Conditions: Non-Hodgkin's Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
This is a open-label, multicenter, non-randomized, study to evaluate the safety, efficacy, and pharmacokinetics of idasanutlin in combination with obinutuzumab in participants with R/R FL and rituximab in combination with idasanutlin in R/R DLBCL. The study will include an initial dose-escalation phase followed by an expansion phase. The dose-escalation phase is designed to determine the recommended phase 2 dose (RP2D) for idasanutlin in combination with obinutuzumab for FL and in combination with rituximab for DLBCL. The expansion phase is designed to further assess the safety and efficacy of obinutuzumab in combination with idasanutlin at the RP2D with the selected regimen in participants with R/R FL and of rituximab in combination with idasanutlin at the RP2D in participants with R/R DLBCL.

Detailed description:

Arms:
arm 1: Participants with diffuse large B-cell lymphoma (DLBCL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 100 milligrams (mg) orally in combination with a fixed dose of obinutuzumab 1000 mg intravenously (IV) for 6 cycles (1 cycle = 28 days). arm 2: Participants with diffuse large B-cell lymphoma (DLBCL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 150 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for 6 cycles (1 cycle = 28 days). arm 3: Participants with diffuse large B-cell lymphoma (DLBCL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 200 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for 6 cycles (1 cycle = 28 days). arm 4: Participants with diffuse large B-cell lymphoma (DLBCL) in this bridging cohort received induction treatment with idasanutlin 150 mg orally in combination with rituximab 375 milligrams per square meter of body surface area (mg/m\^2) IV for 6 cycles (1 cycle = 28 days). arm 5: Participants with diffuse large B-cell lymphoma (DLBCL) in this bridging cohort received induction treatment with idasanutlin 200 mg orally in combination with rituximab 375 mg/m\^2 IV for 6 cycles (1 cycle = 28 days). arm 6: Participants with follicular lymphoma (FL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 100 milligrams (mg) orally in combination with a fixed dose of obinutuzumab 1000 mg intravenously (IV) for 6 cycles (1 cycle = 28 days). arm 7: Participants with follicular lymphoma (FL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 150 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for 6 cycles (1 cycle = 28 days). arm 8: Participants with follicular lymphoma (FL) in this bridging cohort received induction treatment with single-agent obinutuzumab 1000 mg IV for Cycle 1 and then idasanutlin 150 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for Cycles 2-6 (1 cycle = 28 days).

Interventions: intervention 1: Idasanutlin intervention 2: Obinutuzumab intervention 3: Rituximab
Intervention descriptions: intervention 1: Participants received idasanutlin film-coated tablets orally at a starting dose of 100 mg daily on Days 1 to 5 of each 28-day cycle. Escalation was to occur in at least 50-mg increments, and daily doses greater than or equal to (≥) 400 mg will be split into twice daily dosing. intervention 2: Participants received a fixed dose of obinutuzumab 1000 mg intravenous (IV) infusion to be given on Days 1, 8 and 15 of Cycle 1 and on Day 1 of Cycles 2 to 6 (1 cycle = 28 days). For eligible participants with FL, post-induction treatment was to be given at a dose of 1000 mg via IV infusion on Day 1 once every 2 months for a maximum of up to 24 months. intervention 3: Participants received a fixed dose of rituximab, 375 mg/m\^2 IV infusion on Day 1 of Cycles 1-6. Post-induction treatment for eligible participants was to be given at a dose of 375 mg/m\^2 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 
IDASANUTLIN IN PATIENTS WITH RELAPSED OR REFRACTORY 
FOLLICULAR LYMPHOMA AND OBINUTUZUMAB OR 
RITUXIMAB IN COMBINATION WITH IDASANUTLIN IN PATIENTS 
WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL 
LYMPHOMA 
NCT Number: 
NCT02624986 
Document Date: 
Protocol Version 4: 02-March-2017 
 
 
 
 


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. 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
1/Protocol BH29812, Version 4 
PROTOCOL 
TITLE: 
A PHASE IB/II STUDY EVALUATING THE SAFETY 
AND EFFICACY OF OBINUTUZUMAB IN 
COMBINATION WITH IDASANUTLIN IN PATIENTS 
WITH RELAPSED OR REFRACTORY FOLLICULAR 
LYMPHOMA AND OBINUTUZUMAB OR 
RITUXIMAB IN COMBINATION WITH 
IDASANUTLIN IN PATIENTS WITH RELAPSED 
OR REFRACTORY DIFFUSE LARGE B-CELL 
LYMPHOMA 
PROTOCOL NUMBER: 
BH29812 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2015-002100-83 
IND NUMBER: 
127311 
TEST PRODUCTS: 
Obinutuzumab (RO5072759) 
Rituximab (RO0452294) 
Idasanutlin (RO5503781) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  29 June 2015  
Version 2:  14 October 2015 
Version 3: 12 February 2016 
DATE AMENDED: 
Version 4:  See electronic date stamp below. 
 
02-Mar-2017 15:56:23
Title
Approver's Name
Company Signatory (Clinical)
Date and Time (UTC)


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
6/Protocol BH29812, Version 4 
results from the NHL cohorts in these studies and available safety results from all 
patients are summarized below. 
SECTION 1.2.2.1: Clinical Efficacy of Obinutuzumab in Patients with Non-
Hodgkin's Lymphoma 
A Phase III study (GAO4753g) investigated obinutuzumab plus bendamustine (GB) 
compared with bendamustine alone in patients with rituximab-refractory iNHL (n = 396).  
Patients in the GB group who had not experienced disease progression at the end of 
induction received obinutuzumab monotherapy every 2 months for up to 2 years.  On the 
basis of positive results from this study, demonstrating significant improvement in PFS in 
the GB arm with a median PFS of 29 versus 14 months (hazard ratio [HR], 0.52; 95% 
CI 0.39, 0.70; p > 0.0001) (Sehn 2015), the Independent Data Monitoring Committee 
recommended that the study be unblinded to the Sponsor, obinutuzumab was granted 
approval for use in patients with FL who did not respond to or who progressed during 
or after treatment with rituximab or a rituximab-containing regimen (see Section 1.2).   
A Phase III study, BO21223, investigated obinutuzumab plus chemotherapy (G-benda, 
G-CVP, 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 plus chemotherapy 
arm, the independent Data Monitoring Committee recommended that the study be 
unblinded to the Sponsor at a pre-planned interim analysis. 
A Phase III study, BO21005, investigated G-CHOP compared with R-CHOP in 
patients with previously untreated DLBCL.  The study did not meet its primary 
endpoint of PFS difference at final analysis.  Based upon the BO21005 efficacy results, 
this study protocol has been amended (Version 4) to cease evaluating obinutuzumab in 
patients with R/R DLBCL in the expansion phase.  Patients with DLBCL enrolled after 
the identification of the idasanutlin maximum tolerated dose (MTD) in combination 
with obinutuzumab will instead receive idasanutlin in combination with rituximab. 
SECTION 1.2.2.2: Clinical Safety of Obinutuzumab 
As of the safety data cutoff date of 31 October 20144 July 2016, an estimated 
3,2844454 patients with CLL or NHL had been treated with obinutuzumab given as 
monotherapy or in combination with CHOP, bendamustine, fludarabine plus 
cyclophosphamide, or chlorambucil at doses ranging from 50 mg to 2000 mg.  Overall, 
the safety of obinutuzumab monotherapy and obinutuzumab combination therapy was 
manageable. 
SECTION 1.3: BACKGROUND ON IDASANUTLIN 
Figure 1: Regulation of p53 Stability and Activity by MDM2 
The figure has been replaced with an updated schematic. 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
7/Protocol BH29812, Version 4 
SECTION 1.3.1: Nonclinical Experience with Idasanutlin and Obinutuzumab 
or Rituximab 
Obinutuzumab is a humanized glycoengineered type II anti-CD20 monoclonal antibody 
with high-affinity binding to the CD20 antigen; high ADCC and ADCP; low 
complement-dependent cytotoxicity (CDC) activity; and high direct cell death   
induction. 
Rituximab is a chimeric murine/human monoclonal antibody that binds to CD20 and 
eliminates CD20-expressing B cells via a number of different mechanisms, including 
ADCC, CDC, and apoptosis.  
The majority of B-lymphoid malignancies, including NHL and CLL, also express wild-type 
p53 (Imamura et al. 1994).  The non-overlapping and complementary mechanisms of 
action of obinutuzumab or rituximab (direct tumor cell death) and idasanutlin (increased 
apoptosis) may provide superior efficacy in treating B-lymphoid malignancies. 
In in vitro assays, idasanutlin induced concentration-dependent apoptosis in a mantle 
cell lymphoma cell line (Z-138) and in a diffuse large B-cell lymphoma cell line (DOHH-2), 
and the combination with obinutuzumab further enhanced cell death induction.  
Importantly, idasanutlin neither influenced obinutuzumab- or rituximab-mediated ADCC 
activity nor B-cell depletion in healthy human whole blood at concentrations of up to 
1000 nM and did not affect obinutuzumab-mediated NK cell activation (Herting et al. 
2014; Herting et al. 2016). 
In an additional in vivo study using the DoHH-2 DLBCL xenograft model, the 
combination of obinutuzumab or rituximab and idasanutlin also resulted in superior 
efficacy: 94% TGI using a suboptimal dose of obinutuzumab and tumor regression 
(TGI > 100%) using 10 mg/kg of obinutuzumab and 94% TGI using 10 mg/kg of 
rituximab versus the respective monotherapy treatments (see Figure 4). 
Although cross reactivity of idasanutlin with MDM2 is not very strong, cautionCaution 
should be used when interpreting any mouse toxicology data.  It is important to note that 
none of the mice changed more than 20% of weight, weight being the only useful 
toxicology parameter in a xenograft model, and no obvious potential drug-related 
adverse events were observed. 
In summary, nonclinical in vitro and in vivo data strongly support the investigation of 
obinutuzumab or rituximab and idasanutlin combination therapy in clinical studies. 
Figure 4: DoHH-2 DLBCL Xenograft Model:  Tumor Volume Analysis 
The figure has been updated. 
SECTION 1.3.2: Quality Development 
As of 10 June 2015, the SDP formulation has been tested in 24 patients with acute 
myeloid leukemia (AML) and 41 patients with solid tumors and NHL.  In all, 5613 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
9/Protocol BH29812, Version 4 
(cutoff 25 February 2015, 15 April 2016; enrollment ongoing and completion expected 
mid July 2015is complete). 
In a Phase Ib/II study, GH29914, 10 patients have received combination therapy with 
venetoclax and the SDP formulation of idasanutlin until the cutoff date of 13 
September 2016.  Three dosing cohorts have been evaluated to date:  3 patients received 
400 mg/200 mg (venetoclax/idasanutlin), 3 patients received 400 mg/400 mg, and 4 
patients received 600 mg/200 mg. 
Table 1: Completed, Ongoing, and Planned Idasanutlin Studies 
The table has been updated. 
SECTION 1.3.3.1: Clinical Pharmacology Summary 
Only one inactive metabolite RO6802287 (M4) (~25% of parent exposure), which is 
inactive, was identified.  This metabolite was generated by CYP3A4 and CYP2C8 at an 
approximate 50:50 ratio.  A strong CYP3A4 inhibitor, posaconazole, had no impact on 
idasanutlin maximum concentration values (Cmax) but increased AUC values by 32%, 
which suggests a minimal (no clinically significant) drug-drug interaction (DDI) potential 
with a single use of a strong/moderate CYP3A4 or CYP2C8 inhibitor (assuming the same 
minimal effect, as the two isozymes have the metabolic pathway for idasanutlin).  
However, a concomitant second strong/moderate inhibitor of the other CYP pathway 
(e.g., adding CYP2C8 inhibition to CYP3A4 inhibition) may increase idasanutlin 
exposure to a clinically significant level. Because some NHL patients receive 
strong/moderate CYP3A4 inhibitors for prophylactic or treatment purpose, in this 
protocol CYP2C8 inhibitors will be prohibited to prevent double-blockade DDI. UGT1A3 
may be a major clearing enzyme for idasanutlin; its strong inhibitor gemfibrozil is also a 
CYP2C8 inhibitor that will be excluded from the current study.   
As idasanutlin is a substrate for both CYP3A4 and CYP2C8, the known inducers of 
CYP3A4 and CYP2C8 will also be prohibited from the current study to prevent loss of 
exposure for idasanutlin.  
There is no relevant DDI expected between the two combined drugs (neither between 
rituximab and idasanutlin nor between obinutuzumab and idasanutlin) in the present 
study.  No correlation was apparent between idasanutlin plasma concentration and 
QTcF. 
SECTION 1.3.3.2: Clinical Safety of Idasanutlin 
Solid Tumors (Studies NP27872 and NP28902) 
In Study NP28902, all patients in Part 1, Part 2, and Part 3 experienced at least one 
adverse event and the majority of patients (85%) who continued in the optional 
extension part experienced adverse events during this phase of the study.  The five most 
common adverse events reported by the patients in Parts 1, 2, and 3 included diarrhea, 
nausea, vomiting, fatigue, and constipation; whereas, patients who continued in the 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
23/Protocol BH29812, Version 4 
Premedication with a corticosteroid, analgesic/antipyretic, and antihistamine, as 
outlined in Section 4.3.2.6, is required to reduce the incidence and severity of IRRs.  
For anaphylaxis precautions, see Appendix 9. 
Table 8: Administration of First and Subsequent Infusions of Rituximab 
The table has been added. 
SECTION 4.3.2.4: Induction Treatment with Obinutuzumab or Rituximab 
and Idasanutlin 
Patients will receive 6 cycles of induction treatment consisting of obinutuzumab or 
rituximab and idasanutlin as outlined in Table 6.  For patients with FL enrolled in the 
bridging cohort(s), obinutuzumab will be given alone at Cycle 1, and the obinutuzumab 
and idasanutlin combination will be given from Cycles 2 to 6. 
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.  
For patients at increased risk for IRRs (high tumor burden), the first obinutuzumab 
and rituximab infusion may be split and administered over 2 days.  If split, 
obinutuzumab should be given as 100 mg on Day 1 and 900 mg on Day 2.  
Please refer to Section 3 for further details. 
Figure 11: Treatment with Idasanutlin and Obinutuzumab:  Schedule of 
Treatment 
The figure has been added. 
Figure 12: Escalation Phase (DLBCL Bridging Cohort[s]) and Expansion 
Phase with Idasanutlin and Rituximab:  Schedule of Treatment 
The figure has been added. 
Table 9: Premedication 
The table has been updated to reflect the change in regimen. 
SECTION 4.3.3: Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (obinutuzumab, rituximab, and idasanutlin) 
will be provided by the Sponsor.   
SECTION 4.3.4: Post-Study Access to Obinutuzumab, Rituximab, and 
Idasanutlin 
Currently, the Sponsor does not have any plans to provide obinutuzumab, rituximab, or 
idasanutlin or any other study treatments or interventions to patients who have 
completed the study.  The Sponsor will evaluate whether to continue providing 
obinutuzumab, rituximab, and idasanutlin in accordance with the Roche Global Policy 
on Continued Access to Investigational Medicinal Product, available at the following 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
36/Protocol BH29812, Version 4 
It is anticipated that at least one interim analysis per disease indication will be 
conducted during the expansion phase of the study, with the earliest interim analysis 
taking place when at least 15 patients treated have been evaluated for a PET-CT-defined 
CR at EOI.  If, at any interim analysis, a low predictive probability suggests that the 
proportion of patients achieving a PET-CT-defined CR at EOI is lower than desired, the 
IMC will review the data and decide whether to recommend an early decision to stop 
enrollment.  
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 will be provided in an IMC charter. 
 
SECTION 9.2: PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
SECTION 9.5: PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
DataStudy Information at the following Website:  
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.
pdfhttp://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
APPENDIX 1: Schedule of Activities for Patients with Follicular Lymphoma  
(Dose-Escalation and Expansion Phases) 
The appendix has been updated to reflect changes to the protocol.  
APPENDIX 2: Schedule of Activities for Patients with DLBCL  
The appendix has been updated to reflect changes to the protocol.  
APPENDIX 3: Schedule of Pharmacokinetic and Pharmacodynamic (MIC-1) 
Assessments for Obinutuzumab or Rituximab and Idasanutlin in 
Regimen A 
The appendix has been updated to reflect changes to the protocol.  
APPENDIX 4: Schedule of Pharmacokinetic and Pharmacodynamic (MIC 
1) Assessments for Obinutuzumab and Idasanutlin in Regimen B 
The appendix has been added to reflect changes to the protocol. 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
37/Protocol BH29812, Version 4 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 46 
PROTOCOL SYNOPSIS .................................................................................... 47 
1. 
BACKGROUND .......................................................................................... 59 
1.1 
Background on Non-Hodgkin’s Lymphoma ........................... 59 
1.1.1 
Follicular Lymphoma ............................................................. 59 
1.1.2 
Diffuse Large B-Cell Lymphoma ............................................ 59 
1.2 
Background on Obinutuzumab .............................................. 60 
1.2.1 
Nonclinical Studies with Obinutuzumab ................................. 61 
1.2.2 
Clinical Studies with Obinutuzumab ...................................... 61 
1.2.2.1 
Clinical Efficacy of Obinutuzumab in Patients with 
Non-Hodgkin's Lymphoma .................................................... 61 
1.2.2.2 
Clinical Safety of Obinutuzumab ............................................ 62 
1.3 
Background on Idasanutlin .................................................... 63 
1.3.1 
Nonclinical Experience with Idasanutlin and 
Obinutuzumab or Rituximab ................................................. 65 
1.3.2 
Quality Development ............................................................. 68 
1.3.3 
Clinical Studies with RO5045337 and Idasanutlin ................. 69 
1.3.3.1 
Clinical Pharmacology Summary ........................................... 75 
1.3.3.2 
Clinical Safety of Idasanutlin .................................................. 77 
1.4 
Study Rationale and Benefit-Risk Assessment ...................... 79 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 81 
2.1 
Safety Objectives and Endpoints ........................................... 81 
2.2 
Efficacy Objectives ................................................................ 81 
2.2.1 
Primary Efficacy Objective and Endpoint ............................... 81 
2.2.2 
Secondary Efficacy Objectives and Endpoints ...................... 82 
2.2.3 
Exploratory Efficacy Objective and Endpoints ....................... 82 
2.3 
Pharmacokinetic Objectives and Endpoints ........................... 82 
2.4 
Biomarker Objectives and Endpoints ..................................... 83 
3. 
STUDY DESIGN ......................................................................................... 83 
3.1 
Description of Study .............................................................. 83 
3.1.1 
Overview of Study ................................................................. 83 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
38/Protocol BH29812, Version 4 
3.1.2 
Dose-Escalation Phase (Part 1) ............................................ 86 
3.1.2.1 
Definition of Dose-Limiting Toxicity ........................................ 87 
3.1.2.2 
Treatment Regimens ............................................................. 88 
3.1.2.3 
Dose-Toxicity Model with mCRM ........................................... 91 
3.1.3 
Expansion Phase (Part 2) ...................................................... 95 
3.1.4 
Internal Monitoring Committee ............................................... 96 
3.1.5 
Independent Review Committee ............................................ 97 
3.1.6 
Post-Treatment and Survival Follow-Up ................................ 97 
3.2 
End of Study and Length of Study ......................................... 97 
3.3 
Rationale for Study Design .................................................... 97 
3.3.1 
Rationale for Treatment Combination .................................... 97 
3.3.2 
Rationale for Idasanutlin Starting Dose ................................. 98 
3.3.3 
Rationale for Dosing Regimen ............................................... 99 
3.3.4 
Rationale for Pharmacokinetic Assessments ....................... 101 
3.3.5 
Rationale for PET-CT–Defined Complete 
Response as the Primary Efficacy Endpoint ........................ 101 
3.3.6 
Rationale for Biomarker Assessments ................................. 101 
3.3.6.1 
Rationale for Analysis of Known Prognostic 
Factors:  DLBCL Subtype, BCL2, and MYC ........................ 101 
3.3.6.2 
Rationale for p53 and Pharmacodynamic Marker 
Assessments ....................................................................... 102 
3.3.6.3 
Rationale for Assessment of Minimal Residual 
Disease ................................................................................ 103 
4. 
MATERIALS AND METHODS .................................................................. 104 
4.1 
Patients ................................................................................ 104 
4.1.1 
Inclusion Criteria (Escalation and Expansion) ..................... 104 
4.1.2 
Exclusion Criteria ................................................................. 105 
4.2 
Method of Treatment Assignment and Blinding ................... 108 
4.3 
Study Treatment .................................................................. 108 
4.3.1 
Formulation, Packaging, and Handling ................................ 108 
4.3.1.1 
Obinutuzumab ..................................................................... 108 
4.3.1.2 
Rituximab ............................................................................ 108 
4.3.1.3 
Idasanutlin ........................................................................... 109 
4.3.2 
Dosage, Administration, and Compliance ............................ 109 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
39/Protocol BH29812, Version 4 
4.3.2.1 
Obinutuzumab ..................................................................... 109 
4.3.2.2 
Idasanutlin ........................................................................... 113 
4.3.2.3 
Rituximab ............................................................................ 113 
4.3.2.4 
Induction Treatment with Obinutuzumab or 
Rituximab and Idasanutlin .................................................. 115 
4.3.2.5 
Post-Induction Treatment for Patients with FL 
and DLBCL .......................................................................... 117 
4.3.2.6 
Premedication ...................................................................... 117 
4.3.3 
Investigational Medicinal Product Accountability ................. 120 
4.3.4 
Post-Study Access to Obinutuzumab, Rituximab, 
and Idasanutlin .................................................................... 120 
4.4 
Concomitant Therapy .......................................................... 120 
4.4.1 
Permitted Therapy ............................................................... 120 
4.4.2 
Prohibited Therapy .............................................................. 121 
4.5 
Study Assessments ............................................................. 125 
4.5.1 
Informed Consent Forms and Screening Log ...................... 125 
4.5.2 
Medical History and Demographic Data .............................. 125 
4.5.3 
Physical Examinations ......................................................... 126 
4.5.4 
Vital Signs ............................................................................ 126 
4.5.5 
Tumor and Response Evaluations ....................................... 126 
4.5.5.1 
Radiographic Assessments ................................................. 127 
4.5.5.2 
Bone Marrow Assessments ................................................. 127 
4.5.6 
Laboratory, Biomarker, and Other Biological 
Samples ............................................................................... 128 
4.5.6.1 
Local Laboratory Assessments ............................................ 128 
4.5.6.2 
Central Laboratory Assessments ......................................... 128 
4.5.7 
Electrocardiograms .............................................................. 130 
4.5.8 
Samples for Roche Clinical Repository................................ 131 
4.5.8.1 
Overview of the Roche Clinical Repository .......................... 131 
4.5.8.2 
Approval by the Institutional Review Board or 
Ethics Committee ................................................................ 131 
4.5.8.3 
Sample Collection ................................................................ 131 
4.5.8.4 
Confidentiality ...................................................................... 132 
4.5.8.5 
Consent to Participate in the Roche Clinical 
Repository ........................................................................... 133 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
40/Protocol BH29812, Version 4 
4.5.8.6 
Withdrawal from the Roche Clinical Repository ................... 133 
4.5.8.7 
Monitoring and Oversight ..................................................... 133 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation .................................................................... 134 
4.6.1 
Patient Discontinuation ........................................................ 134 
4.6.2 
Study Treatment Discontinuation ......................................... 134 
4.6.3 
Study and Site Discontinuation ............................................ 135 
5. 
ASSESSMENT OF SAFETY ..................................................................... 135 
5.1 
Safety Plan .......................................................................... 135 
5.1.1 
Risks Associated with Obinutuzumab .................................. 136 
5.1.1.1 
Infusion-Related Reactions .................................................. 136 
5.1.1.2 
Tumor Lysis Syndrome ........................................................ 136 
5.1.1.3 
Neutropenia ......................................................................... 137 
5.1.1.4 
Thrombocytopenia ............................................................... 137 
5.1.1.5 
Infections ............................................................................. 137 
5.1.1.6 
Immunizations ..................................................................... 138 
5.1.1.7 
Worsening of Preexisting Cardiac Condition ....................... 138 
5.1.1.8 
Gastrointestinal Perforation ................................................. 138 
5.1.2 
Risks Associated with Rituximab ........................................ 138 
5.1.2.1 
Infusion-Related Reactions .................................................. 138 
5.1.2.2 
Infections (Including Serious Infections) ............................ 139 
5.1.2.3 
Hepatitis B Reactivation...................................................... 139 
5.1.2.4 
Progressive Multifocal Leukoencephalopathy ...................... 139 
5.1.2.5 
Neutropenia (Including Prolonged Neutropenia) ................ 139 
5.1.2.6 
Tumor Lysis Syndrome........................................................ 140 
5.1.2.7 
Impaired Immunization Response ....................................... 140 
5.1.2.8 
Stevens Johnson Syndrome and Toxic Epidermal 
Necrolysis ............................................................................ 140 
5.1.2.9 
Gastrointestinal Perforation ................................................ 140 
5.1.3 
Risks Associated with Idasanutlin ........................................ 140 
5.1.3.1 
Gastrointestinal Disorders .................................................. 141 
5.1.3.2 
Myelosuppression ................................................................ 141 
5.1.3.3 
Infections ............................................................................. 142 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
41/Protocol BH29812, Version 4 
5.1.3.4 
Tumor Lysis Syndrome........................................................ 142 
5.1.3.5 
Electrolyte Disorders ........................................................... 142 
5.1.3.6 
Other Adverse Events.......................................................... 142 
5.1.4 
Risk of Overlapping Toxicities ............................................. 143 
5.1.5 
Management of Specific Adverse Events ............................ 144 
5.1.5.1 
Toxicities during Induction Treatment .................................. 145 
5.1.5.2 
Toxicities during Maintenance Treatment ............................ 151 
5.2 
Safety Parameters and Definitions ...................................... 151 
5.2.1 
Adverse Events ................................................................... 151 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) .................................................................... 152 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................. 153 
5.2.4 
Dose-Limiting Toxicities (Immediately Reportable 
to the Sponsor) .................................................................... 153 
5.2.5 
Selected Adverse Events ..................................................... 153 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .............................................. 154 
5.3.1 
Adverse Event Reporting Period ......................................... 154 
5.3.2 
Eliciting Adverse Event Information ..................................... 155 
5.3.3 
Assessment of Severity of Adverse Events ......................... 155 
5.3.4 
Assessment of Causality of Adverse Events ....................... 155 
5.3.5 
Procedures for Recording Adverse Events .......................... 156 
5.3.5.1 
Infusion-Related Reactions .................................................. 156 
5.3.5.2 
Diagnosis versus Signs and Symptoms............................... 156 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................. 157 
5.3.5.4 
Persistent or Recurrent Adverse Events .............................. 157 
5.3.5.5 
Abnormal Laboratory Values ............................................... 158 
5.3.5.6 
Abnormal Vital Sign Values ................................................. 158 
5.3.5.7 
Abnormal Liver Function Tests ............................................ 159 
5.3.5.8 
Deaths ................................................................................. 159 
5.3.5.9 
Preexisting Medical Conditions ............................................ 160 
5.3.5.10 
Lack of Efficacy or Worsening of Lymphoma ....................... 160 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
42/Protocol BH29812, Version 4 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ........................ 160 
5.3.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 161 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................ 161 
5.4.1 
Emergency Medical Contacts .............................................. 162 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ................... 162 
5.4.2.1 
Events That Occur Prior to Study Treatment 
Initiation ............................................................................... 162 
5.4.2.2 
Events That Occur after Study Treatment 
Initiation ............................................................................... 163 
5.4.3 
Reporting Requirements for Pregnancies ............................ 163 
5.4.3.1 
Pregnancies in Female Patients .......................................... 163 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ............... 163 
5.4.3.3 
Abortions ............................................................................. 164 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 164 
5.5 
Follow-Up of Patients after Adverse Events ........................ 164 
5.5.1 
Investigator Follow-Up ......................................................... 164 
5.5.2 
Sponsor Follow-Up .............................................................. 164 
5.6 
Post-Study Adverse Events ................................................. 165 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 165 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 166 
6.1 
Determination of Sample Size ............................................. 166 
6.2 
Summaries of Patient Characteristics .................................. 167 
6.3 
Safety Analyses ................................................................... 167 
6.4 
Efficacy Analyses ................................................................ 168 
6.4.1 
Primary Efficacy Endpoint .................................................... 168 
6.4.2 
Secondary Efficacy Endpoints ............................................. 168 
6.4.3 
Exploratory Efficacy Endpoints ............................................ 169 
6.5 
Pharmacokinetic Analyses ................................................... 170 
6.6 
Biomarker Analysis .............................................................. 170 
6.7 
Interim Analyses .................................................................. 170 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
43/Protocol BH29812, Version 4 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 171 
7.1 
Data Quality Assurance ....................................................... 171 
7.2 
Electronic Case Report Forms ............................................. 171 
7.3 
Source Data Documentation ................................................ 172 
7.4 
Use of Computerized Systems ............................................ 172 
7.5 
Retention of Records ........................................................... 172 
8. 
ETHICAL CONSIDERATIONS .................................................................. 173 
8.1 
Compliance with Laws and Regulations .............................. 173 
8.2 
Informed Consent ................................................................ 173 
8.3 
Institutional Review Board or Ethics Committee .................. 174 
8.4 
Confidentiality ...................................................................... 175 
8.5 
Financial Disclosure ............................................................ 175 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 175 
9.1 
Study Documentation .......................................................... 175 
9.2 
Protocol Deviations .............................................................. 175 
9.3 
Site Inspections ................................................................... 176 
9.4 
Administrative Structure....................................................... 176 
9.5 
Publication of Data and Protection of 
Trade Secrets ...................................................................... 176 
9.6 
Protocol Amendments ......................................................... 177 
10. REFERENCES ......................................................................................... 178 
 
 
LIST OF TABLES 
Table 1 
Completed, Ongoing, and Planned Idasanutlin Studies .............. 72 
Table 2 
Induction Treatment for Dose-Escalation Phase ......................... 90 
Table 3 
Maintenance Treatment during the Dose-Escalation Phase 
for Patients with Follicular Lymphoma ...................................... 91 
Table 4 
Initial Skeleton of Prior Guesses ................................................. 93 
Table 5 
Hypothetical Trial Realization (Cohort Size = 3) .......................... 94 
Table 6 
Induction Treatment for the Expansion Phase ............................ 96 
Table 7 
Post-Induction Treatment for the Expansion Phase ................... 96 
Table 8 
Administration of First and Subsequent Infusions of 
Rituximab ................................................................................. 114 
Table 9 
Premedication ........................................................................... 118 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
46/Protocol BH29812, Version 4 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE Ib/II STUDY EVALUATING THE SAFETY AND 
EFFICACY OF OBINUTUZUMAB IN COMBINATION 
WITH IDASANUTLIN IN PATIENTS WITH RELAPSED OR 
REFRACTORY FOLLICULAR LYMPHOMA AND 
OBINUTUZUMAB OR RITUXIMAB IN 
COMBINATION WITH IDASANUTLIN IN PATIENTS 
WITH RELAPSED OR REFRACTORY DIFFUSE 
LARGE B-CELL LYMPHOMA  
PROTOCOL NUMBER: 
BH29812 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2015-002100-83 
IND NUMBER: 
127311 
TEST PRODUCT: 
Obinutuzumab (RO5072759) 
Rituximab (RO0452294) 
Idasanutlin (RO5503781) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy 
as instructed by your local study monitor 
 
 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
57/Protocol BH29812, Version 4 
Abbreviation 
Definition 
FDA 
U.S. Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded 
FL 
follicular lymphoma 
FLIPI 
Follicular Lymphoma International Prognostic Index 
G 
obinutuzumab (GA101) 
GB 
obinutuzumab plus bendamustine 
GCB 
germinal-center B cell–like (subgroup) 
G-CHOP 
obinutuzumab in combination with cyclophosphamide, 
doxorubicin, vincristine, and prednisolone or prednisone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GI 
gastrointestinal 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HI 
hematologic improvement  
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
ICH 
International Council for Harmonisation 
IgH 
immunoglobulin heavy 
IHC 
immunohistochemistry 
IMC 
internal monitoring committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
iNHL 
indolent non-Hodgkin’s lymphoma 
IPI 
International Prognostic Index 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
IUD 
intrauterine device 
IV 
intravenous 
IxRS 
interactive voice or Web-based response system 
JC 
John Cunningham 
LMWH 
low-molecular-weight heparin 
LPLV 
last patient, last visit 


 
 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
58/Protocol BH29812, Version 4 
Abbreviation 
Definition 
MBP 
microprecipitated bulk powder  
mCRM 
modified-Continual Reassessment Method with Overdose 
Control  
MDM2 
murine double minute 2  
MIC-1 
macrophage inhibitory cytokine-1 
MLFS 
morphologic leukemia-free state 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NHL 
non-Hodgkin’s lymphoma 
NK 
natural killer 
PD 
pharmacodynamic 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response 
QD 
once daily 
QW 
once weekly 
R-CHOP 
rituximab in combination with cyclophosphamide, 
doxorubicin, vincristine, and prednisolone or prednisone 
RCR 
Roche Clinical Repository 
R-DHAP 
rituximab plus dexamethasone, cytosine arabinoside, and 
cisplatin 
R-ICE 
rituximab plus ifosfamide, carboplatin, and etoposide 
RP2D 
R/R 
recommended Phase II dose 
relapsed or refractory 
SCT 
stem-cell transplantation 
SD 
stable disease 
SDP 
spray-dried powder 
SOC 
System Organ Class 
t1/2 
half-life 
TGI 
tumor growth inhibition 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
65/Protocol BH29812, Version 4 
Figure 1 Regulation of p53 Stability and Activity by MDM2 
 
BAX = BCL-2-associated X protein; BCL-2 = B cell lymphoma 2 protein; CDKs = cyclin-dependent 
kinases; Cyto C = cytochrome C; G1 = Growth 1/Gap 1 phase; G2 = Growth 2/Gap 2 phase; 
M = mitosis; MDM2 = murine double minute 2; NOXA = phorbol-12-myristate-13-acetate-induced 
protein 1, p21 = cyclin-dependent kinase inhibitor 1A (CDKN1A, CIP1); PUMA = p53 upregulated 
modulator of apoptosis; S = synthesis phase. 
 
1.3.1 
Nonclinical Experience with Idasanutlin and Obinutuzumab or 
Rituximab 
Obinutuzumab is a humanized glycoengineered type II anti-CD20 monoclonal antibody 
with high-affinity binding to the CD20 antigen; high ADCC and ADCP; low 
complement-dependent cytotoxicity (CDC) activity; and high direct cell death   
induction. 
Rituximab is a chimeric murine/human monoclonal antibody that binds to CD20 and 
eliminates CD20-expressing B cells via a number of different mechanisms, including 
ADCC, CDC, and apoptosis.  
The majority of B-lymphoid malignancies, including NHL and CLL, also express wild-type 
p53 (Imamura et al. 1994).  The non-overlapping and complementary mechanisms of 
action of obinutuzumab or rituximab (direct tumor cell death) and idasanutlin (increased 
apoptosis) may provide superior efficacy in treating B-lymphoid malignancies. 
In in vitro assays, idasanutlin induced concentration-dependent apoptosis in a mantle 
cell lymphoma cell line (Z-138) and in a diffuse large B-cell lymphoma cell line (DOHH-2), 
and the combination with obinutuzumab further enhanced cell death induction.  
Importantly, idasanutlin neither influenced obinutuzumab- or rituximab-mediated ADCC 


 
 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
66/Protocol BH29812, Version 4 
activity nor B-cell depletion in healthy human whole blood at concentrations of up to 
1000 nM and did not affect obinutuzumab-mediated NK cell activation (Herting et al. 
2014; Herting et al. 2016). 
In vivo single-agent and combination therapy efficacy (inhibition of tumor growth) of 
obinutuzumab and idasanutlin was assessed in two NHL xenograft models. 
In a Z-138 mantle cell lymphoma xenograft study a suboptimal dose of obinutuzumab 
showed 47% TGI and idasanutlin monotherapy showed 67% TGI.  The combination of 
obinutuzumab with idasanutlin resulted in superior TGI of 86% compared with 
single-agent treatment (see Figure 2).  
Figure 2 Z-138 MCL Xenograft Model:  Tumor Growth Inhibition Analysis 
 
IQR = interquartile range; MCL = mantle cell lymphoma; QD = once daily; QW = once weekly. 
Note:  Z-138 xenograft study, tumor growth inhibition (TGI) analysis:  10 animals per treatment 
group, obinutuzumab at a suboptimal dose of 0.5 mg/kg resulted in 47% TGI, idasanutlin at 
80 mg/kg resulted in 67% TGI and the combination of obinutuzumab at 0.5 mg/kg with 
idasanutlin at 80 mg/kg yielded a tumor growth inhibition of 86% on Day 32 after tumor-cell 
inoculation. 
 
The superiority of the combination treatment in the Z-138 xenograft model was also 
demonstrated using a time-to-event analysis and resulted in 5 of 10 tumor-free animals 
on Day 125 (see Figure 3). 


 
 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
67/Protocol BH29812, Version 4 
Figure 3 Z-138 Xenograft Model:  Time-to-Event Analysis 
 
Note:  With 10 animals per treatment group, the combination of obinutuzumab at 0.5 mg/kg with 
idasanutlin at 80 mg/kg resulted in 50% of animals being tumor-free on Day 125 after tumor cell 
inoculation. 
 
In an additional in vivo study using the DoHH-2 DLBCL xenograft model, the 
combination of obinutuzumab or rituximab and idasanutlin also resulted in superior 
efficacy: 94% TGI using a suboptimal dose of obinutuzumab and tumor regression 
(TGI > 100%) using 10 mg/kg of obinutuzumab and 94% TGI using 10 mg/kg of 
rituximab versus the respective monotherapy treatments (see Figure 4). 


 
 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
68/Protocol BH29812, Version 4 
Figure 4 DoHH-2 DLBCL Xenograft Model:  Tumor Volume Analysis 
 
DLBCL = diffuse large B-cell lymphoma; IQR = interquartile range; TGI = tumor growth inhibition. 
Note:  With 10 animals per treatment group, obinutuzumab at a dose of 10 mg/kg resulted in 91% 
TGI, idasanutlin at 30 mg/kg resulted in 56% TGI, and rituximab at 10 mg/kg resulted in 72% TGI.  
The combination of obinutuzumab at 10 mg/kg and idasanutlin at 30 mg/kg resulted in in tumor 
regression (TGI >100%), and the combination of rituximab at 10 mg/kg and idasanutlin at 
30 mg/kg resulted in 99% TGI.  
 
Caution should be used when interpreting any mouse toxicology data.  It is important to 
note that none of the mice changed more than 20% of weight, weight being the only 
useful toxicology parameter in a xenograft model, and no obvious potential drug-related 
adverse events were observed. 
In summary, nonclinical in vitro and in vivo data strongly support the investigation of 
obinutuzumab or rituximab and idasanutlin combination therapy in clinical studies. 
1.3.2 
Quality Development 
Two compounds of the drug family of nutlins binding to an identical binding site have 
been investigated in clinical studies:  RO5045337, a predecessor molecule with lower 
affinity tested in 350 patients in total and a new version, idasanutlin, which is used in all 
ongoing and planned studies.  Tablets with amorphous compound were originally 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
71/Protocol BH29812, Version 4 
Eight of 9 patients were evaluable for response in the Part 1 extension.  Response 
assessments indicated 2 patients each with CR or complete remission with incomplete 
platelet count recovery (CRp) or CRi/MLFS (1 patient bridged to an allogeneic 
transplant and 1 patient discontinued on Day 737), and 2 patients with HI. 
In the Part 2 (idasanutlin plus cytarabine) dose escalation in 22 response-
evaluable patients, there were 6 patients with a best response of CR/CRp, 1 patient with 
CRi/MLFS, and 2 patients each with a PR and HI.  In the Part 2 extension phase of the 
study, 17 patients received idasanutlin monotherapy and 21 patients received 
combination therapy with cytarabine.  More patients treated with idasanutlin plus 
cytarabine achieved CR/CRp than those treated with idasanutlin alone in the Part 2 
extension phase.  A total of 5 of 16 response-evaluable patients achieved a CR/CRp 
following treatment with idasanutlin plus cytarabine; all 5 patients had a CR, with 
1 patient bridged to transplant prior to confirmation but remained as having a CR 
following transplant.  Only 1 of the 17 response-evaluable patients in the Part 2 
extension treated with idasanutlin alone had a CR/CRp. 
Initial analysis of the number of prior regimens for antecedent hematologic disease or 
antecedent malignancy, number of prior therapies for AML, exposure, and best response 
in the study for patients treated with idasanutlin in combination with cytarabine (Part 2, 
Part 2 extension, and Part 4) demonstrated activity in patients who received prior 
cytarabine-containing regimens and had R/R disease.  One patient with AML treated 
with idasanutlin plus cytarabine in Study NP28679 achieved a CR despite harboring a 
TP53 mutation. 
In Part 4 of the study, 10 of 31 response-evaluable patients who were treated with the 
SDP formulation of idasanutlin in combination with cytarabine achieved a CR/CRp 
(9 CRs and 1 CRp) and 3 patients achieved a CRi/MLFS (1 CRi and 2 MLFS) (cutoff 
15 April 2016; enrollment is complete). 
In a Phase Ib/II study, GH29914, 10 patients have received combination therapy with 
venetoclax and the SDP formulation of idasanutlin until the cutoff date of 13 
September 2016.  Three dosing cohorts have been evaluated to date:  3 patients received 
400 mg/200 mg (venetoclax/idasanutlin), 3 patients received 400 mg/400 mg, and 4 
patients received 600 mg/200 mg. 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
77/Protocol BH29812, Version 4 
Drug-Drug Interactions 
Idasanutlin is a cytochrome (CYP) 2C8 inhibitor that could affect concomitant CYP2C8 
substrates at therapeutic exposure levels; its M4 metabolite is an organic 
anion-transporting polypeptide (OATP)-1B1/3 transporter inhibitor that may affect 
concomitant OATP1B1/3 substrates. These are the basis for the prohibited therapy list 
for the present study (see Table 10, Table 11, and Table 12; Section 4.4.2).  
However, idasanutlin is not expected to interact with substrates of deaminases such as 
cytarabine (no interaction observed with cytarabine in Study NP28679).  Analysis of this 
potential interaction will continue throughout the completion of the ongoing Phase I/Ib 
study NP28679 in AML.  
Only one metabolite RO6802287 (M4) (~25% of parent exposure), which is inactive, 
was identified.  This metabolite was generated by CYP3A4 and CYP2C8 at an 
approximate 50:50 ratio.  A strong CYP3A4 inhibitor, posaconazole, had no impact on 
idasanutlin maximum concentration values (Cmax) but increased AUC values by 32%, 
which suggests a minimal (no clinically significant) drug-drug interaction (DDI) potential 
with a single use of a strong/moderate CYP3A4 or CYP2C8 inhibitor (assuming the same 
minimal effect, as the two isozymes have the metabolic pathway for idasanutlin).  
However, a concomitant second strong/moderate inhibitor of the other CYP pathway 
(e.g., adding CYP2C8 inhibition to CYP3A4 inhibition) may increase idasanutlin 
exposure to a clinically significant level. Because some NHL patients receive 
strong/moderate CYP3A4 inhibitors for prophylactic or treatment purpose, in this 
protocol CYP2C8 inhibitors will be prohibited to prevent double-blockade DDI. UGT1A3 
may be a major clearing enzyme for idasanutlin; its strong inhibitor gemfibrozil is also a 
CYP2C8 inhibitor that will be excluded from the current study.   
As idasanutlin is a substrate for both CYP3A4 and CYP2C8, the known inducers of 
CYP3A4 and CYP2C8 will also be prohibited from the current study to prevent loss of 
exposure for idasanutlin.  
There is no relevant DDI expected between the two combined drugs (neither between 
rituximab and idasanutlin nor between obinutuzumab and idasanutlin) in the present 
study.  No correlation was apparent between idasanutlin plasma concentration and 
QTcF. 
See the idasanutlin Investigator’s Brochure (IB) for additional details on nonclinical and 
clinical studies. 
1.3.3.2 
Clinical Safety of Idasanutlin 
Solid Tumors (Studies NP27872 and NP28902) 
A total of 160 patients with advanced malignancies (excluding leukemia) received 
idasanutlin in Study NP27872 (Final Date 2 September 2014; 99 patients) and 
Study NP28902 (cutoff 5 May 2015; 61 patients).  All 99 patients in Study NP27872 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
84/Protocol BH29812, Version 4 
idasanutlin and obinutuzumab in combination from Cycles 2 to 6) to determine 
the RP2D for this regimen.   
RP2D(s) and regimens for FL and DLBCL will be decided at the end of dose-escalation 
phase, and two different RP2Ds and/or regimens may apply for FL and DLBCL, 
respectively. 
In the expansion phase, patients with FL will receive idasanutlin at the RP2D of the 
selected regimen (A or B) in combination with obinutuzumab, and patients with 
DLBCL will receive idasanutlin at the RP2D in combination with rituximab.  
Patients with R/R FL enrolled in the dose-escalation phase may be eligible to receive 
post-induction treatment (referred to as maintenance) with obinutuzumab (see 
Section 3.1.2.2 and Section 3.1.3 for details on treatment regimens).  
Patients with R/R FL enrolled in the expansion phase may be eligible to receive 
maintenance treatment with obinutuzumab and idasanutlin (see Sections 3.1.2.2 and 
3.1.3, respectively, for details on the treatment regimens).   
Patients with R/R DLBCL enrolled in the expansion phase may be eligible to receive 
post-induction treatment (referred to as consolidation) with rituximab and idasanutlin 
(see Section 3.1.3 for details on treatment regimens). 
A study schema is provided in Figure 6.  Refer to Sections 3.1.2 and 3.1.3 for details on 
the treatment regimens.


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
85/Protocol BH29812, Version 4 
 
 
 
Figure 6 Study Schema 
 
 
DLBCL = diffuse large B-cell lymphoma; FL =  follicular lymphoma; RP2D = recommended Phase II dose. 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
93/Protocol BH29812, Version 4 
Table 4 
Initial Skeleton of Prior Guesses 
Dose 
(mg) 
50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 
Prior 
guess 
of risk 
(%) 
3 
8 
15 
22 
30 
38 
45 
52 
58 
65 
68 
71 
74 
77 
79 
82 
 
Figure 7 Illustration of Model for the mCRM Design at Study Start 
(3 Patients Recruited at 100 mg without DLT). 
 
DLT = dose-limiting toxicity; mCRM = modified continual reassessment method with overdose 
control. 
 
The prior model can be characterized as follows:  based on the initial skeleton of prior 
guesses, the a priori MTD point estimate is 250 mg; this is the dose with the highest 
probability to have a DLT probability in the target interval of 25%−35%.  After 3 patients 
were recruited at 100 mg without DLT, the recommended dose (after an update) is 
250 mg.  Furthermore, it is illustrative to consider various hypothetical trial realizations.  
If 3 patients are given the starting dose 100 mg and none of them develop a DLT, then 
the next mCRM dose recommendation is 250 mg.  Afterwards the mCRM 
recommendations are 300 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 
700 mg, and 800 mg if the next cohorts of 3 patients also have no DLT observed each 
time.  The increase is a bit faster (not exceeding the maximum increments specified 
above) if more patients are enrolled into the cohorts.  For example, if the cohorts are 
made with 6 patients rather than 3, all without DLTs, the dose recommended for the 
sequence of cohorts is 100 mg, 250 mg, 300 mg, 300 mg, 350 mg, 400 mg, 600 mg, 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
94/Protocol BH29812, Version 4 
750 mg, and 800 mg.  On the other hand, if DLTs are observed, the next recommended 
dose is (almost) equal to or lower than the current dose.  Specifically, if in the first cohort 
at 100 mg with 3 patients when 1, 2, or 3 DLTs are observed, then the dose 
recommended for the second cohort is 100 mg, 50 mg, or 50 mg, respectively.  If the 
first DLTs are observed in the second cohort of 3 patients at 250 mg and none in the first 
cohort of 100 mg, the dose for the third cohort is recommended as 250 mg, 200 mg, and 
100 mg when 1, 2, or 3 DLTs are observed.  A summary of the subsequent 
recommendation among same principle is provided in Table 5. 
Table 5 
Hypothetical Trial Realization (Cohort Size = 3) 
Observation of First 
DLT at 
Recommended Dose among the Number of DLT Effectively Observed 
1 DLT 
2 DLTs 
3 DLTs 
100 mg 
100 mg 
50 mg 
50 mg 
250 mg 
250 mg 
200 mg 
100 mg 
300 mg 
300 mg 
250 mg 
250 mg 
300 mg 
300 mg 
300 mg 
300 mg 
350 mg 
350 mg 
300 mg 
300 mg 
400 mg 
400 mg 
350 mg 
350 mg 
450 mg 
450 mg 
400 mg 
400 mg 
500 mg 
500 mg 
450 mg 
450 mg 
600 mg 
650 mg 
550 mg 
500 mg 
750 mg 
800 mg 
650 mg 
600 mg 
DLT = dose-limiting toxicity. 
 
After each cohort of patients completes dosing, the posterior distribution of the model 
parameters of the logistic regression model will be updated with the observed DLT 
occurrence data and, hence, an estimate of the next dose, or declaration of MTD, will be 
derived.  In addition relevant demographic, adverse event, laboratory, dose 
administration, and PK (if available) data will be reviewed.  Then, subject to clinical 
judgment, a new cohort of patients will be dosed at the next recommended estimate of 
the MTD or the highest allowable dose based on the pre-specified over-dose constraints, 
whichever is lower.  The design will continue as described, assigning patients to the 
MTD as estimated from all of the DLT data cumulatively, until one of the predefined 
stopping criteria is satisfied or the predetermined sample size of DLT-evaluable patients 
is reached, whichever comes first.  The above described mCRM algorithm will be first 
used for predicting the MTD in the combined FL/DLBCL dose-escalation cohorts where 
idasanutlin is given in combination with obinutuzumab.  A similar mCRM will be then 
employed to support dose escalation in the DLBCL bridging cohorts where idasanutlin 
is given in combination with rituximab and in the FL bridging cohorts in which 
idasanutlin is given in combination with obinutuzumab using Regimen B, if applicable.  


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
108/Protocol BH29812, Version 4 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is a Phase Ib/II, open-label, multicenter, non-randomized study of obinutuzumab in 
combination with idasanutlin in patients with R/R FL and obinutuzumab or rituximab in 
combination with idasanutlin in patients with R/R DLBCL.  During the dose-escalation 
phase, patients with R/R FL or DLBCL will be assigned to dosing groups through an 
interactive voice or Web-based response system (IxRS).  Following determination of 
the MTD of idasanutlin in combination with obinutuzumab, bridging cohort(s) of 
DLBCL patients will be opened to confirm the MTD of idasanutlin in combination with 
rituximab.  Following determination of the MTD of idasanutlin in combination with 
obinutuzumab, bridging cohort(s) of FL patients will be opened to explore a different 
regimen (Regimen B, obinutuzumab alone at Cycle 1 and obinutuzumab in combination 
with idasanutlin at Cycles 2 to 6).  During the expansion phase, patients with R/R FL 
will be treated at the RP2D of idasanutlin plus 1000 mg obinutuzumab with the selected 
regimen, and patients with R/R DLBCL will be treated at the RP2D of idasanutlin plus 
375 mg/m2 rituximab.  
Enrollment tracking will be performed through the IxRS.  Prior to initiating screening, 
study site personnel should confirm through the IxRS that slots within the planned 
escalation or disease expansion cohort 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 for a particular disease cohort.   
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Obinutuzumab  
Obinutuzumab will be supplied by the Sponsor as an investigational medicinal product 
(IMP).  Obinutuzumab will be provided as a single-dose, sterile liquid formulation in a 
50-mL glass vial containing 1000 mg of obinutuzumab.  For information on the 
formulation and handling of obinutuzumab, see the Obinutuzumab Investigator's 
Brochure. 
4.3.1.2 
Rituximab 
Rituximab will be supplied by the Sponsor as an IMP.  Rituximab is packaged in 10-mL 
(100-mg) and 50-mL (500-mg) single-dose, pharmaceutical-grade glass vials at a 
concentration of 10 mg/mL of protein.  The antibody is formulated for IV injection as a 
sterile product in a solution of sodium chloride (pH 6.5) containing polysorbate 80 and 
sodium citrate.  


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
109/Protocol BH29812, Version 4 
For information on the formulation and handling of rituximab, see the Rituximab IV 
Oncology Investigator's Brochure and the Rituximab Pharmacy Manual. 
4.3.1.3 
Idasanutlin 
Idasanutlin will be supplied by the Sponsor as an IMP.  Four different film coated tablets 
with dose strengths of 50 mg (Ro 550-3781/F17), 200 mg (Ro 550-3781/F16), 300 mg 
(Ro 550-3781/F13), and 400 mg (Ro 550-3781/F14) were developed and optimized for 
use in clinical studies as well as for the market in a dose proportional way with respect to 
the tablet kernel.  The film coated tablets contain RO5503781-020 (spray dried powder 
consisting of 50% [w/w] RO5503781 and 50% [w/w] copovidone), microcrystalline 
cellulose, croscarmellose sodium, crospovidone, colloidal silicon dioxide, magnesium 
stearate, and a film coat.  The film coating mixture of Ro 550-3781/F17 (50 mg) and Ro 
550-3781/F16 (200 mg) consists of polyvinyl alcohol, titanium dioxide, polyethylene 
glycol, talc, iron oxide yellow, iron oxide red, and iron oxide black.  The film coating 
mixture of Ro 550-3781/F13 (300 mg) consists of polyvinyl alcohol, titanium dioxide, 
polyethylene glycol and talc, and the one of Ro 550-3781/F14 (400 mg) consists of 
polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow. 
All excipients used in the tablet formulations are widely used in pharmaceutical 
preparations and are of compendial grade. 
Film coated tablets of idasanutlin should be stored under the recommended storage 
conditions, “Do not store above 25°C.” 
4.3.2 
Dosage, Administration, and Compliance 
The treatment regimens are summarized in Table 6, Figure 6, and Section 3.1. 
Guidelines for dosage modification and treatment delays or discontinuation are provided 
in Section 5.1. 
Any overdose or incorrect administration of any of the study treatments should be noted 
on the Study Drug Administration form in the electronic Case Report Form (eCRF).  
Adverse events associated with an overdose or incorrect administration of any 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 (for eligible patients with FL only).   
Obinutuzumab should be administered independent of oral application of idasanutlin 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 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
110/Protocol BH29812, Version 4 
physician.  Obinutuzumab infusions will be administered according to the instructions 
outlined in Figure 9 and Figure 10.  For patients with bulky lymphadenopathy, the 
infusion may be given extremely 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. 
Premedication with a corticosteroid, antihistamine, and analgesics or antipyretic agents, 
as outlined in Section 4.3.2.6, is required to reduce the incidence and severity of IRRs.  
For anaphylaxis precautious, see Appendix 9. 
 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
111/Protocol BH29812, Version 4 
Figure 9 Guidelines for Obinutuzumab Infusion:  First Infusion 
 
 
IRR = infusion-related reaction. 
a All patients should receive full premedication with an oral corticosteroid, antihistamine, and oral analgesic/anti-pyretic prior to the first obinutuzumab infusion.  
Refer to Section 4.3.2.6 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 9. 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
112/Protocol BH29812, Version 4 
Figure 10 Guidelines for Obinutuzumab Infusions:  Second and Subsequent Infusions 
 
 
IRR = infusion-related reaction. 
a Patients should receive full premedication with an oral corticosteroid, antihistamine, and oral analgesic/anti-pyretic prior to the obinutuzumab infusion.  Refer to 
Section 4.3.2.5 for details.  In the case of a recurrent Grade 3 IRR, obinutuzumab may be discontinued at the discretion of the investigator following an individual 
benefit-risk assessment. 
b Patients who experience wheezing, urticaria, or other symptoms of anaphylaxis must receive full premedication prior to all subsequent doses. 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
115/Protocol BH29812, Version 4 
First Infusion (Day 1 of Cycle 1) 
Subsequent Infusions 
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). 
IRR =  infusion-related reaction. 
 
4.3.2.4 
Induction Treatment with Obinutuzumab or Rituximab and 
Idasanutlin 
Patients will receive 6 cycles of induction treatment consisting of obinutuzumab or 
rituximab and idasanutlin as outlined in Table 6.  For patients with FL enrolled in the 
bridging cohort(s), obinutuzumab will be given alone at Cycle 1, and the obinutuzumab 
and idasanutlin combination will be given from Cycles 2 to 6. 
For patients at increased risk for IRRs (high tumor burden), the first obinutuzumab 
and rituximab infusion may be split and administered over 2 days.  If split, 
obinutuzumab should be given as 100 mg on Day 1 and 900 mg on Day 2.  
Please refer to Section 3 for further details. 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
116/Protocol BH29812, Version 4 
Figure 11 Treatment with Idasanutlin and Obinutuzumab:  Schedule of 
Treatment  
Regimen A: Idasanutlin plus obinutuzumab in escalation phase (excluding FL 
bridging cohorts) and expansion phase if Regimen A is chosen: 
 
 
 
BID = twice a day; C = cycle; D = day; IV = intravenous; QD = once a day. 
Note:  Patients will receive study treatment every 28 days for up to 6 cycles. 
 
Regimen B: Idasanutlin plus obinutuzumab in FL bridging cohorts and 
expansion phase if Regimen B is chosen: 
 
 
 
BID = twice a day; C = cycle; D = day; IV = intravenous; QD = once a day. 
Note:  Patients will receive study treatment every 28 days for up to 6 cycles. 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
117/Protocol BH29812, Version 4 
 
Figure 12 Escalation Phase (DLBCL Bridging Cohort[s]) and Expansion 
Phase with Idasanutlin and Rituximab:  Schedule of Treatment 
Idasanutlin plus rituximab regimen: 
 
BID = twice a day; C = cycle; D = day; IV = intravenous; QD = once a day. 
Note:  Patients will receive study treatment every 28 days for up to 6 cycles. 
 
4.3.2.5 
Post-Induction Treatment for Patients with FL and DLBCL 
Please refer to Section 3 for further details. 
4.3.2.6 
Premedication 
Patients should receive premedication as outlined in Table 9. 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
120/Protocol BH29812, Version 4 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (obinutuzumab, rituximab, and idasanutlin) 
will be provided by the Sponsor.  The study site will acknowledge receipt of IMPs using 
the IxRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Study Access to Obinutuzumab, Rituximab, and 
Idasanutlin 
Currently, the Sponsor does not have any plans to provide obinutuzumab, rituximab, or 
idasanutlin or any other study treatments or interventions to patients who have 
completed the study.  The Sponsor will evaluate whether to continue providing 
obinutuzumab, rituximab, and idasanutlin in accordance with the Roche Global Policy 
on Continued Access to Investigational Medicinal Product, available at the following 
Website:  
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 
14 days prior to the screening period to the visit at EOI or at the end of Maintenance or 
consolidation treatment, whichever occurs later.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.  
4.4.1 
Permitted Therapy  
Premedication is permitted as described in Section 4.3.2.6. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
During the dose-escalation phase, granulocyte colony-stimulating factor (G-CSF) is not 
permitted during the first cycle, unless the patient experiences a DLT of neutropenia.   
During the expansion phase, G-CSF is permitted as clinically indicated per American 
Society of Clinical Oncology (ASCO), European Organization for Research and 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
123/Protocol BH29812, Version 4 
Table 11 Prohibited Strong CYP3A4 Inducers 
Inducers (Strong) a 
carbamazepine 
cyproterone 
efavirenz 
enzalutamine  
etravirine 
mitotane  
modafinil 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
rifampicin 
St. John’s wort 
a Concomitant use of idasanutlin with strong CYP3A inducers is to be avoided to prevent 
idasanutlin exposure loss compromising efficacy; consider alternative medications.  If a 
patient requires use of these medications, use with caution and contact the Roche Medical 
Monitor (refer to Section 5.4.1) for guidance.  The inducers are allowed during the study 
only if the patient has completed the DLT evaluation window (if patient is in a dose-
escalation cohort).  
 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
124/Protocol BH29812, Version 4 
 Table 12 Prohibited OATP1B1/3 Substrates 
OATP1B1/2 Substrates  
asunaprevir 
atorvastatin  
atrasentan  
bosentan  
cerivastatin 
danoprevir 
docetaxel  
ezetimibe  
fluvastatin  
fexofenadine  
glyburide  
irinotecan  
nateglinide  
olmesartan  
paclitaxel  
pitavastatin  
pravastatin  
repaglinide  
rifampin  
rosuvastatin  
simvastatin acid  
telmisartan  
valsartan  
 
The above lists of medications are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the internet references provided below when determining whether a certain 
medication should be inhibited by the above rationale.  In addition, the investigator 
should contact the Medical Monitor if questions arise regarding medications not listed 
above.  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
130/Protocol BH29812, Version 4 
Samples collected for biomarker analyses may be used for exploratory biomarker 
research, assay development purposes, and additional safety and immunogenicity 
assessments, as appropriate. 
Based on ongoing analysis of data, the Sponsor may choose to stop any analysis, 
timepoint or sample type if the data does not support a strong scientific justification to 
continue. 
Biological samples will be destroyed within 5 years after the final clinical study report has 
been completed.  Remaining samples will be stored for exploratory research if the 
patient provides Roche Clinical Repository (RCR) consent.  
4.5.7 
Electrocardiograms  
Single, resting, 12-lead ECG recordings will be obtained at specified timepoints, as 
outlined in the schedule of activities (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.  All ECG recordings must be 
performed using a standard high-quality, high-fidelity digital electrocardiograph machine 
equipped with computer-based interval measurements.  Lead placement should be as 
consistent as possible.  ECG recordings must be performed after the patient has been 
resting in a supine position for at least 10 minutes.  All ECGs are to be obtained prior to 
other procedures scheduled at that same time (e.g., vital sign measurements, blood 
draws) and under no conditions while patient is receiving a premedication/study drug IV 
infusion.  Circumstances that may induce changes in heart rate, including environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording.  
For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings.  Paper copies of ECG tracings will be kept as part of the patient’s 
permanent study file at the site.  The following should be recorded in the appropriate 
eCRF:  ECG abnormality (including waveform); heart rate; PQ, PR, RR, and QRS 
intervals; and QT interval and corrected QTcF interval based on the machine readings of 
the individual ECG tracings.  Any morphologic waveform changes or other ECG 
abnormalities must be documented on the eCRF.  
If at a particular postdose timepoint the mean QTcF is > 500 ms and/or 60 ms longer 
than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on 2 
successive ECGs.  Standard-of-care treatment may be instituted per the discretion of the 
investigator.  If a PK sample is not scheduled for that timepoint, an unscheduled PK 
sample should be obtained.  The investigator should also evaluate the patient for 
potential concurrent risk factors (e.g., electrolyte abnormalities, dehydration, 
co-medications known to prolong the QT interval, severe bradycardia) and provide this 
information to the eCRF.  


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
132/Protocol BH29812, Version 4 
 
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the laboratory manual.   
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.8.4 
Confidentiality 
Confidentiality for All Roche Clinical Repository Specimens 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
Additional Confidentiality for Specimens Used for Genetic Research 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens collected for genetic research.  
Upon receipt by the RCR, specimens for genetic research are "double-coded" by 
replacing the patient identification number with a new independent number.  Data 
generated from the use of these specimens and all clinical data transferred from the 
clinical database and considered relevant are also labeled with this same independent 
number.  A “linking key” between the patient identification number and this new 
independent number is stored in a secure database system.  Access to the linking key is 
restricted to authorized individuals and is monitored by audit trail.  Legitimate operational 
reasons for accessing the linking key are documented in a standard operating procedure.  


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
133/Protocol BH29812, Version 4 
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 study 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 BH29812 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 BH29812. 
4.5.8.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice (GCP) 
by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Study 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. 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
136/Protocol BH29812, Version 4 
events, including criteria for dosage modification and treatment delays or discontinuation, 
are provided in Section 5.1.5. 
5.1.1 
Risks Associated with Obinutuzumab 
As of 4 July 2016, the following adverse events are considered to be important 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, gastrointestinal 
perforation, immunogenicity, and second malignancies.  These events, with the 
exception of prolonged B-cell depletion, immunogenicity, and second malignancies, are 
described below.  
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.  Commonly experienced IRRs 
have been characterized by hypotension, fever, chills, flushing, nausea, vomiting, 
hypertension, fatigue, and other symptoms.  
IRRs may be clinically indistinguishable from IgE-mediated allergic or anaphylactic 
reactions; anaphylaxis has been reported in patients treated with obinutuzumab.  
Hypotension may occur during obinutuzumab IV infusions.  Therefore, withholding of 
anti-hypertensive treatments should be considered for 12 hours prior to and throughout 
each obinutuzumab infusion and for the first hour after administration.  Patients at acute 
risk of hypertensive crisis should be evaluated for the benefits and risks of withholding 
their anti-hypertensive medication. 
Patients who have preexisting cardiac or pulmonary conditions should be monitored 
carefully throughout the infusion and the post-infusion period. 
Guidelines for medical management of IRRs and anaphylaxis are provided in 
Section 4.3.2.1 and Appendix 9.  
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 4.3.2.6 (see Table 9).  Additional guidelines for 
management of TLS in this study are provided in Section 5.1.5. 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
145/Protocol BH29812, Version 4 
Table 16 Idasanutlin Dose Reduction Steps 
Initial Dose 
Dose Reduction by (mg) 
Step 1 
Step 2 
Step 3 
100 mg 
minus 50 mg 
No further 
reduction a  
No further reduction a  
150 mg 
minus 50 mg 
No further 
reduction a  
No further reduction a  
200 mg 
minus 50 mg 
minus  
50 mg 
No further reduction a  
250 mg 
minus 100 mg 
minus  
50 mg 
No further reduction a  
300 mg 
minus 100 mg 
minus  
50 mg 
minus  
50 mg 
350 mg 
minus 100 mg 
minus  
100 mg 
minus  
50 mg 
400 mg 
minus 100 mg 
minus  
100 mg 
minus  
50 mg 
a When no further idasanutlin dose reduction is possible, the patient will be discontinued from 
the study. 
 
Guidelines for management of toxicities during induction treatment are provided in 
Section 5.1.5.1.  Guidelines for management of toxicities during maintenance treatment 
are provided in Section 5.1.5.2. 
5.1.5.1 
Toxicities during Induction Treatment 
Hematologic Toxicities  
Table 17 provides guidelines for management of hematologic toxicities that occur during 
induction treatment, with the exception of Days 8 and 15 of Cycle 1.  Table 18 provides 
guidelines for management of hematologic toxicities that occur on Days 8 and 15 of 
Cycle 1, when patients are to receive treatment with obinutuzumab only.  Hematologic 
toxicity is defined as neutropenia, anemia, or thrombocytopenia.  Lymphopenia is not 
considered hematologic toxicity but an expected outcome of therapy.   


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
155/Protocol BH29812, Version 4 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE, v4.0 will be used for 
assessing adverse event severity.  Table 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, v4.0, which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
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 an 
adverse event is considered to be related to any of the study treatment components, 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
163/Protocol BH29812, Version 4 
by scanning and emailing the form with use of 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, all adverse events will be reported until 90 days after 
the last study treatment.  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 with 
use of 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 post-study adverse events 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 for those receiving obinutuzumab and idasanutlin and within 
12 months after the last dose of study treatment for those receiving rituximab and 
idasanutlin.  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 with 
use of the fax number or email address provided to investigators.  Pregnancy should not 
be recorded on the Adverse Event eCRF.  The investigator should discontinue study 
treatment and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose of study treatment.  A Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
164/Protocol BH29812, Version 4 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form with use of 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.  Once the 
authorization has been signed, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  An investigator who is contacted by the male patient or his pregnant 
partner may provide information on the risks of the pregnancy and the possible effects 
on the fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
5.4.3.3 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).   
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
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, 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 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
171/Protocol BH29812, Version 4 
It is anticipated that at least one interim analysis per disease indication will be 
conducted during the expansion phase of the study, with the earliest interim analysis 
taking place when at least 15 patients treated have been evaluated for a PET-CT-defined 
CR at EOI.  If, at any interim analysis, a low predictive probability suggests that the 
proportion of patients achieving a PET-CT-defined CR at EOI is lower than desired, the 
IMC will review the data and decide whether to recommend an early decision to stop 
enrollment.  
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 will be provided 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 will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
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. 


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
172/Protocol BH29812, Version 4 
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 study. 
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 onto 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 study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
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 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
174/Protocol BH29812, Version 4 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
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.  


 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
175/Protocol BH29812, Version 4 
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., last patient, last visit 
[LPLV]). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
177/Protocol BH29812, Version 4 
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 studies only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors’ authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


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Appendix 1  
Schedule of Activities for Patients with Follicular Lymphoma  
(Dose-Escalation and Expansion) (cont.)  
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
189/Protocol BH29812, Version 4 
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. 
ee The screening PET-CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
ff Perform only for patients who have received at least two cycles of induction treatment. 
gg If PET-CT scan is positive at EOI, perform at 12 months after initiation of induction treatment, within 14 days prior to treatment administration. 
hh CT scan of the neck (if clinically indicated), chest, abdomen and pelvis.  If contrast is medically contraindicated (e.g., patients with contrast allergy or impaired renal 
clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically indicated) and a non-contrast CT scan of the chest may be performed.  Combined 
PET/CT scanners may be used to collect diagnostic CT scans but only according to the technical guidelines in the imaging manual.  Screening CT scan must be 
performed within 35 days prior to Day 1 of Cycle 1. 
ii Perform at 12, 18, and 24 months after initiation of induction treatment, within 14 days prior to treatment administration.   
jj Perform only if not done within the previous 3 months. 
kk Perform every 6 months. 
ll Bone marrow biopsy and aspirate must be performed within approximately 3 months prior to Day 1 of Cycle 1. 
mm 
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). 
nn Refer to Section 4.3.2.3 and Section 4.3.2.5 for details on dosing and schedule. 
oo Perform within 7 days prior to Day 1 of Cycle 3. 
pp Regimen will be defined based on available safety, tolerability, PK, and PD data. 
 




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Appendix 2 
Schedule of Activities for Patients with DLBCL (cont.) 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
193/Protocol BH29812, Version 4 
c Consolidation 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 8 months. 
d Patients who complete consolidation treatment or discontinue consolidation treatment prematurely will undergo assessments at the EOC. 
e 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.  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 with FL have completed or discontinued study treatment and all enrolled patients with DLBCL have 
been followed for at least 1 year after they have completed or discontinued study treatment.  
f Informed consent must be documented before any study-specific screening procedure is performed.   
g Vital signs include respiratory rate, pulse rate, body temperature, and systolic and diastolic blood pressures while the patient is in a seated position.  
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.   
h Perform only for patients who will not be receiving consolidation treatment. 
i Vital signs will be measured, a targeted physical examination will be performed, and hematology and serum chemistry will be assessed during 
consolidation every 2 weeks during the first month, every month until EOC.  For rituximab infusions:  Vital signs monitoring during infusion 
should be determined as per local label.   
j All ECGs should be collected prior to and 6 hours after idasanutlin administration or after obinutuzumab/rituximab administration, whichever 
occurs later.  For Cycle 1 Day 5, perform ECG 6 hours post idasanutlin administration only if patient is still at clinic.  
k All ECGs should be collected prior to and 6 hours after idasanutlin administration or after obinutuzumab/rituximab administration, whichever 
occurs later.  ECG will be performed as described on Cycles 4, Days 1 and 5 only.  For Cycle 4 Day 5, perform ECG 6 hours post idasanutlin 
administration only if patient is still at clinic.  
l 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. 
m 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. 


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Appendix 2 
Schedule of Activities for Patients with DLBCL (cont.) 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
195/Protocol BH29812, Version 4 
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 3–4 infections (related and unrelated) in patients who received 
obinutuzumab, 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. 
ii The screening PET-CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
jj Perform only for patients who have received at least two cycles of induction treatment. 
kk CT scan of the neck (if clinically indicated), chest, abdomen and pelvis.  If contrast is medically contraindicated (e.g., patients with contrast allergy 
or impaired renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically indicated) and a non-contrast CT scan of the 
chest may be performed.  Combined PET/CT scanners may be used to collect diagnostic CT scans, but only according to the technical guidelines 
in the imaging manual.  Screening CT scan must be performed within 35 days prior to Day 1 of Cycle 1. 
ll Perform within 7 days prior to Day 1 of Cycle 3. 
mmPerform 4 months after initiation of consolidation treatment. 
nn Perform a CT scan 3 and 6 months after EOI visit, and every 6 months thereafter.  
oo Bone marrow biopsy and aspirate must be performed within approximately 3 months prior to Day 1 of Cycle 1. 
pp For patients with bone marrow involvement at screening, a repeat assessment will be performed at the EOI, during consolidation, or at the EOC 
whenever 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).  Additional bone marrow assessments may be performed at the discretion of the 
investigator. 
qq 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. 
rr Refer to Section 4.3.2.3 and Section 4.3.2.5 for details on dosing and schedule. 
ss   Regimen will be defined based on available safety, tolerability, PK, and PD data. 
 




















 
 
 
Appendix 4 
Schedule of Pharmacokinetic and Pharmacodynamic (MIC-1) Assessments for Obinutuzumab 
and Idasanutlin in Regimen B (cont.) 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
205/Protocol BH29812, Version 4 
ADA = anti-drug antibody; PK = pharmacokinetic; HAHA = human anti-human antibody; MIC-1 = macrophage inhibitory cytokine 1.  
a Samples collected for PK analysis may be used for additional PK, HAHA, and/or ADA assay development and validation, and additional 
immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist. 
b Two tubes for plasma and serum, respectively, at each sampling timepoint. 
c The Cycle 1 Day 1 pre-dose PK sample may be taken any time prior to the first dose that day. 
d If the Cycle 1 Day 1 dose of obinutuzumab is split over two days, take the 30 minutes post end of infusion obinutuzumab PK sample relative 
to the end of the infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded. 


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Appendix 5  
Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) (cont.)  
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
208/Protocol BH29812, Version 4 
 
Revised Criteria for Response Assessment  
Response and Site 
PET-CT–Based Response 
CT-Based Response 
No response or stable disease  
No metabolic response 
Stable disease 
Target nodes/nodal masses, 
extranodal lesions 
Score 4 or 5 b with no significant change in FDG uptake from 
baseline at interim or end of treatment 
< 50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met 
Non-measured lesion 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 


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Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
211/Protocol BH29812, Version 4 
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 
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any work activities.  Up and about > 50% of waking hours 
3 
Capable of only limited self-care; confined to a bed or chair 
> 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead 
 


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Appendix 11  
Simulations among the Statistical Design of mCRM  (cont.) 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
220/Protocol BH29812, Version 4 
Table 3  
Operating Characteristics of the Design under Various 
Scenarios 
Scenario/True 
Toxicity 
True MTD 
(Simulated) 
Maximum 
Dose 
Tested * 
Selected 
Dose* 
Recommenda
tion of 
Selected 
Dose * (%)  
Sample Size* 
[min, n, max] 
1/Prior guess 
250 mg 
400 mg 
250 mg 
48% 
[9, 13, 24] 
2/30% higher 
than prior guess 
200 mg 
400 mg 
250 mg 
49% 
[9, 13, 24] 
3/30% lower 
than prior guess 
350 mg 
750 mg 
30 0mg 
44% 
[9, 14, 39] 
4/80% higher 
than prior guess 
150 mg 
350 mg 
200 mg 
33% 
[9, 15, 27] 
5/toxicity 
increase on the 
tail of prior 
guess 
250 mg 
650 mg 
250 mg 
52% 
[9, 13, 30] 
6/80% lower 
than prior guess 
>800 mg 
800 mg 
800 mg 
33% 
[12, 30, 45] 
7/correlation of 
0.5 in the 
covariance 
matrix 
250 mg 
500 mg 
250 mg 
45% 
[9, 15, 33] 
* Over 500 simulated studies. 
 
 
 


 
 
 
Appendix 11  
Simulations among the Statistical Design of mCRM  (cont.) 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
221/Protocol BH29812, Version 4 
 
Scenario 1: True Toxicity Matches Prior Guesses 
 
 
 
 


 
 
 
Appendix 11  
Simulations among the Statistical Design of mCRM  (cont.) 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
222/Protocol BH29812, Version 4 
 
Scenario 2:  True Toxicity Is 30% Higher 
 
 


 
 
 
Appendix 11  
Simulations among the Statistical Design of mCRM  (cont.) 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
223/Protocol BH29812, Version 4 
 
Scenario 3:  True Toxicity Is 30% Lower 
 
 
 


 
 
 
Appendix 11  
Simulations among the Statistical Design of mCRM  (cont.) 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
224/Protocol BH29812, Version 4 
 
Scenario 4:  True Toxicity Is 80% Higher 
 
 
 


 
 
 
Appendix 11  
Simulations among the Statistical Design of mCRM  (cont.) 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
225/Protocol BH29812, Version 4 
 
Scenario 5:  Steeper Increase on the Tail 
 
 
 


 
 
 
Appendix 11  
Simulations among the Statistical Design of mCRM  (cont.) 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
226/Protocol BH29812, Version 4 
 
Scenario 6:  True Toxicity is 80% Lower than Prior Guesses 
 
 
 


 
 
 
Appendix 11  
Simulations among the Statistical Design of mCRM  (cont.) 
 
Idasanutlin, Rituximab, and Obinutuzumab—F. Hoffmann-La Roche Ltd 
227/Protocol BH29812, Version 4 
 
Scenario 7:  Prior model does include a correlation between  
 
 
 


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