostic assays, on the basis of the following endpoint: 
• 
Association between non-inherited biomarkers and efficacy, safety, PK, or immunogenicity 
endpoints 
 
Study Design 
Description of Study 
This is a Phase Ib/II, open-label, multicenter, non-randomized study that will evaluate the safety, 
efficacy, and pharmacokinetics of G + Pola + V in patients with R/R FL and R + Pola + V in 
patients with R/R DLBCL.   
The study will include an initial dose-escalation phase followed by an expansion phase during 
which polatuzumab vedotin and venetoclax will be given at their RP2Ds.  Patients will 
receive induction treatment with obinutuzumab or rituximab, polatuzumab vedotin, and 
venetoclax.  Patients with FL who achieve a CR, PR, or stable disease at EOI will receive 
post-induction treatment with obinutuzumab and venetoclax, and patients with DLBCL who 
achieve a CR or PR at EOI will receive post-induction treatment with rituximab and 
venetoclax. 
Approximately 113−134 patients are expected be enrolled in this study at approximately 
20−25 investigative sites worldwide.   
All patients will be closely monitored for adverse events throughout the study and for at least 
90 days after the last dose of study treatment.  Adverse events will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
Version 4.0.  An Internal Monitoring Committee (IMC) will be established to monitor patient 
safety throughout the study.   


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To characterize the PK properties of obinutuzumab, rituximab, polatuzumab vedotin, and 
venetoclax, blood samples will be obtained at various timepoints before and during study 
treatment administration. 
Response will be determined by the IRC and the investigator using the Lugano 2014 criteria.  
The primary efficacy endpoint will be based on the IRC assessment of response.   
In this study, a DLT is defined as any one of the following events that occurs during the first 
cycle of treatment and is assessed by the investigator as related to study treatment that is not 
attributed to disease progression or another clearly identified cause: 
• 
Any adverse event of any grade that leads to a delay of more than 14 days in the start of 
the next treatment cycle 
• 
Any Grade 3 or 4 non-hematologic adverse event, with the following exceptions: 
– 
Grade 3 or 4 infusion-related reactions (IRRs) 
Note that IRRs may occur even after a small amount of drug has been 
administered (i.e., IRRs are not dose dependent). 
– 
Grade 3 diarrhea that responds to therapy within 72 hours 
– 
Grade 3 nausea or vomiting that occurs in the absence of premedication and 
responds to adequate therapy within 72 hours 
– 
Grade 3 fatigue that resolves to Grade ≤  2 within 7 days 
– 
Grade 3 laboratory tumor lysis syndrome without manifestations of clinical tumor lysis 
syndrome (i.e., creatinine ≥ 1.5 × upper limit of normal [ULN] and/or renal dysfunction, 
cardiac arrhythmias, seizures, or sudden death) that resolves within 7 days (see 
Appendix 12) 
– 
Grade 3 laboratory abnormality that is asymptomatic and deemed by the investigator 
not to be clinically significant 
– 
Grade 3 elevation in ALT or AST, provided the following criteria are met: 
ALT or AST level is no greater than 8 × ULN 
ALT or AST elevation resolves to Grade < 2 (< 5 × ULN) within 7 days 
Total and direct bilirubin and other laboratory parameters of liver synthetic 
function (e.g., prothrombin time) are normal 
No clinical signs or symptoms of hepatic injury 
• 
Any increase in hepatic transaminase > 3 × baseline AND an increase in direct 
bilirubin > 2 × ULN, WITHOUT any findings of cholestasis or jaundice or signs of hepatic 
dysfunction AND in the absence of other contributory factors (e.g., worsening of metastatic 
disease or concomitant exposure to known hepatotoxic agent or of a documented infectious 
etiology) is suggestive of potential drug-induced liver injury (according to Hy’s Law) and will 
be considered a DLT. 
• 
In patients with Grade 1 ALT or AST elevation at baseline as a result of liver metastases, 
only a Grade ≥ 3 elevation that is also ≥ 3 × baseline lasting > 7 days will be considered 
a DLT.  
• 
Hematologic adverse event that meets any of the following criteria: 
– 
Grade 3 or 4 neutropenia in the presence of sustained fever of > 38°C (lasting 
> 5 days) or a documented infection  
– 
Grade 4 neutropenia lasting > 7 days 


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– 
Grade 3 or 4 thrombocytopenia that results in significant bleeding per investigator 
judgment 
– 
Grade 4 thrombocytopenia lasting > 7 days 
 
Other toxicities occurring during the first cycle that are considered clinically relevant and related 
to study treatment, as determined by the investigator and the Medical Monitor, may also be 
considered DLTs. 
Obinutuzumab Plus Polatuzumab Vedotin Plus Venetoclax Treatment Group 
Treatment Group (Patients with Follicular Lymphoma) 
All patients enrolled in the FL dose-escalation phase will receive induction treatment, 
administered in 21-day cycles.  When study treatments are given on the same day, they will be 
administered sequentially in the following order:  venetoclax, obinutuzumab, and polatuzumab 
vedotin. 
Cycle 1: 
• 
Venetoclax 200, 400, 600, or 800 mg by mouth (PO) once daily on Days 1−21  
• 
Obinutuzumab 1000 mg intravenously (IV) on Days 1, 8, and 15 
• 
Polatuzumab vedotin 1.4 or 1.8 mg/kg IV on Day 1 
 
Cycles 2−6: 
• 
Venetoclax 200, 400, 600, or 800 mg PO once daily on Days 1−21 
• 
Obinutuzumab 1000 mg IV on Day 1 
• 
Polatuzumab vedotin 1.4 or 1.8 mg/kg IV on Day 1 
 
After completion of induction treatment, patients will continue to receive daily venetoclax 
treatment (during Month 1) until response is assessed at EOI.  Venetoclax will be discontinued if 
response assessments at EOI indicate that a patient is not eligible for post-induction treatment 
(referred to as maintenance).  Patients who achieve a CR, PR, or stable disease at EOI will 
receive maintenance treatment with obinutuzumab and venetoclax.  Polatuzumab vedotin will 
not be given as maintenance treatment.  Maintenance treatment will continue until disease 
progression or unacceptable toxicity for up to 24 months.  When study treatments are given on 
the same day, venetoclax will be administered prior to obinutuzumab. 
Maintenance treatment consisting of the following, administered for 24 months (Months 1−24): 
• 
Venetoclax 200, 400, 600, or 800 mg PO once daily for 8 months (Months 1−8) 
• 
Obinutuzumab 1000 mg IV on Day 1 of every other month (i.e., every 2 months) for 
24 months, starting with Month 2 (e.g., Months 2, 4, 6, 8, etc.) 
 
A 3 + 3 dose-escalation schema will be used.  The obinutuzumab dose will remain fixed at 
1000 mg during the dose-escalation phase.  The starting doses in Cohort 1a are 1.4 mg/kg for 
polatuzumab vedotin and 200 mg for venetoclax.  In Cohorts 1−6, dose escalation of 
polatuzumab vedotin and venetoclax will proceed in increments that parallel the magnitude of 
dose increases tested in ongoing Phase Ib trials.  For polatuzumab vedotin, there are 2 possible 
dose levels:  1.4 or 1.8 mg/kg.  For venetoclax, there are 4 dose levels:  200, 400, 600, or 
800 mg.   
Intrapatient dose escalation will be allowed only for the Cohort 1a patients receiving 200 mg of 
venetoclax.  In this cohort, the venetoclax dose may be escalated from 200 mg to 400 mg once 
Cohorts 2 and 3 open after approval by the Medical Monitor.  Intrapatient dose escalation is not 
allowed in other cohorts.   
Dose escalation will occur in accordance with the rules listed below. 
• 
A minimum of 3 patients will initially be enrolled in each cohort.  The first 3 patients in each 
cohort will be sequentially enrolled and dosed at least 48 hours apart. 


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• 
If none of the first 3 DLT-evaluable patients experiences a DLT, the doses in that cohort will 
be deemed safe and tolerable and escalation may continue according to the 
dose-escalation plan described above. 
• 
If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will be expanded to 
at least 6 patients.  If there are no further DLTs in the first 6 DLT-evaluable patients, the 
doses in that cohort will be deemed safe and tolerable and escalation may continue 
according to the dose-escalation plan described above. 
• 
If a DLT is observed in ≥ 33% of patients (e.g., 2 or more of up to 6 patients), the dose 
combination at which this occurs will be considered intolerable and the maximum-tolerated 
dose (MTD) will have been exceeded for polatuzumab vedotin and/or venetoclax in the 
G + Pola + V treatment combination.  However, enrollment may continue in alternative 
cohorts. 
• 
If the MTD is exceeded in any cohort, the highest dose combination at which fewer 
than 33% (e.g.,  2 of 6 DLT-evaluable patients) experience a DLT will be declared the 
combination MTD (i.e., the MTDs for polatuzumab vedotin and venetoclax in the 
G + Pola + V treatment combination). 
• 
If the MTD is not exceeded in any cohort, the highest dose combination administered in this 
study will be declared the maximum administered doses for polatuzumab vedotin and 
venetoclax in the G + Pola + V treatment combination. 
 
If the MTD is exceeded in any cohort, de-escalation of the polatuzumab vedotin dose and/or 
venetoclax dose and adjustment of treatment schedules (e.g., venetoclax treatment on 
Days 1−10) may occur.  It is possible that more than one combination MTD (i.e., potential 
RP2Ds) will be identified, which may consist of different dose or schedule combinations for 
polatuzumab vedotin and venetoclax that are deemed safe and tolerable when combined with a 
fixed dose of obinutuzumab.  If this occurs, it is possible that more than one expansion cohort 
will be enrolled to gather additional safety, PK, and pharmacodynamic data at these RP2Ds and 
schedules.  Additional patients may be enrolled in a given cohort in the absence of DLTs to 
acquire additional safety data for the appropriate dose levels in the expansion phase of the 
study. 
On the basis of a review of real−time safety data and available preliminary PK data, dose 
escalation may be halted or modified by the Sponsor as deemed appropriate. 
Relevant demographic, adverse event, laboratory, dosing administration/intensity, and PK (if 
available) data will be reviewed throughout the study by the Clinical Study Team and prior to 
dose-escalation decisions, which will be made by the Medical Monitor in consultation with the 
Principal Investigator and participating investigators. 
Although the DLT-assessment window is defined as the first treatment cycle (from Day 1 of 
Cycle 1 to Day 1 of Cycle 2), cumulative or late toxicities that occur beyond the first cycle may 
be considered in determination of the RP2Ds.  Prior to opening the R/R FL expansion phase, 
the Clinical Study Team and the Medical Monitor will review the cumulative data, 
recommend the RP2D, and review this with the IMC for approval.   
The expansion phase is designed to further assess the safety and efficacy of polatuzumab 
vedotin and venetoclax at their respective RP2Ds when combined with a fixed dose of 
obinutuzumab in FL patients.   
All patients enrolled in the FL expansion phase will receive induction treatment, administered in 
21-day cycles.  When study treatments are given on the same day, they will be administered 
sequentially in the following order:  venetoclax, obinutuzumab, and polatuzumab vedotin. 
Cycle 1: 
• 
Venetoclax at the RP2D (mg) PO once daily on Days 1−21 
• 
Obinutuzumab 1000 mg IV on Days 1, 8, and 15 
• 
Polatuzumab vedotin at the RP2D (mg/kg) IV on Day 1 
 
Cycles 2−6: 
• 
Venetoclax at the RP2D (mg) PO once daily on Days 1−21 


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• 
Obinutuzumab 1000 mg IV on Day 1 
• 
Polatuzumab vedotin at the RP2D (mg/kg) IV on Day 1 
 
After completion of induction treatment, patients will continue to receive daily venetoclax 
treatment (during Month 1) until response is assessed at EOI.  Venetoclax will be discontinued if 
response assessments at EOI indicate that a patient is not eligible for post-induction treatment.  
Patients with FL who achieve a CR, PR, or stable disease at EOI will receive post-induction 
treatment (referred to as maintenance) with obinutuzumab and venetoclax.  Polatuzumab 
vedotin will not be given as post-induction treatment.  Post-induction treatment will continue until 
disease progression or unacceptable toxicity for up to 24 months for maintenance treatment.  
When study treatments are given on the same day, venetoclax will be administered prior to 
obinutuzumab.   
 
Follicular Lymphoma 
Maintenance treatment consisting of the following, administered for 24 months (Months 1−24): 
• 
Venetoclax at the RP2D (mg) PO once daily for 8 months (Months 1−8) 
• 
Obinutuzumab 1000 mg IV on Day 1 of every other month (i.e., every 2 months) for 
24 months, starting with Month 2 (e.g., Months 2, 4, 6, 8, etc.) 
 
Rituximab Plus Polatuzumab Vedotin Plus Venetoclax Treatment Group (Patients 
with DLBCL) 
Patients enrolled in the DLBCL dose-escalation phase will receive induction treatment, 
administered in 21-day cycles.  When study treatments are given on the same day, they will be 
administered sequentially in the following order:  venetoclax, rituximab, and polatuzumab 
vedotin.   
Cycles 1−6: 
• 
Venetoclax 400, 600, or 800 mg PO once daily on Days 1−21  
• 
Rituximab 375 mg/m2 IV on Day 1 
• 
Polatuzumab vedotin 1.8 mg/kg IV on Day 1 
 
After completion of induction treatment, patients will continue to receive daily venetoclax 
treatment (during Month 1) until response is assessed at EOI.  Venetoclax will be 
discontinued if response assessments at EOI indicate that a patient is not eligible for post-
induction treatment (referred to as consolidation).  Patients who achieve a CR or PR at EOI 
will receive consolidation treatment with rituximab and venetoclax.  Polatuzumab vedotin will 
not be given as consolidation treatment.  Consolidation treatment will continue until disease 
progression or unacceptable toxicity for up to 8 months.  When study treatments are given on 
the same day, venetoclax will be administered prior to rituximab.   
Consolidation treatment consisting of the following, administered for 8 months (Months 1−8): 
• 
Venetoclax 400, 600, or 800 mg PO once daily for 8 months (Months 1−8) 
• 
Rituximab 375 mg/m2 IV on Day 1 of every other month (i.e., every 2 months), starting 
with Month 2 (e.g., Months 2, 4, 6, 8) for 8 months 
 
A standard 3 + 3 dose-escalation schema will be used.  The rituximab and polatuzumab dose 
levels will remain fixed during the dose-escalation phase and only the venetoclax will be dose 
escalated.  The polatuzumab dose of 1.8 mg/kg is based on ongoing Phase II trials.  Intrapatient 
dose escalation is not allowed.   


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Dose escalation will occur in accordance with the rules listed below. 
• 
A minimum of 3 patients will initially be enrolled in each cohort.  The first 3 patients in 
each cohort will be sequentially enrolled and dosed at least 48 hours apart.   
• 
If none of the first 3 DLT-evaluable patients experiences a DLT, the doses in that cohort 
will be deemed safe and tolerable and escalation may continue per the dose-escalation plan 
described above. 
• 
If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will be expanded to 
6 patients.  If there are no further DLTs in the first 6 DLT-evaluable patients, the doses in 
that cohort will be deemed safe and tolerable and escalation may continue per the dose-
escalation plan described above. 
• 
If a DLT is observed in ≥ 33% of patients (e.g., 2 or more of up to 6 DLT-evaluable 
patients), the dose combination at which this occurs will be considered intolerable and the 
MTD will have been exceeded for venetoclax in the R + Pola + V treatment combination.   
• 
If the MTD is exceeded in any cohort, the highest dose combination at which < 33% of 
patients (e.g., 2 of 6 DLT-evaluable patients) experience a DLT will be declared the 
combination MTD (i.e., the MTD venetoclax in the R + Pola + V treatment combination). 
• 
If the MTD is not exceeded at any dose level, the highest dose combination administered in 
this study will be declared the maximum administered dose for polatuzumab vedotin and 
venetoclax in the R + Pola + V treatment combination. 
 
If the MTD is exceeded in any cohort, de-escalation of the venetoclax dose and/or polatuzumab 
vedotin dose, and/or adjustment of treatment schedules (e.g., venetoclax treatment on Days 
1−10) may occur.  Additional patients may be enrolled in a given cohort in the absence of DLTs 
to acquire additional safety data for the appropriate dose levels in the expansion phase of the 
study. 
On the basis of a review of real-time safety data and available preliminary PK data, dose 
escalation may be halted or modified by the Sponsor as deemed appropriate. 
Relevant demographic, adverse event, laboratory, dosing administration/intensity, and PK (if 
available) data will be reviewed prior to dose-escalation decisions, which will be made by the 
Medical Monitor in consultation with the Principal Investigator and participating 
investigators. 
Although the DLT assessment window is defined as the first treatment cycle (from Day 1 of 
Cycle 1 to Day 1 of Cycle 2), cumulative or late toxicities that occur beyond the first cycle may 
be considered in determination of the RP2Ds.  Prior to opening the R/R DLBCL expansion 
phase, the Clinical Study Team and the Medical Monitor will review the cumulative data, 
determine the RP2D, and review this with the IMC for approval.   
The expansion phase is designed to further assess the safety and efficacy of venetoclax when 
combined with a fixed dose of rituximab and polatuzumab vedotin in DLBCL patients.  


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All patients enrolled in the expansion phase will receive induction treatment.  When study 
treatments are given on the same day, they will be administered sequentially in the following 
order:  venetoclax, rituximab, and polatuzumab vedotin. 
Cycles 1−6: 
• 
Venetoclax at the RP2D (mg) PO once daily on Days 1−21 
• 
Rituximab 375 mg/m2 IV on Day 1 
• 
Polatuzumab vedotin 1.8 mg/kg IV on Day 1 
 
After completion of induction treatment, patients will continue to receive daily venetoclax 
treatment (during Month 1) until response is assessed at EOI.  Venetoclax will be discontinued 
if response assessments at EOI indicate that a patient is not eligible for post-induction 
treatment.  Patients with DLBCL who achieve a CR or PR at EOI will receive post-induction 
treatment (referred to as consolidation) with rituximab and venetoclax.  Polatuzumab vedotin 
will not be given as post-induction treatment.  Post-induction treatment will continue until 
disease progression or unacceptable toxicity for up to 8 months for consolidation treatment.  
When study treatments are given on the same day, venetoclax will be administered prior to 
rituximab.   
Diffuse Large B-Cell Lymphoma  
Consolidation treatment consisting of the following, administered for 8 months (Months 1−8): 
• 
Venetoclax at the RP2D (mg) PO once daily for 8 months (Months 1−8) 
• 
Rituximab 375 mg/m2 IV on Day 1 of every other month (i.e., every 2 months) starting 
with Month 2 (i.e., Months 2, 4, 6, 8) for 8 months 
 
Number of Patients 
Approximately 113−134 patients are expected be enrolled in this study at approximately 
20−25 investigative sites worldwide.  This includes approximately 80 patients (40 patients with 
FL and 40 patients with DLBCL) who will be enrolled during the expansion phase. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years 
• 
Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2 
• 
For G + Pola + V treatment group:  R/R FL after treatment with at least 1 prior 
chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody and 
for which no other more appropriate treatment option exists, as determined by the 
investigator 
• 
For R + Pola + V treatment group:  R/R DLBCL after treatment with at least 1 prior 
chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody, with no 
curative option as determined by the investigator 
• 
Histologically documented CD20-positive non-Hodgkin’s lymphoma as determined by the 
local laboratory 
• 
Fluorodeoxyglucose-avid lymphoma (i.e., PET-positive lymphoma) 
• 
At least one bi-dimensionally measurable lesion (> 1.5 cm in its largest dimension by 
CT scan or magnetic resonance imaging) 


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• 
Availability of a representative tumor specimen and the corresponding pathology report for 
retrospective central confirmation of the diagnosis of FL or DLBCL 
If the archival tissue is unavailable or unacceptable, a pretreatment core, excisional, or 
incisional tumor biopsy is required.  Cytological or fine-needle aspiration samples are 
not acceptable.  
If the patient received anti-lymphoma treatment between the time of the most recent 
available biopsy and initiation of study treatment, a core-needle biopsy is strongly 
recommended. 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% 
per year during the treatment period and for at least 12 months after the last dose of 
polatuzumab vedotin, 30 days after the last dose of venetoclax, 12 months after last dose of 
rituximab, or at least 18 months after the last dose of obinutuzumab. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, established, proper use of hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices (IUDs), and copper IUDs. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. 
• 
For men:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below: 
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
< 1% per year during the treatment period and for at least 5 months after the last dose 
of polatuzumab vedotin, 30 days after the last dose of venetoclax, and 3 months after 
the last dose of obinutuzumab or rituximab.  Men must refrain from donating sperm 
for the same period. 
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 5 months after the last dose of polatuzumab 
vedotin, 30 days after the last dose of venetoclax, and 3 months after the last dose of 
obinutuzumab or rituximab.  
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Known CD20-negative status at relapse or progression 
• 
Prior allogeneic stem cell transplant (SCT) 
• 
Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1 
• 
Prior standard or investigational anti-cancer therapy as specified below: 
– 
Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1 
– 
Monoclonal antibody or antibody–drug conjugate therapy within 5 half-lives or 
4 weeks prior to Day 1 of Cycle 1, whichever is longer 
– 
Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule therapy 
within 2 weeks prior to Day 1 of Cycle 1 


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• 
Clinically significant toxicity (other than alopecia) from prior therapy that has not resolved to 
Grade ≤ 2 (per NCI CTCAE v4.0) prior to Day 1 of Cycle 1 
• 
Grade 3b FL 
• 
History of transformation of indolent disease to DLBCL 
• 
Current Grade > 1 peripheral neuropathy 
• 
CNS lymphoma or leptomeningeal infiltration 
• 
Treatment with systemic corticosteroids > 20 mg/day prednisone or equivalent 
Patients who are receiving corticosteroids ≤ 20 mg/day, prednisone or equivalent, for 
non-lymphoma treatment reasons must be documented to be on a stable dose for at 
least 4 weeks prior to Day 1 of Cycle 1.  
If corticosteroid treatment is urgently required for lymphoma symptom control prior to 
the start of study treatment, up to 100 mg/day of prednisone or equivalent can be given 
for a maximum of 5 days, but all tumor assessments must be completed prior to start 
of corticosteroid treatment. 
• 
History of severe allergic or anaphylactic reaction to humanized or murine monoclonal 
antibodies 
• 
Known sensitivity or allergy to murine products or any component of the obinutuzumab, 
rituximab, polatuzumab vedotin, or venetoclax formulations 
• 
Active bacterial, viral, fungal, or other infection  
Caution should be exercised when considering the use of obinutuzumab and 
rituximab in patients with a history of recurring or chronic infections. 
• 
Requirement for warfarin treatment (because of potential drug-drug interactions that may 
increase the exposure of warfarin) 
• 
Treatment with the following agents within 7 days prior to the first dose of venetoclax: 
– 
Strong and moderate CYP3A inhibitors such as fluconazole, ketoconazole, and 
clarithromycin 
– 
Strong and moderate CYP3A inducers such as rifampin and carbamazepine 
• 
Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade that 
contains Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax 
• 
Clinically significant history of liver disease, including viral or other hepatitis, current alcohol 
abuse, or cirrhosis  
• 
Positive for hepatitis B surface antigen, total hepatitis B core antibody, or hepatitis C virus 
antibody at screening 
• 
Known history of HIV positive status 
For patients with unknown HIV status, HIV testing will be performed at screening if 
required by local regulations. 
• 
History of progressive multifocal leukoencephalopathy  
• 
Vaccination with a live virus vaccine within 28 days prior to Day 1 of Cycle 1 
• 
History of other malignancy that could affect compliance with the protocol or interpretation 
of results, with the exception of the following: 
– 
Curatively treated carcinoma in situ of the cervix, good-prognosis ductal carcinoma in 
situ of the breast, basal- or squamous-cell skin cancer, Stage I melanoma, or 
low-grade, early-stage localized prostate cancer 
– 
Any previously treated malignancy that has been in remission without treatment for 
≥ 2 years prior to enrollment 


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• 
Evidence of any significant, uncontrolled concomitant disease that could affect compliance 
with the protocol or interpretation of results, including significant cardiovascular disease 
(such as New York Heart Association Class III or IV cardiac disease, myocardial infarction 
within the previous 6 months, unstable arrhythmia, or unstable angina) or significant 
pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm) 
• 
Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 1, 
or anticipation of a major surgical procedure during the course of the study 
• 
Inadequate hematologic function (unless due to underlying lymphoma), defined as follows: 
– 
Hemoglobin < 9 g/dL 
– 
ANC < 1.5 × 109/L 
– 
Platelet count < 75 × 109/L 
• 
Any of the following abnormal laboratory values (unless due to underlying lymphoma): 
– 
Calculated creatinine clearance < 50 mL/min with the use of 24-hour creatinine 
clearance or modified Cockcroft-Gault equation (eCCr; with use of the ideal body 
mass [IBM] instead of mass): 
(140 − Age) • IBM (kg) • [0.85 if female] 
eCCr = 
72 • serum creatinine (mg/dL) 
Or, if serum creatinine is in μmol/L: 
 
(140 − Age) • IBM (kg) • [1.23 if male, 1.04 if female] 
eCCr = 
serum creatinine (μmol/L) 
– 
AST or ALT > 2.5 × by ULN 
– 
Serum total bilirubin > 1.5 × ULN (or > 3 × ULN for patients with Gilbert syndrome)   
– 
INR or PT > 1.5 × ULN in the absence of therapeutic anticoagulation 
– 
PTT or aPTT > 1.5 × ULN in the absence of a lupus anticoagulant 
• 
Pregnant or lactating, or intending to become pregnant during the study 
Women of childbearing potential must have a negative serum pregnancy test result within 
7 days prior to Day 1 of Cycle 1. 
• 
Life expectancy  < 3 months 
• 
Unable to comply with the study protocol, in the investigator’s judgment 
 
End of Study 
The end of this study is defined as the time when both of the following criteria are met:  
• 
All enrolled FL patients have been followed for at least 90 days after they have completed 
or discontinued study treatment (including induction treatment and maintenance treatment 
as applicable).   
• 
All enrolled DLBCL patients have been followed for at least 1 year after they have 
completed or discontinued study treatment (including induction treatment and consolidation 
treatment as applicable).   
 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4.5 years. 
Length of Study 
The length of study will be the time from screening of the first enrolled patient through 2 years 
after the treatment completion visit for the last enrolled patient.  The length of study is expected 
to be approximately 4.5 years. 


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Investigational Medicinal Products 
The investigational medicinal products used in this study are obinutuzumab, rituximab, 
polatuzumab vedotin, and venetoclax. 
Obinutuzumab Plus Polatuzumab Vedotin Plus Venetoclax Treatment Group 
(Patients with Follicular Lymphoma) 
Obinutuzumab 
• 
Induction:  Patients will receive obinutuzumab 1000 mg IV on Days 1, 8, and 15 of Cycle 1 
and on Day 1 of each subsequent 21-day cycle for up to 6 total cycles.   
• 
Post-Induction:  
Patients will receive obinutuzumab 1000 mg IV every other treatment cycle (i.e., every 
2 months) starting on Cycle 8 through Cycle 30 (i.e., Months 2−24) for approximately 
24 months of additional treatment. 
Polatuzumab Vedotin 
• 
Induction:  Patients will receive polatuzumab vedotin 1.4 mg/kg or 1.8 mg/kg IV on Day 1 of 
each 21-day cycle for a total of 6 cycles.  
• 
In the Phase Ib portion (dose-escalation phase) of the study, the total dose of polatuzumab 
vedotin for each patient will depend on dose level assignment and the patient’s weight on 
Day 1 of Cycle 1 (or within 96 hours before Cycle 1 Day 1). 
• 
In the Phase II portion (dose-expansion phase) of the study, the total dose of polatuzumab 
vedotin for each patient will depend on the RP2D established in the Phase Ib portion and 
the patient’s weight on Day 1 of Cycle 1 (or within 96 hours before Cycle 1 Day 1). 
• 
Post-Induction:  No polatuzumab vedotin will be administered. 
Venetoclax 
• 
Induction:  Patients will receive venetoclax 200 mg, 400 mg, 600 mg, or 800 mg PO daily 
In the Phase Ib portion (dose-escalation phase) of the study, the dose of venetoclax for 
each patient will depend on dose level assignment on Day 1 of Cycle 1. 
In the Phase II portion (dose-expansion phase) of the study, the dose of venetoclax for 
each patient will depend on the RP2D established in the Phase Ib. 
• 
Post-Induction, dose-escalation phase: Patients will receive venetoclax 200 mg, 400 mg, 
600 mg, or 800 mg PO daily (starting on Cycle 7 through Cycle 13) for for approximately 
8 months of additional treatment.   
• 
Post-Induction, expansion phase:  Patients will receive venetoclax at RP2D PO daily 
(starting on Cycle 7 through Cycle 13) for approximately 8 months of additional treatment 
 
Rituximab Plus Polatuzumab Vedotin Plus Venetoclax Treatment Group (Patients 
with DLBCL) 
Rituximab 
• 
Induction:  Patients will receive rituximab 375 mg/m2 IV on Day 1 of Cycles 1−6.   
• 
Post-Induction:  
Patients will receive rituximab 375 mg/m2 IV every other treatment cycle (i.e., every 
2 months) starting with Month 2 (e.g., Months 2, 4, 6, 8) for 8 months 
 
Polatuzumab Vedotin 
• 
Induction:  Patients will receive polatuzumab vedotin 1.8 mg/kg IV on Day 1 of each 21-day 
cycle for a total of 6 cycles.  
• 
In the Phase Ib portion (dose-escalation phase) of the study, the total dose of polatuzumab 
vedotin for each patient will depend on dose level assignment and the patient’s weight on 
Day 1 of Cycle 1 (or within 96 hours before Cycle 1 Day 1). 
• 
In the Phase II portion (dose-expansion phase) of the study, the total dose of polatuzumab 
vedotin for each patient will depend on the RP2D established in the Phase Ib portion and 
the patient’s weight on Day 1 of Cycle 1 (or within 96 hours before Cycle 1 Day 1). 


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• 
Post-Induction:  No polatuzumab vedotin will be administered. 
 
Venetoclax 
• 
Induction:  Patients will receive venetoclax 400 mg, 600 mg, or 800 mg PO daily 
In the Phase Ib portion of the study, the dose of venetoclax for each patient will depend 
on dose level assignment on Day 1 of Cycle 1. 
In the Phase II portion of the study, the dose of venetoclax for each patient will depend 
on the RP2D established in the Phase Ib. 
• 
Post-Induction, dose-escalation phase:  Patients will receive venetoclax 400 mg, 600 mg, or 
800 mg PO once daily (starting on Cycle 7 through Cycle 13) for approximately 8 months 
• 
Post-Induction, dose-expansion phase:  Patients will receive venetoclax at RP2D PO once 
daily (starting on Cycle 7 through Cycle 13) for approximately 8 months of additional 
treatment 
 
Statistical Methods 
Primary Analysis 
Response will be determined on the basis of PET-CT scans or CT scans alone, using the 
Lugano 2014 criteria. 
The primary efficacy endpoint is the proportion of patients achieving a CR at EOI, as 
determined by the IRC on the basis of PET-CT scans according to Lugano 2014.  Point 
estimates will be presented, along with the corresponding 90% Clopper-Pearson exact CIs.  
Patients without a post-baseline tumor assessment will be considered non-responders. 
Determination of Sample Size  
Limited dose finding will be conducted during the dose-escalation phase of this study.  The 
estimated sample size follows from the dose-escalation rules for a standard 3 + 3 algorithm.  It is 
anticipated that enrollment of 6 cohorts of 3−6 patients each, for a total of 21−36 patients, will 
be required to establish the RP2D during the dose-escalation phase for patients with R/R FL.  
There are three possible cohorts of 3−6 patients each, for a total of 12−18 patients with 
replapsed or refractory DLBCL. 
Approximately 80 patients (40 patients with FL and 40 patients with DLBCL) will be enrolled 
during the expansion phase.  Overall, approximately 113−134 patients will be enrolled in this 
study. 
The primary analysis will be estimation of the true proportion of patients expected to obtain a 
PET-CT−defined CR at EOI.   
Data from completed and ongoing studies in similar disease settings will be used as historical 
controls for comparison.  Currently available data indicate that the historical CR rate based on 
PET-CT scans is around 40% for R/R FL and DLBCL.   
A sample size of 40 patients is deemed sufficient to provide adequate precision for the point 
estimate and for the lower bound of the two-sided 90% CI to rule out a clinically uninteresting 
probability of response of < 55%, assuming an observed PET-CT−defined CR rate of 70%. 
Interim Analyses  
It is anticipated that at least one interim analysis will be conducted during the expansion phase 
of the study, when at least 15 patients in each treatment group have been evaluated for PET-
CT−defined CR at the EOI.  Additional analyses may be conducted to guide early stopping of 
enrollment for safety on the basis of observed toxicities and the ability to maintain 
chemotherapy dose intensity. 
During the expansion phase, a modified version of the predictive probability design may be 
used to guide early stopping for futility by comparing the observed proportion of patients who 
achieve a PET-CT−defined CR at EOI in each expansion cohort with that in historical controls.  
The design is based on Lee and Lui 2008 with the modification that the uncertainty in the 
historical control data is fully taken into account by utilizing a beta posterior on the control 
response rate.  Interim analysis decision rules will be based on the predicative probability that 


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the trial will have a positive outcome if carried out to completion and will use the historical 
control data available at the time of analysis.   
If, at any time, an interim analysis suggests that the proportion of patients achieving a 
PET-CT−defined CR for one of the expansion cohorts is lower than expected, the IMC will 
review the data and decide whether to recommend an early decision to stop enrollment in that 
cohort because of futility.   
Additional review of safety and/or efficacy data by the IMC may be requested by and carried out 
at the discretion of the Medical Monitor.  Further details regarding the rules and guidelines of 
data review will be provided to the IMC in an IMC charter. 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
18F-FDG 
18F-fluorodeoxyglucose  
ABC 
activated B cell–like (subgroup) 
acMMAE 
antibody-conjugated mono-methyl auristatin E 
ADC 
antibody–drug conjugate 
AE 
adverse event 
ASCO 
American Society of Clinical Oncology 
ATA 
anti-therapeutic antibody 
AUC 
area under the concentration–time curve 
AUCinf 
area under the concentration–time curve extrapolated 
to infinity 
BCRP 
breast cancer receptor proteins 
BR 
bendumustine plus rituximab 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and 
prednisolone or prednisone 
CL 
clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration 
CR 
complete response 
Cri 
complete response with incomplete bone marrow 
recovery 
CT 
computed tomography 
CVP 
cyclophosphamide, vincristine, and prednisone 
DDI 
drug–drug interaction 
DFS 
disease-free survival 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOP 
delta-opioid receptor 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCCr 
estimation of creatinine clearance 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFS 
event-free survival 
EOI 
end of induction 
EOC 
EORTC 
end of consolidation 
European Organization for Research and Treatment of 
Cancer 


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Abbreviation 
Definition 
ESMO 
European Society for Medical Oncology 
FDA 
United States Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FL 
follicular lymphoma 
FLIPI, FLIPI2 
Follicular Lymphoma International Prognostic Index 
Follicular Lymphoma International Prognostic Index 2 
G 
obinutuzumab (GA101) 
G + Pola + V 
obinutuzumab plus polatuzumab vedotin plus 
venetoclax 
G + V 
obinutuzumab plus venetoclax 
GB 
obinutuzumab plus bendamustine 
GCB 
germinal-center B cell–like (subgroup) 
G-CHP 
obinutuzumab in combination with cyclophosphamide, 
doxorubicin, and prednisone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
HAHA 
human anti-human antibody 
HbA1c 
glycosylated hemoglobin 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
IBM 
ideal body mass 
ICH 
International Conference on Harmonisation 
IHC 
immunohistochemistry 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
iNHL 
indolent non-Hodgkin's lymphoma 
IPI 
International Prognostic Index 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
IUD 
intrauterine device 
IV 
intravenous 
IxRS 
interactive voice or web-based response system 


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Abbreviation 
Definition 
JCV 
John Cunningham virus 
MCL 
mantle cell lymphoma 
MMAE 
mono-methyl auristatin E 
MRD 
minimum residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MZL 
marginal zone lymphoma 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NE 
not estimable 
NHL 
non-Hodgkin’s lymphoma 
NK 
natural killer 
NOAEL 
no observed adverse effect level 
ORR 
objective response rate 
OS 
overall survival 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response 
QTc 
corrected QT interval 
R 
rituximab 
R + Pola + V 
rituximab in combination with polatuzumab vedotin 
and venetoclax 
R + V 
rituximab in combination with venetoclax 
R/R 
relapsed or refractory 
R-CHOP 
rituximab in combination with cyclophosphamide, 
doxorubicin, vincristine, and prednisolone or 
prednisone 
R-CHP 
rituximab in combination with cyclophosphamide, 
doxorubicin, and prednisone 
RCR 
Roche Clinical Repository 
RP2D 
recommended Phase II dose 
SC 
subcutaneous 
SCT 
stem-cell transplantation 
SLL 
small lymphocytic lymphoma 
t1/2 
half-life 


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Abbreviation 
Definition 
TAb 
total antibody 
TIL 
tumor-infiltrating lymphocyte 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
vcMMAE 
valine-citrulline monomethyl auristatin E  
VSS 
volume at steady state 
WM 
Waldenström's macroglobulinemia 
 


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1. 
BACKGROUND 
1.1 
BACKGROUND ON NON-HODGKIN'S LYMPHOMA 
Non-Hodgkin’s lymphoma (NHL) is the most common hematologic malignancy in adults.  
In 2015, there will be an estimated 71,850 new cases and 19,790 deaths due to the 
disease in the United States (SEER 2015).  In Europe, there were an estimated 
93,400 new cases and 37,900 deaths in 2012 (Ferlay et al. 2013).  NHL is most often of 
B-cell origin.  This includes a range of different subtypes of B-cell lymphoma, which are 
broadly divided into indolent and aggressive lymphomas, each with unique 
characteristics. 
1.1.1 
Follicular Lymphoma 
Indolent B-cell lymphomas are a heterogeneous group of malignant lymphomas and 
account for approximately one-third of all NHLs.  Follicular lymphoma (FL) is the most 
common subtype of indolent B-cell lymphoma; it accounts for about 22% of all newly 
diagnosed cases of NHL (Armitage and Weisenburger 1998).  Approximately 90% of the 
cases have a t(14:18) translocation, which juxtaposes BCL2 with the IgH locus and 
results in deregulated expression of Bcl-2.  
FL remains an incurable disease with the currently available therapies.  The addition of 
rituximab (seen as R in drug combination regimens), an anti-CD20 monoclonal antibody, 
to commonly used induction chemotherapy, including cyclophosphamide, doxorubicin, 
vincristine, and prednisone or prednisolone (CHOP); cyclophosphamide, vincristine, and 
prednisone (CVP); fludarabine; or bendamustine (Marcus et al. 2008; Hochster et al. 
2009; Dreyling et al. 2014; Zelenetz et al. 2014), followed by rituximab maintenance 
therapy led to prolonged remission and improved patient outcomes.  Updated results 
from Study MO18264 confirmed the benefit of 2-year rituximab maintenance therapy in 
patients who responded to first-line immunotherapy, with a 6-year progression-free 
survival (PFS) of 59.2% compared with 42.7% in the observation arm (p < 0.0001; 
Salles et al. 2013b).   
Despite significant therapeutic progress with the use of chemoimmunotherapy as 
first-line treatment, most patients will eventually relapse.  Relapses are characterized by 
increasing refractoriness and decreasing duration of response to subsequent lines of 
therapy.  Currently, approved therapies for relapsed FL include rituximab, bendamustine, 
idelalisib (refractory FL), and radioimmunotherapy.  New treatments are needed to 
improve the outcomes for patients with relapsed NHL. 
1.1.2 
Diffuse Large B-Cell Lymphoma 
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive NHL; 
it accounts for approximately 30% of all NHLs diagnosed annually 
(Armitage and Weisenburger 1998).  The use of immunochemotherapy, most 
commonly rituximab plus CHOP (R-CHOP) for newly diagnosed DLBCL, led to a 
significant improvement in survival in patients of all age groups.  In older patients 


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(> 60 years), R-CHOP was associated with a 2-year event-free survival (EFS) rate 
of 57% and a 10-year survival rate of 43.5% (Coiffier et al. 2010).  In younger patients 
(18−60 years old) with favorable prognostic features, R-CHOP demonstrated a 3-year 
EFS rate of 79% and survival rates of 93% and 74.3% at 3 and 6 years, respectively 
(Pfreundschuh et al. 2011).  However, nearly 40% of patients with DLBCL will eventually 
die of relapsed disease or disease that is refractory to first-line therapy.  Patients with a 
high-risk International Prognostic Index (IPI) have a 5-year PFS rate of 40% following 
treatment with R-CHOP (Zhou et al. 2014). 
Second-line therapies include high-dose chemotherapy regimens such as rituximab plus 
ifosfamide, carboplatin, and etoposide or rituximab plus cisplatin, cytosine arabinoside, 
and dexamethasone followed by autologous stem-cell transplantation (SCT).  
Approximately half of patients do not achieve a complete remission after salvage 
treatment (Gisselbrecht et al. 2010).  Moreover, elderly patients or patients with 
comorbidities are often deemed ineligible for this aggressive therapy. 
Specific molecular subsets of DLBCL are associated with an inferior outcome following 
R-CHOP therapy.  Patients with germinal center B cell–like (GCB) DLBCL have a better 
prognosis than patients with activated (non-germinal) B cell−like (ABC) DLBCL, with a 
3-year survival rate of 84% versus 56%, respectively (p < 0.001; Lenz et al. 2008).  
Several genetic abnormalities that are predictive of poor outcomes have been identified 
in DLBCL, including MYC rearrangement, BCL2 and BCL6 overexpression, and TP53 
mutations.  Rearrangement in MYC (MYC-positive DLBCL) has been reported in 
9%−17% of DLBCL cases and often correlates with the GCB DLBCL phenotype 
(Savage et al. 2009; Barrans et al. 2010).  Patients with MYC-negative DLBCL who 
receive R-CHOP have a 5−year survival rate that is markedly worse than patients with 
MYC-positive DLBCL who receive R-CHOP (33% vs. 72%, respectively; 
Savage et al. 2009).  Concurrent MYC and IGH-BCL2 rearrangement (known as 
“double-hit” DLBCL), which is observed in 2%−11% of DLBCL patients, represents a 
subset of DLBCL patients who have inferior outcomes (5-year PFS of 18%; 5-year 
survival of 27%; Savage et al. 2009; Dunleavy et al. 2014).  Mutations in TP53 have 
been described in 18%−30% of patients with DLBCL (Lossos and Morgensztern 2006) 
and are strong predictors of poor overall survival (OS; Young et al. 2008). 
DLBCL remains a disease with a high unmet medical need.  Novel targeted therapies 
are needed to move treatment options beyond R-CHOP. 
1.2 
BACKGROUND ON OBINUTUZUMAB 
Obinutuzumab (also known as GA101 and seen as G in drug combination regimens) 
is a novel glycoengineered type II anti-CD20 antibody.  Compared with rituximab, 
obinutuzumab is characterized by more potent direct B-cell death induction and 
increased affinity for FcγRIII receptors expressed on natural killer (NK) cells, 
macrophages, and monocytes.  This results in enhanced antibody−dependent cellular 
cytotoxicity and antibody−dependent cellular phagocytosis (Beers et al. 2010; 


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Mössner et al. 2010; Herter et al. 2014).  These characteristics confer obinutuzumab 
with enhanced immune effector functions and B cell−depleting activity compared with 
rituximab.  
Obinutuzumab is approved for use in combination with chlorambucil for the treatment of 
patients with previously untreated chronic lymphocytic leukemia (CLL).  Obinutuzumab 
is also approved for use in combination with bendamustine followed by obinutuzumab 
monotherapy for the treatment of patients with FL who did not respond to or who 
progressed during or after treatment with rituximab or a rituximab-containing regimen.   
1.2.1 
Nonclinical Studies with Obinutuzumab 
In nonclinical studies that used blood samples from healthy volunteers, use of 
obinutuzumab demonstrated superior depletion of normal B cells (measured as 
CD19 + depletion; Mössner et al. 2010) as well as depletion of malignant B cells from 
blood samples from patients with CLL (Patz et al. 2011).  Nonclinical xenograft 
experiments performed with obinutuzumab as monotherapy and in combination with 
chemotherapy have consistently showed that obinutuzumab has promising anti-tumor 
activity (Mössner et al. 2010; Dalle et al. 2011) and have demonstrated the superiority of 
obinutuzumab over rituximab (Herting et al. 2014). 
For more detailed information on nonclinical studies of obinutuzumab, please refer to the 
current version of the obinutuzumab Investigator’s Brochure.   
1.2.2 
Clinical Studies with Obinutuzumab 
As of 4 July 2016, clinical data from Roche-sponsored studies on obinutuzumab are 
available from 13 clinical studies, 8 Phase I or II studies (BO20999, BO21003, JO21900, 
BO21000, GAO4915g, GAO4779g, YP25623, and GAO4768g), and 5 Phase III/IIIb 
studies (BO21004, GAO4753g, BO21005, BO21223, and MO28543) in patients with 
NHL or CLL.  Available safety results from all patients and efficacy results from the NHL 
cohorts in these studies are summarized in Sections 1.2.2.1 and 1.2.2.2, respectively.  
Efficacy data from a Phase III study of obinutuzumab (GAO4753g) are also presented. 
For more detailed clinical information on obinutuzumab, including results in the CLL 
cohorts of the clinical studies and clinical pharmacology data, refer to the obinutuzumab 
Investigator’s Brochure. 
1.2.2.1 
Clinical Safety of Obinutuzumab 
As of the safety data cutoff date of 4 July 2016, an estimated 3636 patients with NHL 
(including DLBCL, indolent B-cell lymphoma, and CLL) had been treated with 
obinutuzumab given as monotherapy or in combination with CHOP, bendamustine, 
fludarabine plus cyclophosphamide, or chlorambucil, at doses ranging from 50 mg to 
2000 mg.  The overall safety and toxicity profile of obinutuzumab as monotherapy and 
as combination therapy was manageable. 


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The most frequent causes of death were disease progression and adverse events 
associated with infectious diseases.  This is consistent with the study population and the 
disease under treatment.  In Study GAO4768g, which compared obinutuzumab 1000 mg 
versus 2000 mg, the incidence of deaths did not increase with increased obinutuzumab 
dose (7.5% and 2.6%, respectively). 
Of particular interest, a high incidence of infusion-related reactions (IRRs) was observed 
consistently in all obinutuzumab trials.  The reported incidence of IRRs varied across 
studies.  In the CLL population, the incidence ranged from 66% in previously untreated 
patients who received obinutuzumab plus chlorambucil (Study BO21004) to 100% in 
patients with relapsed or refractory (R/R) disease who received obinutuzumab 
monotherapy (pooled data from Studies BO21003 and BO20999).   
In the NHL population, the incidence of IRRs in studies of obinutuzumab monotherapy 
was 73%−75% (pooled data from Study BO21003 and high-dose NHL cohorts from 
Study BO20999).  In studies of obinutuzumab in combination with either CHOP 
(Study GAO4915g) or bendamustine (Study BO21000), the incidence of IRRs 
considered to be related to obinutuzumab was 56%−59%. 
Other important risks associated or potentially associated with obinutuzumab are tumor 
lysis syndrome (TLS), thrombocytopenia (including acute thrombocytopenia), 
neutropenia (including prolonged and late onset neutropenia), prolonged 
B-cell depletion, infections (including progressive multifocal leukoencephalopathy [PML] 
and hepatitis B virus [HBV] reactivation), worsening of preexisting cardiac conditions, 
impaired immunization response, immunogenicity, gastrointestinal perforation, and 
second malignancies.  The important identified risks associated with obinutuzumab are 
presented in detail in Section 5.1.1 of this protocol and in the Obinutuzumab 
Investigator's Brochure. 
1.2.2.2 
Clinical Efficacy of Obinutuzumab in Patients with 
Non-Hodgkin's Lymphoma 
In studies of obinutuzumab monotherapy in patients with R/R NHL (Studies BO20999, 
BO21003, and JO21900), the proportion of patients who had a response (complete 
response [CR] or partial response [PR]) at the end of treatment (as determined on the 
basis of computed tomography [CT] scans alone) ranged from 28% to 58%.  The CR 
rate ranged from 0% to 19%. 
In early studies of obinutuzumab in combination with chemotherapy (i.e., CHOP or 
bendamustine) in patients with previously untreated or R/R NHL (Studies BO21000, 
GAO4915g, and GAO4753g), the proportion of patients with a CR or PR at the end of 
induction treatment ranged from 69% to 96%.  The CR rate was higher with combination 
therapy (35%−39% in previously untreated FL, 39%−50% in R/R FL, and 55% in 
previously untreated DLBCL) than with monotherapy. 


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A Phase III study, GAO4753g, investigated obinutuzumab plus bendamustine (GB) 
compared with bendamustine alone in patients with rituximab-refractory indolent NHL 
(n = 396).  Patients in the GB group who had not experienced disease progression at the 
end of induction received obinutuzumab monotherapy every 2 months for up to 2 years.  
On the basis of positive results from this study, demonstrating significant improvement in 
PFS in the GB arm, with a median PFS of 29 versus 14 months (hazard ratio [HR]: 0.52; 
95% CI: 0.39, 0.70; p > 0.0001; Sehn et al. 2015), obinutuzumab was granted approval 
for use in patients with FL who did not respond to or who progressed during or after 
treatment with rituximab or a rituximab-containing regimen (see Section 1.2).  
A Phase III study, BO21223, investigated obinutuzumab plus chemotherapy (G-benda, 
G-CVP, G-CHOP) compared with rituximab plus chemotherapy, followed by 
obinutuzumab or rituximab maintenance in patients with previously untreated indolent 
non-Hodgkin's lymphoma (iNHL; FL cohort, n = 1202).  On the basis of positive results 
that demonstrated significant improvement in PFS in the obinutuzumab chemotherapy 
arm, the Independent Data Monitoring Committee recommended that the study be 
unblinded to the Sponsor at a pre-planned interim analysis (Marcus et al. 2016). 
A Phase III study, BO21005, investigated obinutuzumab plus CHOP (G-CHOP) 
compared with rituximab plus CHOP (R-CHOP) in patients with previously untreated 
DLBCL.  The study did not meet its primary endpoint of PFS at final analysis.  Based 
upon the BO21005 efficacy results, this study protocol is amended to cease evaluating 
obinutuzumab in patients with R/R DLBCL; these patients will receive instead 
rituximab in combination with polatuzumab vedotin and venetoclax (Vitolo et al. 2016).   
1.3 
BACKGROUND ON POLATUZUMAB VEDOTIN 
CD79b is a cell-surface antigen whose expression is restricted to all mature B cells 
except plasma cells.  It is expressed in a majority of B cell−derived malignancies, 
including nearly all NHL and CLL samples tested (Dornan et al. 2009).  Antibodies 
bound to CD79b are rapidly internalized, which makes CD79b ideally suited for targeted 
delivery of cytotoxic agents (Polson et al. 2007; Polson et al. 2009).   
Polatuzumab vedotin (DCDS4501A) is an antibody−drug conjugate (ADC) that contains 
a humanized IgG1 anti−human CD79b monoclonal antibody (MCDS4409A) and a potent 
anti-mitotic agent, mono-methyl auristatin E (MMAE), linked through a protease-labile 
linker, maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl.   
MMAE has a mode of action that is similar to that of vincristine, which is a component of 
standard chemotherapy (e.g., R-CHOP used for treatment of lymphoma).  Following 
binding at the cell-surface epitope and internalization of the ADC by the targeted cell, 
MMAE is released following cleavage of the linker by lysosomal enzymes.  MMAE then 
binds to tubulin and disrupts the microtubule network, resulting in inhibition of cell 
division and cell growth (Doronina et al. 2003).  This therapeutic approach takes 
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MMAE, and the increased potency of MMAE compared with vincristine.  It is 
hypothesized that polatuzumab vedotin in combination with other novel agents will 
provide enhanced efficacy and safety to patients with NHL. 
1.3.1 
Nonclinical Studies with Polatuzumab Vedotin 
Comprehensive pharmacologic, pharmacokinetic (PK), pharmacodynamic, and 
toxicology studies were conducted to support the entry of polatuzumab vedotin into 
clinical trials.  Because polatuzumab vedotin specifically recognizes CD79b on B cells of 
humans⎯but not on those of the cynomolgus monkey, rat, or mouse⎯a surrogate ADC 
(DCDS5017A) that binds to cynomolgus monkey CD79b was generated to assess the 
antigen-dependent activities in cynomolgus monkeys.  The structure, binding epitope, 
and binding affinity of the surrogate ADC are similar to that of polatuzumab vedotin.  
Polatuzumab vedotin has demonstrated efficacy in nonclinical mouse xenograft models 
of human CD79b-positive NHL.  Additionally, polatuzumab vedotin when combined with 
rituximab plus chemotherapy (R-CHP or bendamustine) demonstrated better anti-tumor 
activity compared with polatuzumab vedotin as single agent or compared with a current 
standard-of-care regimen (R-CHOP or rituximab plus bendamustine [BR]) in xenograft 
models of NHL.  The pharmacokinetics and safety of polatuzumab vedotin and the 
surrogate ADC were characterized in repeat-dose toxicity studies in rats and 
cynomolgus monkeys.  Polatuzumab vedotin and the surrogate ADC were well tolerated 
in both species at the tested doses.  The predominant antigen-independent findings 
associated with polatuzumab vedotin or surrogate ADC exposure were reversible bone 
marrow toxicity and associated peripheral blood cell effects in both monkeys and rats.  
The PK profiles of polatuzumab vedotin and the surrogate ADC suggested that the 
pharmacokinetics of the ADC were driven mainly by the antibody component (similar 
serum concentration−time profile between ADC and total monoclonal antibody). 
Refer to the Polatuzumab Vedotin Investigator’s Brochure for complete details of the 
biochemical composition and nonclinical studies. 
1.3.2 
Clinical Studies with Polatuzumab Vedotin 
Clinical data on polatuzumab vedotin in patients with NHL or CLL are available from one 
completed Phase I/Ib study (DCS4968g) and the ongoing Phase Ib/II studies (GO27834, 
GO29044, GO29834, BO29561, and GO29365) in patients with B-cell lymphoma.   
DCS4968g evaluated polatuzumab vedotin as a single agent and in combination with 
rituximab in patients with R/R B-cell lymphoma.   
GO27834 is evaluating polatuzumab vedotin in combination with either obinutuzumab 
or rituximab in patients with R/R FL or DLBCL. 
GO29044 is evaluating polatuzumab vedotin in combination with R-CHP or G-CHP in 
patients with newly diagnosed or R/R B-cell lymphoma.   


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GO29365 is evaluating polatuzumab vedotin in combination with bendamustine plus 
rituximab or obinutuzumab in patients with R/R FL or DLBCL.   
GO29834 is evaluating polatuzumab vedotin in combination with lenalidomide and 
either obinutuzumab or rituximab in patients with R/R FL or DLBCL. 
BO29561 is evaluating polatuzumab vedotin in combination with atezolizumab and 
either obinutuzumab or rituximab in patients with R/R FL or DLBCL.   
Available safety results and efficacy results from these studies are summarized in 
Section 1.3.2.1 and Section 1.3.2.2, respectively.   
For more detailed clinical information on polatuzumab vedotin, including clinical 
pharmacology data, refer to the Polatuzumab Vedotin Investigator’s Brochure. 
1.3.2.1 
Clinical Safety of Polatuzumab Vedotin 
Clinical safety data are available from 327 patients with NHL or CLL who received 
polatuzumab vedotin as a single agent (DCS4968g), in combination with rituximab 
(DCS4968g and GO27834), in combination with obinutuzumab (GO27834), in 
combination with obinutuzumab or rituximab plus CHP (GO29044), and in 
combination with obinutuzumab or rituximab plus bendamustine (GO29365). 
In Study DCS4968g, Grade ≥ 3 adverse events were reported in 74% of patients with 
R/R B-cell lymphoma who received single−agent polatuzumab vedotin; the most 
common (reported in ≥ 5% of patients) Grade ≥ 3 adverse events were neutropenia 
(38% of patients), anemia and peripheral sensory neuropathy (9% each), and 
leukopenia (6%).   
In the dose-escalation phase of Study DCS4968g, dose-limiting toxicities (DLTs) of 
Grade 4 neutropenia occurred in 1 of 10 DLT-evaluable patients treated with 2.4 mg/kg 
polatuzumab vedotin and 1 of 9 DLT-evaluable patients treated with 2.4 mg/kg 
polatuzumab vedotin in combination with rituximab.  Polatuzumab vedotin at a dose of 
2.4 mg/kg given every 3 weeks was chosen as the recommended Phase II dose (RP2D) 
when administered as a single agent and in combination with rituximab.  Due to 
additional information about the benefit-risk profile of polatuzumab vedotin at the 
2.4 mg/kg dose, the Sponsor is no longer pursuing the clinical development of the 
2.4 mg/kg dose of polatuzumab vedotin. 
The overall safety profile of polatuzumab vedotin (1.8 mg/kg and 2.4 mg/kg doses) in 
combination with rituximab was comparable to that of single−agent polatuzumab vedotin.  
In Study GO27834, the most frequent (≥ 5%) Grade ≥ 3 adverse events were 
neutropenia (19 of 79 patients [24%]), diarrhea (5 of 79 patients [6%]), and febrile 
neutropenia (4 of 79 patients [5%]).  No fatal adverse events were reported for the 
combination. 


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Serious adverse events were reported for 37% of all patients treated with polatuzumab 
vedotin alone or in combination with rituximab in Studies DCS4968g and GO27834 
combined.  The most frequently reported (≥ 2%) serious adverse events were febrile 
neutropenia (5%), pyrexia (4%), and diarrhea (2%).  In Studies DCS4968g and 
GO27834 combined, 33%−41% of patients discontinued polatuzumab vedotin because 
of an adverse event.  The most frequently reported adverse events leading to 
discontinuation were peripheral sensory neuropathy, peripheral neuropathy, and 
peripheral motor neuropathy. 
In Study GO29044, Grade ≥ 3 adverse events were reported in 19 of 40 patients (48%) 
with B-cell lymphoma who received polatuzumab vedotin (1.8 mg/kg) in combination 
with obinutuzumab or rituximab plus CHP.  The most frequent events (≥ 10% of 
patients) were fatigue (33%), diarrhea (33%), and nausea (30%).  Serious adverse 
events were reported for 33% of patients in this treatment group.     
In Study GO29365, Grade ≥ 3 adverse events were reported in 11 of 21 patients (52%) 
with B-cell lymphoma who received polatuzumab vedotin in combination with 
rituximab plus bendamustine and in 17 of 28 patients (61%) who received polatuzumab 
vedotin in combination with obinutuzumab plus bendamustine.  The most frequent 
events (≥ 10% of patients) were nausea (43%), diarrhea (41%), and fatigue (35%).  
Serious adverse events were reported for 33% of patients receiving polatuzumab 
vedotin in combination with rituxumab plus bendamustine and 39% of patients 
receiving polatuzumab vedotin in combination with obinutuzumab plus bendamustine.   
A total of 44 deaths have been reported:  11 deaths in patients treated with single-agent 
polatuzumab vedotin and 33 in patients treated with polatuzumab vedotin combined 
with rituximab or obinutuzumab.  The majority of deaths were judged as related to 
disease progression. 
1.3.2.2 
Clinical Efficacy of Polatuzumab Vedotin in Patients with 
Non-Hodgkin’s Lymphoma 
Polatuzumab vedotin demonstrated clinical activity as a single agent.  
In Study DCS4968g, at the 2.4-mg/kg dose, objective responses (CR or PR) were 
observed in 7 of 16 patients (44%) with R/R indolent B−cell lymphoma (FL, marginal 
zone lymphoma [MZL], or small lymphocytic lymphoma [SLL]) and 14 of 27 patients 
(52%) with R/R DLBCL.  At a dose of 1.8 mg/kg, a PR was observed in 2 of 4 patients 
with DLBCL and in 2 of 2 patients with MCL, and no objective responses were observed 
in the 5 patients with CLL.  The median duration of response was 6.2 months (95% CI: 
3.3, 19.3 months) for the 2.4 mg/kg dose and 6.6 months (95% CI: 2.3, 11.4 months) for 
the 1.8 mg/kg dose.  At the 2.4-mg/kg dose, median PFS was 7.9 months (95% CI: 3.0, 
11.6 months) for patients with indolent B-cell lymphoma and 5.0 months (95% CI: 2.3, 
6.8 months) for patients with DLBCL.  Median PFS was 4.6 months (95% CI: 1.4, 13.9 
months) for patients with DLBCL treated at the 1.8-mg/kg dose. 


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Polatuzumab vedotin also demonstrated clinical activity when administered in 
combination with rituximab.  In Study DCS4968g, at a dose of 2.4 mg/kg, objective 
responses were observed in 7 of 9 patients with indolent B-cell lymphoma, DLBCL, or 
MCL (78%); 2 of the 7 patients had CRs.  Median duration of response among these 
patients was 12.3 months (95% CI: 4.3, not estimable [NE]).  Median PFS was 
12.5 months (95% CI: 6.9, 17.4 months). 
Preliminary data for patients in Study GO27834 who received polatuzumab vedotin 
(2.4 mg/kg) in combination with rituximab, objective responses were observed in 14 of 
20 patients with R/R FL (70%; 9 patients with CRs) and 21 of 39 patients with R/R 
DLBCL (54%; 8 patients with CRs).  For patients who received polatuzumab vedotin 
(1.8 mg/kg) in combination with rituximab, objective responses were observed in 15 of 
20 patients with FL (75%; 6 patients with CRs).   
Median duration of response was 12.9 months (95% CI: 6.7, NE) and 13.2 months 
(95% CI:  7.2, 21.2) for patients who received polatuzumab vedotin 1.8 mg/kg (FL) or 
2.4 mg/kg (FL or DLBCL), respectively.  At the 2.4 mg/kg dose, median PFS was 
15.1 months (95% CI:  11.8, NE) among the 20 patients with FL and 5.6 months 
(95% CI:  4.2, 12.7) among the 39 patients with DLBCL.  Among the 20 patients with 
R/R FL treated with 1.8 mg/kg polatuzumab vedotin in combination with rituximab, 
median PFS was 18.1 months (95% CI:  9.9, NE).   
For patients in Study GO27834 who received polatuzumab vedotin (1.8 mg/kg) in 
combination with obinutuzumab, overall responses were observed in 8 of 12 patients 
with R/R FL (67%; 1 patient with CR) and 3 of 15 patients with R/R DLBCL (20%; 0 
patients with CR).   
Preliminary data from Study GO29044 in patients treated with polatuzumab vedotin 
(1.0−1.8 mg/kg) in combination with R-CHP showed overall responses in 29 of 
31 patients (94%; 24 patients with CRs).  When polatuzumab vedotin (1.4 or 
1.8 mg/kg) was combined with G-CHP, overall responses were seen in 10 of 12 patients 
(83%; 10 patients with CRs).   
Preliminary data from GO29365 in FL patients treated with polatuzumab vedotin 
(1.8 mg/kg) in combination with bendamustine showed overall responses in 
7 of 7 patients (100%; 2 patients with CRs) when combined with rituximab and in 
3 of 4 patients (75%; 1 patient with CR) when combined with obinutuzumab.  Patients 
with DLBCL treated with polatuzumab vedotin (1.8 mg/kg) in combination with 
bendamustine showed overall responses in 3 of 7 patients (43%; 2 patients with CRs) 
when combined with rituximab and in 6 of 8 patients (75%; 2 patients with CR) when 
combined with obinutuzumab. 


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1.4 
BACKGROUND ON VENETOCLAX 
Venetoclax (synonymous with ABT-199 and GDC-0199) is a highly selective, orally 
available small−molecule Bcl-2 family protein inhibitor that binds with high affinity 
(dissociation constant [Ki] < 0.10 nM) to Bcl-2 and with lower affinity to other Bcl-2 family 
proteins Bcl-XL and Bcl-w (> 480- and > 2000-fold lower affinity than to Bcl-2, 
respectively).  Overexpression of anti−apoptotic Bcl-2 family proteins is associated with 
resistance to chemotherapy, and antagonism of the action of these proteins might 
overcome resistance and enhance response to therapy.  Anti−apoptotic Bcl-2 family 
members are associated with tumor initiation, disease progression, and drug resistance, 
making them compelling targets for anti-tumor therapy. 
1.4.1 
Nonclinical Studies with Venetoclax 
In vitro, venetoclax demonstrated broad cell-killing activity against a panel of lymphoma 
and leukemia cells, including B-cell FL, mantle cell lymphoma (MCL), DLBCL, and acute 
myeloid leukemia.  Venetoclax was especially potent against cell lines that expressed 
high levels of Bcl-2.  Leukemia and lymphoma cell lines that bear the t(14;18) 
translocation were significantly more sensitive to venetoclax than wild−type cell lines. 
Venetoclax inhibited subcutaneous (SC) murine xenograft growth of human tumor cell 
lines derived from acute lymphoblastic leukemia and NHL. 
The PK profile of venetoclax was evaluated in multiple animal species.  In mice, rats, 
monkeys, and dogs, low plasma clearance and low volumes of distribution characterized 
the venetoclax PK profile.  Half-lives ranged from 2.2 hours in monkeys to 12 hours in 
dogs.  Food had a marked effect on the oral bioavailability in dogs. 
Venetoclax demonstrated high protein binding to human, rat, dog, and monkey plasma 
proteins (> 99.9%).  In rats, venetoclax was widely distributed into liver, kidneys, spleen, 
heart, lungs, small intestine, and white fat, but was poorly distributed in testes, brain, 
muscle, and bone.  Liver metabolism was the major route of elimination with biliary 
excretion of the parent drug playing the secondary role in rats.  Venetoclax showed 
moderate metabolic stability in in vitro hepatic systems across species tested, except for 
low to moderate stability in dog hepatocytes. 
In vitro, venetoclax is metabolized by cytochrome (CYP) 3A4 and is a moderate inhibitor 
of CYP2C8 and a potent inhibitor of CYP2C9.  It is not a potent inhibitor of CYP3A4, 
CYP1A2, CYP2B6, CYP2C19, or CYP2D6 (IC50 > 30 μM) and does not induce CYP3A4 
or CYP1A2 at concentrations up to 10 μM.  Venetoclax has the potential to inhibit 
P-glycoprotein (P-gp).   
A more detailed discussion of the nonclinical activity of venetoclax, including 
pharmacokinetic, toxicology, and metabolism, is provided in the current Venetoclax 
Investigator’s Brochure. 


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1.4.2 
Clinical Studies with Venetoclax 
As of 28 November 2014, a total of 639 patients had been dosed with venetoclax in 
AbbVie and Genentech/Roche oncology studies.  Doses administered in venetoclax 
clinical studies ranged from 20 to 1200 mg.  A total of 345 patients with CLL/SLL and 
155 patients with NHL have been treated with venetoclax as single agent or in 
combination (see Appendix 12).  
Two studies, GP28331 and GO27878, include the combination of obinutuzumab and 
venetoclax in CLL and NHL, respectively.  In addition, Study BO25323, a randomized 
Phase III study evaluating the efficacy of obinutuzumab plus venetoclax compared with 
obinutuzumab plus chlorambucil in patients with previously untreated CLL, has recently 
been initiated. 
For more detailed clinical information on venetoclax, including results in the CLL cohorts 
of the clinical studies and clinical pharmacology data, refer to the Venetoclax 
Investigator’s Brochure. 
1.4.2.1 
Clinical Results in Non-Hodgkin’s Lymphoma 
Study M12-175, the first in-human venetoclax monotherapy dose-escalation study, is 
ongoing in patients with R/R CLL/SLL and NHL.  Two DLTs have been reported in 
patients with NHL who were treated with venetoclax in Study M12-175.  Both DLTs 
occurred at the 600-mg dose in Cohort 5 (which enrolled a total of 10 patients and had a 
300-mg lead-in dose and 600-mg designated cohort dose).  One patient experienced a 
DLT of serious Grade 3 febrile neutropenia, and the other patient experienced a DLT of 
non-serious Grade 4 neutropenia.  Dosing was interrupted and patients were treated 
with medication; the events resolved and the patients restarted therapy at a reduced 
venetoclax dose of 300 mg.  No DLTs were reported in Cohorts 6−8, with the maximum 
dose studied of 1200 mg. 
The most common adverse events in the NHL cohort of Study M12-175 were nausea, 
anemia, diarrhea, and fatigue, all occurring in ≥ 20% of patients.  Grade ≥ 3 hematologic 
toxicity was less common in patients with NHL than in patients with CLL.  In Study 
M12-175, 13% of patients with NHL experienced Grade ≥ 3 neutropenia and 10% 
experienced Grade ≥ 3 thrombocytopenia.  
As of 4 December 2014, a total of 105 patients with R/R NHL had been enrolled (70 in 
the dose-escalation cohorts and 35 in the safety expansion cohort) and evaluated for 
objective response following the International Working Group criteria (patients with 
Waldenstrom's macroglobulinemia [WM] were evaluated using the International 
Workshop-WM criteria).  In the dose-escalation cohorts, the objective response rate 
(ORR) was 57%, the CR rate was 11%, and median time in the study was approximately 
6 months.  In the safety expansion cohort, the ORR was 17%, the CR rate was 3%, and 
median time in the study was approximately 3 months.  This group had limited follow-up 
at the time of the clinical cutoff. 


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Study M12-630 is a study of venetoclax in combination with BR in patients with R/R 
NHL.  Patients receive this regimen for 6 cycles.  In Study M12-630, preliminary efficacy 
data are available for 27 patients (17 male patients [63%]) with R/R NHL as of 
7 October 2014.  Hematologic toxicity in Study M12-630 (venetoclax in combination with 
BR in patients with NHL) was not significantly greater than that expected with BR alone.  
The ORR was 64% (18 of 27 evaluable patients): 4 patients (14%) with CR and 
14 patients (50%) with PR.  An additional 3 patients (11%) had stable disease. 
Efficacy data are not yet available for the other NHL studies listed. 
Data on venetoclax and human pregnancy or venetoclax and drug abuse and drug 
dependency are not available. 
Additional details on the clinical activity and safety of venetoclax are provided in the 
Venetoclax Investigator’s Brochure. 
1.4.2.2 
Clinical Pharmacokinetics and Pharmacodynamics 
Preliminary PK data with venetoclax are available from ongoing Studies M12-175, 
M12-630, and M13-365 in patients with hematologic malignancies. 
The venetoclax formulation currently used in clinical studies is a tablet formulation with 
strengths of 10, 50, and 100 mg.  The tablet formulation was orally administered after a 
low-fat meal.  Food increased the bioavailability of venetoclax by 3- to 4-fold.  
Preliminary PK results indicated that the absorption of venetoclax after the oral dosing 
was relatively slow.  Venetoclax plasma concentrations peaked at approximately 6 hours 
after dosing.  The mean terminal-phase elimination half-life of venetoclax was 
approximately 17 hours, and the mean oral clearance was approximately 13 L/hr after a 
single dose.  There was no apparent difference in the pharmacokinetics of venetoclax in 
patients with CLL/SLL or NHL.  The combined data from patients with CLL/SLL and NHL 
suggested that venetoclax exposure was approximately dose proportional across the 
150- to 900-mg dose levels.  In the limited number of patients to date, co-administration 
of BR did not show apparent effect on venetoclax pharmacokinetics. 
1.5 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Progress has been made in the treatment of FL and DLBCL; however, a significant 
number of patients will not be cured of their disease.  Instead, they will experience 
relapse or die of progression or treatment-related toxicity.  Patients who relapsed after 
receiving several prior treatments may not be able to tolerate more bone marrow toxicity, 
which limits their treatment options.  There is a need for the continued development of 
safe and effective therapies for patients with disease that relapses or for those who 
develop refractory disease during or after first-line therapy.  This study will evaluate the 
activity of a novel triplet combination of obinutuzumab or rituximab plus, polatuzumab 
vedotin, and venetoclax.   


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B-cell lymphoma, including FL and DLBCL, express the CD20 antigen, and anti-CD20 
therapy (rituximab) has been demonstrated to provide enhanced anti-tumor activity in 
combination with other agents, leading to increased response rates, PFS, and OS 
(Coiffier et al. 2002, 2007, 2010; Feugier et al. 2005; Hiddemann et al. 2005; 
Habermann  et  al. 2006; Herold et al. 2007; Marcus et al. 2008; 
Pfreundschuh et al. 2008; Salles et  al.  2008).  Rituximab has been accepted as a 
standard component in initial therapy. 
Obinutuzumab has shown superiority over rituximab in a Phase III trial in first-line CLL 
(Goede et al. 2014).  Obinutuzumab was also shown to be superior compared to 
rituximab when combined with chemotherapy in a Phase III trial (BO21223) in 
previously untreated FL patients (Marcus et al. 2016).  The Phase III study GAO4753g 
investigated obinutuzumab combined with bendamustine followed by obinutuzumab 
maintenance compared with bendamustine alone in patients with rituximab-refractory 
iNHL, including FL, and showed improvement in PFS in the GB arm (Sehn et al. 2015).  
Obinutuzumab will be included as the anti-CD20 backbone for patients with R/R FL in 
this study.   
Obinutuzumab did not show superiority compared to rituximab in the Phase III trial 
comparing R-CHOP to G-CHOP in patients with previously untreated DLBLC 
(BO21005; Vitolo et al. 2016).  Based upon the BO21005 efficacy results, this study 
protocol is amended and patients with R/R DLBCL will receive rituximab as the anti-
CD20 backbone in combination with polatuzumab vedotin and venetoclax.   
In addition to the potential of next-generation anti-CD20 therapy to enhance the efficacy 
of current standard immunochemotherapy regimens the development of ADC may have 
the potential to add benefit when combined with standard systemic chemotherapy, or to 
replace these agents, in certain lymphoma combination regimens.  Polatuzumab vedotin 
is an ADC designed for the targeted delivery of MMAE, a potent microtubule inhibitor to 
lymphoma cells that express CD79b.  MMAE has a mechanism of action that is similar to 
that of vincristine.  
Venetoclax is a specific inhibitor of the Bcl-2 anti−apoptotic protein expressed in many 
NHL cells.  Bcl-2 is overexpressed in most FL and many DLBCLs as a consequence of 
the t(14;18) chromosomal translocation or gene amplification and is associated with a 
poor prognosis in multiple tumor types (Cory and Adams 2002; Cory et al. 2003; 
Reed 2008; Iqbal et al. 2011).  Bcl-2 has been shown to contribute to resistance of 
malignant cells to chemotherapies with varied mechanisms of action, consistent with its 
role as an inhibitor of the final common steps of apoptosis and is likely to play a role in 
resistance to the pro-apoptotic activities of immunotherapy and chemotherapy.  In solid 
and hematologic tumor models, anti-mitotic drugs (taxanes and auristatin) were shown 
to modulate Bcl-2 pro-survival proteins to induce cell death in vitro (Haldar et al 1996; 
Poruchynsky et al. 1998; Wertz et al. 2011).  MMAE in polatuzumab vedotin may be able 
to down regulate Mcl-1, a known resistant factor for venetoclax.  Therefore, the addition 


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of venetoclax, a Bcl-2 inhibitor, to a polatuzumab vedotin-containing regimen may have 
the potential to significantly enhance the anti-lymphoma activity and to result in improved 
clinical outcomes.   
Nonclinical data that support the triplet combination of obinutuzumab, polatuzumab 
vedotin, and venetoclax include WSU-DLCL2 model in CB17 severely compromised 
immunodeficient (SCID) mice that demonstrated significantly improved anti-tumor 
activity of the triplet combination over the activity of any treatment regimen alone or 
doublet combination (obinutuzumab plus venetoclax or obinutuzumab plus polatuzumab 
vedotin; see Figure 1). 
Figure 1 Anti-Tumor Activity with Obinutuzumab, Polatuzumab Vedotin, 
and Venetoclax in WSU-DLCL2 Model in CB17 SCID Mice 
 
ADC = antibody drug conjugate (polatuzumab vedotin); 199 = venetoclax; G or 
GA101 = obinutuzumab; SCID = severely compromised immunodeficient mice. 
 
Early clinical data that evaluated obinutuzumab, polatuzumab vedotin, and venetoclax, 
each given as single agents, have demonstrated efficacy but have been associated with 
neutropenia (refer to Section 1.2.2, Section 1.3.2, and Section 1.4.2, respectively). 
Obinutuzumab,  rituximab, polatuzumab vedotin, and venetoclax are known to deplete 
circulating B cells and tumor burden, which may potentially impact the target-mediated 
clearance of obinutuzumab, rituximab, and polatuzumab vedotin.  In R/R FL and 
DLBCL, the baseline B-cell count is very low; therefore, the likelihood of 
pharmacodynamics (B-cell) mediated drug-drug interaction (DDI) is relatively low.  This 


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was confirmed by the observation that no interaction was observed between 
polatuzumab and rituximab in R/R FL and DLBCL. 
The likelihood of cytochrome P450 (CYP) and P-gp mediated DDI among obinutuzumab, 
polatuzumab vedotin, and venetoclax is assessed below.   
First, the risk of cytokine modulation related CYP expression change and the resulted 
DDI is low for polatuzumab vedotin and obinutuzumab because studies in cynomolgous 
monkey and in vitro suggested the risk of systemic cytokine release following anti-CD79 
antibody treatment is low (Schmidt and Wittrup 2009) and obinutuzumab only results in 
highly transient increases in cytokine concentrations in patients after the first infusion.  
Second, in vitro, the MMAE component of polatuzumab vedotin is mainly metabolized by 
CYP3A4.  MMAE did not induce any major CYP450 enzymes.  MMAE inhibits 
CYP3A4/5 as a weak competitive and a time-dependent inhibitor.  Simulations based on 
a physiologically-based PK model (Chen et al. 2015) showed that unconjugated MMAE 
exposure following polatuzumab vedotin administration with strong CYP3A4 inhibitors or 
inducers is unlikely to be altered by > 50%, and MMAE is unlikely to be a perpetrator of 
drug interactions with CYP substrates.  In vitro, MMAE was a substrate but not a potent 
inhibitor of P-gp.  
Third, in vitro, venetoclax is metabolized by CYP3A4.  Venetoclax is a reversible inhibitor 
of UGT1A1, CYP2C9 and CYP2C8.  M27, a primary human metabolite of venetoclax, is 
a reversible inhibitor of UGT1A1, CYP2C9, UGT2B7, CYP2C8, CYP3A4, UGT1A4 and 
UGT1A6 in vitro.  Model prediction suggested that venetoclax and M27 are unlikely to 
cause clinically significant interaction with CYP and UGTs substrates.  Venetoclax is a 
substrate for P-gp and BCRP and has the potential to inhibit P-gp and BCRP. 
Therefore, when polatuzumab vedotin is combined with venetoclax, the risk of 
CYP-mediated DDI risk is low between MMAE and venetoclax (and its major human 
metabolite M27).  It is possible that MMAE exposure may be affected in the presence of 
venetoclax mediated by P-gp.  It is unknown whether the risk of breast cancer resistance 
protein (BCRP)-mediated DDIs exists.  The patients who receive other concomitant 
medications, which are strong P-gp or BCRP inhibitors, should be closely monitored for 
adverse reactions.  
Available nonclinical and clinical data suggest that there is a strong rationale to expect 
an improved benefit-risk profile with the triplet combination of obinutuzumab or 
rituximab, polatuzumab vedotin, and venetoclax.  This novel triplet regimen may have 
the potential to extend treatment-free remissions and decrease toxicity by improving 
upon individual agents used as part of current standard of care.  Patients with 
overlapping toxicities will be closely monitored; such events are expected to be 
manageable in the clinical setting (see Section 5.1.5).   


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2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety, efficacy, and pharmacokinetics of induction treatment 
consisting of obinutuzumab in combination with polatuzumab vedotin and venetoclax 
(G + Pola + V) in patients with R/R FL and rituximab in combination with polatuzumab 
vedotin and venetoclax (R + Pola + V) in patients with R/R DLBCL.  Induction will be 
followed by post-induction treatment with obinutuzumab in combination with venetoclax 
(G + V; referred to as maintenance) in patients with FL who achieve a CR, PR, or stable 
disease at end of induction (EOI) and post-induction treatment with rituximab in 
combination with venetoclax (R + V; referred to as consolidation) in patients with 
DLBCL who achieve a CR or PR at EOI.  Specific objectives and corresponding 
endpoints for the study are outlined in Sections 2.1−2.5. 
In this study, "study treatment" refers to the protocol-mandated treatments under study 
(i.e., obinutuzumab, rituximab, polatuzumab vedotin, and venetoclax). 
2.1 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To determine the RP2D for polatuzumab vedotin and venetoclax when given in 
combination with a fixed dose of obinutuzumab and the RP2D of venetoclax when 
given in combination with a fixed dose of polatuzumab vedotin on the basis of the 
following endpoint: 
– 
Incidence of DLTs during the first cycle of study treatment 
• 
To evaluate the safety and tolerability of G + Pola + V and R + Pola + V on the basis 
of the following outcome measures in the respective combinations: 
– 
Nature, frequency, severity, and timing of adverse events, including DLTs 
– 
Changes in vital signs, ECGs, and clinical laboratory results during and 
following study treatment administration 
 
2.2 
EFFICACY OBJECTIVES 
Response will be determined on the basis of positron emission tomography and 
computed tomography (PET-CT) scans or CT scans alone, using Revised Lugano 
Response Criteria for Malignant Lymphoma (Cheson et al. 2014; see Appendix 4), 
hereinafter referred to as Lugano 2014 criteria.  Response will be determined by an 
Independent Review Committee (IRC) and by the investigator. 
2.2.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of G + Pola + V in 
patients with R/R FL and R + Pola + V in patients with R/R DLBCL on the basis of the 
following endpoint: 
• 
CR at EOI, as determined by the IRC on the basis of PET-CT scans  
 


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2.2.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of G + Pola + V 
and maintenance treatment with G + V in patients with R/R FL and R + Pola + V and 
consolidation treatment with R + V in patients with R/R DLBCL on the basis of the 
following endpoints: 
• 
CR at EOI, as determined by the investigator on the basis of PET-CT scans 
• 
CR at EOI, as determined by the IRC and by the investigator on the basis of CT 
scans alone 
• 
Objective response (defined as a CR or PR) at EOI, as determined by the IRC and 
by the investigator on the basis of PET-CT scans 
• 
Objective response (defined as a CR or PR) at EOI, as determined by the IRC and 
by the investigator on the basis of CT scans alone 
• 
Best response of CR or PR during the study, as determined by the investigator on 
the basis of CT scans alone 
 
2.2.3 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
G + Pola + V and R + Pola + V on the basis of the following endpoints: 
• 
For patients who have positive PET scans at EOI:   
– 
CR at 12 months, as determined by the IRC and by the investigator on the 
basis of PET-CT scans in FL patients 
– 
CR at EOC as determined by the IRC and by the investigator on the basis 
of PET-CT scans in DLBCL patients 
• 
PFS, defined as the time from initiation of study treatment to first occurrence of 
disease progression or relapse, as determined by investigator, or death from any 
cause 
• 
EFS, defined as the time from initiation of study treatment to any treatment failure, 
including disease progression or relapse, as determined by investigator, initiation of 
new anti-lymphoma therapy, or death from any cause, whichever occurs first 
• 
Disease-free survival (DFS), defined, among patients who achieve a CR, as the time 
from the first occurrence of a documented CR to relapse, as determined by the 
investigator, or death from any cause, whichever occurs first 
• 
OS, defined as the time from initiation of study treatment to death from any cause 
 
2.3 
PHARMACOKINETIC OBJECTIVE 
The PK objective for this study is to characterize the PK profiles of obinutuzumab, 
rituximab, polatuzumab vedotin, and venetoclax when given in combination, on the 
basis of the following endpoints: 
• 
Observed serum concentration of obinutuzumab at specified timepoints 
• 
Observed serum concentration of rituximab at specified timepoints 


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• 
Observed serum and plasma concentrations of polatuzumab vedotin and relevant 
analytes (total antibody, antibody-conjugated MMAE [acMMAE] and unconjugated 
MMAE) at specified timepoints 
• 
Observed plasma concentration of venetoclax at specified timepoints 
 
2.4 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to 
obinutuzumab and to polatuzumab vedotin on the basis of the following endpoints: 
• 
Incidence of human anti-human antibodies (HAHAs) to obinutuzumab during the 
study relative to the prevalence of HAHAs at baseline 
• 
Incidence of anti-therapeutic antibody (ATAs) to polatuzumab vedotin during the 
study relative to the prevalence of ATAs at baseline 
 
The exploratory immunogenicity objective for this study is to evaluate potential 
relationships between HAHAs or ATAs and other endpoints on the basis of the following 
endpoint: 
• 
Correlation between HAHA or ATA status and efficacy, safety, or PK endpoints 
 
2.5 
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify non-inherited biomarkers 
that are predictive of response to study treatment (i.e., predictive biomarkers), are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 
are associated with acquired resistance to study treatment, are associated with 
susceptibility to developing adverse events, can provide evidence of study treatment 
activity, can increase the knowledge and understanding of lymphoma biology or study 
treatment mechanism of action, or can contribute to improvement of diagnostic assays, 
on the basis of the following endpoint: 
• 
Association between non-inherited biomarkers (listed in Section 4.5.6) and efficacy, 
safety, PK, or immunogenicity endpoints 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study 
This is a Phase Ib/II, open-label, multicenter, non-randomized study that will evaluate the 
safety, efficacy, and pharmacokinetics of G + Pola + V in patients with R/R FL and 
R + Pola + V in patients with R/R DLBCL.   
The study will include an initial dose-escalation phase followed by an expansion phase 
during which polatuzumab vedotin and venetoclax will be given at their RP2Ds (see 
Sections 3.1.2 and 3.1.2.2).  Patients will receive induction treatment with 
obinutuzumab or rituximab, polatuzumab vedotin, and venetoclax as outlined in 
Sections 3.1.2 and 3.1.3.  Patients with FL who achieve a CR, PR, or stable disease at 


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EOI will receive post-induction treatment with obinutuzumab and venetoclax, and 
patients with DLBCL who achieve a CR or PR at EOI will receive post-induction 
treatment with rituximab and venetoclax (see Sections 3.1.2 and 3.1.3 for details).  A 
study schema is provided in Figure 2. 
Approximately 113−134 patients are expected to be enrolled in this study at 
approximately 20−25 investigative sites worldwide.   


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Figure 2 Study Schema 
 
C = cycle; CR = complete response; D = day; D1C6 = Day 1 of Cycle 6; DLBCL = diffuse large B-cell 
lymphoma; EOI = end of induction; FL = follicular lymphoma; G = obinutuzumab; IV = intravenous; 
M = month; PO = by mouth; Pola = polatuzumab vedotin; PR = partial response; QD = once a day; 
R = rituximab; RP2D = recommended Phase II dose; SD = stable disease; V = venetoclax. 
a After completion of induction treatment, all patients will continue to receive daily venetoclax 
treatment (during Month 1) until response is assessed at EOI.  Venetoclax will be discontinued 
if response assessments at EOI indicate that a patient is not eligible for post-induction 
treatment. 


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All patients will be closely monitored for adverse events throughout the study and for at 
least 90 days after the last dose of study treatment (see Section 5.3.1).  Adverse events 
will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), Version 4.0.  An Internal Monitoring Committee (IMC) 
will be established to monitor patient safety throughout the study (see Section 3.1.4).   
To characterize the PK properties of obinutuzumab, rituximab, polatuzumab vedotin, 
and venetoclax, blood samples will be obtained at various timepoints before and during 
study treatment administration (see Appendix 3 and Appendix 4). 
Response will be determined by the IRC (see Section 3.1.5) and the investigator using 
the Lugano 2014 criteria (see Appendix 5).  The primary efficacy endpoint will be based 
on the IRC assessment of response.  Refer to Section 4.5.5 for details on tumor 
assessments. 
3.1.2 
Obinutuzumab Plus Polatuzumab Vedotin Plus Venetoclax 
Treatment Group (Patients with Follicular Lymphoma) 
3.1.2.1 
Follicular Lymphoma Dose-Escalation Phase 
The purpose of the FL dose-escalation phase is to identify the RP2D for polatuzumab 
vedotin and the RP2D for venetoclax when combined with a fixed dose of obinutuzumab 
as induction treatment.  This dose-escalation phase will include FL patients only; these 
patients may receive post-induction treatment if eligible.  The RP2D will be based on the 
maximum tolerated doses (MTDs) and the totality of data for polatuzumab vedotin and 
venetoclax.  
Approximately 21−39 patients will be enrolled in the FL dose-escalation phase.  Initially, 
the study enrolled 3 patients starting in Cohort 1 at a dose level of 400 mg venetoclax 
and 1.4 mg/kg polatuzumab vedotin.  With Amendment 3, Cohort 1a was added to the 
dose-escalation phase with a starting dose level of 200 mg venetoclax and 1.4 mg/kg 
polatuzumab vedotin.  The original Cohort 1 dose level combination will be repeated to 
gather additional safety data in this dose level.  Dosing cohorts of 3−6 patients each will 
be treated in accordance with the treatment regimen and dose-escalation rules 
described in Sections 3.1.2.1.2 and 3.1.2.1.3, respectively. 
Patients will be closely monitored for adverse events during a DLT assessment window, 
which will be defined as the first treatment cycle (from Day 1 of Cycle 1 to Day 1 of 
Cycle 2).  Adverse events that meet the criteria for DLT, as defined in Section 3.1.2.1.1, 
will be reported to the Sponsor within 24 hours (see Section 5.4.2). 
Patients who discontinue from the study prior to completion of the DLT assessment 
window for reasons other than a DLT will be considered non-evaluable for 
dose-escalation decisions and MTD assessments and will be replaced by an additional 
patient at that same dose level.  Patients who miss one or more doses of polatuzumab 
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assessment window for reasons other than a DLT will also be replaced and considered 
non-evaluable for dose-escalation decisions.  Patients who receive supportive care 
during the DLT assessment window that may confound the evaluation of DLTs may be 
replaced at the discretion of the Medical Monitor. 
3.1.2.1.1 
Definition of Dose-Limiting Toxicity 
In this study, a DLT is defined as any one of the following events that occurs during the 
first cycle of treatment and is assessed by the investigator as related to study treatment 
that is not attributed to disease progression or another clearly identified cause: 
• 
Any adverse event of any grade that leads to a delay of more than 14 days in the 
start of the next treatment cycle 
• 
Any Grade 3 or 4 non-hematologic adverse event, with the following exceptions: 
– 
Grade 3 or 4 IRRs 
Note that IRRs may occur even after a small amount of drug has been 
administered (i.e., IRRs are not dose dependent). 
– 
Grade 3 diarrhea that responds to therapy within 72 hours 
– 
Grade 3 nausea or vomiting that occurs in the absence of premedication and 
responds to adequate therapy within 72 hours 
– 
Grade 3 fatigue that resolves to Grade ≤ 2 within 7 days 
– 
Grade 3 laboratory TLS without manifestations of clinical TLS (i.e., creatinine 
≥ 1.5 × upper limit of normal (ULN) and/or renal dysfunction, cardiac 
arrhythmias, seizures, or sudden death) that resolves within 7 days (see 
Appendix 12) 
– 
Grade 3 laboratory abnormality that is asymptomatic and deemed by the 
investigator not to be clinically significant 
– 
Grade 3 elevation in ALT or AST, provided the following criteria are met: 
ALT or AST level is no greater than 8 × ULN 
ALT or AST elevation resolves to Grade < 2 (< 5 × ULN) within 7 days 
Total and direct bilirubin and other laboratory parameters of liver synthetic 
function (e.g., prothrombin time) are normal 
No clinical signs or symptoms of hepatic injury 
• 
Any increase in hepatic transaminase > 3 × baseline AND an increase in direct 
bilirubin > 2 × ULN, WITHOUT any findings of cholestasis or jaundice or signs of 
hepatic dysfunction AND in the absence of other contributory factors 
(e.g., worsening of metastatic disease or concomitant exposure to known 
hepatotoxic agent or of a documented infectious etiology) is suggestive of potential 
drug-induced liver injury (DILI; according to Hy’s Law) and will be considered a 
DLT. 


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• 
In patients with Grade 1 ALT or AST elevation at baseline as a result of liver 
metastases, only a Grade ≥ 3 elevation that is also ≥ 3 × baseline lasting > 7 days 
will be considered a DLT.  
• 
Hematologic adverse event that meets any of the following criteria: 
– 
Grade 3 or 4 neutropenia in the presence of sustained fever of > 38°C (lasting 
> 5 days) or a documented infection  
– 
Grade 4 neutropenia lasting > 7 days 
– 
Grade 3 or 4 thrombocytopenia that results in significant bleeding per 
investigator judgment 
– 
Grade 4 thrombocytopenia lasting > 7 days 
 
Other toxicities occurring during the first cycle that are considered clinically relevant and 
related to study treatment, as determined by the investigator and the Medical Monitor, 
may also be considered DLTs. 
3.1.2.1.2 
Treatment Regimens for the Follicular Lymphoma 
Dose-Escalation Phase 
All patients enrolled in the dose-escalation phase will receive induction treatment, 
administered in 21-day cycles as shown in Table 1.  When study treatments are given on 
the same day, they will be administered sequentially in the following order:  venetoclax, 
obinutuzumab, and polatuzumab vedotin.   
Table 1 
Induction Treatment for the Follicular Lymphoma 
Dose-Escalation Phase  
 
G + Pola + V (21-Day Cycles) 
Cycle 1 
• Venetoclax 200, 400, 600, or 800 mg PO once daily on Days 1−21  
• Obinutuzumab 1000 mg IV on Days 1, 8, and 15 
• Polatuzumab vedotin 1.4 or 1.8 mg/kg IV on Day 1 
Cycle 2−6 
• Venetoclax 200, 400, 600, or 800 mg PO once daily on Days 1−21 
• Obinutuzumab 1000 mg IV on Day 1 
• Polatuzumab vedotin 1.4 or 1.8 mg/kg IV on Day 1 
G = obinutuzumab; IV = intravenous; PO = by mouth; Pola = polatuzumab vedotin; V = venetoclax. 
Note:  When study treatments are given on the same day, they will be administered sequentially 
in the following order:  venetoclax, obinutuzumab, and polatuzumab vedotin. 
 
After completion of induction treatment, patients will continue to receive daily venetoclax 
treatment (during Month 1) until response is assessed at EOI.  Venetoclax will be 
discontinued if response assessments at EOI indicate that a patient is not eligible for 
post-induction treatment (referred to as maintenance).  Patients who achieve a CR, PR, 
or stable disease at EOI will receive maintenance treatment with obinutuzumab and 
venetoclax, as outlined in Table 2.  Polatuzumab vedotin will not be given as 
maintenance treatment.  Maintenance treatment will continue until disease progression 


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or unacceptable toxicity for up to 24 months.  When study treatments are given on the 
same day, venetoclax will be administered prior to obinutuzumab.   
Table 2 
Maintenance Treatment for the Follicular Lymphoma 
Dose-Escalation Phase  
Maintenance treatment consisting of the following, administered for 24 months (Months 1−24): 
• Venetoclax 200, 400, 600, or 800 mg PO once daily for 8 months (Months 1−8) 
• Obinutuzumab 1000 mg IV on Day 1 of every other month (i.e., every 2 months) for 
24 months, starting with Month 2 (e.g., Months 2, 4, 6, 8, etc.) 
IV = intravenous; PO = by mouth; RP2D = recommended Phase II dose. 
Note:  When study treatments are given on the same day, venetoclax will be administered prior 
to obinutuzumab.  A month is defined as 28 days. 
 
3.1.2.1.3 
Dose-Escalation Rules 
A 3 + 3 dose-escalation schema will be used.  The obinutuzumab dose will remain fixed 
at 1000 mg during the dose-escalation phase.  The starting doses in Cohort 1a are 
1.4 mg/kg for polatuzumab vedotin and 200 mg for venetoclax.  In Cohorts 1−6, dose 
escalation of polatuzumab vedotin and venetoclax will proceed in increments that 
parallel the magnitude of dose increases tested in ongoing Phase Ib trials 
(see Sections 3.3.3.2 and 3.3.3.2.2).  For polatuzumab vedotin, there are 2 possible 
dose levels:  1.4 or 1.8 mg/kg.  For venetoclax, there are 4 dose levels:  200, 400, 600, 
or 800 mg.   
Intrapatient dose escalation will be allowed only for the Cohort 1a patients receiving 
200 mg of venetoclax.  In this cohort, the venetoclax dose may be escalated from 
200 mg to 400 mg once Cohorts 2 and 3 open after approval by the Medical Monitor.  
Intrapatient dose escalation is not allowed in other cohorts.  The FL dose-escalation plan 
is depicted in Figure 3, and the doses for each cohort are summarized in Table 3.   


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Figure 3 Follicular Lymphoma Dose-Escalation Plan 
 
 
If Cohort 1a doses are deemed safe and tolerable, escalation will continue with Cohort 1.  
If Cohort 1 doses are deemed safe and tolerable, escalation will continue with 
simultaneous enrollment of Cohort 2 (only the polatuzumab vedotin dose will increase) 
and Cohort 3 (only the venetoclax dose will increase).  
Escalation to Cohort 4 may occur only if Cohort 2 doses and Cohort 3 doses are 
deemed safe and tolerable.  
If Cohort 4 doses are not tolerable, escalation may continue with Cohort 5 (based on 
tolerated Cohort 3 dose combination, in which only the venetoclax dose will increase).  
If the Cohort 4 doses are safe and tolerable, further escalation will occur with enrollment 
of Cohort 6 (only the venetoclax dose will increase). 


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Table 3 
Follicular Lymphoma Dose-Escalation Cohorts  
Cohort 
Obinutuzumab a 
Polatuzumab Vedotin b
Venetoclax c 
1a 
1000 mg 
1.4 mg/kg 
200 mg 
1 
1000 mg 
1.4 mg/kg 
400 mg 
2 
1000 mg 
1.8 mg/kg 
400 mg 
3 
1000 mg 
1.4 mg/kg 
600 mg 
4 
1000 mg 
1.8 mg/kg 
600 mg 
5 
1000 mg 
1.4 mg/kg 
800 mg 
6 
1000 mg 
1.8 mg/kg 
800 mg 
a Obinutuzumab will be administered intravenously at a fixed dose of 1000 mg.  During 
Cycle 1, obinutuzumab will be administered on Days 1, 8, and 15.  During Cycles 2−6, 
obinutuzumab will be administered on Day 1 only. 
b Polatuzumab vedotin will be administered intravenously on Day 1 of each cycle. 
c Venetoclax will be administered orally every day of each cycle.  Venetoclax should always be 
given before other agents administered on the same day, if applicable. 
 
Dose escalation will occur in accordance with the rules listed below. 
• 
A minimum of 3 patients will initially be enrolled in each cohort.  The first 3 patients 
in each cohort will be sequentially enrolled and dosed at least 48 hours apart.  
• 
If none of the first 3 DLT-evaluable patients experiences a DLT, the doses in that 
cohort will be deemed safe and tolerable and escalation may continue according to 
the dose-escalation plan described above. 
• 
If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will 
be expanded to at least 6 patients.  If there are no further DLTs in the first 
6 DLT-evaluable patients, the doses in that cohort will be deemed safe and 
tolerable and escalation may continue according to the dose-escalation plan 
described above. 
• 
If a DLT is observed in ≥ 33% of patients (e.g., 2 or more of up to 6 patients), the 
dose combination at which this occurs will be considered intolerable and the MTD 
will have been exceeded for polatuzumab vedotin and/or venetoclax in the 
G + Pola + V treatment combination.  However, enrollment may continue in 
alternative cohorts according to the dose-escalation plan described above. 
• 
If the MTD is exceeded in any cohort, the highest dose combination at which fewer 
than 33% (e.g., 2 of 6 DLT-evaluable patients) experience a DLT will be declared 
the combination MTD (i.e., the MTDs for polatuzumab vedotin and venetoclax in 
the G + Pola + V treatment combination). 
• 
If the MTD is not exceeded in any cohort, the highest dose combination 
administered in this study will be declared the maximum administered doses for 
polatuzumab vedotin and venetoclax in the G + Pola + V treatment combination. 
 


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If the MTD is exceeded in any cohort, de-escalation of the polatuzumab vedotin dose 
and/or venetoclax dose and adjustment of treatment schedules (e.g., venetoclax 
treatment on Days 1−10) may occur.  It is possible that more than one combination MTD 
(i.e., potential RP2Ds) will be identified, which may consist of different dose or schedule 
combinations for polatuzumab vedotin and venetoclax that are deemed safe and 
tolerable when combined with a fixed dose of obinutuzumab.  If this occurs, it is possible 
that more than one expansion cohort will be enrolled to gather additional safety, PK, and 
pharmacodynamic data at these RP2Ds and schedules.  Additional patients may be 
enrolled in a given cohort in the absence of DLTs to acquire additional safety data for the 
appropriate dose levels in the expansion phase of the study. 
On the basis of a review of real−time safety data and available preliminary PK data, 
dose escalation may be halted or modified by the Sponsor as deemed appropriate. 
Relevant demographic, adverse event, laboratory, dosing administration/intensity, and 
PK (if available) data will be reviewed throughout the study by the Clinical Study Team 
and prior to dose-escalation decisions, which will be made by the Medical Monitor in 
consultation with the Principal Investigator and participating investigators. 
Although the DLT-assessment window is defined as the first treatment cycle (from Day 1 
of Cycle 1 to Day 1 of Cycle 2), cumulative or late toxicities that occur beyond the first 
cycle may be considered in determination of the RP2Ds.  Prior to opening the R/R FL 
expansion phase, the Clinical Study Team and the Medical Monitor will review the 
cumulative data, recommend the RP2D, and review this with the IMC for approval.   
3.1.2.2 
Follicular Lymphoma Expansion Phase 
The expansion phase is designed to further assess the safety and efficacy of 
polatuzumab vedotin and venetoclax at their respective RP2Ds when combined with a 
fixed dose of obinutuzumab in FL patients.   
Approximately 40 patients with will be enrolled during the expansion phase and treated 
as described below. 
All patients enrolled in the expansion phase will receive induction treatment, 
administered in 21-day cycles as outlined in Table 4.  When study treatments are given 
on the same day, they will be administered sequentially in the following order:  
venetoclax, obinutuzumab, and polatuzumab vedotin. 


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Table 4 
Induction Treatment for the Follicular Lymphoma Expansion 
Phase 
 
G + Pola + V (21-Day Cycles) 
Cycle 1 
• Venetoclax at the RP2D (mg) PO once daily on Days 1−21 
• Obinutuzumab 1000 mg IV on Days 1, 8, and 15 
• Polatuzumab vedotin at the RP2D (mg/kg) IV on Day 1 
Cycles 2−6 • Venetoclax at the RP2D (mg) PO once daily on Days 1−21 
• Obinutuzumab 1000 mg IV on Day 1 
• Polatuzumab vedotin at the RP2D (mg/kg) IV on Day 1 
IV = intravenous; PO = by mouth; RP2D = recommended Phase II dose. 
Note:  Treatments will be administered sequentially in the following order:  venetoclax, 
obinutuzumab, and polatuzumab vedotin. 
 
After completion of induction treatment, patients will continue to receive daily venetoclax 
treatment (during Month 1) until response is assessed at EOI.  Venetoclax will be 
discontinued if response assessments at EOI indicate that a patient is not eligible for 
post-induction treatment.  Patients with FL who achieve a CR, PR, or stable disease at 
EOI will receive post-induction treatment (referred to as maintenance) 
with obinutuzumab and venetoclax, as outlined in Table 5.  Polatuzumab vedotin will not 
be given as post-induction treatment.  Post-induction treatment will continue until 
disease progression or unacceptable toxicity for up to 24 months for maintenance 
treatment.  When study treatments are given on the same day, venetoclax will be 
administered prior to obinutuzumab.   
Table 5 
Post-Induction Treatment for the Follicular Lymphoma 
Expansion Phase 
Patients 
with FL 
Maintenance treatment consisting of the following, administered for 24 months 
(Months 1−24): 
• Venetoclax at the RP2D (mg) PO once daily for 8 months (Months 1−8) 
• Obinutuzumab 1000 mg IV on Day 1 of every other month (i.e., every 2 months) 
for 24 months, starting with Month 2 (e.g., Months 2, 4, 6, 8, etc.) 
FL = follicular lymphoma; IV = intravenous; PO = by mouth; RP2D = recommended Phase II dose. 
Note:  When study treatments are given on the same day, venetoclax will be administered prior 
to obinutuzumab.  A month is defined as 28 days. 
 
The schedules of assessments are provided in Appendix 1 (FL).  
3.1.3 
Rituximab Plus Polatuzumab Vedotin Plus Venetoclax 
Treatment Group (Patients with DLBCL)  
Based on the safety and efficacy results from the Phase III study (BO21005) in patients 
with DLBCL, the protocol has been amended to explore dose-finding of venetoclax in 


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combination with fixed doses of polatuzumab vedotin and rituximab instead of 
obinutuzumab for patients with R/R DLBCL.   
3.1.3.1 
Dose-Escalation Phase in Relapsed or Refractory DLBCL 
Patients 
The DLBCL dose-escalation phase will open with the purpose of identifying the RP2D 
for venetoclax when combined with polatuzumab vedotin at 1.8 mg/kg and rituximab at 
375 mg/m2 as induction treatment in patients with R/R DLBCL.  The dose escalation 
will initiate at the venetoclax 400-mg dose level and increase through Cohorts A, B, 
and C (see Figure 4).   
Approximately 12−18 patients will be enrolled in the DLBCL dose-escalation phase.  
Cohorts of 3−6 patients each will be treated in accordance with the treatment regimens 
and dose-escalation rules described in Section 3.1.3.1.2. 
Patients will be closely monitored for adverse events during the DLT assessment 
window, defined as the first treatment cycle (from Day 1 of Cycle 1 to Day 1 of Cycle 2).  
Adverse events meeting the criteria for DLT, as defined above (see Section 3.1.2.1.1), 
will be reported to the Sponsor within 24 hours (see Section 5.4.2).  
Patients who discontinue from the study prior to completing the DLT assessment 
window for reasons other than a DLT will be considered non-evaluable for 
dose-escalation decisions and RP2D assessments and will be replaced by an additional 
patient at that same dose level.  Patients who miss one dose of polatuzumab vedotin or 
rituximab or five consecutive daily doses of venetoclax during the DLT assessment 
window for reasons other than a DLT will also be replaced and considered 
non-evaluable for dose-escalation decisions.  Patients who receive supportive care 
during the DLT assessment window that may confound the evaluation of DLTs may be 
replaced at the discretion of the Medical Monitor. 
Patients will receive induction treatment with R + Pola + V for a total of six cycles.  
Patients achieving a CR or PR at EOI will be eligible to receive consolidation treatment 
with R + V.  A study schema is provided in Figure 2.   
3.1.3.1.1 
Treatment Regimens for DLBCL Dose-Escalation Phase 
Patients enrolled in the DLBCL dose-escalation phase will receive induction treatment, 
administered in 21-day cycles as shown in Table 6.  When study treatments are given 
on the same day, they will be administered sequentially in the following order:  
venetoclax, rituximab, and polatuzumab vedotin.   


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Table 6 
Induction Treatment for the DLBCL Dose-Escalation Phase  
Cycle 
R + Pola + V (21-Day Cycles) 
Cycles 1-6 
• 
Venetoclax 400, 600, or 800 mg PO once daily on Days 1−21  
• 
Rituximab 375 mg/m2 IV on Day 1 
• 
Polatuzumab vedotin 1.8 mg/kg IV on Day 1 
IV = intravenous; PO = by mouth; R + Pola + V = rituximab in combination with polatuzumab 
vedotin and venetoclax.  
Note:  Treatments will be administered sequentially in the following order:   venetolax, 
rituximab, and polatuzumab vedotin. 
 
After completion of induction treatment, patients will continue to receive daily 
venetoclax treatment (during Month 1) until response is assessed at EOI.  Venetoclax 
will be discontinued if response assessments at EOI indicate that a patient is not 
eligible for post-induction treatment (referred to as consolidation).  Patients who 
achieve a CR or PR at EOI will receive consolidation treatment with rituximab and 
venetoclax, as outlined in Table 7.  Polatuzumab vedotin will not be given as 
consolidation treatment.  Consolidation treatment will continue until disease 
progression or unacceptable toxicity for up to 8 months.  When study treatments are 
given on the same day, venetoclax will be administered prior to rituximab.   
Table 7 
Consolidation Treatment for the DLBCL Dose-Escalation Phase 
Patient 
Population 
Regimen 
Patients with 
DLBCL 
Consolidation treatment consisting of the following, administered for 
approximately 8 months (from Months 1−8): 
• 
Venetoclax 400, 600, or 800 mg PO once daily for 8 months 
(Months 1−8) 
• 
Rituximab 375 mg/m2 IV on Day 1 of every other month (i.e., every 
2 months) starting with Month 2 (i.e., Months 2, 4, 6, and 8) for 
8 months 
DLBCL = diffuse large B-cell lymphoma; IV = intravenous; PO = by mouth; QD = every day.  
Note:  A month is defined as 28 days.  Treatments will be administered sequentially in the 
following order:   venetoclax followed by rituximab. 
 
3.1.3.1.2 
Dose Escalation Rules 
A standard 3 + 3 dose-escalation schema will be used.  The rituximab and polatuzumab 
dose levels will remain fixed during the dose-escalation phase and only the venetoclax 
will be dose escalated.  The polatuzumab dose of 1.8 mg/kg is based on ongoing Phase II 
trials (see Sections 1.3.2 and 3.3.3.3).  Intrapatient dose escalation is not allowed.  The 
overall DLBCL dose-escalation plan is depicted in Figure 4 and Table 8. 


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Figure 4 DLBCL Dose-Escalation Plan 
 
If Cohort A doses are deemed safe and tolerable, escalation will continue with 
enrollment of Cohort B.    
If Cohort B doses are deemed safe and tolerable, escalation will continue with enrollment 
of Cohort C.   
Table 8 
DLBCL Dose-Escalation Cohorts  
Cohort 
Rituximab a 
Polatuzumab Vedotin b 
Venetoclax 
A 
375 mg/m2 
1.8 mg/kg 
400 mg 
B 
375 mg/m2 
1.8 mg/kg 
600 mg 
C 
375 mg/m2 
1.8 mg/kg 
800 mg 
a Rituximab will be administered intravenously at a dose of 375 mg/m2 on Day 1 of each 
21-day cycle of induction 
b Polatuzumab vedotin will be administered intravenously at a dose of 1.8 mg/kg on Day 1 
of each 21-day cycle of induction 
c Venetoclax will be administered orally on Days 1−21 of each 21-day cycle.  
 
Dose escalation will occur in accordance with the rules listed below. 
• 
A minimum of 3 patients will initially be enrolled in each cohort.  The first 
3 patients in each cohort will be sequentially enrolled and dosed at least 48 hours 
apart.   


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• 
If none of the first 3 DLT-evaluable patients experiences a DLT, the doses in that 
cohort will be deemed safe and tolerable and escalation may continue per the 
dose-escalation plan described above. 
• 
If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will 
be expanded to 6 patients.  If there are no further DLTs in the first 
6 DLT-evaluable patients, the doses in that cohort will be deemed safe and tolerable 
and escalation may continue per the dose-escalation plan described above. 
• 
If a DLT is observed in ≥ 33% of patients (e.g., 2 or more of up to 6 DLT-evaluable 
patients), the dose combination at which this occurs will be considered intolerable 
and the MTD will have been exceeded for venetoclax in the R + Pola + V treatment 
combination.   
• 
If the MTD is exceeded in any cohort, the highest dose combination at which < 33% 
of patients (e.g., 2 of 6 DLT-evaluable patients) experience a DLT will be declared 
the combination MTD (i.e., the MTD venetoclax in the R + Pola + V treatment 
combination). 
• 
If the MTD is not exceeded at any dose level, the highest dose combination 
administered in this study will be declared the maximum administered dose for 
polatuzumab vedotin and venetoclax in the R + Pola + V treatment combination. 
 
If the MTD is exceeded in any cohort, de-escalation of the venetoclax dose and/or 
polatuzumab vedotin dose, and/or adjustment of treatment schedules (e.g., venetoclax 
treatment on Days 1−10) may occur.  Additional patients may be enrolled in a given 
cohort in the absence of DLTs to acquire additional safety data for the appropriate dose 
levels in the expansion phase of the study. 
On the basis of a review of real-time safety data and available preliminary PK data, 
dose escalation may be halted or modified by the Sponsor as deemed appropriate. 
Relevant demographic, adverse event, laboratory, dosing administration/intensity, and 
PK (if available) data will be reviewed prior to dose-escalation decisions, which will be 
made by the Medical Monitor in consultation with the Principal Investigator and 
participating investigators. 
Although the DLT assessment window is defined as the first treatment cycle (from 
Day 1 of Cycle 1 to Day 1 of Cycle 2), cumulative or late toxicities that occur beyond 
the first cycle may be considered in determination of the RP2Ds.  Prior to opening the 
R/R DLBCL expansion phase, the Clinical Study Team and the Medical Monitor will 
review the cumulative data, determine the RP2D, and review this information with the 
IMC for approval.   
3.1.3.2 
DLBCL Expansion Phase 
The expansion phase is designed to further assess the safety and efficacy of venetoclax 
when combined with a fixed dose of rituximab and polatuzumab vedotin in DLBCL 
patients.  


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Approximately 40 patients with DLBCL will be enrolled during the expansion phase 
and treated as described below. 
All patients enrolled in the expansion phase will receive induction treatment as 
outlined in Table 9.  When study treatments are given on the same day, they will be 
administered sequentially in the following order:  venetoclax, rituximab, and 
polatuzumab vedotin. 
Table 9 
Induction Treatment for the DLBCL Expansion Phase 
Cycle 
R + Pola + V (21-Day Cycles) 
Cycles 1-6 
Venetoclax at the RP2D (mg) PO once daily on Days 1−21 
Rituximab 375 mg/m2 IV on Day 1 
Polatuzumab vedotin 1.8 mg/kg IV on Day 1 
IV = intravenous; PO = by mouth; R + Pola + V = rituximab in combination with 
polatuzumab vedotin and venetoclax. 
Note:  Treatments will be administered sequentially in the following order:  venetoclax, 
rituximab, and polatuzumab vedotin. 
 
After completion of induction treatment, patients will continue to receive daily 
venetoclax treatment (during Month 1) until response is assessed at EOI.  Venetoclax 
will be discontinued if response assessments at EOI indicate that a patient is not 
eligible for post-induction treatment.  Patients with DLBCL who achieve a CR or PR at 
EOI will receive post-induction treatment (referred to as consolidation) with rituximab 
and venetoclax, as outlined in Table 10.  Polatuzumab vedotin will not be given as post-
induction treatment.  Post-induction treatment will continue until disease progression 
or unacceptable toxicity for up to 8 months for consolidation treatment.  When study 
treatments are given on the same day, venetoclax will be administered prior to 
rituximab.   
Table 10 Consolidation Treatment for the DLBCL Expansion Phase 
Patients 
with 
DLBCL 
Consolidation treatment consisting of the following, administered for 8 months 
(Months 1−8): 
• Venetoclax at the RP2D (mg) PO once daily for 8 months (Months 1−8) 
• Rituximab 375 mg/m2 IV on Day 1 of every other month (i.e., every 2 months)
starting with Month 2 (i.e., Months 2, 4, 6, and 8) for 8 months 
DLBCL = diffuse large B-cell lymphoma; IV = intravenous; PO = by mouth; 
RP2D = recommended Phase II dose. 
Note:  When study treatments are given on the same day, venetoclax will be administered 
prior to rituximab.  A month is defined as 28 days. 
 


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3.1.4 
Internal Monitoring Committee  
An IMC will monitor patient safety throughout the study.  The IMC will include Roche 
representatives from Clinical Science, Drug Safety, Biostatistics, and Statistical 
Programming and Analysis.  In addition to the ongoing assessment of the incidence and 
nature of adverse events (particularly Grade ≥ 3 events), serious adverse events, deaths, 
and laboratory abnormalities assessed by the investigator and the Medical Monitor, the 
IMC will review all necessary cumulative, including data required for determination of the 
RP2Ds, data at regular intervals during the study.  At the time of each review, the IMC 
will make appropriate recommendations (e.g., the study should continue as planned, 
additional analyses should be performed, enrollment should be held pending further 
safety evaluations).  Decisions will be made in consideration of the totality of the 
available data.  Ad hoc meetings may be called in addition to scheduled meetings, as 
necessary, to provide recommendations on management of any potential new safety 
signals.  Specific operational details such as the committee's composition, frequency 
and timing of meetings, members' roles and responsibilities, and data to be reviewed will 
be detailed in an IMC Charter. 
3.1.5 
Independent Review Committee  
An IRC will assess all patients for response on the basis of imaging results and bone 
marrow biopsy results.  The review will consist of 2 parts:  a radiology review and an 
oncology review.  The IRC will consist of radiologists, nuclear medicine experts, and a 
board-certified oncologist with experience in malignant lymphoma.  Specific 
methodological and operational details will be specified in the IRC Charter. 
3.1.6 
Post-Treatment and Survival Follow-Up 
Patients who complete treatment or discontinue treatment for reasons other than 
disease progression will undergo assessments every 3 months during the 
post−treatment follow-up period, which will continue until disease progression, the start 
of new anti-lymphoma treatment, or the end of the study (as defined in Section 3.2), 
whichever occurs first.  Patients who experience disease progression will be evaluated 
for survival status and initiation of new anti-lymphoma treatment every 3 months until the 
end of the study.  Details are provided in the schedules of assessments (see 
Appendix 1 [FL] and Appendix 2 [DLBCL]). 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the time when both of the following criteria are met:  
• 
All enrolled FL patients have been followed for at least 90 days after they have 
completed or discontinued study treatment (including induction treatment and 
maintenance treatment as applicable).    
• 
All enrolled DLBCL patients have been followed for at least 1 year after they have 
completed or discontinued study treatment (including induction treatment and 
consolidation treatment as applicable).   


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The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4.5 years. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Patient Population 
As discussed in Section 1.1.1, despite significant therapeutic progress with the use of 
chemoimmunotherapy as first-line treatment, FL remains essentially an incurable 
disease.  Patients invariably relapse, and active and well-tolerated agents are needed 
following relapse.  DLBCL can be cured in > 50% of cases; however, up to one-third of 
patients have refractory disease of relapse after treatment.  Success rates with salvage 
therapy and autologous transplantation are poor, which highlights the urgent need for 
novel therapeutic approaches for these patients. 
On the basis of a compelling biologic and clinical rationale, as presented in Section 1.5 
the addition of polatuzumab vedotin to obinutuzumab or rituximab and venetoclax is a 
promising approach to expand the number of patients with R/R FL and DLBCL who 
achieve remission and to prolong the duration of response in these patients. 
The study will include an initial dose-escalation phase followed by an expansion phase.  
The objective of the dose-escalation phase is to define the RP2D for venetoclax and the 
RP2D for polatuzumab vedotin when given with obinutuzumab in patients with R/R FL 
and the RP2D for venetoclax when given in combination with polatuzumab at 1.8 
mg/kg and rituximab at 375 mg/m2 in patients with R/R DLBCL.  Although the DLT 
assessment window is the first cycle of treatment, long-term or cumulative toxicities will 
also be assessed and considered for the dose definition.   
3.3.2 
Rationale for the Triplet Combination 
This study combines treatments with different mechanisms of action that have 
demonstrated clinical activity against B-cell lymphoma.  Refer to Appendix 12 for 
descriptions of clinical studies that use the study drugs as single or doublet treatment.  
As mentioned in Section 1.5, there is a strong rationale to expect an improved 
benefit-risk profile with the triplet combination of obinutuzumab or rituximab combined 
with polatuzumab vedotin and venetoclax.  This novel triplet regimen may have the 
potential to extend treatment-free remissions and decrease toxicity by improving upon 
individual agents in the current standard of care.  Overlapping toxicities are anticipated 
and expected to be manageable in the clinical setting (see Section 5.1.6). 
Rituximab is established as a standard of care to treat B-cell lymphomas.  As discussed 
in Section 1.4, the development of obinutuzumab in B-cell malignancies is based on the 
hypothesis that obinutuzumab will be a superior anti-CD20 agent compared to 
rituximab in patients with FL.  This has been demonstrated in CLL (Goede et al. 2014) 
and has been studied in two additional Phase III studies in DLBCL (Study BO21005) 
and FL (Study BO21223).   


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Study BO21223 investigated obinutuzumab plus chemotherapy (G-benda, G-CVP, 
G-CHOP) compared with rituximab plus chemotherapy, followed by obinutuzumab or 
rituximab maintenance in patients with previously untreated iNHL (FL cohort, 
n = 1202) and demonstrated positive results, showing a significant improvement in PFS 
in the obinutuzumab chemotherapy arm.   
Study BO21005 investigated obinutuzumab plus CHOP (G-CHOP) compared with 
rituximab plus CHOP (R-CHOP) in patients with previously untreated DLBCL, and 
this study did not meet its primary endpoint of PFS at final analysis.   
On the basis of the results of these Phase III studies evaluating obinutuzumab in 
combination with chemotherapy in both FL and DLBCL, current protocol amendment 
patients with R/R FL will continue to receive obinutuzumab in combination with 
polatuzumab vedotin and venetoclax, while patients with R/R DLBCL will instead 
receive rituximab in combination with polatuzumab vedotin and venetoclax.   
3.3.3 
Rationale for Dose and Schedule 
3.3.3.1 
Rationale for Obinutuzumab Dosing Regimen in Follicular 
Lymphoma Patients 
The dose and schedule of obinutuzumab in the induction regimen for FL patients will be 
1000 mg intravenously (IV) on Days 1, 8, and 15 of Cycle 1 and Day 1 of each 
subsequent 21-day cycle (Cycles 2−6).  This is based on the recommended dose and 
schedule (6−8 cycles depending on the trial) of obinutuzumab in the ongoing Phase III 
program in patients with NHL.  For this protocol, patients will be treated for 6 cycles 
during the induction phase.   
The dose and schedule of obinutuzumab in the maintenance regimen (FL) will be 
1000 mg IV administered every 2 months for 2 years.  This dosing administration is 
based on the obinutuzumab maintenance regimen that was administered in the Phase III 
GAO4753g study (Sehn et al. 2015).  The GAO4753g study showed that bendamustine 
and obinutuzumab followed by obinutuzumab maintenance was associated with superior 
PFS compared with bendamustine alone (median PFS had not been reached in the 
obinutuzumab plus bendamustine followed by obinutuzumab maintenance arm vs. 
14.9 months in the bendamustine arm; stratified HR = 0.55; 95% CI: 0.40, 0.74; 
p = 0.0001, by log-rank test). 
3.3.3.2 
Rationale for Polatuzumab Vedotin Dosing Regimen  
3.3.3.2.1 
Rationale for Polatuzumab Vedotin Dose in Follicular 
Lymphoma Patients 
For this study, dose escalation of polatuzumab vedotin for R/R FL patients will begin at 
a dose level of 1.4 mg/kg (one dose level below the highest polatuzumab vedotin dose 
currently under development) and will escalate to a final dose of 1.8 mg/kg, if tolerated.  
The polatuzumab vedotin dosing for the FL dose escalation phase is based on the 
experience from the Phase I study (DCS4968g) with single−agent polatuzumab vedotin 


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and the Phase II study (GO27834) with polatuzumab vedotin in combination with 
rituximab in patients with R/R NHL, the majority of whom had R/R FL or DLBCL.  Most 
evidence of anti-tumor activity was observed at doses ≥ 1.8 mg/kg alone or in 
combination with rituximab (Advani et al. 2015; Palanca-Wessels et al. 2015).   
The combination of obinutuzumab with polatuzumab vedotin is being evaluated in 
several ongoing studies (see Table 11) including two Phase Ib/II trials in patients with 
R/R FL.   
Table 11 Polatuzumab Vedotin plus Obinutuzumab-Containing Regimens 
for the Treatment of Follicular Lymphoma 
Study 
GO27834 a 
GO29365 b 
GO29044 c 
Patient population 
R/R FL 
(n = approximately 46) 
R/R FL (n = 26) 
R/R FL (Ph Ib; n = 2) d 
Obinutuzumab dose 
1000 mg 
1000 mg 
1000 mg 
Polatuzumab vedotin 
dose 
1.8 mg/kg 
1.8 mg/kg 
1.4 and 1.8 mg/kg 
Chemotherapy 
⎯ 
bendamustine 
CHP 
1L = first line; CHP = cyclophosphamide, doxorubicin, prednisone; FL = follicular lymphoma; 
NHL = non-Hodgkin’s lymphoma; Ph = phase; R/R = relapsed/refractory. 
a Study GO27834: polatuzumab vedotin and obinutuzumab administered every 21 days for 
8 cycles.  
b Study GO29365: polatuzumab vedotin and BG administered every 21 days (FL) for 6 cycles.  
c Study GO29044: polatuzumab vedotin + obinutuzumab + CHP administered every 21 days for 
6−8 cycles. 
d In the Phase Ib portion of the study, 1 R/R FL patient was treated with polatuzumab vedotin 
at 1.4 mg/kg, and 1 R/F FL patient was treated with polatuzumab vedotin at 1.8 mg/kg 
(Forero-Torres 2016).  
 
In Study GO29044, the starting dose of polatuzumab vedotin was 1.4 mg/kg and was 
escalated to 1.8 mg/kg, in combination with G-CHP.  In study GO29365, the starting 
dose of polatuzumab vedotin is 1.8 mg/kg when combined with G-bendamustine.  Since 
polatuzumab vedotin is being combined with obinutuzumab and chemotherapy (CHP or 
bendamustine) at 1.4 mg/kg or 1.8 mg/kg, dose escalation of polatuzumab vedotin for 
the patients with R/R FL in this study will begin at a dose level of 1.4 mg/kg (1 dose 
level below the highest allowed polatuzumab vedotin dose) and will escalate to a final 
dose of 1.8 mg/kg, if tolerated.  This novel triplet, G + Pola + V, substitutes out the 
standard chemotherapy components with venetoclax, which in this combination may 
have the potential to extend treatment-free remissions and decrease toxicity, compared 
to combinations with standard chemotherapy components. 
Because both obinutuzumab and venetoclax have their own degree of 
myelosuppression, the maximum dose of polatuzumab vedotin, 1.8 mg/kg, which can be 


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studied, may not be reached when combined with standard fixed doses of obinutuzumab 
and varied venetoclax doses and dose de-escalation may be warranted.   
3.3.3.2.2 
Rationale for Polatuzumab Vedotin Dose in DLBCL Patients 
On the basis of the preliminary data from the DLBCL patients treated in Studies 
GO29044 and GO29365 at the dose level of polatuzumab vedotin at 1.8 mg/kg, this 
dose has been shown to be safe and tolerable in combination with rituximab and 
chemotherapy.   
Due to the aggressive nature of DLBCL and the evidence that anti-tumor activity was 
observed at doses ≥ 1.8 mg/kg alone or in combination with rituximab, the higher dose 
level of polatuzumab vedotin is preferredto maximize clinical benefit for the 
R/R DLBCL population which has no standard of care.   
The safety profile of rituximab differs slightly in comparison with obinutuzumab and is 
expected to be tolerated when combined with polatuzumab vedotin and venetoclax.  In 
this amdendment, the R/R DLBCL dose-escalation phase will start at the dose level of 
1.8 mg/kg and only the venetoclax dose will be escalated to determine an RP2D in this 
population.    
3.3.3.2.3 
Rationale for Polatuzumab Vetonin Dosing Schedule in 
Follicular Lymphoma and DLBCL Patients 
The number of induction cycles (six 21-day cycles) is in line with other anti-CD20 plus 
polatuzumab vedotin regimens studied in R/R NHL.   
Polatuzumab vedotin will not be administered as post-induction treatment (consolidation 
for DLBCL or maintenance for FL) owing to the risk of peripheral neuropathy with 
cumulative dosing.  
3.3.3.3 
Rationale for Venetoclax Dosing Regimen 
Venetoclax dosing for this study is based on the experience from the Phase I study 
(M12-175) with single-agent venetoclax in patients with R/R NHL and from the Phase Ib 
study (M12-630) of venetoclax in combination with BR in patients with R/R NHL.  
In NHL, all responses in patients with FL have occurred at doses ≥ 600 mg daily.  
Although nonclinical data exist for synergistic activity at a dose equivalent of 400 mg 
daily (Souers et al. 2013), it is desirable to give venetoclax at the higher doses at which 
single-agent activity has been observed.   
The M12-175 study explored a step-up dosing schedule in order to safely administer 
venetoclax by reducing the risk for TLS.  This study showed safety of initial doses of up 
to 400 mg without clinically significant TLS in NHL.  Final single-agent target doses of up 
to 800 mg have been shown to be tolerable in patients with CLL.  Patients with NHL 
have received single-agent target doses of 1200 mg without DLTs.   


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Furthermore, Study M12-630 has shown tolerability of starting doses of venetoclax of up 
to 600 mg in combination with chemoimmunotherapy without observation of clinically 
significant TLS.  To date, dose escalation is continuing with an 800-mg cohort.  
In patients with R/R FL, the starting dose of venetoclax in this study will be 200 mg.  
Because a case of laboratory TLS in a FL patient treated in this trial at a dose level of 
400 mg venetoclax and 1.4 mg/kg polatuzumab has been observed, the lower venetoclax 
dose level cohort of 200 mg was added in order to collect additional safety information 
for this novel triplet combination.  Given that venetoclax will be given in conjunction with 
obinutuzumab and polatuzumab vedotin, potentially resulting in synergistic toxicities, 
doses of venetoclax up to the MTD achieved when given as monotherapy may not be 
tolerable in this combination.  Following the 200 mg Cohort 1a clearing, subsequent 
dose cohorts will explore progressively higher starting and target doses up to a final daily 
dose of 800 mg if tolerated.  The number of cycles of dosing (six 21-day cycles) is 
designed to provide a treatment duration consistent with other therapies for NHL that 
have been shown to be sufficient to provide durable responses. 
In patients with R/R DLBCL, the starting dose of venetoclax in the dose-escalation 
phase will be 400 mg (Figure 4).  Ongoing studies in the DLBCL population have 
confirmed that the TLS risk with doses up to 800 mg is low.  No cases of TLS occurred 
in DLBCL patients in a trial with 800 mg venetoclax given intermittently at 
Days 4−10 of Cycle 1 and Days 1−10 of Cycles 2−8 in combination with R-CHOP 
(Zelenetz et al. 2016).   The duration of venetoclax dosing is designed to provide 
overlapping exposure with obinutuzumab or rituximab.  Extended dosing of venetoclax 
up to 1 year with obinutuzumab or rituximab will allow exploration of whether additional 
activity is observed during the extended (post-induction) dosing period. 
3.3.3.4 
Rationale for Treatment Duration 
In this study, patients with R/R FL or DLBCL will receive 6 cycles of induction treatment 
followed by post-induction treatment, with the objective to improve the response to 
induction therapy, either by converting a PR to a CR, or by eradicating minimal residual 
disease (MRD) to achieve a molecular response in patients with a clinical CR after 
induction treatment, thus reducing the relapse risk for responders.  In this study, MRD 
levels will be measured during the post-induction period as an additional means to 
evaluate the triple combination as post-induction treatment.   
Despite recent improvements in therapy for FL, including demonstrated benefit from 
2-year rituximab maintenance in patients who responded to first-line 
immunochemotherapy (Study MO18264), FL is still not considered curable, with a 6-year 
PFS of 59.2% (Salles et al. 2013).  A Phase III study, GAO4753g, investigated GB 
compared with bendamustine alone in patients with rituximab-refractory iNHL (n = 396).  
Patients in the GB group who had not experienced disease progression at the end of 
induction received obinutuzumab monotherapy every 2 months for up to 2 years.  On the 
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the GB arm, with a median PFS of 29 versus 14 months (HR, 0.52; 95% CI: 0.39, 0.70; 
p > 0.0001; Sehn et al. 2015), the Independent Data Monitoring Committee 
recommended that the study be unblinded to the Sponsor.  These data support further 
investigation of obinutuzumab in combination with new targeted drugs in the setting of 
induction and maintenance treatment for patients with FL.    
Patients with R/R DLBCL who are not suitable for or do not benefit from consolidative 
autologous transplantation exhibit a poor prognosis.  Responses obtained with different 
rituximab treatment regimens tested in clinical trials (e.g., rituximab in combination with 
bendamustine, with gemcitabine plus oxaliplatin, or with lenalidomide) have been of 
short duration, with the longest reported median PFS of approximately 7 months 
observed in one study of BR (Ohmachi et al. 2013).  Thus, 8 months of consolidation 
treatment, for a total treatment duration of approximately 12 months, is considered to be 
a reasonable exploratory therapeutic approach in patients with R/R DLBCL with an 
anticipated positive benefit-risk ratio.  On the basis of the complementary mechanism of 
action between all 3 study drugs and considering the aggressiveness of R/R DLBCL, the 
study was designed to investigate the safety and efficacy of the triple combination in the 
consolidation setting. 
3.3.4 
Rationale for Positron Emission Tomography-Computed 
Tomography-Defined Complete Response as the Primary 
Efficacy Endpoint 
In DLBCL, the prognostic value of the post-treatment fluorodeoxyglucose (18F-FDG) 
PET-CT scan has been well documented (Thomas et al. 2010; Vitolo et al. 2010).  
PET-CT scans have been implemented in the Lugano 2014 criteria (see Appendix 5) 
and are commonly used to assess efficacy in medical practice and clinical trials in 
lymphoma.  More recently, the value of post-induction PET-CT status has been 
investigated as a prognostic marker for long-term outcomes in patients with FL.  In the 
first-line setting, results from a pooled analysis of 246 patients enrolled in 3 studies and 
who had PET-CT scans available at the end of chemoimmunotherapy showed, with a 
median follow-up of 55 months, a 4-year PFS in PET-CT−positive and PET-CT−negative 
patients of 23.2% (95% CI: 11.1%, 37.9%) versus 63.4% (95% CI: 55.9%, 70.0%; 
p < 0.001), respectively, and a 4-year survival of 87.2% (95% CI: 71.9%, 94.5%) versus 
97.1% (95% CI: 93.2%, 98.8%; p < 0.0001), respectively (Trotman et al. 2014).  In the 
relapsed FL setting, results from a preliminary analysis of the Phase II study (BO21003) 
that compared obinutuzumab to rituximab monotherapy demonstrated that the 
post−induction PET-CT status is strongly prognostic of PFS.  With a median follow-up of 
32.1 months, the risk of disease progression was significantly reduced in 
PET-CT−negative patients compared with PET-CT−positive patients, regardless of the 
assessment criteria, either International Harmonization Project criteria (HR = 0.25; 
95% CI: 0.191, 0.807; p = 0.0083) or European Organization for Research and Treatment 
of Cancer (EORTC) criteria (HR = 0.39; 95% CI: 0.191, 0.807; p = 0.0083; 
Kostakoglu et al. 2014). 


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In response to developments in PET-CT status, the 11th International Conference of 
Malignant Lymphoma imaging group provided an updated guidance for the use of 
PET-CT scan results for lymphoma staging and response assessment (Lugano 2014 
criteria; Cheson et al. 2014).   
3.3.5 
Rationale for Biomarker Assessments 
3.3.5.1 
Rationale for Analysis of Diffuse Large B-Cell Lymphoma 
Subtype, BCL2, and MYC 
There is increasing evidence for prognostic subgroups of DLBCL with differential 
response to standard treatments.  DLBCL cell-of-origin subgroups (ABC and GCB), 
which are defined using gene expression profiling, have been associated with different 
clinical outcomes in patients who receive R-CHOP for DLBCL; GCB subgroups have 
demonstrated an improved prognosis compared with ABC groups (3-year survival rate of 
84% vs. 56%, respectively; p < 0.001; Lenz et al. 2008).  
Similarly, Bcl-2 overexpression has been associated with inferior outcomes in DLBCL 
with standard treatment (Iqbal et al. 2006).  Next-generation sequencing studies have 
shown that BCL2 is the most mutated gene in patients with GCB DLBCL; the mutation is 
observed in up to 35% of cases (Schuetz et al. 2012).  Approximately 9%−17% of 
patients with newly diagnosed DLBCL harbor an underlying MYC rearrangement, and 
these patients are at high risk of treatment failure with R-CHOP (Savage et al. 2009).  
A subset of patients with MYC-positive DLBCL also harbors an additional BCL2 
rearrangement.  These “double-hit” lymphomas are associated with a very poor outcome 
(Savage et al. 2009; Dunleavy et al. 2014).  Overexpression of Bcl-2 and Myc in DLBCL 
has also been observed in the absence of translocation.  This “double-positive” DLBCL 
status is also associated with worse prognosis (Green et al. 2012; Johnson et al. 2012; 
Hu et al. 2013). 
Identification of these molecularly defined prognostic subtypes in DLBCL is critical for 
interpretation of correlative investigations aimed to understand mechanisms of both 
sensitivity and resistance to study treatment. 
3.3.5.2 
Rationale for Assessment of Therapeutic Target Expression 
CD79b is a signal-transducing subunit of the B-cell receptor that is rapidly internalized 
upon antigen binding (Jang et al. 2010).  Activity of ADCs such as polatuzumab vedotin 
may depend on the presence of the target, internalization, and sensitivity to the payload 
drug (Zheng et al. 2009).  To ascertain the expression of CD79b in this study, CD79b 
levels will be assessed. 
Bcl-2 is an anti-apoptotic molecule overexpressed in many hematologic malignancies, 
including DLBCL, either through translocation of the BCL2 gene in juxtaposition with the 
IGH gene t(14;18), through gene amplification, or by other mechanisms 
(Gascoyne et al. 1997).  To evaluate the relationship between Bcl-2 protein expression 
and venetoclax activity in this study, Bcl-2 will be assessed.  


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3.3.5.3 
Rationale for Assessment of Minimum Residual Disease 
MRD measurement is an increasingly recognized tool for response assessment in B-cell 
malignancies.  Circulating lymphoma cells and/or tumor DNA can be detected and 
quantified at low levels as MRD to assess treatment dynamics and monitor patients after 
treatment.  However, there is no scientific proof that MRD is a reliable measure of 
clinical outcome in NHL, and technical validation of novel technologies for MRD 
assessment that have clinical utility is still pending.  
In FL, MRD at end of treatment is likely to be prognostic (Ladetto et al. 2013).  In DLBCL, 
serum MRD was shown to be predictive of early and late progression after first-line 
treatment (Roschewski et al. 2014).  In addition, MRD assessment may complement the 
response assessment, particularly in immune treatment−based regimens, and mitigate 
potential false-positive FDG-PET results caused by infiltration of metabolically active 
immune cells into the tumor (Kurtz et al. 2015).  For these reasons, initially an MRD 
analysis will be performed in FL and subsequently analysis in DLBCL may be performed. 
In this study, MRD will be quantified by circulating lymphoma cells and/or cell-free 
circulating tumor DNA as an exploratory endpoint.   
3.3.5.4 
Rationale for Assessment of Lymphoma−Related Genetic 
Changes and Gene Expression  
Measurement of relevant protein, RNA and, DNA (including Bcl-2 and family members, 
genes associated with apoptosis, and those related to disease biology) will be performed 
at baseline to identify potential biomarkers that may be predictive of efficacy and also to 
understand mechanisms of resistance. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
This study will enroll patients with R/R FL or R/R DLBCL who meet the eligibility criteria 
presented below. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 
(see Appendix 6) 
• 
For G + Pola + V treatment group:  R/R FL after treatment with at least 1 prior 
chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody 
and for which no other more appropriate treatment option exists, as determined by 
the investigator 


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• 
For R + Pola + V treatment group:  R/R DLBCL after treatment with at least 1 prior 
chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody, 
with no curative option as determined by the investigator 
• 
Histologically documented CD20-positive NHL as determined by the local 
laboratory 
• 
FDG-avid lymphoma (i.e., PET-positive lymphoma) 
• 
At least one bi-dimensionally measurable lesion (> 1.5 cm in its largest dimension 
by CT scan or magnetic resonance imaging [MRI]) 
• 
Availability of a representative tumor specimen and the corresponding pathology 
report for retrospective central confirmation of the diagnosis of FL or DLBCL 
If the archival tissue is unavailable or unacceptable, a pretreatment core, 
excisional, or incisional tumor biopsy is required.  Cytological or fine-needle 
aspiration samples are not acceptable.  
Further details are provided in Section 4.5.6. 
If the patient received anti-lymphoma treatment between the time of the most 
recent available biopsy and initiation of study treatment, a core-needle biopsy is 
strongly recommended. 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and for at least 12 months after the 
last dose of polatuzumab vedotin, 30 days after the last dose of venetoclax, 
12 months after last dose of rituximab, or at least 18 months after the last dose of 
obinutuzumab. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices 
(IUDs), and copper IUDs. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• 
For men:  Agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures and agreement to refrain from donating sperm, as 
defined below: 
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of < 1% per year during the treatment period and for at least 


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5 months after the last dose of polatuzumab vedotin, 30 days after the last dose 
of venetoclax, and 3 months after the last dose of obinutuzumab or rituximab.  
Men must refrain from donating sperm for the same period. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 5 months after the last dose of 
polatuzumab vedotin, 30 days after the last dose of venetoclax, and 3 months 
after the last dose of obinutuzumab or rituximab.   
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Known CD20-negative status at relapse or progression 
• 
Prior allogeneic SCT 
• 
Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1 
• 
Prior standard or investigational anti-cancer therapy as specified below: 
– 
Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1 
– 
Monoclonal antibody or ADC therapy within 5 half-lives or 4 weeks prior to 
Day 1 of Cycle 1, whichever is longer 
– 
Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule 
therapy within 2 weeks prior to Day 1 of Cycle 1 
• 
Clinically significant toxicity (other than alopecia) from prior therapy that has not 
resolved to Grade ≤ 2 (per NCI CTCAE v4.0) prior to Day 1 of Cycle 1 
• 
Grade 3b FL 
• 
History of transformation of indolent disease to DLBCL 
• 
Current Grade > 1 peripheral neuropathy 
• 
CNS lymphoma or leptomeningeal infiltration 
• 
Treatment with systemic corticosteroids > 20 mg/day prednisone or equivalent 
Patients who are receiving corticosteroids ≤ 20 mg/day, prednisone or 
equivalent, for non-lymphoma treatment reasons must be documented to be on 
a stable dose for at least 4 weeks prior to Day 1 of Cycle 1.  
If corticosteroid treatment is urgently required for lymphoma symptom control 
prior to the start of study treatment, up to 100 mg/day of prednisone or 
equivalent can be given for a maximum of 5 days, but all tumor assessments 
must be completed prior to start of corticosteroid treatment. 
• 
History of severe allergic or anaphylactic reaction to humanized or murine 
monoclonal antibodies 


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• 
Known sensitivity or allergy to murine products or any component of the 
obinutuzumab, rituximab, polatuzumab vedotin, or venetoclax formulations 
• 
Active bacterial, viral, fungal, or other infection  
Caution should be exercised when considering the use of obinutuzumab and 
rituximab in patients with a history of recurring or chronic infections. 
• 
Requirement for warfarin treatment (because of potential DDIs that may increase 
the exposure of warfarin) 
• 
Treatment with the following agents within 7 days prior to the first dose of 
venetoclax: 
– 
Strong and moderate CYP3A inhibitors such as fluconazole, ketoconazole, 
and clarithromycin (see Appendix 10 for examples) 
– 
Strong and moderate CYP3A inducers such as rifampin and carbamazepine 
(see Appendix 10 for examples) 
• 
Consumption of grapefruit, grapefruit products, Seville oranges (including 
marmalade that contains Seville oranges), or star fruit within 3 days prior to the first 
dose of venetoclax 
• 
Clinically significant history of liver disease, including viral or other hepatitis, current 
alcohol abuse, or cirrhosis  
• 
Positive for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody 
(HBcAb), or hepatitis C virus (HCV) antibody at screening 
• 
Known history of HIV positive status 
For patients with unknown HIV status, HIV testing will be performed at 
screening if required by local regulations. 
• 
History of PML 
• 
Vaccination with a live virus vaccine within 28 days prior to Day 1 of Cycle 1 
• 
History of other malignancy that could affect compliance with the protocol or 
interpretation of results, with the exception of the following: 
– 
Curatively treated carcinoma in situ of the cervix, good-prognosis ductal 
carcinoma in situ of the breast, basal- or squamous-cell skin cancer, 
Stage I melanoma, or low-grade, early-stage localized prostate cancer 
– 
Any previously treated malignancy that has been in remission without 
treatment for ≥ 2 years prior to enrollment 
• 
Evidence of any significant, uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or 
unstable angina) or significant pulmonary disease (such as obstructive pulmonary 
disease or history of bronchospasm) 
• 
Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of 
Cycle 1, or anticipation of a major surgical procedure during the course of the study 


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• 
Inadequate hematologic function (unless due to underlying lymphoma), defined as 
follows: 
– 
Hemoglobin < 9 g/dL 
– 
ANC < 1.5 × 109/L 
– 
Platelet count < 75 × 109/L 
• 
Any of the following abnormal laboratory values (unless due to underlying 
lymphoma): 
– 
Calculated creatinine clearance < 50 mL/min with the use of 24-hour 
creatinine clearance or modified Cockcroft-Gault equation (eCCr; with use of 
the ideal body mass [IBM] instead of mass): 
(140 − Age) • IBM (kg) • [0.85 if female] 
eCCr = 
72 • serum creatinine (mg/dL) 
Or, if serum creatinine is in μmol/L: 
 
(140 − Age) • IBM (kg) • [1.23 if male, 1.04 if female] 
eCCr = 
serum creatinine (μmol/L) 
– 
AST or ALT > 2.5 × by ULN 
– 
Serum total bilirubin > 1.5 × ULN (or > 3 × ULN for patients with Gilbert 
syndrome)   
– 
INR or PT > 1.5 × ULN in the absence of therapeutic anticoagulation 
– 
PTT or aPTT > 1.5 × ULN in the absence of a lupus anticoagulant 
• 
Pregnant or lactating, or intending to become pregnant during the study 
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to Day 1 of Cycle 1. 
• 
Life expectancy  < 3 months 
• 
Unable to comply with the study protocol, in the investigator’s judgment 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is a Phase Ib/II, open-label, multicenter, non-randomized study of G + Pola + V in 
patients with R/R FL and R + Pola + V in patiens with R/R DLBCL.  During the 
dose-escalation phase, patients will be assigned to cohorts with varying polatuzumab 
vedotin (R/R FL dose-finding only) and venetoclax dose combinations, through use of 
an interactive voice or Web-based response system (IxRS).  During the FL expansion 
phase, all patients will be treated at RP2Ds for polatuzumab vedotin and venetoclax.  If 
more than one combination of RP2Ds is identified, patients will be enrolled into multiple 
cohorts to allow for those combinations to be evaluated during the expansion phase.  
Post-induction treatment (for eligible patients only) will depend on lymphoma histology.  
Patients with FL will receive maintenance treatment with obinutuzumab and venetoclax 
for 24 months, and patients with DLBCL will receive consolidation treatment with 
rituximab and venetoclax for 8 months (see Section 3.1 for details).  Patients enrolled in 


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the dose-escalation phase and expansion phase will receive fixed doses of 
obinutuzumab or rituximab. 
Enrollment tracking will be performed through use of the IxRS.  After written informed 
consent has been obtained and preliminary eligibility has been established, the study 
site will submit documentation supporting eligibility to the Sponsor and obtain the 
Sponsor’s approval to enroll the patient.  Once the Sponsor reviews and approves the 
patient for enrollment, the patient number will be assigned and the patient will be 
enrolled via the IxRS. 
4.3 
STUDY TREATMENTS  
The investigational medicinal products (IMPs) for this study are obinutuzumab, 
rituximab, polatuzumab vedotin, and venetoclax. 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Obinutuzumab  
Obinutuzumab will be supplied by the Sponsor as a single-dose, sterile liquid formulation 
in a 50-mL glass vial that contains 1000 mg of obinutuzumab.  For information on the 
formulation and handling of obinutuzumab, see the pharmacy manual and the 
Obinutuzumab Investigator's Brochure.  
4.3.1.2 
Rituximab 
Rituximab will be supplied by the Sponsor as an IMP.  Rituximab is packaged in 10-mL 
(100-mg) and 50-mL (500-mg) single-dose, pharmaceutical-grade glass vials at a 
concentration of 10 mg/mL of protein.  The antibody is formulated for IV injection as a 
sterile product in a solution of sodium chloride (pH 6.5) containing polysorbate 80 and 
sodium citrate.  For information on the formulation and handling of rituximab, see the 
pharmacy manual and the Rituximab Investigator's Brochure. 
4.3.1.3 
Polatuzumab Vedotin 
Polatuzumab vedotin will be supplied by the Sponsor as a sterile, white to off-white, 
preservative-free lyophilisate in single-use vials.  For information on the formulation and 
handling of polatuzumab vedotin, see the pharmacy manual and the Polatuzumab 
Vedotin Investigator's Brochure. 
4.3.1.4 
Venetoclax 
Venetoclax will be supplied by the Sponsor as oral film-coated tablets of 100-mg 
strength in high-density polyethylene plastic bottles.  For information on the formulation 
and handling of venetoclax, see the pharmacy manual and the Venetoclax Investigator’s 
Brochure. 
4.3.2 
Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1 and depicted in Figure 5. 


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Patients enrolled in the dose-escalation phase or the expansion phase will receive six 
21-day cycles of induction treatment with obinutuzumab or rituximab, polatuzumab 
vedotin, and venetoclax.  When study treatments are given on the same day, they will be 
administered sequentially in the following order:  venetoclax, obinutuzumab or rituximab, 
and polatuzumab vedotin.  
After completion of induction treatment, patients in both phases will continue to receive 
daily venetoclax treatment (during Month 1) until response is assessed at EOI.  However, 
venetoclax will be discontinued if response assessments at EOI indicate that a patient is 
not eligible for post-induction treatment.   
During both phases, patients with DLBCL who achieve a CR or PR at EOI will receive 
post-induction treatment (referred to as consolidation) with venetoclax and rituximab for 
8 months, and patients with FL who achieve a CR, PR, or stable disease at EOI will 
receive post-induction treatment (referred to as maintenance) with venetoclax for 
8 months and obinutuzumab for 24 months.  When study treatments are given on the 
same day, venetoclax will be administered prior to obinutuzumab or rituximab. 


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Figure 5 Induction and Post-Induction Treatment Regimens 
 
DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; IV = intravenous; PO = by mouth; RP2D = recommended Phase II dose. 


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Any overdose or incorrect administration of any of the study treatments should be noted 
on the Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event eCRF. 
4.3.2.1 
Obinutuzumab 
Obinutuzumab will be administered by IV infusion at an absolute (flat) dose of 1000 mg 
on Days 1, 8, and 15 of the first cycle and on Day 1 of each subsequent cycle during 
induction treatment, and on Day 1 of every other month (i.e., every 2 months) during 
maintenance treatment (eligible patients with FL only).  A month is defined as 28 days. 
Obinutuzumab should be administered as an IV infusion through a dedicated line in an 
environment in which full resuscitation facilities are immediately available and under the 
close supervision of an experienced health care provider.  Obinutuzumab infusions will 
be administered according to the instructions outlined in Figure 6 and Figure 7.  For 
patients with bulky lymphadenopathy, the infusion may be given slowly over a longer 
period of time, or the dose may be split and given over more than 1 day.  
No dose modifications for obinutuzumab are allowed.  Guidelines for treatment delays or 
discontinuation are provided in Section 5.1. 
Premedication with a corticosteroid, antihistamine, and analgesic/antipyretic, as outlined 
in Section 4.3.2.5, is required to reduce the incidence and severity of IRRs.  
For anaphylaxis precautions, see Appendix 9. 
 


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Figure 6 Guidelines for Obinutuzumab Infusions:  First Infusion 
 
IRR = infusion-related reaction; IV = intravenous. 
a All patients should receive full premedication with an oral corticosteroid, antihistamine, and oral analgesic/anti-pyretic prior to the first obinutuzumab infusion.  
Refer to Section 4.3.2.5 for details. 
b Supportive treatment should include acetaminophen/paracetamol and an antihistamine such as diphenhydramine, if not administered within the previous 4 hours.  
IV saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may require antihistamines, oxygen, corticosteroids (e.g., 100 mg oral prednisone 
or equivalent), and/or bronchodilators.  For anaphylaxis precautions, see Appendix 9. 


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Figure 7 Guidelines for Obinutuzumab Infusions:   Second and Subsequent Infusions 
 
IRR = infusion-related reaction. 
a Patients should receive full premedication with an oral corticosteroid, antihistamine, and oral analgesic/anti-pyretic prior to the obinutuzumab infusion.  Refer to 
Section 4.3.2.5 for details.  In the case of a recurrent Grade 3 IRR, obinutuzumab may be discontinued at the discretion of the investigator, following an 
individual benefit-risk assessment.  In the case of a recurrent Grade 3 IRR, obinutuzumab may be discontinued at the discretion of the 
investigator, following an individual benefit-risk assessment. 
b Patients who experience wheezing, urticaria, or other symptoms of anaphylaxis must receive full premedication prior to all subsequent doses. 
 


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4.3.2.2 
Rituximab 
Rituximab will be administered by IV infusion at the dose of 375 mg/m2 on Day 1 of 
Cycles 1−6 during induction treatment and on Day 1 of every other month (i.e., every 
2 months) during consolidation treatment for patients with R/R DLBCL.   
Body surface area (BSA) will be determined at screening and should be used to 
calculate the dose of rituximab throughout the study unless the patient’s weight 
increases or decreases by > 10% from screening, in which case BSA should be 
recalculated and used for subsequent dosing.  In obese patients (defined as body mass 
index ≥ 30 kg/m2), there is no BSA cap and actual body weight, not adjusted weight, is 
recommended.  Empiric dose adjustment for obese patients may be implemented per 
institutional guidelines. 
The infusion of rituximab may be split over 2 days if the patient is at increased risk for 
an IRR (high tumor burden or high peripheral lymphocyte count).  Administration of 
rituximab may be continued on the following day, if needed, for patients who experience 
an adverse event during the rituximab infusion.  
If a dose of rituximab is split over 2 days, both infusions must occur with appropriate 
premedication (see Section 4.3.2.5) and at the first infusion rate (see Table 12). 
Rituximab infusions will be administered according to the instructions in Table 12.  If 
a patient tolerates the first cycle of study treatment without significant infusion 
reactions, rituximab may be administered as a rapid infusion (over 60−90 minutes) in 
accordance with local institutional guidelines. 
During the treatment period, rituximab must be administered to patients in a setting 
where full emergency resuscitation facilities are immediately available.  Patients should 
be under close supervision of the investigator at all times.  
Rituximab should be administered as a slow IV infusion through a dedicated line.  After 
the end of the first infusion, the IV line or central venous catheter should remain in 
place for ≥ 2 hours in order to administer IV drugs, if necessary.  If no adverse events 
occur after 2 hours, the IV line may be removed or the central venous catheter may be 
de-accessed.  For subsequent infusions, the IV line or central venous catheter should 
remain in place for at least 1 hour after the end of the infusion.  If no adverse events 
occur after 1 hour, the IV line may be removed or the central venous catheter may be 
de-accessed. 


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Table 12 Administration of First and Subsequent Infusions of Rituximab 
First Infusion (Day 1 of Cycle 1) 
Subsequent Infusions 
• 
Begin infusion at an initial 
rate of 50 mg/hr. 
• 
If no infusion-related or 
hypersensitivity reaction 
occurs, increase the infusion 
rate in 50-mg/hr increments 
every 30 minutes to a 
maximum of 400 mg/hr. 
• 
If a reaction develops, stop or 
slow the infusion.  
Administer medications and 
supportive care in accordance 
with institutional guidelines.  
If the reaction has resolved, 
resume the infusion at a 50% 
reduction in rate (i.e., 50% of 
rate being used at the time 
when the reaction occurred). 
• 
If the patient experienced an infusion-
related or hypersensitivity reaction 
during the prior infusion, use full 
premedication, including 100 mg of 
prednisone/prednisolone or 80 mg of 
methylprednisolone or equivalent 
(until no further IRR occurs); begin 
infusion at an initial rate of 50 mg/hr; 
and follow instructions for first 
infusion. 
• 
If the patient tolerated the prior 
infusion well (defined by an absence of 
Grade 2 reactions during a final 
infusion rate of ≥ 100 mg/hr), begin 
infusion at a rate of 100 mg/hr. 
• 
If no reaction occurs, increase the 
infusion rate in 100-mg/hr increments 
every 30 minutes to a maximum of 
400 mg/hr. 
• 
If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If the 
reaction has resolved, resume the 
infusion at a 50% reduction in rate 
(i.e., 50% of rate being used at the 
time when the reaction occurred). 
 
No dose modification for rituximab is allowed.  Guidelines for treatment delays or 
discontinuation are provided in Section 5.1.6. 
Premedication with a corticosteroid, analgesic/antipyretic, and antihistamine, as 
outlined in Section 4.3.2.5, is required to reduce the incidence and severity of IRRs.  
For anaphylaxis precautions, see Appendix 9. 
4.3.2.3 
Polatuzumab Vedotin 
For R/R FL, during the dose-escalation phase, the dose of polatuzumab vedotin for 
each patient will depend on dose assignment (1.4 or 1.8 mg/kg).  During the expansion 
phase, the dose of polatuzumab vedotin for each patient will depend on the RP2D 
established during the dose-escalation phase.  For R/R DLBCL, during the dose-
escalation phase and the expansion phase, the dose of polatuzumab vedotin will be fixed 
at 1.8 mg/kg.  Polatuzumab vedotin will be administered by IV infusion on Day 1 of each 
cycle, during induction treatment only. 


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The patient’s weight obtained during screening (Day −28 to Day −1) should be used for 
dose determination for all treatment cycles.  If the patient’s weight within 96 hours prior 
to Day 1 of a given treatment cycle is > 10% from the weight obtained during screening, 
the new weight should be used to calculate the dose.  The weight that triggered a dose 
adjustment will be taken as the new reference weight for future dose adjustments.  All 
subsequent doses should be modified accordingly. 
After reconstitution with Sterile Water for Injection (SWFI) and dilution into IV bags that 
contain isotonic sodium chloride solution (0.9% NaCl), polatuzumab vedotin will be 
administered by IV infusion using a dedicated standard administration set with 0.2-μm or 
0.22-μm in-line filters at a final polatuzumab vedotin concentration determined by the 
patient-specific dose.  Compatibility of polatuzumab vedotin with IV bags, infusion lines, 
filters, and other infusion aids has been established with items made of specific 
materials of construction.  Please consult the pharmacy manual and the Polatuzumab 
Vedotin Investigator’s Brochure for a list of compatible materials and specific dose 
preparation instructions. 
The initial dose will be administered to patients who are well hydrated over 
90 (± 10) minutes.  Premedication (e.g., 500−1000 mg of oral acetaminophen or 
paracetamol and 50−100 mg diphenhydramine as per institutional standard practice) 
may be administered to an individual patient before administration of polatuzumab 
vedotin.  Administration of corticosteroids is permitted at the discretion of the treating 
physician.  If IRRs are observed with the first infusion in the absence of premedication, 
premedication must be administered before subsequent doses. 
The polatuzumab vedotin infusion may be slowed or interrupted for patients who 
experience infusion-associated symptoms.  Following the initial dose, patients will be 
observed for 90 minutes for fever, chills, rigors, hypotension, nausea, or other 
infusion-associated symptoms.  If prior infusions have been well tolerated, subsequent 
doses of polatuzumab vedotin may be administered over 30 (± 10) minutes, followed by 
a 30-minute observation period after the infusion. 
There will be no dose reductions of polatuzumab vedotin for any toxicity except 
neurotoxicity (see Table 21 in Section 5.1.7.3). 
4.3.2.4 
Venetoclax 
During the dose-escalation phase, the dose of venetoclax for each patient will depend 
on dose assignment (200, 400, 600, or 800 mg).  During the expansion phase, the dose 
of venetoclax for each patient will depend on the RP2D established during the 
dose-escalation phase.  Venetoclax will be taken orally once daily.  After completion of 
induction treatment, patients in both phases will continue to receive daily venetoclax 
treatment (during Month 1) until response is assessed at EOI.  However, venetoclax will 
be discontinued if response assessments at EOI indicate that a patient is not eligible for 
post-induction treatment.  Eligible patients will continue to take venetoclax at the 


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designated daily dose for 8 months, as part of the post-induction treatment regimen.  
Alternative dosing schedules may be explored.  Venetoclax should always be given 
before other agents administered on the same day, if applicable. 
All patients who receive venetoclax must receive prophylaxis for TLS (see Section 5.1.6) 
before the initiation of venetoclax in the G + Pola + V and R + Pola + V combination 
treatment.  Patients who receive venetoclax who are at high risk for TLS or with 
compromised renal function must be hospitalized on the first day of Cycle 1 (see 
Section 5.1.6.2). 
Patients will self-administer venetoclax tablets by mouth once daily.  Each dose of 
venetoclax will be taken orally once daily with approximately 240 mL of water within 
approximately 30 minutes after the completion of breakfast or the subject’s first meal of 
the day.  A meal containing approximately 30% of the total caloric content from fat is 
recommended to ensure adequate absorption of venetoclax.  The Standard American 
Heart Association Healthy (Low-Fat) Breakfast includes 1 box cereal (30-40 g), skim milk 
(240 mL), 1 boiled egg, 1 slice of toast, and margarine (10 g) for approximately 520 Kcal 
with approximately 17 grams of fat.   
On days that pre-dose PK sampling is required, the patient’s first meal of the day 
(e.g., breakfast) will be consumed in the morning at the clinic, and venetoclax dosing will 
occur in the clinic after completion of the meal to facilitate PK sampling. 
If vomiting occurs within 15 minutes after taking venetoclax and all expelled tablets are 
still intact, another dose may be provided.  If tablets are not identified, or if any are not 
intact, no replacement dose is to be given.  In cases where a dose of venetoclax is 
missed or forgotten, the patient should take the dose as soon as possible and ensure 
that the dose is taken with food within 8 hours after the scheduled time of the missed 
dose.  Otherwise, the missed dose should not be taken. 
Patient compliance with the assigned daily dose of venetoclax will be assessed by 
standard pill counts.  Bottles that contain venetoclax tablets will be given to patients at 
regular scheduled visits.  Previously distributed bottles will be returned to the clinic, and 
tablets will be counted.  Any discrepancy will be resolved with the patient at each clinic 
visit and documented in the patient record. 
Guidelines for venetoclax dosage modification and treatment interruption or 
discontinuation are provided in Section 5.1.7.1. 
4.3.2.5 
Premedication 
Patients should receive premedication as outlined in Table 13.


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Table 13 Premedication 
Timepoint 
Patients who Require 
Premedication 
Premedication 
Administration 
• All patients 
• Oral corticosteroid a 
Complete ≥ 1 hour prior to obinutuzumab or rituximab 
infusion. 
• All patients 
• Antihistamine drug b 
• Oral analgesic/ 
anti-pyretic c 
Administer ≥ 30 minutes prior to obinutuzumab or rituximab 
infusion. 
Cycle 1 Day 1 
• All patients 
• Allopurinol or suitable 
alternative such as 
rasburicase, along 
with adequate 
hydration 
Administer prior to venetoclax. 
• Patients with no IRR 
during the previous 
infusion 
• Oral analgesic/ 
anti-pyretic c 
Administer  
 ≥ 30 minutes prior to obinutuzumab infusion.  For patients 
receiving rituximab, premedicaion may be omitted at the 
investigator’s discretion. 
• Patients with Grade 
1 or 2 IRR during 
the previous 
infusion 
• Antihistamine drug b
• Oral analgesic/ 
anti-pyretic c 
Administer ≥ 30 minutes prior to obinutuzumab or 
rituximab infusion. 
• Oral corticosteroid a 
Complete ≥ 1 hour prior to obinutuzumab or rituximab 
infusion. 
Cycle 1,  
Days 8 and 15 
 
Cycles 2 and beyond, 
Day 1 
• Patients with 
Grade 3 IRR, 
wheezing, urticaria, 
or other symptoms 
of anaphylaxis 
during the previous 
infusion 
• Patients with bulky 
disease 
• Antihistamine drug b 
• Oral analgesic/ 
anti-pyretic c 
Administer ≥ 30 minutes prior to obinutuzumab or rituximab 
infusion. 


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Timepoint 
Patients who Require 
Premedication 
Premedication 
Administration 
• Patients still at risk 
for tumor lysis 
syndrome 
• Allopurinol or suitable 
alternative such as 
rasburicase, along 
with adequate 
hydration 
Administer prior to obinutuzumab or rituximab infusion. 
IRR = infusion-related reaction. 
a Treat with 100 mg of prednisone or prednisolone, 20 mg of dexamethasone, or 80 mg of methylprednisolone.  Hydrocortisone should 
not be used, as it has not been effective in reducing rates of IRR. 
b For example, 50 mg of diphenhydramine. 
c For example, 1000 mg of acetaminophen/paracetamol. 


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4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (obinutuzumab, rituximab, polatuzumab 
vedotin, and venetoclax) will be provided by the Sponsor.  The study site will 
acknowledge receipt of IMPs using the IxRS to confirm the shipment condition and 
content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Trial Access to Obinutuzumab, Rituximab, Polatuzumab 
Vedotin, and Venetoclax 
Currently, the Sponsor does not have any plans to provide obinutuzumab, rituximab, 
polatuzumab vedotin, venetoclax, or any other study treatments or interventions to 
patients who have completed the study.  The Sponsor will evaluate whether to continue 
to provide obinutuzumab, rituximab, polatuzumab vedotin, and venetoclax in 
accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to the screening period to the visit at EOI or at the end of post-induction 
treatment, whichever occurs later.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.  
4.4.1 
Permitted Therapy  
Premedication is permitted as described in Section 4.3.2.5: 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
Patients who receive concomitant medication that could possibly worsen 
thrombocytopenia-related events (e.g., platelet inhibitors and anticoagulants) may be at 
greater risk of bleeding.  Replace prior vitamin K antagonist therapy with 
low-molecular-weight heparin (LMWH) prior to Day 1 of Cycle 1.   


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Hematopoietic growth factors are allowed if clinically indicated and used in accordance 
with the prescribing information.  G-CSF may be administered in each cycle of therapy 
as primary prophylaxis for neutropenia, per American Society of Clinical Oncology 
(ASCO), EORTC, and European Society for Medical Oncology (ESMO) guidelines 
(Smith et al. 2006) or per each site’s institutional standards. 
Prophylactic treatment with antibiotics should be administered as per standard practice.   
Necessary supportive measures for optimal medical care will be given throughout the 
study according to institutional standards. 
4.4.2 
Prohibited and Cautionary Therapy for Concomitant 
Medications 
Use of the following therapies (excluding protocol-specified treatments) is prohibited 
during the study: 
• 
Any anti-cancer therapy, approved or investigational, other than intrathecal CNS 
prophylaxis 
• 
Hormonal therapy other than contraceptives, stable hormone-replacement therapy, 
or megestrol acetate 
• 
Biologic agents other than hematopoietic growth factors (as described in 
Section 4.4.1) 
• 
Vaccination with live vaccines is not recommended during treatment with 
obinutuzumab or rituximab and until B-cell recovery 
 
Use of the following concomitant medications is prohibited within 7 days before the first 
dose and during the study: 
• 
Steroid therapy for antineoplastic intent 
• 
Strong and moderate CYP3A inhibitors such as fluconazole, ketoconazole, and 
clarithromycin (see Appendix 10 for examples) 
• 
Strong and moderate CYP3A inducers such as rifampin, carbamazepine, 
phenytoin, and St. John’s wort (see Appendix 10 for examples) 
 
Concomitant medications that fall into the categories below could potentially lead to 
adverse reaction(s) and should be considered cautionary (except where noted).  If a 
potential study patient is taking any of the medications in the categories described 
below, the investigator will assess and document the use of medications known or 
suspected to fall in the following medication categories: 
• 
Weak CYP3A inducers 
• 
Weak CYP3A inhibitors 
• 
P-gp substrates 
• 
BCRP substrates 


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• 
OATP1B1/1B3 substrates 
• 
P-gp inhibitors 
• 
BCRP inhibitors 
• 
OATP1B1/B3 inhibitors 
• 
Warfarin should be used with caution during the study.  The investigator should 
discuss the use of other anticoagulation therapies, such as systemic or low 
molecular weight heparin, with the Medical Monitor. 
 
A sample list of excluded medications and cautionary medications that fall into the 
categories within this section can be found in Appendix 10.  It is not possible to produce 
an exhaustive list of medications that fall into these categories, so if in question, refer to 
the appropriate product label. 
4.4.3 
Prohibited Food 
Use of the following foods is prohibited during the study and for at least 3 days before 
initiation of study treatment: 
• 
Grapefruit 
• 
Grapefruit juice 
• 
Products that contain grapefruit 
• 
Seville oranges (including marmalade that contains Seville oranges) 
• 
Star fruit 
 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 and Appendix 2 for the schedule of assessments performed 
during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent, and within the defined window, may be used as screening and baseline 
assessments (see Appendix 1 and Appendix 2); such tests do not need to be repeated 
for screening purposes (e.g., screening tumor assessment).   


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Study treatment should be initiated within 28 days after the Informed Consent Form has 
been signed. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, reproductive status, 
smoking history, and alcohol and drug abuse.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within 7 days prior to the screening period 
will be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
The following clinical parameters relative to disease history, diagnosis, and prognostic 
indices will be recorded at screening:  
• 
Date of initial diagnosis 
• 
ECOG Performance Status (seeAppendix 6) 
• 
B symptoms (unexplained fever > 38°C, night sweats, unexplained weight loss 
> 10% of body weight over 6 months)  
• 
Ann Arbor staging (see Appendix 7) 
• 
For patients with FL:  Follicular Lymphoma International Prognostic Index (FLIPI) 
and FLIPI2 (see Appendix 8) 
• 
For patients with DLBCL:  IPI (see Appendix 8) 
• 
Previous lines of anti-lymphoma treatment and response to prior therapy, date of 
disease progression in relation to start date of prior therapy, and date of last dose 
of prior therapy 
 
4.5.3 
Physical Examinations 
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurological systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
As part of tumor assessment, the physical examination should include evaluation for the 
presence of enlarged nodes, palpable hepatomegaly, and splenomegaly.  This 
information will be recorded on the appropriate tumor assessment eCRF. 
At subsequent visits (or as clinically indicated), targeted (limited, symptom-directed) 
physical examinations should be performed.  Targeted physical examinations should be 
limited to systems of primary relevance (e.g., cardiovascular and respiratory systems), 
systems associated with symptoms (newly emergent or monitored from baseline), and 


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areas associated with tumor assessment (lymph nodes, liver, spleen, and any other 
areas identified at baseline; see Section 4.5.5).   
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF. 
4.5.4 
Vital Signs  
Vital signs will include measurements of respiratory rate, pulse rate, body temperature, 
and systolic and diastolic blood pressures while the patient is in a seated position.  Vital 
sign measurements will be performed as outlined in the schedules of assessments 
(see Appendix 1  and Appendix 2), but the associated data, other than the data collected 
at screening, do not need to be recorded on the eCRF (except in the case of an adverse 
event). 
4.5.5 
Tumor and Response Evaluations  
All evaluable or measurable disease must be documented at screening and re-assessed 
at each subsequent tumor evaluation.  Response will be assessed by the IRC and the 
investigator on the basis of physical examinations (see Section 4.5.3) and PET and 
CT scans using the Lugano 2014 criteria (see Appendix 5), taking into account results of 
bone marrow examinations for patients with bone marrow involvement at screening. 
In this study, the Lugano 2014 criteria for a PET-CT−based CR have been slightly 
modified to require normal bone marrow for patients with bone marrow involvement at 
screening.  Additionally, designation of PET-CT−based PR requires that CT-based 
response criteria for a CR or PR be met in addition to the PET-CT−based response 
criteria for a PR (see Appendix 5).  
4.5.5.1 
Radiographic Assessments 
PET scans should include the base of the skull to mid-thigh region.  Full body PET scans 
should be performed when clinically appropriate. 
CT with oral and IV contrast should include chest, abdomen, and pelvic scans.  
CT scans of the neck should be included if clinically indicated (i.e., if evidence of disease 
upon physical examination) and must be repeated throughout the study if there is 
disease involvement at baseline.   
PET-CT scans and diagnostic CT scans should be acquired according to a standardized 
imaging manual, which will be provided to all sites.  Diagnostic CT scans obtained as a 
part of a combined PET-CT scans are allowable as long as they are acquired according 
to the standardized imaging manual. 
If contrast is medically contraindicated (e.g., patients with contrast allergy or impaired 
renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically 


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indicated) and a non-contrast CT scan of the chest may be performed.  If MRI scans 
cannot be obtained, CT scans without contrast are permitted as long as this allows 
consistent and precise measurement of the targeted lesions during the study treatment 
period. 
The same radiographic assessment modality must be used for all response evaluations 
to ensure consistency across different timepoints (including unscheduled assessments). 
A full tumor assessment, including radiographic assessment, must be performed any 
time disease progression or relapse is suspected. 
Additional details regarding imaging procedures will be provided in the Imaging Manual. 
4.5.5.2 
Bone Marrow Assessments 
Bone marrow examinations are required at screening for staging purposes in all patients 
and should be performed within approximately 3 months prior to Day 1 of Cycle 1.  
If bone marrow infiltration is present at screening, a bone marrow biopsy is required at 
the EOI response assessment for all patients who may have achieved a CR.  In patients 
with a PR and continued bone marrow involvement, a subsequent bone marrow 
examination may be required to confirm a CR at a later timepoint. 
Any additional (unscheduled) bone marrow examinations performed during the study will 
be at the discretion of the investigator.  
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
Local Laboratory Assessments 
Samples for the following laboratory tests will be analyzed at the study site's local 
laboratory for analysis: 
• 
Hematology:  hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
percent or absolute WBC differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells)  
• 
Chemistry panel (serum or plasma):  sodium, potassium, glucose, BUN or urea, 
creatinine, calculated CrCl, calcium, total bilirubin, direct bilirubin, total protein, 
albumin, ALT, AST, alkaline phosphatase, LDH, uric acid, phosphate, glycosylated 
hemoglobin (HbA1c), amylase, and lipase (amylase and lipase only during 
induction).  HbA1c will be measured only at Screening and can be obtained in a non-
fasting state. 
• 
β2 microglobulin 
• 
Coagulation:  INR, aPTT (or PTT), PT 
• 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening (within 7 days of Day 1 of Cycle 1). 


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• 
Viral serology  
Hepatitis B testing includes HBsAg and total HBcAb.  
Hepatitis C testing includes HCV antibody. 
HIV (if required per local regulatory requirements) 
• 
Quantitative immunogloblulins:  IgA, IgG, and IgM 
 
Central Laboratory Assessments 
The following samples will be sent to one or several Sponsor-designated central 
laboratories or to the Sponsor for analysis: 
• 
Serum samples for obinutuzumab PK analysis using a validated assay 
• 
Serum samples for rituximab PK analysis using a validated assay 
• 
Serum and plasma samples for assessment of PK of polatuzumab vedotin and 
relevant analytes using a validated assay 
• 
Plasma samples for venetoclax PK analysis using a validated assay.  If appropriate, 
pharmacokinetics of other relevant metabolites may also be evaluated. 
• 
Serum samples for assessment of obinutuzumab HAHAs using a validated assay 
• 
Serum samples for assessment of ATAs to polatuzumab vedotin using a validated 
assay 
• 
Tumor tissue samples and the corresponding pathology report, for retrospective 
central confirmation of the diagnosis of FL or DLBCL and for exploratory research 
on candidate biomarkers (see Table 14). 
The specimen must contain adequate evaluable tumor cells (≥ 20% for 
excisional biopsy and ≥ 50% for core biopsy).  
Formalin-fixed paraffin-embedded tissue blocks are preferred over slides.  
Tissue blocks that are not formalin fixed will be accepted in countries that use a 
fixative other than paraformaldehyde, but information on the type of fixative 
should be included.  If a tissue block is not available, a minimum of 20 serial, 
freshly cut, unstained slides accompanied by a tumor block punch may be sent.  
A tumor block or tumor block punch is required for construction of a tissue 
microarray. 
If archival tissue is unavailable or unacceptable according to above criteria, a 
pretreatment core needle, excisional, or incisional tumor biopsy is required.  
Cytological or fine-needle aspiration samples are not acceptable.  
If the patient has had anti-lymphoma treatment between the time of the prior 
biopsy and the time of study treatment initiation, a core-needle biopsy is 
recommended. 
The sample should be shipped according to instructions provided in the 
laboratory manual.  The remainder of the archival tissue blocks will be returned 
to the local pathology laboratory, according to country-specific procedures after 
the clinical study report has been published or upon request. 


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• 
Tumor tissue samples obtained at the time of progression (unless no adequate 
tumor site is accessible) for exploratory research on candidate biomarkers (see 
Table 14) 
• 
Whole blood samples for isolation of peripheral blood mononuclear cells and 
plasma for exploratory research on candidate biomarkers (see Table 14) 
• 
Whole blood samples for lymphocyte immunophenotyping (see Table 14) 
 
Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in Table 14.  Results from exploratory biomarker research will not be shared with 
investigators or study participants, unless required by law, given the complexity and 
exploratory nature of these analyses. 
Table 14 Proposed Non-Inherited Biomarkers 
Sample Type 
Timing 
Proposed  
Non-Inherited Biomarkers 
Archival or fresh 
pre-treatment, and 
progression tumor tissue  
Prior to study (archival) or 
baseline (fresh); at disease 
progression 
• For DLBCL patients only:  DLBCL 
cell-of-origin subtype (ABC vs. GCB), 
BCL2, MYC 
• For both DLBCL and FL 
patients:  Target expression BCL2 
and CD79b  
• Lymphoma-related genetic changes 
(DNA) and gene expression (mRNA) 
or protein expression (IHC) 
associated with response or potential 
resistance 
• Lymphoma index clone in MRD  
Peripheral blood 
mononuclear cells and 
plasma isolated from 
whole blood 
Baseline, subsequent 
timepoints during treatment 
• Circulating lymphoma cells and/or 
cell-free circulating tumor DNA 
(detection of minimal residual 
disease)  
Whole blood 
Baseline and subsequent 
timepoints during and after 
treatment 
• Lymphocyte immunophenotyping, 
including B-cell counts (CD19), T-cell 
counts (CD3, CD4, and CD8), and 
NK-cell counts (CD16 and CD56) 
ABC = activated B cell–like; DBLCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; 
GCB = germinal-center B cell–like; IHC = immunohistochemistry; MRD = minimum residual 
disease; mRNA = messenger RNA; NK = natural killer. 
Note:  Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in this table. 
 
Samples collected for PK and immunogenicity analyses may be used for PK assay 
development purposes and additional safety and immunogenicity assessments, as 
appropriate. 


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Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research, biological samples will be destroyed when the final 
Clinical Study Report has been completed, with the following exception(s): 
Serum [or plasma] samples collected for PK and immunogenicity (ATA) analysis may 
be needed for additional PK and ATA assay development and validation, and additional 
immunogenicity characterization; therefore, these samples will be destroyed no later 
than 5 years after the final Clinical Study Report has been completed (see 
Section 4.5.8). 
4.5.7 
Electrocardiograms  
Single, resting, 12-lead ECG recordings will be obtained at specified timepoints, as 
outlined in the schedules of assessments (see Appendix 1 and Appendix 2), and may be 
obtained at unscheduled timepoints as clinically indicated.  ECGs for each patient should 
be obtained using the same machine wherever possible.  Interpretation of the ECG 
should be performed by the investigator.   
4.5.7.1 
Multigated Acquisition Scan/Echocardiogram 
MUGA scans will be obtained prior to treatment to assess left ventricular ejection fraction 
(LVEF; see Appendix 1).  Echocardiogram may be used if MUGA is not available.  Any 
clinically significant changes in cardiac function must be reported within 7 days. 
4.5.8 
Samples for Roche Clinical Repository  
4.5.8.1 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future. 
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug 
absorption and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 


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4.5.8.2 
Approval by the Institutional Review Board or 
Ethics Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (see Section 4.5.8) will not be 
applicable at that site. 
4.5.8.3 
Sample Collection 
The following samples and derivatives thereof (e.g., DNA, RNA, proteins, peptides) will 
be collected for research purposes, including but not limited to research on dynamic 
(non-inherited) and genetic (inherited) biomarkers related to obinutuzumab, rituximab, 
polatuzumab vedotin, venetoclax, or other types of cancer: 
• 
Peripheral blood (i.e., whole blood) 
• 
Remaining tumor tissue from lymph node biopsy (archival and/or fresh biopsy) 
• 
Remaining peripheral blood (e.g. whole blood, PBMCs, plasma, and serum) 
 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.   
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.8.4 
Confidentiality 
Confidentiality for All Roche Clinical Repository Specimens 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  


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The aggregate results of any research conducted using RCR specimens will be available 
in accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
Additional Confidentiality for Specimens Used for Genetic Research 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens collected for genetic research.  
Upon receipt by the RCR, specimens for genetic research are "double-coded" by 
replacing the patient identification number with a new independent number.  Data 
generated from the use of these specimens and all clinical data transferred from the 
clinical database and considered relevant are also labeled with this same independent 
number.  A "linking key" between the patient identification number and this new 
independent number is stored in a secure database system.  Access to the linking key is 
restricted to authorized individuals and is monitored by audit trail.  Legitimate operational 
reasons for accessing the linking key are documented in a standard operating procedure.  
Access to the linking key for any other reason requires written approval from the Pharma 
Repository Governance Committee and Roche's Legal Department, as applicable. 
4.5.8.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.5.8.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 


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from Study GO29833 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study GO29833. 
4.5.8.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice (GCP) 
by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance (e.g., consistent failure to show up for scheduled visits) 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn. 
If a patient withdraws consent, this request must be documented in the source 
documents and signed by the investigator.  Study personnel may use a public 
information source (e.g., county records) to obtain information about survival status. 
4.6.2 
Study Treatment Discontinuation 
Study treatment should be permanently discontinued in patients who experience any of 
the following: 
• 
Anaphylaxis, acute respiratory distress, or Grade 4 IRR 
If a Grade 3 IRR is recurrent during the second or subsequent cycles, study 
treatment may be discontinued at the discretion of the investigator, following an 
individual benefit-risk assessment.   


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• 
Any adverse event that meets criteria for permanent discontinuation per guidelines 
provided in Section 5.1  
• 
Disease progression 
• 
Pregnancy 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 
Patients who discontinue study treatment will not be replaced, except as outlined below: 
• 
During the dose-escalation phase, patients who discontinue study treatment prior to 
completion of the DLT assessment window for reasons other than a DLT will be 
replaced by an additional patient at that same dose level. 
• 
Patients who discontinue before having received at least one dose of each 
component of the combination will be replaced. 
 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigators if the Sponsor decides to discontinue the study.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) 
guideline for GCP 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Polatuzumab vedotin is not a marketed product, and venetoclax is not approved for R/R 
FL or DLBCL.  Obinutuzumab is only approved in combination with bendamustine for 
the treatment of R/R FL and rituximab is not approved for the treatment of R/R DLBCL.  
Clinical development is ongoing.  The safety plan for patients in this study is based on 
clinical experience with obinutuzumab, rituximab, polatuzumab vedotin, and venetoclax 


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in completed and ongoing studies.  The anticipated important safety risks of 
obinutuzumab, rituximab, polatuzumab vedotin, and venetoclax are outlined below.  
Please refer to the Obinutuzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax 
Investigator's Brochures for a complete summary of safety information.  
Several measures will be taken to ensure the safety of patients participating in this trial.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities 
(see Section 4.1).  Patients will undergo adequate safety monitoring during the study, 
including assessment of the nature, frequency, and severity of adverse events, as 
described in this section and in Section 4.5.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment delays or 
discontinuation, have been provided (see Section 5.1.7).   
5.1.1 
Risks Associated with Obinutuzumab 
To date, the following adverse events are considered to be important identified risks 
associated with obinutuzumab:  IRRs, TLS, thrombocytopenia (including acute 
thrombocytopenia), neutropenia (including prolonged and late-onset neutropenia), 
infections (including PML and HBV reactivation), prolonged B-cell depletion, impaired 
immunization response, worsening of preexisting cardiac conditions, and gastrointestinal 
perforation. 
5.1.1.1 
Infusion-Related Reactions 
IRRs have been reported predominantly during the first infusion of obinutuzumab.  
The incidence and severity of IRRs decreased substantially with the second and 
subsequent infusions.  In the majority of patients, IRRs were mild or moderate and 
resolved with the slowing or interruption of the infusion and supportive care.  
The commonly experienced IRRs have been characterized by hypotension, fever, chills, 
flushing, nausea, vomiting, hypertension, fatigue, and other symptoms.  
IRRs may be clinically indistinguishable from IgE−mediated allergic or anaphylactic 
reactions; anaphylaxis has been reported in patients treated with obinutuzumab. 
Hypotension may occur during obinutuzumab IV infusions.  Therefore, withholding of 
anti-hypertensive 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 anti-hypertensive medication. 
Patients who have preexisting cardiac or pulmonary conditions should be monitored 
carefully throughout the infusion and the postinfusion period. 
Guidelines for medical management of IRRs and anaphylaxis are provided in 
Section 4.3.2.1 and Appendix 9.  


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5.1.1.2 
Tumor Lysis Syndrome 
TLS, including fatal events, has been reported with obinutuzumab administration.  
Patients should receive adequate hydration and premedication with allopurinol or an 
alternative uricostatic as indicated in Section 4.3.2.5 (see Table 13).  Additional 
guidelines for management of TLS in this study are provided in Section 5.1.6. 
5.1.1.3 
Neutropenia 
Grade 3 or 4 neutropenia, including febrile neutropenia, has been reported with 
obinutuzumab administration.  Neutropenia resolved spontaneously or with use of 
hematopoietic growth factors.  Patients who experience Grade 3 or 4 neutropenia 
should be closely monitored until neutrophil values return to at least Grade 2.  Cases of 
late-onset neutropenia (ANC < 1000 cells/μL occurring ≥ 28 days after obinutuzumab 
treatment has been completed or stopped) or prolonged neutropenia 
(ANC < 1000 cells/μL that does not resolve after 28 days without obinutuzumab 
treatment) have also been reported.  The use of G-CSF is allowed for treatment of 
neutropenia in this study.  Prophylactic treatment with antibiotics should be administered 
as per standard practice.  Guidelines for primary prophylaxis with G-CSF are provided in 
Section 5.1.7.2.  
5.1.1.4 
Thrombocytopenia 
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia 
(occurring within 24 hours after the infusion), has been observed during treatment with 
obinutuzumab.  In CLL patients exposed to obinutuzumab, fatal hemorrhagic events 
have also been reported during Cycle 1.  A clear relationship between thrombocytopenia 
and hemorrhagic events has not been established.  Patients who receive concomitant 
medication that could possibly worsen thrombocytopenia-related events (e.g., platelet 
inhibitors and anticoagulants) may be at greater risk of bleeding.  Replace prior 
vitamin K antagonist therapy with LMWH prior to Day 1 of Cycle 1.  Use of all 
concomitant therapies, which could possibly worsen thrombocytopenia-related events 
such as platelet inhibitors and anticoagulants, should also be taken into consideration, 
especially during the first cycle.  Patients should be closely monitored for 
thrombocytopenia, especially during the first cycle.  For patients who experience 
thrombocytopenia, regular laboratory tests should be performed until the event resolves, 
and dose delays should be considered in case of severe or life-threatening 
thrombocytopenia.  Transfusion of blood products (i.e., platelet transfusion) may be 
performed at the discretion of the treating physician, according to institutional practice.  
5.1.1.5 
Infections 
On the basis of its mechanism of action, resulting in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections.  Obinutuzumab 
should not be administered to patients with active infection, and caution should be 
exercised when including patients with a history of recurrent or chronic infections.   


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Serious bacterial, fungal, and new or reactivated viral infections can occur during and 
following the completion of obinutuzumab therapy.  Fatal infections have been reported. 
Reactivation of hepatitis B in patients with chronic hepatitis (HBsAg positive) with 
evidence of prior hepatitis B exposure, or in patients who are carriers (HBsAg negative 
and anti-HBc positive) has been reported with other anti-CD20 antibodies.  The risk is 
increased particularly when anti-CD20 antibodies are administered with 
immunosuppressive therapies, such as steroids or chemotherapy.  Particular attention 
should be given to patients who have previously received highly immunosuppressive 
treatment, such as high-dose chemotherapy and SCT.  Patients positive for HBsAg or 
HBcAb are not eligible for this study. 
John Cunningham virus (JCV) infection that results in PML has been reported in patients 
treated with obinutuzumab.  The diagnosis of PML should be considered in any patient 
who presents with new-onset neurologic manifestations.  The symptoms of PML are 
unspecific and can vary depending on the affected region of the brain.  Motor symptoms 
with corticospinal tract findings (e.g., muscular weakness, paralysis, and sensory 
disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are 
common.  Some signs or symptoms regarded as “cortical” (e.g., aphasia or visual-spatial 
disorientation) may occur.  Evaluation of PML includes, but is not limited to, consultation 
with a neurologist, brain MRI, and lumbar puncture (cerebrospinal fluid testing for JCV 
DNA).  Additional guidelines for medical management of PML in this study are provided 
in Section 5.1.7.2. 
5.1.1.6 
Impaired Immunization Response 
The safety of immunization with live or attenuated viral vaccines following 
obinutuzumab therapy has not been studied, and vaccination with live virus vaccines is 
not recommended during treatment and until B-cell recovery. 
5.1.1.7 
Worsening of Preexisting Cardiac Condition 
In patients with underlying cardiac disease and treated with obinutuzumab, adverse 
events such as angina pectoris, acute coronary syndrome, myocardial infarction, heart 
failure, and arrhythmias, including atrial fibrillation and tachyarrhythmia, have been 
observed.  These events may occur as part of an IRR and can be fatal.  Therefore, 
patients with a history of cardiac disease should be monitored closely.  In addition, these 
patients should be hydrated with caution to prevent a potential fluid overload. 
5.1.1.8 
Gastrointestinal Perforation 
Gastrointestinal perforation has been reported in patients with NHL treated with 
obinutuzumab, including fatal events.  Patients with gastrointestinal involvement should 
be monitored for signs of gastrointestinal perforation. 


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5.1.2 
Risks Associated with Rituximab 
The following adverse events are considered to be important risks associated or 
potentially associated with rituximab:  IRRs, infections (including severe infections), 
PML, Hepatitis B reactivation, neutropenia (including prolonged neutropenia), TLS, 
impaired immunization response, severe skin reactions (Stevens-Johnson 
syndrome/toxic epidermal necrolysis), and GI perforation.  Details for these risks are 
provided below; refer to the Rituximab Investigator’s Brochure for full information. 
5.1.2.1 
Infusion-Related Reactions 
Acute IRRs are very common in patients receiving rituximab (occurring in ≥ 10% of 
patients) based on clinical trial experience.  However, serious IRRs are uncommonly 
reported (occurring in ≥ 1 of 1,000 and < 1 of 100 patients) and are rarely fatal 
(occurring in ≥ 1 of 10,000 and <  1 of 1,000 patients).  Most IRRs occur with the first 
administration of rituximab.  Most IRRs are mild to moderate in severity (Grade 1 or 2) 
and can be managed by slowing or stopping the rituximab infusion.  IRRs can be severe 
and, in rare cases, can result in death.  Rituximab-induced IRRs consist of a cluster of 
symptoms and signs occurring during or within 24 hours of a rituximab infusion, 
which may be related to cytokine release and/or other chemical mediators, and these 
acute IRRs overlap with “cytokine release syndrome.”  Anaphylactic and other 
hypersensitivity reactions have been reported following rituximab administration, and 
clinical manifestations of these reactions are similar to cytokine release syndrome.  In 
contrast to cytokine release syndrome, true hypersensitivity reactions typically occur 
within minutes of starting the rituximab infusion. 
5.1.2.2 
Infections (Including Serious Infections) 
Serious infections, including fatal bacterial, fungal, and new or reactivated viral 
infections, can occur during and up to 1 year following completion of rituximab-based 
therapy.   
5.1.2.3 
Hepatitis B Reactivation 
Reactivation of hepatitis B ranges from asymptomatic reactivations (detected by 
changes in laboratory parameters only) to fulminant liver failure and death.  Patients 
with chronic hepatitis B (HBsAg positive) viral infection are at risk for reactivation 
and will be excluded from the study.  Patients with evidence of prior hepatitis B 
exposure or who are carriers (defined as HBsAg negative and anti-HBcAb positive) are 
at a lower risk for reactivation.  Patients who demonstrate evidence of reactivation 
while receiving an appropriate anti-viral therapy will be discontinued from study 
treatment. 
5.1.2.4 
Progressive Multifocal Leukoencephalopathy 
Rare cases of PML have also been reported in patients treated with rituximab alone or 
in combination with other immunosuppressive medications (Goldberg et al. 2002; 
Calabrese et al. 2007; Carson and Bennett 2009).  In a review of 57 patients who 
developed PML after rituximab administration, all patients had received prior therapies 


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with alkylating agents, corticosteroids, purine analogs, or drugs to prevent allogeneic 
stem cell or solid-organ graft rejection.  The diagnosis of PML in any patient treated 
with rituximab is rare, but it should be suspected in any patient who develops 
new-onset neurologic manifestations.  The majority of patients with hematologic 
malignancies diagnosed with PML received rituximab in combination with 
chemotherapy or as part of a hematopoietic SCT.  Most cases of PML were diagnosed 
within 12 months of the patients’ last infusion of rituximab. 
5.1.2.5 
Neutropenia (Including Prolonged Neutropenia) 
Neutropenia is very common in patients receiving rituximab (occurring in ≥ 10% of 
patients) based on clinical trial experience.  However, delayed onset neutropenia is very 
rare (occurring in < 1 of 10,000 patients), and the incidence of prolonged neutropenia is 
unknown.  Neutropenia may lead to serious or overwhelming infection, especially if 
profound (Grades 3−4), prolonged, associated with breaches in natural mucosal barriers 
(e.g., diarrhea and/or mucositis), and/or other immunological defects (e.g., lymphopenia, 
hypogammaglobulinemia, and acquired immunodeficiency syndrome).  Despite an 
increase in incidence of neutropenia and Grade 3−4 neutropenia associated with 
rituximab, most studies have not reported a significant increase in serious neutropenic 
infections. 
5.1.2.6 
Tumor Lysis Syndrome 
Patients treated with rituximab may be at risk for TLS.  Severe TLS is very rare in 
patients receiving rituximab (occurring in < 1 of 10,000 patients), based on 
postmarketing experience.  Signs and symptoms (e.g., hyperuricemia, hyperkalemia, 
hypocalcemia, hyperphosphatemia, acute renal failure, and elevated LDH) that are 
consistent with TLS have been reported to occur after the first rituximab IV infusion in 
patients with high numbers of circulating malignant lymphocytes.  A high number of 
circulating malignant cells (≥ 25,000/mm3) or high tumor burden confers a greater risk 
of TLS.  For patients with evidence of TLS, rituximab should be discontinued, and the 
patient should be treated as clinically indicated. 
5.1.2.7 
Impaired Immunization Response 
B-cell depletion is expected (and desired) during rituximab therapy and is directly 
related to its mechanism of action. In theory, peripheral B-cell depletion may reduce the 
effectiveness of immunization, since patients may not be able to mount an effective 
humoral immune response to foreign antigens. 
5.1.2.8 
Severe Skin Reactions: Stevens-Johnson Syndrome and Toxic 
Epidermal Necrolysis  
Severe reactions, including fatal mucocutaneous reactions, can occur in patients 
receiving rituximab.  The onset of these reactions in patients treated with rituximab has 
varied from 1 to 13 weeks following rituximab exposure.  The majority of the 
Stevens-Johnson syndrome and toxic epidermal necrolysis cases reported with 
rituximab were associated with additional risk factors.  Fatal outcome also appeared to 


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increase in patients who were exposed to multiple risk factors for Stevens-Johnson 
syndrome and toxic epidermal necrolysis. 
5.1.2.9 
Gastrointestinal Perforation 
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, can 
occur in patients receiving rituximab in combination with chemotherapy.  In 
postmarketing reports of rituximab, the mean time to documented GI perforation was 
6 days (range:  1−77 days) in patients with NHL. 
5.1.3 
Risks Associated with Polatuzumab Vedotin  
The clinical safety profile of polatuzumab vedotin based on clinical data obtained in the 
ongoing Phase I and Phase II studies is summarized in Section 1.3.  On the basis of 
clinical data to date, the following known and suspected risks are described below.  
Refer also to the current version of Investigator’s Brochure for complete and updated 
details. 
5.1.3.1 
Identified Risks 
Based on clinical experience with polatuzumab vedotin in patients treated in the current 
Phase I and Phase II studies, neutropenia and peripheral neuropathy are identified risks 
of polatuzumab vedotin.  
Neutropenia 
Neutropenia and neutropenia-associated events resulted in protocol-mandated dose 
reductions and/or delays.  Serious neutropenia, including febrile neutropenia, has been 
reported during treatment with polatuzumab vedotin.  Patients with inadequate 
hematologic function will be excluded from this study (see Section 4.1.2). Adequate 
hematologic function should be confirmed before initiation of study treatment.  Patients 
who receive study treatment will be regularly monitored for evidence of marrow toxicity 
with complete blood counts.  Treatment may be delayed for hematologic toxicities as 
described in Section 5.1.7.2.  The use of G-CSF for neutropenia is described in 
Section 5.1.7.2. 
Peripheral Neuropathy 
Patients who receive polatuzumab vedotin may develop or experience worsening of 
peripheral neuropathy.  Patients in clinical trials with polatuzumab vedotin should be 
monitored for symptoms of neuropathy (sensory and/or motor), including hypoesthesia, 
hyperesthesia, paresthesia, dysesthesia, discomfort, a burning sensation, weakness, 
gait disturbance, or neuropathic pain.  Patients who experience new or worsening 
peripheral neuropathy may require a dose delay or discontinuation of treatment and 
should be managed according to the protocol.   


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5.1.3.2 
Potential Risks 
Infections 
Neutropenia is a known risk for polatuzumab vedotin.  Reports in the literature state that 
granulocytopenia is a major predisposing factor to infections in patients with B-cell 
lymphoma.  The reported incidence of infection in chemotherapy courses for B-cell 
lymphoma associated with < 500 granulocytes/μL was higher than those with 
≥ 500 granulocytes/μL. 
Progressive Multifocal Leukoencephalopathy 
One case of PML was reported in an 
-year-old female with R/R FL after receiving one 
cycle of polatuzumab vedotin in combination with obinutuzumab and bendamustine.  
MRI showed changes suggestive of PML.  Cerebrospinal fluid test for JCV by 
polymerase chain reaction was negative.  Confounders included previous lines of anti-
CD20 therapies and concurrent use of obinutuzumab.  Additional details of the case can 
be found in the Polatuzumab Vedotin Investigator’s Brochure.    
Infusion-Related Events 
Because of the potential for infusion reactions, administration of polatuzumab vedotin 
will be performed in a setting with access to emergency equipment and staff who are 
trained to monitor and respond to medical emergencies.  All patients will be monitored 
for infusion reactions during the infusion and immediately.  Precautions for suspected 
anaphylactic reaction during study drug infusions are provided in Section 4.3.2.5.  The 
initial dose of polatuzumab vedotin may be administered with premedication with 
acetaminophen, antihistamines, or corticosteroids per institutional standard practice at 
the discretion of the Investigator.  Premedication should be instituted for subsequent 
doses if IRRs are observed in patients who receive their first dose of polatuzumab 
vedotin without premedications (see Section 4.3.2.5).  Significant issues with 
polatuzumab vedotin IRRs have not been observed. 
Similar considerations regarding infusion reactions are applicable for obinutuzumab.  
Refer to Section 4.3.2.5 for additional information.   
Tumor Lysis Syndrome  
There is a potential risk of TLS if treatment with polatuzumab vedotin results in the rapid 
destruction of a large number of tumor cells.  Patients will receive tumor lysis prophylaxis 
(e.g., allopurinol ≥ 300 mg/day orally or a suitable alternative treatment [according to 
institutional practice] starting prior to study treatment) and must be well hydrated before 
the initiation of study treatment at Cycle 1 Day 1.  Patients should continue to receive 
repeated prophylaxis with allopurinol and adequate hydration before each subsequent 
infusion, as deemed appropriate by the investigator.   
One case of Grade 3 laboratory TLS was reported in this ongoing study.  The patient 
was at high risk for TLS due to bulky disease and decreased renal function.  Potassium 
and phosphorous levels were elevated, while serum creatinine levels remained normal 


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and patient was asymptomatic.  The TLS event was considered related to all 3 study 
treatments and resolved in 4 days with supportive care.  One case of TLS attributed to 
polatuzumab vedotin has been reported (GO27834); however, the laboratory elevations 
did not meet the Howard criteria for TLS (see Appendix 13).  The suspected TLS event 
resolved after 3 days of supportive care (see polatuzumab vedotin IB for case details).   
Bone Marrow Toxicity 
Patients with inadequate hematologic function will be excluded from this study 
(see Section 4.1.2).  Patients who receive study treatment will be regularly monitored for 
evidence of marrow toxicity with complete blood counts.  Treatment may be delayed for 
hematologic toxicities as described in Section 5.1.7.2.  
Transfusion support for anemia and thrombocytopenia is also permitted at the discretion 
of the treating physician. 
Immunogenicity 
As with any recombinant antibody, polatuzumab vedotin may elicit an immune response 
and patients may develop antibodies against polatuzumab vedotin.  Patients will be 
closely monitored for any potential immune response to polatuzumab vedotin.  
Appropriate screening, confirmatory, and characterization assays will be employed to 
assess ATAs before, during, and after the treatment with polatuzumab vedotin.   
Reproductive Toxicity 
Adverse effects on human reproduction and fertility are anticipated with the 
administration of polatuzumab vedotin given the mechanism of action of MMAE.  
Standard exclusion criteria are used to ensure that patients of childbearing potential 
(male or female) are using adequate contraceptive methods.  
Specific Gastrointestinal Toxicity  
Diarrhea, constipation, anorexia, nausea, and vomiting have been reported frequently as 
treatment-emergent adverse events in Studies DCS4968g and GO27834 with 
polatuzumab vedotin.  Diarrhea has been responsible for study drug modification and 
discontinuations. 
Hyperglycemia 
Hyperglycemia has been observed in patients treated with polatuzumab vedotin as well 
as with other ADCs that use the same vc-MMAE platform.  Hyperglycemia has been 
reversible upon holding or discontinuing treatment of the ADCs and/or initiation or 
adjustment of anti-hyperglycemic medications. 
Hepatotoxicity 
Hepatotoxicity has been observed in patients treated with polatuzumab vedotin in both 
the Phase I and Phase II trials.  Although the relationship between hepatotoxicity and 
polatuzumab vedotin has not been definitively determined, transient, dose-related 


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increases in hepatic enzymes were noted in nonclinical rat studies.  No hepatotoxicity 
was noted following administration of the surrogate ADC in cynomolgus monkeys.  
Elevations of transaminases have been reported in patients who received polatuzumab 
vedotin and have ranged in intensity from Grades 1 to 3.  These elevations have been 
reversible with and without dose modification. 
5.1.4 
Risks Associated with Venetoclax 
Phase I experience with venetoclax has demonstrated that it is generally well tolerated, 
and toxicities appear to be mostly manageable and/or reversible; see the Venetoclax 
Investigator’s Brochure for more information. 
On the basis of clinical data to date, the following known and suspected risks with 
venetoclax are described below.  Guidelines around the management of these risks 
through dose and schedule modifications are described in Section 5.1.7.1, Table 16, and 
Table 17.  
5.1.4.1 
Tumor Lysis Syndrome 
To date, the principal adverse reaction associated with venetoclax in the ongoing 
single-agent Phase I dose-escalation study M12-175 has been TLS (primarily, but not 
exclusively, related to the first dose).  TLS, including cases that have led to clinical 
sequelae and death, has been observed in patients with CLL at venetoclax doses of 
≥ 50 mg.  Clinically relevant TLS has been observed only in patients with CLL (highest 
risk in patients with nodes ≥ 10 cm in size or absolute lymphocyte count ≥ 25 × 109/L if 
nodes size is ≥ 5 cm) and not in NHL (other than MCL) patients to date.  Very few cases 
of non-clinically relevant electrolyte changes (e.g., elevated phosphate levels marginally 
above the ULN and 25% changes from baseline in uric acid levels that remained within 
the normal reference range) have been observed in NHL patients to date.  However, 
TLS is a risk for patients with NHL who are treated with high cell−killing agents.  The risk 
is greatest for those with bulky disease, elevated pretreatment LDH levels, elevated 
leukocyte count, and dehydration.  Patients with bulky disease, defined as any lymph 
node ≥ 10 cm on the screening CT scan, are considered at higher risk of TLS.  In light of 
potential synergy between venetoclax, obinutuzumab, and polatuzumab vedotin, 
rigorous TLS monitoring and prophylaxis will be instituted in this study 
(see Section 5.1.6). 
5.1.4.2 
Cytopenia 
Effects on lymphocyte numbers are expected on the basis of the mechanism of action, 
and modest reductions in neutrophils have been observed with venetoclax therapy in 
patients.  Thrombocytopenia and anemia have been reported with venetoclax in the 
ongoing Phase I, single-agent, dose-escalation study M12-175 that is being conducted 
in heavily pretreated patients with CLL and NHL.  In most cases, the condition was 
preexisting.  Adverse events of neutropenia and thrombocytopenia, including Grade ≥ 3 
events, have been reported in the oncology studies, with a slightly higher frequency in 


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studies in which venetoclax was combined with other chemotherapeutic agents.  In this 
study, blood counts will be monitored closely throughout treatment (see the schedules of 
assessments in Appendix 1  and Appendix 2).  Growth factors are permitted according to 
local practice, and patients will be monitored and treated promptly in case of infections.  
Dose interruptions or reductions will be allowed on the basis of toxicity. 
5.1.4.3 
Infectious Complications 
Infections of various types have occurred in patients in the ongoing, Phase I, 
single-agent dose-escalation study M12-175.  NHL can be associated with impaired 
immune function and increased infections; it is unclear whether or how much the 
incidence could be further increased because of obinutuzumab, polatuzumab vedotin 
and venetoclax treatment.  Patients in this study will be closely monitored for infections, 
and prompt therapy will be instituted as necessary.  Patients are allowed to receive 
concomitant prophylactic anti-infective therapy at the investigator’s discretion. 
5.1.4.4 
Effects on Cardiac Function 
Nonclinical studies demonstrated decreases in cardiac function of approximately 20% in 
healthy laboratory animals.  No patterns of adverse events indicating changes in cardiac 
function have been reported in clinical studies to date.  However, the number of patients 
exposed and the duration of exposure are still relatively low.  Patients enrolled in this 
study are required to have ECGs and assessments of left ventricular ejection fraction at 
screening and as clinically indicated afterwards. 
5.1.4.5 
Effects on Fertility 
There is a potential for decreased spermatogenesis.  Male patients who are considering 
preservation of fertility should bank sperm before treatment with venetoclax.  Long-term 
effects of venetoclax on either male or female reproductive potential are unknown. 
5.1.4.6 
Drug Interactions 
DDIs may occur with venetoclax.  See Section 4.4 and Appendix 10 for a list of 
medications that are to be excluded or used with caution in patients who receive 
venetoclax. 
5.1.5 
Risks of Overlapping Toxicities 
The overlapping toxicities from the combined administration of obinutuzumab or 
rituximab, polatuzumab vedotin, and venetoclax are anticipated in this clinical trial and 
will be closely monitored and managed throughout the study.  
Rituximab was safely combined with polatuzumab vedotin in patients with R/R FL or 
DLBCL.  Grade 3 or 4 neutropenia (21%) appeared to be the most important 
hematologic adverse event associated with this combination.  When given as 
monotherapy for the treatment of patients with R/R NHL, obinutuzumab was associated 
with a 5% incidence of Grade 3−4 neutropenia.  Because obinutuzumab is expected to 
have an incidence of neutropenia that is higher than that with rituximab monotherapy, 


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there is a risk of increase incidence of neutropenia.  Obinutuzumab and polatuzumab 
vedotin for the treatment of patients with R/R FL or DLBCL is currently being assessed 
in Study GO27834.  Any applicable findings from this study that affect patient safety will 
be applied to this study.  
Venetoclax has also been associated with hematologic adverse events, including 
neutropenia.  Therefore, the combination of obinutuzumab or rituximab, polatuzumab 
vedotin, and venetoclax is anticipated to have overlapping hematologic toxicity and will 
be closely monitored. Guidelines for management of patients who develop hematologic 
toxicities are provided in Section 5.1.6.  In addition to the standard hematologic 
monitoring, patients enrolled in this study will be closely monitored for evidence of 
infections.  
There is the identified risk of TLS if treatment with obinutuzumab or rituximab or 
venetoclax and a theoretical risk for polatuzumab vedotin since these agents can result 
in the rapid destruction of a large number of tumor cells.  Therefore, overlapping toxicity 
in regard to TLS cannot be excluded.  Guidelines for management of patients who 
develop TLS are provided in Section 5.1.6. 
5.1.6 
Prophylaxis and Monitoring for Tumor Lysis Syndrome 
TLS is a risk for patients with NHL who are treated with high cell−killing agents.  Risk is 
highest for those with bulky disease, circulating lymphoma cells, elevated pretreatment 
LDH levels, elevated leukocyte count, impaired renal function, and dehydration.  Patients 
with bulky disease, defined as any lymph node ≥ 10 cm on the screening CT scan, are 
considered to potentially be at higher risk of TLS and must be hospitalized for more 
intensive monitoring during the initial dose of venetoclax.  Patients who do not meet 
these criteria may be considered at high risk for TLS and may be hospitalized per 
discussion with the investigator and Medical Monitor. 
5.1.6.1 
Prophylaxis and Monitoring for All Patients 
All patients must receive prophylaxis for TLS before the initiation of the first dose of 
G + Pola + V, as outlined in Table 15.  


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Table 15 Prophylaxis and Assessments for Tumor Lysis Syndrome 
 
High Risk 
Regular Risk 
Definition 
• 
Bulky disease, defined as:   
o Any lymph node ≥ 10 cm on 
the screening CT scan 
• 
Circulating lymphoma cells 
• 
Other characteristics deemed by the 
investigator to confer high risk of TLS 
• 
All other patients not meeting 
definition of high risk 
Hospitalization 
Required for intensive monitoring during 
initial dose of venetoclax 
(See Hospitalization section below). 
Not required, but may be hospitalized per 
discussion with the investigator and 
Medical Monitor 
TLS prophylaxis 
All patients must receive prophylaxis for TLS, which will include: 
• 
Appropriate hydration, which consists of a fluid intake of approximately 2−3 L/day 
starting 24−48 hours before the start of treatment, which can occur as oral intake 
or intravenous fluids 
• 
Administration of an agent to reduce uric acid (such as allopurinol 300 mg/day 
orally beginning 72 hours before dose and continuing for 3−7 days afterward) or 
rasburicase IV (for high-risk patients with elevated uric acid levels before 
treatment, or when otherwise judged to be appropriate by the investigator) until 
normalization of serum uric acid and other laboratory evidence of TLS 
(e.g., elevated serum LDH levels).   
• 
Laboratory results should be reviewed and electrolyte values should not 
demonstrate any clinically significant abnormalities before the first dose of 
venetoclax, or the patient should receive additional prophylactic treatment and 
hydration before the initiation of dosing. 
Assessments 
On the day of the initial visit with administration of venetoclax (Cycle 1, Day 1): 
• 
Serial vital signs will be recorded  
• 
Chemistry and hematology samples will be drawn (see Appendix 1 and 
Appendix 2): 
 − Before the dose (0−4 hours before venetoclax administration).  Predose 
laboratory samples should be drawn within 0−4 hours before venetoclax 
administration.  These samples are to be sent immediately to the laboratory and 
the investigator or designee must review the results promptly.  If laboratory 
values from within 24 hours have demonstrated no clinically significant 
abnormalities, the chemistry and hematologic values drawn on the day of initial 
venetoclax administration prior to dosing are not required to be reviewed prior to 
dose administration.  However, these predose (0−4 hours) labs should still be 
drawn and these values will serve a baseline for later laboratory values in the 
assessment of laboratory evidence of TLS.   
 − 8 hours following the dose  
 − 12 hours following the dose (only for hospitalized patients)  
 − 24 hours following the dose   
Laboratory results 24 hours postdose must be reviewed before the patient 
receives the dose of venetoclax for that day (i.e., Day 2).   
Patients who develop electrolyte changes suggestive of TLS should undergo 
aggressive management and further monitoring as outlined in Appendix 9.  
Patients still at risk of TLS before the subsequent dose should receive adequate 
prophylaxis and monitoring. 
LDH = lactate dehydrogenase; TLS = tumor lysis syndrome. 


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5.1.6.2 
Hospitalization for Patients at Higher Risk for Tumor Lysis 
Syndrome 
Patients exhibiting specific characteristics at screening or initiation of venetoclax 
treatment are considered to be at high risk of developing TLS and must be hospitalized 
for more intensive monitoring for the initial dose of venetoclax.  These patients are 
identified by the presence of any of the following: 
• 
Any lymph node ≥ 10 cm on the screening CT scan 
• 
Circulating lymphoma cells, defined by out of range (high) Absolute Lymphocyte 
Count (ALC) or the presence of abnormal cells in the peripheral blood differential  
 
In addition to characteristics requiring mandatory hospitalization, other patient 
characteristics may suggest an increased risk of TLS.  These include, but are not limited 
to, the following: 
• 
Overall disease burden (e.g. several enlarged lymph nodes, even if none reaching 
10 cm) 
• 
Elevated LDH levels 
• 
Impaired renal function (CrCl < 80 mL/min) 
• 
Extensive bone marrow involvement 
• 
Dehydration 
 
Hospitalization is not mandatory for patients exhibiting above characteristics, but these 
and any other factors considered relevant to TLS should be considered in an overall 
assessment of the patient’s state and their risk of TLS.  Investigators should use their 
judgment in assessing TLS risk for their patients.  Any patient that an investigator or 
other clinical provider considers to be at risk for TLS for the first dose of venetoclax, may 
be hospitalized and should be discussed with the Medical Monitor.  
Hospitalization Procedures 
Hospitalization will begin the evening before the first dose of venetoclax and continue for 
approximately 24 hours after.  Upon admission, serum chemistry and hematology 
laboratory samples should be drawn and IV hydration should be started with a target of 
150−200 ml/hr or as clinically appropriate.  Laboratory results should be reviewed, and 
electrolyte values should not demonstrate clinically significant abnormalities before the 
first dose of venetoclax; otherwise, the patient should receive additional prophylactic 
treatment and hydration before the initiation of dosing.  A nephrology (or acute dialysis) 
service must be consulted/contacted upon hospital admission (per institutional 
standards) to ensure emergency dialysis is available and the appropriate staff is aware 
and prepared to handle any necessary intervention for TLS.  Telemetry should also be 
considered. 
Serial vital signs and TLS laboratory samples will be drawn (serum chemistry as defined 
in Section 4.5.6) before the first dose of venetoclax and at 8-, 12-, and 24-hours 


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postdose; additionally, hematologic samples will be drawn at 8- and 24-hours postdose 
(see Appendix 1  and Appendix 2).  These samples are to be sent STAT to the 
laboratory and the investigator or designee must review the results promptly.  Laboratory 
values obtained before the dose of venetoclax are to be used to determine whether a 
patient developed a change related to TLS.  Laboratory results from 24-hours postdose 
must be reviewed before the patient receives the dose of venetoclax for that day.  
Patients who develop electrolyte changes suggestive of TLS should undergo aggressive 
management and further monitoring per Appendix 11, Recommendations for Initial 
Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome.  
Patients determined by the investigator to be at particularly high risk for TLS may, in 
addition to hospitalization, delay the start of venetoclax to Day 8 in Cycle 1 following 
discussion with the Medical Monitor.   
5.1.7 
Management of Specific Adverse Events 
Patients should be assessed clinically before each study treatment administration.  
Guidelines for management of toxicities are based on laboratory values obtained within 
72 hours prior to Day 1 of each cycle during induction or each month during 
maintenance (FL) or consolidation (DLBCL) or within 24 hours prior to Days 8 and 15 of 
Cycle 1 for patients receiving obinutuzumab.  Dosing will occur only if a patient’s clinical 
assessment and laboratory test values are acceptable.   
There will be no dose reductions of obinutuzumab or rituximab.  There will be no dose 
reductions of polatuzumab vedotin for any toxicity except neurotoxicity (see 
Section 5.1.7.2).  For patients receiving obinutuzumab, if toxicity occurs before Cycle 1 
Day 8 or Cycle 1 Day 15, these doses of obinutuzumab will not be skipped but given 
after resolution of toxicity.  Study treatment may be delayed for toxicity for a maximum 
amount of time (e.g., 21 days), as specified in the tables below.  If study treatment is 
delayed for longer than the specified maximum, study treatment will be permanently 
discontinued.  When a treatment cycle is delayed because of toxicity resulting from any 
component of the regimen, all study treatments should be held and resumed together to 
remain synchronized.  If one drug is discontinued, treatment with the other two drugs 
may be continued for patients experiencing clinical benefit as determined by the 
investigator after discussing with the Medical Monitor. 
Treatment delays apply to all toxicities described below; dose modifications apply only to 
toxicities that are considered to be related to any of the study treatment components.  
Depending on causality, toxicities that occur during the cycle and subside prior to the 
next cycle may not trigger the suggested dose modifications. 
Guidelines for management of toxicities during induction treatment are provided in 
Section 5.1.7.2.  Guidelines for management of toxicities during consolidation or 
maintenance treatment are provided in Section 5.1.7.3. 


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5.1.7.1 
Venetoclax Dose Reduction and Re-Escalation Steps  
The dose of venetoclax may be reduced according to the following dose reduction steps 
based on the starting dose.  Re-escalation is permitted by investigator after discussion 
with the Medical Monitor if toxicity improves to Grade ≤ 1.   
Table 16 Venetoclax Dose Reduction Steps during Induction 
 
Dose Reduction 
Starting Dose 
Step 1 
Step 2 
800 mg 
600 mg 
400 mg 
600 mg 
400 mg 
200 mg 
400 mg 
200 mg 
100 mg 
200 mg 
100 mg 
none 
 
Table 17 Venetoclax Dose Reduction Steps during Maintenance 
 
Dose Reduction 
Starting Dose 
Step 1 
Step 2 
Step 3 
Step 4 
800 mg 
600 mg 
400 mg 
200 mg 
100 mg 
600 mg 
400 mg 
200 mg 
100 mg 
none 
400 mg 
200 mg 
100 mg 
none 
none 
200 mg 
100 mg 
none 
none 
none 
 
5.1.7.2 
Toxicities during Induction Treatment 
Hematologic Toxicities during Induction Treatment 
Hematologic toxicity is defined as neutropenia, anemia, or thrombocytopenia.  
Lymphopenia is not considered hematologic toxicity but an expected outcome of therapy.  
Table 18 provides guidelines for management of hematologic toxicities that occur during 
induction treatment, with the exception of Days 8 and 15 of Cycle 1555.  Table 19 
provides guidelines for management of hematologic toxicities that occur at Days 8 and 
15 of Cycle 1, when patients are to receive treatment with obinutuzumab only. 


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Table 18 Guidelines for Management of Hematologic Toxicities That Occur 
during Induction Treatment (Except Days 8 and 15 of Cycle 1 for 
Patients Receiving Obinutuzumab) 
Event 
Action to Be Taken 
Grade 3 or 4 
hematologic 
toxicity a,b 
For patients who have had one or no prior venetoclax dose reductions: 
• Withhold study treatment.a 
• Administer RBCs or platelets as required. 
• If patient has not already initiated G-CSF, initiate prophylactic G-CSF for 
current and subsequent cycles. 
• For patients who develop platelet count of < 20,000/μL while receiving 
LMWH, reduce the dose of LMWH.  For patients who develop platelet count 
of < 20,000/μL while receiving platelet inhibitors, consider temporarily 
withholding platelet inhibitors. 
• If improvement to Grade ≤ 2 or baseline occurs within 7 days after the 
scheduled date for the next cycle, resume obinutuzumab or rituximab and 
polatuzumab vedotin at full dose and resume venetoclax at current dose. 
• If improvement to Grade ≤ 2 or baseline occurs within 8−14 days after the 
scheduled date for the next cycle, resume obinutuzumab or rituximab and 
polatuzumab vedotin at full dose and resume venetoclax at a reduced 
dose a,b for current and subsequent cycles per guidelines in Table 16.  
No more than 2 dose level reductions from the original dose of venetoclax 
are allowed during induction. 
• If study treatment is withheld for > 21 days, permanently discontinue study 
treatment. 
For patients who have had two prior venetoclax dose reductions: 
• Permanently discontinue study treatment. 
G-CSF = granulocyte colony-stimulating factor; LMWH = low molecular weight heparin. 
a Treatment delays apply to all toxicities; dose modifications apply only to toxicities that are 
considered to be related to any of the study treatment components.  Toxicities that occur 
during the cycle and subside prior to the next cycle should not trigger the suggested dose 
modifications. 
b If cytopenia is thought to be caused mainly by B-cell lymphoma infiltration of the bone 
marrow, the investigator may decide not to reduce the venetoclax dose. 
 


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Table 19 Guidelines for Management of Hematologic Toxicities That Occur 
on Days 8 and 15 of Cycle 1 for Patients Receiving 
Obinutuzumab 
Event 
Action to Be Taken 
Febrile neutropenia or 
neutropenia with infection 
• Withhold obinutuzumab and venetoclax until resolution of fever 
and infection (as applicable). 
• If the event is ongoing at Day 1 Cycle 2, follow instructions in 
Table 20. 
Note:  Obinutuzumab and venetoclax should not be withheld for 
asymptomatic neutropenia. 
Severe 
thrombocytopenia a or 
bleeding 
• Withhold obinutuzumab and venetoclax until platelet 
count ≥ 50,000/μL and resolution of bleeding. 
• If receiving LMWH, reduce the dose. 
• If receiving platelet inhibitors, consider temporarily withholding 
platelet inhibitors. 
• If the event is ongoing at Day 1 Cycle 2, follow instructions in 
Table 18. 
LMWH = low-molecular-weight heparin. 
a Severe thrombocytopenia is defined as a platelet count <10,000/μL for patients who are not 
receiving concomitant anticoagulants or platelet inhibitors and <20,000/μL for patients who 
are receiving concomitant anticoagulants or platelet inhibitors. 
 
Non-Hematologic Toxicities during Induction Treatment 
Table 20 provides guidelines for management of non-hematologic toxicities that occur 
during induction treatment. 




 
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 Table 20 Guidelines for Management of Non-Hematologic Toxicities That Occur During Induction (cont.)  
Event 
Grade 
Action to Be Taken 
Grade 4 
• Permanently discontinue polatuzumab vedotin and all other study treatment. 
Neurotoxicity  
Grade 2 
or 3 
• Withhold study treatment. a 
• If improvement to Grade ≤ 1 within 21 days, resume study treatment for current and subsequent cycles as 
follows: 
– 
Resume obinutuzumab or rituximab at full dose  
– 
Resume venetoclax at current dosea 
– 
For patients who started at 1.8 mg/kg, resume polatuzumab vedotin at the permanently reduced dose of 
1.4 mg/kg; for patients who started at 1.4 mg/kg, permanently discontinue polatuzumab vedotin a  
Grade 3 
or 4 
For patients who have had no prior dose reductions: 
• Withhold study treatment. a 
• If improvement to Grade ≤ 1 or baseline, resume obinutuzumab or rituximab and polatuzumab vedotin at full 
dose and resume venetoclax at next lower dose a for current and subsequent cycles per guidelines in 
Table 16. 
For patients who have had one prior dose reduction: 
Grade 4 events 
• Permanently discontinue study treatment. 
Grade 3 events 
• Withhold study treatment. a 
• If improvement to Grade ≤ 1 or baseline, resume obinutuzumab or rituximab and polatuzumab vedotin at full 
dose and resume venetoclax at next lower dose a for subsequent cycles per guidelines in Table 16.  No more 
than two dose level reductions from the original dose of venetoclax are allowed during induction. 
For patients who have had two prior dose reductions: 
• Permanently discontinue study treatment. 
Other 
non-hematologic 
toxicities (i.e., not 
described above), 
excluding alopecia, 
nausea, and vomiting  
Grade 2 
• Withhold study treatment.a 
• If improvement to Grade ≤ 1 or baseline, resume obinutuzumab or rituximab and polatuzumab vedotin at full 
dose and resume venetoclax at current dose. 
IRR = infusion-related reaction; PML = progressive multifocal leukoencephalopathy; TLS = tumor lysis syndrome; ULN = upper limit normal. 
a Treatment delays apply to all events; dose modifications apply only to events that are considered to be related to any of the study treatment 
components.  Toxicities that occur during the cycle and subside prior to the next cycle should not trigger the suggested dose modifications. 


 
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5.1.7.3 
Toxicities during Consolidation or Maintenance Treatment 
Table 21 provides guidelines for management of toxicities that occur during 
consolidation or maintenance treatment. 
Table 21 Guidelines for Management of Toxicities That Occur during 
Consolidation or Maintenance Treatment 
Event 
Action to Be Taken 
Hematologic toxicity: 
Grade 3 or 4 
• Withhold obinutuzumab or rituximab and venetoclax. 
• Administer G-CSF for neutropenia per institutional guidelines. 
• Administer RBCs or platelets as required. 
• If improvement to Grade ≤ 2, resume obinutuzumab or 
rituximab at full dose and resume venetoclax at next lower 
dose a for subsequent cycles per guidelines in Table 16.  
Patients who are not eligible for further venetoclax dose 
reductions per Table 17 should be permanently discontinued." 
• If study treatment is withheld for > 42 days, permanently 
discontinue study treatment.  
Non-hematologic toxicity: 
Grade ≥ 2 
• Withhold obinutuzumab or rituximab and venetoclax. 
• If improvement to Grade ≤ 1 or baseline, resume obinutuzumab 
or rituximab at full dose and resume venetoclax at next lower 
dose a for subsequent cycles per guidelines in Table 16.  
Patients who are not eligible for further venetoclax dose 
reductions per Table 17 should be permanently discontinued. 
• If study treatment is withheld for > 42 days, permanently 
discontinue study treatment. 
G-CSF = granulocyte colony-stimulating factor. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 


 
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• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment. 
• 
Adverse events that are related to a protocol-mandated intervention, including 
those that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to 
the Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study treatment 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize 
the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 


 
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5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.7) 
• 
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 any of the study treatment components is suspected. 
• 
TLS of any grade, irrespective of causality 
• 
Grade 4 thrombocytopenia 
• 
Grade ≥ 3 infection 
• 
Second malignancies 
 
5.2.4 
Dose-Limiting Toxicities (Immediately Reportable to 
the Sponsor) 
During the DLT assessment window, adverse events identified as DLTs, as defined in 
Section 3.1.2.1.1, are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.5 
Selected Adverse Events 
Selected adverse events in this study are defined as adverse events for which additional 
data collection or analyses will be performed.  Selected adverse events do not require 
immediate reporting if they are not serious (except for TLS). 
The following adverse events are considered selected adverse events: 
• 
Thrombocytopenia, including acute thrombocytopenia (events that occur during and 
within 24 hours following obinutuzumab infusion) 
• 
Hepatitis B reactivation 
• 
Cardiac events 
• 
TLS 
• 
IRRs 


 
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• 
All infections, including PML 
• 
Neutropenia, including prolonged neutropenia (neutropenia < 1000 cells/μL that 
does not resolve after 28 days without obinutuzumab treatment) and late-onset 
neutropenia (neutropenia < 1000 cells/μL occurring ≥ 28 days after obinutuzumab 
treatment has been completed or stopped)  
• 
Peripheral neuropathy (motor and/or sensory) 
• 
Gastrointestinal perforation 
 
Events for which additional data collection will be required are PML and hepatitis B 
reactivation. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4−5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study treatment, all adverse events will be reported until 90 days 
after the last dose of study treatment.  After this period, the investigator should report 
any serious adverse events that are believed to be related to prior study treatment and 
events of second malignancies for patients who received obinutuzumab 
(see Section 5.6). 
An exception is for FL patients receiving obinutuzumab, where Grade 3 and 4 infections 
(both related and unrelated) should be reported until up to 2 years after the last dose of 
obinutuzumab.  


 
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5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 22 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 22 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 


 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to any of the study treatment 
components, indicating "yes" or "no" accordingly.  The following guidance should be 
taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study treatment 
• 
Course of the event, considering especially the effects of study treatment 
modifications or discontinuation, or reintroduction of study treatment (as applicable) 
• 
Known association of the event with the study treatment or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non−treatment-related factors that are known to be associated with the 
occurrence of the event 
 
For patients who receive combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions  
Adverse events that occur during or within 24 hours after the end of study treatment 
infusion and are judged to be related to infusion of any of the study treatment 
components should be captured as a diagnosis (e.g., "infusion-related reaction") on the 
Adverse Event eCRF.  If possible, avoid ambiguous terms such as "systemic reaction."  
Associated signs and symptoms should be recorded on the dedicated Infusion-Related 
Reaction eCRF.  If a patient experiences both a local and systemic reaction to the same 
dose of study treatment, each reaction should be recorded separately on the Adverse 
Event eCRF, with signs and symptoms also recorded separately on the dedicated 
Infusion-Related Reaction eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF 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 


 
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at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decrease in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 


 
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5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 


 
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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol−specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of lymphoma should be recorded only on the 
Study Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study treatment, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  An IMC will monitor the 
frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 


 
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be replaced by the established cause of death.  The term"sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.   
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Lymphoma 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on the Lugano 2014 criteria (see Appendix 5).  In rare cases, 
the determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document progression through use of objective 
criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or insertion of access device for study treatment administration)  
This includes planned hospitalization for TLS prophylaxis and monitoring 
(i.e., Cycle 1 Day 1 hospitalization) 


 
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• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
An event that leads to hospitalization under the following circumstance is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in 
Drug Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  Additionally, all adverse 
events associated with an overdose or incorrect administration of study treatment should 
be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
No experience with overdosage is available from human clinical trials.  In clinical trials 
with obinutuzumab doses ranging from 50 mg, up to and including 2000 mg per infusion, 
have been administered.  The incidence and intensity of adverse reactions reported in 
these studies did not appear to be dose dependent. 
Patients who experience overdose should have immediate interruption or reduction of 
their infusion and should be closely supervised.  Consideration should be given to the 
need for regular monitoring of blood cell count and for increased risk of infections while 
patients are B cell depleted. 
No safety data related to overdosing of polatuzumab vedotin or venetoclax are available. 


 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to any of the study treatments: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Dose-limiting toxicities (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for All Sites 
Medical Monitor: 
, Pharm.D. (primary) 
Telephone No.: 
 
Mobile Telephone No.: 
  
 
Medical Monitor: 
, Pharm.D. (secondary) 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor Responsible (listed above and/or on the Roche Medical Emergency List), and 
track all calls.  The Emergency Medical Call Center Help Desk will be available 24 hours 


 
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per day, 7 days per week.  Toll-free numbers for the Help Desk, as well as Medical 
Monitor contact information, will be distributed to all investigators. 
5.4.2 
Reporting Requirements for Serious Adverse Events, Adverse 
Events of Special Interest, and Dose-Limiting Toxicities 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 
5.4.2.2 
Events That Occur after Study Treatment Initiation 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment.  After this 
period, the investigator should report any serious adverse events that are believed to be 
related to prior study treatment (see Section 5.6).  An exception is for FL patients 
receiving obinutuzumab, where Grade 3 and 4 infections (both related and unrelated) 
should be reported until up to 2 years after the last dose of obinutuzumab.  DLTs will be 
reported during the DLT assessment window.  Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Roche Safety Risk Management by the 
EDC system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting events after the adverse events reporting period are provided 
in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 18 months after the last 
dose of study treatment.  A Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 


 
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the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose for obinutuzumab or rituximab, 30 days after the last dose 
of venetoclax, and 5 months after last dose of polatuzumab vedotin.  A Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Attempts should be made to collect and report details 
of the course and outcome of any pregnancy in the partner of a male patient exposed to 
study treatment.  The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
After the authorization has been signed, the investigator will submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician. 
5.4.3.3 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).   
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 


 
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5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome.   
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
90 days after the last dose of study treatment), if the event is believed to be related to 
prior study treatment.  The sponsor should also be notified of events of second 
malignancies after the end of the adverse event reporting period for patients who 
received obinutuzumab.   
An exception is for FL patients receiving obinutuzumab, where Grade 3–4 infections 
(both related and unrelated) should be reported until up to 2 years after the last dose of 
obinutuzumab.  
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators. 
During survival follow-up, deaths attributed to progression of lymphoma should be 
recorded only on the Study Completion/Early Discontinuation eCRF. 


 
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5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
Obinutuzumab Investigator's Brochure 
• 
Rituximab Investigator’s Brochure 
• 
Polatuzumab Vedotin Investigator's Brochure 
• 
Venetoclax in combination with Obinutuzumab Investigator's Brochure  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This is a Phase Ib/II, open-label, multicenter, non-randomized study of obinutuzumab in 
combination with polatuzumab vedotin and venetoclax (G + Pola + V) in patients with R/R 
FL and rituximab in combination with polatuzumab vedotin and venetoclax 
(R + Pola + V) in patients with R/R DLBCL. 
The dose-escalation phase in patients with FL is designed to determine the RP2D for 
both polatuzumab vedotin and venetoclax when combined with fixed doses of 
obinutuzumab (1000 mg).  The dose-escalation phase in patients with DLBCL is 
designed to determine the RP2D of venetoclax when combined with fixed doses of 
polatuzumab vedotin (1.8 mg/kg) and rituximab (375 mg/m2).  The expansion phase is 
designed to assess the safety and efficacy of polatuzumab vedotin and venetoclax at 
their respective RP2Ds in combination with obinutuzumab or rituximab.  
Study data will be summarized separately for each phase.  Data from the 
dose-escalation phase will be summarized by cohort (assigned dose level).  Data from 
the expansion phase will be summarized by histological subtype (i.e., FL or DLBCL). 
Data will be summarized as warranted, and listings will be used in place of tables when 
the sample sizes are small. 


 
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6.1 
DETERMINATION OF SAMPLE SIZE 
Limited dose finding will be conducted during the dose-escalation phase of this study.  
The estimated sample size follows from the dose-escalation rules for a standard 3 + 3 
algorithm, as outlined in Section 3.1.  It is anticipated that enrollment of 6 cohorts of 
3−6 patients each, for a total of 21−36 patients, will be required to establish the RP2D 
during the dose-escalation phase for patients with R/R FL.  There are 3 possible cohorts 
of 3−6 patients each, for a total of 12−18 patients with replapsed or refractory DLBCL. 
Approximately 80 patients (40 patients with FL and 40 patients with DLBCL) will be 
enrolled during the expansion phase.  Overall, approximately 113−134 patients will be 
enrolled in this study. 
The primary analysis will be estimation of the true proportion of patients expected to 
obtain a PET-CT−defined CR at EOI.   
Data from completed and ongoing studies in similar disease settings will be used as 
historical controls for comparison.  Currently available data indicate that the historical 
CR rate based on PET-CT scans is around 40% for R/R FL and DLBCL.   
Table 23 provides 90% Clopper-Pearson exact CIs for the probability of achieving an 
EOI PET-CT−defined CR for a range of observed proportions based on a sample of 
40 patients.  A sample size of 40 patients is deemed sufficient to provide adequate 
precision for the point estimate and for the lower bound of the two-sided 90% CI to rule 
out a clinically uninteresting probability of response of < 55%, assuming an observed 
PET-CT−defined CR rate of 70%. 
Table 23 Potential 90% CI Estimates for the True Probability of Achieving a 
PET-CT−Defined Complete Response at End of Induction 
Observed Proportion of Patients 
Who Achieve a PET-CT−Defined CR at EOI 
Two-Sided 90% Clopper-Pearson CI  
for True Population PET-CT−Defined CR 
0.50 
0.55 
(0.36, 0.64) 
(0.41, 0.68) 
0.60 
(0.46, 0.73) 
0.65 
(0.51, 0.77) 
0.70 
(0.56, 0.82) 
0.75 
(0.61, 0.86) 
CR = complete response; CT = computed tomography; EOI = end of induction; PET = positron 
emission tomography. 
Note that lower limit of two-sided 90% CI is equivalent to one-sided 95% CI. 
 


 
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6.2 
SUMMARIES OF PATIENT CHARACTERISTICS 
Enrollment, major protocol violations, and discontinuations from the study will be listed.  
The incidence of treatment discontinuation for reasons other than disease progression 
will be tabulated.   
Data related to the administration of study treatment components will be listed, and any 
dose modifications will be flagged.  The number of doses, treatment cycles, average 
dose received, and relative dose intensity for each study treatment will be summarized 
using descriptive statistics (mean, standard deviation, median, and range). 
6.3 
DEFINITION OF ANALYSIS POPULATIONS 
The following populations are defined: 
• 
The primary safety and efficacy populations will include patients who receive at 
least one dose of any component of the combination.   
• 
The intent-to-treat population will include all patients enrolled in the study. 
 
6.4 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics, such as age, sex, race, and duration of 
malignancy, will be summarized using descriptive statistics (mean, standard deviation, 
median, and range) for continuous variables and frequencies and percentages for 
categorical variables. 
6.5 
SAFETY ANALYSES 
The safety analyses will include all treated patients (i.e., patients who received any 
amount of study treatment).  Patients in the dose-escalation phase will be summarized 
by cohort and histology type, and patients in the expansion phase will be summarized 
by histology type (FL or DLBCL).  
Safety will be assessed through summaries of adverse events and changes from 
baseline laboratory test results, shift-tables of ECGs findings, and vital signs. 
All adverse events occurring on or after first study treatment will be summarized by 
mapped term, appropriate thesaurus levels, and NCI CTCAE v4.0 grade.  All serious 
adverse events, adverse events of special interest, and selected adverse events will be 
summarized and listed.   
Deaths reported during the treatment period and during post-treatment follow-up will be 
listed and summarized. 
Relevant laboratory results will be displayed by time, with Grade 3 and 4 values 
identified as appropriate. 


 
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6.6 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include the primary efficacy 
population and the intent-to-treat population for patients enrolled in the expansion 
phase, with patients grouped according to histologic subtype, and will be performed by 
treatment group.  In addition, patients with FL and DLBCL who received polatuzumab 
vedotin and venetoclax at the RP2D during the dose-escalation phases will be pooled for 
analysis by histology with patients treated in the expansion phase at the same dose 
levels. 
Response will be determined on the basis of PET-CT scans or CT scans alone, using 
the Lugano 2014 criteria (see Appendix 5). 
6.6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients achieving a CR at EOI, as 
determined by the IRC on the basis of PET-CT scans according to Lugano 2014.  Point 
estimates will be presented, along with the corresponding 90% Clopper-Pearson exact 
CIs.  Patients without a post-baseline tumor assessment will be considered 
non-responders. 
6.6.2 
Secondary Efficacy Endpoints 
The secondary efficacy analyses will be estimation of the pro portion of patients who 
achieve each of the following endpoints:  
• 
CR at EOI, as determined by the investigator on the basis of PET-CT scans 
• 
CR at EOI, as determined by the IRC and by the investigator on the basis of CT 
scans alone 
• 
Objective response (defined as a CR or PR) at EOI, as determined by the IRC and 
by the investigator on the basis of PET-CT scans 
• 
Objective response (defined as a CR or PR) at EOI, as determined by the IRC and 
by the investigator on the basis of CT scans alone 
• 
Best response of CR or PR during the study, as determined by the investigator on 
the basis of CT scans alone 
 
Point estimates will be presented, along with the corresponding two-sided 90% 
Clopper-Pearson exact CIs.  Patients without a post-baseline tumor assessment will be 
considered non-responders. 
6.6.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy analyses will include estimation of the proportion of patients 
achieving each of the following endpoints:  
• 
For patients who have positive PET scans at EOI:   
– 
CR at 12 months, as determined by the IRC and by the investigator on the 
basis of PET-CT scans, in FL patients 


 
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– 
CR at EOC, as determined by the IRC and by the investigator on the basis 
of PET-CT scans, in DLBCL patients 
 
Point estimates will be presented, along with the corresponding two-sided 90% 
Clopper-Pearson exact CIs.  Patients without a post-baseline tumor assessment will be 
considered non-responders. 
Exploratory efficacy analyses will also be performed on the following endpoints:  
• 
PFS 
• 
EFS 
• 
DFS 
• 
OS 
 
PFS, EFS, DFS, and OS will be summarized descriptively using the Kaplan-Meier 
method (Kaplan and Meier 1958).  For the PFS, EFS, and DFS analyses, data for 
patients without an event of interest will be censored at the date of the last tumor 
assessment.  For patients without post-baseline tumor assessments, data will be 
censored at the date of initiation of study treatment plus 1.  For the OS analysis, data for 
patients who have not died will be censored at the date the patient was last known to be 
alive.  Where medians are reached, the corresponding estimated median will be 
provided, along with the 95% CI using the method of Brookmeyer and Crowley (1982).  
In addition, landmark estimates of the proportion of patients who are event free at 
6 months, 9 months, 1 year, and 2 years will be provided, along with 95% asymptotic CIs 
using Greenwood’s formula for standard errors. 
6.7 
PHARMACOKINETIC ANALYSES 
The PK population for analysis will include all patients who have at least one evaluable 
PK sample post dose for at least one analyte. 
Serum or plasma concentrations of obinutuzumab, rituximab, polatuzumab vedotin and 
relevant analytes, and venetoclax will be tabulated and plotted over time after 
appropriate grouping.  Summary statistics of concentration data will be computed for 
each scheduled sampling time for each analyte after appropriate grouping.  Interpatient 
variability and drug accumulation after multiple doses will be evaluated as appropriate.  
Compartmental, non-compartmental, and/or population approaches will be considered 
as appropriate.  Potential correlations between PK variability and pharmacodynamic, 
efficacy, and safety endpoints may be explored by exploratory graphical analysis and 
PK-pharmacodynamic modeling.  The exploratory analyses may be reported separately 
from the CSR.   
The assessment of PK parameters and related analyses will be performed per the 
Sponsor’s discretion, taking into consideration the appropriateness of the PK data 
collected and the trial outcome.  At the discretion of the Sponsor, all analyses may be 


 
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extended to include relevant biotransformation products of venetoclax or polatuzumab 
vedotin. 
6.8 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with at least one predose and 
one postdose HAHA or ATA assessment, with patients grouped according to histology. 
The numbers and proportions of HAHA- or ATA-positive patients and HAHA- or 
ATA-negative patients during both the treatment and follow-up periods will be 
summarized by histology group.  Patients are considered to be HAHA- or ATA-positive 
if they are HAHA- or ATA-negative at baseline but develop an HAHA or ATA response 
following study drug administration (treatment-induced HAHA or ATA response), or if 
they are HAHA- or ATA-positive at baseline and the titer of 1 or more post-baseline 
samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline 
sample (treatment-enhanced HAHA or ATA response).  Patients are considered to be 
HAHA- or ATA-negative if they are HAHA- or ATA-negative at baseline and all 
post-baseline samples are negative, or if they are HAHA- or ATA-positive at baseline 
but do not have any post-baseline samples with a titer that is at least 4-fold greater than 
the titer of the baseline sample (treatment unaffected). 
The relationship between HAHA or ATA status and safety, efficacy, PK, and biomarker 
endpoints will be analyzed and reported descriptively via subgroup analyses.  
Considering the historically low immunogenicity rate of rituximab in NHL patients, 
human anti-chimeric antibodies against rituximab will not be monitored in this study. 
6.9 
BIOMARKER ANALYSES 
Exploratory analyses of biomarkers related to tumor biology and study treatment 
mechanisms of action will be conducted.  Analyses will assess the prognostic and/or 
predictive value of candidate biomarker for each histological subtype with respect to both 
IRC- and investigator-assessed outcomes.  Specifically, the association between 
candidate biomarkers and PET-CT−defined CR rate and OR rate, and potentially other 
measures of efficacy and safety, will be explored to assess potential prognostic or 
predictive value.  These analyses may not be included in the final study report because 
of their exploratory nature.  In addition to analysis in the context of this study, data will 
also be explored in aggregate with data from other studies. 
6.10 
INTERIM ANALYSES 
It is anticipated that at least one interim analysis will be conducted during the expansion 
phase of the study, when at least 15 patients in each treatment group have been 
evaluated for PET-CT−defined CR at the EOI.  Additional analyses may be conducted to 
guide early stopping of enrollment for safety on the basis of observed toxicities and the 
ability to maintain chemotherapy dose intensity. 


 
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During the expansion phase, a modified version of the predictive probability design 
(Lee and Lui 2008) may be used to guide early stopping for futility by comparing the 
observed proportion of patients who achieve a PET-CT−defined CR at EOI in each 
expansion cohort with that in historical controls.  The design is based on Lee and Lui 
2008 with the modification that the uncertainty in the historical control data is fully 
taken into account by utilizing a beta posterior on the control response rate.  Interim 
analysis decision rules will be based on the predicative probability that the trial will 
have a positive outcome if carried out to completion and will use the historical control 
data available at the time of analysis.   
If, at any time, an interim analysis suggests that the proportion of patients achieving a 
PET-CT−defined CR for one of the expansion cohorts is lower than expected, the IMC 
will review the data and decide whether to recommend an early decision to stop 
enrollment in that cohort because of futility.   
Additional review of safety and/or efficacy data by the IMC may be requested by and 
carried out at the discretion of the Medical Monitor.  Further details regarding the rules 
and guidelines of data review will be provided to the IMC in an IMC charter. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and any other 
externally-generated electronic study data will be sent directly to the Sponsor, using the 
Sponsor’s standard procedures to handle and process the electronic transfer of these 
data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 


 
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7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 


 
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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting).  
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
Application will comply with U.S. Food and Drug Administration (FDA) regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union (E.U.) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/EC−approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 


 
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objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 


 
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policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., 1 year after the last 
patient has completed the study). 
9. 
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 


 
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the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by Roche or an authorized representative. 
EDC will be used for this study.  An IxRS will be used to assign patient numbers.  
A central laboratory will be used for a subset of laboratory assessments as specified in 
Section 4.5.6; otherwise, local laboratories will be used.  A central independent review 
facility will be used to collect PET-CT and CT scans, and the IRC will perform 
independent assessments of response for all patients enrolled in the study (separate 
IRC Charter will contain all details).  Data from this study will be shared with an Expert 
Scientific Committee that will provide scientific input for the benefit-risk assessment.  
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 


 
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an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors’ authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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antibody drug conjugates. Mol Cancer Ther 2009;8:2937−46. 
Zhou Z, Sehn LH, Rademaker A, et al. An enhanced International Prognostic Index 
(NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab 
era. Blood 2014;123:837−42. 




 
 
Appendix 1 Schedule of Assessments for Patients with Follicular Lymphoma (cont.) 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
200 
Screening a 
Induction (21-day cycles) 
EOI 
Maint. (24 months)
EOM c 
Cycle 1  
( ± 1 d) 
Cycle 2 
( ± 2 d) 
Cycles 3−6
( ± 2 d) 
Monthly
(±3 d) 
Every  
2 months
(± 1 wk) 
Assessment/Procedure 
D −28 
to 
D −1 
D −14 
to 
D −1
D1 D8 D15
D1 
D1 
After last 
induction 
dose b 
D1 
D1 
35 days 
after last 
dose 
Post- 
Treatment 
FU Period 
(q3m) d 
Survival 
FU 
Period 
(q3m) d 
Coagulation (INR, aPTT [or PTT], 
and PT) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test q 
 
x 
 
 
 
x 
x 
x  
 
 
x 
 
 
Hepatitis B and C testing r 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative IgA, IgG, IgM 
 
 
x o 
 
 
 
 
x 
x s 
x 
x t 
 
HAHA sample for obinutuzumab 
 
 
x u (See Appendix 3) 
 
ATA sample for polatuzumab vedotin 
 
 
x u (See Appendix 3) 
 
PK sample for obinutuzumab 
 
 
x u (See Appendix 3) 
 
PK sample for polatuzumab vedotin 
 
 
x u (See Appendix 3) 
 
PK sample for venetoclax 
 
 
x u (See Appendix 3) 
 
 
Whole blood for MRD v 
 
 
x o 
 
 
 
 
x 
x s 
 
 
 
Whole blood for lymphocyte 
immunophenotyping w 
 
 
x o 
 
x o 
x o 
x o 
x 
x s 
x 
x t 
 


 
 
Appendix 1 Schedule of Assessments for Patients with Follicular Lymphoma (cont.) 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
201 
Screening a 
Induction (21-day cycles) 
EOI 
Maint. (24 months)
EOM c 
Cycle 1  
(± 1 d) 
Cycle 2 
(± 2 d) 
Cycles 3−6
(± 2 d) 
Monthly
(±3 d) 
Every  
2 months
(± 1 wk) 
Assessment/Procedure 
D −28 
to 
D −1 
D −14 
to 
D −1
D1 D8 D15
D1 
D1 
After last 
induction 
dose b 
D1 
D1 
35 days 
after last 
dose 
Post- 
Treatment
FU Period 
(q3m) d 
Survival 
FU 
Period 
(q3m) d 
Optional peripheral blood sample for 
RCR x 
 
 
(x) 
 
 
 
 
 
 
 
 
 
 
Tumor tissue specimen  
x y 
 
 
 
 
 
 
(x z) 
 
Concomitant medications aa 
x 
To be recorded continually until end of treatment aa 
 
 
Adverse events bb 
x 
To be assessed continually bb 
PET-CT scan 
x cc 
 
 
 
 
 
 
x dd 
x ee 
 
 
 
CT scan ff 
x ff 
 
 
 
 
xgg 
 
x dd 
x s 
x hh 
xii 
 
Bone marrow biopsy and aspirate  
x jj 
 
 
 
 
 
 
x dd,kk 
x kk 
x hh,kk 
 
 
Obinutuzumab ll 
 
 
x 
x 
x 
x 
x 
 
 
x 
 
 
 
Polatuzumab vedotin 
ll 
 
 
x 
 
 
x 
x 
 
 
 
 
 
 
Study 
treatment 
administration 
Venetoclax ll 
 
 
x (daily) 
 
x (daily) 
 
 
 
New anti-lymphoma treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
ATA = anti-therapeutic antibody; CT = computed tomography; D = day; Discont. = discontinuation; ECOG = Eastern Cooperative Oncology Group; 
eCRF = electronic Case Report Form; EOI = end of induction; EOM = end of maintenance; FLIPI = Follicular Lymphoma International Prognostic Index; 
FU = follow-up; HAHA = human anti-human antibody; Maint. = maintenance; MRD = minimal residual disease; MRI = magnetic resonance imaging; 
NK = natural killer; PBMC = peripheral blood mononuclear cell; PET = positron emission tomography; PK = pharmacokinetic; q3m = every 3 months; 
RCR = Roche Clinical Repository; wk = week; (x) = conditional/optional. 
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 


 
 
Appendix 1 Schedule of Assessments for Patients with Follicular Lymphoma (cont.) 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
202 
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the case 
of an adverse event).   
a The screening period starts with the signing of the Informed Consent Form.  Results of standard-of-care tests or examinations performed prior to 
obtaining informed consent and within the defined window may be used as screening and baseline assessments; such tests do not need to be 
repeated for screening purposes. 
b EOI assessments should be performed 6−8 weeks after Day 1 of the last induction cycle.  As an exception, patients who discontinue induction 
treatment prematurely because of an adverse event may undergo EOI assessments 4−8 weeks after their last dose of study treatment. 
c Patients who complete maintenance treatment or discontinue maintenance treatment prematurely will undergo assessments at EOM. 
d Patients who complete treatment or discontinue treatment for reasons other than disease progression will undergo assessments every 3 months 
during the post-treatment FU period, which will continue until disease progression, the start of new anti-lymphoma treatment, or the end of the 
study, whichever occurs first.  The first post-treatment FU visit is 3 months after the EOI visit for patients who do not receive maintenance treatment 
and 3 months after the last dose for patients who receive maintenance treatment.  Patients who experience disease progression will undergo limited 
assessments every 3 months during the survival FU period, which will continue until the end of the study.  The end of the study is defined as the 
time when all enrolled FL patients have completed or discontinued study treatment and all enrolled DLBCL patients have been followed for at least 
1 year after they have completed or discontinued study treatment.  
e Informed consent must be documented before any study-specific screening procedure is performed.   
f Vital signs include respiratory rate, pulse rate, body temperature, and systolic and diastolic blood pressures while the patient is in a seated position.  
Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.  For obinutuzumab infusions:  For the first cycle and for patients who 
experience an infusion-related reaction, vital signs will be measured prior to the infusion, every 15 (± 5) minutes for the first 90 minutes of the 
infusion, and then every 30 ( ± 10) minutes until 1 hour after completion of the infusion.  For the second and subsequent cycles, vital signs will be 
measured every 30 minutes during the infusion, except in patients who had experienced an infusion-related reaction during a prior infusion.  For 
polatuzumab vedotin infusions:  During the administration of polatuzumab vedotin, vital signs should be assessed before the start of the infusion, 
every 15 (± 5) minutes during the infusion, at the end of the infusion and every 30 (± 10) minutes for 90 minutes following completion of dosing at 
Cycle 1 and 30 (± 10) minutes following completion of dosing in subsequent cycles.’ 
g Note that ECGs and ECHO/MUGA scans will be performed at other timepoints as needed.   
h Perform only in patients who will not be receiving maintenance treatment. 
i Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions 
eCRF. 
 


 
 
Appendix 1 Schedule of Assessments for Patients with Follicular Lymphoma (cont.) 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
203 
j As part of tumor assessment, the physical examination should include evaluation for the presence of enlarged nodes, palpable hepatomegaly, and 
splenomegaly.  This information will be recorded on the appropriate tumor assessment eCRF. 
k Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly emergent or 
monitored from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas identified at baseline).  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
l Unexplained fever  > 38°C, night sweats, unexplained weight loss  > 10% of body weight over 6 months. 
m Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent or absolute WBC differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells). 
n Screening laboratory assessments may be used for Day 1 of Cycle 1 if performed within 24 hours prior to Day 1 of Cycle 1.  Additional hematology 
and chemistry samples must be drawn 0−4 hours predose and 8 and 24 hours postdose on Day 1 of Cycle 1 to monitor for TLS, with an additional 
chemistry sample at 12 hours after venetoclax dose for hospitalized patients.  Note that the sample at 24 hours postdose will actually be obtained 
on Day 2 of Cycle 1.   
o Perform hematology and chemistry tests within 72 hours prior to Day 1 of each cycle during induction or each month during maintenance, and 
within 24 hours prior to Days 8 and 15 of Cycle 1.  For β2 microglobulin and quantitative IgA, IgG, IgM: C1D1 requires predose collection.  Samples for 
exploratory biomarker research should be collected at the same time as hematology and chemistry samples, but test results are not required prior 
to treatment administration. 
p Chemistry panel includes sodium, potassium, glucose, BUN or urea, creatinine, calculated CrCl, calcium, total bilirubin, direct bilirubin, total protein, 
albumin, ALT, AST, alkaline phosphatase, LDH, uric acid, phosphate, glycosylated hemoglobin (HbA1c), amylase, and lipase (amylase and lipase 
only during induction).  HbA1c will be measured only at Screening and can be obtained in a non-fasting state. 
q All women of childbearing potential will have a serum pregnancy test at screening within 7 days prior to Day 1 of Cycle 1.  In addition a serum or 
urine pregnancy test must be performed prior to Day 1 of each subsequent cycle of study treatment (laboratory samples may be obtained up to 
72 hours before start of study treatment administration on Day 1 of the treatment cycle).  If any urine pregnancy test is positive, study treatment will 
be delayed until the patient pregnancy status is confirmed by a serum pregnancy test.  If serum pregnancy test is positive, the patient will be 
permanently discontinued from study treatment. 
r Includes hepatitis B surface antigen, total hepatitis B core antibody, and hepatitis C virus antibody.  HIV test should also be performed if required by 
local regulatory requirements.  
s Perform at 12, 18, and 24 months after initiation of induction treatment, within 14 days prior to treatment administration.   
t Perform every 3 months until recovery to either normal range or baseline level, disease progression, or the start of new anti-lymphoma treatment, 
whichever occurs first. 
u See Appendix 3 for detailed schedule. 
v Includes circulating lymphoma cells and/or cell-free circulating tumor DNA. 


 
 
Appendix 1 Schedule of Assessments for Patients with Follicular Lymphoma (cont.) 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
204 
w Includes B-cell counts (CD19), T-cell counts (CD3, CD4, and CD8), and NK cell counts (CD16 and CD56). 
x Requires separate patient consent for RCR participation.  Not applicable for a site that has not been granted approval for RCR sampling. 
y Availability of adequate archival (obtained within 12 months prior to the initiation of study treatment) or freshly biopsied tumor tissue samples should 
be confirmed at screening (see Section 4.5.6 for details). 
z A sample will be collected at the time of progression unless no adequate tumor site is accessible. 
aa Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to the screening period until the EOI or EOM visit, whichever occurs later. 
bb After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 90 days after the last dose of study 
treatment.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be 
related to prior study treatment (see Section 5.6).  An exception is Grade 3 or 4 infections (both related and unrelated), which should be reported 
until up to 2 years after the last dose of obinutuzumab.  The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort 
should be made to follow all serious adverse events considered to be related to any of the study treatment components or trial-related procedures 
until a final outcome can be reported. 
cc The screening PET-CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
dd Perform only for patients who have received at least 2 cycles of induction treatment. 
ee If PET-CT scan is positive at EOI, perform at 12 months after initiation of induction treatment, within 14 days prior to treatment administration. 
ff CT scan of the neck (if clinically indicated), chest, abdomen and pelvis.  If contrast is medically contraindicated (e.g., patients with contrast allergy 
or impaired renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically indicated) and a non-contrast CT scan of the chest 
may be performed.  Combined PET/CT scanners may be used to collect diagnostic CT scans, but only according to the technical guidelines in the 
imaging manual.  Screening CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
gg Perform within 7 days prior to Day 1 of Cycle 3. 
hh Perform only if not done within previous 3 months.  
ii Perform every 6 months. 
jj Bone marrow biopsy and aspirate must be performed within approximately 3 months prior to Day 1 of Cycle 1. 
kk For patients with bone marrow involvement at screening, a repeat assessment will be performed at EOI if there is radiologic evidence of a complete 
response, and during maintenance or at EOM if there is radiologic evidence of a complete response or if clinically indicated (e.g., if there is clinical 
suspicion of progressive disease in the bone marrow with no radiologic evidence of progression). 
ll Refer to Section 4.3.2 for details on dosing and schedule. 
 




 
 
Appendix 2 Schedule of Assessments for Patients with DLBCL (cont.) 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
206 
Screening a 
Induction  
(21-day cycles) 
EOI 
Consolidation 
(28-day cycles) 
EOC c 
Cycle 1  
(± 1 d) 
Cycle 
2  
(± 2 d) 
Cycles 
3−6 
(± 2 d) 
Cycles 7−14 
Months 1-8 
(± 3 days) 
Assessment/Procedure 
D −28 
to 
D −1 
D −1
4 to 
D −1 
D1 
D
8 
D15 
D1 
D1 
After last 
induction 
dose b 
D1 
35 days 
after last 
dose 
Post- 
Treatment
FU Period 
(q3m) d 
Survival 
FU 
Period 
(q3m) d 
Hematology m 
 
x 
x n,o 
 
x o 
x o 
x o 
x h 
x o 
x  
 
 
Chemistry panel (serum or plasma) 
p 
 
x 
x n,o 
 
xo 
x o 
x o 
x h 
x o 
x 
 
 
Coagulation (INR, aPTT [or PTT], 
and PT) 
 
x 
 
 
 
 
 
 
 
 
 
 
Pregnancy test q 
 
x 
 
 
 
x 
x 
x  
 
x 
 
 
Hepatitis B and C testing r 
x 
 
 
 
 
 
 
 
 
 
 
 
Quantitative IgA, IgG, IgM 
 
 
x o 
 
 
 
 
x 
 
x 
x 
 
ATA sample for polatuzumab 
vedotin 
 
 
x s (see Appendix 4) 
 
PK sample for rituximab 
 
 
x s (see Appendix 4) 
 
PK sample for polatuzumab vedotin 
 
 
x s (see Appendix 4) 
 
PK sample for venetoclax 
 
 
x s (see Appendix 4)  
 
 
 
 
 
Whole blood for MRD t 
 
 
x o
 
 
 
 
x 
x 
(at end of C10) 
x 
 
 
Whole blood for lymphocyte 
immunophenotyping u 
 
 
x o
 
x o 
x o 
x o 
x 
x 
(at end of C10) 
x 
x 
 
 


 
 
Appendix 2 Schedule of Assessments for Patients with DLBCL (cont.) 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
207 
Screening a 
Induction  
(21-day cycles) 
EOI 
Consolidation 
(28-day cycles) 
EOC c 
Cycle 1  
(± 1 d) 
Cycle 2  
(± 2 d) 
Cycles 3−6 
(± 2 d) 
Cycles 7−14 
Months 1-8 
(± 3 days) 
Assessment/Procedure 
D −28 
to 
D −1 
D −14 
to 
D −1 
D1
D8
D15 
D1 
D1 
After last 
induction 
dose b 
D1 
35 days 
after last 
dose 
Post- 
Treatment
FU Period 
(q3m) d 
Survival 
FU Period 
(q3m) d 
Optional peripheral blood sample for 
RCR v 
 
 
x 
 
 
 
 
 
 
 
 
 
Tumor tissue specimen  
x w 
 
 
 
 
 
 
(x x) 
 
Concomitant medications y 
x 
To be recorded continually until end of treatment y 
 
 
Adverse events z 
x 
To be recorded continually z 
PET-CT scan 
x aa 
 
 
 
 
 
 
x bb 
x cc 
 
 
CT scan dd 
x dd 
 
 
 
 
x ee 
 
x bb 
At end of C10 
x ff 
x gg 
 
Bone marrow biopsy and aspirate  
x hh 
 
 
 
 
 
 
x bb,ii 
x ii 
x ff,ii 
 
 
Rituximabjj 
 
 
x 
 
 
x 
x 
 
x 
 
 
 
Polatuzumab 
vedotin jj 
 
 
x 
 
 
x 
x 
 
 
 
 
 
Study treatment 
administration 
Venetoclax jj 
 
 
x (daily) 
 
x (daily) 
 
 
 
New anti-lymphoma treatment 
 
 
 
 
 
 
 
 
 
 
x 
x 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations:  ATA = anti-therapeutic antibody; C = cycle; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; CT = computed tomography; 
D = day; Discont. = discontinuation; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic Case Report Form; EOC = end of consolidation; 
EOI = end of induction; FU = follow-up; IPI = International Prognostic Index; LVEF = left ventricular ejection fraction; MRD = minimal residual disease; 
MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; NK = natural killer; PBMC = peripheral blood mononuclear cell; PET = positron 
emission tomography; PK = pharmacokinetic; q3m = every 3 months; RCR = Roche Clinical Repository; wk = week. 
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 


 
 
Appendix 2 Schedule of Assessments for Patients with DLBCL (cont.) 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
208 
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the case of an 
adverse event).   
a The screening period starts with the signing of the Informed Consent Form.  Results of standard-of-care tests or examinations performed prior to obtaining 
informed consent and within the defined window may be used as screening and baseline assessments; such tests do not need to be repeated for 
screening purposes. 
b EOI assessments should be performed 6−8 weeks after Day 1 of the last induction cycle.  As an exception, patients who discontinue induction treatment 
prematurely because of an adverse event may undergo EOI assessments 4−8 weeks after their last dose of study treatment. 
c Patients who complete consolidation treatment or discontinue consolidation treatment prematurely will undergo assessments at EOC. 
d Patients who complete treatment or discontinue treatment for reasons other than disease progression will undergo assessments every 3 months during the 
post-treatment FU period, which will continue until disease progression, the start of new anti-lymphoma treatment, or the end of the study, whichever 
occurs first.  The first post-treatment FU visit is 3 months after the EOI visit for patients who do not receive consolidation treatment and 3 months after the 
last dose for patients who receive consolidation treatment.  Patients who experience disease progression will undergo limited assessments every 3 months 
during the survival FU period, which will continue until the end of the study.  The end of the study is defined as the time when all enrolled FL patients have 
completed or discontinued study treatment and all enrolled DLBCL patients have been followed for at least 1 year after they have completed or 
discontinued study treatment.  
e Informed consent must be documented before any study-specific screening procedure is performed.   
f Vital signs include respiratory rate, pulse rate, body temperature, and systolic and diastolic blood pressures while the patient is in a seated position.  
Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF.  For rituximab infusions:  Vital signs monitoring during infusion should be determined 
as per local label.  For polatuzumab vedotin infusions:  During the administration of polatuzumab vedotin, vital signs should be assessed before the start of 
the infusion, every 15 (± 5) minutes during the infusion, at the end of the infusion and every 30 (± 10) minutes for 90 minutes following completion of dosing 
at Cycle 1 and 30 (± 10) minutes following completion of dosing in subsequent cycles. 
g Note that ECGs and ECHO/MUGA scans will be performed at other timepoints as needed.   
h Perform only in patients who will not be receiving consolidation treatment. 
i Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF. 
j As part of tumor assessment, the physical examination should include evaluation for the presence of enlarged nodes, palpable hepatomegaly, and 
splenomegaly.  This information will be recorded on the appropriate tumor assessment eCRF. 
k Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly emergent or monitored 
from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas identified at baseline).  Record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF. 


 
 
Appendix 2 Schedule of Assessments for Patients with DLBCL (cont.) 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
209 
l Unexplained fever  > 38°C, night sweats, unexplained weight loss  > 10% of body weight over 6 months. 
m Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent or absolute WBC differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells). 
n Screening laboratory assessments may be used for Day 1 of Cycle 1 if performed within 24 hours prior to Day 1 of Cycle 1.  Additional hematology and 
chemistry samples must be drawn 0−4 hours predose and 8 and 24 hours postdose on Day 1 of Cycle 1 to monitor for TLS with an additional 
chemistry sample at 12 hours post venetoclax dose for hospitalized patients.  Note that the 24-hour sample will actually be obtained on Day 2 of Cycle 1.   
o Perform hematology and chemistry tests within 72 hours prior to Day 1 of each cycle during induction or each month during consolidation.  For β2 
microglobulin and quantitative IgA, IgG, IgM: C1D1 requires predose collection.  Samples for exploratory biomarker research should be collected at the 
same time as hematology and chemistry samples, but test results are not required prior to treatment administration. 
p Chemistry panel includes sodium, potassium, glucose, BUN or urea, creatinine, calculated CrCl, calcium, total bilirubin, direct bilirubin, total protein, 
albumin, ALT, AST, alkaline phosphatase, LDH, uric acid, phosphate, glycosylated hemoglobin (HbA1c), amylase, and lipase (amylase and lipase only 
during induction).  HbA1c will be measured only at Screening and can be obtained in a non-fasting state. 
q All women of childbearing potential will have a serum pregnancy test at screening within 7 days prior to Day 1 of Cycle 1.  In addition, a serum or urine 
pregnancy test must be performed prior to Day 1 of each subsequent cycle of study treatment (laboratory samples may be obtained up to 72 hours before 
start of study treatment administration on Day 1 of the treatment cycle).  If any urine pregnancy test is positive, study treatment will be delayed until the 
patient pregnancy status is confirmed by a serum pregnancy test.  If serum pregnancy test is positive, the patient will be permanently discontinued from 
study treatment. 
r Includes hepatitis B surface antigen, total hepatitis B core antibody, and hepatitis C virus antibody.  HIV testing should also be performed if required by 
local regulatory requirements.  
s See Appendix 4 for detailed schedule. 
t Includes circulating lymphoma cells and/or cell-free circulating tumor DNA. 
u Includes B-cell counts (CD19), T-cell counts (CD3, CD4, and CD8), and NK-cell counts (CD16 and CD56). 
v Requires separate patient consent for RCR participation.  Not applicable for a site that has not been granted approval for RCR sampling. 
w Availability of adequate archival (obtained within 6 months prior to the initiation of study treatment) or freshly biopsied tumor tissue samples should be 
confirmed at screening (see Section 4.5.6 for details). 
x A sample will be collected at the time of progression unless no adequate tumor site is accessible. 
y Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to the screening period until the EOI or EOM visit, whichever occurs later. 
z After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated intervention 
should be reported.  After initiation of study treatment, all adverse events will be reported until 90 days the last dose of study treatment.  After this period, 


 
 
Appendix 2 Schedule of Assessments for Patients with DLBCL (cont.) 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
210 
the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study treatment 
(see Section 5.6).  An exception is made for Grade 3–4 infections (related and unrelated), which should be reported until up to 2 years after the last dose of 
study treatment.  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as 
stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events 
considered to be related to any of the study treatment components or trial-related procedures until a final outcome can be reported.  
aa The screening PET-CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
bb Perform only for patients who have received at least 2 cycles of induction treatment. 
cc If PET-CT scan is positive at EOI, perform repeat PET-CT at EOC.  
dd CT scan of the neck (if clinically indicated), chest, abdomen and pelvis.  If contrast is medically contraindicated (e.g., patients with contrast allergy or 
impaired renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically indicated) and a non-contrast CT scan of the chest may be 
performed.  Combined PET/CT scanners may be used to collect diagnostic CT scans, but only according to the technical guidelines in the imaging manual.  
Screening CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
ee Perform within 7 days prior to Day 1 of Cycle 3. 
ff Perform only if not done within the previous 3 months. 
gg Perform every 6 months. 
hh Bone marrow biopsy and aspirate must be performed within 3 approximately months prior to Day 1 of Cycle 1. 
ii For patients with bone marrow involvement at screening, a repeat assessment will be performed at EOI if there is radiologic evidence of a complete 
response, and during consolidation and at EOC if clinically indicated (e.g., if there is clinical suspicion of progressive disease in the bone marrow with no 
radiologic evidence of progression). 
jj Refer to Section 4.3.2 for details on dosing and schedule. 






 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
213 
Appendix 3 Pharmacokinetic and Immunogenicity Sampling Schedule for Obinutuzumab 
Polatuzumab Vedotin, and Venetoclax in Relapsed or Refractory Follicular Lymphoma Patients 
(cont.) 
Study Visit 
Serum 
Obinutuzumab PK 
Samplea,b 
Serum Polatuzumab 
Vedotin PK Sample 
for Total  
Antibody a,b 
Plasma Polatuzumab 
Vedotin PK Sample 
for Antibody 
Conjugated MMAE 
and Unconjugated 
MMAE a 
Plasma Venetoclax 
PK Sample a, c 
Serum Obinutuzumab 
HAHA Samplea 
Serum Polatuzumab 
Vedotin ATA 
Sample a 
Maintenance Phase (Post-induction for FL Patients; 28-day cycles; 1 month = 28 days) 
Month 2 
Day 1 
Pre-infusion (within 5 
hr prior to dose) 
– 
– 
 
– 
– 
Month 8 
Day 1 
Pre-infusion (within 5 
hr prior to dose) 
– 
– 
– 
– 
– 
Month 14 
Day 1 
Pre-infusion (within 5 
hr prior to dose) 
– 
– 
– 
– 
= 
Month 20 
Day 1 
Pre-infusion (within 5 
hr prior to dose) 
– 
– 
– 
– 
– 
Treatment Discontinuation 
Anytime during visit 
Anytime during visit 
– 
– 
Anytime during visit 
Anytime during visit
 


 
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Appendix 3 Pharmacokinetic and Immunogenicity Sampling Schedule for Obinutuzumab 
Polatuzumab Vedotin, and Venetoclax in Relapsed or Refractory Follicular Lymphoma Patients 
(cont.) 
Study Visit 
Serum 
Obinutuzumab PK 
Samplea,b 
Serum Polatuzumab 
Vedotin PK Sample 
for Total  
Antibody a,b 
Plasma Polatuzumab 
Vedotin PK Sample 
for Antibody 
Conjugated MMAE 
and Unconjugated 
MMAE a 
Plasma Venetoclax 
PK Sample a, c 
Serum Obinutuzumab 
HAHA Samplea 
Serum Polatuzumab 
Vedotin ATA 
Sample a 
120 ± 30 days after last dose 
of obinutuzumab and 
polatuzumab (as appropriate 
for sample) 
Anytime during visit 
Anytime during visit 
– 
– 
Anytime during visit 
Anytime during visit
1-2 years after last dose of 
obinutuzumab 
Anytime during visit 
(if patient in clinic) 
Anytime during visit 
– 
– 
Anytime during visit (if 
patient in clinic) 
Anytime during visit 
(if patient in clinic) 
ATA = anti-therapeutic antibody; DLBCL = diffuse large B-cell lymphoma; EOI=end of infusion; FL = follicular lymphoma; HAHA = human anti-human antibody; 
hr = hour; min = minute; MMAE = mono-methyl auristatin E; “  −  “=not applicable; PK = pharmacokinetic.  
a Sample collection timing is relative to specified drug. 
b Samples collected for PK, HAHA, and ATA analysis may be used for additional PK, HAHA, and/or ATA assay development and validation, 
and additional immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist. 
c On venetoclax PK sampling visits, the venetoclax dose will be taken at the clinic appointment. 
d If the Cycle 1 Day 1 dose of obinutuzumab is split over two days, take the 30 minutes post-end of infusion obinutuzumab PK sample relative to 
the end of the infusion on Day 2 and ensure that the date and time of the PK collection are accurately recorded. 






 
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Appendix 4 Pharmacokinetic and Immunogenicity Sampling Schedule for Rituximab, 
Polatuzumab Vedotin, and Venetoclax in Relapsed or Refractory DLBCL Patients (cont.)  
Study Visit 
Serum Rituximab 
PK Sample a,b 
Serum Polatuzumab 
Vedotin PK Sample for 
Total Antibody a,b 
Plasma Polatuzumab 
Vedotin PK Sample 
for Antibody 
Conjugated MMAE 
and Unconjugated 
MMAE a 
Plasma Venetoclax 
PK Sample a,c 
Serum Polatuzumab 
Vedotin ATA 
Sample a 
Cycle 4 
Day 1 
Pre-infusion 
(within 5 hr prior 
to dose) 
Pre-infusion (within 5 
hr prior to dose) 
Pre-infusion (within 5 
hr prior to dose); 
30 ± 10 min after end 
of infusion 
Pre-dose (within 1 hr 
prior to dose) 
Pre-infusion (within 
5 hr prior to dose) 
Cycle 6 
(End of 
Induction) 
Day 1 
Pre-infusion 
(within 5 hr prior 
to dose); 
30 ± 10 min after 
end of infusion 
– 
Pre-infusion (within 5 
hr prior to dose) 
Pre-dose (within 1 hr 
prior to dose) 
– 
Consolidation Phase (Post-induction for DLBCL Patients; 28-day cycles; 1 month = 28 days) 
Treatment 
Discontinuation 
– 
Anytime during visit
 
– 
Anytime during visit
120 days after last dose 
of polatuzumab 
– 
Anytime during visit
– 
– 
Anytime during visit
1−2 years after last dose 
of polatuzumab 
– 
Anytime during visit
– 
– 
Anytime during visit


 
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Appendix 4 Pharmacokinetic and Immunogenicity Sampling Schedule for Rituximab, 
Polatuzumab Vedotin, and Venetoclax in Relapsed or Refractory DLBCL Patients (cont.)  
ATA = anti-therapeutic antibody; DLBCL = diffuse large B-cell lymphoma; EOI = end of infusion; hr = hour; min = minute; 
MMAE = mono-methyl auristatin E; “–“ = not applicable; PK = pharmacokinetic.  
a Sample collection timing is relative to specified drug. 
b Samples collected for PK and ATA analysis may be used for additional PK and ATA assay development and validation and additional 
immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist. 
c On venetoclax PK sampling visits, the venetoclax dose will be taken at the clinic appointment. 
d If the Cycle 1 Day 1 dose of rituximab is split over 2 days, take the 30 minutes post end of infusion rituximab PK sample relative to the 
end of the infusion on Day 2 and ensure that the date and time of the PK collection are accurately recorded. 


 
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Appendix 5 Modified Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) 
In this study, the designation of a complete response (CR) using positron emission tomography and computed tomography 
(PET-CT)−based response requires normal bone marrow by morphology for patients with bone marrow involvement at baseline.  If 
indeterminate by morphology, immunohistochemistry should be negative.  Additionally, designation of PET-CT−based PR requires 
that CT-based response criteria for a CR or PR be met in addition to the PET-CT−based response criteria for a PR. 
Revised Criteria for Response Assessment  
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3 a with or without a residual mass on 5PS b 
It is recognized that in Waldeyer’s ring or extranodal sites 
with high physiologic uptake or with activation within 
spleen or marrow (e.g., with chemotherapy or myeloid 
colony-stimulating factors), uptake may be greater than 
normal mediastinum and/or liver.  In this circumstance, 
complete metabolic response may be inferred if uptake 
at sites of initial involvement is no greater than 
surrounding normal tissue even if the tissue has high 
physiologic uptake. 
Target nodes/nodal masses must regress to  ≤ 1.5 cm in 
LDi 
No extralymphatic sites of disease 
Non-measured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if indeterminate, IHC negative 
 
 


 
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Appendix 5 Modified Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.) 
 
Revised Criteria for Response Assessment  
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Partial 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score 4 or 5 b with reduced uptake compared with baseline 
and residual mass(es) of any size 
≥ 50% decrease in SPD of up to 6 target measurable nodes 
and extranodal sites 
 
At interim, these findings suggest responding disease 
When a lesion is too small to measure on CT, assign 
5 mm × 5 mm as the default value 
 
At end of treatment, these findings indicate residual disease When no longer visible, 0 × 0 mm 
For a node  > 5 mm × 5 mm, but smaller than normal, use 
actual measurement for calculation 
Non-measured lesion 
Not applicable 
Absent/normal, regressed, but no increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by  > 50% in length beyond 
normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed).  If there are persistent focal changes in the 
marrow in the context of a nodal response, consideration 
should be given to further evaluation with MRI or biopsy 
or an interval scan. 
Not applicable 
 


 
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Appendix 5 Modified Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.) 
 
Revised Criteria for Response Assessment  
Response and Site 
PET-CT–Based Response 
CT-Based Response 
No response or stable disease  
No metabolic response 
Stable disease 
Target nodes/nodal masses, 
extranodal lesions 
Score 4 or 5 b with no significant change in FDG uptake 
from baseline at interim or end of treatment 
< 50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met 
Non-measured lesion 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
 


 
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Appendix 5 Modified Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.) 
 
Revised Criteria for Response Assessment  
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Progressive disease 
Progressive metabolic disease 
Progressive disease requires at least 1 of the following  
Individual target nodes/nodal 
masses 
Score 4 or 5 b with an increase in intensity of uptake from 
baseline and/or 
PPD progression: 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at interim or 
end-of-treatment assessment 
An individual node/lesion must be abnormal with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions  ≤ 2 cm 
1.0 cm for lesions  > 2 cm 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase 
beyond baseline (e.g., a 15-cm spleen must increase 
to > 16 cm).  If no prior splenomegaly, must increase by 
at least 2 cm from baseline. 
New or recurrent splenomegaly  
New or clear progression of preexisting non-measured 
lesions 
New lesions 
New FDG-avid foci consistent with lymphoma rather than 
another etiology (e.g., infection, inflammation); if 
uncertain regarding etiology of new lesions, biopsy or 
interval scan may be considered 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in 
any axis, its presence must be unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size unequivocally attributable 
to lymphoma 


 
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Appendix 5 Modified Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.) 
 
Revised Criteria for Response Assessment  
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; GI = gastrointestinal; IHC = immunohistochemistry; LDi = longest transverse 
diameter of a lesion; MRI = magnetic resonance imaging; PET = positron emission tomography; PPD = cross product of the LDi and perpendicular 
diameter; SDi = shortest axis perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for multiple lesions. 
a A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.  However, in trials 
involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment).  
Measured dominant lesions:  Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters.  Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas.  
Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation.  
Non-measured lesions:  Any disease not selected as measured; dominant disease and truly assessable disease should be considered not measured.  
These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to 
follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other 
lesions that cannot be confirmed and followed by imaging.  In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake 
may be greater than in the mediastinum with complete metabolic response, but should be no higher than surrounding normal physiologic uptake 
(e.g., with marrow activation as a result of chemotherapy or myeloid growth factors). 
b PET 5PS:  1 = no uptake above background; 2 = uptake ≤ mediastinum; 3 = uptake > mediastinum but ≤ liver; 4 = uptake moderately > liver; 5 = uptake 
markedly higher than liver and/or new lesions; X = new areas of uptake unlikely to be related to lymphoma.  
 


 
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Appendix 6 ECOG Performance Status Scale 
Grade 
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 housework or office work).
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about > 50% of waking hours. 
3 
Capable of only limited self-care; confined to a bed or chair > 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 7 Ann Arbor Staging 
Grade 
Description 
Stage I 
Involvement of a single lymph node region (I) or of a single 
extralymphatic organ or site (IE) a 
Stage II 
Involvement of two or more lymph node regions or lymphatic 
structures on the same side of the diaphragm alone (II) or with 
involvement of limited, contiguous extralymphatic organ or tissue 
(IIE) 
Stage III 
Involvement of lymph node regions on both sides of the diaphragm 
(III), which may include the spleen (IIIS) or limited, contiguous 
extralymphatic organ or site (IIIE), or both (IIIES) 
Stage IV b 
Diffuse or disseminated foci of involvement of one or more 
extralymphatic organs or tissues, with or without associated 
lymphatic involvement 
Note:  All cases are subclassified to indicate the absence (A) or presence (B) of the systemic 
B symptoms of significant unexplained fever (> 38°C), night sweats, or unexplained weight loss 
exceeding 10% of body weight during the 6 months prior to diagnosis. 
a The designation “E” generally refers to extranodal contiguous extension (i.e., proximal or 
contiguous extranodal disease) that can be encompassed within an irradiation field appropriate 
for nodal disease of the same anatomic extent.  A single extralymphatic site as the only site of 
disease should be classified as IE, rather than Stage IV. 
b Involvement of bone marrow at screening will always qualify for Ann Arbor Stage IV and 
should be recorded as extranodal involvement. 
Adapted from: 
Carbone PP, Kaplan HS, Musshoff K, et al. Report of the committee on Hodgkin’s disease 
staging classification. Cancer Res 1971;31:1860−1. 
Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the 
evaluation and staging of patients with Hodgkin’s disease: Cotswolds Meeting. J Clin Oncol 
1989;7:1630−6. 


 
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Appendix 8 Follicular Lymphoma International Prognostic 
Index and International Prognostic Index 
Table 1 Follicular Lymphoma International Prognostic Index 
FLIPI Risk Factor 
 
Ann Arbor Stage III or IV 
 
Age  > 60 years 
 
Serum LDH > 1 × ULN 
 
Anemia (hemoglobin  < 120 g/L) 
 
Involved nodal areas > 4 
 
 
 
FLIPI Risk Group 
Number of FLIPI Risk Factors 
Low 
0 or 1 
Intermediate 
2 
High 
3 to 5 
FDG = fluorodeoxyglucose; FLIPI = Follicular Lymphoma International Prognostic Index; 
PET = positron emission tomography; ULN = upper limit of normal. 
Note:  The results of FDG-PET should not be taken into account for calculation of FLIPI since this 
prognostic score was established without FDG-PET. 
Adapted from: 
Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. 
Blood 2004;104:1258–64. 
 


 
 
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Appendix 8 Follicular Lymphoma International Prognostic 
Index and International Prognostic Index (cont.)  
Table 2 Follicular Lymphoma International Prognostic Index 2 
FLIPI2 Risk Factor 
 
Bone marrow involvement 
 
Age > 60 years 
 
β2 microglobulin > 1 × ULN 
 
Anemia (hemoglobin  < 120 g/L) 
 
Longest diameter of largest involved node > 6 cm 
 
 
FLIPI2 Risk Group 
Number of FLIPI2 Risk Factors 
Low 
0  
Intermediate 
1 or 2 
High 
3 to 5 
FDG = fluorodeoxyglucose; FLIPI2 = Follicular Lymphoma International Prognostic Index 2; 
PET = positron emission tomography; ULN = upper limit of normal. 
Note:  The results of FDG-PET should not be taken into account for calculation of FLIPI2 since 
this prognostic score was established without FDG-PET. 
Adapted from: 
Federico M, Bellei M, Marcheselli L, et al. Follicular Lymphoma International Prognostic Index 2: 
a new prognostic index for follicular lymphoma developed by the International Follicular 
Lymphoma Prognostic Factor Project. J Clin Oncol 2009;27:4555−62. 
 


 
 
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Appendix 8 Follicular Lymphoma International Prognostic 
Index and International Prognostic Index (cont.)  
Table 3 International Prognostic Index 
IPI Risk Factor 
 
Ann Arbor Stage III or IV 
 
Age > 60 years 
 
Serum LDH  > 1 ×  ULN 
 
ECOG Performance Status ≥ 2 
 
Extranodal involvement ≥ 2 
 
 
IPI Risk Group 
Number of IPI Risk Factors 
Low 
0 or 1 
Low − Intermediate 
2 
High − Intermediate 
3 
High 
4 or 5 
ECOG = Eastern Cooperative Oncology Group; FDG = fluorodeoxyglucose; IPI = International 
Prognostic Index; PET = positron emission tomography; ULN = upper limit of normal. 
Note:  The results of FDG-PET should not be taken into account for calculation of IPI since this 
prognostic score was established without FDG-PET. 
Adapted from:   
Shipp MA, Harrington DP, Anderson JR, et al. A predictive model for aggressive non-Hodgkin’s 
lymphoma. N Engl J Med 1993;329:987−94. 


 
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Appendix 9 Anaphylaxis Precautions 
EQUIPMENT NEEDED 
• 
Tourniquet 
• 
Oxygen 
• 
Epinephrine for subcutaneous, intravenous (IV), and/or endotracheal use in 
accordance with standard practice  
• 
Antihistamines 
• 
Corticosteroids 
• 
IV infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, the 
following procedures should be performed: 
• 
Stop the study treatment infusion. 
• 
Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
treatment.  Do not obstruct arterial flow in the limb. 
• 
Maintain an adequate airway. 
• 
Administer glucocorticoids, antihistamines, epinephrine, or other medications as 
required by patient status and directed by the physician in charge. 
• 
Continue to observe the patient and document observations. 




 
 
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Appendix 10 Sample List of Excluded and Cautionary Medications (cont.)  
Note that this is not an exhaustive list.  For an updated list, see the following link:   
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm  
In addition to the medications listed in this table, subjects receiving venetoclax should not consume grapefruit, grapefruit products, Seville oranges 
(including marmalade containing Seville oranges), or Star fruits. 
* 
These are anticancer agents; consult Genentech/Roche Medical Monitor before use. 
 


 
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Appendix 11 Recommendations for Initial Management of 
Electrolyte Imbalances and Prevention of Tumor Lysis 
Syndrome  
Within the first 24 hours after the first dose of venetoclax, if any of the following 
laboratory criteria are met, the patient should be hospitalized for monitoring and the 
investigator notified.  No additional venetoclax doses should be administered until 
resolution.  A rising serum potassium level is a medical emergency. 
In the event of a suspected anaphylactic reaction during the study treatment infusion, the 
following procedures should be performed: 
• 
Nephrology (or acute dialysis service) must be consulted/contacted on admission 
(per institutional standards to ensure emergency dialysis is available). 
• 
IV fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at least 
1 mL/kg/h rounded to the nearest 10 mL (target:  150 to 200 mL/hr, not < 50 mL/hr).  
Modification of fluid rate should also be considered for individuals with specific 
medical needs. 
• 
Monitor for symptoms or signs of tumor lysis syndrome (TLS; e.g., fever, chills, 
tachycardia, nausea, vomiting, diarrhea, diaphoresis, hypotension, muscle aches, 
weakness, paresthesias, mental status changes, confusion, and seizures).  If any 
clinical features are observed, recheck potassium, phosphorus, uric acid, calcium, 
and creatinine immediately (within 1 hour). 
• 
Vital signs should be taken at time of all blood draws or any intervention. 
• 
The management recommendations below focus on the minimum initial responses 
required.  If a diagnosis of TLS is established, ongoing intensive monitoring and 
multidisciplinary management will be as per institutional protocols. 
 
Recommendations for initial management of patients with electrolyte imbalances and 
prevention of TLS are presented in the following table.  


 
 
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Appendix 11 Recommendations for Initial Management of 
Electrolyte Imbalances and Prevention of Tumor Lysis 
Syndrome (cont.)  
Abnormality 
Management Recommendations 
Hyperkalemia (including rapidly rising potassium) 
Potassium ≥ 0.5 mmol/L 
increase from prior value 
(even if potassium within 
normal limits [WNL]) 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour STAT.  If further ≥ 0.2 mmol/L increase in 
potassium, but still less than the ULN, manage as per potassium 
greater than or equal to the ULN.  Otherwise recheck in 1 hour. 
• 
Resume per protocol testing if change in potassium is 
< 0.2 mmol/L, and potassium less than the ULN, and no other 
evidence of tumor lysis. 
• 
At discretion of investigator, may recheck prior to hospitalization. 
If stable or decreased, and still WNL, hospitalization is at the 
discretion of the investigator.  Potassium, phosphorus, uric acid, 
calcium, and creatinine must be rechecked within 24 hours. 
Potassium > upper limit of 
normal 
• 
Perform ECG STAT and commence telemetry. 
• 
Nephrology notification with consideration of initiating dialysis 
• 
Administer Kayexalate 60 g (or Resonium A 60 g). 
• 
Administer furosemide 20 mg IV × 1. 
• 
Administer calcium gluconate 100 to 200 mg/kg IV slowly if there 
is ECG/telemetry evidence of life-threatening arrhythmias. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour STAT.  
• 
If potassium less than the ULN 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium, and creatinine 1, 2, and 4 hours 
later, if no other evidence of tumor lysis. 
Potassium ≥ 6.0 mmol/L 
(6.0 mEq/L) and/or 
symptomatic 
(e.g., muscle cramps, 
weakness, paresthesias, 
nausea, vomiting, 
diarrhea) 
• 
Perform ECG STAT and commence telemetry. 
• 
Nephrology assessment with consideration of initiating dialysis 
• 
Administer Kayexalate 60 g (or Resonium A 60 g). 
• 
Administer furosemide 20 mg IV × 1. 
• 
Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV. 
• 
Administer sodium bicarbonate 1 to 2 mEq/kg IV push. 
If sodium bicarbonate is used, rasburicase should not be 
used as this may exacerbate calcium phosphate 
precipitation. 
• 
Administer calcium gluconate 100 to 200 mg/kg IV slowly if there 
is ECG/telemetry evidence of life-threatening arrhythmias.  Do 
not administer in same IV line as sodium bicarbonate. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine every hour STAT. 
ECG = electrocardiogram; IV = intravenous; STAT = immediately; ULN = upper limit of normal; 
WNL = within normal limits. 


 
 
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Appendix 11 Recommendations for Initial Management of 
Electrolyte Imbalances and Prevention of Tumor Lysis 
Syndrome (cont.)  
Abnormality 
Management Recommendations 
Hyperuricemia 
Uric acid ≥ 8.0 mg/dL 
(476 µmol/L) 
• 
Consider rasburicase (dose per institutional guidelines). 
If rasburicase is used, sodium bicarbonate should not be used 
as this may exacerbate calcium phosphate precipitation. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour STAT. 
Uric acid ≥ 10 mg/dL 
(595 µmol/L) 
OR 
Uric acid ≥ 8.0 mg/dL 
(476 µmol/L) with 25% 
increase and creatinine 
increase ≥ 0.3 mg/dL 
(≥ 0.027 mmol/L) from 
pre-dose level 
• 
Administer rasburicase (dose per institutional guidelines). 
If rasburicase is used, sodium bicarbonate should not be used 
as this may exacerbate calcium phosphate precipitation. 
• 
Consult nephrology. 
• 
Recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour STAT. 
• 
If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium, and creatinine 2 and 4 hours 
later, if no other evidence of tumor lysis. 
Hypocalcemia 
Calcium ≤ 7.0 mg/dL 
(1.75 mmol/L) 
AND 
Patient symptomatic 
(e.g., muscle cramps, 
hypotension, tetany, 
cardiac arrhythmias) 
• 
Administer calcium gluconate 50 to 100 mg/kg IV slowly with 
ECG monitoring. 
• 
Telemetry. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour STAT. 
• 
If calcium normalized 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium, and creatinine 2 and 4 hours 
later, if no other evidence of tumor lysis. 
• 
Calculate corrected calcium and check ionized calcium if 
albumin low. 
ECG = electrocardiogram; IV = intravenous; STAT = immediately; ULN = upper limit of normal; 
WNL = within normal limits. 
 


 
 
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Appendix 11 Recommendations for Initial Management of 
Electrolyte Imbalances and Prevention of Tumor Lysis 
Syndrome (cont.)  
Abnormality 
Management Recommendations 
Hyperphosphatemia 
Phosphorus  ≥ 5.0 mg/dL 
(1.615 mmol/L) with 
≥ 0.5 mg/dL 
(0.16 mmol/L) increase 
• 
Administer a phosphate binder (e.g., aluminum hydroxide, 
calcium carbonate, sevelamer hydroxide, or lanthanum 
carbonate). 
• 
Nephrology notification (dialysis required for 
phosphorus ≥ 10 mg/dL) 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour STAT. 
• 
If phosphorus < 5.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium, and creatinine 2 and 4 hours 
later, if no other evidence of tumor lysis. 
Creatinine 
Increase ≥ 25% from 
baseline 
• 
Start or increase rate of IV fluids. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 to 2 hours STAT. 
ECG = electrocardiogram; IV = intravenous; STAT = immediately; ULN = upper limit of normal; 
WNL = within normal limits. 
 
ONGOING DOSING OF VENETOCLAX 
Management of electrolyte changes from last value at intervals > 24 hours after either 
the first dose (e.g., 48 or 72 hours) are as below.  Note:  If the patient is hospitalized, no 
additional venetoclax doses should be administered until resolution. 
• 
For potassium, admit patient for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or any 
level greater than the upper limit of normal. 
• 
Refer to the management guidelines for electrolyte changes observed within the 
first 24 hours after either the first dose or dose increase (table above). 
• 
If a smaller potassium increase is observed that does not meet the criteria for 
admission above, recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 24 hours and confirm no evidence of tumor lysis prior to further 
venetoclax dosing. 
• 
For uric acid, calcium, phosphorus, and creatinine, refer to the management 
guidelines for electrolyte changes observed within the first 24 hours after either the 
first dose or dose increase (see table above).


 
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Appendix 12 Clinical Studies of Study Drugs as Single Treatments and Part of Doublet Treatment 
Regimens 
TREATMENT REGIMENS FOR RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA 
 
Single Agents 
Doublet−Anti-CD20 +  
Polatuzumab Vedotin 
 
Obinutuzumab 
(Salles et al. 2013b) 
Polatuzumab Vedotin 
(Palanca-Wessels 
et al. 2015) 
Venetoclax 
(Study M12-175) a 
R +  
Polatuzumab Vedotin 
(Advani et al. 2015) 
G +  
Polatuzumab Vedotin 
(Study GO27834) 
N 
22 (20 FL, 1 MZL, 1 
SLL) 
47 
105 (all NHL) 
20 
46 (to be enrolled) 
Half-life 
29.7 days b 
5.33 days for 
acMMAE; 
6.35 days for TAb 
approximately 
3−6 days for 
unconjugated MMAE c 
17 hours 
 ⎯  
 ⎯   
Anti-CD20 dose 
G:  1600/800 mg 
 ⎯  
 ⎯  
R:  375 mg/m2 
q3w × 8 cycles 
G: 1000 mg D1, D8, 
D15 in C1, then D1 in 
C2−8 
Polatuzumab vedotin 
dose 
⎯  
2.4 mg/kg (n = 43) 
1.8 mg/kg (n = 4) 
 ⎯  
1.8 mg/kg 
1.8 mg/kg 
Venetoclax dose 
 ⎯  
 ⎯  
50−1200 mg QD 
 ⎯  
 ⎯  
ORR 
54.5% 
52% (DLBCL) 
53% (iNHL) 
57% 
75% 
Results not available 
CR/CRu 
9.1% 
10% (DLBCL) 
20% (iNHL) 
11% 
10% 
Results not available 
DoR 
17.2 months 
 ⎯  
 ⎯  
 ⎯  
Results not available 
PFS 
11.9 months 
151 days (DLBCL) 
264 days (iNHL) 
 ⎯  
Not reached 
Results not available 
 


 
 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
237 
Appendix 12 Clinical Studies of Study Drugs as Single Treatments and Part of Doublet Treatment 
Regimens (cont.) 
 
 
Single Agents 
Doublet−Anti-CD20 +  
Polatuzumab Vedotin 
 
Obinutuzumab 
(Salles et al. 2013b) 
Polatuzumab Vedotin 
(Palanca-Wessels et al. 
2015) 
Venetoclax 
(Study M12-175) a 
R +  
Polatuzumab Vedotin 
(Advani et al. 2015) 
G +  
Polatuzumab Vedotin 
(Study GO27834) 
Hematologic toxicity 
and infection (G3, G4) 
Neutropenia (n = 3) 
FN (n = 1) 
TCP (n = 1) 
infection (n = 1) 
Neutropenia (n = 5) 
Anemia (17.1%) 
lymphocyte decrease 
(14.3%) 
Neutropenia (35%) 
FN (10%) 
Results not available 
Neurotoxicity 
NR 
G1/2 (42%) 
G3/4 (10%) 
 ⎯  
G2/3/4 (25%) 
Results not available 
Abbreviations:  acMMAE = antibody conjugate mono methyl auristatin E; C = cycle; CR = complete response; CRu = complete response unconfirmed; 
D = day; DLBCL = diffuse large B-cell lymphoma; DoR = duration of response; FL = follicular lymphoma; FN = febrile neutropenia; G = obinutuzumab; 
G1/2 = Grade 1 or 2; G3/4 = Grade 3 or 4; G2/3/4 = Grade 2, 3, or 4; G3 = Grade 3; G4 = Grade 4; iNHL = indolent non-Hodgkin’s lymphoma; 
MMAE = mono-methyl auristatin E; MZL = marginal zone lymphoma; NHL = non-Hodgkin’s lymphoma; NR = not reported; q3w = every 3 weeks; QD = daily; 
ORR = objective response rate; PFS = progression-free survival; R = rituximab; SLL = small lymphocytic lymphoma; TAb = total antibody; 
TCP = thrombocytopenia. 
a Venetoclax Investigator’s Brochure. 
b Gazyva U.S. Prescribing Information. 
c Polatuzumab Vedotin Investigator’s Brochure. 
  
 
 


 
 
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238 
Appendix 12 Clinical Studies of Study Drugs as Single Treatments and Part of Doublet Treatment 
Regimens (cont.) 
 
TREATMENT REGIMENS FOR RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA 
 
Single Agents 
Doublet−Anti-CD20 +  
Polatuzumab Vedotin 
 
Obinutuzumab 
(Morschhauser et al. 
2013; Salles et al. 
2013b) 
Polatuzumab Vedotin 
(Palanca-Wessels 
et al. 2015) 
Venetoclax 
(Study 
M12-175)a 
R +  
Polatuzumab Vedotin 
(Morschhauser et al. 
2014) 
G +  
Polatuzumab Vedotin 
(Study GO27834) 
N 
19 
15 DLBCL, 4 MCL 
47 
105 (all NHL) 
39 
46 (to be enrolled) 
Half-life 
29.7 days b 
5.33 days for 
acMMAE 
6.35 days for TAb 
approximately 
3−6 days for 
unconjugated MMAEc 
17 hours 
 ⎯  
 ⎯   
Anti-CD20 dose 
G:  1600/800 mg 
 ⎯  
 ⎯  
R:  375 mg/m2  
G: 1000 mg D1,D8, D15 in 
C1, then D1 in C2−8 
Polatuzumab vedotin 
dose 
 ⎯  
2.4 mg/kg (n = 43) 
1.8 mg/kg (n = 4) 
 ⎯  
2.4 mg/kg 
1.8 mg/kg 
Venetoclax dose 
 ⎯  
 ⎯  
50−1200 mg QD 
 ⎯  
 ⎯  
ORR 
32% 
52% (DLBCL) 
53% (iNHL) 
57% 
56% 
Results not available 
CR/CRu 
0% 
10% (DLBCL) 
20% (iNHL) 
11% 
15% 
Results not available 
DoR 
9.8 months 
 ⎯  
 ⎯  
 ⎯  
Results not available 
PFS 
2.7 months 
151 days (DLBCL) 
264 days (iNHL) 
 ⎯  
5.4 months 
Results not available 
 


 
 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
239 
Appendix 12 Clinical Studies of Study Drugs as Single Treatments and Part of Doublet Treatment 
Regimens (cont.) 
 
 
Single Agents 
Doublet−Anti-CD20 +  
Polatuzumab Vedotin 
 
Obinutuzumab 
(Morschhauser et al. 
2013; Salles et al. 
2013b) 
Polatuzumab Vedotin 
(Palanca-Wessels et al. 
2015) 
Venetoclax 
(Study M12-175)a 
R +  
Polatuzumab Vedotin
(Morschhauser et al. 
2014) 
G +  
Polatuzumab Vedotin 
(Study GO27834) 
Hematologic 
toxicity and 
infection (G3, G4) 
Neutropenia (n = 1) 
 
Neutropenia (n = 5) 
Anemia (17.1%) 
lymphocyte 
decrease (14.3%) 
Neutropenia (24%) 
FN (10%) 
Results not available 
Neurotoxicity 
NR 
G1/2 (42%) 
G3/4 (10%) 
 ⎯  
Any grade (39%) 
Results not available 
Abbreviations:  acMMAE = antibody conjugate mono methyl auristatin E; C = cycle; CR = complete response; CRu = complete response unconfirmed; 
D = day; DLBCL = diffuse large B-cell lymphoma; DoR = duration of response; FN = febrile neutropenia; G = obinutuzumab; G1/2 = Grade 1 or 2; 
G3/4 = Grade 3 or 4; G2/3/4 = Grade 2, 3, or 4; G3 = Grade 3; G4 = Grade 4; iNHL = indolent non-Hodgkin’s lymphoma; MCL = mantle cell lymphoma; 
MMAE = mono-methyl auristatin E; NHL = non-Hodgkin’s lymphoma; NR = not reported; QD = daily; ORR = objective response rate; 
PFS = progression-free survival; R = rituximab; TAb = total antibody. 
a Venetoclax Investigator’s Brochure. 
b Gazyva U.S. Prescribing Information. 
c Polatuzumab Vedotin Investigator’s Brochure. 


 
Obinutzumab, Rituximab, Polatuzumab Vedotin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol GO29833, Version 4  
 
 
 
 
 
 
 
 
240 
 
 
Appendix 13 Diagnostic Criteria for Tumor Lysis Syndrome 
Lab Value 
Lab Value Threshold 
Uric acid 
≥ 476 μmol/L (8 mg/dL) 
Potassium 
≥ 6 mmol/L (6 mEq/L) 
Phosphorus 
≥ 1.45 mmol/L (4.5 mg/dL) 
Lab Changes 
Calcium 
≤ 1.75 mmol/L (7 mg/dL) 
2 or more of above lab changes or if change is more than 25% from baseline 
Occurs within 3 days before or 7 days after therapy 
Laboratory TLS 
Cairo-Bishop Definition 
Laboratory TLS accompanied by cardiac arrhythmia, sudden death, seizure, or acute 
renal failure (serum creatinine ≥ 1.5× ULN) 
Clinical TLS 
2 or more above lab changes occur simultaneously 
25% change is not a criteria 
Laboratory TLS 
Howard Definition  
(in addition to Cairo-Bishop 
definition) 
Symptomatic hypocalcemia 
Clinical TLS 
TLS = Tumor Lysis Syndrome; ULN = upper limit of normal.