Conditions: Relapsed or Refractory Follicular Lymphoma, Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 114
Healthy volunteers: no

Brief summary:
This study will evaluate the safety, efficacy, and pharmacokinetics of induction treatment with obinutuzumab, polatuzumab vedotin, and lenalidomide in participants with relapsed or refractory (R/R) follicular lymphoma (FL) and rituximab in combination with polatuzumab vedotin and lenalidomide in participants with R/R diffuse large B-cell lymphoma (DLBCL), followed by post-induction treatment with obinutuzumab in combination with lenalidomide in participants with FL who achieve a complete response (CR), partial response (PR), or stable disease (SD) at end of induction (EOI) and post-induction treatment with rituximab plus lenalidomide in participants with DLBCL who achieve a CR or PR at EOI.

Detailed description:

Arms:
arm 1: Participants with R/R FL will receive 6 months of induction treatment with polatuzumab vedotin and lenalidomide at escalating doses to identify the recommended Phase 2 dose (RP2D) for polatuzumab vedotin and lenalidomide when combined with a fixed dose of obinutuzumab. Those who achieve CR, PR, or SD at the EOI (6-8 weeks after Day 1 of Cycle 6) will be eligible to receive a 24-month maintenance regimen consisting of lenalidomide and obinutuzumab, to be initiated 8 weeks after Day 1 of Cycle 6 (induction cycle). arm 2: Participants with R/R DLBCL will receive 6 months of induction treatment with fixed dose of polatuzumab vedotin and rituximab along with dose escalating lenalidomide. Lenalidomide will be administered at escalating doses to identify the recommended Phase 2 dose (RP2D) for lenalidomide. Those who achieve CR and PR at the EOI (6-8 weeks after Day 1 of Cycle 6) will be eligible to receive a 6-month consolidation regimen consisting of lenalidomide and rituximab, to be initiated 8 weeks after Day 1 of Cycle 6 (induction cycle). arm 3: Participants with R/R FL who received induction treatment with polatuzumab vedotin and lenalidomide, in addition to obinutuzumab and achieved CR, PR, or SD at the EOI (6-8 weeks after Day 1 of Cycle 6) will receive a 24-months maintenance regimen consisting of lenalidomide and obinutuzumab for first 12 months followed by obinutuzumab treatment for next 12 months. Post-induction therapy will start 8 weeks after Cycle 6 Day 1. arm 4: Participants with R/R DLBCL who received induction treatment with polatuzumab vedotin and lenalidomide in addition to rituximab and achieved CR or PR at the EOI (6-8 weeks after Day 1 of Cycle 6) will receive a 6-month consolidation regimen consisting of lenalidomide and rituximab. Post-induction therapy will start 8 weeks after Cycle 6 Day 1.

Interventions: intervention 1: Lenalidomide intervention 2: Obinutuzumab intervention 3: Polatuzumab Vedotin intervention 4: Rituximab
Intervention descriptions: intervention 1: All participants will receive lenalidomide oral capsules at doses of 10, 15, or 20 milligrams (mg) on Days 1 to 21 of each 28-day cycle for up to 6 Cycles in dose escalation phase followed by post-induction treatment at a dose of 10 mg once daily on Days 1 to 21 of each subsequent 28-day cycle. Post-induction lenalidomide may continue for up to 12 months until disease progression or unacceptable toxicity for participants with R/R FL and up to 6 months until disease progression or unacceptable toxicity for participants with R/R DLBCL. intervention 2: Participants will receive a fixed dose of obinutuzumab, 1000 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 followed by post-induction treatment at a dose of 1000 mg via IV infusion on Day 1 of every other month for up to 24 months until disease progression or unacceptable toxicity. intervention 3: Participants with R/R FL will receive polatuzumab vedotin via IV infusion at doses of 1.4 or 1.8 milligrams per kilogram (mg/kg) on Day 1 of each 28-day cycle for up to 6 months during induction treatment. Participants wit R/R DLBCL will receive polatuzumab vedotin via IV infusion at dose 1.8 mg/kg on Day 1 of each 28-day cycle for up to 6 months during induction treatment. intervention 4: Participants will receive a fixed dose of rituximab, 375 mg/m\^2 via intravenous (IV) infusion to be given on Days 1 of Cycle 1 to 6 followed by post-induction treatment at a dose of 375 mg/m\^2 via IV infusion on Day 1 of every other month for up to 6 months, until disease progression or unacceptable toxicity.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: A Phase Ib/II Study Evaluating the Safety and Efficacy of 
Obinutuzumab in Combination With Polatuzumab Vedotin and 
Lenalidomide in Patients With Relapsed or Refractory Follicular 
Lymphoma and Rituximab in Combination With Polatuzumab Vedotin 
and Lenalidomide in Patients With Relapsed or Refractory Diffuse 
Large B-Cell Lymphoma 
NCT Number: NCT02600897 
Document Dates: Protocol Version 2: 19-January-2017 
 
 
 


 
Title
19-Jan-2017 19:13:19
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. 
 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
Protocol GO29834, Version 2 
PROTOCOL 
TITLE: 
A PHASE Ib/II STUDY EVALUATING THE SAFETY 
AND EFFICACY OF OBINUTUZUMAB IN 
COMBINATION WITH POLATUZUMAB VEDOTIN 
AND LENALIDOMIDE IN PATIENTS WITH 
RELAPSED OR REFRACTORY FOLLICULAR 
LYMPHOMA AND RITUXIMAB IN 
COMBINATION WITH POLATUZUMAB 
VEDOTIN AND LENALIDOMIDE IN PATIENTS 
WITH RELAPSED OR REFRACTORY DIFFUSE 
LARGE B-CELL LYMPHOMA 
PROTOCOL NUMBER: GO29834 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-001999-22 
IND NUMBER: 
109409 
TEST PRODUCT: 
Obinutuzumab (RO5072759) 
Rituximab (RO0452294) 
Polatuzumab vedotin (DCDS4501A; RO5541077) 
Lenalidomide 
MEDICAL MONITOR: 
, Pharm.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  4 August 2015 
DATE AMENDED: 
Version 2:  See electronic date stamp below 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
2/Protocol GO29834, Version 2 
PROTOCOL AMENDMENT, VERSION 2 
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 lenalidomide in combination with rituximab 
instead of obinutuzumab (see Section 3.1.3).  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 prednisolone or 
prednisone (CHOP) chemotherapy in patients with previously untreated DLBCL did 
not improve the primary endpoint of progression-free survival compared with the 
standard regimen of rituximab plus CHOP chemotherapy. 
The background (Sections 1.2 and 1.3), rationale (Sections 1.4 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 lenalidomide when combined with 
rituximab (375 mg/m2) and polatuzumab vedotin at the 1.8-mg/kg dose 
(Sections 3.1.2 and 3.1.3). 
• 
Rituximab will be provided by the Sponsor as an investigational medicinal product.  
This information 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 have been updated accordingly (Section 5.1.5).   
• 
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 latest Polatuzumab 
Vedotin Investigator’s Brochure, Version 7 (July 2016). 
• 
Collection of human anti-chimeric antibodies in relation to rituximab has been added 
as immunogenicity objective (Section 2.4, Section 4.5.6, and Appendix 2).  
• 
Clarification has been made that patients who experience a dose-limiting toxicity 
(DLT) during the DLT observation period may continue treatment if determined by 
investigator in consultation with Sponsor that it is safe to continue treatment and 
there is potential for clinical benefit in their judgment (Section 3.1.2.1). 
• 
The definitions of DLT criteria around non-hematologic toxicities have been clarified, 
including exceptions for events that are considered predictable, manageable per 
standard of care, and reversible on the basis of experience with individual study 
medications (Section 3.1.2.1.1). 
• 
Enrollment rules into the dose-escalation phase have been updated for patients’ 
safety considerations.  A sequential enrollment instead of a parallel enrollment will 
be used for each of the 2 dosing groups (i.e., the 3 patients in each cohort will be 
enrolled at least 48 hours apart; Section 3.1.2.1.3). 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
3/Protocol GO29834, Version 2 
• 
Inclusion criteria have been clarified for patients with R/R DLBCL who have been 
treated with a chemoimmunotherapy regimen that included an anti-CD20 
monoclonal antibody (Section 4.1.1). 
• 
The pregnancy prevention plan guidelines have been clarified for patients using 
lenalidomide (Section 4.1.1).  
• 
The period for contraception has been updated to align with each individual 
molecule (Section 4.1.1).  
• 
The exclusion of patients with Grade 3b follicular lymphoma and a history of 
transformation of indolent disease to DLBCL has been added in order to focus on a 
more homogenous patient population (Section 4.1.2). 
• 
The exclusion criteria of abnormal laboratory values for calculated creatinine 
clearance has been changed from 60 mL/min to 50 mL/min to allow patients with 
mild renal insufficiency to be enrolled (Section 4.1.2).   
• 
The classification of second malignancy has been changed from a selected adverse 
event to an adverse event of special interest in order to more closely monitor this 
adverse event.  The duration of reporting has been extended (Sections 5.3.1 
and 5.6).   
• 
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).   
• 
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 6 and Table 13 
have been updated accordingly.  
• 
Thyroid hormone monitoring (thyroid-stimulating hormone, triiodothyronine, 
thyroxine) has been added at baseline and every 3 months (Section 4.5.6, 
Appendix 1, and Appendix 2).  
• 
Recommendations on management of dermatologic toxicities has been updated to 
consider lenalidomide dose reduction or allow resuming current dose in the case of 
a Grade 2 or Grade 3 rash without blistering (Table 19).  
• 
Reasons for permanent discontinuation of all drugs in the event of certain 
dermatologic toxicities have been updated to align with lenalidomide labeling 
recommendations (Table 19).  
• 
Populations to be analyzed have been defined (Section 6.2). 
• 
Interim analysis has been clarified, including specification 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 safety objective has been clarified:  RP2D will not be determined for 
polatuzumab vedotin in patients with R/R DLBCL, as it will be a fixed dose 
(Section 2.1). 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
4/Protocol GO29834, Version 2 
• 
The secondary efficacy objective has been clarified:   Complete response (CR) at 
end of induction (EOI) on the basis of computed tomography (CT) alone is to be 
determined by the Independent Review Committee in addition to the investigator 
(Sections 2.2.2 and 6.6.2). 
• 
The exploratory efficacy objective has been clarified:   If a patient with DLBCL has a 
positive positron emission tomography (PET)-CT scan at EOI, then they should 
have PET-CT scan repeated at end of consolidation (Section 2.2.3, Section 6.6.3, 
and footnote ”jj” in Appendix 2). 
• 
The number of patients in the study has been updated (Sections 3.1.1, 3.1.2, 
and 6.1). 
• 
The prohibited therapies have been updated to clarify that vaccination with live 
vaccines is not recommended during treatment with obinutuzumab or rituximab and 
until B-cell recovery (Section 4.4.2). 
• 
Clarification has been made that tumor tissue samples at time of progression are 
only optional if investigator is unable to access the tumor site in order to promote 
obtaining samples (Section 4.5.6).  
• 
The Modified Lugano Criteria has been clarified for designation of PET-CT on the 
basis of partial response (PR) to also include requirement of a CR or PR on 
CT-based response criteria (Section 4.5.5; Appendix 5). 
• 
Post-treatment pregnancy testing time window has been clarified for lenalidomide at 
Days 14 and 28 following the last dose of study treatment (footnote ”p” in 
Appendix 1; footnote ”p” in Appendix 2). 
• 
Time window has been clarified for drawing β2 microglobiulin and quantitative IgA, 
IgG, and IgM as predose collections on C1D1 (footnote ”m” in Appendix 1; footnote 
”m” in Appendix 2). 
• 
Timing of when CBC should be monitored has been clarified to every week for first 
8 weeks of lenalidomide treatment (footnote ”m” in Appendix 1; footnote ”m” in 
Appendix 2).  
• 
Timing of when interim scan should be done has been clarified to within 7 days prior 
to Day 1 of Cycle 3 (footnote ”ff” in Appendix 1; footnote ”dd” in Appendix 2).   
• 
Pharmacokinetic and immunogenicity sampling schedule time windows have been 
clarified (Appendix 3 and Appendix 4). 
 
Substantive new information appears in italics.  Additional minor changes have been 
made to improve clarity and consistency.  This amendment represents cumulative 
changes to the original protocol. 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
5/Protocol GO29834, Version 2 
PROTOCOL AMENDMENT, VERSION 2: 
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 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.  
Obinutuzumab is currently being investigated in a large clinical program, including 
multiple head to head Phase III studies versus rituximab in indolent B cell lymphoma 
and DLBCL. 
SECTION 1.2.2:  Clinical Studies with Obinutuzumab 
To date, 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 studies (GAO4735g, BO21004/CLL11, MO28543, BO21223, and 
BO21005).  Available efficacy results from the non-Hodgkin’s lymphoma (NHL) cohorts 
in these studies and available safety results from all patients are summarized below.  In 
addition, two Phase III studies in patients with previously untreated CLL (Study BO21004) 
or rituximab refractory iNHL (Study GAO4753g) have reached their primary endpoint 
PFS.  Studies BO21223 (in previously untreated iNHL) and BO21005 (in previously 
untreated DLBCL) have passed futility analyses on efficacy, are ongoing, and remain 
blinded.   
SECTION 1.2.2.1:  Clinical Efficacy of Obinutuzumab in Patients with B-Cell 
Lymphoma 
In early studies of obinutuzumab in combination with chemotherapy (e.g., CHOP, 
bendamustine) in patients with previously untreated, or R/R B-cell lymphoma (Studies 
BO21000, GAO4915g, and GAO4753g), the proportion of patients with a CR or PR at 
the end of induction (EOI) 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. 
Phase III Study GAO4753g investigated obinutuzumab plus bendamustine (G-benda) 
compared with bendamustine alone in patients with rituximab-refractory indolent NHL 
(iNHL; n = 396).  Patients in the G-benda arm who had not experienced disease 
progression at EOI 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 G-benda arm, with a median investigator-assessed PFS of 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
6/Protocol GO29834, Version 2 
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).   
Phase III Study BO21223 investigated obinutuzumab plus chemotherapy (G-benda, 
obinutuzumab plus CVP [G-CVP], obinutuzumab plus CHOP [G-CHOP]) compared 
with rituximab plus chemotherapy, followed by obinutuzumab or rituximab 
maintenance in patients with previously untreated 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). 
Phase III Study BO21005 investigated 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 lenalidomide (Vitolo et al. 2016).   
SECTION 1.2.2.2:  Clinical Safety of Obinutuzumab 
As of 4 July 2016 To date, an estimated 36363484 patients with B-cell lymphoma 
(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 to 
2000 mg.  Overall, the safety of obinutuzumab monotherapy and obinutuzumab 
combination therapy was manageable. 
SECTION 1.3.2:  Clinical Studies with Polatuzumab Vedotin 
To date, clinical data on polatuzumab vedotin are available from one completed 
Phase I/Ib study (DCS4968g) one ongoing Phase Ib/II study (GO27834), and from one 
ongoing Ib/II study (GO29044) and the ongoing Phase Ib/II Studies GO27834, GO29044, 
GO29833, BO29561, and GO29365 in patients with B-cell lymphoma or CLL.   
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 rituximab plus 
cyclophosphamide, doxorubicin, and prednisone (R-CHP) or obinutuzumab plus 
cyclophosphamide, doxorubicin, and prednisone (G-CHP) in patients with newly 
diagnosed or R/R B-cell lymphoma.   


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
7/Protocol GO29834, Version 2 
GO29365 is evaluating polatuzumab vedotin in combination with bendamustine plus 
rituximab or obinutuzumab in patients with R/R FL or DLBCL.   
Available efficacy and safety results from these studies are summarized in 
Sections 1.3.2.1 and 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 focusing 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 Efficacy of Polatuzumab Vedotin in Patients with 
B-Cell 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. 
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 relapsed or refractory indolent B cell lymphoma (FL, MZL, or SLL) 
and 4.9 months (95% CI:  2.5, 6.7 months) for patients with relapsed or refractory 
DLBCL. 
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 those 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 show that for patients in Study GO27834 who received polatuzumab 
vedotin (2.4 mg/kg) in combination with rituximab overall responses were observed in 
14 of 20 patients with R/R FL (70%; 9 8 patients with CRs) and 21 22 of 39 patients with 
R/R DLBCL (54 56%;8 6 patients with CRs).  For patients who received polatuzumab 
vedotin (1.8mg/kg) in combination with rituximab, objective responses were observed in 
15 of 20 patients with FL (75%; 6 patients with CRs).   


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
8/Protocol GO29834, Version 2 
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 months) among the 39 patients with DLBCL.  Among the 20 patients with 
R/RFL treated with 1.8 mg/kg polatuzumab vedotin in combination with rituximab, the 
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 patient with CR) when 
combined with obinutuzumab. 
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). 
SECTION 1.3.2.2:  Clinical Safety of Polatuzumab Vedotin 
Clinical safety data are available from 180327 patients with B-cell lymphoma 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 G-CHP or R-CHP (GO29044), or 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 and 1.4 mg/kg) in 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
9/Protocol GO29834, Version 2 
combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone 
(R CHP) in Study GO29044.  Efficacy 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 
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 G-CHP or R-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 rituximab 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 deaths in patients treated with polatuzumab vedotin 
combined with rituximab or obinutuzumab.  The majority of deaths were judged as 
related to disease progression. 
Limited safety data from 7 patients receiving single agent polatuzumab vedotin in an 
ongoing Phase I study (JO29138) are provided in the polatuzumab vedotin Investigator's 
Brochure. 
SECTION 1.4:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
This study will evaluate the activity of a novel triplet combination of obinutuzumab or 
rituximab plus polatuzumab vedotin and lenalidomide. 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
10/Protocol GO29834, Version 2 
[…] 
Obinutuzumab has shown superiority over rituximab in a Phase III study in first-line CLL 
(Goede et al. 2014).    Obinutuzumab is being compared with rituximab in two large 
Phase III studies in patients with previously untreated DLBCL (Study BO21005) or 
previously untreated indolent B cell lymphomas, including FL (Study BO21223).  
Assuming these studies demonstrate greater clinical benefit with obinutuzumab  versus 
rituximab containing regimens, potentially altering the standard of care in B cell 
lymphoma, it will be important to also assess the safety and efficacy of incorporating 
obinutuzumab into treatment regimens.  A fourth Obinutuzumab showed clinical benefit 
compared to rituximab when combined with chemotherapy in a Phase III trial 
(BO21223) in patients with previously untreated indolent B-cell lymphomas, including 
FL (Marcus et al. 2016).  A Phase III study, GAO4753g, evaluated patients with 
rituximab-refractory indolent B-cell lymphoma, including patients with FL, and showed 
improvement in PFS with obinutuzumab  added to bendamustine followed by 
obinutuzumab maintenance compared with bendamustine alone (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 
(BO21005) comparing R-CHOP to G-CHOP in patients with previously untreated 
DLBLC (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 lenalidomide.   
[…] 
On the basis of the distinct mechanisms of action (MOAs) for each molecule and the 
current available clinical data, there is a strong rationale to expect an improved 
benefit-risk profile with the triplet combination of obinutuzumab or rituximab plus 
polatuzumab vedotin and lenalidomide.  This novel triplet regimen may have the 
potential to extend treatment-free remissions and to decrease toxicity by improving upon 
individual agents used as part of current standard of care, which includes traditional 
chemotherapy.  Early clinical data that evaluated obinutuzumab, rituximab, 
polatuzumab vedotin, and lenalidomide each as single-agents has been associated with 
neutropenia.  Rituximab and polatuzumab vedotin and rituximab and lenalidomide 
doublet combinations have also been associated with neutropenia.  The replacement of 
rituximab with obinutuzumab (Study GO27834 [obinutuzumab plus polatuzumab vedotin 
{G + Pola}] and GALEN [obinutuzumab plus lenalidomide {G + Len}]) in these doublets is 
anticipated to be associated with treatment-related neutropenia.  Patients with 
overlapping toxicities will be closely monitored; such events are expected to be 
manageable in the clinical setting, and drug-drug interactions (DDIs) are unlikely to 
occur (see Sections 5.1.5 and 5.1.6). 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
11/Protocol GO29834, Version 2 
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 lenalidomide 
(G + Pola + Len) in patients with R/R FL or DLBCL and rituximab in combination with 
polatuzumab vedotin and lenalidomide (R + Pola + Len) in patients with R/R DLBCL, 
followed by post-induction treatment with G + Len (referred to as maintenance) in patients 
with FL who achieve a CR, PR, or stable disease at EOI and post-induction treatment 
with rituximab plus lenalidomide (R + Len; 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 below. 
In this study, "study treatment" refers to the protocol-mandated treatments under study 
(i.e., obinutuzumab, rituximab, polatuzumab vedotin, and lenalidomide). 
SECTION 2.1:  SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To determine the RP2Ds for polatuzumab vedotin and lenalidomide when given in 
combination with a fixed dose of obinutuzumab and the RP2D of lenalidomide when 
given in combination with a fixed dose of polatuzumab vedotin and rituximab 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 + Len and R + Pola + Len on the 
basis of the following endpoints 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 
SECTION 2.2.1:  Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of induction 
treatment with G + Pola + Len in R/R FL and R + Pola + Len in 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 induction 
treatment with G + Pola + Len and maintenance treatment with G + Len in R/R FL and of 
induction treatment with R + Pola + Len and consolidation treatment with R + Len in 
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 
 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
12/Protocol GO29834, Version 2 
SECTION 2.2.3:  Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
G + Pola + Len and R + Pola + Len 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 end of consolidation (EOC), as determined by the IRC and by the 
investigator on the basis of PET-CT scans, in DLBCL patients 
 
SECTION 2.3:  PHARMACOKINETIC OBJECTIVE 
The PK objective for this study is to characterize the PK profiles of obinutuzumab, 
rituximab, polatuzumab vedotin, and lenalidomide when given in combination on the 
basis of the following endpoints: 
• 
Observed serum obinutuzumab concentration at specified timepoints 
• 
Observed serum rituximab concentration at specified timepoints 
• 
Observed serum and plasma concentrations of polatuzumab vedotin and relevant 
analytes (TAb, acMMAE, and unconjugated MMAE) at specified timepoints 
• 
Observed plasma lenalidomide concentration at specified timepoints 
 
SECTION 2.4:  IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to 
obinutuzumab, rituximab, 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 human anti-chimeric antibodies (HACAs) to rituximab during the 
study relative to the prevalence of HACAs at baseline 
• 
Incidence of 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 HACAs, and or ATAs on the basis of the following 
endpoint: 
• 
Correlation between HAHA or HACA, and or ATA status and respective efficacy, 
safety, or PK endpoints 
 
SECTION 3.1.1:  Overview of Study 
This Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study will 
evaluate the safety, efficacy, and pharmacokinetics of G + Pola + Len in patients with R/R 
FL or and R + Pola + Len in patients with R/R DLBCL.   


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
13/Protocol GO29834, Version 2 
The study will include an initial dose-escalation phase designed to determine the RP2D 
for polatuzumab vedotin and the RP2D for lenalidomide in this treatment combination 
(see Section 3.1.2), followed by an expansion phase, during which polatuzumab vedotin 
and lenalidomide will be given at their RP2Ds (see Sections 3.1.2 and 3.1.2.2).   
Approximately 98−116110−128 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 (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 lenalidomide, blood samples will be obtained at various timepoints before and 
during study treatment administration. 
FIGURE 1:  Study Schema 
Figure 1 has been revised to add rituximab and to clarify maintenance and consolidation 
treatment. 
SECTION 3.1.2:  OBINUTUZUMAB PLUS POLATUZUMAB VEDOTIN PLUS 
LENALIDOMIDE TREATMENT GROUP (PATIENTS WITH FOLLICULAR 
LYMPHOMA) (NEW HEADING) 
This section heading has been added to differentiate the FL and DLBCL groups.  Further 
changes to this section are summarized as follows. 
SECTION 3.1.2.1:  Dose-Escalation Phase 
The purpose of the FL dose-escalation phase is to identify the RP2D for polatuzumab 
vedotin and the RP2D for lenalidomide when combined with a fixed dose of 
obinutuzumab as induction treatment.  This These dose-escalation phase will include 
FL patients only; these patients may receive post-induction treatment if eligible (see 
Section 3.3.1).   
Approximately 18−3330 patients will be enrolled in the FL 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 3.1.2.1.3. 
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 below (see Section 3.1.2.1.1), 
will be reported to the Sponsor within 24 hours (see Section 5.4.2).  


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
14/Protocol GO29834, Version 2 
Patients experiencing a DLT during the DLT assessment period will permanently 
discontinue study treatment. may continue receiving study treatment once the event has 
resolved, if determined by investigator in consultation with Sponsor that it is safe to 
continue treatment and there is potential for clinical benefit in their judgment.   
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 or more doses of polatuzumab vedotin or 
obinutuzumab or five consecutive daily doses of lenalidomide 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 do not receive all study 
treatment for any reason will also be replaced.  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 3.1.2.1.1:  Definition of Dose-Limiting Toxicity 
In this study, a DLT is defined as any one of the following events occurring during the 
first cycle of treatment and assessed by the investigator as related to study treatment 
that is not attributed to disease progression or another clearly identified cause: 
• 
Adverse Any adverse event of any grade that leads to a delay of > 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 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 fatigue that resolves to Grade ≤ 2 within 7 days 
– 
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 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
15/Protocol GO29834, Version 2 
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 
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 to be clinically 
relevant and related to study treatment, as determined by the investigator and the 
Medical Monitor may also be considered DLTs. 
SECTION 3.1.2.1.1:  Treatment Regimens for the Follicular Lymphoma 
Dose-Escalation Phase 
The section title was revised to clarify that this phase is specific to the FL cohort. 
TABLE 1:  Post-Induction Treatment for the Follicular Lymphoma 
Expansion Phase  
The Table 1 title was revised to clarify that this phase is specific to the FL cohort. 
TABLE 2:  Maintenance Treatment for the Follicular Lymphoma Dose-
Escalation Phase 
The Table 2 title was revised to clarify that this phase is specific to the FL cohort. 
SECTION 3.1.2.1.3:  Dose-Escalation Rules 
A standard 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 1 are 1.4 mg/kg for polatuzumab vedotin and 10 mg for lenalidomide.  In 
Cohorts 2−6, dose escalation of polatuzumab vedotin and lenalidomide will proceed in 
increments that parallel the magnitude of dose increases tested in ongoing Phase Ib 
studies (see Sections 3.3.3.2 and 3.3.3.2.2).  For polatuzumab vedotin, there are two 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
16/Protocol GO29834, Version 2 
possible dose levels:  1.4 or 1.8 mg/kg.  For lenalidomide, there are three possible dose 
levels (10, 15, or 20 mg).  Intrapatient dose escalation is not allowed.  The overall FL 
dose-escalation plan is depicted in Figure 2, and the doses for each cohort are 
summarized in Table 3.   
[…] 
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.   
[…] 
Relevant demographic, adverse event, laboratory, dose 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 IMC in 
consultation with the Principal Investigator and participating investigators.   
Although the DLT assessment window is defined as the first treatment cycle, cumulative 
or late toxicities occurring beyond the first cycle may be considered when determining 
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 2:  Follicular Lymphoma Dose-Escalation Plan 
The Figure 2 title was revised to clarify that this phase is specific to the FL cohort. 
TABLE 3:  Follicular Lymphoma Dose-Escalation Cohorts 
The Table 3 title was revised to clarify that this phase is specific to the FL cohort. 
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 lenalidomide 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. 
[…] 
Patients with DLBCL who achieve a CR or PR at EOI will receive post induction 
treatment (referred to as consolidation) with obinutuzumab and lenalidomide, and p 
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 
lenalidomide, as outlined in Table 5.  Polatuzumab vedotin will not be given during the 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
17/Protocol GO29834, Version 2 
post-induction phase.  Post-induction treatment should start 8 weeks (±1 week) after 
Day 1 of the final cycle of induction and will continue until disease progression or 
unacceptable toxicity, for up to 6 months for consolidation treatment and 24 months for 
maintenance treatment. 
TABLE 4:  Induction Treatment for Follicular Lymphoma Expansion Plan 
The Table 4 title was revised to clarify that this phase is specific to the FL cohort. 
TABLE 5:  Post-Induction Treatment for the Follicular Lymphoma 
Expansion Phase  
Table 5 has been revised to clarify that this phase is specific to the FL cohort and to 
remove the regimen for patients with DLBCL. 
SECTION 3.1.3:  Rituximab plus  Polatuzumab Vedotin plus  Lenalidomide 
Treatment Group (Patients with Relapsed or Refractory 
Diffuse Large B-Cell Lymphoma) (NEW SECTION) 
Based on the safety and efficacy results from the Phase III BO21005 study in patients 
with DLBCL, the protocol has been amended to explore dose-finding of lenalidomide 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 (NEW SECTION) 
The DLBCL dose-escalation phase will open with the purpose of identifying the RP2D 
for lenalidomide 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 lenalidomide 10-mg dose level and increase through Cohorts A, B, 
and C (see Figure 3).   
Approximately 12−18 patients will be enrolled in the R/R DLBCL dose-escalation phase.  
Cohorts of 3−6 patients each will be treated in accordance with the treatment regimens 
and dose-escalation rules described below.   
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 below (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 or more doses of polatuzumab 
vedotin or rituximab or five consecutive daily doses of lenalidomide 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 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
18/Protocol GO29834, Version 2 
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 + Len for a total of six cycles.  
Patients achieving a CR or PR at EOI will be eligible to receive consolidation treatment 
with R + Len.  A study schema is provided in Figure 1.   
Treatment Regimens for DLBCL Dose-Escalation Phase 
Patients enrolled in the DLBCL-dose-escalation phase will receive induction treatment, 
administered in 28-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:  
lenalidomide, rituximab, and polatuzumab vedotin.   
Patients who achieve a CR or PR at EOI will receive consolidation treatment with 
R + Len, as outlined in Table 7.  Polatuzumab vedotin will not be given as maintenance 
treatment.  Consolidation treatment should start 8 weeks (± 1 week) after Day 1 of 
Cycle 6 and will continue for 6 months until disease progression or unacceptable 
toxicity.  
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 
lenalidomide 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 3.   
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 lenalidomide in the R + Pola + Len 
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 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
19/Protocol GO29834, Version 2 
the combination MTD (i.e., the MTDs lenalidomide in the R + Pola + Len 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 lenalidomide in the R + Pola + Len treatment combination. 
 
If the MTD is exceeded in any cohort, de-escalation of the lenalidomide dose and/or 
polatuzumab vedotin dose, and/or adjustment of treatment schedules (e.g., lenalidomide 
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, dose administration/intensity, and 
PK (if available) data will be reviewed prior to dose-escalation decisions, which will be 
objectively 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, 
cumulative or late toxicities occurring beyond the first cycle may be considered when 
determining 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.   
TABLE 6:  Induction Treatment for the DLBCL Dose-Escalation Phase 
Table 6 has been added.  Subsequent tables have been renumbered accordingly. 
TABLE 7:  Consolidation Treatment for the Dose-Escalation Phase  
Table 7 has been added.  Subsequent tables have been renumbered accordingly. 
FIGURE 3:  DLBCL Dose-Escalation Plan 
Figure 3 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 lenalidomide 
when combined with a fixed dose of rituximab and polatuzumab vedotin in DLBCL 
patients.  


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
20/Protocol GO29834, Version 2 
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:  lenalidomide, rituximab, and 
polatuzumab vedotin. 
Patients with DLBCL who achieve a CR or PR at EOI will receive post-induction 
treatment (referred to as consolidation) with rituximab and lenalidomide as outlined in 
Table 10.  Polatuzumab vedotin will not be given during the post-induction phase.  
Post-induction treatment should start 8 weeks (± 1 week) after Day 1 of the final cycle 
of induction and will continue until disease progression or unacceptable toxicity, for up 
to 6 months for consolidation treatment. 
TABLE 9:  Induction Treatment for the DLBCL Expansion Phase 
Table 9 has been added.  Subsequent tables have been renumbered accordingly. 
TABLE 10:  Post-Induction 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 patients with FL have been followed for at least 90 days after they have 
completed or discontinued study treatment (including induction treatment and 
maintenance treatment as applicable).  
 
SECTION 3.3.1:  Rationale for Patient Population 
On the basis of a compelling biologic and clinical rationale, as presented in Section 1.4, 
the addition of polatuzumab vedotin to obinutuzumab or rituximab and lenalidomide is a 
promising approach to expand the number of patients with R/R FL and DLBCL who 
achieve remission and to prolong response duration 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 lenalidomide and 
the RP2D dose for polatuzumab vedotin when given with obinutuzumab in patients with 
R/R FL and the RP2D for lenalidomide 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.  The doses identified 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
21/Protocol GO29834, Version 2 
in patients with FL during the dose escalation phase will then be applied to patients in 
the expansion phase (including patients with FL and DLBCL), where efficacy data will be 
collected and safety will be continually monitored. 
SECTION 3.3.2:  Rationale for the Triplet Combination 
As discussed in Section 1.4, there is a strong MOA and clinical rationale to expect an 
improved benefit-risk profile with the triplet combination of obinutuzumab or rituximab, 
polatuzumab vedotin, and lenalidomide over standard immunochemotherapy regimens.  
The hypothesis is that 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 5.1.5).  
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 is anticipated to be demonstrated in two 
additional Phase III studies in DLBCL and FL.   
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 G-CHOP compared with 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, patients with R/R FL in this 
current protocol amendment will continue to receive obinutuzumab in combination 
with polatuzumab vedotin and lenalidomide, while patients with R/R DLBCL will 
instead receive rituximab in combination with polatuzumab vedotin and lenalidomide. 
SECTION 3.3.2.1:  Rituximab and Polatuzumab Vedotin Combination 
During its early development, polatuzumab vedotin treatment has been investigated as a 
single agent and in combination with rituximab.  On the basis of available Phase I and II 
data (see Section 3.3.3.2 and Appendix 11), polatuzumab vedotin as a single agent and 
combined with rituximab has shown clinical activity in heavily pretreated patients with 
R/R B-cell lymphoma (Palanca-Wessels et al. 2012; Morschhauser et al. 2014a).  In 
both studies, patients received rituximab 375 mg/m2 and polatuzumab vedotin up to 2.4 
mg/kg Q3W for up to 1 year, progression, or unacceptable toxicity.  The ongoing Study 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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GO27834 has also shown preliminary safety and efficacy results evaluating the 
combination of rituximab and polatuzumab vedotin 1.8 mg/kg.   
SECTION 3.3.2.2:  Obinutuzumab and Polatuzumab Vedotin Combination 
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 relapsed or refractory DLBCL and in relapsed or refractory B cell 
lymphoma and previously untreated DLBCL.    As these new data emerge, these will be 
assessed and applied to update this study, if required.  Preliminary results from these 
studies show safety and efficacy at the polatuzumab vedotin 1.8-mg/kg dose level when 
combined with obinutuzumab, every 3 weeks for 6−8 cycles as described in Section 
1.3.2.  
SECTION 3.3.3.1:  Rationale for Obinutuzumab Dose and Schedule in 
Patients with Follicular Lymphoma   
The dose and schedule for obinutuzumab in this study will be fixed for the induction and 
the maintenance (FL) or consolidation (DLBCL) components of the study, and 
obinutuzumab will not be dose-escalated.  This is based on the recommended dose and 
schedule (6−8 cycles depending on the trial) of obinutuzumab in the ongoing from the 
Phase III program in patients with B-cell lymphoma.   
[…] 
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 
Study GAO4753g (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 a 
total of 3 doses.  The consolidation regimen was modeled after the FL maintenance 
therapy.  
SECTION 3.3.3.2.1:  Rationale for Polatuzumab Vedotin Dose in Patients 
with Follicular Lymphoma   
For this study, dose escalation of polatuzumab vedotin for patients with R/R FL will 
begin at a dose level of 1.4 mg/kg (one dose level below the highest allowed 
polatuzumab vedotin dose currently under development) and will escalate to a final 
dose of 1.8 mg/kg, if tolerated.  The initial polatuzumab vedotin dose and schedule for 
this study were 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 relapsed and refractory B-cell 
lymphoma, the majority of which had FL or DLBCL.  Most evidence of anti-tumor activity 
was observed at doses  ≥ 1.8 mg/kg alone or in combination with rituximab.  
[…] 


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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 relapsed or refractory DLBCL and in relapsed or refractory B cell lymphoma 
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 combinedin combination with G-CHP.  
In Study GO29365, the starting dose of polatuzumab vedotin is 1.8 mg/kg when 
combined with obinutuzumab and bendamustine.  Since polatuzumab vedotin is being 
combined with obinutuzumab and chemotherapy (CHP or bendamustine) at 1.4 or 
1.8 mg/kg, for patients with R/R FL in this study, dose escalation of polatuzumab 
vedotin will begin at a dose level of 1.4 mg/kg (one dose level below the highest allowed 
polatuzumab vedotin dose level in clinical development) and will escalate to a final dose 
of 1.8 mg/kg, if tolerated.  This novel triplet, G + Pola + Len, substitutes out the standard 
chemotherapy components with lenalidomide, 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 + Obinutuzumab−Containing Regimens 
for the Treatment of Follicular Lymphoma  
Table 11 has been revised to specify the FL patient population and remove the DLBCL 
patient population.  Subsequent tables have been renumbered accordingly. 
SECTION 3.3.3.2.2:  Rationale for Polatuzumab Vedotin Dose in Patients 
with DLBCL (NEW SECTION) 
On the basis of the preliminary data from the patients with DLBCL treated in 
Studies GO29044 and GO29365, the dose level of polatuzumab vedotin at 1.8 mg/kg 
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 preferred to 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 at 1.8 mg/kg and 
lenalidomide; hence, in this amendment, the R/R DLBCL dose-escalation phase will 
start at the dose level of 1.8 mg/kg and only the lenalidomide dose will be escalated to 
determine an RP2D in this population.    


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SECTION 3.3.3.2.3:  Rationale for Polatuzumab Vedotin Dosing Schedule 
in Patients with Follicular Lymphoma and DLBCL 
The number of induction cycles (six 2128-day cycles) of the G + Pola + Len regimen that 
will be evaluated in this study is consistent with rituximab plus lenalidomide and 
obinutuzumab plus lenalidomide regimens used to treat B cell lymphoma. is in line with 
other anti-CD20 plus polatuzumab vedotin regimens studied in R/R NHL.   
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, 6 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 three 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 phase For G + Pola + Len treatment 
group:  R/R FL after treatment with at least one 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 lymphoma classified as either of the 
following:For R + Pola + Len treatment group:   
Relapsed or refractory FL after treatment with at least one 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 
R/R DLBCL after treatment with at least one prior chemoimmunotherapy 
regimen that included an anti-CD20 monoclonal antibody in patients who are 
not eligible for autologous stem-cell transplantation or who have experienced 
disease progression following treatment with high-dose chemotherapy plus 
autologous stem-cell transplantation 
• 
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-needle, excisional, or incisional tumor biopsy is required.  Cytological or 
fine-needle aspiration samples are not acceptable.  


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If the patient received anti-lymphoma treatment between the time of the most 
recent available biopsy and initiation of study treatment, a repeat core-needle 
biopsy is strongly recommended.   
Further details are provided in Section 4.5.6.   
• 
Agreement to comply with all local requirements of the lenalidomide risk 
minimization plan 
In every country where lenalidomide has been approved, a risk minimization 
plan, which includes a pregnancy prevention program, is in place.  The risk 
minimization plan should be followed by patients using lenalidomide. 
US sites only:  Per standard Revlimid REMS™ requirements, all physicians 
who prescribe lenalidomide for research subjects enrolled in this study and all 
research subjects enrolled in this study must be registered in and must comply 
with all requirements of the Revlimid REMS™ program.  
For Ex-US sites only:  Subjects will be counseled on pregnancy prevention 
prior to medication being dispensed to ensure that the subject has complied 
with all requirements, including use of birth control and pregnancy testing, 
and that the subject understands the risks associated with lenalidomide.  This 
step will be documented with a completed Education and Counseling Guidance 
Document (refer to Lenalidomide Pregnancy Prevention Risk Management 
Plans), and no drug will be dispensed until this step occurs.  Counseling 
includes verification with the subject that required pregnancy testing was 
performed and results were negative.  A Lenalidomide Information Sheet (refer 
to Lenalidomide Pregnancy Prevention Risk Management Plans) will be 
supplied with each medication dispensed.  All requirements must be followed 
by each site as noted within the Lenalidomide Pregnancy Prevention Risk 
Management Plans. 
In addition, because lenalidomide will be administered in combination with 
obinutuzumab, rituximab, and polatuzumab vedotin, patients must comply with 
contraceptive measures designed to ensure safe administration of all three 
study treatments as outlined below.  
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including 
at least one method with a failure rate of < 1% per year, for at least 28 days prior to 
Day 1 of Cycle 1, during the treatment period (including periods of treatment 
interruption), and for at least 12 months after the last dose of polatuzumab vedotin, 
28 days after the last dose of lenalidomide, 12 months after the last dose of 
rituximab, and 18 months after the last dose of obinutuzumab study treatment 
• 
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: 


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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, 28 days after the last dose 
of lenalidomide, and 3 months after the last dose of obinutuzumab or rituximab.  
study treatment.  Men must refrain from donating sperm during this 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, 28 days after the last dose of lenalidomide, and 3 months 
after the last dose of obinutuzumab or rituximab study treatment to avoid 
exposing the embryo. 
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 
• 
Grade 3b follicular lymphoma 
• 
History of transformation of indolent disease to DLBCL 
• 
Prior standard or investigational anti-cancer therapy as specified below: 
Lenalidomide, fludarabine, or alemtuzumab within 12 months prior to Day 1 of 
Cycle1 
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 obinutuzumab, 
rituximab, polatuzumab vedotin, or lenalidomide 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. 
• 
Any of the following abnormal laboratory values (unless due to underlying 
lymphoma): 
Calculated creatinine clearance < 6050 mL/min (using the Cockcroft-Gault 
formula; see Appendix 7) 
 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT 
This is a Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study of 
G + Pola + Len in patients with R/R FL or and R + Pola + Len in patients with R/R DLBCL.  
During the dose-escalation phase, patients with relapsed or refractory FL will be 


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assigned to cohorts with varying polatuzumab vedotin (R/R FL dose-finding only) and 
lenalidomide dose combinations, through use of an interactive voice or web-based 
response system (IxRS).  During the FL expansion phase, all patients with R/R FL will 
receive obinutuzumab in combination with lenalidomide at the FL RP2D and 
polatuzumab vedotin at the RP2D as induction treatment.  During the DLBCL 
expansion phase, patients with R/R DLBCL will receive rituximab and polatuzumab in 
combination with lenalidomide at the DLBCL RP2D.  Post-induction treatment (for 
eligible patients only) will depend on lymphoma histology.  Patients with FL will receive 
maintenance treatment with obinutuzumab and lenalidomide, and patients with DLBCL 
will receive consolidation treatment with obinutuzumabrituximab and lenalidomide (see 
Section 3.1.1 for details). 
SECTION 4.3:  STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are obinutuzumab, 
rituximab, polatuzumab vedotin, and lenalidomide. 
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 
28-day cycles of induction treatment with obinutuzumab or rituximab, polatuzumab 
vedotin, and lenalidomide.  When study treatments are given on the same day, they will 
be administered sequentially in the following order:  lenalidomide, obinutuzumab or 
rituximab, and polatuzumab vedotin.  
Patients with DLBCL who achieve a CR or PR at EOI will receive post-induction 
treatment (referred to as consolidation) with lenalidomide and obinutuzumabrituximab, 
and patients with FL who achieve a CR, PR, or SD at EOI will receive post-induction 
treatment (referred to as maintenance) with lenalidomide and obinutuzumab.  When 
study treatments are given on the same day, lenalidomide will be administered prior to 
obinutuzumab or rituximab. 
Post-induction treatment should start 8 weeks (± 1 week) after Day 1 of the final cycle of 
induction and will continue until disease progression or unacceptable toxicity for up to 
2 years for maintenance treatment or 1 year 6 months for consolidation treatment. 
Treatment regimens are summarized in Table 1, Table 2, Table 4, and Table 5 for R/R 
FL patients and Table 6, Table 7, Table 9, and Table 10 for R/R DLBCL patients 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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(see Section 3.1) and depicted in Figure 4.  All eligible patients in both dose-escalation 
and expansion phases should receive induction and post-induction (if indicated) therapy. 
FIGURE 4:  Induction and Post-Induction Treatment Regimen  
Figure 4 has been revised to include rituximab. 
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 treatment (eligible patients with DLBCL only) or maintenance treatment 
(eligible patients with FL only).  A month is defined as 28 days. 
FIGURE 6:  Guidelines for Obinutuzumab Infusions:  Second and 
Subsequent Infusions 
Figure 6 has been revised to clarify second and subsequent infusions by IRR grade. 
SECTION 4.3.2.2:  Rituximab (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.  
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 


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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 5.1.6. 
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 8. 
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 
For R/R FL, during 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 4.3.2.5:  Premedication and Other Required Medication 
Lenalidomide increases the risk of thromboembolism.  All patients will be required to 
take daily aspirin (7581−100 mg) for TE prophylaxis during lenalidomide treatment and 
until 28 days after the last dose of lenalidomide.  Patients who are unable to tolerate 
aspirin, patients with a history of TE, and patients at high risk of TE should receive 
warfarin or low-molecular-weight heparin (LMWH).   
Patients should receive premedication as outlined in Table 13. 
TABLE 13:  Premedication 
Table 13 has been revised to include rituximab and to add premedication information for 
patients by IRR grade. 
 SECTION 4.3.3:  Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (obinutuzumab, rituximab, polatuzumab 
vedotin, and lenalidomide) 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.  Lenalidomide will be dispensed to 


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sites in the United States via the Celgene REMS™ system.  For sites outside the United 
States, lenalidomide will be dispensed to sites through the study IxRS.  Sites will be 
trained on lenalidomide specific requirements by their study monitors.   
SECTION 4.3.4:  Post-Trial Access to Obinutuzumab, Rituximab, 
Polatuzumab Vedotin, and Lenalidomide 
Currently, the Sponsor does not have any plans to provide obinutuzumab, rituximab, 
and polatuzumab vedotin, or any other study treatments or interventions to patients who 
have completed the study.  The Sponsor will evaluate whether to continue providing 
obinutuzumab, rituximab, or and polatuzumab vedotin 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 
SECTION 4.4:  CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
728 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. 
SECTION 4.4.2:  Prohibited Therapy 
Use of the following therapies (excluding protocol-specified treatments) is prohibited 
during the study: 
• 
Any anti-cancer therapy, approved or investigational, other than intrathecal central 
nervous system 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 4.5.5:  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 PET and CT scans, using the Lugano 2014 criteria, 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 


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response criteria for a CR or PR be met in addition to the PET-CT-based response 
criteria for a PR (see Appendix 5). 
SECTION 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, and 
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 creatinine clearance, calcium, total bilirubin, direct bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase, LDH, uric acid, 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. 
• 
Thyroid-stimulating hormone, triiodothyronine, thyroxine 
• 
β2 microglobulin 
• 
Coagulation:  INR, aPTT (or PTT), and PT 
• 
Pregnancy test 
All women of childbearing potential must have two negative serum pregnancy 
test results (minimum sensitivity, 25 mIU/mL) prior to initiating therapy:  at 
10−14 days prior to Day 1 of Cycle 1 and within 24 hours prior to Day 1 of 
Cycle 1.  Urine pregnancy tests will be performed at specified subsequent visits 
(see Appendix 1 and Appendix 2).  If a urine pregnancy test is positive, it must 
be confirmed by a serum pregnancy test. 
• 
Viral serology  
Hepatitis B testing includes HBsAg and total HBcAb 
Hepatitis C testing includes HCV antibody 
HIV testing (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 polatuzumab vedotin PK analysis using a validated 
assay 
• 
Plasma samples for lenalidomide PK analysis using a validated assay 
• 
Serum samples for assessment of obinutuzumab HAHAs using a validated assay 


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• 
Serum samples for assessment of rituximab HACAs using a validated assay 
• 
Serum samples for assessment of polatuzumab vedotin ATAs using a validated 
assay 
• 
Tumor tissue samples (obtained within 6 months prior to the initiation of study 
treatment for DLBCL or within 12 months prior to the initiation of study treatment for 
FL) and the corresponding pathology report for retrospective central confirmation of 
the original 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 available biopsy was performed more than 12 months prior to Day 1 of 
Cycle 1, or the patient received anti-lymphoma treatment between the time of 
the most recent available biopsy and Day 1 of Cycle 1, a core-needle biopsy is 
strongly 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. 
• 
Optional t Tumor biopsy samples obtained at the time of progression (unless no 
adequate tumor site is accessible) for exploratory research on candidate biomarkers 
(see Table 14) 
• 
Plasma samples for exploratory research on candidate biomarkers (see Table 14) 
• 
Whole blood samples for exploratory research on candidate biomarkers (see 
Table 14) 
• 
Whole blood samples for isolation of peripheral blood mononuclear cells for 
exploratory research on candidate biomarkers (see Table 14). 
• 
Whole blood for lymphocyte immunophenotyping (see Table 14) 
Samples collected for PK and immunogenicity analyses may be used for 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 Biological samples will be destroyed when the final clinical study report 
has been completed, unless the patient gives specific consent for the leftover 
samples to be stored for optional exploratory research (see Section 4.5.8). 
 
TABLE 14:  Proposed Non-Inherited Biomarkers 
Table 14 has been revised to remove information about peripheral blood mononuclear 
cells. 
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, lenalidomide, B-cell lymphoma, 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, peripheral blood mononuclear cells 
[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 
completing 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, pPatients who discontinue study treatment prior to 
receiving at least one dose of each component of the combination will be replaced. 
 
SECTION 5.1:  SAFETY PLAN 
Polatuzumab vedotin is not a marketed product, and obinutuzumab and lenalidomide 
isare not approved for the treatment of patients with R/R FL.  Obinutuzumab is only 
approved in combination with bendamustine for the treatment of R/R FL.  Rituximab 
and lenalidomide are not approved for the treatment of patients with 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 
lenalidomide in completed and ongoing studies.  The anticipated important safety risks 
of obinutuzumab, rituximab, polatuzumab vedotin, and lenalidomide are outlined below.  
Please refer to the Obinutuzumab, Rituximab, and Polatuzumab Vedotin Investigator’s 


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Brochures and the lenalidomide Summary of Product Characteristics (SmPC) for a 
complete summary of safety information.  
SECTION 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. 
SECTION 5.1.1.6:  Immunizations 
The safety of immunization with live or attenuated viral virus 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), 
PML, hepatitis B reactivation, neutropenia (including prolonged neutropenia), TLS, 
impaired immunization response, severe skin reactions (Stevens-Johnson syndrome 
[SJS]/toxic epidermal necrolysis [TEN]), 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 (Grades 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 that 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. 


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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. 
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 (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. 


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SECTION 5.1.2.6:  Tumor Lysis Syndrome (NEW SECTION) 
Patients treated with rituximab may be at risk for TLS.  Severe tumor 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, as patients may not be able to mount an effective 
humoral immune response to foreign antigens. 
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 1to 13 weeks following rituximab exposure.  The majority of the 
Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) 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 SJS/TEN. 
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 5.1.3.1: Identified Risks Known Risks Associated with 
Polatuzumab Vedotin 
The title of this section was revised. 
SECTION 5.1.3.2:  Potential Risks Associated with Polatuzumab Vedotin 
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.  Patients receiving chemotherapy for B-cell lymphoma with a granulocyte 
count of  < 500 cells/μL experienced a higher incidence of infections than those with a 
count of  > 500 cells/μL. 


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Progressive Multifocal Leukoencephalopathy (NEW SECTION) 
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 JC virus by PCR 
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 4.3.2.3).  Precautions for suspected anaphylactic reaction during study drug 
infusions are provided in Section 4.3.2.3.  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 4.3.2.3).  Significant issues with polatuzumab vedotin IRRs have not been 
observed. 
Similar considerations regarding infusion reactions are applicable for obinutuzumab.  
Refer to Section 4.3.2.1 for additional information.   
Tumor Lysis Syndrome  
There is the potential theoretical risk of TLS if treatment with polatuzumab vedotin 
results in the rapid destruction of a large number of tumor cells.  If any evidence of this 
occurs during the study, tumor lysis prophylaxis measures will be instituted.  Patients 
who are considered to have a high tumor burden (e.g., lymphocyte count ≥ 25 × 109/L or 
bulky lymphadenopathy) and who are considered to be at risk for tumor lysis by the 
investigator will receive tumor lysis prophylaxis (e.g., allopurinol ≥ 300 mg/day orally or a 
suitable alternative treatment [according to institutional practice] starting 12−24 hours 
before study treatment) and must be well hydrated before the initiation of study 
treatment on Day 1 of Cycle 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 TLS attributed to polatuzumab vedotin has been reported (Study GO27834); 
however, the laboratory elevations did not meet the Howard criteria for TLS (see 
Appendix 12).  The suspected TLS event resolved after 3 days of supportive care.  
One case of Grade 3 Laboratory TLS was reported in the ongoing Phase Ib/II 
Study GO29833 combining polatuzumab vedotin, obinutuzumab, and venetolax.  


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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 the patient was asymptomatic.  The TLS event was considered 
related to all three study treatments and resolved in 4 days with supportive care (see 
Polatuzumab Vedotin Investigator's Brochure for case details.   
SECTION 5.1.4.1:  Embryo-Fetal Toxicity 
Lenalidomide must not be taken by patients who are pregnant.  In every country where 
lenalidomide has been approved, a risk minimization plan, which includes a pregnancy 
prevention program, is in place.  Investigators must ensure that all specific local 
requirements that are applicable to the safe and effective use of lenalidomide are fulfilled 
prior to administration to patients.  The risk minimization plan should be followed by 
prescribers and by patients using lenalidomide, with one exception:  Because 
lenalidomide will be administered in combination with polatuzumab vedotin and 
obinutuzumab or rituximab, patients must comply with contraceptive measures 
designed to ensure safe administration of all fourthree study treatments, as outlined in 
Section 4.1.1.  Pregnancy testing and counseling should be performed if a patient 
misses her period or has unusual/irregular menstrual bleeding.  Treatment with 
lenalidomide must be discontinued until it is confirmed that the patient is not pregnant 
SECTION 5.1.4.8:  Renal Impairment 
Lenalidomide is substantially excreted by the kidney.  Patients with renal impairment 
(i.e., calculated creatinine clearance <60 50 mL/min) will not be enrolled in this study.   
SECTION 5.1.4.12:  Cardiovascular Reactions (NEW SECTION) 
Cases of serious adverse cardiovascular events, including atrial fibrillation, myocardial 
infarction, and cardiac failure occurred more frequently in patients with CLL treated 
with lenalidomide compared to single agent chlorambucil.  Patients will be monitored 
for the development of cardiac toxicities.   
SECTION 5.1.4.13:  Impaired Stem Cell Mobilization (NEW SECTION) 
Patients have been reported to show a decrease in the number of CD34+ cells collected 
after treatment with lenalidomide.  Early referral to a transplant center is recommended 
in patients who are autologous SCT candidates.   
SECTION 5.1.5:  Risk of Overlapping Toxicities 
The anticipated toxicities from the combined administration of obinutuzumab or 
rituximab with polatuzumab vedotin and lenalidomide are expected to be manageable 
in the clinical setting and will be closely monitored throughout the study.  
[…] 
Both rituximab and lenalidomide have been associated with dermatologic reactions such 
as SJS and TEN, and the risk of overlapping toxicities will be monitored.  Guidelines 


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for management of patients who develop dermatologic toxicities are provided in 
Table 19.   
SECTION 5.1.6:  Risk of Overlapping Toxicities 
The risk for clinically relevant PK DDIs between study treatments is low.  First, 
obinutuzumab, rituximab, and polatuzumab vedotin are not anticipated to interact 
directly with CYP isoforms or other drug–metabolizing enzymes or drug transporters.  
Cytokine modulation may be considered as an indirect mechanism through which a 
monoclonal antibody could alter CYP expression.  However, treatment with 
obinutuzumab results in only transient increases in cytokine levels after the first infusion, 
and no increases are observed after subsequent infusions.  In vitro (human PBMCs) and 
in vivo (cynomolgus monkeys) treatment with anti-CD79 antibodies (i.e., the same 
antigen target as polatuzumab vedotin) showed a low risk for release of systemic pro-
inflammatory cytokines.  Taken together, these results suggest that both obinutuzumab 
and polatuzumab vedotin are unlikely to precipitate DDIs via indirect effects on cytokines.   
Second, lenalidomide is primarily excreted in the urine.  Lenalidomide is not a substrate, 
inhibitor, or inducer of the CYP group of enzymes (Kumar et al. 2009).  In vitro, the 
MMAE component of polatuzumab vedotin is mainly metabolized by CYP3A4, and it is 
mainly eliminated by biliary secretion in vivo.  Both lenalidomide and MMAE are 
substrates but not inhibitors of P-gp.  Owing to the different elimination pathways for 
lenalidomide and MMAE, the risk of CYP-mediated and transporter-mediated DDI risk is 
low when polatuzumab vedotin is combined with lenalidomide.   
In addition, simulation results suggest that unconjugated MMAE exposure is likely to be 
altered by  < 50% when polatuzumab vedotin is co-administered with strong CYP3A 
inhibitors or inducers.  Therefore, patients who receive concomitant medications that are 
strong CYP3A or P-gp inhibitors should be closely monitored for adverse reactions. 
In summary, clinically relevant PK DDIs are unlikely to occur between lenalidomide, 
obinutuzumab, rituximab, and polatuzumab vedotin.  
SECTION 5.1.7:  Management of Specific Adverse Events 
Treatment delays apply to all toxicities described below; dose modifications apply only to 
toxicities that are considered to be related to lenalidomide or polatuzumab vedotin (only 
for peripheral neuropathy).  There will be no dose reductions of obinutuzumab or 
rituximab.  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.   
SECTION 5.1.7.1:  Polatuzumab Vedotin Dose-Reduction Steps 
The dose of polatuzumab vedotin may be reduced due to neurotoxicity only according 
to the following dose reduction steps based on the starting dose (see Table 15 and 
Table 19). 


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SECTION 5.1.7.2:  Lenalidomide Dose-Reduction Steps 
The dose of lenalidomide may be reduced in 5-mg increments one or two times during 
induction or post-induction, depending on the starting dose, as outlined in Table 16.  
There will be no more than one dose reduction per treatment cycle.  If the lenalidomide 
dose is reduced to 5 mg during induction, the maintenance or consolidation dose may be 
escalated to start at 10 mg in post-induction if considered safe per investigator 
judgment in consultation with the Sponsor.  In all other cases, if the lenalidomide dose 
is reduced, re-escalation is not permitted. 
SECTION 5.1.7.3:  Hematologic Toxicities during Induction Treatment 
Hematologic toxicity is defined as neutropenia, anemia, or thrombocytopenia.  
Lymphopenia is not considered a hematologic toxicity, but rather an expected outcome 
of therapy.   Table 16 provides guidelines for management of hematologic toxicities that 
occur during induction treatment, with the exception of Days 8 and 15 of Cycle 1 for 
patients receiving obinutuzumab.  Table 17 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. 
TABLE 17:  Guidelines for Management of Hematologic Toxicities That 
Occur during Induction Treatment (Except Days 8 and 15 of Cycle 1 for 
Patients Receiving Obinutuzumab) 
The Table 17 title has been revised to specify the cohort of patients receiving 
obinutuzumab.  The table has also been revised to include rituximab. 
TABLE 18:  Guidelines for Management of Hematologic Toxicities That 
Occur on Days 8 and 15 of Cycle 1 for Patients Receiving Obinutuzumab 
The Table 18 title has been revised to specify the cohort of patients receiving 
obinutuzumab.  
TABLE 19:  Guidelines for Management of Non-Hematologic Toxicities 
During Induction 
The Table 19 title has been revised to specify the induction period, and table content has 
been updated.   
TABLE 20:  Guidelines for Management of Toxicities that Occur during 
Consolidation or Maintenance Treatment 
Table 20 has been revised to include rituximab and to clarify lenalidomide dose 
reduction.  


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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 the FL patients, 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 
treatment. obinutuzumab.   
SECTION 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 independent monitoring 
committee (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.  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 


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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 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").  During survival follow up, deaths attributed to progression of lymphoma should 
be recorded only on the Study Completion/Early Discontinuation eCRF. 
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) 
• 
Non serious 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).  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 


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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 post study adverse events reporting period are 
provided in Section 5.6. 
SECTION 5.6:  POST STUDY 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 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. 
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 FormeCRF 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. 
SECTION 5.7:  EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious 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 document: 
• 
Obinutuzumab Investigator's Brochure (Oncology) 


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• 
Rituximab Investigator’s Brochure (Oncology) 
• 
Polatuzumab Vedotin Investigator's Brochure 
• 
Lenalidomide SmPC  
 
SECTION 6:  STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This Phase Ib/II, open-label, multicenter, non-randomized study will evaluate the safety, 
efficacy, and pharmacokinetics of G + Pola + Len in patients with R/R FL and 
R + Pola + Len in patients with R/R or DLBCL. 
The study will include an initial dose-escalation phase followed by an expansion phase.  
The dose-escalation phase will include in FL patients only, and it is designed to 
determine the RP2Ds for both polatuzumab vedotin and lenalidomide when combined 
with fixed doses of obinutuzumab in patients with relapsed or refractory FL.  The 
dose-escalation phase in DLBCL patients is designed to determine the RP2D of 
lenalidomide when combined with fixed doses of polatuzumab vedotin (1.8 mg/kg) and 
rituximab (375 mg/m2).  During the expansion phase, additional patients with R/R FL or 
DLBCL will undergo treatment with polatuzumab vedotin and lenalidomide 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 histologic 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. 
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 5 or six 
cohorts of 3−6 patients each, for a total of 18−30 36 patients, will be required to establish 
the RP2D during the dose-escalation phase for patients with R/R FL.  An additional 3 
possible cohorts of 3−6 patients each, for a total of 12−18 patients will be required to 
establish the RP2D during the dose-escalation phase for patients with R/R DLBCL.  
Approximately 80 patients (40 patients with FL and 40 patients with DLBCL) will be 
enrolled during the expansion phase.  Overall, approximately 110−128 98−116 patients 
will be enrolled in the study. 
The primary efficacy analysis will be the 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 40% for R/R FL and DLBCL.   


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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 65%−70%.   
SECTION 6.2:  DEFINITION OF ANALYSIS POPULATION 
The following populations are defined: 
• 
The primary safety and efficacy populations will include patients who received at 
least one dose of any component of the combination.   
• 
The intent-to-treat population 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).  Data for patients in the dose-escalation phase will be 
summarized by cohort and histology type, and data for patients in the expansion phase 
will be summarized by histologic subtype (FL or DLBCL).   
Safety will be assessed through summaries of adverse events and changes from 
baseline in 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, Version 4.0 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 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 all 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 lenalidomide 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. 


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SECTION 6.6.2:  Secondary Efficacy Endpoint 
The secondary efficacy analyses will be estimation of the proportion of patients 
achieving 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 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. 
SECTION 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 
– 
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 
Plasma/serum concentrations of obinutuzumab, rituximab, polatuzumab vedotin, and 
lenalidomide will be tabulated, summarized, and plotted after appropriate grouping.  As 
appropriate, PK parameters (e.g., area under the curve [AUC], time to maximum 
concentration [tmax], maximum concentration [Cmax], half-life [t1/2]) may also be calculated, 
tabulated, and summarized after appropriate grouping.  Additional PK and PK/PD 
analyses (e.g., population modelling including pooled analyses across studies) may also 
be performed as appropriate.  If done, these additional analyses may be reported 
separately from the CSR.  At the discretion of the Sponsor, all analyses may be 
extended to include relevant biotransformation products of polatuzumab vedotin or 
lenalidomide. 
SECTION 6.8:  IMMUNOGENICITY ANALYSES 
The numbers and proportions of post-treatment HAHA- or HACA-, and ATA-positive 
patients and HAHA- or HACA-, and ATA-negative patients at baseline and during both 
the treatment and follow-up periods will be summarized by histologic subtype.  Patients 


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are considered to be ATA positive if they are ATA negative at baseline but develop an 
ATA response following study treatment administration (treatment-induced ATA 
response) or if they are ATA positive at baseline and the titer of one 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 ATA response).  Patients are considered to be 
ATA negative if they are ATA negative at baseline and all post-baseline samples are 
negative or if they are 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 HACA, and ATA status and safety, efficacy, PK, and 
biomarker endpoints will be explored as appropriate. 
SECTION 6.10:  INTERIM ANALYSES 
It is anticipated that at least two interim analyses, one per histology, will be conducted 
during the expansion phase of the study, when at least 15 patients in each histology 
have been evaluated for PET-CT−defined CR at 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 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 
indication-specific expansion cohort with that in historical controls.  Updated estimates 
for the assumed historical control PET-CT−defined CR rate will be available from 
currently ongoing studies by the time of the first interim analysis.  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 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 indication-specific expansion cohorts is lower or 
higher than expected, the IMC will review the data and decide whether to recommend an 
early decision to stop enrollment in that subgroup.  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. 


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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 Diffuse Large 
B-Cell Lymphoma 
The schedule of assessments for patients with DLBCL has been revised to reflect the 
changes to the protocol. 
APPENDIX 3:  Pharmacokinetic and Immunogenicity Sampling Schedule 
for Obinutuzumab, Polatuzumab Vedotin, and Lenalidomide 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 Lenalidomide in Relapsed or 
Refractory DLBCL Patients 
Appendix 4 has been added.  Subsequent appendices have been renumbered 
accordingly. 
APPENDIX 5:  Modified Lugano Response Criteria for Malignant 
Lymphoma 
(Cheson et al. 2014) 
Appendix 5 has been revised to add “modified” to the title and to clarify designation of 
PET-CT based PR. 
APPENDIX 12:  Diagnostic Criteria for Tumor Lysis Syndrome 
Appendix 12 has been added. 
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......................................... 59 
PROTOCOL SYNOPSIS .................................................................................... 60 
1. 
BACKGROUND .......................................................................................... 74 
1.1 
Background on B-Cell Lymphoma......................................... 74 
1.1.1 
Follicular Lymphoma ............................................................. 74 
1.1.2 
Diffuse Large B-Cell Lymphoma............................................ 74 
1.2 
Background on Obinutuzumab .............................................. 75 
1.2.1 
Nonclinical Studies with Obinutuzumab................................. 76 
1.2.2 
Clinical Studies with Obinutuzumab ...................................... 76 
1.2.2.1 
Clinical Efficacy of Obinutuzumab in Patients with 
B-Cell Lymphoma .................................................................. 76 
1.2.2.2 
Clinical Safety of Obinutuzumab............................................ 77 
1.2.2.3 
Clinical Pharmacokinetics of Obinutuzumab.......................... 78 
1.3 
Background on Polatuzumab Vedotin ................................... 78 
1.3.1 
Nonclinical Studies with Polatuzumab Vedotin...................... 79 
1.3.2 
Clinical Studies with Polatuzumab Vedotin............................ 80 
1.3.2.1 
Clinical Efficacy of Polatuzumab Vedotin in 
Patients with B-Cell Lymphoma............................................. 80 
1.3.2.2 
Clinical Safety of Polatuzumab Vedotin................................. 81 
1.3.2.3 
Clinical Pharmacokinetics of Polatuzumab 
Vedotin.................................................................................. 83 
1.4 
Study Rationale and Benefit-Risk Assessment...................... 83 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 85 
2.1 
Safety Objectives................................................................... 85 
2.2 
Efficacy Objectives ................................................................ 86 
2.2.1 
Primary Efficacy Objective..................................................... 86 
2.2.2 
Secondary Efficacy Objective................................................ 86 
2.2.3 
Exploratory Efficacy Objective............................................... 86 
2.3 
Pharmacokinetic Objective .................................................... 87 
2.4 
Immunogenicity Objectives.................................................... 87 
2.5 
Biomarker Objective .............................................................. 88 


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3. 
STUDY DESIGN ......................................................................................... 88 
3.1 
Description of Study .............................................................. 88 
3.1.1 
Overview of Study ................................................................. 88 
3.1.2 
Obinutuzumab plus Polatuzumab Vedotin plus 
Lenalidomide Treatment Group (Patients with 
Follicular Lymphoma) ........................................................... 90 
3.1.2.1 
Dose-Escalation Phase......................................................... 90 
3.1.2.2 
Follicular Lymphoma Expansion Phase ............................... 95 
3.1.3 
Rituximab plus Polatuzumab Vedotin 
plus  Lenalidomide Treatment Group (Patients 
with Relapsed or Refractory Diffuse Large B-Cell 
Lymphoma)............................................................................ 96 
3.1.3.1 
Dose-Escalation Phase ........................................................... 97 
3.1.3.2 
DLBCL Expansion Phase ..................................................... 100 
3.1.4 
Internal Monitoring Committee............................................. 101 
3.1.5 
Independent Review Committee.......................................... 102 
3.1.6 
Post-Treatment and Survival Follow-Up .............................. 102 
3.2 
End of Study and Length of Study....................................... 102 
3.3 
Rationale for Study Design.................................................. 103 
3.3.1 
Rationale for Patient Population .......................................... 103 
3.3.2 
Rationale for the Triplet Combination .................................. 103 
3.3.2.1 
Rituximab and Polatuzumab Vedotin 
Combination ........................................................................ 104 
3.3.2.2 
Obinutuzumab and Polatuzumab Vedotin 
Combination ........................................................................ 104 
3.3.2.3 
Rituximab and Lenalidomide Combination........................... 104 
3.3.2.4 
Obinutuzumab and Lenalidomide Combination ................... 105 
3.3.3 
Rationale for Dose and Schedule........................................ 106 
3.3.3.1 
Rationale for Obinutuzumab Dose and Schedule 
in Patients with Follicular Lymphoma................................ 106 
3.3.3.2 
Rationale for Polatuzumab Vedotin Dosing 
Regimen.............................................................................. 107 
3.3.3.3 
Rationale for Lenalidomide Dose and Schedule .................. 109 
3.3.3.4 
Rationale for Treatment Duration......................................... 109 
3.3.4 
Rationale for PET-CT-Defined Complete 
Response as the Primary Efficacy Endpoint ........................ 111 


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3.3.5 
Rationale for Biomarker Assessments................................. 111 
3.3.5.1 
Rationale for Analysis of DLBCL Subtype, BCL2, 
and MYC.............................................................................. 111 
3.3.5.2 
Rationale for Assessment of Therapeutic Target 
Expression........................................................................... 112 
3.3.5.3 
Rationale for Assessment of Minimal Residual 
Disease............................................................................... 112 
3.3.5.4 
Rationale for Assessment of Lymphoma-Related 
Genetic Changes and Gene Expression ............................. 113 
4. 
MATERIALS AND METHODS .................................................................. 113 
4.1 
Patients................................................................................ 113 
4.1.1 
Inclusion Criteria.................................................................. 113 
4.1.2 
Exclusion Criteria................................................................. 115 
4.2 
Method of Treatment Assignment........................................ 117 
4.3 
Study Treatment.................................................................. 118 
4.3.1 
Formulation, Packaging, and Handling................................ 118 
4.3.1.1 
Obinutuzumab ..................................................................... 118 
4.3.1.2 
Rituximab........................................................................... 118 
4.3.1.3 
Polatuzumab Vedotin......................................................... 118 
4.3.1.4 
Lenalidomide...................................................................... 119 
4.3.2 
Dosage, Administration, and Compliance............................ 119 
4.3.2.1 
Obinutuzumab.................................................................... 121 
4.3.2.2 
Rituximab............................................................................. 124 
4.3.2.3 
Polatuzumab Vedotin......................................................... 125 
4.3.2.4 
Lenalidomide...................................................................... 126 
4.3.2.5 
Premedication and Other Required Medication ................. 127 
4.3.3 
Investigational Medicinal Product Accountability ................. 129 
4.3.4 
Post-Trial Access to Obinutuzumab, Rituximab,    
Polatuzumab Vedotin, and Lenalidomide............................ 129 
4.4 
Concomitant Therapy .......................................................... 129 
4.4.1 
Permitted Therapy ............................................................... 129 
4.4.2 
Prohibited Therapy .............................................................. 131 
4.5 
Study Assessments ............................................................. 131 
4.5.1 
Informed Consent Forms and Screening Log...................... 131 


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4.5.2 
Medical History and Demographic Data .............................. 131 
4.5.3 
Physical Examinations......................................................... 132 
4.5.4 
Vital Signs............................................................................ 132 
4.5.5 
Tumor and Response Evaluations....................................... 133 
4.5.5.1 
Radiographic Assessments................................................ 133 
4.5.5.2 
Bone Marrow Assessments ............................................... 134 
4.5.6 
Laboratory, Biomarker, and Other Biological 
Samples .............................................................................. 134 
4.5.7 
Electrocardiograms.............................................................. 137 
4.5.8 
Samples for Roche Clinical Repository................................ 137 
4.5.8.1 
Overview of the Roche Clinical Repository ........................ 137 
4.5.8.2 
Approval by the Institutional Review Board or 
Ethics Committee................................................................ 137 
4.5.8.3 
Sample Collection.............................................................. 138 
4.5.8.4 
Confidentiality .................................................................... 138 
4.5.8.5 
Consent to Participate in the Roche Clinical 
Repository........................................................................... 139 
4.5.8.6 
Withdrawal from the Roche Clinical Repository ................. 139 
4.5.8.7 
Monitoring and Oversight................................................... 139 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation.................................................................... 140 
4.6.1 
Patient Discontinuation........................................................ 140 
4.6.2 
Study Treatment Discontinuation......................................... 140 
4.6.3 
Study and Site Discontinuation............................................ 141 
5. 
ASSESSMENT OF SAFETY..................................................................... 141 
5.1 
Safety Plan .......................................................................... 141 
5.1.1 
Risks Associated with Obinutuzumab.................................. 142 
5.1.1.1 
Infusion-Related Reactions................................................ 142 
5.1.1.2 
Tumor Lysis Syndrome ...................................................... 143 
5.1.1.3 
Neutropenia ....................................................................... 143 
5.1.1.4 
Thrombocytopenia ............................................................. 143 
5.1.1.5 
Infections............................................................................ 143 
5.1.1.6 
Immunizations.................................................................... 144 
5.1.1.7 
Worsening of Preexisting Cardiac Condition...................... 144 


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5.1.1.8 
Gastrointestinal Perforation................................................ 144 
5.1.2 
Risks Associated with Rituximab............................................. 144 
5.1.2.1 
Infusion-Related Reactions ..................................................... 145 
5.1.2.2 
Infections (Including Serious Infections).................................. 145 
5.1.2.3 
Hepatitis B Reactivation......................................................... 145 
5.1.2.4 
Progressive Multifocal Leukoencephalopathy............................ 145 
5.1.2.5 
Neutropenia (Including Prolonged Neutropenia)...................... 146 
5.1.2.6 
Tumor Lysis Syndrome.......................................................... 146 
5.1.2.7 
Impaired Immunization Response ........................................... 146 
5.1.2.8 
Severe Skin Reactions:  Stevens-Johnson Syndrome 
and Toxic Epidermal Necrolysis............................................. 146 
5.1.2.9 
Gastrointestinal Perforation ................................................... 146 
5.1.3 
Risks Associated with Polatuzumab Vedotin....................... 147 
5.1.3.1 
Identified Risks .................................................................... 147 
5.1.3.2 
Potential Risks ................................................................... 147 
5.1.4 
Risks Associated with Lenalidomide.................................... 150 
5.1.4.1 
Embryo-Fetal Toxicity ........................................................ 150 
5.1.4.2 
Hematologic Toxicity.......................................................... 150 
5.1.4.3 
Venous and Arterial Thromboembolism............................. 150 
5.1.4.4 
Tumor Flare Reaction ........................................................ 151 
5.1.4.5 
Severe Skin Reactions....................................................... 151 
5.1.4.6 
Tumor Lysis Syndrome ...................................................... 151 
5.1.4.7 
Hepatotoxicity .................................................................... 151 
5.1.4.8 
Renal Impairment............................................................... 151 
5.1.4.9 
Thyroid Disorders............................................................... 151 
5.1.4.10 
Peripheral Neuropathy........................................................ 151 
5.1.4.11 
Second Primary Malignancies............................................ 152 
5.1.4.12 
Cardiovascular Reactions .................................................. 152 
5.1.4.13 
Impaired Stem Cell Mobilization ...................................... 152 
5.1.5 
Risk of Overlapping Toxicities ............................................. 152 
5.1.6 
Risk of Drug-Drug Interactions ............................................ 153 
5.1.7 
Management of Specific Adverse Events ............................ 154 
5.1.7.1 
Polatuzumab Vedotin Dose-Reduction Steps .................... 154 
5.1.7.2 
Lenalidomide Dose-Reduction Steps................................. 154 


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5.1.7.3 
Hematologic Toxicities during Induction 
Treatment............................................................................ 155 
5.1.7.4 
Toxicities during Consolidation or Maintenance 
Treatment............................................................................ 162 
5.2 
Safety Parameters and Definitions ...................................... 162 
5.2.1 
Adverse Events ................................................................... 162 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 163 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ................................................. 164 
5.2.4 
Dose-Limiting Toxicities (Immediately Reportable 
to the Sponsor).................................................................... 164 
5.2.5 
Selected Adverse Events..................................................... 164 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 165 
5.3.1 
Adverse Event Reporting Period ......................................... 165 
5.3.2 
Eliciting Adverse Event Information ..................................... 166 
5.3.3 
Assessment of Severity of Adverse Events ......................... 166 
5.3.4 
Assessment of Causality of Adverse Events ....................... 166 
5.3.5 
Procedures for Recording Adverse Events.......................... 167 
5.3.5.1 
Infusion-Related Reactions................................................. 167 
5.3.5.2 
Diagnosis versus Signs and Symptoms.............................. 167 
5.3.5.3 
Adverse Events that Are Secondary to Other 
Events.................................................................................. 168 
5.3.5.4 
Persistent or Recurrent Adverse Events ............................ 168 
5.3.5.5 
Abnormal Laboratory Values.............................................. 169 
5.3.5.6 
Abnormal Vital Sign Values................................................ 169 
5.3.5.7 
Abnormal Liver Function Tests .......................................... 170 
5.3.5.8 
Deaths ............................................................................... 170 
5.3.5.9 
Preexisting Medical Conditions.......................................... 171 
5.3.5.10 
Lack of Efficacy or Worsening of Lymphoma.................... 171 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ..................... 171 
5.3.5.12 
Adverse Events Associated with an Overdose 
or Error in Treatment Administration.................................. 172 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 172 


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5.4.1 
Emergency Medical Contacts.............................................. 173 
5.4.2 
Reporting Requirements for Serious Adverse 
Events, Adverse Events of Special Interest, and 
Dose-Limiting Toxicities...................................................... 174 
5.4.2.1 
Events that Occur prior to Study Treatment 
Initiation............................................................................... 174 
5.4.2.2 
Events that Occur after Study Treatment 
Initiation.............................................................................. 174 
5.4.3 
Reporting Requirements for Pregnancies............................ 174 
5.4.3.1 
Pregnancies in Female Patients ......................................... 174 
5.4.3.2 
Pregnancies in Female Partners of Male Patients............... 175 
5.4.3.3 
Exposure of Pregnant Female to Lenalidomide ................. 175 
5.4.3.4 
Abortions............................................................................ 175 
5.4.3.5 
Congenital Anomalies/Birth Defects................................... 175 
5.5 
Follow-Up of Patients after Adverse Events ........................ 176 
5.5.1 
Investigator Follow-Up......................................................... 176 
5.5.2 
Sponsor Follow-Up .............................................................. 176 
5.6 
Adverse Events that Occur after the Adverse 
Event Reporting Period........................................................ 176 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 177 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 177 
6.1 
Determination of Sample Size ............................................. 178 
6.2 
Definition of Analysis Populations .......................................... 179 
6.3 
Summaries of Conduct of Study.......................................... 179 
6.4 
Summaries of Demographic and Baseline 
Characteristics..................................................................... 179 
6.5 
Safety Analyses................................................................... 180 
6.6 
Efficacy Analyses ................................................................ 180 
6.6.1 
Primary Efficacy Endpoint.................................................... 180 
6.6.2 
Secondary Efficacy Endpoints............................................. 180 
6.6.3 
Exploratory Efficacy Endpoints............................................ 181 
6.7 
Pharmacokinetic Analyses................................................... 182 
6.8 
Immunogenicity Analyses.................................................... 182 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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6.9 
Biomarker Analyses............................................................. 182 
6.10 
Interim Analyses.................................................................. 183 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 183 
7.1 
Data Quality Assurance....................................................... 183 
7.2 
Electronic Case Report Forms............................................. 184 
7.3 
Source Data Documentation................................................ 184 
7.4 
Use of Computerized Systems ............................................ 185 
7.5 
Retention of Records........................................................... 185 
8. 
ETHICAL CONSIDERATIONS.................................................................. 185 
8.1 
Compliance with Laws and Regulations .............................. 185 
8.2 
Informed Consent ................................................................ 185 
8.3 
Institutional Review Board or Ethics Committee.................. 186 
8.4 
Confidentiality...................................................................... 187 
8.5 
Financial Disclosure ............................................................ 187 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 187 
9.1 
Study Documentation .......................................................... 187 
9.2 
Protocol Deviations.............................................................. 188 
9.3 
Site Inspections ................................................................... 188 
9.4 
Administrative Structure....................................................... 188 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 188 
9.6 
Protocol Amendments ......................................................... 189 
10. REFERENCES ......................................................................................... 190 
 


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LIST OF TABLES 
Table 1 
Induction Treatment for the Follicular Lymphoma Dose-
Escalation Phase ........................................................................ 92 
Table 2 
Maintenance Treatment for the Follicular Lymphoma Dose-
Escalation Phase ........................................................................ 92 
Table 3 
Follicular Lymphoma Dose-Escalation Cohorts.......................... 94 
Table 4 
Induction Treatment for the Follicular Lymphoma Expansion 
Phase.......................................................................................... 96 
Table 5 
Post-Induction Treatment for the Follicular Lymphoma 
Expansion Phase........................................................................ 96 
Table 6 
Induction Treatment for the DLBCL Dose-Escalation Phase...... 98 
Table 7 
Consolidation Treatment for the Dose-Escalation Phase ............ 98 
Table 8 
DLBCL Dose-Escalation Cohorts................................................ 99 
Table 9 
Induction Treatment for the DLBCL Expansion Phase............. 101 
Table 10 
Post-Induction Treatment for the DLBCL Expansion Phase .... 101 
Table 11 
Polatuzumab Vedotin plus Obinutuzumab−Containing 
Regimens for the Treatment of Follicular Lymphoma .............. 108 
Table 12 
Administration of First and Subsequent Infusions of 
Rituximab.................................................................................. 125 
Table 13 
Premedication........................................................................... 128 
Table 14 
Proposed Non-Inherited Biomarkers......................................... 136 
Table 15 
Polatuzumab Vedotin Dose-Reduction Steps ........................... 154 
Table 16 
Lenalidomide Dose-Reduction Steps........................................ 155 
Table 17 
Guidelines for Management of Hematologic Toxicities That 
Occur during Induction Treatment (Except Days 8 and 15 of 
Cycle 1 for Patients Receiving Obinutuzumab)........................ 156 
Table 18 
Guidelines for Management of Hematologic Toxicities That 
Occur on Days 8 and 15 of Cycle 1 for Patients Receiving 
Obinutuzumab.......................................................................... 157 
Table 19 
Guidelines for Management of Non-Hematologic Toxicities 
During Induction........................................................................ 158 
Table 20 
Guidelines for Management of Toxicities that Occur during 
Consolidation or Maintenance Treatment ................................. 162 
Table 21 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 166 
Table 22 
Potential 90% CI for the True Probability of Achieving a PET-
CT−Defined Complete Response at End of Induction............... 179 
 


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LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 89 
Figure 2 
Follicular Lymphoma Dose-Escalation Plan............................... 93 
Figure 3 
DLBCL Dose-Escalation Plan..................................................... 99 
Figure 4 
Induction and Post-Induction Treatment Regimen.................... 120 
Figure 5 
Guidelines for Obinutuzumab Infusions:  First Infusion............. 122 
Figure 6 
Guidelines for Obinutuzumab Infusions:  Second and 
Subsequent Infusions................................................................ 123 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments for Patients with Follicular 
Lymphoma ................................................................................ 197 
Appendix 2 
Schedule of Assessments for Patients with Diffuse Large B-
Cell Lymphoma......................................................................... 203 
Appendix 3 
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Obinutuzumab, Polatuzumab Vedotin, and Lenalidomide in 
Relapsed or Refractory FL Patients .......................................... 209 
Appendix 4 
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Rituximab, Polatuzumab Vedotin, and Lenalidomide 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 
Calculation of Creatinine Clearance Using the 
Cockcroft-Gault Formula........................................................... 225 
Appendix 8 
Anaphylaxis Precautions........................................................... 226 
Appendix 9 
Ann Arbor Staging..................................................................... 227 
Appendix 10 Follicular Lymphoma International Prognostic Index and 
International Prognostic Index................................................... 228 
Appendix 11 
Treatment of Relapsed or Refractory Follicular and Diffuse 
Large B-Cell Lymphomas ......................................................... 231 
Appendix 12 
Diagnostic Criteria for Tumor Lysis Syndrome........................ 236 
 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
59/Protocol GO29834, Version 2 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE Ib/II STUDY EVALUATING THE SAFETY 
AND EFFICACY OF OBINUTUZUMAB IN 
COMBINATION WITH POLATUZUMAB VEDOTIN 
AND LENALIDOMIDE IN PATIENTS WITH 
RELAPSED OR REFRACTORY FOLLICULAR 
LYMPHOMA AND RITUXIMAB IN 
COMBINATION WITH POLATUZUMAB 
VEDOTIN AND LENALIDOMIDE IN PATIENTS 
WITH RELAPSED OR REFRACTORY DIFFUSE 
LARGE B-CELL LYMPHOMA 
PROTOCOL NUMBER: GO29834 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-001999-22 
IND NUMBER: 
109409 
TEST PRODUCT: 
Obinutuzumab (RO5072759) 
Rituximab (RO0452294) 
Polatuzumab vedotin (DCDS4501A; RO5541077)  
Lenalidomide  
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.   


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
60/Protocol GO29834, Version 2 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE Ib/II STUDY EVALUATING THE SAFETY AND 
EFFICACY OF OBINUTUZUMAB IN COMBINATION WITH 
POLATUZUMAB VEDOTIN AND LENALIDOMIDE IN PATIENTS 
WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA 
AND RITUXIMAB IN COMBINATION WITH 
POLATUZUMAB VEDOTIN AND LENALIDOMIDE IN 
PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE 
LARGE B-CELL LYMPHOMA 
PROTOCOL NUMBER: 
GO29834 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2015-001999-22 
IND NUMBER: 
109409 
TEST PRODUCT: 
Obinutuzumab (RO5072759) 
Rituximab (RO0452294) 
Polatuzumab vedotin (DCDS4501A; RO5541077)  
Lenalidomide  
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 lenalidomide 
(G + Pola + Len) in patients with relapsed or refractory (R/R) follicular lymphoma (FL) and 
rituximab in combination with polatuzumab vedotin and lenalidomide (R + Pola + Len) in 
patients with R/R DLBCL, followed by post-induction treatment with obinutuzumab in 
combination with lenalidomide (G + Len) (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 post-induction treatment with rituximab plus lenalidomide (R + Len) (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 below. 
In this study, "study treatment" refers to the protocol-mandated treatments under study (i.e., 
obinutuzumab, rituximab, polatuzumab vedotin, and lenalidomide). 
Safety Objective 
The safety objectives for this study are as follows: 
• 
To determine the recommended Phase II dose (RP2D) for polatuzumab vedotin and 
lenalidomide when given in combination with a fixed dose of obinutuzumab and the RP2D 
of lenalidomide when given in combination with a fixed dose of polatuzumab vedotin and 
rituximab on the basis of the following endpoint: 
Incidence of dose-limiting toxicities (DLTs) during the first cycle of study treatment 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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• 
To evaluate the safety and tolerability of G + Pola + Len and R + Pola + Len on the basis of 
the following endpoints 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 Objective 
Response will be determined on the basis of positron emission tomography (PET) and 
computed tomography (CT) scans or CT scans alone, using Revised Lugano Response Criteria 
for Malignant Lymphoma, hereinafter referred to as the Lugano 2014 criteria.  Response will be 
determined by an Independent Review Committee (IRC) and by the investigator. 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of induction treatment 
with G + Pola + Len in R/R FL and R + Pola + Len in 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 
 
Secondary Efficacy Objectives 
The secondary efficacy objective for this study is to evaluate the efficacy of induction treatment 
with G + Pola + Len and maintenance treatment with G + Len in R/R FL and of induction 
treatment with R + Pola + Len and consolidation treatment with R + Len in 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 
 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
G + Pola + Len and R + Pola + Len 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 end of 
consolidation (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, defined, among patients achieving 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 
• 
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 lenalidomide when given in combination 
on the basis of the following endpoints: 
• 
Observed serum obinutuzumab concentration at specified timepoints 
• 
Observed serum rituximab concentration 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 E) at specified timepoints 
• 
Observed plasma lenalidomide concentration at specified timepoints 
 
Immunogenicity Objectives 
The immunogenicity objective for this study is to evaluate the immune response to 
obinutuzumab, rituximab, and 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 human anti-chimeric antibodies (HACAs) to rituximab during the study 
relative to the prevalence of HACAs at baseline 
• 
Incidence of anti-therapeutic antibodies (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 HACAs, and ATAs on the basis of the following endpoint: 
• 
Correlation between HAHA or HACA, and ATA status and respective 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, pharmacokinetics, or 
immunogenicity endpoints 
 
Study Design 
Description of Study 
This Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study will evaluate 
the safety, efficacy, and pharmacokinetics of G + Pola + Len in patients with R/R FL and 
R + Pola + Len 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 lenalidomide 
will be given at their RP2Ds.   
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.   
To characterize the PK properties of obinutuzumab, rituximab, polatuzumab vedotin, and 
lenalidomide, blood samples will be obtained at various timepoints before and during study 
treatment administration. 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
63/Protocol GO29834, Version 2 
Response will be determined by the IRC and the investigator using the Lugano 2014 criteria.  
The primary efficacy endpoint will be based on IRC assessment of response.   
Number of Patients 
Approximately 110−128 patients are expected be enrolled in this study, at approximately 
20−25 investigative sites worldwide. 
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 + Len treatment group:  R/R FL after treatment with at least one 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 + Len treatment group:  R/R DLBCL after treatment with at least one prior 
chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody in 
patients who are not eligible for autologous stem-cell transplantation or who have 
experienced disease progression following treatment with high-dose chemotherapy plus 
autologous stem-cell transplantation 
• 
Histologically documented CD20-positive B-cell 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) 
• 
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-needle, 
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 repeat core-needle biopsy is 
strongly recommended.   
• 
Agreement to abstain from donating blood during the treatment period (including periods of 
treatment interruption) and for 28 days after the last dose of study treatment 
• 
Agreement not to share study medication with another person 
• 
Agreement to comply with all local requirements of the lenalidomide risk minimization plan 
In every country where lenalidomide has been approved, a risk minimization plan, 
which includes a pregnancy prevention program, is in place.  The risk minimization plan 
should be followed by patients using lenalidomide.   
US sites only:  Per standard Revlimid REMS™ requirements, all physicians who 
prescribe lenalidomide for research subjects enrolled into this study, and all research 
subjects enrolled into this study, must be registered in and must comply with all 
requirements of the Revlimid REMS™ program.  
For Ex-US sites only:  Subjects will be counseled on pregnancy prevention prior to 
medication being dispensed to ensure that the subject has complied with all 
requirements including use of birth control and pregnancy testing and that the 
subject understands the risks associated with lenalidomide.  This step will be 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
64/Protocol GO29834, Version 2 
documented with a completed Education and Counseling Guidance Document (refer 
to Lenalidomide Pregnancy Prevention Risk Management Plans), and no drug will be 
dispensed until this step occurs.  Counseling includes verification with the subject 
that required pregnancy testing was performed and results were negative.  A 
Lenalidomide Information Sheet (refer to Lenalidomide Pregnancy Prevention Risk 
Management Plans) will be supplied with each medication dispense.  All requirements 
must be followed by each site as noted within the Lenalidomide Pregnancy Prevention 
Risk Management Plans. 
In addition, because lenalidomide will be administered in combination with 
obinutuzumab, rituximab, and polatuzumab vedotin, patients must comply with 
contraceptive measures designed to ensure safe administration of all study treatments 
as outlined below.  
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including at least 
one method with a failure rate of  < 1% per year, for at least 12 months after the last dose of 
polatuzumab vedotin, 28 days after the last dose of lenalidomide, 12 months after the last 
dose of rituximab, and 28 days prior to Day 1 of Cycle 1, during the treatment period 
(including periods of treatment interruption), and for 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 (≥ 24 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 progestogen-only hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.  Combined oral contraceptives are not recommended 
because of the increased risk of venous and arterial thromboembolism (TE) in patients 
taking lenalidomide. 
Barrier methods may be used as the second contraceptive method but must always be 
supplemented with the use of a spermicide. 
• 
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, 28 days after the last dose of lenalidomide, and 3 months 
after the last dose of obinutuzumab or rituximab.  Men must refrain from donating 
sperm during this 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, 
28 days after the last dose of lenalidomide, and 3 months after the last dose of 
obinutuzumab or rituximab to avoid exposing the embryo.  
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. 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
65/Protocol GO29834, Version 2 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Grade 3b follicular lymphoma 
• 
History of transformation of indolent disease to DLBCL 
• 
Known CD20-negative status at relapse or progression 
• 
Central nervous system lymphoma or leptomeningeal infiltration 
• 
Prior allogeneic stem-cell transplantation (SCT) 
• 
Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1 
• 
History of resistance to lenalidomide or response duration of < 1 year (for patients who had 
a response to a prior lenalidomide-containing regimen)  
• 
Prior standard or investigational anti-cancer therapy as specified below: 
Lenalidomide, fludarabine, or alemtuzumab within 12 months prior to Day 1 of Cycle1 
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 
• 
Clinically significant toxicity (other than alopecia) from prior therapy that has not resolved to 
Grade  ≤ 2 (per NCI CTCAE, Version 4.0) prior to Day 1 of Cycle 1 
• 
Treatment with systemic immunosuppressive medications, including, but not limited to, 
prednisone, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor agents 
within 2 weeks prior to Day 1 of Cycle 1 
Treatment with inhaled corticosteroids and mineralocorticoids is permitted. 
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 
initiation 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 obinutuzumab, 
rituximab, polatuzumab vedotin, or lenalidomide formulations 
• 
History of erythema multiforme, Grade  ≥ 3 rash, or desquamation (blistering) following prior 
treatment with immunomodulatory derivatives such as thalidomide and lenalidomide 
• 
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. 
• 
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 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
66/Protocol GO29834, Version 2 
Any previously treated malignancy that has been in remission without treatment for  ≥ 2 
years prior to enrollment 
• 
Contraindication to treatment for TE prophylaxis  
• 
Grade  ≥ 2 neuropathy 
• 
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 intravenous (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 (using the Cockcroft-Gault formula) 
AST or ALT  > 2.5 × upper limit of normal (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 two negative serum pregnancy test results 
(minimum sensitivity, 25 mIU/mL) prior to initiating therapy:  at 10−14 days prior to 
Day 1 of Cycle 1 and within 24 hours 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 patients with FL 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 patients with DLBCL have been followed for at least 1 year after they have 
completed or discontinued study treatment (including induction treatment and consolidation 
treatment as applicable). 
 
Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 5 years. 
Investigational Medicinal Products 
The investigational medicinal products for this study are obinutuzumab, rituximab, 
polatuzumab vedotin, and lenalidomide. 
Dosing Schedule for Patients with Relapsed or Refractory Follicular Lymphoma 
Obinutuzumab 
Dose-Escalation Phase, Induction 
Patients will receive obinutuzumab 1000 mg IV on Days 1, 8, and 15 of Cycle 1 and on Day 1 of 
each subsequent 28-day cycle for up to a total of 6 cycles. 


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Expansion Phase, Induction 
Patients will receive obinutuzumab 1000 mg IV on Days 1, 8, and 15 of Cycle 1 and on Day 1 of 
each subsequent 28-day cycle for up to a total of 6 cycles. 
Post-Induction (Maintenance Treatment) 
Patients will receive obinutuzumab 1000 mg IV on Day 1 of every other month (i.e., every 
2 months), starting with Month 1 (i.e., Months 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23) for a 
maximum of 24 months 
Polatuzumab Vedotin 
Dose-Escalation Phase, Induction 
Patients will receive polatuzumab vedotin 1.4 or 1.8 mg/kg IV on Day 1 of each 28-day cycle for 
up to 6 cycles. 
Expansion Phase, Induction 
Patients will receive polatuzumab vedotin RP2D (mg) by mouth (PO) on Day 1 of each 28-day 
cycle for up to 6 cycles. 
Post-Induction (Maintenance) 
No polatuzumab vedotin will be administered. 
Lenalidomide 
Dose-Escalation Phase, Induction 
Patients will receive lenalidomide 10, 15, or 20 mg PO once daily on Days 1−21 of each 28-day 
cycle for up to 6 cycles. 
Expansion Phase, Induction 
Patients will receive lenalidomide RP2D (mg) PO once daily on Days 1−21 of each 28-day cycle 
for up to 6 cycles. 
Post-Induction 
Patients will receive lenalidomide 10 mg PO once daily on Days 1−21 of each month for a 
maximum of 12 months  
Dosing Schedule for Patients with Relapsed or Refractory DLBCL 
Rituximab 
Dose-Escalation Phase, Induction 
Patients will receive rituximab 375 mg/m2 IV on Day 1 of each 28-day cycle for up to 6 cycles. 
Expansion Phase, Induction 
Patients will receive rituximab 375 mg/m2 IV on Day 1of every other month (i.e., every 
2 months) starting with Month 1 (i.e., Months 1, 3, 5) for up to 6 cycles. 
Post-Induction 
Patients will receive rituximab 375 mg/m2 IV on Day 1 of every other month for (i.e,  every 
2 months starting with Month 1 (i.e., Months 1, 3, 5) a maximum of 6 months of additional 
treatment. 
Polatuzumab Vedotin 
Dose-Escalation Phase, Induction 
Patients will receive polatuzumab vedotin 1.8 mg/kg IV on Day 1 of each 28-day cycle for up 
to 6 cycles. 
Expansion Phase, Induction 
Patients will receive polatuzumab vedotin 1.8 mg/kg IV on Day 1 of each 28-day cycle for up 
to 6 cycles. 
Post-Induction 
No polatuzumab vedotin will be administered. 


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Lenalidomide 
Dose-Escalation Phase, Induction 
Patients will receive lenalidomide 10, 15, or 20 mg PO once daily on Days 1−21 of each 
28-day cycle for up to 6 cycles. 
Expansion Phase, Induction 
Patients will receive lenalidomide RP2D (mg) PO once daily on Days 1−21 of each 28-day 
cycle for up to 6 cycles. 
Expansion Phase, Post-Induction 
Patients will receive lenalidomide 10 mg PO once daily on Days 1−21 of each month for a 
maximum of 6 months  
Statistical Methods 
Primary Analysis 
Safety 
The safety analyses will include all treated patients (i.e., patients who received any amount of 
study treatment).  Data for patients in the dose-escalation phase will be summarized by cohort 
and histology type, and data for patients in the expansion phase will be summarized by 
histologic subtype (FL or DLBCL).  
Safety will be assessed through summaries of adverse events and changes from baseline in 
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, Version 4.0 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. 
Efficacy 
The primary efficacy analysis will be estimation of the proportion of patients achieving a CR at 
EOI, as determined by the IRC through use of the PET-CT-based Lugano 2014 criteria.  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. 
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 5 cohorts of 3−6 patients each, for a total of 18−30 patients, will 
be required to establish the RP2D during the dose-escalation phase for patients with R/R FL.  
An additional 3 possible cohorts of 3−6 patients each, for a total of 12−18 patients will be 
required to establish the RP2D during the dose-escalation phase for patients with R/R DLBCL. 
Approximately 80 patients (40 patients with FL and 40 patients with DLBCL) will be enrolled 
during the expansion phase.  Overall, approximately 110−128 patients will be enrolled in the 
study. 
The primary efficacy analysis will be the 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 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%. 


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Interim Analyses 
It is anticipated that at least two interim analyses, one per histology, will be conducted during 
the expansion phase of the study, when at least 15 patients in each histology have been 
evaluated for PET-CT-defined CR at 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 indication specific expansion cohort with that in 
historical controls.  Updated estimates for the assumed historical control PET-CT-defined CR 
rate will be available from currently ongoing studies by the time of the first interim analysis.  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 indication specific 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 subgroup.   
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. 
 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
1L 
first line 
ABC 
activated (non-germinal) B cell–like (subgroup) 
acMMAE 
antibody-conjugated MMAE 
ADC  
antibody-drug conjugate 
AML 
acute myelogenous leukemia 
ASCO 
American Society of Clinical Oncology 
ATA 
anti-therapeutic antibody 
AUCinf 
area under the concentration-time curve extrapolated to 
infinity 
BSA 
body surface area 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and 
prednisolone or prednisone 
CHP 
cyclophosphamide, doxorubicin, and prednisone or 
prednisolone  
CI 
confidence interval 
CL 
clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration 
CR 
complete response 
CRu 
complete response unconfirmed 
CT 
computed tomography 
CVP 
cyclophosphamide, vincristine, and prednisone 
DFS 
disease-free survival 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DVT 
deep vein thrombosis 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFS 
event-free survival 
EOC 
end of consolidation  
EOI 
end of induction 
EORTC 
European Organization for Research and Treatment of 
Cancer 
ESMO 
European Society for Medical Oncology 
FDA 
United States Food and Drug Administration 


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FDG 
fluorodeoxyglucose 
FL 
follicular lymphoma 
FLIPI, FLIPI2 
Follicular Lymphoma International Prognostic Index 
Follicular Lymphoma International Prognostic Index 2 
G 
obinutuzumab (GA101) 
G-benda 
obinutuzumab plus bendamustine 
G-CHOP 
obinutuzumab in combination with cyclophosphamide, 
doxorubicin, vincristine, and prednisolone or prednisone 
G-CHP 
obinutuzumab plus cyclophosphamide, doxorubicin, and 
prednisone 
G-CVP 
obinutuzumab in combination with cyclophosphamide, 
vincristine, and prednisone 
G + Len 
obinutuzumab plus lenalidomide 
G + Pola 
obinutuzumab plus polatuzumab vedotin 
G + Pola + Len 
obinutuzumab plus polatuzumab vedotin plus lenalidomide 
GCB 
germinal center B cell–like (subgroup) 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
HACA  
anti-chimeric antibodies 
HAHA 
human anti-human antibody 
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 
ICH 
International Council for Harmonisation 
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 
IV 
intravenous 
IxRS 
interactive voice or web-based response system 
Len 
lenalidomide 
LMWH 
low-molecular-weight heparin 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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MAD 
maximum administered dose 
MCL 
mantle cell lymphoma 
MC-VC-PABC 
maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl 
MDS 
myelodysplastic syndrome 
MMAE 
mono-methyl auristatin E 
MOA 
mechanism of action 
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 evaluable 
NHL 
non-Hodgkin’s lymphoma 
NK 
natural killer 
OS 
overall survival 
P 
polatuzumab vedotin  
PD 
pharmacodynamic 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PO 
by mouth 
Pola 
polatuzumab vedotin 
PR 
partial response 
Q3W 
every 3 weeks 
R-CHOP 
rituximab in combination with cyclophosphamide, 
doxorubicin, vincristine, and prednisolone or prednisone 
R-CHP 
rituximab plus cyclophosphamide, doxorubicin, and 
prednisone or prednisolone 
RCR 
Roche Clinical Repository 
R-DHAP 
rituximab plus cisplatin, cytosine arabinoside, and 
dexamethasone 
R-ICE 
rituximab plus ifosfamide, carboplatin, and etoposide 
R + Len 
rituximab plus lenalidomide 
R + Pola + Len 
rituximab plus polatuzumab vedotin plus lenalidomide 
RP2D 
recommended Phase II dose 
R/R 
relapsed or refractory 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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SCT 
stem-cell transplantation 
SJS 
Stevens-Johnson syndrome 
SLL 
small lymphocytic lymphoma 
SmPC 
Summary of Product Characteristics 
SWFI 
Sterile Water for Injection  
t½ 
half-life  
TAb 
total antibody 
TE 
thromboembolism 
TEN 
toxic epidermal necrolysis 
TFR 
tumor flare reaction 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
Vss 
volume of distribution at steady state 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON B-CELL LYMPHOMA 
B-cell lymphoma is the most common hematologic malignancy in adults.  In 2013, there 
were an estimated 69,740 new cases and 19,020 deaths due to the disease in the 
United States (Siegel et al. 2013).  In Europe, there were an estimated 93,400 new 
cases and 37,900 deaths in 2012 (Ferlay et al. 2013).  Non-Hodgkin’s lymphoma is most 
often of B-cell origin, including a wide range of different subtypes of B-cell lymphoma, 
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 B-cell lymphomas.  Follicular lymphoma (FL) is 
the most common subtype of indolent B-cell lymphoma, accounting for about 22% of all 
newly diagnosed cases of B-cell lymphoma (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, an anti-CD20 monoclonal antibody, to commonly used induction 
chemotherapy, including CHOP (cyclophosphamide, doxorubicin, vincristine, and 
prednisolone or prednisone), CVP (cyclophosphamide, vincristine, and prednisone), 
fludarabine, or bendamustine (Zelenetz et al. 2014; Dreyling 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 in patients responding 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.  Thus, new treatments are needed to improve the outcome for these patients. 
1.1.2 
Diffuse Large B-Cell Lymphoma 
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell 
lymphoma, accounting for approximately 30% of all B-cell lymphomas diagnosed 
annually (Armitage and Weisenburger 1998).  The use of immunochemotherapy, most 
commonly rituximab + CHOP (R-CHOP), for newly diagnosed DLBCL led to a significant 
improvement in survival in patients of all age groups.  In older patients (> 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) 
with favorable prognostic features, R-CHOP demonstrated a 3-year EFS rate of 79% 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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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 only 40% following 
treatment with R-CHOP (Zhou et al. 2014). 
Second-line therapies include high-dose chemotherapy regimens such as R-ICE 
(rituximab plus ifosfamide, carboplatin, and etoposide) or R-DHAP (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 had 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 predictive of poor outcome 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 ("double-hit" DLBCL), observed in 2%−11% of patients with 
DLBCL, represents a DLBCL subset with an inferior outcome (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 approximately 20% of patients with DLBCL (Lossos and 
Morgensztern 2006) and are strong predictors of poor overall survival (OS; Young et al. 
2008; Xu-Monette et al. 2012). 
DLBCL remains a high unmet medical need for which novel targeted therapies are 
needed to move the field beyond R-CHOP. 
1.2 
BACKGROUND ON OBINUTUZUMAB 
Obinutuzumab (also known as GA101) 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, resulting in enhanced 
antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis 
(Beers et al. 2010; Mössner et al. 2010; Herter et al. 2014).  Together, these 
characteristics confer obinutuzumab with enhanced immune effector functions and B-cell 
depleting activity compared with rituximab.  


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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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, obinutuzumab demonstrated superior depletion of normal B cells 
(measured as CD19+ depletion) from the blood of healthy volunteers (Mössner et al. 
2010) as well as malignant B cells from the blood of patients with CLL (Patz et al. 2011).  
Nonclinical xenograft experiments performed with obinutuzumab as monotherapy and in 
combination with chemotherapy have consistently showed promising anti-tumor activity 
of obinutuzumab (Mössner et al. 2010; Dalle et al. 2011) and have demonstrated the 
superiority of obinutuzumab over rituximab (Herting et al. 2014). 
For more detailed nonclinical information on 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 studies (GAO4735g, BO21004/CLL11, MO28543, BO21223, and BO21005).  
Available efficacy results from the non-Hodgkin’s lymphoma (NHL) cohorts in these 
studies and available safety results from all patients are summarized below  
For more detailed clinical information on obinutuzumab, including results in the CLL 
cohorts of the clinical studies and clinical pharmacology data, please refer to the 
Obinutuzumab Investigator’s Brochure. 
1.2.2.1 
Clinical Efficacy of Obinutuzumab in Patients with B-Cell 
Lymphoma 
In studies of obinutuzumab monotherapy in patients with relapsed or refractory (R/R) B-
cell lymphoma (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 (e.g., CHOP, 
bendamustine) in patients with previously untreated, or R/R B-cell lymphoma (Studies 
BO21000, GAO4915g, and GAO4753g), the proportion of patients with a CR or PR at 
the end of induction (EOI) 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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Phase III Study GAO4753g investigated obinutuzumab plus bendamustine (G-benda) 
compared with bendamustine alone in patients with rituximab-refractory indolent NHL 
(iNHL; n = 396).  Patients in the G-benda arm who had not experienced disease 
progression at EOI 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 G-benda arm, with a median investigator-assessed 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).   
Phase III Study BO21223 investigated obinutuzumab plus chemotherapy (G-benda, 
obinutuzumab plus CVP [G-CVP], obinutuzumab plus CHOP [G-CHOP]) compared 
with rituximab plus chemotherapy, followed by obinutuzumab or rituximab 
maintenance in patients with previously untreated 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). 
Phase III Study BO21005 investigated 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 lenalidomide (Vitolo et al. 2016).   
1.2.2.2 
Clinical Safety of Obinutuzumab 
As of 4 July 2016, an estimated 3636 patients with B-cell lymphoma (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 to 2000 mg.  Overall, the 
safety of obinutuzumab monotherapy and obinutuzumab combination therapy was 
manageable. 
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 (obinutuzumab 1000 mg vs. 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 


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patients receiving obinutuzumab plus chlorambucil (Study BO21004) to 100% in patients 
with R/R disease who received obinutuzumab monotherapy (pooled data from Studies 
BO21003 and BO20999, CLL cohorts).   
In the B-cell lymphoma population, the incidence of IRRs in studies of obinutuzumab 
monotherapy was 75.1% (pooled data from Study BO21003 and from high-dose B-cell 
lymphoma cohorts from Study BO20999).  In studies of obinutuzumab in combination 
with either CHOP (Study GAO4915g) or bendamustine (Study BO21000), the incidence 
of IRRs, regardless the relationship with obinutuzumab, was 70%−78%. 
Other important risks associated or potentially associated with obinutuzumab are tumor 
lysis syndrome (TLS), thrombocytopenia (including acute thrombocytopenia), 
neutropenia, prolonged B-cell depletion, infections (including progressive multifocal 
leukoencephalopathy [PML] and hepatitis B virus [HBV] reactivation), worsening of 
preexisting cardiac conditions, gastrointestinal (GI) perforation, impaired immunization 
response, immunogenicity, 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. 
1.2.2.3 
Clinical Pharmacokinetics of Obinutuzumab 
A two-compartment pharmacokinetic model composed of a linear clearance pathway 
and a nonlinear, time-varying clearance pathway adequately described serum 
obinutuzumab concentration data.  Terminal obinutuzumab clearance and half-life are 
approximately 0.09 L/day and 28.4 days, respectively.  The initial clearance of 
obinutuzumab was approximately 2.8 times higher than the steady-state clearance, 
consistent with a decrease in the time-varying clearance component, which is high at the 
start of treatment and declines with repeated cycles of obinutuzumab treatment.  The 
time-varying clearance pathway is consistent with the target-mediated drug disposition 
such that, at the start of treatment, there is a large quantity of CD20-positive cells that 
rapidly bind obinutuzumab.  Repeated dosing of obinutuzumab saturates the pool of 
CD20-positive cells, hence reducing this component in clearance.  The linear clearance 
pathway is consistent with the catabolism of IgG antibodies and is therefore independent 
of CD20-positive cells.  Additional details can be found in the Obinutuzumab 
Investigator’s Brochure. 
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 B-cell lymphoma 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 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
79/Protocol GO29834, Version 2 
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 
advantage of the specific targeting capability of the antibody, the cytotoxic activity of 
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 B-cell lymphoma. 
1.3.1 
Nonclinical Studies with Polatuzumab Vedotin 
Comprehensive pharmacologic, pharmacokinetic (PK), pharmacodynamics (PD), 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 murine xenograft models 
of human CD79b-positive B-cell lymphoma.  Additionally, when combined with rituximab 
plus chemotherapy (rituximab in combination with cyclophosphamide, doxorubicin, and 
prednisone or prednisolone [CHP] or bendamustine), polatuzumab vedotin 
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) in xenograft models of B-cell lymphoma.  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 the 
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 the ADC 
and total monoclonal antibody). 
Refer to the Polatuzumab Vedotin Investigator’s Brochure for complete details of the 
biochemical composition and nonclinical studies. 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
80/Protocol GO29834, Version 2 
1.3.2 
Clinical Studies with Polatuzumab Vedotin 
To date, clinical data on polatuzumab vedotin are available from one completed 
Phase I/Ib study (DCS4968g) and the ongoing Phase Ib/II Studies GO27834, GO29044, 
GO29833, 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 rituximab plus 
cyclophosphamide, doxorubicin, and prednisone (R-CHP) or obinutuzumab plus 
cyclophosphamide, doxorubicin, and prednisone (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.   
Available efficacy and safety results from these studies are summarized in 
Sections 1.3.2.1 and 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 Efficacy of Polatuzumab Vedotin in Patients with B-Cell 
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. 
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 those 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). 


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Preliminary data show that for patients in Study GO27834 who received polatuzumab 
vedotin (2.4 mg/kg) in combination with rituximab overall 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 
(1.8mg/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 months) 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, 
the 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 patient with CR) when 
combined with obinutuzumab. 
1.3.2.2 
Clinical Safety of Polatuzumab Vedotin 
Clinical safety data are available from 327 patients with B-cell lymphoma 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 G-CHP or R-CHP (GO29044), or 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 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
82/Protocol GO29834, Version 2 
common (occurring 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 (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 
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- 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.   
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% to  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 G-CHP or R-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 rituximab plus bendamustine and 39% of patients 
receiving polatuzumab vedotin in combination with obinutuzumab plus bendamustine.   


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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A total of 44 deaths have been reported:  11 deaths in patients treated with single-agent 
polatuzumab vedotin and 33 deaths in patients treated with polatuzumab vedotin 
combined with rituximab or obinutuzumab.  The majority of deaths were judged as 
related to disease progression. 
1.3.2.3 
Clinical Pharmacokinetics of Polatuzumab Vedotin 
The pharmacokinetics of antibody-conjugated MMAE (acMMAE), total antibody (TAb), 
and unconjugated MMAE appear to be dose-proportional across the dose range of 
0.1−2.4 mg/kg of polatuzumab vedotin.  At the polatuzumab vedotin dose level of 
2.4 mg/kg, mean half-life values range from 5.2 to 6.3 days for acMMAE and from 6.2 to 
8.1 days for TAb.  The mean clearance values range from 16.2 to 23.8 mL/day/kg for 
acMMAE and from 11.4 to 28.0 mL/day/kg for TAb, which suggests that the disposition 
of acMMAE, as characterized by a small steady-state volume of distribution and slow 
clearance, is largely dominated by its antibody component.  Across doses tested 
(0.1−2.4 mg/kg), the exposure of acMMAE (e.g., Cmax, AUCinf) is, on average, 100 to 
150- and ~50-fold higher than the corresponding unconjugated MMAE exposure.  MMAE 
peak concentrations are reached 2−3 days after dosing.  The mean half-life for 
unconjugated MMAE is 2.9−6.4 days, which is similar to the corresponding value for 
acMMAE and suggestive of formation rate-limited kinetics of unconjugated MMAE due to 
the ADC catabolism.   Combination with the anti-CD20 antibody rituximab does not 
appear to affect the PK of acMMAE, TAb, and unconjugated MMAE in the R/R BCL 
patient population. 
1.4 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Progress has been made in the treatment of FL and DLBCL; however, a significant 
number of patients will relapse or die of progression or treatment-related toxicity.  
Patients who relapse after receiving several prior treatments may not be able to tolerate 
more bone marrow toxicity, thereby limiting their treatment options.  There is a need for 
the continued development of safe and effective therapies for patients with disease that 
relapses and for patients 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 lenalidomide. 
B-cell lymphomas, including FL and DLBCL, express the CD20 antigen, and anti-CD20 
therapy (rituximab) has been demonstrated to provide enhanced anti-tumor activity when 
given in combination with other agents, leading to increased response rates, PFS, and 
OS (Coiffier et al. 2002; Coiffier et al. 2007; Coiffier et al. 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).  This has led to the acceptance of 
rituximab as a standard component in initial therapy.   
Obinutuzumab has shown superiority over rituximab in a Phase III study in first-line CLL 
(Goede et al. 2014).  Obinutuzumab showed clinical benefit compared to rituximab 
when combined with chemotherapy in a Phase III trial (BO21223) in patients with 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
84/Protocol GO29834, Version 2 
previously untreated indolent B-cell lymphomas, including FL (Marcus et al. 2016).  A 
Phase III study, GAO4753g, evaluated patients with rituximab-refractory indolent B-cell 
lymphoma, including patients with FL, and showed improvement in PFS with 
obinutuzumab  added to bendamustine followed by obinutuzumab maintenance 
compared with bendamustine alone (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 
(BO21005) comparing R-CHOP to G-CHOP in patients with previously untreated 
DLBLC (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 lenalidomide.   
In addition to the potential for obinutuzumab as the next-generation anti-CD20 therapy to 
enhance the efficacy of current standard immunochemotherapy regimens in patients 
with FL, ADCs may have added benefit when combined with standard systemic 
chemotherapy, or 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 expressing CD79b.  MMAE has a mechanism of 
action similar to that of vincristine and is hypothesized to be a more targeted therapy.  
To date, Phase Ib/II data suggest that polatuzumab vedotin in combination with 
rituximab has activity in R/R FL and DLBCL, with a generally acceptable safety and 
tolerability profile.  Additionally, several ongoing Phase Ib/II studies are assessing the 
safety and clinical activity of the combination of obinutuzumab and polatuzumab vedotin 
alone and in combination with chemotherapy (see Section 3.3.3.2 for details).  
Lenalidomide, a thalidomide analogue, is a potent immunomodulatory agent with activity 
in lymphoid malignancies occurring primarily through immune modulation and direct 
anti-tumor effects.  Although lenalidomide has not been approved for the treatment of 
R/R FL and DLBCL, clinical activity has been demonstrated with lenalidomide as a 
single agent (Wiernik et al. 2008; Witzig et al. 2009, 2011) or in combination with 
rituximab (Zinzani et al. 2011, 2013; Leonard et al. 2012; Tuscano et al. 2014; 
Wang et al. 2013).  Obinutuzumab in combination with lenalidomide is currently being 
evaluated in an ongoing Phase Ib/II study sponsored by the Lymphoma Academic 
Research Organisation (GALEN study) in patients with R/R FL and aggressive 
lymphoma (DLBCL and mantle cell lymphoma [MCL]).  This study evaluated a fixed 
dose of obinutuzumab in combination with lenalidomide doses of 10−25 mg/day.  
Preliminary data indicate a manageable safety profile.  An increased incidence of Grade 
3/4 neutropenia was reported.  Of the 19 evaluable patients, 13 (68%) achieved an 
overall response (see Section 3.3.3.2.2 for details).   
On the basis of the distinct mechanisms of action (MOAs) for each molecule and the 
current available clinical data, there is a strong rationale to expect an improved 
benefit-risk profile with the triplet combination of obinutuzumab or rituximab plus 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
85/Protocol GO29834, Version 2 
polatuzumab vedotin and lenalidomide.  This novel triplet regimen may have the 
potential to extend treatment-free remissions and to decrease toxicity by improving upon 
individual agents used as part of current standard of care, which includes traditional 
chemotherapy.  Early clinical data that evaluated obinutuzumab, rituximab, 
polatuzumab vedotin, and lenalidomide each as single-agents has been associated with 
neutropenia.  Rituximab and polatuzumab vedotin and rituximab and lenalidomide 
doublet combinations have also been associated with neutropenia.  The replacement of 
rituximab with obinutuzumab (Study GO27834 [obinutuzumab plus polatuzumab vedotin 
{G + Pola}] and GALEN [obinutuzumab plus lenalidomide {G + Len}]) in these doublets is 
anticipated to be associated with treatment-related neutropenia.  Patients with 
overlapping toxicities will be closely monitored; such events are expected to be 
manageable in the clinical setting, and drug-drug interactions (DDIs) are unlikely to 
occur (see Sections 5.1.5 and 5.1.6). 
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 lenalidomide 
(G + Pola + Len) in patients with R/R FL and rituximab in combination with polatuzumab 
vedotin and lenalidomide (R + Pola + Len) in patients with R/R DLBCL, followed by 
post-induction treatment with G + Len (referred to as maintenance) in patients with FL 
who achieve a CR, PR, or stable disease at EOI and post-induction treatment with 
rituximab plus lenalidomide (R + Len; 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 below. 
In this study, "study treatment" refers to the protocol-mandated treatments under study 
(i.e., obinutuzumab, rituximab, polatuzumab vedotin, and lenalidomide). 
2.1 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To determine the RP2D for polatuzumab vedotin and lenalidomide when given in 
combination with a fixed dose of obinutuzumab and the RP2D of lenalidomide when 
given in combination with a fixed dose of polatuzumab vedotin and rituximab 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 + Len and R + Pola + Len on the 
basis of the following endpoints 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 
 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
86/Protocol GO29834, Version 2 
2.2 
EFFICACY OBJECTIVES 
Response will be determined on the basis of positron emission tomography (PET) and 
computed tomography (CT) scans or CT scans alone, using Revised Lugano Response 
Criteria for Malignant Lymphoma (Cheson et al. 2014), hereinafter referred to as the 
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 induction 
treatment with G + Pola + Len in R/R FL and R + Pola + Len in 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  
 
2.2.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of induction 
treatment with G + Pola + Len and maintenance treatment with G + Len in R/R FL and of 
induction treatment with R + Pola + Len and consolidation treatment with R + Len in 
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 + Len and R + Pola + Len 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 end of consolidation (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 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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• 
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 achieving 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 (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 lenalidomide when given in combination on the 
basis of the following endpoints: 
• 
Observed serum obinutuzumab concentration at specified timepoints 
• 
Observed serum rituximab concentration at specified timepoints 
• 
Observed serum and plasma concentrations of polatuzumab vedotin and relevant 
analytes (TAb, acMMAE, and unconjugated MMAE) at specified timepoints 
• 
Observed plasma lenalidomide concentration at specified timepoints 
 
2.4 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to 
obinutuzumab, rituximab, 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 human anti-chimeric antibodies (HACAs) to rituximab during the 
study relative to the prevalence of HACAs at baseline 
• 
Incidence of 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 HACAs, and ATAs on the basis of the following 
endpoint: 
• 
Correlation between HAHA or HACA, and ATA status and respective efficacy, 
safety, or PK endpoints 
 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
88/Protocol GO29834, Version 2 
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, pharmacokinetics, or immunogenicity endpoints 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study 
This Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study will 
evaluate the safety, efficacy, and pharmacokinetics of G + Pola + Len in patients with R/R 
FL and R + Pola + Len 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 lenalidomide will be given at their RP2Ds (see 
Sections 3.1.2 and 3.1.2.2).   
Approximately 110−128 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 (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 lenalidomide, blood samples will be obtained at various timepoints before and 
during study treatment administration. 
Response will be determined by the IRC (see Section 3.1.5) and the investigator using 
the Lugano 2014 criteria.  The primary efficacy endpoint will be based on IRC 
assessment of response.  Refer to Section 4.5.5 for details on tumor assessments. 
Schedules of assessments are provided in Appendix 1, Appendix 2, and Appendix 3.  
The Lugano Response Criteria are provided in Appendix 5. 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
89/Protocol GO29834, Version 2 
Figure 1 Study Schema 
 
C = cycle; CR = complete response; D = day; DLBCL = diffuse large B-cell lymphoma; EOI = end of induction; FL = follicular lymphoma; 
G = obinutuzumab; Len = lenalidomide; PO = by mouth; Pola = polatuzumab vedotin; PR = partial response; QD = every day; Q2M=every 2 months; 
R=rituximab; RP2D = recommended Phase II dose; SD = stable disease. 
Notes:  Each cycle is 28 days.  A month is defined as 28 days.  
a FL patients enrolled in the dose-escalation phase who achieve a CR, PR, or SD at EOI may receive maintenance treatment with G + Len 
following the maintenance schedule outlined for patients with FL during the expansion phase. 
b Maintenance and consolidation treatment should start 8 weeks (± 1 week) after Day 1 of Cycle 6. 
c DLBCL patients enrolled in the dose-escalation phase who achieve a CR or PR at EOI may receive consolidation treatment with R + Len 
following the maintenance schedule outlined for patients with DLBCL during the expansion phase.


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
90/Protocol GO29834, Version 2 
3.1.2 
Obinutuzumab plus Polatuzumab Vedotin plus Lenalidomide 
Treatment Group (Patients with Follicular Lymphoma) 
3.1.2.1 
Dose-Escalation Phase 
The purpose of the FL dose-escalation phase is to identify the RP2D for polatuzumab 
vedotin and the RP2D for lenalidomide 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 (see 
Section 3.3.1).   
Approximately 18−30 patients will be enrolled in the FL 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 3.1.2.1.3. 
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 below (see Section 3.1.2.1.1), 
will be reported to the Sponsor within 24 hours (see Section 5.4.2).  
Patients experiencing a DLT during the DLT assessment period may continue receiving 
study treatment once the event has resolved, if determined by investigator in 
consultation with Sponsor that it is safe to continue treatment and there is potential for 
clinical benefit in their judgment.   
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 1 or more doses of polatuzumab vedotin or 
obinutuzumab or 5 consecutive daily doses of lenalidomide 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. 
3.1.2.1.1 
Definition of Dose-Limiting Toxicity 
In this study, a DLT is defined as any one of the following events occurring during the 
first cycle of treatment and 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 > 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). 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
91/Protocol GO29834, Version 2 
– 
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 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 fatigue that resolves to Grade ≤ 2 within 7 days 
– 
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 
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 to be 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 28-day cycles as shown in Table 1.  When study treatments are given on 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
92/Protocol GO29834, Version 2 
the same day, they will be administered sequentially in the following order:  lenalidomide, 
obinutuzumab, and polatuzumab vedotin.   
Table 1 
Induction Treatment for the Follicular Lymphoma Dose-
Escalation Phase 
Cycle 
G + Pola + Len (28-Day Cycles) 
Cycle 1 
• 
Lenalidomide 10 mg, 15 mg, or 20 mg PO once daily on Days 1−21  
• 
Obinutuzumab 1000 mg IV on Days 1, 8, and 15 
• 
Polatuzumab vedotin 1.4 mg/kg or 1.8 mg/kg IV on Day 1 
Cycles 2−6 
• 
Lenalidomide 10 mg, 15 mg, or 20 mg PO once daily on Days 1−21 
• 
Obinutuzumab 1000 mg IV on Day 1 
• 
Polatuzumab vedotin 1.4 mg/kg or 1.8 mg/kg IV on Day 1  
G + Pola + Len  = obinutuzumab in combination with polatuzumab vedotin and lenalidomide; 
IV = intravenous; PO = by mouth.  
Note:  Treatments will be administered sequentially in the following order:  lenalidomide, 
obinutuzumab, and polatuzumab vedotin. 
 
Patients who achieve a CR, a PR, or stable disease at EOI will receive maintenance 
treatment with G + Len, as outlined in Table 2.  Polatuzumab vedotin will not be given as 
maintenance treatment.  Maintenance treatment should start 8 weeks (±1 week) after 
Day 1 of Cycle 6 and will continue until disease progression or unacceptable toxicity for 
up to 24 months.  
Table 2 
Maintenance Treatment for the Follicular Lymphoma Dose-
Escalation Phase 
Patient Population 
Regimen 
Patients with FL 
Maintenance treatment consisting of the following, administered for 
approximately 24 months (from Months 1−24): 
• 
Lenalidomide 10 mg PO once daily on Days 1−21 of each month for a 
maximum of 12 months  
• 
Obinutuzumab 1000 mg IV on Day 1 of every other month (i.e., every 
2 months) for a maximum of 24 months 
FL = follicular lymphoma; IV = intravenous; PO = by mouth.  
Notes:  A month is defined as 28 days.  Treatments will be administered sequentially in the 
following order:  lenalidomide followed by obinutuzumab. 
 
3.1.2.1.3 
Dose-Escalation Rules 
A standard 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 1 are 1.4 mg/kg for polatuzumab vedotin and 10 mg for lenalidomide.  In 
Cohorts 2−6, dose escalation of polatuzumab vedotin and lenalidomide will proceed in 




Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
94/Protocol GO29834, Version 2 
Table 3 
Follicular Lymphoma Dose-Escalation Cohorts  
Cohort 
Obinutuzumab a 
Polatuzumab Vedotin b 
Lenalidomide c 
1 
1000 mg 
1.4 mg/kg 
10 mg 
2 
1000 mg 
1.8 mg/kg 
10 mg 
3 
1000 mg 
1.4 mg/kg 
15 mg 
4 
1000 mg 
1.8 mg/kg 
15 mg 
5 
1000 mg 
1.4 mg/kg 
20 mg 
6 
1000 mg 
1.8 mg/kg 
20 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 28-day cycle. 
c Lenalidomide will be administered orally on Days 1−21 of each 28-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.   
• 
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 polatuzumab vedotin and/or lenalidomide 
in the G + Pola + Len 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 < 33% 
of patients (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 lenalidomide in 
the G + Pola + Len 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 lenalidomide in the G + Pola + Len treatment combination. 
 
If the MTD is exceeded in any cohort, de-escalation of the polatuzumab vedotin dose 
and/or the lenalidomide dose and adjustment of treatment schedules (e.g., lenalidomide 
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 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
95/Protocol GO29834, Version 2 
combinations for polatuzumab vedotin and lenalidomide 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 
PD 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, dose 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, cumulative 
or late toxicities occurring beyond the first cycle may be considered when determining 
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 lenalidomide at their respective RP2Ds when combined with a 
fixed dose of obinutuzumab in FL patients.  
Approximately 40 patients with FL 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 4.  When study treatments are given on the same day, they will be administered 
sequentially in the following order:  lenalidomide, obinutuzumab, and polatuzumab 
vedotin. 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
96/Protocol GO29834, Version 2 
Table 4 
Induction Treatment for the Follicular Lymphoma Expansion 
Phase 
Cycle 
G + Pola + Len (28-Day Cycles) 
Cycle 1 
• 
Lenalidomide 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  
• 
Lenalidomide 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 
G + Pola + Len  = obinutuzumab in combination with polatuzumab vedotin and lenalidomide; 
IV = intravenous; PO = by mouth; RP2D = recommended Phase II dose.  
Note:  Treatments will be administered sequentially in the following order:  lenalidomide, 
obinutuzumab, and polatuzumab vedotin. 
 
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 
lenalidomide, as outlined in Table 5.  Polatuzumab vedotin will not be given during the 
post-induction phase.  Post-induction treatment should start 8 weeks (±1 week) after 
Day 1 of the final cycle of induction and will continue until disease progression or 
unacceptable toxicity, for up to 24 months for maintenance treatment. 
Table 5 
Post-Induction Treatment for the Follicular Lymphoma 
Expansion Phase 
Patient Population 
Regimen 
Patients with FL 
Maintenance treatment consisting of the following, administered for 
approximately 24 months (from Months 1−24): 
• 
Lenalidomide 10 mg PO once daily on Days 1−21 of each month for a 
maximum of 12 months  
• 
Obinutuzumab 1000 mg IV on Day 1 of every other month (i.e., every 
2 months), starting with Month 1 (i.e., Months 1, 3, 5, 7, 9, 11, 13, 15, 17, 
19, 21, and 23) for a maximum of 24 months 
FL = follicular lymphoma; IV = intravenous; PO = by mouth.  
Notes:  A month is defined as 28 days.  Treatments will be administered sequentially in the 
following order:  lenalidomide followed by obinutuzumab. 
 
3.1.3 
Rituximab plus Polatuzumab Vedotin plus  Lenalidomide 
Treatment Group (Patients with Relapsed or Refractory 
Diffuse Large B-Cell Lymphoma) 
Based on the safety and efficacy results from the Phase III BO21005 study in patients 
with DLBCL, the protocol has been amended to explore dose-finding of lenalidomide in 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
97/Protocol GO29834, Version 2 
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 
The DLBCL dose-escalation phase will open with the purpose of identifying the RP2D 
for lenalidomide 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 lenalidomide 10-mg dose level and increase through Cohorts A, B, 
and C (see Figure 3).   
Approximately 12−18 patients will be enrolled in the R/R DLBCL dose-escalation phase.  
Cohorts of 3−6 patients each will be treated in accordance with the treatment regimens 
and dose-escalation rules described below.   
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 below (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 or more doses of polatuzumab 
vedotin or rituximab or five consecutive daily doses of lenalidomide 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 + Len for a total of six cycles.  
Patients achieving a CR or PR at EOI will be eligible to receive consolidation treatment 
with R + Len.  A study schema is provided in Figure 1 .   
Treatment Regimens for DLBCL Dose-Escalation Phase 
Patients enrolled in the DLBCL-dose-escalation phase will receive induction treatment, 
administered in 28-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:  
lenalidomide, rituximab, and polatuzumab vedotin.   


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
98/Protocol GO29834, Version 2 
Table 6 
Induction Treatment for the DLBCL Dose-Escalation Phase 
Cycle 
R + Pola + Len (28-Day Cycles) 
Cycles 1−6 
• 
Lenalidomide 10 mg, 15 mg, or 20 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 + Len = rituximab in combination with 
polatuzumab vedotin and lenalidomide.  
Note:  Treatments will be administered sequentially in the following order:  lenalidomide, 
rituximab, and polatuzumab vedotin. 
 
Patients who achieve a CR or PR at EOI will receive consolidation treatment with 
R + Len, as outlined in Table 7.  Polatuzumab vedotin will not be given as maintenance 
treatment.  Consolidation treatment should start 8 weeks (± 1 week) after Day 1 of 
Cycle 6 and will continue for 6 months until disease progression or unacceptable 
toxicity.  
Table 7 
Consolidation Treatment for the Dose-Escalation Phase 
Patient 
Population 
Regimen 
Patients with 
DLBCL 
Consolidation treatment consisting of the following, administered for 
approximately 6 months (from Months 1−6): 
• 
Lenalidomide 10 mg PO once daily on Days 1−21 of each month for a 
maximum of 6 months 
• 
Rituximab 375 mg/m2 IV on Day 1 of every other month (i.e,  every 
2 months starting with Month 1 (i.e., Months 1, 3, 5) 
DLBCL = diffuse large B-cell lymphoma; IV = intravenous; PO = by mouth.  
Notes:  A month is defined as 28 days.  Treatments will be administered sequentially in the 
following order:  lenalidomide followed by rituximab. 
 
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 
lenalidomide 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 3.   


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
99/Protocol GO29834, Version 2 
Figure 3 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 
Lenalidomide c 
A 
375 mg/m2 
1.8 mg/kg 
10 mg 
B 
375 mg/m2 
1.8 mg/kg 
15 mg 
C 
375 mg/m2 
1.8 mg/kg 
20 mg 
DLBCL = diffuse large B-cell lymphoma; IV = intravenous; PO = by mouth. 
a Rituximab will be administered at a dose of 375 mg/m2 IV on Day 1 of each 28-day cycle 
of induction. 
b Polatuzumab vedotin will be administered at a dose of 1.8 mg/kg IV on Day 1 of each 
28-day cycle of induction. 
c Lenalidomide will be administered at doses of 10 mg, 15 mg, or 20 mg PO once daily on 
Days 1−21 of each 28-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.   
• 
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. 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
100/Protocol GO29834, Version 2 
• 
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 lenalidomide in the R + Pola + Len 
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 MTDs lenalidomide in the R + Pola + Len 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 lenalidomide in the R + Pola + Len treatment combination. 
 
If the MTD is exceeded in any cohort, de-escalation of the lenalidomide dose and/or 
polatuzumab vedotin dose, and/or adjustment of treatment schedules (e.g., lenalidomide 
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, dose administration/intensity, and 
PK (if available) data will be reviewed prior to dose-escalation decisions, which will be 
objectively 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, 
cumulative or late toxicities occurring beyond the first cycle may be considered when 
determining 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.   
3.1.3.2 
DLBCL Expansion Phase 
The expansion phase is designed to further assess the safety and efficacy of lenalidomide 
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. 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
101/Protocol GO29834, Version 2 
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:  lenalidomide, rituximab, and 
polatuzumab vedotin. 
Table 9 
Induction Treatment for the DLBCL Expansion Phase 
Cycle 
R + Pola + Len (28-Day Cycles) 
Cycles 1−6 
Lenalidomide 10 mg, 15 mg, or 20 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 
DLBCL = diffuse large B-cell lymphoma; IV = intravenous; PO = by mouth; 
R + Pola + Len = rituximab in combination with polatuzumab vedotin and lenalidomide.  
Note:  Treatments will be administered sequentially in the following order:  lenalidomide, 
rituximab, and polatuzumab vedotin. 
 
Patients with DLBCL who achieve a CR or PR at EOI will receive post-induction 
treatment (referred to as consolidation) with rituximab and lenalidomide as outlined in 
Table 10.  Polatuzumab vedotin will not be given during the post-induction phase.  
Post-induction treatment should start 8 weeks (± 1 week) after Day 1 of the final cycle 
of induction and will continue until disease progression or unacceptable toxicity, for up 
to 6 months for consolidation treatment. 
Table 10 Post-Induction Treatment for the DLBCL Expansion Phase 
Patient 
Population 
Regimen 
Patients with 
DLBCL 
Consolidation treatment consisting of the following, administered for 
approximately 6 months (Months 1−6): 
• 
Lenalidomide 10 mg PO once daily on Days 1−21 of each month, for a 
maximum of 6 months  
• 
Rituximab 375mg/m2 IV on Day 1 of every other month (i.e., every 
2 months) starting with Month 1 (i.e., Months 1, 3, 5) 
DLBCL = diffuse large B-cell lymphoma; IV = intravenous; PO = by mouth.  
Notes:  A month is defined as 28 days.  Treatments will be administered sequentially in the 
following order:  lenalidomide followed by rituximab. 
 
3.1.4 
Internal Monitoring Committee  
An IMC will monitor patient safety throughout the study.  The IMC will include, but will 
not be limited to, 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 


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events, deaths, and laboratory abnormalities performed by the investigator and the 
Medical Monitor, the IMC will review all necessary cumulative 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, or 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 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 an 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 below), 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 and 
Appendix 2). 
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 patients with FL 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 patients with DLBCL 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 5 years. 


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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 subsequent active and well-tolerated agents 
are needed.  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, highlighting the urgent need for novel 
therapeutic approaches for these patients. 
On the basis of a compelling biologic and clinical rationale, as presented in Section 1.4, 
the addition of polatuzumab vedotin to obinutuzumab or rituximab and lenalidomide is a 
promising approach to expand the number of patients with R/R FL and DLBCL who 
achieve remission and to prolong response duration 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 lenalidomide and 
the RP2D dose for polatuzumab vedotin when given with obinutuzumab in patients with 
R/R FL and the RP2D for lenalidomide 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 MOA that have demonstrated clinical 
activity against B-cell lymphoma.  Refer to Appendix 11 for descriptions of clinical 
studies that use the study drugs as single or doublet treatment.  
As discussed in Section 1.4, there is a strong MOA and clinical rationale to expect an 
improved benefit-risk profile with the triplet combination of obinutuzumab or rituximab, 
polatuzumab vedotin, and lenalidomide over standard immunochemotherapy regimens.  
The hypothesis is that 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 5.1.5).  
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 
and FL.   
Study BO21223 investigated obinutuzumab plus chemotherapy (G-benda, G-CVP, 
G-CHOP) compared with rituximab plus chemotherapy, followed by obinutuzumab or 


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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 G-CHOP compared with 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, patients with R/R FL in this 
current protocol amendment will continue to receive obinutuzumab in combination 
with polatuzumab vedotin and lenalidomide, while patients with R/R DLBCL will 
instead receive rituximab in combination with polatuzumab vedotin and lenalidomide. 
In the following sections, data generated for rituximab in combination with either 
polatuzumab vedotin or lenalidomide are also provided to further support the 
combination of an anti-CD20 antibody with polatuzumab vedotin and lenalidomide. 
3.3.2.1 
Rituximab and Polatuzumab Vedotin Combination 
During its early development, polatuzumab vedotin treatment has been investigated as a 
single agent and in combination with rituximab.  On the basis of available Phase I and II 
data (see Section 3.3.3.2 and Appendix 11), polatuzumab vedotin as a single agent and 
combined with rituximab has shown clinical activity in heavily pretreated patients with 
R/R B-cell lymphoma (Palanca-Wessels et al. 2012; Morschhauser et al. 2014a).  In 
both studies, patients received rituximab 375 mg/m2 and polatuzumab vedotin up to 2.4 
mg/kg Q3W for up to 1 year, progression, or unacceptable toxicity.  The ongoing Study 
GO27834 has also shown preliminary safety and efficacy results evaluating the 
combination of rituximab and polatuzumab vedotin 1.8 mg/kg.   
3.3.2.2 
Obinutuzumab and Polatuzumab Vedotin Combination 
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.  Preliminary results from these studies show safety and efficacy at the 
polatuzumab vedotin 1.8-mg/kg dose level when combined with obinutuzumab, every 3 
weeks for 6−8 cycles as described in Section 1.3.2.  
3.3.2.3 
Rituximab and Lenalidomide Combination 
The thalidomide analogue lenalidomide is currently approved for the treatment of 
multiple myeloma, deletion 5q myelodysplastic syndromes, and MCL as Revlimid.  
Nonclinical studies demonstrated that T-cell immune synapse dysfunction in FL can be 
restored with lenalidomide (Ramsay et al. 2009).  In addition, lenalidomide has been 
shown to reduce T regulatory cells and activate CD8 T cells (Kater et al. 2014).  E3 
ligase protein cereblon (encoded by the CRBN gene) is the molecular target of 
lenalidomide.  Lenalidomide binding to CRBN mediated its direct anti-tumor effects and 


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is also required for T-cell production of interleukin-2 and tumor necrosis factor α 
(Lopez-Girona et al. 2012).  
In nonclinical studies, lenalidomide combined with rituximab resulted in anti-tumor 
effects via increased NK-cell function, enhanced antibody-dependent cell-mediated 
cytotoxicity, and improved NK cell−mediated synapse formation (Wu et al. 2008; 
Zhang et al. 2009).   
Although lenalidomide has not been approved for the treatment of R/R FL and DLBCL, 
clinical activity has been demonstrated in the treatment of both R/R indolent and 
aggressive B-cell lymphoma with lenalidomide as a single agent (Wiernik et al. 2008; 
Witzig et al. 2009, 2011) or in combination with rituximab (Zinzani et al. 2011, 2013; 
Leonard et al. 2012; Tuscano et al. 2014; Wang et al. 2013) or obinutuzumab 
(Morschhauser et al. 2014b) (see Appendix 11). 
3.3.2.4 
Obinutuzumab and Lenalidomide Combination 
Because the combination of lenalidomide and rituximab has been shown to be 
synergistic in nonclinical models and in patients with relapsed and first-line FL, replacing 
rituximab with obinutuzumab in combination with lenalidomide might be even more 
efficient than the lenalidomide and rituximab combination. 
The combination of obinutuzumab with lenalidomide has been evaluated in nonclinical 
studies using the MCL Z138 xenograft model in SCID-beige mice.  Results from these 
studies demonstrated greater anti-tumor efficacy than either single agent and superior 
activity to the combination of lenalidomide with rituximab (data available upon request 
[RDR 1064289]). 
The combination of obinutuzumab with lenalidomide is currently being investigated in an 
ongoing Phase Ib/II study sponsored by the Lymphoma Academic Research 
Organisation (GALEN study) as induction and maintenance treatment in patients with 
R/R FL and aggressive lymphoma (DLBCL and MCL).  The recommended dose of 
lenalidomide was established at 20 mg/day on the basis of an increased incidence of 
Grade 3 or 4 neutropenia between Cycles 2 and 6 at the next higher dose of 25 mg/day 
(Morschhauser et al. 2014).  The most common adverse events observed during the 
dose-escalation phase (all grades,  ≥ 20% patients) were neutropenia (10/19; 53%), 
constipation (10/19; 53%) asthenia (7/19; 37%), upper respiratory tract infection (7/19; 
37%), rash/cutaneous eruption (5/19; 26%), cough (5/19; 26%), diarrhea (4/19; 21%), 
and fever (4/19, 21%).  Grade 3/4 adverse events occurring in  ≥ 2 patients only 
consisted of neutropenia (8/19; 42%).  IRRs occurred in 3 patients and did not exceed 
Grade 2.  Preliminary efficacy data available from the dose-escalation phase of the study 
are encouraging, with an overall response according to Cheson et al. 1999 criteria of 
68% (13 of 19 evaluable patients), including 7 patients with a CR; 3 patients with a CR, 
unconfirmed; and 3 patients with a PR (Morschhauser et al. 2014).  Enrollment in the 
expansion phase at 20 mg/day (Phase II part) is in progress.  Available preliminary 


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unpublished data (cutoff date:  30 September 2014) for 45 patients evaluable for safety 
during the induction period (Cycles 1−6) show a median of 5 induction cycles (range:  
2−6 cycles) received.  The following hematologic adverse events (all grades) were 
reported:  neutropenia (17/45; 37.8%), febrile neutropenia (3/45; 6.7%), anemia (8/45; 
17.8%), and thrombocytopenia (5/45; 11.1%).  The most common (occurring in  > 10% of 
patients) non-hematologic adverse events (all grades) were constipation (9/45; 20%); 
rash (7/45; 15.6%); cough (7/45; 15.6%); asthenia (6/45; 13.3%); and fatigue, diarrhea, 
and pruritus (5/45; 11.1% each). 
As mentioned in Section 1.4, there is a strong rationale for enhanced activity with 
combination therapy as well as apparent limited additional toxicity that argues that 
exploration of the G + Pola + Len combination is appropriate.  This novel triplet regimen 
may have the potential to extend treatment-free remissions and decrease toxicity by 
improving upon individual agents in current standard of care and incorporating a 
targeted chemotherapy regimen. 
3.3.3 
Rationale for Dose and Schedule 
3.3.3.1 
Rationale for Obinutuzumab Dose and Schedule in Patients 
with Follicular Lymphoma 
The dose and schedule for obinutuzumab in this study will be fixed for the induction and 
the maintenance components of the study, and obinutuzumab will not be dose-
escalated.  This is based on the recommended dose and schedule (6−8 cycles 
depending on the trial) of obinutuzumab from the Phase III program in patients with B-
cell lymphoma.   
The dose and schedule of obinutuzumab in the induction regimen will be 1000 mg IV on 
Days 1, 8, and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle 
(Cycles 2−6). 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 
Study GAO4753g (Sehn et al. 2015).  Study GAO4753g 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 and bendamustine followed by obinutuzumab maintenance arm vs. 
14.9 months in the bendamustine arm; stratified hazard ratio [HR] = 0.55; 
95% CI: 0.40, 0.74; p = 0.0001, by log-rank test). 


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3.3.3.2 
Rationale for Polatuzumab Vedotin Dosing Regimen 
3.3.3.2.1 
Rationale for Polatuzumab Vedotin Dose in Patients with 
Folllicular Lymphoma 
For this study, dose escalation of polatuzumab vedotin for patients with R/R FL 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 initial polatuzumab vedotin dose and schedule for this study were 
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 relapsed and refractory B-cell lymphoma, the 
majority of which had FL or DLBCL.  Most evidence of anti-tumor activity was observed 
at doses  ≥ 1.8 mg/kg alone or in combination with rituximab.  
Evidence from Study DCS4968g indicated that duration of study treatment might be 
limited by tolerability to polatuzumab vedotin at a dose of 2.4 mg/kg.  Specifically, 
peripheral neuropathy (sensory and/or motor) has been identified as a known risk (see 
Section 5.1.3.1).  Because of the chronic course and incurability of indolent B-cell 
lymphoma, treatment paradigms are increasingly emphasizing tolerability to treatment in 
addition to efficacy.  As polatuzumab vedotin has shown single-agent activity at the 
1.8-mg/kg dose level (Palanca-Wessels et al. 2012), an additional cohort was opened 
with the purpose of determining whether lower doses of polatuzumab vedotin (1.8 mg/kg) 
in combination with standard doses of rituximab result in improved tolerability while 
maintaining efficacy in FL.   
An analysis comparing the 2.4- and 1.8-mg/kg polatuzumab vedotin dose levels in 
combination with rituximab was reported (Advani et al. 2015).  A high objective response 
rate was observed at both doses (76% at 2.4 mg/kg and 75% at 1.8 mg/kg), with a 
higher rate of CRs at 2.4 mg/kg (44% at 2.4 mg/kg and 10% at 1.8 mg/kg).  Adverse 
events and discontinuation rates were reduced at both doses if only the first 8 cycles are 
considered versus through study completion.  Therefore, to minimize the risk for the 
potential development of peripheral neuropathy (sensory and/or motor), treatment with 
polatuzumab vedotin was limited to a maximum of 6-month duration, corresponding to 
6−8 cycles as defined per the protocol.  Further, in all current studies, the maximum 
dose of polatuzumab vedotin was limited to 1.8 mg/kg per the dose defined in the 
protocol.   
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.   


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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 = 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 
CHP = cyclophosphamide, doxorubicin, prednisone; FL = follicular lymphoma; Ph = phase; 
R/R = relapsed or refractory. 
a Study GO27834:  polatuzumab vedotin and obinutuzumab administered every 21 days for 
8 cycles.  
b Study GO29365:  polatuzumab vedotin, bendamustine, and obinutuzumab administered 
every 21 days (FL) for 6 cycles.  
c Study GO29044:  polatuzumab vedotin plus  obinutuzumab plus CHP administered every 21 
days for 6−8 cycles. 
d In the Phase Ib portion of the study, 1 patient with R/R FL was treated with polatuzumab 
vedotin at 1.4 mg/kg and 1 patient with R/R FL was treated with polatuzumab vedotin at 
1.8 mg/kg (Forero-Torres et al. 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 obinutuzumab and 
bendamustine.  Since polatuzumab vedotin is being combined with obinutuzumab and 
chemotherapy (CHP or bendamustine) at 1.4 or 1.8 mg/kg, for patients with R/R FL in 
this study, dose escalation of polatuzumab vedotin will begin at a dose level of 1.4 
mg/kg (one dose level below the highest polatuzumab vedotin dose level in clinical 
development) and will escalate to a final dose of 1.8 mg/kg, if tolerated.  This novel triplet, 
G + Pola + Len, substitutes out the standard chemotherapy components with lenalidomide, 
which in this combination may have the potential to extend treatment-free remissions 
and decrease toxicity, compared to combinations with standard chemotherapy 
components. 
3.3.3.2.2 
Rationale for Polatuzumab Vedotin Dose in Patients with 
DLBCL 
On the basis of the preliminary data from the patients with DLBCL treated in 
Studies GO29044 and GO29365, the dose level of polatuzumab vedotin at 1.8 mg/kg 
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 


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level of polatuzumab vedotin is preferred to 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 at 1.8 mg/kg and 
lenalidomide; hence, in this amendment, the R/R DLBCL dose-escalation phase will 
start at the dose level of 1.8 mg/kg and only the lenalidomide dose will be escalated to 
determine an RP2D in this population.    
3.3.3.2.3 
Rationale for Polatuzumab Vedotin Dosing Schedule in 
Patients with Follicular Lymphoma and DLBCL 
The number of induction cycles (six 28-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 Lenalidomide Dose and Schedule 
For the induction phase of the dose-escalation study, the lenalidomide starting dose will 
be 10 mg (two dose levels below the recommended expansion dose in combination with 
obinutuzumab in Phase Ib study) and will escalate to 15 mg and then to a final dose of 
20 mg, if tolerated.  Patients enrolled in the expansion study will receive lenalidomide at 
the RP2D during induction.  The lenalidomide dose and schedule for this study were 
primarily based on the experience from the Phase Ib study (GALEN) that evaluated the 
combination of lenalidomide with obinutuzumab (Morschhauser et al. 2014b).  The MTD 
of lenalidomide was not reached; however, the recommended dose of lenalidomide 
established was 20 mg when combined with obinutuzumab for R/R FL or DLBCL on the 
basis of the increased incidence of Grade 3/4 neutropenia between Cycles 2 and 6 at 
25 mg (see Section 3.3.2.4 for details). 
The optimal use of lenalidomide in maintenance/consolidation therapy is under active 
investigation.  In combination with rituximab, the most common schedule of lenalidomide 
has been 20 mg administered on Days 1−21 of each 28-day cycle in R/R B-cell 
lymphoma (Leonard et al. 2012; Wang et al. 2013; Zinzani et al. 2013). 
For the post-induction phase of this study, the lenalidomide dose will be 10 mg 
administered on Days 1−21 of each month for a maximum of 12 months (additional 
1 year of treatment) for patients with R/R FL and for a maximum of 6 months (total of 1 
year of treatment inclusive of induction phase) for patients with R/R DLBCL.  This 
schedule is based on the post-induction schedule administered in the GALEN study.   
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 


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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 of 
evaluating the benefits of the triple combination as post-induction treatment (see 
Section 3.3.5.3).   
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. 2013b).  A Phase III study, GAO4753g, investigated 
obinutuzumab plus bendamustine (GB) compared with bendamustine alone in patients 
with rituximab-refractory indolent B-cell lymphoma (n = 396).  Patients in the GB group 
who had not experienced disease progression at EOI 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 (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. 
The combination of obinutuzumab with lenalidomide is currently being investigated in an 
ongoing Phase Ib/II study (GALEN) as induction and maintenance treatment in patients 
with R/R FL.  In the GALEN study, maintenance treatment consists of obinutuzumab 
administered every 2 months for 2 years and lenalidomide administered on Days 1−21 of 
each 28-day cycle for 1 year, and the same obinutuzumab and lenalidomide dosing 
schedule will be employed in this study.  
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, 6 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 three 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. 


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3.3.4 
Rationale for PET-CT-Defined Complete Response as the 
Primary Efficacy Endpoint 
In DLBCL, the prognostic value of the post-treatment fluorodeoxyglucose (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 (Cheson et al. 2014) and are 
commonly used to assess efficacy in medical practice and clinical trials of lymphoma.  
More recently, the value of post-induction PET-CT status has been investigated as a 
prognostic marker for long-term outcome in patients with FL.  In the first-line setting, 
results from a pooled analysis of 246 patients enrolled in three studies and having 
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 Phase II study (BO21003) 
comparing obinutuzumab versus 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). 
In response to developments involving 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 (see Appendix 5; 
Cheson et al. 2014).  
3.3.5 
Rationale for Biomarker Assessments  
3.3.5.1 
Rationale for Analysis of DLBCL Subtype, BCL2, and MYC 
DLBCL cell-of-origin prognostic subgroups (ABC and GCB), defined using gene 
expression profiling, have been associated with different clinical outcomes in patients 
receiving R-CHOP for DLBCL, with GCB subgroups demonstrating an improved 
prognosis than ABC groups (3-year survival rate of 84% vs. 56%, respectively; p < 0.001) 
(Lenz et al. 2008).  Moreover, non-GCB patients preferentially respond to lenalidomide 
(Hernandez-Ilizaliturri et al. 2011).   
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, 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 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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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 (Dunleavy et al. 2014; 
Savage et al. 2009).  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; Hu et al. 2013; Johnson et al. 2012). 
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).  The activity of ADCs like polatuzumab depends 
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 
expression will be measured in the mandatory archival tissue. 
3.3.5.3 
Rationale for Assessment of Minimal Residual Disease 
MRD measurement is an increasingly recognized tool for response assessment in B-cell 
malignancies.  Circulating lymphoma cells and circulating tumor DNA can be detected 
and quantified at low levels as MRD to assess depth of response and monitor patients 
for possible disease recurrence.  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 predict 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 PET-CT results caused by infiltration of metabolically active immune cells 
into the tumor (Kurtz et al. 2014).  For these reasons, initial MRD analysis will be 
performed in patients with FL, and subsequent analysis in patients with DLBCL may be 
performed. 
In this study, MRD will be quantified by circulating lymphoma cells and circulating tumor 
DNA as an exploratory endpoint.  The lymphoma clone will be identified in DNA from the 
lymphoma tissue specimen.  MRD levels will be determined in blood samples collected 
prior to dosing and during treatment to explore a pharmacodynamic (PD) relationship.  
MRD assessments will be performed at EOI to allow for an evaluation of the depth of 
response, and during and after post-induction treatment to allow for an evaluation of 
long-term response or possible disease recurrence. 


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3.3.5.4 
Rationale for Assessment of Lymphoma-Related Genetic 
Changes and Gene Expression  
Measurement of relevant protein, RNA, and DNA from tissue specimens will be 
assessed for biomarkers associated with disease biology (immune gene expression 
profiles and disease subtype gene expression patterns and associated mutations, i.e., 
MYD88 and CD79b), mechanism of action of study drugs (i.e., including but not limited 
to regulated substrates of lenalidomide, i.e., CRBN, MYC, IRF4, or immune repertoire 
signatures), mechanisms of resistance, and improvement of diagnostic assays. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
This study will enroll patients with FL or 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 + Len treatment group:  R/R FL after treatment with at least one 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 + Len treatment group:  R/R DLBCL after treatment with at least one 
prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal 
antibody in patients who are not eligible for autologous stem-cell transplantation or 
who have experienced disease progression following treatment with high-dose 
chemotherapy plus autologous stem-cell transplantation 
• 
Histologically documented CD20-positive B-cell lymphoma 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-needle, excisional, or incisional tumor biopsy is required.  Cytological or 
fine-needle aspiration samples are not acceptable.  


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If the patient received anti-lymphoma treatment between the time of the most 
recent available biopsy and initiation of study treatment, a repeat core-needle 
biopsy is strongly recommended.   
Further details are provided in Section 4.5.6.   
• 
Agreement to abstain from donating blood during the treatment period (including 
periods of treatment interruption) and for 28 days after the last dose of study 
treatment 
• 
Agreement not to share study medication with another person 
• 
Agreement to comply with all local requirements of the lenalidomide risk 
minimization plan 
In every country where lenalidomide has been approved, a risk minimization 
plan, which includes a pregnancy prevention program, is in place.  The risk 
minimization plan should be followed by patients using lenalidomide. 
US sites only:  Per standard Revlimid REMS™ requirements, all physicians 
who prescribe lenalidomide for research subjects enrolled in this study and all 
research subjects enrolled in this study must be registered in and must comply 
with all requirements of the Revlimid REMS™ program.  
For Ex-US sites only:  Subjects will be counseled on pregnancy prevention 
prior to medication being dispensed to ensure that the subject has complied 
with all requirements, including use of birth control and pregnancy testing, 
and that the subject understands the risks associated with lenalidomide.  This 
step will be documented with a completed Education and Counseling Guidance 
Document (refer to Lenalidomide Pregnancy Prevention Risk Management 
Plans), and no drug will be dispensed until this step occurs.  Counseling 
includes verification with the subject that required pregnancy testing was 
performed and results were negative.  A Lenalidomide Information Sheet (refer 
to Lenalidomide Pregnancy Prevention Risk Management Plans) will be 
supplied with each medication dispensed.  All requirements must be followed 
by each site as noted within the Lenalidomide Pregnancy Prevention Risk 
Management Plans. 
In addition, because lenalidomide will be administered in combination with 
obinutuzumab, rituximab, and polatuzumab vedotin, patients must comply with 
contraceptive measures designed to ensure safe administration of all study 
treatments as outlined below.  
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including 
at least one method with a failure rate of < 1% per year, for at least 28 days prior to 
Day 1 of Cycle 1, during the treatment period (including periods of treatment 
interruption), and for at least 12 months after the last dose of polatuzumab vedotin, 
28 days after the last dose of lenalidomide, 12 months after the last dose of 
rituximab, and 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 (≥ 24 continuous months of 


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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 
progestogen-only hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.  
Combined oral contraceptives are not recommended because of the increased 
risk of venous and arterial thromboembolism (TE) in patients taking 
lenalidomide. 
Barrier methods may be used as the second contraceptive method but must 
always be supplemented with the use of a spermicide. 
• 
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, 28 days after the last dose 
of lenalidomide, and 3 months after the last dose of obinutuzumab or rituximab.  
Men must refrain from donating sperm during this 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, 28 days after the last dose of lenalidomide, and 3 months 
after the last dose of obinutuzumab or rituximab to avoid exposing the embryo. 
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: 
• 
Grade 3b follicular lymphoma 
• 
History of transformation of indolent disease to DLBCL 
• 
Known CD20-negative status at relapse or progression 
• 
Central nervous system lymphoma or leptomeningeal infiltration 
• 
Prior allogeneic SCT 
• 
Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1 


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• 
History of resistance to lenalidomide or response duration of < 1 year (for patients 
who had a response to a prior lenalidomide-containing regimen)  
• 
Prior standard or investigational anti-cancer therapy as specified below: 
Lenalidomide, fludarabine, or alemtuzumab within 12 months prior to Day 1 of 
Cycle1 
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, Version 4.0) prior to Day 1 of Cycle 1 
• 
Treatment with systemic immunosuppressive medications, including, but not limited 
to, prednisone, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis 
factor agents within 2 weeks prior to Day 1 of Cycle 1 
Treatment with inhaled corticosteroids and mineralocorticoids is permitted. 
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 initiation 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 obinutuzumab, 
rituximab, polatuzumab vedotin, or lenalidomide formulations 
• 
History of erythema multiforme, Grade  ≥ 3 rash, or desquamation (blistering) 
following prior treatment with immunomodulatory derivatives such as thalidomide 
and lenalidomide 
• 
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. 
• 
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 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: 


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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 
• 
Contraindication to treatment for TE prophylaxis (see Section 4.3.2.5) 
• 
Grade ≥ 2 neuropathy 
• 
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 (using the Cockcroft-Gault formula; 
see Appendix 7) 
AST or ALT > 2.5 × 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 two negative serum pregnancy test 
results (minimum sensitivity, 25 mIU/mL) prior to initiating therapy:  at 
10−14 days prior to Day 1 of Cycle 1 and within 24 hours 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, dose-escalation study of 
G + Pola + Len in patients with R/R FL and R + Pola + Len in patients with R/R DLBCL.  


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During the dose-escalation phase, patients will be assigned to cohorts with varying 
polatuzumab vedotin (R/R FL dose-finding only) and lenalidomide dose combinations, 
through use of an interactive voice or web-based response system (IxRS).  During the 
FL expansion phase, patients with R/R FL will receive obinutuzumab in combination 
with lenalidomide at the FL RP2D and polatuzumab vedotin at the RP2D as induction 
treatment.  During the DLBCL expansion phase, patients with R/R DLBCL will receive 
rituximab and polatuzumab in combination with lenalidomide at the DLBCL RP2D.  
Post-induction treatment (for eligible patients only) will depend on lymphoma histology.  
Patients with FL will receive maintenance treatment with obinutuzumab and lenalidomide, 
and patients with DLBCL will receive consolidation treatment with rituximab and 
lenalidomide (see Section 3.1.1 for details). 
Enrollment tracking will be performed through use of the IxRS.  Prior to initiating 
screening, the study site should confirm via the IxRS that slots are available for 
enrollment.  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.  The Sponsor will communicate to the sites 
impending closure of screening. 
4.3 
STUDY TREATMENT  
The investigational medicinal products (IMPs) for this study are obinutuzumab, 
rituximab, polatuzumab vedotin, and lenalidomide. 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Obinutuzumab  
Obinutuzumab will be provided as a single-dose, sterile liquid formulation in a 50-mL 
glass vial containing 1000 mg/40 mL of obinutuzumab.  In addition to the drug substance, 
the liquid is also composed of histidine, trehalose, and poloxamer 188. For information 
on the formulation and handling of obinutuzumab, see the pharmacy manual and the 
Obinutuzumab Investigator's Brochure (oncology) and local prescribing information. 
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 


Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
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handling of polatuzumab vedotin, see the pharmacy manual and the Polatuzumab 
Vedotin Investigator's Brochure. 
4.3.1.4 
Lenalidomide 
Lenalidomide will be supplied by the Sponsor as 5-, 10-, 15-, and 20-mg capsules.   
Female caretakers of patients taking lenalidomide who are of childbearing potential 
should not handle or administer lenalidomide unless they are wearing gloves.  
Lenalidomide should be stored at room temperature away from direct sunlight and 
should be protected from excessive heat and cold. 
For information on the formulation and handling of lenalidomide, see the local 
prescribing information for lenalidomide. 
4.3.2 
Dosage, Administration, and Compliance 
Patients enrolled in the dose-escalation phase or the expansion phase will receive six 
28-day cycles of induction treatment with obinutuzumab or rituximab, polatuzumab 
vedotin, and lenalidomide.  When study treatments are given on the same day, they will 
be administered sequentially in the following order:  lenalidomide, obinutuzumab or 
rituximab, and polatuzumab vedotin.  
Patients with DLBCL who achieve a CR or PR at EOI will receive post-induction 
treatment (referred to as consolidation) with lenalidomide and rituximab, and patients 
with FL who achieve a CR, PR, or SD at EOI will receive post-induction treatment 
(referred to as maintenance) with lenalidomide and obinutuzumab.  When study 
treatments are given on the same day, lenalidomide will be administered prior to 
obinutuzumab or rituximab. 
Post-induction treatment should start 8 weeks (± 1 week) after Day 1 of the final cycle of 
induction and will continue until disease progression or unacceptable toxicity for up to 
2 years for maintenance treatment or 6 months for consolidation treatment. 
Treatment regimens are summarized in Table 1, Table 2, Table 4, and Table 5 for R/R 
FL patients and Table 6, Table 7, Table 9, and Table 10 for R/R DLBCL patients 
(see Section 3.1) and depicted in Figure 4.  All eligible patients in both dose-escalation 
and expansion phases should receive induction and post-induction (if indicated) therapy. 


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Figure 4 Induction and Post-Induction Treatment Regimen 
 
DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; IV = intravenous; PO = by mouth; RP2D = recommended Phase II dose. 
Notes:  During induction, treatments will be administered sequentially in the following order:  lenalidomide, obinutuzumab or rituximab, and 
polatuzumab vedotin.  During post-induction, treatment will be administered in the following order:  lenalidomide followed by obinutuzumab or 
rituximab. 


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Premedication and treatment for TE prophylaxis should be administered as described in 
Section 4.3.2.5. 
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 physician.  Obinutuzumab infusions will be 
administered according to the instructions outlined in Figure 5 and Figure 6.   
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 modification for obinutuzumab is allowed.  Guidelines for treatment delays or 
discontinuation are provided in Section 5.1.7.  
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 8. 


 
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Figure 5 Guidelines for Obinutuzumab Infusions:  First Infusion 
 
IRR = infusion-related reaction. 
a All patients should receive full premedication with an oral corticosteroid, antihistamine, and oral analgesic/antipyretic 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.  Intravenous 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 8. 


 
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Figure 6 Guidelines for Obinutuzumab Infusions:  Second and Subsequent Infusions 
 
IRR = infusion-related reaction; q30 = every 30. 
a Patients should receive full premedication with an oral corticosteroid, antihistamine, and oral analgesic/antipyretic prior to the 
obinutuzumab infusion.  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.  
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 8. 
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. 
The patient’s weight obtained during screening (Days −28 to −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 


 
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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 
containing isotonic sodium chloride solution (0.9% NaCl), polatuzumab vedotin will be 
administered by IV infusion using dedicated standard administration sets with 0.2- 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 
experiencing 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. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.7. 
4.3.2.4 
Lenalidomide 
Lenalidomide will be administered orally once daily on Days 1−21 of Cycles 1−6 (28-day 
cycles) during induction treatment and on Days 1−21 of each month during consolidation 
or first 12 months of maintenance treatment.  During the dose-escalation phase, 
lenalidomide will be administered at a dose of 10, 15, or 20 mg (dose may be de-
escalated to 5 mg).  During the expansion phase, lenalidomide will be administered at 
the RP2D during induction treatment and at 10 mg during consolidation or maintenance 
treatment. 
Lenalidomide capsules should be swallowed whole with water and should not be broken, 
chewed, or opened.  The capsules may be taken with or without food, except on 
lenalidomide PK sampling days (see Appendix 3), where the patient should fast (water 


 
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allowed) at least 2 hours before and at least 1 hour after the lenalidomide dose.  On 
lenalidomide PK sampling visits, lenalidomide dose will be taken in the clinic.   
Lenalidomide should be administered at approximately the same time each day.  If a 
dose of lenalidomide is missed and it has been  < 12 hours since the time of the 
scheduled dose, the patient may take the missed dose.  If it has been  > 12 hours, the 
dose should be skipped and the next dose should be taken at the regularly scheduled 
time.  Two doses should not be taken at the same time.  If a dose had been vomited, the 
dose should not be re-taken. 
At each cycle, each patient will be supplied with only enough lenalidomide for that cycle.  
A drug diary will be provided to the patient to record oral administration of doses, 
including the date and time.  Patients will be instructed to return empty bottles or unused 
capsules.  The investigator is responsible for monitoring patient compliance by 
monitoring the patient diary and counting unused capsules. 
4.3.2.5 
Premedication and Other Required Medication 
Lenalidomide increases the risk of thromboembolism.  All patients will be required to 
take daily aspirin (75−100 mg) for TE prophylaxis during lenalidomide treatment and until 
28 days after the last dose of lenalidomide.  Patients who are unable to tolerate aspirin, 
patients with a history of TE, and patients at high risk of TE should receive warfarin or 
low-molecular-weight heparin (LMWH).   
Patients should receive premedication as outlined in Table 13. 


 
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Table 13 Premedication 
Timepoint 
Patients Requiring Premedication 
Premedication 
Administration 
• All patients 
• Oral corticosteroid a 
Complete ≥ 1 hour prior to obinutuzumab or 
rituximab infusion 
• All patients 
• Antihistamine drug b 
• Oral analgesic/antipyretic c 
Administer ≥ 30 minutes prior to obinutuzumab 
or rituximab infusion 
Cycle 1,  
Day 1 
• Patients at risk for TLS (e.g., because 
of bulky disease or renal impairment 
[creatinine clearance < 70 mL/min]) 
• Allopurinol or suitable alternative, 
such as rasburicase, along with 
adequate hydration 
Administer prior to obinutuzumab or rituximab 
infusion 
• Patients with no IRR during the 
previous infusion 
• Oral analgesic/anti-pyretic c 
Administer at least 30 minutes prior to 
obinutuzumab infusion.  For patients receiving 
rituximab, premedication may be omitted at 
the investigator’s discretion.   
• Patients with Grade 1 or 2 IRR 
during the previous infusion 
• Antihistamine drug b 
• Oral analgesic/antipyretic c 
Administer ≥  30 minutes prior to 
obinutuzumab or rituximab infusion 
• Oral corticosteroid a 
Complete ≥ 1 hour prior to obinutuzumab or 
rituximab infusion 
• Patients with Grade 3 IRR, wheezing, 
urticarial, or other symptoms of 
anaphylaxis during the previous 
infusion 
• Patients with bulky disease 
• Antihistamine drug b 
• Oral analgesic/antipyretic c 
Administer ≥ 30 minutes prior to obinutuzumab 
or rituximab infusion 
Cycle 1,  
Days 8 and 15 
 
Cycles 2 and 
Beyond, 
Day 1 
• Patients still at risk for TLS 
• Allopurinol or suitable alternative, 
such as rasburicase, along with 
adequate hydration 
Administer prior to obinutuzumab or rituximab 
infusion 
IRR = infusion-related reaction; TLS = tumor lysis syndrome. 
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 lenalidomide) 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.  Lenalidomide will be dispensed to 
sites in the United States via the Celgene REMS™ system.  For sites outside the United 
States, lenalidomide will be dispensed to sites through the study IxRS.  Sites will be 
trained on lenalidomide specific requirements by their study monitors.   
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 Lenalidomide 
Currently, the Sponsor does not have any plans to provide obinutuzumab, rituximab, 
polatuzumab vedotin, or any other study treatments or interventions to patients who 
have completed the study.  The Sponsor will evaluate whether to continue providing 
obinutuzumab, rituximab, or polatuzumab vedotin 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 
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 
TE prophylaxis treatment and premedication should be administered as described in 
Section 4.3.2.5. 
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 


 
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(ASCO), EORTC, and European Society for Medical Oncology (ESMO) guidelines 
(Smith et al. 2006) or per each site’s institutional standards. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.  However, it must be noted that 
erythropoietic agents or other agents that may increase the risk of thrombosis, such as 
estrogen-containing therapies (e.g., oral contraceptives), should be used with caution, 
because of the increased risk of TE in patients taking lenalidomide.  Suitable methods of 
contraception are presented in Section 4.1.1. 
Patients using concomitant medication that could possibly worsen 
thrombocytopenia-related events (e.g., platelet inhibitors and anticoagulants) may be at 
greater risk of bleeding.  When possible, replace prior vitamin K antagonist therapy with 
LMWH prior to Day 1 of Cycle 1.   
Patients who are receiving digoxin should undergo periodic monitoring of digoxin plasma 
levels, in accordance with clinical judgment and based on standard clinical practice, 
because of potential drug interactions with lenalidomide. 
Drug-drug interactions between warfarin and lenalidomide have been excluded.  
However, a close monitoring of PT and INR is recommended in patients receiving 
warfarin.  
There is an increased risk of rhabdomyolysis when statins are administered with 
lenalidomide, which may be simply additive.  Enhanced clinical and laboratory 
monitoring is warranted notably during the first weeks of treatment. 
On the basis of simulations, unconjugated MMAE exposure following polatuzumab 
vedotin administration with CYP3A4 inhibitors or inducers is unlikely to be altered by 
more than 50%.  Furthermore, MMAE is unlikely a perpetrator of drug interactions.  The 
patients who receive strong CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors in 
combination with polatuzumab vedotin will be closely monitored for adverse reactions if 
any. 
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.   


 
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4.4.2 
Prohibited Therapy 
Use of the following therapies (excluding protocol-specified treatments) is prohibited 
during the study: 
• 
Any anti-cancer therapy, approved or investigational, other than intrathecal central 
nervous system 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 
 
4.5 
STUDY ASSESSMENTS  
See Appendix 1, Appendix 2, and Appendix 3 for the schedules 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 by the investigator 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).   
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. 


 
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The following clinical parameters relative to disease history, diagnosis, and prognostic 
indices will be recorded at screening:  
• 
Date of initial diagnosis 
• 
ECOG Performance Status (see Appendix 6) 
• 
Ann Arbor staging (see Appendix 9) 
• 
For patients with FL:  Follicular Lymphoma International Prognostic Index (FLIPI) 
and Follicular Lymphoma International Prognostic Index 2 (FLIPI2) (see 
Appendix 10) 
• 
For patients with DLBCL:  IPI (see Appendix 10) 
• 
B symptoms (unexplained fever > 38°C, night sweats, and unexplained weight loss 
> 10% of body weight over 6 months)  
• 
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.  Height and weight will be 
recorded.   
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 
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 


 
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(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 PET and CT scans, using the Lugano 2014 criteria, 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 scans 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. 
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.  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. 


 
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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, and 
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 creatinine clearance, calcium, total bilirubin, direct bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase, LDH, uric acid, 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. 
• 
Thyroid-stimulating hormone, triiodothyronine, thyroxine 
• 
β2 microglobulin 
• 
Coagulation:  INR, aPTT (or PTT), and PT 
• 
Pregnancy test 
All women of childbearing potential must have two negative serum pregnancy 
test results (minimum sensitivity, 25 mIU/mL) prior to initiating therapy:  at 
10−14 days prior to Day 1 of Cycle 1 and within 24 hours prior to Day 1 of 
Cycle 1.  Urine pregnancy tests will be performed at specified subsequent visits 
(see Appendix 1 and Appendix 2).  If a urine pregnancy test is positive, it must 
be confirmed by a serum pregnancy test. 
• 
Viral serology  
Hepatitis B testing includes HBsAg and total HBcAb 
Hepatitis C testing includes HCV antibody 
HIV testing (if required per local regulatory requirements) 
• 
Quantitative immunogloblulins:  IgA, IgG, and IgM 
 


 
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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 polatuzumab vedotin PK analysis using a validated 
assay 
• 
Plasma samples for lenalidomide PK analysis using a validated assay 
• 
Serum samples for assessment of obinutuzumab HAHAs using a validated assay 
• 
Serum samples for assessment of rituximab HACAs using a validated assay 
• 
Serum samples for assessment of polatuzumab vedotin ATAs using a validated 
assay 
• 
Tumor tissue samples (obtained within 6 months prior to the initiation of study 
treatment for DLBCL or within 12 months prior to the initiation of study treatment for 
FL) 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 available biopsy was performed more than 12 months prior to Day 1 of 
Cycle 1, or the patient received anti-lymphoma treatment between the time of 
the most recent available biopsy and Day 1 of Cycle 1, a core-needle biopsy is 
strongly 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. 
• 
Tumor biopsy samples obtained at the time of progression (unless no adequate 
tumor site is accessible) for exploratory research on candidate biomarkers (see 
Table 14) 
• 
Plasma samples for exploratory research on candidate biomarkers (see Table 14) 


 
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• 
Whole blood samples for exploratory research on candidate biomarkers (see 
Table 14) 
• 
Whole blood for lymphocyte immunophenotyping (see Table 14) 
 
Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in Table 14. 
Table 14 Proposed Non-Inherited Biomarkers 
Sample Type 
Timing 
Proposed Non-Inherited Biomarkers 
Archival or fresh 
pretreatment and 
progression tumor 
tissue  
Prior to study (archival) or 
baseline (fresh) and 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, immune 
infiltrate, cereblon (and surrogates)  
• Lymphoma-related genetic changes 
(DNA) and gene expression (mRNA) or 
protein expression (IHC associated with 
response or potential resistance) 
• Lymphoma index clone in MRD 
Plasma isolated from 
whole blood 
Baseline and subsequent 
timepoints during treatment 
(patients who enroll in the 
expansion phase only) 
• 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) 
Plasma 
Baseline (predose and 
postdose) and subsequent 
timepoints (predose) during 
treatment 
• Cytokines characteristic of T-cell 
activation and lenalidomide activity (e.g., 
IL-8 and IFNγ) 
ABC = activated B cell–like; DBLCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; 
GCB = germinal-center B cell–like; IFNγ = interferon γ; IHC = immunohistochemistry; 
IL-8 = interleukin 8; NK-cell = natural killer cell. 
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 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. 
4.5.8 
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 
 
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 (IRB) or Ethics Committee (EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 


 
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approval for RCR sampling, this section of the protocol (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, lenalidomide, B-cell lymphoma, 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, plasma, and serum) 
 
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 RCR 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.  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. 


 
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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 
from Study GO29834 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 GO29834. 
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 


 
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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 that 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.   
• 
Any adverse event that meets criteria for permanent discontinuation per guidelines 
provided in Section 5.1 
• 
Pregnancy 
• 
Disease progression 
 


 
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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 
completing 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 prior to receiving 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 Council for 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 lenalidomide is not approved for 
the treatment of patients with R/R FL.  Obinutuzumab is only approved in combination 
with bendamustine for the treatment of R/R FL.  Rituximab and lenalidomide are not 
approved for the treatment of patients with 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 lenalidomide in completed and 
ongoing studies.  The anticipated important safety risks of obinutuzumab, rituximab, 
polatuzumab vedotin, and lenalidomide are outlined below.  Please refer to the 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin Investigator’s Brochures and the 


 
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lenalidomide Summary of Product Characteristics (SmPC) 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 
antihypertensive treatments should be considered for 12 hours prior to and throughout 
each obinutuzumab infusion and for the first hour after administration.  Patients at acute 
risk of hypertensive crisis should be evaluated for the benefits and risks of withholding 
their antihypertensive medication. 
Patients who have preexisting cardiac or pulmonary conditions should be monitored 
carefully throughout the infusion and the post-infusion period. 
Guidelines for medical management of IRRs and anaphylaxis are provided in 
Section 4.3.2.1 and Appendix 8.  


 
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5.1.1.2 
Tumor Lysis Syndrome 
TLS, including fatal events, has been reported with obinutuzumab administration.  
Patients at risk for TLS (e.g., because of bulky disease or renal insufficiency) should 
receive adequate hydration and premedication with allopurinol or an alternative 
uricostatic agent as indicated in Section 4.3.2.5 (see Table 13).  Additional guidelines for 
management of TLS in this study are provided in Section 5.1.7.3 (see Table 19). 
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 4.4.1.  
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 patients with CLL exposed to obinutuzumab, fatal hemorrhagic events 
have also been reported in Cycle 1.  A clear relationship between thrombocytopenia and 
hemorrhagic events has not been established.  Patients receiving concomitant 
medication that could possibly worsen thrombocytopenia-related events (e.g., platelet 
inhibitors and anticoagulants) may be at greater risk of bleeding.  When possible, 
replace prior vitamin K antagonist therapy with LMWH prior to Day 1 of Cycle 1.  
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.   
Serious bacterial, fungal, and new or reactivated viral infections can occur during and 
following the completion of obinutuzumab therapy.  Fatal infections have been reported. 


 
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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.  Patients positive for 
HbsAg or HbcAb are not eligible for this study. 
JC viral infection resulting in PML has been reported in patients treated with 
obinutuzumab.  The diagnosis of PML should be considered in any patient presenting 
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 JC 
viral DNA).  Additional guidelines for medical management of PML in this study are 
provided in Section 5.1.7. 
5.1.1.6 
Immunizations 
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 
GI perforation has been reported in patients with B-cell lymphoma treated with 
obinutuzumab, including fatal events.  Patients with GI involvement should be monitored 
for signs of GI perforation. 
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 
[SJS]/toxic epidermal necrolysis [TEN]), and GI perforation.  Details for these risks are 
provided below; refer to the Rituximab Investigator’s Brochure for full information. 


 
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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 (Grades 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 that 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 
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. 


 
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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 tumor 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, as 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 1to 13 weeks following rituximab exposure.  The majority of the SJS/TEN 
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 SJS/TEN. 
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. 


 
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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 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.  Guidelines 
around the management of these risks through dose and schedule modifications are 
described in Section 5.1.7.  Refer also to the current Polatuzumab Vedotin Investigator’s 
Brochure for complete and updated details. 
5.1.3.1 
Identified Risks  
On the basis of clinical experience with polatuzumab vedotin in patients treated in the 
current Phase I and 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).  Patients 
receiving 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 5.1.7.3.  The use of G-CSF for neutropenia is described in 
Section 4.4.1. 
Peripheral Neuropathy 
Patients receiving 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 experiencing new or worsening 
peripheral neuropathy may require a dose delay, change in dose, or discontinuation of 
treatment and should be managed according to the protocol.  Study treatment dose and 
schedule modifications for peripheral neuropathy are described in Section 5.1.7.3. 
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.  Patients receiving chemotherapy for B-cell lymphoma with a granulocyte 
count of  < 500 cells/μL experienced a higher incidence of infections than those with a 
count of  > 500 cells/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.  


 
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MRI showed changes suggestive of PML. Cerebrospinal fluid test for JC virus by PCR 
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.  Precautions for 
suspected anaphylactic reaction during study drug infusions are provided in 
Section 4.3.2.3.  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 4.3.2.3).  Significant 
issues with polatuzumab vedotin IRRs have not been observed. 
Similar considerations regarding infusion reactions are applicable for obinutuzumab.  
Refer to Section 4.3.2.1 for additional information.   
Tumor Lysis Syndrome  
There is the potential risk of TLS if treatment with polatuzumab vedotin results in the 
rapid destruction of a large number of tumor cells.  If any evidence of this occurs during 
the study, tumor lysis prophylaxis measures will be instituted.  Patients who are 
considered to have a high tumor burden (e.g., lymphocyte count ≥ 25 × 109/L or bulky 
lymphadenopathy) and who are considered to be at risk for tumor lysis by the 
investigator will receive tumor lysis prophylaxis (e.g., allopurinol ≥ 300 mg/day orally or a 
suitable alternative treatment [according to institutional practice] starting 12−24 hours 
before study treatment) and must be well hydrated before the initiation of study 
treatment on Day 1 of Cycle 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 TLS attributed to polatuzumab vedotin has been reported (Study GO27834); 
however, the laboratory elevations did not meet the Howard criteria for TLS (see 
Appendix 12).  The suspected TLS event resolved after 3 days of supportive care.  
One case of Grade 3 Laboratory TLS was reported in the ongoing Phase Ib/II 
Study GO29833 combining polatuzumab vedotin, obinutuzumab, and venetolax.  
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 the patient was asymptomatic.  The TLS event was considered 
related to all three study treatments and resolved in 4 days with supportive care (see 
Polatuzumab Vedotin Investigator's Brochure for case details.   


 
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Bone Marrow Toxicity 
Patients with inadequate hematologic function will be excluded from this study (see 
Section 4.1.2).  Patients receiving 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 5.1.7.3.  
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 II trials.  Although the relationship between hepatotoxicity and 
polatuzumab vedotin has not been definitively determined, transient, dose-related 
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 receiving polatuzumab 
vedotin and have ranged in intensity from Grades 1-3.  These have been reversible with 
and without dose modification. 


 
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5.1.4 
Risks Associated with Lenalidomide 
5.1.4.1 
Embryo-Fetal Toxicity 
Lenalidomide, a thalidomide analogue, is structurally related to thalidomide, a known 
human teratogenic active substance that causes severe life-threatening birth defects.  In 
a developmental study in monkeys, lenalidomide caused limb abnormalities similar to 
birth defects caused by thalidomide in humans.  If taken during pregnancy, lenalidomide 
is expected to have a teratogenic effect in humans. 
Lenalidomide must not be taken by patients who are pregnant.  In every country where 
lenalidomide has been approved, a risk minimization plan, which includes a pregnancy 
prevention program, is in place.  Investigators must ensure that all specific local 
requirements that are applicable to the safe and effective use of lenalidomide are fulfilled 
prior to administration to patients.  The risk minimization plan should be followed by 
prescribers and by patients using lenalidomide, with one exception:  Because 
lenalidomide will be administered in combination with polatuzumab vedotin and 
obinutuzumab or rituximab, patients must comply with contraceptive measures 
designed to ensure safe administration of all four study treatments, as outlined in 
Section 4.1.1.  Pregnancy testing and counseling should be performed if a patient 
misses her period or has unusual/irregular menstrual bleeding.  Treatment with 
lenalidomide must be discontinued until it is confirmed that the patient is not pregnant. 
5.1.4.2 
Hematologic Toxicity 
Lenalidomide can cause significant neutropenia and thrombocytopenia.  Patients should 
have their complete blood counts monitored weekly for the first 8 weeks and at least 
monthly thereafter.  
5.1.4.3 
Venous and Arterial Thromboembolism 
Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary 
embolism) have occurred in patients treated with lenalidomide.  Prophylactic 
anti-thrombotic medicines are recommended, especially in patients with additional 
thrombotic risk factors.  The decision to take prophylactic measures should be made 
after a careful assessment of a patient’s underlying risk factors.  Thromboprophylaxis is 
presented in Section 4.3.2.5. 
Patients with known risk factors for thromboembolism, including prior thrombosis, should 
be closely monitored.  Action should be taken to try to minimize all modifiable risk factors 
(e.g., smoking, hypertension, and hyperlipidemia).  Concomitant administration of 
erythropoietic agents or previous history of thromboembolic events may also increase 
thrombotic risk in these patients.  Therefore, erythropoietic agents, or other agents that 
may increase the risk of thrombosis (such as hormone replacement therapy), should be 
used with caution.  A hemoglobin concentration of > 12 g/dL should lead to 
discontinuation of erythropoietic agents. 


 
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Patients and physicians are advised to be observant for the signs and symptoms of 
thromboembolism.  Patients should be instructed to seek medical care if they develop 
symptoms such as shortness of breath, chest pain, or arm or leg swelling.  
5.1.4.4 
Tumor Flare Reaction 
Tumor flare reaction (TFR) has occurred during investigational use of lenalidomide for 
treatment of CLL and lymphoma, and is characterized by tender lymph node swelling, 
low grade fever, pain, and rash.  Monitoring and evaluation for TFR are recommended in 
patients taking lenalidomide.  TFR may mimic disease progression.  Guidelines for the 
management of TFR are presented in Table 19.   
5.1.4.5 
Severe Skin Reactions 
Angioedema and serious dermatologic reactions including SJS and TEN have been 
reported during treatment with lenalidomide.  These events can be fatal.  Guidelines for 
the management of severe skin reactions are presented in Table 19.  Patients with a 
history of erythema multiforme, Grade  ≥ 3 rash, or blistering following prior treatment 
with immunomodulatory derivatives (such as thalidomide and lenalidomide) will not be 
enrolled in the study. 
5.1.4.6 
Tumor Lysis Syndrome 
Fatal instances of TLS have been reported during treatment with lenalidomide.  Patients 
at risk for TLS are those with high tumor burden prior to treatment.  These patients 
should be monitored closely, and appropriate precautions should be taken. 
5.1.4.7 
Hepatotoxicity 
Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide 
in combination with dexamethasone.  The mechanism of drug-induced hepatotoxicity is 
unknown.  Preexisting viral liver disease, elevated baseline liver enzymes, and 
concomitant medications may be risk factors.  Liver enzymes are to be monitored 
periodically.  Guidelines for the management of hepatotoxicity are presented in Table 19.  
5.1.4.8 
Renal Impairment 
Lenalidomide is substantially excreted by the kidney.  Patients with renal impairment 
(i.e., calculated creatinine clearance <50 mL/min) will not be enrolled in this study.  
Renal function will be monitored during the study, and the lenalidomide dose may be 
adjusted as outlined in Section 5.1.7.2 (see Table 19). 
5.1.4.9 
Thyroid Disorders 
Cases of hypothyroidism and cases of hyperthyroidism have been reported during 
treatment with lenalidomide.  Optimal control of co-morbid conditions influencing thyroid 
function is recommended before initiating lenalidomide treatment.  . 
5.1.4.10 
Peripheral Neuropathy 
Lenalidomide is structurally related to thalidomide, which is known to induce severe 
peripheral neuropathy.  There was no increase in peripheral neuropathy observed with 


 
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the long-term use of lenalidomide for the treatment of newly diagnosed multiple 
myeloma. 
5.1.4.11 
Second Primary Malignancies 
Patients with multiple myeloma treated with lenalidomide in studies that included 
melphalan and SCT had a higher incidence of second primary malignancies, particularly 
acute myelogenous leukemia and Hodgkin’s lymphoma.  Patients are to be monitored 
for the development of second malignancies.  
5.1.4.12 
Cardiovascular Reactions 
Cases of serious adverse cardiovascular events, including atrial fibrillation, myocardial 
infarction, and cardiac failure occurred more frequently in patients with CLL treated 
with lenalidomide compared to single agent chlorambucil.  Patients will be monitored 
for the development of cardiac toxicities.   
5.1.4.13 
Impaired Stem Cell Mobilization 
Patients have been reported to show a decrease in the number of CD34+ cells collected 
after treatment with lenalidomide.  Early referral to a transplant center is recommended 
in patients who are autologous SCT candidates.   
5.1.5 
Risk of Overlapping Toxicities 
The anticipated toxicities from the combined administration of obinutuzumab or 
rituximab with polatuzumab vedotin and lenalidomide are expected to be manageable 
in the clinical setting and will be closely monitored 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 B-cell lymphoma, obinutuzumab was 
associated with 5% Grade 3 or 4 neutropenia.  Because obinutuzumab is expected to 
have an incidence of neutropenia that is higher 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.  As these new data emerge, they will be assessed and applied to update this 
study if required.   
Lenalidomide has also been associated with hematologic adverse events, including 
neutropenia.  When lenalidomide was combined with obinutuzumab, the incidence of 
Grade 3 or 4 neutropenia was reported to be 33.3% (Morschhauser et al. 2014b).  
Therefore, the combination of G + Pola + Len is anticipated to result in overlapping 
hematologic toxicity, for which patients will be closely monitored.  Guidelines for the 
management of patients who develop hematologic toxicities are provided in 
Sections 5.1.7.3 and 5.1.7.4.  In addition to the standard hematologic monitoring, 
patients enrolled in this study will be closely monitored for evidence of infections. 


 
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Because both polatuzumab vedotin and lenalidomide have been associated with a risk 
of peripheral sensory neuropathy, it is unknown whether this risk may be increased 
when they are combined.  Therefore, peripheral neuropathy will be closely monitored, 
and guidelines for management for patients who develop neurotoxicity (i.e., peripheral 
neuropathy, sensory and/or motor) are provided in Sections 5.1.3.1 and 5.1.4.10, and in 
Table 19. 
There is an identified risk of TLS if treated with obinutuzumab, rituximab, or 
lenalidomide and a theoretical risk if treated with polatuzumab vedotin because 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 Table 19. 
Both rituximab and lenalidomide have been associated with dermatologic reactions such 
as SJS and TEN, and the risk of overlapping toxicities will be monitored.  Guidelines 
for management of patients who develop dermatologic toxicities are provided in 
Table 19.   
5.1.6 
Risk of Drug-Drug Interactions 
The risk for clinically relevant PK DDIs between study treatments is low.  First, 
obinutuzumab, rituximab, and polatuzumab vedotin are not anticipated to interact 
directly with CYP isoforms or other drug–metabolizing enzymes or drug transporters.  
Cytokine modulation may be considered as an indirect mechanism through which a 
monoclonal antibody could alter CYP expression.  However, treatment with 
obinutuzumab results in only transient increases in cytokine levels after the first infusion, 
and no increases are observed after subsequent infusions.  In vitro (human PBMCs) and 
in vivo (cynomolgus monkeys) treatment with anti-CD79 antibodies (i.e., the same 
antigen target as polatuzumab vedotin) showed a low risk for release of systemic pro-
inflammatory cytokines.  Taken together, these results suggest that both obinutuzumab 
and polatuzumab vedotin are unlikely to precipitate DDIs via indirect effects on cytokines.   
Second, lenalidomide is primarily excreted in the urine.  Lenalidomide is not a substrate, 
inhibitor, or inducer of the CYP group of enzymes (Kumar et al. 2009).  In vitro, the 
MMAE component of polatuzumab vedotin is mainly metabolized by CYP3A4, and it is 
mainly eliminated by biliary secretion in vivo.  Both lenalidomide and MMAE are 
substrates but not inhibitors of P-gp.  Owing to the different elimination pathways for 
lenalidomide and MMAE, the risk of CYP-mediated and transporter-mediated DDI risk is 
low when polatuzumab vedotin is combined with lenalidomide.   
In addition, simulation results suggest that unconjugated MMAE exposure is likely to be 
altered by  < 50% when polatuzumab vedotin is co-administered with strong CYP3A 
inhibitors or inducers.  Therefore, patients who receive concomitant medications that are 
strong CYP3A or P-gp inhibitors should be closely monitored for adverse reactions. 






 
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Table 17 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 on a lenalidomide dose  ≥ 10 mg who have had one or no prior 
lenalidomide 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. 
• 
Permanently discontinue study treatment if any of the following events occur: 
– 
Grade 3 or 4 thrombocytopenia that results in significant bleeding per 
investigator judgment 
– 
Recurrent Grade 3 or 4 neutropenia associated with fever > 38°C lasting 
> 5 days or documented infection despite use of G-CSF and after one 
lenalidomide dose reduction 
– 
Recurrent Grade 4 neutropenia or thrombocytopenia lasting > 7 days 
despite use of G-CSF (for neutropenia) and after one lenalidomide dose 
reduction 
• 
If improvement to Grade ≤ 2 or baseline ≤ 14 days after the scheduled date for 
the next cycle, resume obinutuzumab or rituximab and polatuzumab vedotin 
at full dose and resume lenalidomide at current dose. 
• 
If improvement to Grade ≤ 2 or baseline 15−21 days after the scheduled date 
for the next cycle, resume obinutuzumab or rituximab and polatuzumab 
vedotin at full dose and resume lenalidomide at a reduced dose per guidelines 
in Section 5.1.7 a,b for current and subsequent cycles. 
• 
If study treatment is withheld for > 21 days, permanently discontinue study 
treatment. 
For patients who have had two prior dose reductions: 
• 
Permanently discontinue study treatment. 
G = obinutuzumab; 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 lenalidomide dose. 
 


 
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Table 18 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 
documented 
infection 
• 
Withhold obinutuzumab and lenalidomide until resolution of fever and 
infection (as applicable). 
• 
If the event is ongoing at Day 1 of Cycle 2, follow instructions in 
Table 17. 
Note:  Obinutuzumab and lenalidomide should not be withheld for 
asymptomatic neutropenia. 
Severe 
thrombocytopenia a 
or bleeding 
• 
Withhold obinutuzumab and lenalidomide until platelet count 
is  ≥ 50,000/μL and there is 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 of Cycle 2, follow instructions in 
Table 17. 
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 19 provides guidelines for management of non-hematologic toxicities that occur 
during induction treatment. 


 
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Table 19 Guidelines for Management of Non-Hematologic Toxicities During Induction 
Event 
Action to Be Taken 
General guidance for treatment 
delays and discontinuation 
– If study treatment is withheld for > 21 days because of a toxicity that is attributable to study treatment, 
permanently discontinue study treatment. 
– When a treatment cycle is delayed because of toxicity resulting from any component of the regimen, all study 
treatment 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 discussion with the Medical Monitor. 
IRRs and anaphylaxis 
– Guidelines for the management of IRRs are provided in Section 4.3.2.1 for obinutuzumab, Section 4.3.2.2 for 
rituximab, and Section 4.3.2.3 for polatuzumab vedotin.  
– In case of anaphylaxis, study treatment should be permanently discontinued. 
Renal toxicity 
– Adjust the dose of lenalidomide a as outlined below: 
• 
If creatinine clearance is ≥ 30 but < 50 mL/min, lenalidomide should be given at a dose of 10 mg/day. 
• 
If creatinine clearance is < 30 mL/min and dialysis is not required, lenalidomide should be given at a 
dose of 10 mg every other day. 
• 
If creatinine clearance is < 30 mL/min and dialysis is required, lenalidomide should be given at a dose of 
5 mg/day.  On dialysis days, the dose should be administered after dialysis. 
Clinical TLS b 
– Withhold study treatment. 
– Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, 
including dialysis as indicated.  Rasburicase therapy (if approved by the local health authority) may be 
administered as needed to reduce hyperuricemia. 
– If symptoms resolve completely, resume obinutuzumab or rituximab and polatuzumab vedotin at full dose 
and resume lenalidomide at a reduced dose a per guidelines in Section 5.1.7.2 for current and subsequent 
cycles. 
– Perform chemistry panel every other day for the first week after re-initiation of lenalidomide. 
TLS 
Laboratory TLS b 
– Withhold study treatment. 
– Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care as 
clinically indicated. 
– If laboratory abnormalities have resolved completely, resume obinutuzumab or rituximab and polatuzumab 
vedotin at full dose and resume lenalidomide at a reduced dose a per guidelines in Section 5.1.7.2 for current 
and subsequent cycles. 


 
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Table 19 Guidelines for Management of Non-Hematologic Toxicities During Induction (cont.)  
Event 
Action to Be Taken 
New-onset neurologic manifestations 
suggestive of PML 
– Withhold study treatment.a 
– Consult with a neurologist if PML is suspected (refer to Section 5.1.1.5 for guidance on investigations). 
– If PML is ruled out, resume obinutuzumab or rituximab at full dose and resume polatuzumab vedotin and 
lenalidomide at current dose.  
– If PML is confirmed, permanently discontinue study treatment.  
AST, ALT, or bilirubin increase: 
Grade ≥ 3 (or ≥10× ULN for patients 
with liver involvement) 
– Withhold study treatment and monitor liver enzymes at least every 7 days. 
– Investigate etiology.   
– If improvement to Grade ≤ 1, resume obinutuzumab or rituximab and polatuzumab vedotin at full dose 
and resume lenalidomide at a reduced dose a per guidelines in Section 5.1.7.2 for current and subsequent 
cycles. 
– Permanently discontinue study treatment for life-threatening liver toxicity. 
Grade 3−4 c 
– Withhold study treatment. 
– Administer corticosteroids, NSAIDs, and/or narcotic analgesics at investigator's discretion. 
– If improvement to Grade ≤ 1, resume obinutuzumab or rituximab and polatuzumab vedotin at full dose 
and resume lenalidomide at a reduced dose a per guidelines in Section 5.1.7.2 for current and subsequent 
cycles. 
Tumor flare 
reaction 
Grade 1−2 c 
– Continue study treatment. 
– Administer corticosteroids, NSAIDs, and/or narcotic analgesics at investigator's discretion. 


 
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Table 19 Guidelines for Management of Non-Hematologic Toxicities During Induction (cont.)  
Event 
Action to Be Taken 
Grade 4 
– Permanently discontinue polatuzumab vedotin and all other study treatments. 
Neurotoxicity  
Grade 2 or 3 
– Withhold study treatment.a 
– If improvement to Grade ≤ 1 within 21 days, resume study treatments for current and subsequent cycles 
as follows (see guidelines in Section 5.1.7): 
– 
Resume obinutuzumab or rituximab at full dose.  
– 
For patients who started at 1.8 mg/kg, resume polatuzumab vedotin at a reduced dose of 
1.4 mg/kg per guidelines in Section 5.1.7.1; for patients who started at 1.4 mg/kg, permanently 
discontinue polatuzumab vedotin. a 
– 
Resume lenalidomide at a reduced dose a per guidelines in Section 5.1.7.2.  
Grade 3 with 
blistering or Grade 4 
– Permanently discontinue study treatment. 
Dermatologic 
toxicity: 
Grade ≥ 2 
Grade 2 or Grade 3 
without blistering 
First occurrence: 
– Withhold study treatment and evaluate patient at least every 7 days. 
– Investigate etiology.  Consult with a dermatologist. 
– Topical or parenteral corticosteroids may be required. 
– If improvement to Grade ≤ 1, resume obinutuzumab or rituximab and polatuzumab vedotin at full dose 
and consider resuming lenalidomide at a reduced dose a per guidelines in Section 5.1.7.2 or continue 
current dose for current and subsequent cycles. 
– Permanently discontinue all drugs in the event of angioedema, exfoliative or bullous rash, or if SJS or 
TEN is suspected. 
Second occurrence: 
– Permanently discontinue study treatment.  
Venous thrombosis or embolism  
– Withhold lenalidomide. 
– Start anticoagulation treatment. 
– After patient has been stabilized on anticoagulants and any complications of the thromboembolic event 
have been managed, lenalidomide may be resumed at current dose at investigator’s discretion, 
dependent upon a benefit-risk assessment.  
– Anticoagulants should be continued during the course of lenalidomide treatment. 


 
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Table 19 Guidelines for Management of Non-Hematologic Toxicities During Induction (cont.)  
Event 
Action to Be Taken 
Grade 3 or 4 
Grade 4 events 
– Permanently discontinue study treatment. 
Grade 3 events 
– Withhold study treatment. 
– If improvement to Grade ≤ 1 or baseline, resume obinutuzumab or rituximab at full dose and, if the event 
is considered related to lenalidomide, resume lenalidomide accordingly at a reduced dose as per 
guidelines in Section 5.1.7.2 for current and subsequent cycles.  
– No more than two dose reductions of lenalidomide are allowed. 
Other 
non-hematologic 
toxicities (i.e., not 
described 
above), excluding 
alopecia, nausea, 
and vomiting  
Grade 2 
– Withhold study treatment. 
– If improvement to Grade ≤ 1 or baseline, resume obinutuzumab or rituximab and polatuzumab vedotin at 
full dose and consider resuming lenalidomide at a reduced dose a per guidelines in Section 5.1.7.2 or 
continue current dose for current and subsequent cycles. 
CT = computed tomography; DBLCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; G-CSF = granulocyte colony-stimulating factor; 
IRR = infusion-related reaction; LMWH = low-molecular-weight heparin; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events; NSAID = nonsteroidal anti-inflammatory drug; PML = progressive multifocal leukoencephalopathy; SJS = Stevens-Johnson 
syndrome; TEN = toxic epidermal necrolysis; TLS = tumor lysis syndrome; ULN = upper limit of normal. 
a Dose modifications apply only to events that are considered to be related to lenalidomide.   
b According to Cairo-Bishop classification system. 
c Graded according to NCI CTCAE, Version 3.0. 
 


 
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5.1.7.4 
Toxicities during Consolidation or Maintenance Treatment 
Table 20 provides guidelines for management of toxicities that occur during 
consolidation or maintenance treatment. 
Table 20 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 lenalidomide.  
– Administer G-CSF for neutropenia per institutional guidelines. 
– Administer RBCs or platelets as required. 
– If improvement to Grade ≤ 2, resume obinutuzumab or rituximab 
and lenalidomide at same dose.  Lenalidomide dose may be 
reduced by one dose level per investigator judgment following 
discussion with the medical monitor.   
– If study treatment is withheld for > 42 days, permanently 
discontinue study treatment.  
Non-hematologic toxicity: 
Grade ≥ 2 
– Withhold obinutuzumab or rituximab and lenalidomide.  
– If improvement to Grade ≤ 1 or baseline, administer study 
treatment at full dose.  Lenalidomide dose may be reduced by one 
dose level per investigator judgment following discussion with the 
medical monitor.   
– 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 non-serious 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 
criteria; 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 
• 
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 occurring during and 
within 24 hours following obinutuzumab infusion) 
• 
Hepatitis B reactivation 
• 
Cardiac events 
• 
TLS 
• 
IRRs 
• 
All infections, including PML 


 
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• 
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 the FL patients, 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 (Version 4.0) will be used 
for assessing adverse event severity.  Table 21 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 21 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 (Version 4.0), 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. 
 
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 


 
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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 receiving 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 
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. 


 
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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 increase 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 whether 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 a non-serious 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)  


 
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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 
Treatment 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.  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 lenalidomide are 
available. 
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 


 
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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/Roche Medical Responsible: 
, Pharm.D. (primary) 
Telephone No.: 
 
Mobile Telephone No.: 
  
 
Medical Monitor/Roche Medical Responsible: 
, 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 
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 per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  


 
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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).  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 
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 


 
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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 
5 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 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 
Exposure of Pregnant Female to Lenalidomide 
If a pregnant female not enrolled in the study (e.g., caregiver or pharmacist) is exposed 
to lenalidomide, the Adverse Event 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 exposure), either by faxing or by scanning and emailing the form 
using the fax number or email address provided to investigators.  The woman should be 
referred to an obstetrician or gynecologist, preferably one who is experienced in 
reproductive toxicity, for further evaluation and counseling. 
5.4.3.4 
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).   
5.4.3.5 
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 
study-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, non-serious 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 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 study 
treatment. 
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 non-serious 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 document: 
• 
Obinutuzumab Investigator's Brochure (Oncology) 
• 
Rituximab Investigator’s Brochure (Oncology) 
• 
Polatuzumab Vedotin Investigator's Brochure 
• 
Lenalidomide SmPC  
 
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 Phase Ib/II, open-label, multicenter, non-randomized study will evaluate the safety, 
efficacy, and pharmacokinetics of G + Pola + Len in patients with R/R FL and 
R + Pola + Len in patients with R/R DLBCL. 
The study will include an initial dose-escalation phase followed by an expansion phase.  
The dose-escalation phase in FL patients is designed to determine the RP2Ds for both 
polatuzumab vedotin and lenalidomide when combined with fixed doses of 
obinutuzumab.  The dose-escalation phase in DLBCL patients is designed to determine 
the RP2D of lenalidomide when combined with fixed doses of polatuzumab vedotin (1.8 
mg/kg) and rituximab (375 mg/m2).  During the expansion phase, additional patients 
with R/R FL or DLBCL will undergo treatment with polatuzumab vedotin and 
lenalidomide 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 histologic 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 5 cohorts of 
3−6 patients each, for a total of 18−30 patients, will be required to establish the RP2D 
during the dose-escalation phase for patients with R/R FL.  An additional 3 possible 
cohorts of 3−6 patients each, for a total of 12−18 patients will be required to establish 
the RP2D during the dose-escalation phase for patients with R/R DLBCL.  
Approximately 80 patients (40 patients with FL and 40 patients with DLBCL) will be 
enrolled during the expansion phase.  Overall, approximately 110−128 patients will be 
enrolled in the study. 
The primary efficacy analysis will be the 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 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%.   
Table 22 lists the two-sided 90% Clopper-Pearson exact CIs for the true probability of 
achieving a PET-CT−defined CR at EOI for a range of observed proportions based on a 
sample of 40 patients. 


 
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Table 22 Potential 90% CI 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 a for 
True Population PET-CT−Defined CR 
0.50 
(0.36, 0.64) 
0.55 
(0.40. 0.68) 
0.60 
(0.46, 0.73) 
0.65 
(0.51, 0.77) 
0.70 
(0.56, 0.82) 
0.72 
(0.58, 0.83) 
0.75 
(0.61, 0.86) 
0.80 
(0.66, 0.89) 
0.85 
(0.72, 0.93) 
CI = confidence interval; CR = complete response; CT = computed tomography; EOI = end of 
induction; PET = positron emission tomography. 
a Note that the lower limit of a two-sided 90% CI is equivalent to a one-sided 95% CI. 
 
6.2 
DEFINITION OF ANALYSIS POPULATIONS 
The following populations are defined: 
• 
The primary safety and efficacy populations will include patients who received at 
least one dose of any component of the combination.   
• 
The intent-to-treat population will include all patients enrolled in the study. 
 
6.3 
SUMMARIES OF CONDUCT OF STUDY 
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 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 treatment component will be 
summarized using descriptive statistics (mean, standard deviation, median, and range). 
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. 


 
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6.5 
SAFETY ANALYSES 
The safety analyses will include all treated patients (i.e., patients who received any 
amount of study treatment).  Data for patients in the dose-escalation phase will be 
summarized by cohort and histology type, and data for patients in the expansion phase 
will be summarized by histologic subtype (FL or DLBCL).   
Safety will be assessed through summaries of adverse events and changes from 
baseline in 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, Version 4.0 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. 
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 lenalidomide 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 analysis will be estimation of the proportion of patients achieving a 
CR at EOI, as determined by the IRC through use of the PET-CT−based Lugano 2014 
criteria.  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. 
6.6.2 
Secondary Efficacy Endpoints 
The secondary efficacy analyses will be estimation of the proportion of patients 
achieving each of the following endpoints:  
• 
CR at EOI, as determined by the investigator on the basis of PET-CT scans 


 
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• 
CR at EOI, as determined by the IRC and 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 
– 
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 estimated using the method of Brookmeyer and 
Crowley (1982).  In addition, landmark estimates of the proportion of patients who are 


 
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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 
Plasma/serum concentrations of obinutuzumab, rituximab, polatuzumab vedotin, and 
lenalidomide will be tabulated, summarized, and plotted after appropriate grouping.  As 
appropriate, PK parameters (e.g., area under the curve [AUC], time to maximum 
concentration [tmax], maximum concentration [Cmax], half-life [t1/2]) may also be calculated, 
tabulated, and summarized after appropriate grouping.  Additional PK and PK/PD 
analyses (e.g., population modelling including pooled analyses across studies) may also 
be performed as appropriate.  If done, these additional analyses may be reported 
separately from the CSR.  At the discretion of the Sponsor, all analyses may be 
extended to include relevant biotransformation products of polatuzumab vedotin or 
lenalidomide. 
6.8 
IMMUNOGENICITY ANALYSES 
The numbers and proportions of post-treatment HAHA- or HACA-, and ATA-positive 
patients and HAHA- or HACA-, and ATA-negative patients at baseline and during both 
the treatment and follow-up periods will be summarized by histologic subtype.  Patients 
are considered to be ATA positive if they are ATA negative at baseline but develop an 
ATA response following study treatment administration (treatment-induced ATA 
response) or if they are ATA positive at baseline and the titer of one 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 ATA response).  Patients are considered to be 
ATA negative if they are ATA negative at baseline and all post-baseline samples are 
negative or if they are 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 HACA, and ATA status and safety, efficacy, PK, and 
biomarker endpoints will be explored as appropriate. 
6.9 
BIOMARKER ANALYSES 
Exploratory analyses of biomarkers related to tumor biology and study treatment MOA 
will be conducted.  Analyses will assess the prognostic and/or predictive value of 
candidate biomarkers separately for each histologic subtype with respect to both IRC- 
and investigator-assessed outcomes.  Specifically, the association between candidate 
biomarkers and PET-CT−defined CR rate and objective response (CR + PR) 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. 


 
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6.10 
INTERIM ANALYSES 
It is anticipated that at least two interim analyses, one per histology, will be conducted 
during the expansion phase of the study, when at least 15 patients in each histology 
have been evaluated for PET-CT−defined CR at 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 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 
indication-specific expansion cohort with that in historical controls.  Updated estimates 
for the assumed historical control PET-CT−defined CR rate will be available from 
currently ongoing studies by the time of the first interim analysis.  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 indication-specific 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 subgroup.   
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. 


 
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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. 
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. 


 
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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 
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 Good 
Clinical Practice 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. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union 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. 


 
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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 
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 of 1996 (HIPAA).  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.  


 
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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, 
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 


 
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amendments, Informed Consent Forms, and documentation of IRB/EC and governmental 
approval.  In addition, at the end of the study, the investigator will receive 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. 
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. 
Electronic data capture 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.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.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 
an IMP for which a marketing authorization application has been filed or approved in any 


 
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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). 


 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
190/Protocol GO29834, Version 2 
10. 
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Appendix 1  
Schedule of Assessments for Patients with Follicular Lymphoma (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
198/Protocol GO29834, Version 2 
 
Screening a 
Induction  
(6-months; 28-day cycles) 
EOI 
Maintenance 
 (24 months) 
EOM b 
 
Cycle 1  
(± 1 d) 
Cycles 2−6 
(± 2 d) 
After Last 
Induction 
Dose c 
Monthly
(± 3 
days) 
Every 
2 months
(± 1 wk)
35 Days 
after Last  
Dose 
Post- 
Treatment
FU Period 
(Q3M) d 
Surviva
l FU 
Period 
(Q3M) d
 
D −28 
to 
D −1 
D −14 
to 
D −1
D1
D8 D15 D22
D1 
D8 
D15
D22 
 
D1 
D1 
 
 
 
Coagulation (INR, aPTT [or PTT], 
and PT) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test p 
 
x p 
x p 
x p 
x p 
x p 
x p 
 
 
Hepatitis B and C testing q 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV testing q 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative IgA, IgG, IgM 
 
 
x m 
 
 
 
 
 
 
 
x 
x r 
x 
x s 
 
HAHA sample for obinutuzumab 
 
 
x t (see Appendix 3) 
 
ATA sample for polatuzumab 
vedotin 
 
 
x t (see Appendix 3) 
 
PK sample for obinutuzumab 
 
 
x t (see Appendix 3) 
 
PK sample for polatuzumab vedotin 
 
 
x t (see Appendix 3) 
 
PK sample for lenalidomide 
 
 
x t (see Appendix 3) 
 
Whole blood for MRD u  
 
 
x m,u
 
 
 
 
 
 
 
x u 
x r, u 
 
 
 
Whole blood for lymphocyte 
immunophenotyping v 
 
 
x m 
 
x m 
 
x m 
 
 
 
x 
x r 
x 
x s 
 
Plasma  for cytokine analysis 
 
 
x m
 
 
 
x m, n
 
 
 
 
 
 
 
 
 
Optional peripheral blood sample for 
RCR w 
 
 
x m 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 1  
Schedule of Assessments for Patients with Follicular Lymphoma (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
199/Protocol GO29834, Version 2 
 
Screening a 
Induction  
(6-months; 28-day cycles) 
EOI 
Maintenance 
 (24 months) 
EOM b 
 
Cycle 1  
(± 1 d) 
Cycles 2−6 
(± 2 d) 
After Last 
Induction 
Dose c 
Monthly
(± 3 
days) 
Every 
2 months
(± 1 wk)
35 Days 
after Last  
Dose 
Post- 
Treatment
FU Period 
(Q3M) d 
Surviva
l FU 
Period 
(Q3M) d
 
D −28 
to 
D −1 
D −14 
to 
D −1
D1
D8 D15 D22
D1
D8 
D15
D22 
 
D1 
D1 
 
 
 
Tumor tissue specimen   
x x 
 
 
 
 
 
 
 
 
 
(xy) 
 
Concomitant medications 
x z 
To be recorded continually until end of treatment z 
 
 
Adverse events aa 
x 
To be assessed continually aa 
PET-CT scan 
x bb 
 
 
 
 
 
 
 
 
 
x cc 
x dd 
 
 
 
CT scan ee 
x ee 
 
 
 
 
 
x ff 
x cc 
x ff 
x gg 
xhh 
 
Bone marrow biopsy and aspirate  
x ii 
 
 
 
 
 
 
 
 
 
x cc,jj 
x jj 
x gg,jj 
 
 
Obinutuzumab kk 
 
 
x 
x 
x 
 
x 
 
 
 
 
 
x 
 
 
 
Polatuzumab 
vedotin kk 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Study 
treatment 
administration 
Lenalidomide kk 
 
 
D1−21 
 
 
D1−21 
 
D1−21 
 
 
 
 
New anti-lymphoma treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
ATA = anti-therapeutic antibody; CT = computed tomography; D = day; 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; MRD = minimal residual disease; MRI = magnetic resonance imaging; PET = positron emission tomography; PK = pharmacokinetic; Q3M = every 
3 months; RCR = Roche Clinical Repository;T4 = thyroxine; TSH = thyroid-stimulating hormone; wk = week.  
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  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 


Appendix 1  
Schedule of Assessments for Patients with Follicular Lymphoma (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
200/Protocol GO29834, Version 2 
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 Patients who complete maintenance treatment or discontinue maintenance treatment prematurely will undergo assessments at EOM. 
c 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. 
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 patients have completed or 
discontinued study treatment or when the Sponsor ends the study.  
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 Perform only in patients who will not be receiving maintenance treatment. 
h 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. 
I 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. 
j 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. 
k Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent or absolute WBC differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 


Appendix 1  
Schedule of Assessments for Patients with Follicular Lymphoma (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
201/Protocol GO29834, Version 2 
l Screening laboratory assessments may be used for Day 1 of Cycle 1 if performed within 72 hours prior to Day 1 of Cycle 1. 
m 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 other timepoints during induction treatment.  CBC to be monitored every week for first 8 weeks of lenalidomide treatment.  Samples for exploratory 
biomarker research should be collected at the same time as hematology and chemistry samples.  For β2 microglobulin and Quantitative IgA, IgG, IgM:  
C1D1 requires predose collection.  For plasma cytokine analysis:  C1D1 requires predose collection and 2-hour postdose collection.  All other timepoints 
thereafter will be predose.  
n Cycles 2 and 3 only. 
o Includes sodium, potassium, glucose, BUN or urea, creatinine, calculated creatinine clearance, calcium, total bilirubin, direct bilirubin, total protein, albumin, 
ALT, AST, alkaline phosphatase, amylase, lipase, LDH, and uric acid (amylase and lipase only during induction). 
p All women of childbearing potential will have two negative serum pregnancy test results prior to initiating treatment:  at 10−14 days prior to Day 1 of Cycle 1 and 
within 24 hours prior to Day 1 of Cycle 1.  Urine pregnancy tests are required after treatment initiation (including times of treatment interruption) as follows:  
every week during the first cycle and then every 4 weeks during treatment for women with regular menstrual cycles or every 2 weeks during treatment for 
women with irregular menstrual cycles, any time the patient misses her period or has unusual menstrual bleeding, at the time of treatment discontinuation, and 
at Days 14 and 28 following the last dose of study treatment.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
q 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 
requirements. 
r Perform at the same time as tumor assessments at 12, 18, and 24 months after initiation of induction treatment. 
s 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. 
t See Appendix 3 for detailed PK collection schedule. 
u Perform only for patients enrolled in the expansion phase.  Includes circulating lymphoma cells and/or cell-free circulating tumor DNA. 
v Includes B-cell counts (CD19), T-cell counts (CD3, CD4, and CD8), and NK-cell counts (CD16 and CD56). 
w Requires separate patient consent for RCR participation.  Not applicable for a site that has not been granted approval for RCR sampling. 
x 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). 
y A tumor biopsy sample will be collected at the time of progression unless no adequate tumor site is accessible. 
z 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. 
 


Appendix 1  
Schedule of Assessments for Patients with Follicular Lymphoma (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
202/Protocol GO29834, Version 2 
aa 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 made for Grade 3 and 4 infections (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. 
bb The screening PET-CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
cc Perform only for patients who have received at least two cycles of induction treatment. 
dd If PET-CT scan is positive at EOI, perform at 12 months after initiation of induction treatment, within 14 days prior to treatment administration. 
ee Includes 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.  The 
screening CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
ff Perform within 7 days prior to Day 1 of Cycle 3 and at 12, 18, and 24 months after initiation of induction treatment. 
gg Perform only if not done within the previous 3 months. 
hh Perform every 6 months. 
ii Bone marrow biopsy and aspirate must be performed within approximately 3 months prior to Day 1 of Cycle 1. 
jj 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). 
kk Refer to Section 4.3.2 for details on dosing and schedule.  At each cycle, each patient will be supplied with only enough lenalidomide for that cycle.  During 
maintenance treatment, lenalidomide will be administered for a maximum of 12 months. 




Appendix 2  
Schedule of Assessments for Patients with Diffuse Large B-Cell Lymphoma (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
204/Protocol GO29834, Version 2 
 
Screening a 
Induction  
(6-months; 28-day cycles) 
EOI 
Consolidation 
 (6 months) 
EOC b 
 
Cycle 1  
(± 1 d) 
Cycles 2−6 
(± 2 d) 
After Last 
Induction 
Dose c 
Monthly
(± 3 
days) 
Every 
2 months
(± 1 wk)
35 Days 
after Last  
Dose 
Post- 
Treatment
FU Period 
(Q3M) d 
Survival 
FU 
Period 
(Q3M) d
 
D −28 
to 
D −1 
D −14 
to 
D −1 
D1 
D8
D15
D22 
D1 
D8 D15
D22 
 
D1 
D1 
 
 
 
Coagulation (INR, aPTT [or PTT], 
and PT) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test p 
 
x p 
x p 
x p 
x p 
x p 
x p 
 
 
Hepatitis B and C testing q 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV testing q 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative IgA, IgG, IgM 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
x  
 
HACA sample for rituximab 
 
 
x r (see Appendix 4) 
 
ATA sample for polatuzumab 
vedotin 
 
 
x r (see Appendix 4) 
 
PK sample for rituximab 
 
 
x r (see Appendix 4) 
 
PK sample for polatuzumab vedotin 
 
 
x r (see Appendix 4) 
 
PK sample for lenalidomide 
 
 
x r (see Appendix 4) 
 
Whole blood for MRD s 
 
 
x m,s
 
 
 
 
 
 
 
x s 
At Month 3 s 
 
 
 
Whole blood for lymphocyte 
immunophenotyping t 
 
 
x m 
 
x m 
 
x m 
 
 
 
x 
 
 
x 
x u 
 
 


Appendix 2  
Schedule of Assessments for Patients with Diffuse Large B-Cell Lymphoma (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
205/Protocol GO29834, Version 2 
 
Screening a 
Induction  
(6-months; 28-day cycles) 
EOI 
Consolidation 
 (6 months) 
EOC b 
 
Cycle 1  
(± 1 d) 
Cycles 2−6 
(± 2 d) 
After Last 
Induction 
Dose c 
Monthly
(± 3 
days) 
Every 
2 months
(± 1 wk)
35 Days 
after Last  
Dose 
Post- 
Treatment
FU Period 
(Q3M) d 
Survival 
FU 
Period 
(Q3M) d
 
D −28 
to 
D −1 
D −14 
to 
D −1 
D1 
D8
D15
D22 
D1 
D8 
D15
D22 
 
D1 
D1 
 
 
 
Plasma for cytokine analysis 
 
 
x m 
 
 
 
x m, n
 
 
 
 
 
 
 
 
 
Optional peripheral blood sample for 
RCR v 
 
 
x m 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue specimen  
x w 
 
 
 
 
 
 
 
 
 
(xx) 
 
Concomitant medications 
x y 
To be recorded continually until end of treatment y 
 
 
Adverse events z 
x 
To be assessed continually z 
PET-CT scan 
x aa 
 
 
 
 
 
 
 
 
 
x bb 
 
x jj 
 
 
CT scan cc 
x cc 
 
 
 
 
 
x dd 
x bb 
At end of Month 3
x ee 
x ff 
 
Bone marrow biopsy and aspirate  
x gg 
 
 
 
 
 
 
 
 
 
x bb, hh 
x hh 
x ee, hh 
 
 
Rituximabii 
 
 
x 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
Polatuzumab 
vedotin ii 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Study 
treatment 
administration 
Lenalidomide ii 
 
 
D1−21 
 
 
D1−21 
 
D1−21 
 
 
 
 
New anti-lymphoma treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
ATA = anti-therapeutic antibody; CT = computed tomography; D = day; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic Case Report Form; 
EOC = end of consolidation; EOI = end of induction; FU = follow-up; HAHA = human anti-human antibody; IPI = International Prognostic Index; MRD = minimal 
residual disease; MRI = magnetic resonance imaging; PET = positron emission tomography; PK = pharmacokinetic; Q3M = every 3 months; RCR = Roche Clinical 
Repository; wk = week. 


Appendix 2  
Schedule of Assessments for Patients with Diffuse Large B-Cell Lymphoma (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
206/Protocol GO29834, Version 2 
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  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 Patients who complete consolidation treatment or discontinue consolidation treatment prematurely will undergo assessments at EOC. 
c 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. 
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 patients 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 Perform only in patients who will not be receiving consolidation treatment. 
h 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. 
i 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. 
j 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 Diffuse Large B-Cell Lymphoma (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
207/Protocol GO29834, Version 2 
k Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent or absolute WBC differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 
l Screening laboratory assessments may be used for Day 1 of Cycle 1 if performed within 72 hours prior to Day 1 of Cycle 1. 
m Perform hematology and chemistry tests within 72 hours prior to Day 1 of each cycle during induction or each month during consolidation, and within 24 hours 
prior to other timepoints during induction treatment.  CBC to be monitored every week during first 8 weeks of lenalidomide therapy.  Samples for exploratory 
biomarker research should be collected at the same time as hematology and chemistry samples.  For β2 microglobulin and Quantitative IgA, IgG, IgM:  
C1D1 requires predose collection.  For plasma cytokine analysis:  C1D1 requires predose collection and 2-hour post-dose collection.  All other timepoints 
thereafter will be predose.  
n Cycles 2 and 3 only. 
o Includes sodium, potassium, glucose, BUN or urea, creatinine, calculated creatinine clearance, calcium, total bilirubin, direct bilirubin, total protein, albumin, ALT, 
AST, alkaline phosphatase, amylase, lipase, LDH, and uric acid (amylase and lipase only during induction). 
p All women of childbearing potential will have two negative serum pregnancy test results prior to initiating treatment:  at 10−14 days prior to Day 1 of Cycle 1 and 
within 24 hours prior to Day 1 of Cycle 1.  Urine pregnancy tests are required after treatment initiation (including times of treatment interruption) as follows:  every 
week during the first cycle and then every 4 weeks during treatment for women with regular menstrual cycles or every 2 weeks during treatment for women with 
irregular menstrual cycles, any time the patient misses her period or has unusual menstrual bleeding, at the time of treatment discontinuation, and at Days 14 
and 28 following the last dose of study treatment.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
q 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. 
r See Appendix 4 for detailed PK collection schedule. 
s Perform only for patients enrolled in the expansion phase.  Includes circulating lymphoma cells and/or cell-free circulating tumor DNA. 
t Includes B-cell counts (CD19), T-cell counts (CD3, CD4, and CD8), and NK-cell counts (CD16 and CD56). 
u 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. 
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 tumor biopsy 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 to the visit at EOI or at the end of post-induction treatment, whichever occurs later. 
 


Appendix 2  
Schedule of Assessments for Patients with Diffuse Large B-Cell Lymphoma (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
208/Protocol GO29834, Version 2 
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 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).  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 two cycles of induction treatment. 
cc Includes 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.  The 
screening CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
dd Perform within 7 days prior to Day 1 of Cycle 3.   
ee Perform only if not done within the previous 3 months. 
ff Perform every 6 months. 
gg Bone marrow biopsy and aspirate must be performed within approximately 3 months prior to Day 1 of Cycle 1. 
hh 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 or at EOC 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). 
ii Refer to Section 4.3.2 for details on dosing and schedule.  At each cycle, each patient will be supplied with only enough lenalidomide for that cycle.  During 
consolidation treatment, lenalidomide will be administered for a maximum of 6 months. 
jj If PET-CT scan is positive at EOI, perform repeat PET-CT at EOC. 


 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
209/Protocol GO29834, Version 2 
Appendix 3  
Pharmacokinetic and Immunogenicity Sampling Schedule for Obinutuzumab, Polatuzumab 
Vedotin, and Lenalidomide in Relapsed or Refractory FL Patients 
Study Visit 
Serum 
Obinutuzumab 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 
Lenalidomide PK 
Sample a 
Serum 
Obinutuzumab 
HAHA Sample a 
Serum Polatuzumab 
Vedotin ATA 
Sample a 
Dose-Escalation Phase (FL Patients; 28-Day Cycles) 
Day 1 
Pre-infusion 
(anytime prior to 
dose); 
30 ± 10 min after 
end of infusiond 
Pre-infusion 
(anytime prior to 
dose) 
Pre-infusion 
(anytime prior to 
dose); 
30 ± 10 min after 
end of infusion 
Predose 
(anytime prior to 
dose); 
2 hr post-dose  
(± 10 min) c 
Pre-infusion 
(anytime prior to 
dose) 
Pre-infusion 
(anytime prior to dose)
Day 8 
– 
– 
Anytime during 
visit 
– 
– 
– 
Cycle 1 
Day 15 
– 
– 
Anytime during 
visit 
Predose (within15 
min prior to dose);
0.5 hr (± 5 min), 
1 hr (± 5 min,  
2 hr (± 10 min),  
4 hr (± 10 min),  
8 hr post-dose  
(± 30 min) c 
– 
– 
Cycle 2 
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-infusion 
(within 5 hr prior to 
dose); 
30 ± 10 min after 
end of infusion 
– 
– 
Pre-infusion (within 
5 hr prior to dose) 




 
 
Appendix 3  
Pharmacokinetic and Immunogenicity Sampling Schedule for Obinutuzumab, Polatuzumab 
Vedotin, and Lenalidomide in Relapsed or Refractory FL Patients (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
211/Protocol GO29834, Version 2 
Study Visit 
Serum 
Obinutuzumab 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 
Lenalidomide PK 
Sample a 
Serum 
Obinutuzumab 
HAHA Sample a 
Serum Polatuzumab 
Vedotin ATA 
Sample a 
to dose); 
0.5hr (± 5 min),  
1hr (± 5 min,  
2 hr (± 10 min),  
4hr (± 10 min),  
8 hr post-dose  
(± 30 min) c  
Cycle 2 
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-infusion 
(within 5 hr prior to 
dose); 
30 ± 10 min after 
end of infusion 
– 
– 
Pre-infusion 
(within 5 hr prior to 
dose) 
 
Cycle 4 
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-infusion  
(within 5 hr prior to 
dose); 
30 ± 10 min after 
end of infusion 
– 
– 
Pre-infusion  
(within 5 hr prior to 
dose) 




 
 
Appendix 3  
Pharmacokinetic and Immunogenicity Sampling Schedule for Obinutuzumab, Polatuzumab 
Vedotin, and Lenalidomide in Relapsed or Refractory FL Patients (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
213/Protocol GO29834, Version 2 
Study Visit 
Serum 
Obinutuzumab 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 
Lenalidomide PK 
Sample a 
Serum 
Obinutuzumab 
HAHA Sample a 
Serum Polatuzumab 
Vedotin ATA 
Sample a 
Treatment discontinuation 
Anytime during 
visit 
Anytime during 
visit 
 
– 
Anytime during 
visit 
Anytime during visit
20 ± 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) 


 
 
Appendix 3  
Pharmacokinetic and Immunogenicity Sampling Schedule for Obinutuzumab, Polatuzumab 
Vedotin, and Lenalidomide in Relapsed or Refractory FL Patients (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
214/Protocol GO29834, Version 2 
ATA = anti-therapeutic antibody; HAHA = human anti-human antibody; “ – “ = 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 lenalidomide PK sampling visits, lenalidomide 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. 








 
 
 
Appendix 4  
Pharmacokinetic and Immunogenicity Sampling Schedule for Rituximab, Polatuzumab Vedotin, 
and Lenalidomide in Relapsed or Refractory DLBCL Patients (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
218/Protocol GO29834, Version 2 
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 
Lenalidomide PK 
Sample a 
Serum Rituximab 
HACA Sample a 
Serum 
Polatuzumab 
Vedotin ATA 
Sample a 
ATA = anti-therapeutic antibody; HACA = human anti-chimeric antibody; “ – “ = not applicable; PK = pharmacokinetic. 
a Sample collection timing is relative to specified drug. 
b Samples collected for PK, HACA, and ATA analysis may be used for additional PK, HACA, and ATA assay development and validation and 
additionalimmunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist. 
c On lenalidomide PK sampling visits, lenalidomide dose will be taken at the clinic appointment. 
d  If the Cycle 1 Day 1 dose of rituximab is split over two 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. 


 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
219/Protocol GO29834, Version 2 
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 


 
Appendix 5  
Modified Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
220/Protocol GO29834, Version 2 
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 
 


 
Appendix 5  
Modified Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
221/Protocol GO29834, Version 2 
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 
 


 
Appendix 5  
Modified Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
222/Protocol GO29834, Version 2 
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 


 
Appendix 5  
Modified Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014) (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
223/Protocol GO29834, Version 2 
New lesions 
New FDG-avid foci consistent with lymphoma rather 
than another etiology (e.g., infection, inflammation); if 
uncertain regarding etiology of new lesions, biopsy or 
interval scan may be considered 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in 
any axis, its presence must be unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size unequivocally attributable 
to lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
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.  
 


 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
224/Protocol GO29834, Version 2 
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. 
 


 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
225/Protocol GO29834, Version 2 
Appendix 7  
Calculation of Creatinine Clearance Using the 
Cockcroft-Gault Formula 
 
Creatinine clearance (men) = (140 − Age) × Lean Body Weight (kg) 
Serum Creatinine (mg/dL) × 72 
 
Creatinine clearance (women) = 0.85 × (140 − Age) × Lean Body Weight (kg) 
Serum Creatinine (mg/dL) × 72 
 
Taken from:  Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function 
from adjusted serum creatinine [editorial]. Nephron 1992;62:249. 


 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
226/Protocol GO29834, Version 2 
Appendix 8  
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. 
 


 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
227/Protocol GO29834, Version 2 
Appendix 9  
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. 
 


 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
228/Protocol GO29834, Version 2 
Appendix 10 
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 
0−1 
Intermediate 
2 
High 
3−5 
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. 
 


Appendix 10 
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
229/Protocol GO29834, Version 2 
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 
1−2 
High 
3−5 
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. 
 


Appendix 10 
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index (cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
230/Protocol GO29834, Version 2 
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. 
 


 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
231/Protocol GO29834, Version 2 
Appendix 11  
Treatment of Relapsed or Refractory Follicular and Diffuse Large B-Cell Lymphomas 
Table 1 
Treatment Regimens for Relapsed or Refractory Follicular Lymphoma 
 
Single Agents 
Doublet  
Anti-CD20 + Polatuzumab 
Vedotin 
Doublet 
Anti-CD20 + Lenalidomide 
 
Obinutuzumab a 
Polatuzumab Vedotin b 
Lenalidomide c 
R + Pola d 
G + Pola 
(GO27834) 
R-Len e 
R + Len f 
G + Len g 
Number of 
patients 
22 
 (20 FL, 1 MZL,  
1 SLL) 
47 
43 
 (22 FL, 18 SLL, 3 
MZL) 
20 
46 (will enroll) 
27 (iNHL) 
44 
19 
Anti-CD20 
dose 
G: 1600/800 mg 
− 
− 
R: 375 mg/m2 
Q3W × 8 cycles
G: 1000 mg D1, 
8, 15 in C1, then 
D1 in C2-8 
R: 375 mg/m2 
on D15 in C1, 
then QW × 4 
doses 
R: 375 mg/m2 
QW × 4 
G: 1000 mg 
D8, 15, 22 in 
C1, then D1 
in C2-6 
Pola dose 
− 
2.4 mg/kg (n = 43)  
1.8 mg/kg (n = 4) 
 −  
1.8 mg/kg 
1.8 mg/kg 
− 
− 
− 
Len dose 
− 
− 
25 mg  
D1-22/28  
× 52 weeks 
− 
− 
25 mg  
D1-22/28 
 × 52 weeks 
15 mg in C1, 
then 20 mg in 
C2-12 on 
D1-22/28 × 12 
10, 15, 20, 25 
mg on D1-21 
in C1, then 
D2-22 C2-6 
ORR 
CR/CRu 
DoR 
PFS 
54.5% 
9.1% 
17.2 m 
11.9 m 
52% (DLBCL)/53% iNHL
10% (DLBCL)/20% iNHL
 −  
151 d (DLBCL)/264 d 
(iNHL) 
27% 
9% 
> 16.5 m (all pt) 
4.4 m (all pt) 
75% 
10% 
 −  
NR 
Results not 
available 
74% 
44% 
15.4 m 
12.4 m 
75% 
32% 
 −  
2 year 
68% 
10 pt 
 −  
 −  
Heme 
toxicity & 
infection 
(Grade 3/4) 
Neutropenia 
(n = 3) 
FN (n = 1) 
TCP (n = 1) 
Infection (n = 1) 
Neutropenia (n = 5) 
Neutropenia 46%
FN 2% 
TCP 20% 
Neutropenia 
35% 
FN 10% 
Results not 
available 
Neutropenia 
55% 
Neutropenia 
19% 
Neutropenia 
53% 
Infection 37%


 
Appendix 11  
Treatment Regimens for Relapsed or Refractory Follicular and Diffuse Large B-Cell Lymphomas 
(cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
232/Protocol GO29834, Version 2 
 
Single Agents 
Doublet  
Anti-CD20 + Polatuzumab 
Vedotin 
Doublet 
Anti-CD20 + Lenalidomide 
 
Obinutuzumab a 
Polatuzumab Vedotin b 
Lenalidomide c 
R + Pola d 
G + Pola 
(GO27834) 
R-Len e 
R + Len f 
G + Len g 
Neuro-
toxicity 
NR 
Grade 1/2: 42% 
Grade 3/4: 10% 
NR 
Grade 2-4: 
25% 
Results not 
available 
NR 
NR 
NR 
C = cycle; CR = complete response; CRu = CR unconfirmed; D = day; DLBCL = diffuse large B-cell lymphoma; DoR = duration of response; FL = follicular 
lymphoma; FN = febrile neutropenia; G = obinutuzumab; iNHL = indolent non-Hodgkin’s lymphoma; Len = lenalidomide; m = months; MZL = marginal zone 
lymphoma; NR = not reported; ORR = overall response rate; PFS = progression-free survival; Pola = polatuzumab vedotin; pt = patients; Q3W= every 3 weeks; 
QW = once per week; R = rituximab; SLL = small lymphocytic lymphoma; TCP = thrombocytopenia; wk = week. 
a Salles G, Morschhauser F, Solal-Celigny P, et al. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the 
phase II GAUGUIN study. J Clin Oncol 2013a;31:2920−26. 
b Palanca-Wessels MC, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79b antibody-drug conjugate polatuzumab vedotin in relapsed or refractory 
B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase I study. Lancet Oncol 2015;16(6):704-15. 
c Witzig TE, Wiernik PH, Moore T, et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's lymphoma. 
J Clin Oncol 2009;27:5404-9. 
d Advani R, Flinn I, Sharman J, et al. Two doses of polatuzumab vedotin (PoV, anti CD79b antibody-drug conjugate) in patients (pts) with relapsed/refractory (RR) 
follicular lymphoma (FL): durable responses at lower dose level [abstract]. J Clin Oncol 2015;Abstract 8503. 
e Tuscano JM, Dutia M, Chee K, et al. Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-
Hodgkin lymphoma. Br J Haematol 2014;165:375-81. 
f Leonard J, Jung SH, Johnson JL, et al. CALGB 50401: a randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent 
follicular lymphoma [abstract]. ASCO 2012;Abstract 8000. 
g Morschhauser F, Flinn I, Advani RH, et al. Updated results of a phase II randomized study (ROMULUS) of polatuzumab vedotin or pinatuzumab vedotin plus 
rituximab in patients with relapsed/refractory non-Hodgkin lymphoma [abstract]. Blood 2014;124:Abstract 4457. 
 


 
Appendix 11  
Treatment Regimens for Relapsed or Refractory Follicular and Diffuse Large B-Cell Lymphomas 
(cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
233/Protocol GO29834, Version 2 
Table 2 
Treatment Regimens for Relapsed or Refractory DLBCL 
 
Single Agents 
Doublet 
Anti-CD20 + Polatuzumab Vedotin 
Doublet 
Anti-CD20 + Lenalidomide 
 
Obinutuzumab a 
Polatuzumab Vedotin b 
Lenalidomide c 
Lenalidomide d 
R + Pola e 
G + Pola 
(GO27834) 
R + Len f 
() 
R +Len g,h 
Number of 
patients 
19 
(15 DLBCL,  
4 MCL) 
47 
26 
108 
39 
46 (will enroll) 
45 
23 
Anti-CD20 
dose 
G: 1600/800 mg 
− 
− 
− 
R: 375 mg/m2 
G: 1000 mg D1, 
8, 15 in C1, then 
D1 in C2-8 
R: 375 mg/m2
R: 375 mg/m2 
Pola dose 
− 
2.4 mg/kg (n = 43) 
1.8 mg/kg (n = 4) 
− 
− 
2.4 mg/kg 
1.8 mg/kg 
− 
− 
Len dose 
− 
− 
25 mg D1-22/28 
× 52 wk 
25 mg D1-22/28 
until PD 
 
− 
20 mg 
D1-22/28 × 52 
wk 
15 mg in C1, 
then  
20 mg in C2-12 
on  
D1-22/28 × 52 
wk 
ORR 
CR/CRu 
DoR 
PFS 
32% 
0% 
9.8 m 
2.7 m 
52% (DLBCL)/53% 
iNHL 
10% (DLBCL)/20% 
iNHL 
− 
151 d (DLBCL)/264 d 
(iNHL) 
19% 
12% 
− 
− 
28% 
7% 
4.6 m 
2.7 m 
56% 
15% 
− 
5.4 m 
Results not 
available 
33% 
20% 
10.2 m 
3.7 m 
35% 
30% 
32 m 
1-year DFS: 
35% 


 
Appendix 11  
Treatment Regimens for Relapsed or Refractory Follicular and Diffuse Large B-Cell Lymphomas 
(cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
234/Protocol GO29834, Version 2 
 
Single Agents 
Doublet 
Anti-CD20 + Polatuzumab Vedotin 
Doublet 
Anti-CD20 + Lenalidomide 
 
Obinutuzumab a 
Polatuzumab Vedotin b 
Lenalidomide c 
Lenalidomide d 
R + Pola e 
G + Pola 
(GO27834) 
R + Len f 
() 
R +Len g,h 
Heme 
toxicity & 
infection 
(Grade 
3/4) 
Neutropenia 
(n = 1) 
Neutropenia (n = 5) 
Neutropenia 33%
FN 6% 
Neutropenia 
41% 
FN 2% 
Neutropenia 
24% 
FN 4% 
Results not 
available 
Neutropenia 
53% 
FN 34% 
Neutropenia 
30% 
FN 14% 
Neuro-
toxicity 
NR 
Grade 1/2: 42% 
Grade 3/4: 10% 
NR 
NR 
39% (any 
grade) 
Results not 
available 
NR 
NR 


 
Appendix 11  
Treatment Regimens for Relapsed or Refractory Follicular and Diffuse Large B-Cell Lymphomas 
(cont.) 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
235/Protocol GO29834, Version 2 
 
Single Agents 
Doublet 
Anti-CD20 + Polatuzumab Vedotin 
Doublet 
Anti-CD20 + Lenalidomide 
 
Obinutuzumab a 
Polatuzumab Vedotin b 
Lenalidomide c 
Lenalidomide d 
R + Pola e 
G + Pola 
(GO27834) 
R + Len f 
() 
R +Len g,h 
C = cycle; CR = complete response; CRu = CR unconfirmed; D = day; DFS = disease-free survival; DLBCL = diffuse large B-cell lymphoma; DoR  = duration of 
response; FL = follicular lymphoma; FN = febrile neutropenia; G = obinutuzumab; iNHL = indolent non-Hodgkin’s lymphoma; Len = lenalidomide; m = months; 
MCL = mantel zone lymphoma; NR = not reported; ORR = overall response rate; PD = progressive disease; PFS = progression-free survival; Pola = polatuzumab 
vedotin; pt = patients; Q3W = every 3 weeks; QW = once per week; R = rituximab; SLL = small lymphocytic lymphoma; TCP = thrombocytopenia; wk = week. 
a Morschhauser F, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-Cell lymphoma or mantle-cell 
lymphoma: results from the phase II GAUGUIN study. J Clin Oncol 2013;31:2912-19. 
b Palanca-Wessels MC, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79b antibody-drug conjugate polatuzumab vedotin in relapsed or refractory 
B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase I study. Lancet Oncol 2015;16(6):704-15. 
c Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol 
2008;26:4952-7. 
d Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's 
lymphoma. Ann Oncol 2011;22:1622-7. 
e Morschhauser F, Flinn I, Advani RH, et al. Updated results of a phase II randomized study (ROMULUS) of polatuzumab vedotin or pinatuzumab vedotin plus 
rituximab in patients with relapsed/refractory non-Hodgkin lymphoma [abstract]. Blood 2014;124:Abstract 4457. 
f Wang M, Fowler N, Wagner-Bartak N, et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a 
phase II clinical trial. Leukemia 2013;27:1902-9. 
g Zinzani PL, Pellegrini C, Derenzini E, et al. Long-term efficacy of the combination of lenalidomide and rituximab in elderly relapsed/refractory diffuse large B-cell 
lymphoma patients. Hematol Oncol 2013;31:223-4 
h Zinzani PL, Pellegrini C, Gandolfi L, et al. Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: 
a phase 2 trial. Clin Lymphoma Myeloma Leuk 2011;11:462-6. 
 
 


 
Obinutuzumab, Rituximab, and Polatuzumab Vedotin—F. Hoffmann-La Roche Ltd 
236/Protocol GO29834, Version 2 
Appendix 12 
Diagnostic Criteria for Tumor Lysis Syndrome 
Lab Value Threshold 
Uric acid 
 ≥ 476 μmol/L (8 mg/dL) 
Potassium 
 ≥ 6mmol/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.