Clinical trial NCT02055820
Conditions: Lymphoma, Non-Hodgkin
Sponsor: Hoffmann-La Roche
Start date: 2013-11-17; Completion date: 2019-06-28
Enrollment: 267 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, open-label, dose-finding study of venetoclax administered orally in combination with rituximab (R) or obinutuzumab (G) and standard doses of cyclophosphamide, doxorubicin, vincristine and oral prednisone (CHOP) in participants with Non-Hodgkin's Lymphoma (NHL). The study consisted of 2 stages: a dose-finding Phase Ib stage and a Phase II expansion stage. In the Phase I portion of the study, participants were randomized to one of 2 treatment arms venetoclax in combination with R-CHOP (Arm A) and venetoclax in combination with G-CHOP (Arm B) and explored the doses of venetoclax in combination with R-CHOP and G-CHOP. The maximum tolerated dose (MTD) of venetoclax in combination with R-CHOP and G-CHOP was determined during the dose-finding stage. For the Phase II portion of the study, the venetoclax dose for venetoclax + R-CHOP was on a non-continuous dosing schedule as determined by the Phase Ib portion of the study based on safety and tolerability observed in participants treated in the dose escalation portion of the study. On 17 July 2016, Roche/Genentech as the sponsor of Study BO21005 (Goya study), a Phase III study that evaluated G CHOP versus R-CHOP in 1L DLBCL, informed through a press release that the primary endpoint of investigator-assessed PFS was not met. Given these results, Arm B (venetoclax + G-CHOP) was not expanded in Phase II in patients who are first-line with DLBCL.

Detailed description:

Arms: arm 1: Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. arm 2: Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Interventions: intervention 1: Venetoclax intervention 2: Cyclophosphamide intervention 3: Obinutuzumab intervention 4: Rituximab intervention 5: Doxorubicin intervention 6: Vincristine intervention 7: Prednisone
Intervention descriptions: intervention 1: Venetoclax 200 to 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4-10 of Cycle 1 and Days 1-10 of Cycles 2-8 during Phase I and MTD will be administered according to the same schedule during Phase II. intervention 2: Cyclophosphamide 750 milligrams per square meter (mg/m\^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6. intervention 3: Obinutuzumab will be administered by IV infusion as an absolute dose of 1000 mg on Days 1, 8, 15 of Cycle 1 and Day 1 of Cycles 2-8 (cycle length = 21 days). intervention 4: Rituximab 375 mg/m\^2 dose will be administered IV on Day 1 of every 21-day cycle. intervention 5: Doxorubicin 50 mg/m\^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6. intervention 6: Vincristine 1.4 mg/m\^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6. intervention 7: Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Protocol documents:
Prot_002.pdf: 
Official Title:  
A Phase IB/II, Open-Label Study Evaluating the Safety and 
Pharmacokinetics of GDC-0199 (ABT-199) in Combination With Rituximab 
(R) or Obinutuzumab (G) Plus Cyclophosphamide, Doxorubicin, 
Vincristine, and Prednisone (CHOP) in Patients with B-cell Non-Hodgkin’s 
Lymphoma (NHL) and DLBCL 
 
NCT Number:   
NCT02055820 
 
Document Dates:  
Protocol version 8: 10-Oct-16 




Venetoclax (GDC-0199)⎯F. Hoffmann-La Roche Ltd 
2/Protocol GO27878, Version 8 
PROTOCOL AMENDMENT, VERSION 8:   
RATIONALE 
This amendment replaces Version 7 of Protocol GO27878.  Changes to the protocol, 
along with a rationale for each change, are summarized below:   
• 
Venetoclax nonclinical toxicology section updated based on recent data findings 
• 
Twelve month PFS was added as a secondary efficacy objective to align with 
Section 3.3.3, where it was already included as a secondary efficacy outcome 
measure (Section 2.2.2). 
• 
Information was added regarding the decision to not open Arm B in Phase II in 
DLBCL on the basis of information from the GOYA study results (Section 3.2.3). 
• 
The following inclusion/exclusion criteria were updated:   
Measurable lesions must also be FDG avid on PET to ensure the primary 
efficacy objective can be assessed and to align with other Roche/Genentech 
protocols (Section 4.1.2.3). 
Patients with discordant bone marrow (i.e., low grade histology in bone marrow) 
may be considered for the study as the outcomes are consistent with DLBCL 
(per published research) (Section 4.1.3.2). 
Patients with AST and ALT > 2.5 × ULN due to disease involvement may be 
considered for the study as it is expected that lymphoma treatment will 
normalize these values (Section 4.1.3.3). 
Primary mediastinal DLBCL will be excluded as primary mediastinal DLBCL has 
different clinical and pathological features than DLBCL and standard treatment 
(Section 4.1.3.3). 
The remission duration as a prerequisite for enrolling a patient with prior 
malignancy treated with surgery only has been reduced from ≥ 5 years 
to ≥ 3 years to align with other protocols for comparison (Section 4.1.3.3). 
• 
The recommendation for the low fat breakfast to be consumed prior to venetoclax 
dosing was modified due to new clinical pharmacology information from other 
venetoclax studies and to align with other Roche/Genentech protocols 
(Section 4.3.1.2). 
• 
The guideline for TLS prophylaxis was updated based on a recent analysis of 
laboratory TLS cases observed in venetoclax studies in NHL and to align with other 
NHL studies being conducted at Roche/Genentech (Section 4.4.1.5.1). 
• 
Survival Follow-up Section was added to ensure data can be collected for Overall 
Survival analyses (Section 4.5.7). 
• 
Post-Trial Access to study drugs section was updated to the current protocol 
template (Section 4.8). 
• 
The 
 Medical Responsible Contacts Information (Rest of World) was 
updated to reflect changes to the appointed contacts (Section 5.3.1). 


 
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• 
IPI score criteria was added to Appendix 7 to ensure IPI score is calculated 
accurately by site staff prior to study entry. 
• 
Double positive (DP) was changed to double expressor (DE) throughout the text as 
per recent update to WHO nomenclature.  
• 
Section 6.1 (investigator requirements) was updated to remove the exclusion from 
expedited reporting of anticipated events. 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
 


Venetoclax (GDC-0199)⎯F. Hoffmann-La Roche Ltd 
4/Protocol GO27878, Version 8 
PROTOCOL AMENDMENT, VERSION 8:   
SUMMARY OF CHANGES 
GLOBAL CHANGES 
• 
The term double positive (DP) was replaced with double expressor (DE). 
• 
Abbreviations have been updated, where appropriate, due to the addition of text. 
 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.2.2.2:  Venetoclax Nonclinical Toxicology 
The nonclinical toxicology of venetoclax has been evaluated in repeat dose studies of 
up to 4 weeks’ duration with once daily (QD) oral dosing and with up to 4  and 26 week 
recovery periods in mice and 26 week recovery periods in dogs.  In addition, 
venetoclax has been tested in safety pharmacology studies (cardiovascular [CV], 
respiratory, and neurofunctional) and in genetic toxicity tests (Ames and in vitro 
chromosome aberrations assays).  A severely toxic dose to 10% of rodents was not 
identified in mice up to and including the highest dose of 600 mg/kg/day (overall mean 
area under the concentration time curve [AUC] from Time 0 to 24 hours 
[AUC0−24] = 91.5 μg • h/mL and maximum concentration observed [Cmax] =  7.2 μg/mL).  In 
dogs, the highest non severely toxic dose was 150 mg/kg/day, but as a result of 
overlapping exposures between the mid  and high doses, the highest non severely toxic 
dose was defined as the mid dose of 50 mg/kg/day (overall mean 
AUC0−24 = 472 μg • h/mL and Cmax = 27.4 μg/mL). 
Consistent with expected pharmacological activity, venetoclax caused moderate to 
marked decreases in lymphocytes including both T  and B cell subsets, and 
corresponding lymphoid depletion was observed in the spleen, lymph nodes, 
gut associated lymphoid tissue (mice), and Peyer’s patches (dogs).  In dogs after 
4−6 months of recovery, B cell counts reversed non−dose dependently to 25%−111% of 
individual baseline (mean reversal to 54% of baseline average).  T cell subsets reversed 
more readily and showed more dose dependence in recovery time and extent.  
Additional hematological effects included reductions in red cell mass (hemoglobin, 
hematocrit) that were adverse at 600 mg/kg/day in mice and at 150 mg/kg/day in dogs. 
In dogs, venetoclax produced severe decreases in the numbers of spermatogonia after 
4 weeks of dosing with progression to severe decreases in all germ cells in testes during 
the 4 week recovery period.  The translatability of the findings to humans is unknown, 
but this change may be related to venetoclax pharmacology because one or more 
members of the Bcl 2 family of proteins play a role in spermatogenesis (Yan et al. 2003). 
In an anesthetized dog CV model given intravenous (IV) doses of venetoclax, mild 
reductions in cardiac output (−11% to −19%) and myocardial contractility (dP/dtmax; 


 
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5/Protocol GO27878, Version 8 
−6% to −13%) were observed at plasma concentrations of ≥ 16 μg/mL and ≥ 32 μg/mL 
respectively, compared with 6 dogs given vehicle; however, no effects on blood pressure, 
heart rate, or ECG parameters were observed in either the anesthetized dog study or 
conscious dog CV studies that used telemeterized animals. 
In an ongoing 9 month chronic toxicity study in dogs, change in the hair coat from 
normal to increased amounts of white hair was observed after 3 months of dosing at 6 or 
20 mg/kg/day (mid  and high doses, respectively).  On the basis of a similar finding of 
gray hair coat in BCL2 /− null mice, the dog hair coat change is likely to be an effect of 
Bcl 2 inhibition on melanocyte stem cells, but potential effects on patients are unknown.  
In addition, Bcl 2 in melanocytes might be involved in auditory and retinal protection, and 
inhibition of Bcl 2 by venetoclax could predispose to hearing loss or visual effects.  The 
meaning of these animal findings for humans is not known, but an event of hearing loss 
has been reported in 1 patient with chronic lymphocytic leukemia (CLL) who received 
venetoclax.  Patients will be monitored for ocular and auditory findings. 
Other nonclinical findings in dogs included non severe, cutaneous swelling at high dose, 
post dose emesis, salivation, and fecal alterations during the dosing period.  Microscopic 
findings of single cell necrosis in the gall bladder epithelium, stomach, exocrine 
pancreas, and epididymides were considered to be an effect of Bcl 2 inhibition but were 
of minimal magnitude and not associated with loss of mucosal integrity. 
There were no consistent effects on respiratory or neurological function, and both in vitro 
genetic toxicity test results were negative. 
Toxicology assessments completed to date with venetoclax are general toxicology 
studies with periods of once-daily oral dosing ranging from 2 weeks to 6 months in mice, 
from 2 weeks to 13 weeks in rats, and from 1 week to 9 weeks in dogs; in vitro and 
in vivo genetic toxicology; embryo-fetal development in female mice and rabbits; and 
fertility and early embryonic development in male and female mice.  The maximum 
steady state venetoclax plasma exposures (mean area under the concentration-time 
curve [AUC]) achieved in the IND-enabling 4 week studies were 92 µg • h/mL (at 
600 mg/kg/day) in mice and 572 µg • h/mL (at 150 mg/kg/day) in dogs.  In the chronic 
toxicity studies, AUCs reached 34.1 µg•h/mL (at 300 mg/kg/day) in mice and 
86 µg • h/mL (at 20 mg/kg/day) in dogs.  In rats, exposures were higher in females than 
in males; at dosages of 150 and 400 mg/kg/day in the 13 week maximum tolerated dose 
study, exposures ranged up to 83.1−127.8 µg • h/mL in females and up to 
26.4−44.2 µg • h/mL in males. 
The primary toxicities associated with venetoclax administration included effects on the 
hematologic system (decreased lymphocytes and erythrocytes) in mice, rats, and dogs; 
the male dog reproductive system (testicular germ cell depletion); and embryo-fetal 
toxicity in mice. 


 
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In mice, rats, and dogs, venetoclax produced generally dose-related decreases in 
lymphocytes in the peripheral blood (of up to 75% in mice, up to 64% in rats, and up 
to 81% in dogs) and in lymphoid tissues.  In dogs, the recovery of lymphocyte counts 
(total lymphocytes, CD4 + and CD8 + T cells and mature B cells) was prolonged, 
requiring up to 18 weeks after completion of 2 weeks of dosing.  B cells were the most 
sensitive lymphocyte subtype based on the magnitude of decrease and/or the length of 
time required for recovery (i.e., 25%−111% of individual baseline; mean reversal to 
54% of baseline average).  T-cell subsets reversed more readily and showed more 
dose-dependence in recovery time and extent.  Decreases of lymphocytes in lymphoid 
tissues were reversible in mice and reversible to partially reversible in dogs.  
Venetoclax-related decreases in lymphocytes in blood and lymphoid tissues are 
considered pharmacologically-mediated and non-adverse (Marsden and Strasser, 2003). 
In the 4 week mouse and dog studies, dose-related reversible decreases in RBC mass 
were observed.  Effects on RBC mass were typified by hemoglobin decreases.  At the 
highest dosages administered, decreases in hemoglobin reached -21% in mice at 
600 mg/kg/day and -23% in dogs at 150 mg/kg/day, and were considered to be adverse 
based on a criterion of -20% decrease.  In rats, decreases in hemoglobin were more 
severe than in mice and dogs at comparable exposures and reached 30% to 49% at 
≥ 150 mg/kg/day in females.  Hematologic parameters (lymphocyte counts and RBC 
mass) are readily monitored in clinical trial subjects. 
In dogs, venetoclax produced adverse, non-reversible, non−dose-related microscopic 
findings of testicular germ cell depletion at all dosages tested; there were no testicular 
effects in mice.  The translatability of the testicular findings in dogs to humans is 
unknown, but this change may be related to venetoclax pharmacology, as one or more 
members of the Bcl-2 family of proteins play a role in spermatogenesis 
(Olderied et al. 2001; Sugiyama et al. 2001; Yan et al. 2003).  No effects of venetoclax 
have been identified in female reproductive tissues in mice or dogs in general toxicology 
studies. 
Venetoclax resulted in increased post-implantation loss and decreased fetal body 
weights in the mouse embryo-fetal development study at the highest dosage 
administered (150 mg/kg/day); the no-observed-adverse-effect level was defined at the 
mid-dose of 50 mg/kg/day.  Venetoclax was not teratogenic, and there were no other 
effects on development or fertility. 
Additional noteworthy effects of venetoclax included white hair coat discoloration in 
dogs (occurring after approximately 3 months of dosing in the 9 month study) and 
single cell necrosis in various epithelial tissues (gallbladder, exocrine pancreas, 
stomach, exocrine pancreas, and epididymides) in dogs.  Single cell necrosis was 
minimal except for non−dose-dependent minimal to mild single cell necrosis in the 
pylorus of the stomach at ≥ 2 mg/kg/day in the 9 month study.  After 4 weeks of dosing 
and a 4 week recovery period, reversibility was observed in the gallbladder and exocrine 


 
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7/Protocol GO27878, Version 8 
pancreas, but minimal single cell necrosis was still present in the epididymides and 
prostate (potentially related to the testicular effects) and in the stomach.  Single cell 
necrosis was considered not to be adverse due to its minimal to mild magnitude and 
because no loss of mucosal integrity was observed histopathologically.  The hair coat 
change correlated histopathologically with decreased pigment in hair follicle bulbs, and 
is consistent with the pharmacologic inhibition of Bcl-2 by venetoclax, leading to Bcl-2 
functional loss in hair follicle melanocytes dependent on Bcl-2 for survival 
(Yamamura et al. 1996)  A dedicated physical examination of the skin and extensive 
ophthalmic examinations determined that pigmentation of the skin and in the eye 
(particularly, the iris and fundus) of the dog appeared unaffected.  This was confirmed 
by the absence of associated histopathologic findings in skin (other than in hair follicles) 
and in the eye.  Consequently, white hair coat discoloration was considered non-adverse; 
reversibility has not been assessed. 
Minor effects of venetoclax were:  mild, dose-related, transient post-dose emesis, 
increased salivation, and fecal alterations (unformed or watery feces); minimally 
increased pigment in Kupffer cells and macrophages in the liver and gallbladder, 
respectively; and clinical signs of skin swelling, all in dogs.  With regard to the latter 
finding, dogs at the high dosage of 150 mg/kg/day in the 4 week study had clinical signs 
of swelling of the skin on the ears, head (cranial area), and forepaws and/or hindpaws.  
Most but not all animals (8 of 10 dogs) were affected, and in three dogs the swelling 
reaction was observed after the first dose.  The clinical signs were transient and 
sporadic in occurrence, and were absent during the recovery period.  A mechanistic 
basis for the swelling reactions was not established, but the clinical signs were mild to 
moderate in severity and reversible, and there were no signs of anaphylaxis. 
There was no evidence of in vitro or in vivo genetic toxicity of venetoclax, nor was 
there evidence of phototoxicity. 
Venetoclax was tested in a battery of safety pharmacology assays, and produced no 
effects in the CNS/neurobehavioral or respiratory studies in mice at oral doses up to 
and including the highest oral dose of 600 mg/kg.  No effects on QTc were observed up 
to a maximum plasma concentration of 46 μg/mL in dogs.  In conscious dogs, 
venetoclax did not produce any cardiovascular effects up to and including the highest 
oral dose of 150 mg/kg (maximum concentration observed [Cmax] = 16 μg/mL).  In the 
anesthetized dog at higher plasma concentrations, venetoclax produced mild reductions 
in myocardial contractility (-6% to -13%) and cardiac output (-11% to -19%) at 
plasma concentrations of ≥ 16 μg/mL and ≥ 32 μg/mL, respectively.  These 
concentrations are greater than the plasma concentration of venetoclax in humans 
(average Cmax = 6.09 μg/mL at the 1200 mg/day dose). 


 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
8/Protocol GO27878, Version 8 
SECTION 2.1:  PRIMARY OBJECTIVES 
The primary objectives of the Phase II portion of the study are the following: 
• 
To make a preliminary assessment of efficacy as measured by CR rate at end of 
treatment determined by positron emission tomography and/or computed 
tomography (PET-CT) scans (see Appendix 2) of the combination of venetoclax and 
R-CHOP administered to patients with previously untreated DLBCL 
• 
To make an assessment of efficacy, as measured by CR rates at end of treatment 
determined by PET-CT scans, of the combination of venetoclax and R-CHOP 
administered to patients with previously untreated DLBCL co-expressing both Bcl-2 
and c-Myc proteins (i.e., DPDE-DLBCL) 
 
SECTION 2.2.2:  Secondary Efficacy Objective 
The secondary efficacy objectives of this study include the following: 
• 
To make a preliminary assessment of efficacy when venetoclax and R-CHOP are 
administered in combination to patients with previously untreated DLBCL, as 
measured by: 
OR rate 
CR rate as determined by CT scan 
Response durationDOR 
PFS  
12 month PFS estimate  
 
SECTION 3.1:  DESCRIPTION OF THE STUDY 
After the first 20 patients in the R CHOP arm of the Phase For the Phase II R-CHOP 
arm portion of the study, after the first 20 patients have completed Cycles 1 and 2 of 
study treatment, the Internal Monitoring Committee (IMC) and Scientific Oversight 
Committee (SOC; see Section 3.1.1) will meet to review safety data for all patients 
treated in both the Phase Ib and Phase II portions of the study in order to confirm the 
safety and tolerability of the combination therapy at the venetoclax dose chosen at the 
end of Phase Ib. 
SECTION 3.1.1:  Internal Monitoring Committee and Scientific Oversight 
Committee 
The study will enroll approximately 24−4860 patients during the dose-finding stage and 
approximately 180−200 patients in the Phase II portion at approximately 69 investigative 
sites in North America, the European Union, and Asia Pacific. 
SECTION 3.1.2:  Phase Ib:  Dose-Finding 
Each study arm (R-CHOP in Arm A or G-CHOP in Arm B) will have up to four 
dose-finding cohorts exploring venetoclax doses and dosing schedule ranging from 
200 to 800 mg. with a maximum dosinge administration schedules of a maximum 10 
days per cycle.   


 
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9/Protocol GO27878, Version 8 
SECTION 3.1.2.1:  Cohort Dosing Regimen 
Cycle 1 
• 
Oral dosing of venetoclax will then continue through Day 10 of Cycle 1 and 
Days 1-10 of Cycles 2 through 8.   or alternative dose administration schedules, 
that include oral administration of venetoclax on Days 4−8 in Cycle 1 and Days 
1−5 in Cycles 2−8. 
SECTION 3.1.2.2:  Dose Escalation Guidelines 
Dosing with venetoclax will begin on Day 4 of Cycle 1 (or 3 days after the first CHOP 
dose, see Section 3.1.2.1) and continue to be administered daily through Day 8 
or Day 10 of Cycle 1 and then on Days 1−5 or Days 1−10 for Cycles 2−8 for up to 
eight 21-day cycles of combination therapy with R-CHOP or G-CHOP. 
If the administration of venetoclax results in unacceptable toxicity on Days 4−10 of 
Cycle 1 and Days 1−10 of Cycles 2-8 schedule or other proposed alternative dose 
administration schedules then alternative dose regimens of venetoclax (e.g., venetoclax 
administered on Days 1–3 or 1–7 of 21) or lower doses of venetoclax may be substituted 
in subsequent cohorts. 
SECTION 3.1.3:  Phase II: Expansion 
Because effects of Bcl-2 inhibition may differ depending on both the level of Bcl-2 
expression and the molecular milieu (see Section 1.3), activity of the combination will be 
explored in specific molecular subsets, including Bcl-2 high, Bcl-2 low, 
Bcl-2- overexpression and c-Myc overexpression (DPE), and GCB and ABC subtypes of 
DLBCL. 
Enrollment into the R-CHOP cohort of patients with both Bcl-2 high and Bcl-2 low 
DLBCL will continue until approximately 50 patients with DPDE-DLBCL (approximately 
160−200 patients total; see Section 4.10.6.  Patients with Bcl 2 low/negative and 
c Myc low DLBCL will be included and ABC versus GCB subset analysis will be 
performed, but enrollment numbers will not be gated to these groups.  Enrollment into 
the G CHOP cohort will continue until at least 20 patients have been enrolled.   
Thereafter, patients will be followed in the clinic every 3 months for safety and disease 
assessments for up to 2 years after the last patient is enrolled has completed treatment 
or until death or study termination, whichever occurs first. 
SECTION 3.1.4:  Discontinuation of Venetoclax plus R-CHOP or G-CHOP 
Patients who discontinue venetoclax plus R-CHOP or venetoclax plus G-CHOP for 
reasons other than PD should remain in the study have a documented response 
assessment and continue to be followed until disease progression or even after institution 
of alternative therapy.  Theyse patients should continue with follow-up visits every 
3 months to collect information on disease progression, and /or initiation of an 
alternative lymphoma therapy, and.  After PD, patients will also continue to be followed 
for OS yearly (see Section 4.5.5). 


 
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SECTION 3.2.3:  Rationale for Venetoclax Dose Selection in the Phase II 
Portion of the Study 
On 17 July 2016, Roche/Genentech as the sponsor of Study BO21005 (Goya study), a 
Phase III study that evaluated G CHOP versus R-CHOP in 1L DLBCL, informed 
through a press release that the primary endpoint of investigator-assessed PFS was not 
met.  Given these results, Arm B (venetoclax + G-CHOP) will not be expanded in Phase 
II in patients who are first-line with DLBCL. 
SECTION 3.2.9:  Rationale for Collecting Tumor Biopsies and Peripheral 
Blood for Biomarker Studies 
The following samples will be collected to enable the evaluation of the parameters listed 
above: 
• 
AAn FFPE tumor biopsy sample must be collected at disease progression and sent 
to the central laboratory to evaluate venetoclax resistance mechanisms.  The 
sample must be a tissue block or 20 unstained serial slides. 
 
SECTION 3.4.1.1:  Tumor Lysis Syndrome 
Hospitalization will be required at initial venetoclax dosing for patients who are 
determined to be at high risk of TLS as a result of bulky disease (i.e., any lymphoma 
mass ≥ 10 cm and/or evidence of circulating lymphoma cells).   
SECTION 3.4.2.1.1:  Management of Severe Infusion-Related Reactions 
Patients who require close monitoring during the first and all subsequent infusions 
include patients with preexisting cardiac and pulmonary conditions, patients with prior 
clinically significant cardiopulmonary adverse events, and patients with high numbers of 
circulating malignant cells (≥ 25,000 cells/μL) with or without evidence of high tumor 
burden. 
SECTION 3.4.2.2:  Tumor Lysis Syndrome 
The risks of TLS appear to be greater in patients with high numbers of circulating 
malignant cells (≥ 25,000 cells/μL) or high tumor burden. 
SECTION 4.1.2.3:  All Patients 
Patients must meet the following criteria for study entry: 
• 
At least one bi-dimensionally measurable lymphoma lesion on CT scan defined as 
> 1.5 cm in its longest dimension, which is also FDG avid by screening PET scan. 
• 
Adequate hematologic function (unless caused by underlying disease, as 
established by extensive bone marrow involvement or as a result of hypersplenism 
secondary to the involvement of the spleen by lymphoma per the investigator) 
defined as follows: 
Hemoglobin ≥ 9 g/dL 
Absolute neutrophil countANC ≥ 1.5 × 109/L 
 


 
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SECTION 4.1.3.2:  Patients Enrolled in the Phase II Portion of the Study 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with transformed lymphoma (patients with discordant bone marrow 
involvement(i.e., low grade histology in bone marrow) may be considered after 
discussion with the Medical Monitor) 
 
SECTION 4.1.3.3:  All Patients 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
CNS lymphoma or primary mediastinal DLBCL 
• 
History of other malignancy that could affect compliance with the protocol or 
interpretation of results 
Patients with a malignancy that has been treated with surgery alone with 
curative intent will also be excluded, unless the malignancy has been in 
documented remission without treatment for ≥ 53 years prior to enrollment. 
• 
Received the following agents within 7 days prior to the first dose of venetoclax: 
Steroid therapy for anti-neoplastic intent within 7 days prior to the first dose of 
study drug.Cycle 1 Day 1.  See steroid use guidelines in Section 4.4.1 for 
specific exceptions. 
• 
Any of the following abnormal laboratory values: 
AST or ALT > 2.5 × ULN (unless due to disease involvement; Medical Monitor to 
be consulted prior to enrollment) 
 
SECTION 4.3.1.2:  Dosage, Administration, and Storage 
Each dose of venetoclax will be taken with approximately 240 mL of water within 30 
minutes after the completion of a low fat breakfast or the patient's first meal of the day.  
A meal containing approximately 30% of the total caloric content from fat is 
recommended to ensure adequate absorption of venetoclax.  On days that pre-dose PK 
sampling is required, the patient’s first meal of the day (e.g., breakfast) will be 
consumed in the morning at the clinic, and venetoclax dosing will occur in the 
morningclinic after the completion of a low fat breakfast the meal or the patient's first 
meal of the day at the clinic to facilitate PK sampling.  Examples of a low fat breakfast 
include 2 slices of white toast with 1 tablespoon of low fat margarine and 1 tablespoon of 
jelly and 8 ounces of skim milk (319 calories and 8.2 g fat) or 1 cup of cereal, 8 ounces 
of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 
calories and 2 g fat). 
The recommended breakfast is as follows:   
1 box cereal (30–40 g) 
Skim milk (240 mL) 
1 boiled egg 
1 slice toast (15 g) 


 
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Margarine (10 g)  
 
Total calories should be approximately 520 Kcal; 30% of the total caloric content of the 
meal is from fat. Total grams of fat should be approximately 17 grams. 
SECTION 4.3.3.8:  Management of Infusion Related Reactions and 
Anaphylaxis 
Table 2 
Management of Infusion-Related Symptoms 
Infusion-Related Symptoms a 
Guidance 
Grades 1 and 2 
Slow or withhold infusion. 
Give supportive treatment b. 
Upon symptom resolution, may resume infusion-rate 
escalation. 
Grade 3 
Discontinue infusion. 
Give supportive treatment b. 
Upon symptom resolution, may resume infusion rate 
escalation. 
Note:  If the same adverse event recurs with same severity, 
treatment must be permanently discontinued. 
Grade 4 
Discontinue infusion immediately, treat symptoms aggressively, 
and do not restart drug. 
IV = intravenous. 
a Refer to National Cancer Institute Common Terminology Criteria for Adverse Events, 
(Version 4.0) for the grading of symptoms.  This table does not refer to management of 
IgE-mediated allergic reactions, which should be managed as directed in Section 4.4.1.6. 
b Supportive treatment:  Patients should be treated with acetaminophen and an antihistamine 
such as diphenhydramine hydrochloride if they have not been received in the previous 
4 hours.  IV saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may 
require antihistamines, oxygen, corticosteroids (e.g., 100 mg of IV prednisolone or 
equivalent), and/or bronchodilators.  For hypotension, patients may require vasopressors. 
 
SECTION 4.3.5:  Administration of Granulocyte Colony-Stimulating Factor 
All patients must receive G-CSF as primary prophylaxis for neutropenia starting with 
Cycle 1 and continuing through each additional cycle of studyCHOP therapy received. 
SECTION 4.4.1:  Concomitant Therapy 
Steroid use not otherwise dictated by the protocol CHOP treatment will follow the 
guidelines outlined below: 
• 
Corticosteroid use > 30 mg/day of prednisone or equivalent:  Not allowed within 
7 days prior to first doseCycle 1 Day 1 except as specified below 
 
SECTION 4.4.1.3:  Treatment and Prophylaxis of Neutropenia 
G-CSF should be administered as primary prophylaxis starting with Cycle 1 of therapy 
and continue through each cycle of CHOP therapy received for all patients unless there 
is a medical contraindication or the investigator feels it is not in the patient’s best interest 
to receive G-CSF. 


 
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SECTION 4.4.1.5:  Prophylaxis for Tumor Lysis Syndrome 
TLS is a risk for patients with NHL who are treated with high cell-killing agents.  The risk 
of TLS is a continuum based on multiple factors that include tumor burden and 
comorbidities.  Risk is highest for those with bulky disease, elevated absolute 
lymphocyte count, elevated pretreatment lactate dehydrogenase (LDH) levels, elevated 
leukocyte count, compromised renal function, and dehydration.  Patients All patients 
should undergo tumor burden assessment with bulky disease, defined as any lymph 
node ≥ 8 cm on the screening CT scan, and/or lymphocytosis due to circulating 
lymphoma cells, are considered at higher risk of TLS and must be hospitalized for more 
intensive monitoring during the initial dose, CBC with WBC differential, and blood 
chemistry (potassium, uric acid, phosphorus, calcium, and creatinine).  Pre-existing 
chemistry abnormalities should be corrected prior to initiation of treatment with 
venetoclax.   
SECTION 4.4.1.5.1:  Hospitalization 
Patients exhibiting specific characteristics at higherscreening or initiation of venetoclax 
treatment are considered to be at high risk for development of TLS (and must be 
hospitalized for more intensive prophylaxis and monitored during for the initial dose of 
venetoclax.  These patients are identified by the presence of any of the following:   
• 
Any lymph node ≥ 8mass ≥  10 cm and/or on the screening CT scan 
• 
Circulating lymphoma cells) must be hospitalized for the initial dose of venetoclax.  
defined by oOut-of-range (high) absolute lymphocyte count (ALC) or the presence 
of abnormal cells in the peripheral blood differential signifying circulating 
lymphoma cells 
 
In addition to characteristics requiring mandatory hospitalization, other patient 
characteristics may suggest an increased risk of TLS.  These include but are not limited 
to the following:   
• 
Overall disease burden (e.g., several enlarged lymph nodes, even if none reaching 
10 cm) 
• 
Elevated LDH levels 
• 
Compromised renal function, as evidenced by low CRCL 
• 
Extensive bone marrow involvement 
• 
Dehydration 
 
Hospitalization should also be considered is not mandatory for patients who exhibit 
these characteristics, but these and any other factors that are considered relevant to 
TLS should be considered in the overall assessment of the patient’s state and their risk 
to develop TLS.  Investigators should use their judgment in their assessment of the 
patient’s risk of TLS development and may choose to hospitalize any patient they 
consider to be at risk for the development of TLS during the first dose of venetoclax, 


 
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with creatinine clearance < 80 mL/min, in discussion with the Medical Monitor.approval of 
the Medical Monitor.  
SECTION 4.4.1.8:  Other Concomitant Medications 
G-CSF will be administered as primary prophylaxis in each cycle of CHOP therapy (see 
Section 4.4.1.3).  
SECTION 4.4.2:  Excluded Therapy 
Table 4 
Excluded and Cautionary Medications 
Excluded Medications 
Anti-cancer therapies including chemotherapy, radiotherapy, or other investigational therapy, 
including targeted small molecule agents: 
Excluded 5 half lives28 days prior to first dose and throughout venetoclax 
administration.  
Biologic agents (e.g., monoclonal antibodies) for anti-neoplastic intent: 
Excluded 8 weeks prior to first dose and throughout venetoclax administration 
Grapefruit, grapefruit products, Seville oranges (including marmalade containing 
Seville oranges) or star fruit: 
Excluded 3 days prior to first dose and throughout venetoclax administration 
 
SECTION 4.5.1.4:  Tumor and Response Evaluation 
All measurable disease must be documented at screening by a Diagnostic quality CT 
scan and a combined PET-CT scan with a diagnostic quality CT component. and 
re assessed at each subsequent tumor evaluation.  Response assessments will be 
determined by the investigator on the basis of imaging studies and bone marrow 
examinations (if appropriate), with the use of the modified Lugano Classification 
(Cheson et al. 2014; see Appendix 2).  A five-point scale score is required as part of the 
PET scan response.   
Patients will be evaluated for disease response by PET-CT imaging after Cycle 4 and at 
6 to 8 weeks after Day 1 of Cycle 8 or last cycle received.  A bone marrow examination 
must be repeated only to confirm a CR if it was previously positive, if it was not 
performed, or if it was indeterminate at screening. 
Diagnostic-quality CT scan with use of oral and IV contrast (unless medically 
contraindicated) must be obtained at baseline, after Cycle 4 and at end of treatment 
evaluation (6 to 8 weeks after Day 1 of Cycle 8 or last cycle received).  If PET-CT with 
diagnostic CT is not obtainable, a separate diagnostic CT scan must be performed at 
these two timepoints in addition to the PET scans. 
CT scans (with oral and IV contrast, unless medically contraindicated) will be performed 
every 6 months for 2 years and as clinically indicated during these follow ups.  If a 


 
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patient exhibits clinical signs of possible disease progression (i.e., increased or de novo 
enlargement of liver, spleen or lymph nodes on physical examination), additional 
assessments including PET-CT or contrast-enhanced CT scan and/or bone marrow 
must be performed to evaluate for PD. 
CT scans (with contrast) should include chest, abdomen, and pelvis scans; CT scans of 
the neck should be included if clinically indicated (MRIs may be used instead of CT 
scans in patients for whom CT scans are contraindicated).  CT scans for response 
assessment may be limited to areas of prior involvement only if required by local 
regulatory authorities.  Provision will be made to collect and store the CT scans should a 
radiology review be required in the future. 
Bone marrow examinations should include biopsy and/or aspirate for morphology and 
flow cytometry and are required at screening.  If positive or indeterminate at screening, 
a subsequent bone marrow examination is required only to confirm a CR. 
SECTION 4.5.1.5.1:  Central Laboratory Assessments 
• 
PK assays 
Serum samples will be obtained for measurement of rituximab or 
obinutuzumab concentrations and EDTA-anticoagulated; plasma samples will 
be obtained for measurement of venetoclax or CHOP concentrations at 
timepoints noted in Appendix 3.  The samples  will be sent to the central 
laboratory  and then to a Sponsor designated bioanalytical laboratory or to the 
Sponsor or  designee for analysis.  Relevant biotransformation products of 
study treatment may also be analyzed at the discretion of the Sponsor. 
 
SECTION 4.5.2:  Screening and Pretreatment Assessments 
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within 21 days prior to first dose of study drug may be used (bone marrow 
examination could have been performed up to 3 months prior to Cycle 1 Day 1, if the 
laboratory report is available and if the tumor biopsy sample can be obtained from initial 
diagnosis); such tests do not need to be repeated for screening. 
SECTION 4.5.6:  Follow-Up Assessments 
Patients will be followed for response until disease progression, death, initiation of 
another NHL therapy, or study closure, whichever occurs first.  Study closure will occur 
approximately 2 years after the last patient has been enrolled. 
SECTION 4.5.7:  Survival Follow-Up Assessments 
Survival follow-up information will be collected via telephone calls, patient medical 
records, and/or clinic visits approximately every 6 months until death, lost to follow-up, 
consent withdrawal, or study termination by Roche, whichever occurs first.  All 
patients will be followed for survival and new anti-lymphoma therapy information 
unless the patient requests to be withdrawn from follow-up (this request must be 


 
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documented in the source documents and signed by the investigator), is lost to follow-
up, dies, or the study is terminated by the Sponsor, whichever occurs first.  If the 
patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status only if permitted per 
local regulations. 
Study closure will occur approximately 2 years after the last patient has completed 
treatment. 
SECTION 4.8:  POST-STUDY ACCESS TO VENETOCLAX, 
OBINUTUZUMAB, AND RITUXIMAB 
Continued access to venetoclax, CHOP, rituximab, and/or obinutuzumab is not 
guaranteed after the end of the study.  After the patient’s participation in the study ends, 
the patient or the patient’s health plan will need to pay for medicines and clinic, hospital, 
and doctors’ services that are part of the patient’s regular medical care. 
The Sponsor will offer post-study access to the study drug (venetoclax, obinutuzumab, 
and rituximab) free of charge to eligible patients in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after completing the study if any of 
the following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for NHL/DLBCL 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for NHL/DLBCL  
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 


 
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SECTION 4.10.4.1:  Tumor Assessment Data 
ITT population andAll patients in the extension cohort who receive any amount of 
venetoclax or R-CHOP/G-CHOP will be included in the activity analysis. 
SECTION 4.10.4.2:  Interim Analyses 
An extension of the predictive probability design (Lee and Liu 2008) will be used to guide 
stopping by comparing CR rates in the venetoclax + R-CHOP arm with historical controls 
using R-CHOP.   
SECTION 4.10.6:  Determination of Sample Size 
The sample size of 20 for the G CHOP + venetoclax Arm in the Phase II portion is 
expected to be sufficient to obtain a preliminary estimate of the percentage of patients 
with compromised chemotherapy dose intensity. 
SECTION 5.1:  SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events including 
serious adverse events, selected adverse events upon emerging data, and adverse 
events of special interest, measurement of protocol-specified safety laboratory 
assessments, measurement of protocol-specified vital signs, and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study. 
SECTION 5.1.2:  Serious Adverse Event (Immediately Reportable to the 
Sponsor) 
“Serious” is a regulatory definition and is based on patient or event outcome or action 
criteria usually associated with events that pose a threat to a patient’s life or vital 
functions.  Seriousness (not severity) serves as the guide for defining regulatory 
reporting obligations. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately via the Adverse Event eCRF (i.e., no more than 24 hours after learning of 
the event; see Section 5.3.2 for reporting instructions). 
SECTION 5.1.3:  Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately via the Adverse Event eCRF (i.e., no more than 24 hours after 
learning of the event; see Section 5.3.2 for reporting instructions).   
SECTION 5.2.1:  Adverse Event Reporting Period 
After this period, the investigator should report any deaths, serious adverse events or 
adverse events of special interest that are believed to be related to prior study drug 
treatment (see Section 5.5). 




 
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investigators (see "Protocol Administrative and Contact Information & List of 
Investigators").   
SECTION 5.5:  POST-STUDY ADVERSE EVENTS 
At the time of study treatment completion or study treatment discontinuation, the 
investigator should instruct each patient to report to the investigator any subsequent 
adverse events that the patient’s personal physician believes could be related to prior 
study drug treatment or study procedures.   
The investigator should report these events directly to Roche Safety Risk Management 
via telephone or via fax machine or scanned and emailed with the use the Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form and fax cover sheet 
(see "Protocol Administrative and Contact Information & List of Investigators"). 
SECTION 5.6:  EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
Certain adverse events (e.g., known consequences of the underlying disease or 
common co morbidities in the study population) are anticipated to occur in the study 
population at some frequency independent of drug exposure and will be excluded from 
expedited reporting.  A list of such anticipated events will be provided to drug safety 
operations and to health authorities upon request.   
Although exempted from expedited reporting to certain health authorities and IRBs/ECs 
as individual cases, these Serious Adverse Events must be reported to the Sponsors 
within 24 hours of the site being made aware of the serious adverse event as defined in 
Section 5.3.2. 
REFERENCES 
Three references were added and one deleted to support added or modified text in the 
amendment. 
APPENDIX 1:  Schedule of Assessments 
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
APPENDIX 2:  The Modified Lugano Classification:  Revised Criteria for 
Response Assessment 
The Lugano Classification described by Cheson (2014), is presented in the Revised 
Criteria for Response Assessment table with the following modifications:  (1) For 
complete response (CR), if the bone marrow was involved by lymphoma or 
indeterminate prior to treatment, the infiltrate must have cleared on repeat bone marrow 
biopsy; (2) For PET-CT-based partial response (PR), CT criteria for PR (or CR) must 
also be met. 
The table in Appendix 2 was updated to reflect these modifications. 


 
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APPENDIX 3:  Pharmacokinetic Samples 
The word “blood” was added to each of the table titles: 
Table 1 
Pharmacokinetic Blood Sampling for Venetoclax + R-CHOP 
(ARM A) in Phase I 
Table 2 
Pharmacokinetic Blood Sampling for Venetoclax + G-CHOP (Arm 
B) in Phase I 
Table 3 
Pharmacokinetic Blood Sampling in Phase II for Approximately 
the First 20 Patients in Arm A  
Table 4 
Pharmacokinetic Blood Sampling in Remaining Phase II Patients 
Footnote C was modified: 
Note that the window for the participating sites must be adjusted to -2 + 1 day (rather 
than ± 2 days) for this visit in order to get an appropriate pre dose PK sample. 
APPENDIX 7:  International Prognostic Index and Ann Arbor Staging 
Classification 
Appendix 7 was added.  
International Prognostic Index 
The International Prognostic Index for aggressive non-Hodgkin’s lymphoma identifies 
five significant risk factors that are prognostic of overall survival (OS): 
Risk Factors 
Ann-Arbor Stage III or IV 
Age > 60 years 
Elevated LDH 
ECOG performance status ≥ 2 
Extranodal involvement≥ 2 
IPI Risk Group 
Number of IPI Risk Factors 
Low 
0 or 1 
Low-intermediate 
2 
High-intermediate 
3 
High 
4 or 5 
ECOG = Eastern Cooperative Oncology Group; IPI = International Prognostic Index. 
 


 
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Ann Arbor Staging Classification for Hodgkin and Non-Hodgkin’s 
Lymphoma 
Stage I 
Involvement of a single lymph node region (I) or of a single extralymphatic 
organ or site (IE) a 
Stage II 
Involvement of two or more lymph node regions or lymphatic structures on the 
same side of the diaphragm alone (II) or with involvement of limited, contiguous 
extralymphatic organ or tissue (IIE) 
Stage III 
Involvement of lymph node regions on both sides of the diaphragm (III) which 
may include the spleen (IIIS) or limited, contiguous extralymphatic organ or site 
(IIIE), or both (IIIES) 
Stage IV 
Diffuse or disseminated foci of involvement of one or more extralymphatic organs 
or tissues, with or without associated lymphatic involvement 
a The designation “E” generally refers to extranodal contiguous extension (i.e., proximal 
or contiguous extranodal disease) that can be encompassed within an irradiation field 
appropriate for nodal disease of the same anatomic extent.  A single extralymphatic site as 
the only site of disease should be classified as IE, rather than Stage IV. 
 
All cases are subclassified to indicate the absence (A) or presence (B) of the 
systemic (“B”) symptoms of significant unexplained fever (> 38˚C), night sweats, or 
unexplained weight loss exceeding 10% of body weight during the 6 months prior to 
diagnosis.   
Clinical stage refers to the extent of disease determined by diagnostic tests following a 
single diagnostic biopsy.  If a second biopsy of any kind is obtained, even if negative, 
the term pathologic stage is used. 
Adapted from: 
1. 
Carbone PP, Kaplan HS, Musshoff K, et al. Report of the committee on Hodgkin’s 
disease staging classification. Cancer Res 1971;31:1860–1. 
2. 
Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to 
discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds 
meeting. J Clin Oncol 1989;7:1630–6. 
 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol. 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 31 
PROTOCOL SYNOPSIS .................................................................................... 32 
1. 
BACKGROUND .......................................................................................... 46 
1.1 
Background on Disease......................................................... 46 
1.1.1 
Indolent Non-Hodgkin’s Lymphoma....................................... 46 
1.1.2 
Diffuse Large B-Cell Lymphoma............................................ 46 
1.2 
Background on the Molecules ............................................... 48 
1.2.1 
Bcl-2 Protein Family .............................................................. 48 
1.2.2 
Venetoclax............................................................................. 48 
1.2.2.1 
Venetoclax Nonclinical Activity and 
Pharmacokinetic Profile......................................................... 48 
1.2.2.2 
Venetoclax Nonclinical Toxicology ........................................ 49 
1.2.2.3 
Venetoclax Clinical Experience ............................................. 52 
1.2.2.4 
Clinical Pharmacokinetics and 
Pharmacodynamics ............................................................... 54 
1.2.3 
Obinutuzumab ....................................................................... 55 
1.2.3.1 
Obinutuzumab Mechanism of Action ..................................... 55 
1.2.3.2 
Obinutuzumab Nonclinical Toxicology................................... 55 
1.2.3.3 
Obinutuzumab Nonclinical Efficacy ....................................... 56 
1.2.3.4 
Obinutuzumab Clinical Experience........................................ 57 
1.2.3.5 
Obinutuzumab Pharmacokinetics and 
Pharmacodynamics ............................................................... 58 
1.3 
Study Rationale ..................................................................... 58 
2. 
OBJECTIVES.............................................................................................. 59 
2.1 
Primary Objectives ................................................................ 59 
2.2 
Secondary Objectives............................................................ 60 
2.2.1 
Pharmacokinetic Objectives .................................................. 60 
2.2.2 
Secondary Efficacy Objectives .............................................. 60 
2.2.3 
Exploratory Objectives........................................................... 61 
3. 
STUDY DESIGN ......................................................................................... 61 
3.1 
Description of the Study......................................................... 61 


 
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3.1.1 
Internal Monitoring Committee and Scientific 
Oversight Committee............................................................. 62 
3.1.2 
Phase Ib: Dose-Finding ......................................................... 64 
3.1.2.1 
Cohort Dosing Regimen ........................................................ 64 
3.1.2.2 
Dose-Escalation Guidelines................................................... 65 
3.1.2.3 
Dose-Escalation Rules and Determination of 
Dose-Limiting Toxicity............................................................ 66 
3.1.2.4 
Definition of Dose-Limiting Toxicity........................................ 67 
3.1.3 
Phase II: Expansion............................................................... 68 
3.1.4 
Discontinuation of Venetoclax Plus R-CHOP or 
G-CHOP ................................................................................ 69 
3.2 
Rationale for Study Design.................................................... 70 
3.2.1 
Benefit/Risk Assessment....................................................... 70 
3.2.2 
Rationale for Venetoclax Dose Selection in the 
Phase I Portion of the Study.................................................. 71 
3.2.3 
Rationale for Venetoclax Dose Selection in the 
Phase II Portion of the Study................................................. 72 
3.2.4 
Rationale for R-CHOP Dosing............................................... 73 
3.2.5 
Rationale for G-CHOP Dosing............................................... 73 
3.2.6 
Rationale for Dosing Schedule .............................................. 74 
3.2.7 
Rationale for Treatment of Patients with 
Previously Untreated DLBCL................................................. 75 
3.2.8 
Rationale for Pharmacokinetic Assessments......................... 75 
3.2.9 
Rationale for Collecting Tumor Biopsies and 
Peripheral Blood for Biomarker Studies................................. 76 
3.3 
Outcome Measures ............................................................... 77 
3.3.1 
Safety Outcome Measures .................................................... 77 
3.3.2 
Pharmacokinetic Outcome Measures.................................... 78 
3.3.3 
Efficacy Outcome Measures.................................................. 78 
3.3.4 
Exploratory Assessments ...................................................... 79 
3.4 
Safety Plan ............................................................................ 79 
3.4.1 
Risks Associated with Venetoclax and Their 
Management.......................................................................... 80 
3.4.1.1 
Tumor Lysis Syndrome.......................................................... 80 
3.4.1.2 
Cytopenias............................................................................. 80 


 
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3.4.1.3 
Infections ............................................................................... 80 
3.4.1.4 
Decreased Spermatogenesis ................................................ 81 
3.4.1.5 
Drug-Drug Interaction ............................................................ 81 
3.4.2 
Risks Associated with Rituximab Therapy and 
Their Management ................................................................ 81 
3.4.2.1 
Infusion-Related Reactions.................................................... 81 
3.4.2.2 
Tumor Lysis Syndrome.......................................................... 82 
3.4.2.3 
Hepatitis B Reactivation with Related Fulminant 
Hepatitis and Other Viral Infections ....................................... 82 
3.4.2.4 
Cardiovascular Events........................................................... 83 
3.4.2.5 
Bowel Obstruction and Perforation........................................ 83 
3.4.2.6 
Immunization ......................................................................... 84 
3.4.3 
Risks Associated with Obinutuzumab Therapy...................... 84 
3.4.3.1 
Infusion-Related Reactions and Hypersensitivity 
Reactions (Including Anaphylaxis)......................................... 84 
3.4.3.2 
Tumor Lysis Syndrome.......................................................... 85 
3.4.3.3 
Thrombocytopenia and Neutropenia ..................................... 85 
3.4.3.4 
Anti-Therapeutic Antibody ..................................................... 85 
3.4.3.5 
Infection................................................................................. 86 
3.4.3.6 
Gastrointestinal Perforation ................................................... 86 
3.4.4 
Risks Associated with CHOP Chemotherapy ........................ 86 
3.4.5 
Risks Associated with the Combination of 
Venetoclax plus R-CHOP or G-CHOP................................... 86 
3.5 
Ethical Considerations........................................................... 87 
3.6 
Administrative Structure......................................................... 88 
3.7 
Independent Review Committee............................................ 88 
3.8 
Compliance with Laws and Regulations ................................ 88 
4. 
MATERIALS AND METHODS .................................................................... 89 
4.1 
Patients.................................................................................. 89 
4.1.1 
Patient Selection.................................................................... 89 
4.1.2 
Inclusion Criteria.................................................................... 89 
4.1.2.1 
Patients Enrolled in the Dose-Finding Portion of 
the Study ............................................................................... 89 


 
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4.1.2.2 
Patients Enrolled in the Phase II Portion of the 
Study ..................................................................................... 89 
4.1.2.3 
All Patients............................................................................. 89 
4.1.3 
Exclusion Criteria................................................................... 90 
4.1.3.1 
Patients Enrolled in the Dose-Finding Portion of 
the Study ............................................................................... 90 
4.1.3.2 
Patients Enrolled in the Phase II Portion of the 
Study ..................................................................................... 90 
4.1.3.3 
All Patients............................................................................. 90 
4.1.4 
Criteria for Tumor Biopsy Tissue ........................................... 92 
4.2 
Method of Treatment Assignment.......................................... 93 
4.3 
Study Treatment.................................................................... 94 
4.3.1 
Venetoclax............................................................................. 94 
4.3.1.1 
Formulation............................................................................ 94 
4.3.1.2 
Dosage, Administration, and Storage .................................... 94 
4.3.1.3 
Dosage Delays and Modification ........................................... 95 
4.3.2 
Rituximab............................................................................... 95 
4.3.2.1 
Formulation............................................................................ 95 
4.3.2.2 
Dosage, Administration, and Storage .................................... 95 
4.3.2.3 
Dosage Modification .............................................................. 96 
4.3.3 
Obinutuzumab ....................................................................... 97 
4.3.3.1 
Formulation............................................................................ 97 
4.3.3.2 
Handling and Storage............................................................ 97 
4.3.3.3 
Obinutuzumab Dose and Schedule ....................................... 97 
4.3.3.4 
Obinutuzumab Preparation.................................................... 97 
4.3.3.5 
Obinutuzumab Administration................................................ 98 
4.3.3.6 
Premedication........................................................................ 99 
4.3.3.7 
Management of Tumor Lysis Syndrome.............................. 100 
4.3.3.8 
Management of Infusion-Related Reactions and 
Anaphylaxis ......................................................................... 100 
4.3.3.9 
Cardiac or Pulmonary Events.............................................. 101 
4.3.3.10 
Dosage Modification or Delay.............................................. 101 
4.3.4 
CHOP Chemotherapy.......................................................... 101 
4.3.4.1 
Dosage and Administration.................................................. 101 


 
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4.3.4.2 
Dosage Modification or Delay.............................................. 102 
4.3.5 
Administration of Granulocyte Colony-Stimulating 
Factor .................................................................................. 102 
4.3.6 
Dosage Delays and Modifications ....................................... 102 
4.3.6.1 
Dosage Delays and Modifications: Venetoclax, 
Rituximab, Obinutuzumab, and CHOP 
Chemotherapy..................................................................... 102 
4.3.7 
Permanent Treatment Discontinuation Criteria.................... 109 
4.3.7.1 
Permanent Treatment Discontinuation Criteria for 
Venetoclax........................................................................... 109 
4.3.7.2 
Permanent Treatment Discontinuation Criteria for 
Rituximab or Obinutuzumab ................................................ 109 
4.3.7.3 
R-CHOP or G-CHOP Chemotherapy................................... 109 
4.4 
Concomitant and Excluded Therapies................................. 109 
4.4.1 
Concomitant Therapy .......................................................... 109 
4.4.1.1 
CNS Prophylaxis ................................................................. 110 
4.4.1.2 
Prophylaxis for Hemorrhagic Cystitis................................... 110 
4.4.1.3 
Treatment and Prophylaxis of Neutropenia ......................... 110 
4.4.1.4 
Premedication before Rituximab or 
Obinutuzumab Therapy ....................................................... 111 
4.4.1.5 
Prophylaxis for Tumor Lysis Syndrome ............................... 111 
4.4.1.6 
Infection Prophylaxis ........................................................... 113 
4.4.1.7 
Monitoring and Treatment for Hepatitis B 
Reactivation......................................................................... 113 
4.4.1.8 
Other Concomitant Medications .......................................... 114 
4.4.2 
Excluded Therapy................................................................ 115 
4.5 
Study Assessments ............................................................. 117 
4.5.1 
Definitions of Study Assessments ....................................... 117 
4.5.1.1 
Medical History and Demographics..................................... 117 
4.5.1.2 
Vital Signs............................................................................ 117 
4.5.1.3 
Physical Examination .......................................................... 117 
4.5.1.4 
Tumor and Response Evaluation ........................................ 117 
4.5.1.5 
Laboratory Assessments ..................................................... 118 
4.5.1.6 
Electrocardiogram ............................................................... 119 
4.5.1.7 
MUGA/Echocardiogram....................................................... 119 


 
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4.5.2 
Screening and Pretreatment Assessments.......................... 119 
4.5.3 
Roche Clinical Repository.................................................... 120 
4.5.3.1 
Overview of the Roche Clinical Repository.......................... 120 
4.5.3.2 
Approval by the Institutional Review Board or 
Ethics Committee ................................................................ 120 
4.5.3.3 
Sample Collection................................................................ 121 
4.5.3.4 
Confidentiality...................................................................... 121 
4.5.3.5 
Consent to Participate in the Roche Clinical 
Repository ........................................................................... 122 
4.5.3.6 
Withdrawal from the Roche Clinical Repository................... 122 
4.5.3.7 
Monitoring and Oversight..................................................... 122 
4.5.4 
Assessments during Treatment........................................... 123 
4.5.5 
End of Treatment Visit ......................................................... 123 
4.5.6 
Follow-Up Assessments ...................................................... 123 
4.5.7 
Survival Follow-Up Assessments ........................................ 123 
4.6 
Patient Discontinuation........................................................ 124 
4.7 
Study Discontinuation.......................................................... 124 
4.8 
Post-Study Access to Venetoclax, Obinutuzumab, 
and Rituximab...................................................................... 124 
4.9 
Assay Methods.................................................................... 125 
4.10 
Statistical Methods .............................................................. 125 
4.10.1 
Analysis of the Conduct of the Study................................... 126 
4.10.2 
Safety Analyses................................................................... 126 
4.10.3 
Pharmacokinetic and Pharmacodynamic 
Analyses.............................................................................. 126 
4.10.4 
Activity Analyses.................................................................. 127 
4.10.4.1 
Tumor Assessment Data ..................................................... 127 
4.10.4.2 
Interim Analyses .................................................................. 127 
4.10.4.3 
Predictive Diagnostics ......................................................... 128 
4.10.5 
Exploratory Analyses........................................................... 128 
4.10.6 
Determination of Sample Size ............................................. 128 
4.11 
Data Quality Assurance....................................................... 129 
5. 
ASSESSMENT OF SAFETY..................................................................... 129 
5.1 
Safety Parameters and Definitions ...................................... 129 


 
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5.1.1 
Adverse Event ..................................................................... 130 
5.1.2 
Serious Adverse Event (Immediately Reportable 
to the Sponsor).................................................................... 130 
5.1.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 131 
5.2 
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 131 
5.2.1 
Adverse Event Reporting Period ......................................... 132 
5.2.2 
Eliciting Adverse Events ...................................................... 132 
5.2.3 
Assessment of Severity of Adverse Events ......................... 132 
5.2.4 
Assessment of Causality of Adverse Events ....................... 133 
5.2.5 
Procedures for Recording Adverse Events.......................... 134 
5.2.5.1 
Infusion-Related Reactions.................................................. 134 
5.2.5.2 
Diagnosis versus Signs and Symptoms............................... 134 
5.2.5.3 
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 135 
5.2.5.4 
Persistent or Recurrent Adverse Events.............................. 135 
5.2.5.5 
Abnormal Laboratory Values ............................................... 136 
5.2.5.6 
Abnormal Vital Sign Values ................................................. 136 
5.2.5.7 
Abnormal Liver Function Tests............................................ 137 
5.2.5.8 
Deaths ................................................................................. 137 
5.2.5.9 
Preexisting Medical Conditions............................................ 138 
5.2.5.10 
Lack of Efficacy or Worsening of Lymphoma....................... 138 
5.2.5.11 
Hospitalization or Prolonged Hospitalization........................ 138 
5.2.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 139 
5.3 
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 139 
5.3.1 
Emergency Medical Contacts.............................................. 140 
5.3.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 140 
5.3.2.1 
Events Occurring prior to Initiation of Study Drug................ 140 
5.3.2.2 
Events Occurring after Initiation of Study Drug.................... 140 
5.3.3 
Reporting Requirements for Pregnancies............................ 141 
5.3.3.1 
Pregnancies in Female Patients.......................................... 141 


 
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5.3.3.2 
Pregnancies in Female Partners of Male Patients............... 142 
5.3.3.3 
Abortions ............................................................................. 142 
5.3.3.4 
Congenital Anomalies/Birth Defects .................................... 142 
5.4 
Follow-Up of Patients after Adverse Events ........................ 142 
5.4.1 
Investigator Follow-Up......................................................... 142 
5.4.2 
Sponsor Follow-Up .............................................................. 143 
5.5 
Post-Study Adverse Events................................................. 143 
5.6 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 143 
6. 
INVESTIGATOR REQUIREMENTS.......................................................... 144 
6.1 
Study Initiation..................................................................... 144 
6.2 
Study Completion ................................................................ 145 
6.3 
Informed Consent Form....................................................... 145 
6.3.1 
Optional Research Informed Consent ................................. 146 
6.4 
Communication with the Institutional Review 
Board or Ethics Committee.................................................. 146 
6.5 
Study Monitoring Requirements .......................................... 147 
6.6 
Electronic Case Report Forms............................................. 147 
6.7 
Source Data Documentation................................................ 147 
6.8 
Use of Computerized Systems ............................................ 148 
6.9 
Study Medication Accountability.......................................... 148 
6.10 
Disclosure of Data ............................................................... 149 
6.11 
Retention of Records........................................................... 149 
7. 
REFERENCES ......................................................................................... 150 
 
 
LIST OF TABLES 
Table 1 
Administration of First and Subsequent Infusions 
of Obinutuzumab......................................................................... 99 
Table 2 
Management of Infusion-Related Symptoms ............................ 101 
Table 3 
Guidelines for Dose Delay or Modification of Venetoclax, 
Rituximab, or Obinutuzumab and CHOP Chemotherapy.......... 104 
Table 4 
Excluded and Cautionary Medications...................................... 116 


 
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Table 5 
95% Confidence Intervals for Expected Observed Rates for 
Sample Sizes............................................................................ 129 
Table 6 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 133 
Table 7 
Causal Attribution Guidance ..................................................... 134 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema............................................................................. 63 
Figure 2 
Venetoclax Dose-Finding Cohorts .............................................. 66 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 154 
Appendix 2 
The Modified Lugano Classification:  Revised Criteria for 
Response Assessment ............................................................. 159 
Appendix 3 
Pharmacokinetic Samples......................................................... 164 
Appendix 4 
Anaphylaxis Management......................................................... 167 
Appendix 5 
Sample List of Excluded and Cautionary Medications .............. 168 
Appendix 6 
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome in the 
Setting of Treatment with Venetoclax ....................................... 169 
Appendix 7 
International Prognostic Index and Ann Arbor Staging 
Classification............................................................................. 173 


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
31/Protocol GO27878, Version 8 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IB/II, OPEN-LABEL STUDY EVALUATING 
THE SAFETY AND PHARMACOKINETICS OF 
GDC-0199 (ABT-199) IN COMBINATION WITH 
RITUXIMAB (R) OR OBINUTUZUMAB (G) PLUS 
CYCLOPHOSPHAMIDE, DOXORUBICIN, 
VINCRISTINE, AND PREDNISONE (CHOP) IN 
PATIENTS WITH B-CELL NON-HODGKIN’S 
LYMPHOMA (NHL) AND DLBCL 
PROTOCOL NUMBER: GO27878 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2013-003749-40 
IND NUMBER: 
115045 
TEST PRODUCTS: 
Venetoclax (GDC-0199, ABT-199; RO5537382) 
Obinutuzumab (GA101; RO5072759) 
MEDICAL MONITOR: 
, M.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. 
 


Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
32/Protocol GO27878, Version 8 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IB/II, OPEN-LABEL STUDY EVALUATING 
THE SAFETY AND PHARMACOKINETICS OF 
GDC-0199 (ABT-199) IN COMBINATION WITH 
RITUXIMAB (R) OR OBINUTUZUMAB (G) PLUS 
CYCLOPHOSPHAMIDE, DOXORUBICIN, 
VINCRISTINE, AND PREDNISONE (CHOP) IN 
PATIENTS WITH B-CELL NON-HODGKIN’S 
LYMPHOMA (NHL) AND DLBCL 
PROTOCOL NUMBER: 
GO27878 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2013-003749-40 
IND NUMBER: 
115045 
TEST PRODUCTS: 
Venetoclax (GDC-0199, ABT-199) 
Obinutuzumab (GA101; RO5072759) 
PHASE: 
Ib/II 
INDICATION: 
B-cell non-Hodgkin’s lymphoma 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Primary Efficacy Objectives 
The primary objective of the Phase I portion of the study is the following: 
• 
To estimate the maximum tolerated dosing schedule for venetoclax given in combination 
with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or 
obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP) to 
patients with B-cell non-Hodgkin’s lymphoma (NHL), either previously untreated or 
relapsed/refractory after a maximum of one prior therapy 
 
The primary objectives of the Phase II portion of the study are the following: 
• 
To assess the safety and tolerability of the combination of venetoclax and R-CHOP or 
G-CHOP administered to patients with previously untreated diffuse large B-cell lymphoma 
(DLBCL) 
• 
To make a preliminary assessment of efficacy as measured by complete response (CR) 
rate at end of treatment determined by positron emission tomography and/or computed 
tomography (PET-CT) scans of the combination of venetoclax and R-CHOP administered to 
patients with previously untreated DLBCL 
• 
To make an assessment of efficacy, as measured by CR rates at end of treatment 
determined by PET-CT scans, of the combination of venetoclax and R-CHOP administered 
to patients with previously untreated DLBCL co-expressing both Bcl-2 and c-Myc proteins 
(i.e., double expressor (DE)-DLBCL) 
 


 
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Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives of this study are the following: 
• 
To characterize the pharmacokinetics of venetoclax and relevant metabolites when 
administered in combination with R-CHOP or G-CHOP in the relapsed/refractory or 
previously untreated setting in NHL 
• 
To characterize the pharmacokinetics of rituximab, obinutuzumab, and prednisone when 
administered in combination with venetoclax in patients with relapsed/refractory or 
previously untreated B-cell NHL 
• 
To confirm exposure to cyclophosphamide, doxorubicin, and vincristine when given in 
combination with rituximab, obinutuzumab, and/or venetoclax 
 
Secondary Efficacy Objectives 
The secondary efficacy objectives of this study include the following: 
• 
To make a preliminary assessment of efficacy when venetoclax and R-CHOP are 
administered in combination to patients with previously untreated DLBCL, as measured by: 
 
Objective response (OR) rate 
 
CR rate as determined by CT scan 
 
Duration of response (DOR) 
 
Progression-free survival (PFS)  
• 
12 month PFS estimate  
• 
Overall survival (OS) 
• 
To make a preliminary assessment of efficacy when venetoclax and G-CHOP are 
administered in combination, as measured by OR rate, CR rate, and PFS. 
 
Exploratory Objectives 
The exploratory objectives of this study are the following: 
• 
To make a preliminary assessment of potential biomarkers that might predict disease 
response or resistance to treatment with the venetoclax plus R-CHOP or G-CHOP 
combinations in the relapsed or previously untreated setting: 
Bcl-2 and Bcl-2 family protein expression, including Bcl-xl and Mcl-1, by 
immunohistochemistry (IHC) 
BCL2 and c-MYC copy number gain by fluorescence in situ hybridization (FISH) and 
translocation t(14;18) by FISH 
Expression of transcripts for Bcl-2 family members, other apoptotic genes, and genes 
associated with ABC or GCB subtypes of DLBCL 
Subgroups relevant to DLBCL biology that are defined genetically or by poor prognosis, 
including CD79b, Myd88, CARD11, TNFAIP3, epigenetic markers, and MYC 
translocation 
• 
To make a preliminary assessment of the efficacy of venetoclax and R-CHOP in different 
potential prognostic subgroups, including DLBCL genotypic subtypes (e.g., ABC; GCB), 
high Bcl-2 (Bcl-2-positive) expression, as well as patients displaying BCL2 and MYC 
translocations (Double Hit) 
• 
To make a preliminary assessment of minimal residual disease (MRD) as a prognostic 
marker in DLBCL 
• 
To evaluate the prognostic significance of interim PET assessment in this setting 
 
Study Design 
Description of Study 
This is a Phase Ib/II, multicenter, open-label, dose-finding study of venetoclax administered 
orally in combination with rituximab or obinutuzumab and standard doses of CHOP in patients 


 
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with NHL.  The study will consist of two stages:  a dose-finding Phase Ib stage and a Phase II 
expansion stage.  In the Phase I portion of the study, two parallel treatment arms will explore 
doses of venetoclax ranging from 200 to 800 mg administered in combination with R-CHOP and 
G-CHOP.  Patients will be treated for a total of eight cycles (six cycles of CHOP and eight 
cycles of venetoclax + rituximab or venetoclax + obinutuzumab).  Each cycle will consist 
of 21 days.  Patients who experience ongoing response without excessive toxicity may receive 
up to eight cycles of CHOP following discussion between the investigator and the Medical 
Monitor.  The maximum tolerated dose (MTD) of venetoclax in combination with R-CHOP and 
G-CHOP will be determined separately for each arm during the dose-finding stage.   
The dose and dose schedule for venetoclax for each arm determined in Phase I will be used in 
the Phase II expansion stage for that arm. 
For the Phase II portion of the study, the venetoclax dose for Arm A is 800 mg on a 
non-continuous dosing schedule of Cycle 1 Days 4−10 and Cycles 2−8 Days 1−10, as 
determined by the Phase Ib portion of the study based on safety and tolerability observed in 
patients treated in the dose escalation portion of the study.   
If there are concerns about the tolerability of the Phase II dose at any time during the Phase II 
study, a lower dose or an alternative dosing schedule for venetoclax + R-CHOP or G-CHOP 
may be explored on a case by case basis based on the guideline.  
For the Phase II R-CHOP arm of the study, after the first 20 patients have completed Cycles 1 
and 2 of study treatment, the Internal Monitoring Committee (IMC) and Scientific Oversight 
Committee (SOC) will meet to review safety data for all patients treated in both the Phase Ib 
and Phase II portions of the study in order to confirm the safety and tolerability of the 
combination therapy at the venetoclax dose chosen at the end of Phase Ib.  Enrollment will 
continue while the interim safety analysis is being conducted.   
On the basis of this review, changes may be made to the dose or the dosing schedule of the 
Phase II.  
Number of Patients 
The study will enroll approximately 24−60 patients during the dose-finding stage and 
approximately 180−200 patients in the Phase II portion at approximately 69 investigative sites in 
North America, the European Union, and Asia Pacific. 
Target Population:  Inclusions Criteria 
Patients must meet the following criteria for study entry: 
Patients enrolled in the Dose Finding Portion of the Study: 
• 
Patients must have histologically confirmed B-cell NHL (and have never received previous 
R-CHOP treatment), except mantle cell lymphoma (MCL) or small lymphocytic lymphoma 
(SLL), in order to enroll in this portion of the study 
• 
Any relapsed/refractory patients that are enrolled during the dose escalation should have 
received only a single previous treatment regimen 
 
Patients Enrolled in the Phase II Portion of the Study: 
• 
Patients must have previously untreated CD20-positive DLBCL and International Prognostic 
Index (IPI) score must be 2−5 in order to enroll in this portion of the study. 
 
All Patients 
• 
Signed informed consent form(s) 
• 
At least one bi-dimensionally measurable lymphoma lesion on CT scan defined as > 1.5 cm 
in its longest dimension, which is also 18F-fleurodeoxyglucose (FDG) avid by screening 
PET scan. 
• 
Ability and willingness to comply with the study protocol procedures 
• 
Age ≥ 18 years 
• 
Confirmed availability of archival or freshly biopsied tumor tissue meeting protocol defined 
specifications prior to study enrollment 


 
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• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 
• 
Adequate hematologic function (unless because of underlying disease, as established by 
extensive bone marrow involvement or as a result of hypersplenism secondary to the 
involvement of the spleen by lymphoma per the investigator) defined as follows: 
 
Hemoglobin ≥ 9 g/dL 
 
ANC ≥ 1.5 × 109/L 
 
Platelet count ≥ 75 × 109/L 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy−induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use single or combined non-hormonal contraceptive methods that result in a failure rate of 
< 1% per year during the treatment period and for at least 12 months after the last dose of 
rituximab or 18 months after the last dose of obinutuzumab 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception 
• 
Non-vasectomized male patients must practice at least one of the following methods of birth 
control throughout the duration of study participation and for at least 12 months after 
completing therapy with rituximab or 18 months after completing therapy with obinutuzumab: 
A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is 
taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at 
least 3 months prior to study drug administration 
Total abstinence from sexual intercourse; double-barrier method (condom + diaphragm 
or cervical cup with spermicidal, contraceptive sponge, jellies, or cream) 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• 
Males must agree to abstain from sperm donation for at least 12 months after the last dose 
of rituximab or 18 months after the last obinutuzumab dose. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Patients enrolled in the Dose-Finding Portion of the Study 
• 
Patients with MCL or SLL histology will be excluded from study entry 
 
Patients Enrolled in the Phase II Portion of the Study 
• 
Patients with transformed lymphoma (patients with discordant bone marrow 
involvement(i.e., low grade histology in bone marrow) may be considered after discussion 
with the Medical Monitor) 
• 
Prior therapy for NHL 
 
All Patients 
• 
History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies or known sensitivity or allergy to murine products 
• 
Contraindication to receive any of the individual components of CHOP, rituximab or 
obinutuzumab 
• 
Prior anthracycline therapy 
• 
Ongoing corticosteroid use > 30 mg/day of prednisone or equivalent.  Patients who received 
corticosteroid treatment with ≤ 30 mg/day of prednisone or equivalent must be documented 
to be on a stable dose of at least 4 weeks’ duration prior to Cycle 1 Day 1.  Patients may 
have received a brief (< 7 days) course of systemic steroids (≤ 100 mg prednisone 
equivalent per day) prior to initiation of study therapy for control of lymphoma-related 
symptoms. 


 
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• 
CNS lymphoma or primary mediastinal DLBCL 
• 
Vaccination with live vaccines within 28 days prior to treatment 
• 
Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1.  
• 
History of other malignancy that could affect compliance with the protocol or interpretation 
of results 
Patients with a history of curatively treated basal or squamous cell carcinoma or Stage 
1 melanoma of the skin or in situ carcinoma of the cervix are eligible. 
Patients with a malignancy that has been treated with surgery alone with curative intent 
will also be excluded, unless the malignancy has been in documented remission 
without treatment for ≥ 3 years prior to enrollment. 
• 
Evidence of significant, uncontrolled concomitant diseases that could affect compliance with 
the protocol or interpretation of results or that could increase risk to the patient, including 
renal disease that would preclude chemotherapy administration or pulmonary disease 
(including obstructive pulmonary disease and history of bronchospasm) 
• 
Significant cardiovascular disease (such as New York Heart Association Class III or IV 
cardiac disease, congestive heart failure, myocardial infarction within the past 6 months, 
unstable arrhythmias, or unstable angina) or significant pulmonary disease 
(including obstructive pulmonary disease and history of bronchospasm) 
• 
Left ventricular ejection fraction < 50% as defined by multiple-gated acquisition (MUGA).  
Echocardiogram may be used if MUGA is not available. 
• 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment, or any major episode of infection 
requiring treatment with IV antibiotics or hospitalization (relating to the completion of the 
course of antibiotics) within 4 weeks prior to Cycle 1 Day 1 
• 
Received the following agents within 7 days prior to the first dose of venetoclax: 
Steroid therapy for anti-neoplastic intent within 7 days prior to Cycle 1 Day 1.  
Strong and moderate CYP3A inhibitors  
Strong and moderate CYP3A inducers  
Consumed grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or star fruit within 3 days prior to the first dose of 
venetoclax. 
• 
Clinically significant history of liver disease, including viral or other hepatitis, current alcohol 
abuse, or cirrhosis 
• 
Presence of positive test results for hepatitis B (HBcAb) or hepatitis C (hepatitis C virus 
[HCV] antibody  
Patients who are positive for HCV antibody must be negative for HCV by polymerase 
chain reaction (PCR) to be eligible for study participation 
Patients with occult or prior hepatitis B virus (HBV) infection (defined as positive total 
HBcAb and negative hepatitis B surface antigen [HBsAg]) may be included if HBV DNA 
is undetectable.  These patients must be willing to undergo monthly DNA testing. 
• 
Known infection with HIV or human T-cell leukemia virus 1 
• 
Women who are pregnant or lactating 
• 
Recent major surgery (within 6 weeks prior to the start of Cycle 1 Day 1), other than for 
diagnosis 
• 
Any of the following abnormal laboratory values: 
Calculated estimated creatinine clearance (CRCL)  < 50 mL/min with the use of the 
24-hour creatinine clearance or modified Cockcroft-Gault equation (with the use of 
ideal body mass [IBM] instead of mass): 


 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
37/Protocol GO27878, Version 8 
(140−Age) × IBM (kg) × [0.85 if female] 
CRCL =  
72 • serum creatinine (mg/dL) 
Or, if serum creatinine is in μmol/L: 
 
(140−Age) × IBM (kg) × [1.23 if male, 1.04 if female] 
CRCL =  
serum creatinine (μmol/L) 
 
AST or ALT > 2.5 × ULN (unless due to disease involvement; Medical Monitor to be 
consulted prior to enrollment) 
Total bilirubin ≥ 1.5 × ULN (or > 3 × ULN for patients with documented Gilbert syndrome) 
INR  > 1.5 × ULN for patients not receiving therapeutic anticoagulation 
PTT or aPTT > 1.5 × ULN 
 
Length of Study 
The length of study will be the time from screening of the first patient through 2 years following 
completion of study treatment of the last patients enrolled.  This time is expected to be 
approximately 60 months. 
End of Study 
The end of study will be defined as 2 years following completion of treatment of the last patient 
enrolled. 
Outcome Measures 
Efficacy Outcome Measures  
The following activity outcome measures will be assessed: 
• 
Primary outcome measures: 
CR, as defined by PET-CT scan as well as bone marrow examination when applicable 
• 
Secondary outcome measures: 
 
CR, as defined by CT scan and bone marrow examination, when applicable 
 
OR, defined as a PR or CR 
DOR, defined as the first occurrence of a documented response until the time of 
relapse or death from any cause 
PFS, defined as the time from date of first dose of study drug to the first occurrence of 
progression, relapse, or death while in the study, where death while in the study is 
defined as death from any cause within 12 weeks of the last tumor assessment  
 
PFS at 12 months 
 
Relative dose intensity 
OS, defined as the time from date of first dose of study drug until the date of death 
from any cause.  For patients who have not died, survival data will be censored at the 
date of last contact. 
 
OR and disease progression will be determined with use of the modified Lugano Classification:  
Revised Criteria for Response Assessment. 
Safety Outcome Measures  
The safety and tolerability of the combination of venetoclax plus R-CHOP or G-CHOP will be 
assessed using the following primary safety outcome measure: 
• 
Incidence and nature of combination dose-limiting toxicity (DLTs) 
 


 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
38/Protocol GO27878, Version 8 
In addition, safety will be assessed using the following secondary safety outcome measures: 
• 
Incidence, nature, and severity of adverse events and serious adverse events graded 
according to National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0 (NCI CTCAE v4.0).  Adverse events of special interest include Grade 4 
neutropenic fever, Grade ≥ 3 infusion-related reactions (IRR) to rituximab or obinutuzumab, 
and Grade ≥ 4 tumor lysis syndrome (TLS). 
• 
Change in clinical laboratory results (including hematology and chemistry) and vital signs 
• 
Maintenance of relative dose intensity of CHOP chemotherapy 
 
Pharmacokinetic Outcome Measures  
The following PK parameters will be derived from the plasma concentration-time profile of 
prednisone, venetoclax, and relevant metabolites following administration when appropriate, as 
data allow: 
• 
Total plasma exposure (AUC) 
• 
Time to maximum observed plasma concentration (tmax) 
• 
Maximum plasma concentration observed in plasma (Cmax) 
• 
Minimum plasma concentration under steady-state conditions within a dosing interval (Cmin) 
in plasma 
 
The following PK parameters will be determined from the concentration-time profiles of 
rituximab, obinutuzumab, and cyclophosphamide, vincristine, and doxorubicin (CHO) 
components, as applicable: 
• 
Cmax in serum or plasma, as appropriate 
• 
Cmin in serum or plasma, as appropriate 
 
Other PK parameters such as clearance, volume of distribution (V), and half-life may also be 
calculated as data allow. 
Exploratory Outcome Measures 
The following correlative biology measures will be assessed: 
• 
Bcl-2 high (Bcl-2 positive) as defined by IHC and Bcl-2 family protein expression by 
immunohistochemistry (IHC) 
• 
BCL2 and c-MYC copy number gain by FISH and translocation t(14;18) by FISH 
• 
Expression of transcripts for Bcl-2 family members, other apoptotic genes, and genes 
associated with the activated B cell-like (ABC) or germinal center B cell-like (GCB) subtypes 
of DLBCL 
• 
Subgroups relevant to DLBCL biology, including CD79b, Myd88, CARD11, TNFAIP3, 
epigenetic markers, and MYC translocation 
 
Investigational Medicinal Products 
The Investigational Medicinal Products used in this study are venetoclax, rituximab, and 
obinutuzumab (GA101).  
 
Venetoclax 
The venetoclax tablets will be packaged in high-density polyethylene plastic bottles to 
accommodate the study design.  Each bottle will be labeled per local regulatory requirements.  
A desiccant canister may be included in the bottle.  The tablets must be stored at 15°C−25°C 
(59°F−77°F).  If supplied with a desiccant, the desiccant canister should be returned to the 
bottle directly after each tablet removal. 
Study patients will self-administer venetoclax tablets by mouth once daily (QD).  Each dose of 
venetoclax will be taken with approximately 240 mL of water within 30 minutes after the 
completion of breakfast or the patient's first meal of the day.  A meal containing approximately 
30% of the total caloric content from fat is recommended to ensure adequate absorption of 


 
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venetoclax.  On days that pre-dose PK sampling is required, the patient’s first meal of the day 
(e.g., breakfast) will be consumed in the morning at the clinic, and venetoclax dosing will 
occur in the clinic after completion the meal to facilitate PK sampling. 
On days when venetoclax plus R-CHOP or G-CHOP are given, the order of study treatment 
administration will be venetoclax prior to rituximab or obinutuzumab, and rituximab or 
obinutuzumab prior to CHOP (with the exception of the first dose of prednisone in each cycle).  
On days when both venetoclax and prednisone are given, venetoclax will be taken prior to 
prednisone.  If vomiting occurs within 15 minutes after taking venetoclax and all expelled tablets 
are still intact, another dose may be given and the second dose noted in the drug log.  
Otherwise, no replacement dose is to be given.  In cases where a dose of venetoclax is missed 
or forgotten, the patient should take the dose as soon as possible and ensure that the minimal 
interval between the current dose and the next dose is at least 16 hours in order to avoid 
excessive drug accumulation after the next dose.  Patients will be instructed to record the date 
and time they take their daily dose of venetoclax and prednisone.  Diaries will be provided by 
the Sponsor for this purpose.  Venetoclax must be stored according to labeled storage 
conditions. 
All patients must receive prophylaxis for TLS prior to the initiation of venetoclax plus R-CHOP or 
G-CHOP study treatment. 
Rituximab 
Rituximab (Rituxan®/MabThera®) is a sterile, clear, colorless, preservative-free liquid 
concentrate for intravenous (IV) administration.  Rituximab is supplied at a concentration of 
10 mg/mL in 100-mg (10 mL) and 500-mg (50 mL) single-use vials.  The product is formulated 
for IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, and 
0.7 mg/mL polysorbate 80, after reconstitution with Sterile Water for Injection.  The pH is 
adjusted to 6.5.  Vials are for single use.  Each vial and carton will contain a label (either 
single-panel or booklet) affixed to the vial or carton per individual country requirements. 
Rituximab will be administered intravenously once per 21-day cycle in combination with CHOP 
for up to six cycles and as a single agent for two additional cycles.  Patients who experience 
ongoing response without excessive toxicity may receive up to eight cycles of CHOP following 
discussion between the investigator and the Medical Monitor.  The infusion of 375 mg/m2 will be 
based on the patient’s body surface area (BSA) at screening and will remain the same 
throughout the study unless there is a > 10% change in body weight.  On a given day, rituximab 
should be given after venetoclax and prior to CHOP (with the exception of the first dose of 
prednisone in each cycle). 
Rituximab should not be administered as an IV push or bolus.  IRRs may occur.  Premedication 
consisting of acetaminophen, diphenhydramine (or other suitable antihistamine), and a single 
dose of hydrocortisone (up to 100 mg or an equivalent dose of methylprednisolone) may also be 
administered beginning with the first infusion.  Premedication may attenuate IRRs.  Because 
transient hypotension may occur during rituximab infusion, consideration should be given to 
withholding antihypertensive medications for 12 hours prior to rituximab infusion. 
There will be no rituximab dose modification in this study.  Patients who are at high risk for IRR 
or TLS complications may, at the investigator’s discretion, receive their initial dose of rituximab 
split over 2 consecutive days (e.g., 125 mg/m2 on Cycle 1 Day 1, 250 mg/m2 on Cycle 1 Day 2). 
If the patient tolerates the first infusion well, subsequent rituximab infusions may be 
administered at an initial rate of 100 mg/hr and increased in 100-mg/hr increments at 30-minute 
intervals to a maximum of 400 mg/hr, as tolerated or per an institution’s standard of care IV 
administration procedure. 
Any NCI CTCAE v4.0 toxicity Grade ≥ 3 in severity that is deemed related to rituximab treatment 
will require interruption of study treatment until resolution to Grade ≤ 1.  Resumption of rituximab 
treatment may be considered in patients with resolution of toxicities to Grade ≤ 2 within 3 weeks 
at the discretion of the investigator after consultation with the study Medical Monitor.  Failure of 
such toxicities to resolve after 3 weeks of suspended study treatment will require permanent 
discontinuation of rituximab. 
Patients who discontinue rituximab because of rituximab-related toxicity may continue to receive 
CHOP and/or venetoclax only after consultation by the investigator with the Medical Monitor. 


 
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Obinutuzumab 
Obinutuzumab is provided as a single-dose, sterile liquid formulation in a 50 mL 
pharmaceutical-grade glass vial containing a nominal 1000 mg of obinutuzumab (G3 material).  
The formulated drug product consists of 25 mg/mL drug substance (G3) formulated in histidine, 
trehalose, and poloxamer 188.  The vial contains 41 mL (with 2.5% overfill). 
The recommended storage conditions for the obinutuzumab drug product are between 2°C and 
8°C and protect from light.  Chemical and physical in-use stability for obinutuzumab dilutions in 
0.9% sodium chloride (NaCl) has been demonstrated for 24 hours at 2°C−8°C and at ambient 
temperature and ambient room lighting.  The prepared diluted product should be used 
immediately.  If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user and would normally not be longer than 24 hours at 2°C−8°C.  
Obinutuzumab should not be frozen or shaken.  Mix gently.  All transfer procedures require 
strict compliance with aseptic techniques.  Do not use an additional in-line filter; this will avoid 
potential adsorption. 
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose of 1000 mg in 
combination with CHOP for up to six cycles and as a single agent for two additional cycles.  
Patients who experience ongoing response without excessive toxicity may receive up to 
eight cycles of CHOP following discussion between the investigator and the Medical Monitor.  
On a given day, obinutuzumab should be given after venetoclax and prior to CHOP (with the 
exception of the first dose of prednisone in each cycle), and patients should be observed for 
30 minutes prior to starting CHOP.  Patients at high risk for IRR or TLS complications may, at 
the investigator’s discretion, receive their obinutuzumab dose split over 2 consecutive days (e.g., 
100 mg on Day 1, 900 mg on Day 2).  During Cycle 1, obinutuzumab will also be administered 
on Days 8 and 15. 
Non-Investigational Medicinal Products 
CHOP Chemotherapy 
CHOP chemotherapy consists of IV cyclophosphamide, IV doxorubicin, vincristine administered 
by IV push, and oral prednisone or prednisolone.  Standard CHOP will be administered for six 
21-day cycles.  Patients who experience ongoing response without excessive toxicity may 
receive up to eight cycles of CHOP following discussion between the investigator and the 
Medical Monitor. 
• 
Cyclophosphamide 750 mg/m2 administered intravenously on Day 1 
• 
Doxorubicin 50 mg/m2 administered intravenously on Day 1 
• 
Vincristine 1.4 mg/m2 administered by IV push on Day 1 with a cap of 2.0 mg 
• 
Prednisone 100 mg/day orally (PO) on Days 1−5 
 
Permitted Concomitant Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by a patient from 7 days prior to 
screening through 30 days after the last dose of venetoclax or CHOP, or 90 days after the last 
dose of rituximab or obinutuzumab, whichever is later.  All concomitant medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.  
Patients who are receiving oral contraceptives, stable doses of hormone replacement therapy, 
or other maintenance therapy should continue their use. 
Steroid use not otherwise dictated by the protocol CHOP treatment will follow the guidelines 
outlined below: 
• 
Corticosteroid use > 30 mg/day of prednisone or equivalent:  Not allowed within 7 days prior 
to Cycle 1 Day 1 except as specified below 
• 
Corticosteroid use 15−30 mg/day of prednisone or equivalent:  Must be documented to be 
on a stable dose of at least 4 weeks’ duration prior to first dose of study drug. 
• 
Corticosteroid use < 15 mg/day of prednisone or equivalent:  Allowed 
 


 
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Exceptions to the above guidelines: 
• 
Corticosteroid used for malignancy-related symptom control (up to 100 mg/day of 
prednisone or equivalent) prior to initiation of study treatment.  Once study treatment has 
been given, corticosteroid use may be tapered down (must be ≤ pre-study treatment dose) 
for no more than 5 days. 
• 
Premedication for rituximab or obinutuzumab infusions, as indicated per protocol and/or site 
local practice (may replace dose of CHOP prednisone) 
• 
Inhaled corticosteroids for the treatment of asthma or chronic obstructive pulmonary 
disease 
• 
Topical steroids 
• 
Replacement corticosteroid therapy for an inherited or acquired deficiency 
• 
Steroid use to treat emergent issues not related to anti-neoplastic intent is allowed for no 
more than 7 days per event.  For steroid treatment > 7 days, the Medical Monitor must be 
consulted to discuss allowing the patient to continue treatment. 
 
Excluded Therapy 
Patients who are discontinued from study treatment will be followed for safety outcomes for 
30 days following the patient’s last dose of venetoclax or CHOP (or 90 days following the 
patient’s last dose of rituximab or obinutuzumab, whichever is later) or until the patient receives 
another anti-cancer therapy, whichever occurs first. 
Use of the following therapies is prohibited during the study: 
• 
Cytotoxic chemotherapy.  Supplemental systemic therapy for prophylaxis of CNS disease is 
permitted according to institutional practice only after primary response assessment and 
must be recorded in the eCRF. 
• 
Radiotherapy prior to primary response assessment 
• 
Immunotherapy 
• 
Hormone therapy (other than contraceptives, hormone replacement therapy, or megestrol 
acetate) 
• 
Any therapies intended for the treatment of lymphoma/leukemia whether U.S. Food and 
Drug Administration (FDA) approved or experimental (outside of this study) 
• 
Warfarin may be co-administered with venetoclax with caution and with the guidance of the 
Medical Monitor. 
 
The following concomitant medications are not allowed from 7 days prior to the first dose of 
study drug and during venetoclax administration: 
• 
Corticosteroid use > 30 mg/day of prednisone or equivalent (with some exceptions). 
• 
Strong and moderate CYP3A4 inducers 
 
The following concomitant medications are not allowed from 7 days prior to the administration of 
the first dose of study drug:   
• 
Strong and moderate CYP3A inhibitors 
• 
Strong and Moderate CYP3A inducers  
 
Exclude strong and moderate CYP3A inhibitors through the DLT assessment period and 
consider alternative medications.  If a patient requires use of these medications while he or she 
is receiving the target dose of venetoclax, once the DLT assessment period is complete, use 
with caution and reduce the venetoclax dose by 2-fold for moderate inhibitors and 4-fold for 
strong inhibitors during co-administration. 
After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax dose is increased 
back to the initial maintenance/target dose. 


 
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• 
Exclude strong and moderate CYP3A inducers through the DLT assessment period and 
consider alternative medications.  If a patient requires use of these medications while he or 
she is receiving the target dose of venetoclax, once the DLT assessment is complete, use 
with caution and contact the Medical Monitor for guidance. 
 
Statistical Methods 
Primary Analysis 
The final analysis will be based on patient data collected through study discontinuation.  
Analyses will be based on treated patients (i.e., patients who have received any amount of 
R/G-CHOP or venetoclax).  Analyses will be provided separately for the dose-finding and 
extension cohorts where appropriate.  Data from patients who receive R-CHOP or G-CHOP 
only (i.e., have not received any venetoclax), will be summarized separately. 
Determination of Sample Size 
The sample size for the dose-finding stage is based on a modified 3 + 3 design in order to guide 
dose and schedule selection for the Phase II portion on the basis of DLTs.  The expected 
enrollment for the dose-finding stage is 3−6 patients per dose level in each of the 
R-CHOP + venetoclax and G-CHOP + venetoclax arms. 
The sample size for the R-CHOP + venetoclax arm in Phase II is based on obtaining a sufficient 
number for estimation of PET-negative CR rate in patients with DE (Bcl-2 and c-Myc 
co-expressing) DLBCL, overall, for Bcl-2 high patients, and within each of four mutually 
exclusive biological subgroups:  Bcl-2 high and ABC, Bcl-2 high and GCB, Bcl-2 low and ABC, 
and Bcl-2 low and GCB.  The expected enrollment for the R-CHOP + venetoclax arm in Phase II 
is approximately 160−200 patients in order to enroll approximately 50 DE-DLBCL patients, 
approximately 80−100 Bcl-2 high patients, and approximately 40−50 patients in each of the two 
Bcl-2 high subgroups.  With 50 patients, 95% confidence intervals for estimation of CR would 
have a margin of error not exceeding 16%.  The margin of error would decrease to 9% with 150 
patients and to 8% with 200 patients  
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABC 
activated B cell-like 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from time 0 to time 24 hours 
ALL 
acute lymphoblastic leukemia 
anti-HBc 
anti-hepatitis B core antibody 
BR 
bendamustine and rituximab 
BSA 
body surface area 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration observed in serum or plasma, as appropriate 
Cmin 
minimum concentration under steady-state conditions within a dosing interval 
in serum or plasma 
CHO 
cyclophosphamide, vincristine, and doxorubicin 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CR 
complete response 
CRCL 
creatine clearance 
CRi 
incomplete marrow recovery 
CT 
computed tomography 
CV 
cardiovascular 
DE 
double expressor 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
FDA 
U.S. Food and Drug Administration 
FDG 
18F-fleurodeoxyglucose 
FISH 
fluorescence in situ hybridization 
FL 
follicular lymphoma 
G 
obinutuzumab (GA101) 
GCB 
germinal center B cell-like 
G-CHOP 
obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 


 
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Abbreviation 
Definition 
GI 
gastrointestinal 
HBV 
hepatitis B virus 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HD 
high dose 
HIPAA 
U.S. Health Insurance Portability and Accountability Act 
IBM 
ideal body mass 
ICH 
International Conference on Harmonisation 
IHC 
immunohistochemistry 
IL 
interleukin 
IMC 
Internal Monitoring Committee 
IND 
Investigational New Drug 
IPI 
International Prognostic Index 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
IV 
intravenous 
IxRS 
interactive voice/ Web response system 
JC 
John Cunningham 
Ki 
dissociation constant 
LD 
low dose 
LDi 
longest transverse diameter of a lesion 
MCL 
mantle cell lymphoma 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition  
NaCl 
sodium chloride 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin’s lymphoma 
NK 
natural killer 
OS 
overall survival 
OR 
objective response 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 


 
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Abbreviation 
Definition 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PO 
orally 
PR 
partial response 
PVC 
polyvinylchloride 
QD 
once daily 
R 
rituximab 
R-CHOP 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
RCR 
Roche Clinical Repository 
SC 
subcutaneous 
SLL 
small lymphocytic lymphoma 
SOC 
Scientific Oversight Committee 
SPD 
sum of the product of the diameters 
TLS 
tumor lysis syndrome 
TMA 
tissue microarray 
tmax 
time to maximum observed plasma concentration 
ULN 
upper limit of normal 
V 
volume of distribution 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON DISEASE 
1.1.1 
Indolent Non-Hodgkin’s Lymphoma 
Non-Hodgkin’s lymphoma (NHL) is the most common hematologic malignancy in adults.  
It is estimated that in 2010 there were 93,172 new cases of NHL in Europe and 
65,540 new cases of NHL in the United States (GLOBOCAN 2008; 
American Cancer Society 2010).  The majority of NHLs (also known as malignant 
lymphoma) is of B-cell origin and characterized by the expression of a membrane 
antigen, CD20, that is important in cell cycle initiation and differentiation.  NHL can be 
divided into aggressive and indolent NHL.  Indolent NHLs are a heterogeneous group of 
malignant lymphomas and account for about one-third of all NHLs.  Follicular lymphoma 
(FL) is the most common subtype of indolent NHL in the Western hemisphere and is 
associated with follicle center B cells that typically contain the BCL2 chromosome 
translocation t(14:18) that leads to overexpression of the intracellular anti-apoptotic 
protein Bcl-2.  Although FL is the most common subtype of indolent NHL, there are also 
several histological non-follicular subtypes including marginal zone lymphoma, 
Waldenström's macroglobulinemia (also known as lymphoplasmacytic lymphoma), and 
small lymphocytic lymphoma (SLL).  Early-stage indolent NHL may be effectively treated 
with radiation therapy, but advanced stages remain incurable. 
The clinical course of indolent NHL is characterized by remission and relapse.  Although 
there is no agreed-upon standard therapy for indolent NHL, rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a common 
regimen that results in high response rates and long remission duration in many patients, 
particularly in those patients with FL (Czuczman et al. 1999).  The disease initially 
responds to radiation and/or immunochemotherapy with conventional agents, but 
patients eventually suffer multiple relapses distinguished by increasing refractoriness 
and decreasing duration of response (DOR) in subsequent lines of therapy.  Patients 
with advanced stage disease are not considered curable with conventional treatment 
and ultimately die from recurrent disease or treatment-related toxicity.  Therefore, there 
is a need for the development of new treatments that could improve both response and 
survival rates of patients with indolent NHL. 
1.1.2 
Diffuse Large B-Cell Lymphoma 
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL, comprising 
approximately 30% of all NHL cases.  Approximately 75% of patients with DLBCL who 
are treated with current standard R-CHOP therapy achieve a complete remission, and 
50%−60% of patients are cured of their disease with this treatment. 
Although there is currently no way to prospectively identify individual patients who will be 
cured, clinical factors are used to define prognostic risk groups associated with 
predictive outcomes.  The International Prognostic Index (IPI) is a prognostic tool that 
uses five clinical factors to predict outcome of patients with aggressive NHL.  The IPI 


 
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defines four distinct prognostic subgroups depending on the number of negative 
prognostic factors at diagnosis.  Although patients with low IPI (i.e., with no or only one 
negative prognostic finding) have overall excellent outcomes with 3-year 
progression-free survival (PFS) of 80%−90% (Sehn et al. 2007; Advani et al. 2010), 
patients with higher risk have poorer outcomes with 3-year PFS ranging from 33% to 
70%. 
For patients who are not cured by first-line therapy, high-dose (HD) chemotherapy 
followed by autologous stem cell transplantation offers a second chance for cure in a 
minority of cases.  However, approximately half of patients will not respond to 
subsequent therapy because of refractory disease (Gisselbrecht et al. 2010) and a 
significant number are ineligible for this aggressive therapy because of age or 
comorbidities. 
Patients who either relapse after or are ineligible for stem cell transplantation as a result 
of refractory disease or frailty have poor outcomes.  Responses to subsequent therapies 
range from 10%−35% in most cases (Robertson et al. 2007; Coleman et al. 2008; 
Wiernik et al. 2008), with only occasional durable responses.  The fact that most patients 
who are not cured with the use of the standard front-line R-CHOP or comparable 
immunochemotherapy will die of lymphoma underscores the need for novel approaches 
to initial treatment of this aggressive disease. 
Bcl-2 is an anti-apoptotic molecule overexpressed in many hematologic malignancies 
including many DLBCLs, either through translocation of the BCL2 gene in juxtaposition 
with the IGH gene t(14;18), through gene amplification, or by other mechanisms 
(Gascoyne et al. 1997; Davis et al. 2001).  Bcl-2 protein inhibits death of lymphoma cells 
in response to chemotherapy and other anti-neoplastic agents including rituximab (R).  
Overexpression of BCL2 has been shown to be associated with inferior outcomes in 
DLBCL with standard treatment (Iqbal et al. 2011; Hu et al. 2013; Visco et al. 2013).  
The frequent overexpression of BCL2 combined with its contribution to therapy 
resistance makes BCL2 inhibition an attractive therapeutic target in DLBCL. 
DLBCL is a molecularly heterogeneous disease with different molecular subtypes that 
have been identified with the use of gene expression profiling (Rosenwald et al. 2002).  
The two major subtypes, germinal center B cell-like (GCB) and activated B 
cell−like (ABC), show activation of different oncogenic and survival pathways.  
Furthermore, they are associated with different prognoses, with survival being 
significantly better in patients with GCB-DLBCL than in those with ABC-DLBCL.  
Although evidence for a prognostic effect of BCL2 is greatest in the GCB subtype, both 
GCB- and ABC-DLBCL overexpress BCL2 in approximately 50% of cases, arguing for 
biological relevance of BCL2 in both subtypes.  The implications of BCL2 inhibition in 
each subtype are unknown, supporting the need to investigate the activity of BCL2 
inhibition in combination with chemotherapy in each subgroup.  Patients with expression 
of both Bcl-2 and c-Myc proteins (i.e., double expressor- [DE-] DLBCL) have been 


 
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recently identified as a poor prognostic subgroup, characterized in part by 
overexpression of BCL2, for whom the addition of venetoclax (GDC-0199) might add 
substantial therapeutic benefit.  Patients with (DE-) DLBCL, even in the absence of 
chromosomal translocation, have an inferior outcome when compared with patients with 
DLBCL that does not express both proteins, and thus represent a poor-prognosis group 
in need of effective therapies (Green et al. 2012; Johnson et al. 2012; Hu et al. 2013; 
Valera et al. 2013).  Since BCL2 expression contributes to the pathogenesis of some 
types of lymphoid malignancies, including DLBCL, the inhibition of BCL2 function with 
venetoclax could restore the sensitivity of tumor cells to the current standard therapy, 
R-CHOP, and therefore could provide an effective new therapy for this group with a high, 
unmet medical need. 
Patients with chromosomal translocations in BCL2 and MYC (i.e. Double Hit) have also 
been identified as a poor prognostic subgroup (Savage et al. 2009; Barrans et al. 2010) 
and also comprise a subgroup of patients with an unmet medical need. 
1.2 
BACKGROUND ON THE MOLECULES 
1.2.1 
Bcl-2 Protein Family 
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway.  
The BCL2 oncogene was first identified in FL where the t(14;18) chromosomal 
translocation results in significant overexpression of the protein in B cells.  The BCL2 
family of genes encodes a family of closely related proteins that possess either 
pro-apoptotic or anti-apoptotic activity and share up to four BCL2 homology domains 
(Cory and Adams 2002; Borner 2003; Cory et al. 2003).  BCL2 overexpression is a 
major contributor to the pathogenesis of many types of lymphoid malignancies and has 
been implicated as a cause of chemotherapy resistance. 
1.2.2 
Venetoclax 
1.2.2.1 
Venetoclax Nonclinical Activity and Pharmacokinetic Profile 
Venetoclax (synonymous with GDC-0199 and ABT-199; venetoclax will be used 
throughout the protocol) is a highly selective, orally available small molecule Bcl-2 family 
protein inhibitor that binds with high affinity (dissociation constant [Ki] < 0.10 nM) to Bcl-2 
and with lower affinity to other Bcl-2 family proteins Bcl-XL and Bcl-w (> 480-fold 
and > 2000-fold lower affinity than to Bcl-2, respectively).  Overexpression of 
anti-apoptotic Bcl-2 family proteins is associated with resistance to chemotherapy and 
antagonism of the action of these proteins might overcome resistance and enhance 
response to therapy.  Anti-apoptotic Bcl-2 family members are associated with tumor 
initiation, disease progression, and drug resistance, making them compelling targets for 
anti-tumor therapy. 
In vitro, venetoclax has demonstrated broad cell-killing activity against a panel of 
lymphoma and leukemia cells including B-cell FL, mantle cell lymphoma (MCL), DLBCL, 
and acute myeloid leukemia.  Venetoclax was especially potent against cell lines 


 
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expressing high levels of Bcl-2.  Leukemia and lymphoma cell lines bearing the t(14;18) 
translocation were significantly more sensitive to venetoclax than were wild-type cell 
lines. 
Venetoclax inhibited subcutaneous (SC) murine xenograft growth of human tumor cell 
lines derived from acute lymphoblastic leukemia (ALL) and NHL. 
The pharmacokinetic (PK) profile of venetoclax was evaluated in multiple animal species.  
In mice, rats, monkeys, and dogs, low plasma clearance and low volumes of distribution 
characterized the venetoclax PK profile.  Half-lives ranged from 2.2 hours in monkeys to 
12 hours in dogs.  Food had a marked effect on the oral bioavailability in dogs, with a 
30%−50% higher plasma concentration compared with fasted animals. 
Venetoclax demonstrated high protein binding to human, rat, dog, and monkey plasma 
proteins (> 99.9%).  In rats, venetoclax was widely distributed into liver, kidneys, spleen, 
heart, lungs, small intestine, and white fat but was poorly distributed in testes, brain, 
muscle, and bone.  Liver metabolism was the major route of elimination, with biliary 
excretion of the parent drug playing the secondary role in rats.  Venetoclax showed 
moderate metabolic stability in in vitro hepatic systems across species tested, except for 
low to moderate stability in dog hepatocytes. 
In vitro, venetoclax was metabolized by CYP3A4; thus, co-administration of venetoclax 
with drugs that inhibit CYP3A4, is predicted to cause a significant increase in the 
exposure of venetoclax.  Venetoclax is a substrate for P-gp and BCRP.  Active uptake of 
venetoclax was not observed in cells overexpressing OATP1B1, OATP1B3, or OCT1 
indicating that venetoclax is not a substrate for those transporters in vitro. 
On the basis of in vitro results, venetoclax was a P-gp, BCRP, and OATP1B1 inhibitor.  
It was not a potent in vitro inhibitor of CYP3A4, CYP1A2, CYP2B6, or CYP2D6 
(IC50 > 30 μM); and it did not induce CYP3A4 or CYP1A2 at concentrations up to 10 μM.  
Venetoclax is also not predicted to cause inhibition of CYP2C19, CYP2C8, CYP2C9, 
and UGT1A1 at clinically relevant concentrations.  It is not an inhibitor of UGT1A4, 
UGT1A6, UGT1A9, or UGT2B7. 
A more detailed discussion of the nonclinical activity of venetoclax including 
pharmacokinetics and metabolism can be found in the ABT-199/GDC-0199 
Investigator’s Brochure. 
1.2.2.2 
Venetoclax Nonclinical Toxicology 
Toxicology assessments completed to date with venetoclax are general toxicology 
studies with periods of once-daily oral dosing ranging from 2 weeks to 6 months in mice, 
from 2 weeks to 13 weeks in rats, and from 1 week to 9 weeks in dogs; in vitro and 
in vivo genetic toxicology; embryo-fetal development in female mice and rabbits; and 
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steady state venetoclax plasma exposures (mean area under the concentration-time 
curve [AUC]) achieved in the IND-enabling 4 week studies were 92 µg • h/mL (at 
600 mg/kg/day) in mice and 572 µg • h/mL (at 150 mg/kg/day) in dogs.  In the chronic 
toxicity studies, AUCs reached 34.1 µg•h/mL (at 300 mg/kg/day) in mice and 
86 µg • h/mL (at 20 mg/kg/day) in dogs.  In rats, exposures were higher in females than 
in males; at dosages of 150 and 400 mg/kg/day in the 13 week maximum tolerated dose 
study, exposures ranged up to 83.1−127.8 µg • h/mL in females and up to 
26.4−44.2 µg • h/mL in males. 
The primary toxicities associated with venetoclax administration included effects on the 
hematologic system (decreased lymphocytes and erythrocytes) in mice, rats, and dogs; 
the male dog reproductive system (testicular germ cell depletion); and embryo-fetal 
toxicity in mice. 
In mice, rats, and dogs, venetoclax produced generally dose-related decreases in 
lymphocytes in the peripheral blood (of up to 75% in mice, up to 64% in rats, and up 
to 81% in dogs) and in lymphoid tissues.  In dogs, the recovery of lymphocyte counts 
(total lymphocytes, CD4 + and CD8 + T cells and mature B cells) was prolonged, 
requiring up to 18 weeks after completion of 2 weeks of dosing.  B cells were the most 
sensitive lymphocyte subtype based on the magnitude of decrease and/or the length of 
time required for recovery (i.e., 25%−111% of individual baseline; mean reversal to 
54% of baseline average).  T-cell subsets reversed more readily and showed more 
dose-dependence in recovery time and extent.  Decreases of lymphocytes in lymphoid 
tissues were reversible in mice and reversible to partially reversible in dogs.  
Venetoclax-related decreases in lymphocytes in blood and lymphoid tissues are 
considered pharmacologically-mediated and non-adverse (Marsden and Strasser, 2003). 
In the 4 week mouse and dog studies, dose-related reversible decreases in RBC mass 
were observed.  Effects on RBC mass were typified by hemoglobin decreases.  At the 
highest dosages administered, decreases in hemoglobin reached -21% in mice at 
600 mg/kg/day and -23% in dogs at 150 mg/kg/day, and were considered to be adverse 
based on a criterion of -20% decrease.  In rats, decreases in hemoglobin were more 
severe than in mice and dogs at comparable exposures and reached 30% to 49% at 
≥ 150 mg/kg/day in females.  Hematologic parameters (lymphocyte counts and RBC 
mass) are readily monitored in clinical trial subjects. 
In dogs, venetoclax produced adverse, non-reversible, non−dose-related microscopic 
findings of testicular germ cell depletion at all dosages tested; there were no testicular 
effects in mice.  The translatability of the testicular findings in dogs to humans is 
unknown, but this change may be related to venetoclax pharmacology, as one or more 
members of the Bcl-2 family of proteins play a role in spermatogenesis 
(Olderied et al. 2001; Sugiyama et al. 2001; Yan et al. 2003).  No effects of venetoclax 
have been identified in female reproductive tissues in mice or dogs in general toxicology 
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Venetoclax resulted in increased post-implantation loss and decreased fetal body 
weights in the mouse embryo-fetal development study at the highest dosage 
administered (150 mg/kg/day); the no-observed-adverse-effect level was defined at the 
mid-dose of 50 mg/kg/day.  Venetoclax was not teratogenic, and there were no other 
effects on development or fertility. 
Additional noteworthy effects of venetoclax included white hair coat discoloration in 
dogs (occurring after approximately 3 months of dosing in the 9 month study) and 
single cell necrosis in various epithelial tissues (gallbladder, exocrine pancreas, 
stomach, exocrine pancreas, and epididymides) in dogs.  Single cell necrosis was 
minimal except for non−dose-dependent minimal to mild single cell necrosis in the 
pylorus of the stomach at ≥ 2 mg/kg/day in the 9 month study.  After 4 weeks of dosing 
and a 4 week recovery period, reversibility was observed in the gallbladder and exocrine 
pancreas, but minimal single cell necrosis was still present in the epididymides and 
prostate (potentially related to the testicular effects) and in the stomach.  Single cell 
necrosis was considered not to be adverse due to its minimal to mild magnitude and 
because no loss of mucosal integrity was observed histopathologically.  The hair coat 
change correlated histopathologically with decreased pigment in hair follicle bulbs, and 
is consistent with the pharmacologic inhibition of Bcl-2 by venetoclax, leading to Bcl-2 
functional loss in hair follicle melanocytes dependent on Bcl-2 for survival 
(Yamamura et al. 1996)  A dedicated physical examination of the skin and extensive 
ophthalmic examinations determined that pigmentation of the skin and in the eye 
(particularly, the iris and fundus) of the dog appeared unaffected.  This was confirmed 
by the absence of associated histopathologic findings in skin (other than in hair follicles) 
and in the eye.  Consequently, white hair coat discoloration was considered non-adverse; 
reversibility has not been assessed. 
Minor effects of venetoclax were:  mild, dose-related, transient post-dose emesis, 
increased salivation, and fecal alterations (unformed or watery feces); minimally 
increased pigment in Kupffer cells and macrophages in the liver and gallbladder, 
respectively; and clinical signs of skin swelling, all in dogs.  With regard to the latter 
finding, dogs at the high dosage of 150 mg/kg/day in the 4 week study had clinical signs 
of swelling of the skin on the ears, head (cranial area), and forepaws and/or hindpaws.  
Most but not all animals (8 of 10 dogs) were affected, and in three dogs the swelling 
reaction was observed after the first dose.  The clinical signs were transient and 
sporadic in occurrence, and were absent during the recovery period.  A mechanistic 
basis for the swelling reactions was not established, but the clinical signs were mild to 
moderate in severity and reversible, and there were no signs of anaphylaxis. 
There was no evidence of in vitro or in vivo genetic toxicity of venetoclax, nor was 
there evidence of phototoxicity. 
Venetoclax was tested in a battery of safety pharmacology assays, and produced no 
effects in the CNS/neurobehavioral or respiratory studies in mice at oral doses up to 


 
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and including the highest oral dose of 600 mg/kg.  No effects on QTc were observed up 
to a maximum plasma concentration of 46 μg/mL in dogs.  In conscious dogs, 
venetoclax did not produce any cardiovascular effects up to and including the highest 
oral dose of 150 mg/kg (maximum concentration observed [Cmax] = 16 μg/mL).  In the 
anesthetized dog at higher plasma concentrations, venetoclax produced mild reductions 
in myocardial contractility (-6% to -13%) and cardiac output (-11% to -19%) at 
plasma concentrations of ≥ 16 μg/mL and ≥ 32 μg/mL, respectively.  These 
concentrations are greater than the plasma concentration of venetoclax in humans 
(average Cmax = 6.09 μg/mL at the 1200 mg/day dose). 
See the ABT-199/Venetoclax Investigator’s Brochure for details of the nonclinical studies.  
1.2.2.3 
Venetoclax Clinical Experience 
As of 30 June 2013, a total of 137 patients were dosed with venetoclax in AbbVie and 
Genentech/Roche oncology studies.  Doses administered in venetoclax clinical studies 
have ranged from 20 to 1200 mg. 
The first-in-human venetoclax monotherapy dose-escalation study (Study M12-175) is 
ongoing in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/SLL 
and NHL.  Study M13-365 (venetoclax and rituximab administered in combination to 
patients with relapsed or refractory CLL), Study M12-630 (venetoclax administered in 
combination with bendamustine and rituximab [BR] to patients with relapsed/refractory 
NHL), and Study GP28331 (venetoclax administered in combination with obinutuzumab 
to patients with relapsed or refractory CLL) are also ongoing. 
Study M12-175 includes patients with relapsed/refractory CLL/SLL (treatment Arm A) or 
NHL (treatment Arm B).  Patients receive daily dosing until progressive disease (PD) or 
unacceptable toxicity. 
Study M13-365 includes patients with relapsed/refractory CLL.  Patients receive 
venetoclax starting at 50 mg/day, and the dose is escalated to the target cohort dose of 
venetoclax over 3 weeks, followed by continual daily dosing of venetoclax at the target 
cohort dose until disease progression.  Rituximab is administered starting on 
Week 4 Day 1 at 375 mg/m2 followed by subsequent administrations of 500 mg/m2 
rituximab on Day 1 of Weeks 5, 6, 10, 14, 18, 22, and 26. 
Study M12-630 is a study of venetoclax administered in combination with BR to patients 
with relapsed /refractory NHL.  Patients receive venetoclax starting at 50 mg/day for 
3 days with each 28-day cycle of BR, continuing for 6 cycles.  Venetoclax dose and 
duration per cycle are escalated in consecutive cohorts. 
Study GP28331 includes patients with relapsed/refractory CLL.  Patients receive 
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initiated.  Obinutuzumab is administered at a dose of 1000 mg, with the first dose split 
over 2 days. 
Preliminary safety, PK, and efficacy data are summarized below on the basis of data 
cutoff dates of 11 January 2013 for safety listings. 
Dose-limiting toxicity (DLT) assessments are available for patients enrolled in 
Study M12-175 (through Cohort 8 with a target venetoclax dose of 1200 mg), 
Study M13-365 (through Cohort 3 with a target venetoclax dose of 400 mg), and 
Study M12-630 (through Cohort 2 with a target venetoclax dose of 100 mg for 3 days 
with each cycle of BR). 
Seven DLTs of tumor lysis syndrome (TLS) and two DLTs of fatalities in the setting of 
TLS were reported in the venetoclax clinical program for patients with CLL/SLL 
(Studies M12-175 and M13-365).  Six DLTs of TLS occurred in Study M12-175 at either 
the starting dose of 100 or 200 mg venetoclax (3 patients in Cohort 1) or the lower 
lead-in dose of 50 mg venetoclax implemented to minimize the risk of TLS (1 patient 
each in Cohorts 2 and 4).  The sixth DLT of TLS occurred at the maximum designated 
cohort dose administered in the study (Cohort 8; 1200 mg), and the patient experienced 
sudden death.  In Study M13-365, there was a single DLT of death caused by 
Grade 5 hyperkalemia in a setting of TLS at the 50-mg lead-in dose.  In addition, single 
non-DLT adverse events of TLS were reported in 1 patient with MCL in Study M12-175 
and in 1 patient with CLL in Study M13-365.  Events of laboratory TLS were also 
observed in 2 patients during dosing in Study GP28331 at lead-in doses of 50 mg 
venetoclax. 
In Study GP28331, 4 patients received study treatment; 3 patients received venetoclax 
for between 3 and 15 days and 1 patient received obinutuzumab and a single dose of 
venetoclax.  All patients discontinued therapy when the study was put on temporary hold 
after two TLS-related deaths occurred in other clinical studies.  In this study, the only 
reported adverse event related to venetoclax was a serious event of hyperphosphatemia 
in the setting of laboratory TLS that occurred after the third dose of venetoclax in a 
patient who had not received obinutuzumab.  The event resolved with IV hydration and 
discontinuation of study therapy. 
Two DLTs were reported in patients with NHL treated with venetoclax 
(Studies M12-175 and M12-630).  Both DLTs occurred in Study M12-175 at the 
600-mg dose in Cohort 5.  This study enrolled a total of 10 patients with a 300-mg 
lead-in dose and a designated cohort dose of 600 mg.  One patient experienced a DLT 
of serious Grade 3 febrile neutropenia and the other patient experienced a DLT of 
non-serious Grade 4 neutropenia.  Dosing was interrupted and patients were treated 
with medication; the events resolved and the patients restarted therapy at a reduced 
dose of 300 mg.  No DLTs were reported in Cohort 6 at the designated cohort dose of 
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Additional DLTs included 1 case each of histiocytosis hematophagic and 
thrombocytopenia in patients with CLL (both considered related to rituximab rather 
than venetoclax). 
Grade ≥ 3 hematologic toxicity was common in patients with CLL who received 
venetoclax, but less common in patients with NHL.  With single-agent venetoclax in 
Study M12-175, 37.5% of patients with CLL experienced Grade 3 or 4 neutropenia and 
7% experienced Grade 3 or 4 thrombocytopenia, whereas 13% of patients with NHL 
experienced Grade ≥ 3 neutropenia and 10% experienced Grade ≥ 3 thrombocytopenia.  
Hematologic toxicity in Study M12-630 (venetoclax in combination with BR in NHL) was 
not significantly greater than that expected with BR alone. 
Data on venetoclax and human pregnancy or venetoclax and drug abuse and drug 
dependency are not available. 
Preliminary efficacy data based on investigator assessment of radiographic data 
available as of 30 June 2013 are presented below for Study M12-175; efficacy data are 
not yet available for other venetoclax studies.  In treatment Arm A, 54 of 56 patients 
were considered evaluable for response (i.e., completed the Week 6 evaluation or 
discontinued prior to Week 6).  Objective response (OR) was reported in 46 of 
54 evaluable patients (85.2%) in treatment Arm A:  5 patients (8.9%) experienced 
complete response (CR), 2 patients (3.7%) experienced CR with incomplete marrow 
recovery (CRi), and 39 patients (72.2%) experienced partial response (PR).  In treatment 
Arm B, 32 patients with NHL were considered evaluable for response.  OR was reported 
in 17  of 32 patients (53%) in treatment Arm B:  3 patients (9.4%) had a CR and 
14 patients (53.7%) had a PR.  All 8 patients (100%) with MCL in treatment Arm B 
experienced a PR. 
Details and most current data are provided in the ABT-199/Venetoclax Investigator’s 
Brochure. 
1.2.2.4 
Clinical Pharmacokinetics and Pharmacodynamics 
Preliminary PK data for venetoclax are available from ongoing oncology 
Studies M12-175, M12-630, and M13-365 in patients with hematologic malignancies. 
The venetoclax formulation currently used in clinical studies is a tablet formulation with 
strengths of 10, 50, and 100 mg.  The tablet formulation was orally administered after a 
low-fat meal.  Food increased the bioavailability of venetoclax by 3- to 4-fold.  
Preliminary PK results indicated that the absorption of venetoclax after the oral dosing 
was relatively slow.  Venetoclax plasma concentrations peaked at approximately 6 hours 
after dosing.  The mean terminal phase elimination half-life of venetoclax was 
approximately 17 hours and the mean oral clearance was approximately 13 L/hr after a 
single dose.  There was no apparent difference in the pharmacokinetics of 
venetoclax between patients with CLL/SLL or NHL.  The combined data from patients 


 
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with CLL/SLL and NHL suggested that venetoclax exposure was approximately dose 
proportional across the 150- to 900-mg dose levels.  In the limited number of patients to 
date, co-administration of BR did not show apparent impact on venetoclax 
pharmacokinetics. 
Details and most current data are provided in the ABT-199/Venetoclax Investigator’s 
Brochure. 
1.2.3 
Obinutuzumab 
1.2.3.1 
Obinutuzumab Mechanism of Action 
Obinutuzumab ([G], synonymous with GA101 and RO5072759; the term obinutuzumab 
will be used throughout the protocol) is a humanized and glycoengineered monoclonal 
antibody derived by humanization of the parental B-Ly1 mouse antibody and subsequent 
glycoengineering leading to the following characteristics (Mössner et al. 2010): 
• 
High-affinity binding to CD20 
• 
Type II binding to the CD20 epitope, leading to low complement-dependent 
cytotoxicity related to the recognition of the CD20 epitope and the lack of 
CD20 localization into lipid rafts after binding of the monoclonal antibody to CD20  
• 
Compared with the chimeric Type I anti-CD20 antibody rituximab, increased 
antibody-dependent cell-mediated cytotoxicity (ADCC) related to an improved 
binding of obinutuzumab to the different allotypes of FcγRIIIa expressed by natural 
killer cells and monocytes 
• 
Compared with rituximab, increased direct cell-death induction related to an elbow 
hinge amino exchange of the Fab region and Type II binding of the CD20 epitope 
 
Given the significantly greater ADCC and direct cell-death induction, it is possible that 
obinutuzumab may have greater efficacy than rituximab, particularly in the 80%−85% of 
patients who are carriers of the FcγRIIIa low-affinity receptor polymorphism 
(FF/FV genotype), because such patients may have decreased overall survival (OS) 
compared with patients with the high-affinity (V/V) polymorphism who demonstrate 
improved survival following therapy with chemotherapy plus either rituximab or 
I131-tositumomab (Persky et al. 2012). 
Obinutuzumab is currently being explored in lymphoid malignancies, such as DLBCL, FL, 
and CLL.  Preliminary data suggest possible increased anti-lymphoma efficacy over 
rituximab, a hypothesis that is currently being explored in several randomized trials 
including a Phase III study of R-CHOP versus obinutuzumab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone (G-CHOP) in DLBCL (Study BO21005). 
1.2.3.2 
Obinutuzumab Nonclinical Toxicology 
The nonclinical toxicology of obinutuzumab has been evaluated in repeat-dose studies in 
cynomolgus monkeys given weekly intravenously (30-minute infusion) for up to 
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50 mg/kg in the 26-week study resulted in a steady-state AUC from Time 0 to 24 hours 
(AUC0−24) exposure of 341,000 μg • hr/mL that is approximately 61-fold above that of the 
clinical exposure of 5584 μg • hr/mL. 
Consistent with expected pharmacological activity, obinutuzumab caused marked 
decreases in B cells with corresponding lymphoid depletion in spleen and lymph nodes.  
Circulating CD40-positive mature B cells began to reverse after several months without 
treatment and maximally reversed to 7%−152% of baseline by 37 weeks.  In addition, 
transient decreases in natural killer (NK) cells were observed; this finding is consistent 
with the pharmacological effect of FcγRIIIa binding.  Suspected opportunistic infections 
in as many as three unscheduled deaths were considered a possible secondary result of 
B-cell depletion. 
Obinutuzumab was immunogenic in the cynomolgus monkey; this immunogenicity led to 
reduced systemic exposures in several animals and abrogation of the pharmacological 
activity.  Hypersensitivity reactions were noted that included systemic inflammation and 
infiltrates consistent with immune-complex−mediated hypersensitivity reactions such as 
arteritis/periarteritis, glomerulonephritis, and serosal/adventitial inflammation and led to 
unscheduled termination in 6 animals. 
Both the clinical IV formulation of obinutuzumab and the SC formulation were locally well 
tolerated across studies.  No effects were present in male and female reproductive 
parameters included in the 26-week IV-dose study.  No obinutuzumab-related effects 
were observed on CNS, respiratory, or cardiovascular (CV) functions. 
Significant increases in cytokine secretion caused by obinutuzumab were measured in 
in vitro assays with the use of undiluted human whole blood, indicating that 
obinutuzumab has an increased propensity to trigger first infusion-related cytokine 
release in patients. 
See the Obinutuzumab Investigator’s Brochure for details on the nonclinical studies. 
1.2.3.3 
Obinutuzumab Nonclinical Efficacy 
Obinutuzumab has demonstrated in vivo efficacy superior to rituximab in various human 
lymphoma xenograft models.  Both antibodies were tested in human SUDHL-4 cells 
(a DLBCL model) subcutaneously injected in severe combined immunodeficient beige 
mice.  Rituximab administration was started when tumors were established and rapidly 
growing.  Results showed that rituximab at 10 mg/kg inhibited tumor growth compared 
with rituximab at 1 mg/kg; however, increasing the rituximab dose to 30 mg/kg did not 
result in increased efficacy.  In contrast, obinutuzumab showed a dose-dependent 
increase in efficacy in the range of 1−30 mg/kg.  Results showed complete tumor 
regression in all animals and lasting tumor eradication in 9 of 10 animals at the highest 
dose of 30 mg/kg and in 1 of 10 animals at a dose of 10 mg/kg. 


 
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Additional studies have also shown similar results, with obinutuzumab treatment 
controlling tumor growth, whereas vehicle- and rituximab-treated tumors were not 
controlled (Mössner et al. 2010). 
See the Obinutuzumab Investigator’s Brochure for details on the nonclinical studies. 
1.2.3.4 
Obinutuzumab Clinical Experience 
As of July 2013, more than 1900 patients with CD20-positive malignant disease have 
been treated with obinutuzumab in clinical trials.  Clinical data for obinutuzumab are 
available from six clinical trials including three Phase I and/or Phase II studies of 
obinutuzumab monotherapy, a Phase Ib chemotherapy combination study in NHL 
(Study BO21000), and two Phase III studies (Study BO21004 in CLL and 
Study GA04753g in NHL). 
Infusion-related reactions (IRRs), mostly Grades 1 and 2, are the most common adverse 
events observed during therapy.  IRRs have been associated predominantly with the 
first infusion and generally occur early during the infusion, shortly after the infusion, or, in 
some cases, up to 24 hours after the completion of the infusion.  In a few patients, 
concurrent signs of laboratory TLS were observed.  The incidence and intensity of IRRs 
decreased with subsequent infusions of obinutuzumab.  Other frequently observed 
adverse events include infections and neutropenia.  On the basis of preliminary 
observations, extensive tumor burden may be a predisposing factor for the occurrence of 
some IRRs.  Grades 3−4 thrombocytopenia and neutropenia, including febrile 
neutropenia, have been reported with obinutuzumab and were associated predominantly 
with treatment of CLL rather than NHL.  Given its anticipated mode of action that results 
in profound B-cell depletion, obinutuzumab may be associated with an increased risk of 
infections during and after treatment. 
Data from Study BO20999 (obinutuzumab monotherapy) showed safety and efficacy of 
single-agent obinutuzumab in patients with relapsed indolent and aggressive lymphomas.  
Responses were seen at both lower (400 mg) and higher (800 and 1600 mg) doses, 
although responses increased at the higher dose, with 54% of patients with indolent 
lymphoma and 32% of patients with aggressive lymphomas showing PR or CR at end of 
treatment (Morschhauser et al. 2013; Salles et al. 2013). 
Study BO21000 evaluated obinutuzumab in combination with chemotherapy, both 
fludarabine/cyclophosphamide and CHOP (Radford et al. 2013).  Both chemotherapy 
combinations were shown to be feasible in patients with previously untreated or 
relapsed/refractory FL with response rates of > 90% for both regimens.  Safety was 
acceptable with no new or unexpected adverse effects observed.  The most common 
adverse event was neutropenia. 
Data from obinutuzumab in combination with chlorambucil in patients with CLL 
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with a hazard ratio for PFS of 0.14.  IRRs were common and neutropenia occurred at 
increased frequency with the combination therapy, but there was no increase in 
infections or treatment-related deaths. 
See the Obinutuzumab Investigator’s Brochure for additional details on the clinical 
studies. 
1.2.3.5 
Obinutuzumab Pharmacokinetics and Pharmacodynamics 
A two-compartment model comprising a time-varying clearance pathway and a linear 
clearance pathway provides an adequate description of the pharmacokinetics of 
obinutuzumab following IV administration in Studies BO20999 and BO21003.  Following 
the infusion of obinutuzumab, the elimination appears to be characterized by a linear 
clearance pathway that is dependent on time (i.e., starting at a typical value of 
630 mL/day and then gradually decreasing to an asymptote of 60 mL/day at steady 
state).  Tumor burden may potentially contribute significantly to the clearance of 
obinutuzumab, especially at the beginning of treatment when CD20-positive tumor cells 
are most abundant.  As tumor burden decreases, the clearance reaches an asymptote 
that is believed to be primarily a function of the proteolytic metabolic clearance.  
Therefore, some patients with a high tumor burden may appear to clear the drug from 
the plasma faster than patients with a low tumor burden because obinutuzumab binds to 
the CD20-positive tumor cells and is effectively removed from the plasma.  Therefore, 
the clearance of the drug will vary with time, because repeated treatments with 
obinutuzumab will reduce the quantity of CD20-positive tumor cells.  Consequently, the 
number of obinutuzumab administrations during the first cycle of treatment may be 
expected to reduce the number of CD20-positive tumor cells, thus minimizing the impact 
of the time-varying clearance pathway on obinutuzumab exposure. 
Treatment with obinutuzumab resulted in extensive B-cell depletion, with all patients 
showing a reduction in B-cell counts to absolute zero at some stage of their treatment 
cycle.  Overall, there has been no notable increase in complement levels before and 
after infusion, but transient changes have been observed in the levels of interleukin 
(IL)-6 and IL-8 before and after infusion. 
1.3 
STUDY RATIONALE 
B-cell NHL cells, including DLBCL, express CD20 antigen.  Anti-CD20 therapy (rituximab) 
has been demonstrated to provide enhanced anti-tumor activity in combination with 
other agents targeting the disease (Coiffier et al. 2002; Hiddemann et al. 2005), leading 
to acceptance of R-CHOP as standard of care in most DLBCL and a common choice of 
therapy for other B-cell NHL.  However, significant room for improvement exists.  BCL2 
is overexpressed in most FL and many DLBCLs as a consequence of the t(14;18) 
chromosomal translocation or gene amplification and is associated with a poor prognosis 
in DLBCL (Iqbal et al. 2011).  Bcl-2 is likely to play a role in resistance to the 
pro-apoptotic activities of chemoimmunotherapeutic regimens, such as R-CHOP.  
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enhance the anti-leukemic activity of the regimen and to result in improved clinical 
outcomes.  Navitoclax is an inhibitor of Bcl-2 previously studied in the clinic that, 
because of its concomitant inhibition of Bcl-xL (a survival factor for platelets), causes 
dose-related thrombocytopenia.  Nonclinical data supporting the combination of 
R-CHOP and Bcl-2 inhibitors include murine xenograft models that demonstrated 
significantly improved anti-lymphoma activity of the combination of R-CHOP and 
navitoclax (ABT-263) over the activity of either treatment regimen alone 
(Ackler et al. 2010). 
Obinutuzumab is currently being compared with rituximab in combination with CHOP 
chemotherapy in a randomized trial in patients with DLBCL (Study BO21005).  
If obinutuzumab proves to be superior to rituximab, the standard of care would change to 
G-CHOP.  Therefore, the combination of venetoclax with both R-CHOP and G-CHOP 
will be examined in this study. 
DLBCL is a molecularly heterogeneous disease, with a variety of molecular subtypes 
identified through gene expression profiling (Rosenwald et al. 2002).  The two major 
subtypes, GCB and ABC, show activation of oncogenic and survival pathways that differ 
from each other and are associated with different prognoses.  Although evidence for a 
prognostic effect of Bcl-2 is greatest in the GCB subtype, both GCB and ABC DLBCL 
overexpress Bcl-2 in approximately 50% of cases, arguing for biological relevance of 
Bcl-2 in both subtypes.  The implications of Bcl-2 inhibition in each subtype are 
unknown; therefore, after the appropriate dose is identified, the combination will be 
investigated in an expanded cohort with enough patients in each molecular subgroup to 
obtain preliminary information regarding activity in each group. 
This study will explore the safety of the combination of venetoclax plus R-CHOP or 
G-CHOP in patients with B-cell NHL who are believed to be appropriate candidates for 
R-CHOP therapy during initial dose-finding cohorts and will further explore safety and 
efficacy in Phase II cohorts of patients with previously untreated DLBCL in order to 
identify appropriate populations for evaluation in a Phase III setting.  In addition, efficacy 
of venetoclax plus R-CHOP in the subgroup of patients with DE-DLBCL will be explored.  
DE-DLBCL is a recently defined poor prognostic subgroup, characterized in part by 
overexpression of Bcl-2, for whom the addition of venetoclax might add substantial 
therapeutic benefit. 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objective of the Phase I portion of the study is the following: 
• 
To estimate the maximum tolerated dosing schedule for venetoclax given in 
combination with R-CHOP or G-CHOP to patients with B-cell NHL, either previously 
untreated or relapsed/refractory after a maximum of one prior therapy 
 


 
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The primary objectives of the Phase II portion of the study are the following: 
• 
To assess the safety and tolerability of the combination of venetoclax and R-CHOP 
or G-CHOP administered to patients with previously untreated DLBCL 
• 
To make a preliminary assessment of efficacy as measured by CR rate at end of 
treatment determined by positron emission tomography and/or computed 
tomography (PET-CT) scans (see Appendix 2) of the combination of venetoclax and 
R-CHOP administered to patients with previously untreated DLBCL 
• 
To make an assessment of efficacy, as measured by CR rates at end of treatment 
determined by PET-CT scans, of the combination of venetoclax and R-CHOP 
administered to patients with previously untreated DLBCL co-expressing both Bcl-2 
and c-Myc proteins (i.e., DE-DLBCL) 
 
2.2 
SECONDARY OBJECTIVES 
2.2.1 
Pharmacokinetic Objectives 
The PK objectives of this study are the following: 
• 
To characterize the pharmacokinetics of venetoclax and relevant metabolites when 
administered in combination with R-CHOP or G-CHOP in the relapsed/refractory or 
previously untreated setting in NHL 
• 
To characterize the pharmacokinetics of rituximab, obinutuzumab, and prednisone 
when administered in combination with venetoclax in patients with 
relapsed/refractory or previously untreated B-cell NHL 
• 
To confirm exposure to cyclophosphamide, doxorubicin, and vincristine when given 
in combination with rituximab, obinutuzumab, and/or venetoclax 
 
2.2.2 
Secondary Efficacy Objectives 
The secondary efficacy objectives of this study include the following: 
• 
To make a preliminary assessment of efficacy when venetoclax and R-CHOP are 
administered in combination to patients with previously untreated DLBCL, as 
measured by: 
OR rate 
CR rate as determined by CT scan 
DOR 
PFS  
12 month PFS estimate  
OS 
• 
To make a preliminary assessment of efficacy when venetoclax and G-CHOP are 
administered in combination, as measured by OR rate, CR rate, and PFS. 
 


 
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2.2.3 
Exploratory Objectives 
The exploratory objectives of this study are the following: 
• 
To make a preliminary assessment of potential biomarkers that might predict 
disease response or resistance to treatment with the venetoclax plus R-CHOP or 
G-CHOP combinations in the relapsed or previously untreated setting: 
Bcl-2 and Bcl-2 family protein expression, including Bcl-xl and Mcl-1, by 
immunohistochemistry (IHC) 
BCL2 and c-MYC copy number gain by fluorescence in situ hybridization (FISH) 
and translocation t(14;18) by FISH 
Expression of transcripts for Bcl-2 family members, other apoptotic genes, and 
genes associated with ABC or GCB subtypes of DLBCL 
Subgroups relevant to DLBCL biology that are defined genetically or by poor 
prognosis, including CD79b, Myd88, CARD11, TNFAIP3, epigenetic markers, 
and MYC translocation 
• 
To make a preliminary assessment of the efficacy of venetoclax and R-CHOP in 
different potential prognostic subgroups, including DLBCL genotypic subtypes 
(e.g., ABC; GCB), high Bcl-2 (Bcl-2-positive) expression, as well as patients 
displaying BCL2 and MYC translocations (Double Hit) 
• 
To make a preliminary assessment of minimal residual disease (MRD) as a 
prognostic marker in DLBCL 
• 
To evaluate the prognostic significance of interim PET assessment in this setting 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase Ib/II, multicenter, open-label, dose-finding study of venetoclax 
administered orally in combination with rituximab or obinutuzumab and standard doses 
of CHOP in patients with NHL.  The study will consist of two stages:  a dose-finding 
Phase Ib stage and a Phase II expansion stage.  In the Phase I portion of the study, two 
parallel treatment arms will explore doses of venetoclax ranging from 200 to 800 mg 
administered in combination with R-CHOP and G-CHOP (see Figure 1).  Patients will be 
treated for a total of eight cycles (six cycles of CHOP and eight cycles of 
venetoclax + rituximab or venetoclax + obinutuzumab).  Each cycle will consist of 21 days.  
Patients who experience ongoing response without excessive toxicity may receive 
up to eight cycles of CHOP following discussion between the investigator and the 
Medical Monitor.  The maximum tolerated dose (MTD) of venetoclax in combination with 
R-CHOP and G-CHOP will be determined separately for each arm during the 
dose-finding stage.   
The dose and dose schedule for venetoclax for each arm determined in Phase I will be 
used in the Phase II expansion stage for that arm. 


 
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For the Phase II portion of the study, the venetoclax dose for Arm A is 800 mg on a 
non-continuous dosing schedule of Cycle 1 Days 4−10 and Cycles 2−8 Days 1−10, as 
determined by the Phase Ib portion of the study based on safety and tolerability 
observed in patients treated in the dose escalation portion of the study 
(see Section 3.2.3 for justification).   
If there are concerns about the tolerability of the Phase II dose at any time during the 
Phase II study, a lower dose or an alternative dosing schedule for venetoclax + R-CHOP 
or G-CHOP may be explored on a case by case basis based on the guideline provided 
in Section 4.3.  
For the Phase II R-CHOP arm of the study, after the first 20 patients have completed 
Cycles 1 and 2 of study treatment, the Internal Monitoring Committee (IMC) and 
Scientific Oversight Committee (SOC; see Section 3.1.1) will meet to review safety data 
for all patients treated in both the Phase Ib and Phase II portions of the study in order to 
confirm the safety and tolerability of the combination therapy at the venetoclax dose 
chosen at the end of Phase Ib.  Enrollment will continue while the interim safety analysis 
is being conducted.   
On the basis of this review, changes may be made to the dose or the dosing schedule of 
the Phase II (see Section 3.2.3). 
3.1.1 
Internal Monitoring Committee and Scientific Oversight 
Committee 
An IMC and a SOC will be established to monitor patient safety in both phases of the 
study.  The IMC and SOC will provide a recommendation for each treatment arm on the 
venetoclax dose to be taken forward into the Phase II portion of the study after 
completion of the dose-escalation phase and will provide a further recommendation at 
the Phase II interim safety analysis on the safety of this dose.  The IMC will include the 
Sponsor’s Medical Monitor and at least one other medical doctor/Clinical Science 
representative not directly involved in the study as well as representatives from drug 
safety, biostatistics, and statistical programming and analysis.  The IMC will continue to 
conduct periodic interim reviews of safety data quarterly during Phase II or more 
frequently as needed.  The SOC will comprise experts in DLBCL who are investigators 
for this study in order to provide guidance and a review of safety-related events.  
Separate SOC/IMC agreements will outline each committee's composition, meeting 
timelines, and members' roles and responsibilities.  The committee members will review 
all potential cases of serious adverse events, Grade 3 and 4 adverse events, and deaths 
as specified in the SOC/IMC agreement.  The SOC will be kept apprised of all relevant 
efficacy and safety data from this study and other related clinical trials.  Ad hoc meetings 
may be called in addition to scheduled meetings as necessary to provide 
recommendations on management of any new safety issues.  The Sponsor will make 
final decisions regarding protocol procedures and modifications. 


 
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Figure 1 Study Schema 
 
C = cycle; D = day; G = obinutuzumab; CHOP = cyclophosphamide, doxorubicin, vincristine, and 
prednisone; R = rituximab. 
 
The study will consist of two stages:  a dose-finding Phase Ib stage and a Phase II 
expansion stage.  The MTD of venetoclax in combination with R-CHOP and G-CHOP 
will be determined separately for each arm during the dose-finding stage.  The MTD and 
dosing schedule for venetoclax for each arm will be used in the Phase II stage for that 
arm, unless safety or tolerability signals suggest a lower dose will be more appropriate 
when combining with R-CHOP and G-CHOP.  The study will enroll approximately 
24−60 patients during the dose-finding stage and approximately 180−200 patients in the 
Phase II portion at approximately 69 investigative sites in North America, the European 
Union, and Asia Pacific. 
Patients will be evaluated for safety, tolerability, and pharmacokinetics of study 
treatment.  Assessments for anti-tumor activity will be performed following four cycles of 
study treatment (i.e., during Cycle 4, between Days 15 and 21) and at the completion of 
study treatment. 


 
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3.1.2 
Phase Ib:  Dose-Finding 
Each study arm (R-CHOP in Arm A or G-CHOP in Arm B) will have four dose-finding 
cohorts exploring venetoclax doses and dosing schedules ranging from 200 to 800 mg. 
with a maximum dose administration schedule of 10 days per cycle.  Patients will be 
allocated to a study arm in sequential fashion, starting with Arm A, Cohort 1.  Priority for 
enrollment when more than one arm is open to enrollment will be Arm A followed by 
Arm B.  In previous studies conducted with single-agent venetoclax, TLS has been 
observed after the first dose, particularly in patients with CLL at doses ≥ 50 mg/day.  
Clinically significant TLS was not observed in patients with NHL, other than in MCL; 
therefore, patients with MCL are excluded from this study.  However, TLS is a known 
risk following initiation of chemotherapy and anti-CD20 therapy in DLBCL.  It is possible 
that, with the combination of venetoclax and chemoimmunotherapy, an increased rate 
and severity of TLS could occur.  In order to mitigate the risk for TLS, venetoclax will be 
initiated following initiation of CHOP (see Section 3.1.2.1).  Additional prophylactic 
measures for mitigating the risk of TLS are described in Section 4.4.1.2. 
3.1.2.1 
Cohort Dosing Regimen 
Cycle 1 
• 
Patients in the R-CHOP arm will receive the first rituximab infusion (375 mg/m2), 
administered per package insert (along with standard premedications) on 
Day 1 (Cycle 1 Day 1).  Rituximab administration guidelines are outlined in 
Section 4.3.2.2. 
• 
Patients in the G-CHOP arm will receive their first obinutuzumab infusion 
(1000 mg) on Day 1 (Cycle 1 Day 1) along with standard premedication.  During 
Cycle 1, obinutuzumab will also be administered on Days 8 and 15.  Obinutuzumab 
administration guidelines are outlined in Section 4.3.3. 
• 
Note:  On the basis of a risk assessment for TLS and IRR by the investigator, 
patients with high tumor burden or those who cannot tolerate the full dose of 
rituximab or obinutuzumab in a single day because of adverse events may receive 
the antibody infusion split over 2 days or receive the first cycle as an inpatient, if 
necessary. 
• 
Following rituximab or obinutuzumab infusion, patients will receive CHOP 
chemotherapy, per standard administration procedures, along with standard 
premedications (see Section 4.3.4).  Note that the first prednisone dose for each 
cycle should be administered prior to rituximab or obinutuzumab. 
• 
Oral dosing of venetoclax will start on Day 4 of the first cycle (Cycle 1 Day 4).  In the 
event that CHOP dosing is delayed (for any reason), initiation of venetoclax dosing 
should also be delayed and then started 3 days following CHOP.  For example, if 
CHOP is first administered on Day 2, venetoclax dosing should be started on Day 5.  
Patients will be monitored for signs of acute TLS for at least 8 hours after the 
first venetoclax dose (see Section 4.4.1.2).   
• 
Oral dosing of venetoclax will then continue through Day 10 of Cycle 1 and 
Days 1-10 of Cycles 2 through 8 or alternative dose administration schedules, that 


 
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include oral administration of venetoclax on Days 4−8 in Cycle 1 and Days 1−5 in 
Cycles 2−8. 
• 
Guidelines for TLS prophylaxis were modified for high-risk TLS patients to consider 
starting at a lower dose of venetoclax and reaching the specified dose in a step-wise 
fashion in discussion with the Medical Monitor to prevent or promptly treat TLS (see 
Section 4.4.1.5) 
 
Cycles 2−6 
Patients will continue to receive an oral dose of venetoclax on Days 1-10.  On Day 1 of 
each cycle, venetoclax will be administered prior to any infusions.  Rituximab or 
obinutuzumab will be administered on Day 1 along with CHOP per standard 
administration guidelines.   
Cycles 7−8 
Patients will continue to receive an oral dose of venetoclax on Days 1-10.  On Day 1 of 
Cycles 7 and 8, venetoclax will be administered prior to infusion of rituximab or 
obinutuzumab.  Patients who experience ongoing response without excessive toxicity 
may receive up to eight cycles of CHOP following discussion between the investigator 
and the Medical Monitor. 
On days that pre-dose PK sampling is required, venetoclax and prednisone dosing will 
occur in the clinic to facilitate PK sampling. 
Patients should be pre-medicated with antihistamines and acetaminophen 
(corticosteroids if necessary) for rituximab infusion per the package insert, per 
Section 4.3.3.6 for obinutuzumab infusion, and with anti-emetics and IV hydration per 
institutional policy and standard of practice. 
3.1.2.2 
Dose-Escalation Guidelines 
Dosing with venetoclax will begin on Day 4 of Cycle 1 (or 3 days after the first CHOP 
dose, see Section 3.1.2.1) and continue to be administered daily through Day 8 
or Day 10 of Cycle 1 and then on Days 1−5 or Days 1−10 for Cycles 2−8 for up to 
eight 21-day cycles of combination therapy with R-CHOP or G-CHOP.  For each arm, if 
the cohort dosing regimen is determined to be tolerable and to not exceed the MTD (as 
described in Section 3.1.2.3), dose escalation of venetoclax will proceed to the 
subsequent cohorts.  All subsequent cohorts will start venetoclax on Day 4 of Cycle 1 
(or 3 days after the first CHOP dose; see Section 3.1.2.1 and Figure 2).  Venetoclax will 
continue to be administered at the target cohort dose schedule through Cycle 8 (Cycle 8 
Day 10). 


 
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Figure 2 Venetoclax Dose-Finding Cohorts 
 
C = cycle; D = day; W = week. 
 
If the administration of venetoclax results in unacceptable toxicity on Days 4−10 of 
Cycle 1 and Days 1−10 of Cycles 2-8 schedule or other proposed alternative dose 
administration schedules then alternative dose regimens of venetoclax (e.g., venetoclax 
administered on Days 1–3 or 1–7 of 21) or lower doses of venetoclax may be substituted 
in subsequent cohorts.  If clinically significant TLS is observed at initiation of the 
administration of venetoclax, alternative doses and dose administration schedules will be 
explored (e.g., initiate the administration of a lower dose with a gradual dose escalation 
to the target dose).  If clinically significant TLS is not observed in this study in the initial 
cohorts then venetoclax dosing starting at Cycle 1 Day 1 or Day 2 may be explored.  If 
venetoclax dosing starts at Cycle 1 Day 1 or 2 then the DLT observation period would be 
shortened to one cycle) (see Section 3.4.1.1).  Dose modification of R-CHOP or 
G-CHOP (delays and reductions) because of myelosuppression will be made per 
Section 4.5.6. 
3.1.2.3 
Dose-Escalation Rules and Determination of Dose-Limiting 
Toxicity 
The following dose-escalation rules will apply: 
• 
DLTs in this study are defined as qualifying events occurring during the DLT 
observation period (see Section 3.1.2.4) experienced during combination therapy 
with venetoclax plus R-CHOP or G-CHOP. 
• 
Dose escalation will be pursued using a modified 3 + 3 design.  At least 3 patients 
will be enrolled in each arm per Cohort.  Additional patients may be enrolled at each 
dose level/dose schedule. 
• 
If none of the first 3 evaluable patients experience a DLT during the DLT 
observation period prior to dose escalation (0 of at least 3 patients), then the next 
dose cohort (as described in Section 3.1.2.1) may be evaluated.  Available data 
from all patients receiving study drug will be considered in dose escalation decisions. 


 
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• 
If DLT is observed in 1 patient at a given dose level during the DLT observation 
period prior to dose escalation, additional patients will be enrolled at that dose level 
until at least 6 evaluable patients have completed the DLT observation window or 
until a second DLT occurs. 
• 
If no additional patients experience a DLT during the DLT observation period (≤ 1 of 
at least 6 evaluable patients), then the next dose cohort (as described in 
Section 3.1.2.1) may be evaluated. 
• 
If an additional DLT is observed after expanding beyond 3 evaluable patients 
(≥ 2 DLTs out of at least 6 evaluable patients or in one-third or more of patients if the 
cohort includes more than 6 patients), further enrollment at that dose schedule will 
be halted and that dose will either be declared as exceeding the MTD or a different 
dose administration regimen will be implemented, in which case dose escalation 
may resume.  
 
Alternative dose administration regimens (e.g., shorter non-continuous dose 
administration of venetoclax) may be explored, as described in Section 3.1.2.2, 
depending upon the toxicity profile observed. 
Dose cohorts resulting in DLTs in less than one-third of a minimum of 6 patients will be 
considered for further study in the Phase II part of the study. 
The highest (or most dose-intensive) dose administration regimen that results in DLTs in 
less than one-third of a minimum of 6 patients will be declared the MTD. 
3.1.2.4 
Definition of Dose-Limiting Toxicity 
All adverse events, including DLTs, are to be reported according to instructions in 
Section 5.1.3 and graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0).  If a patient 
experiences a DLT, he or she will be treated according to clinical practice and will be 
monitored for resolution of the toxicity.  Decrease in B cells, lymphopenia, and 
leukopenia caused by lymphopenia will not be considered DLTs but instead are 
expected pharmacodynamic outcomes of study treatment.  Any Grade ≥ 3 adverse event 
that is attributed to having a reasonable possibility of being related to the combined 
administration of venetoclax plus R-CHOP or G-CHOP, that cannot be attributed by the 
investigator to an alternative, clearly identifiable cause such as tumor progression, 
concurrent illness or medical condition, or concomitant medication and that occurs 
during the DLT observation period (beginning of venetoclax administration through the 
end of Cycle 2) will be considered a DLT for dose-escalation purposes.  Grade 3 or 4 
neutropenia or thrombocytopenia identified on Day 1 of Cycle 2 or 3, resulting in dose 
delay is considered a DLT. 


 
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The following events are exceptions and will not be considered DLTs: 
• 
Grade 3 or 4 lymphopenia, which is an expected outcome of therapy 
• 
Grade 3 or 4 neutropenia that is not accompanied by temperature elevation (oral or 
tympanic temperature of ≥ 100.4°F [38°C]) and improves to Grade ≤ 2 (or to ≥ 80% 
of the baseline value, whichever is lower) by Day 1 of the next cycle 
• 
Grade 3 neutropenic fever 
• 
Grade 3 or 4 leukopenia as a result of lymphocyte depletion 
• 
Grade 3 or 4 thrombocytopenia that does not result in bleeding and improves to 
Grade ≤ 2 (or to ≥ 80% of the baseline value, whichever is lower) by Day 1 of the 
next cycle without platelet transfusion 
• 
Grade 3 or 4 anemia 
• 
Grade 3 laboratory TLS without manifestations of clinical TLS (i.e., creatinine 
≥ 1.5 times  the upper limit of normal [ULN] and/or renal dysfunction, cardiac 
arrhythmias, seizures, or sudden death) 
• 
Grade 3 nausea or vomiting ≤ 7 days (in the absence of premedication or that can 
be managed with oral or IV anti-emetics) 
• 
Reversible Grade 3 infusion related toxicities (including symptoms such as fever, 
chills/rigors, nausea, vomiting, pruritus, headache, rhinitis, rash, and hypotension) 
occurring during or within 24 hours after completing an infusion and resolving within 
24 hours with a reduced infusion rate, supportive care, and/or administration of 
corticosteroids 
 
If a patient experiences a DLT as described above, the patient will be observed for 
resolution of the toxicity.  If the DLT resolves to Grade ≤ 2 (or ≥ 80% of the baseline 
value) within 2 weeks and it is determined to be in the patient’s best interest to continue 
study treatment (after discussion between the treating investigator and the 
Medical Monitor), the patient may continue to receive study treatment, provided that the 
study treatment dose modifications are made as agreed to between the investigator(s) 
and the Medical Monitor. 
If Grade 3 or 4 neutropenia and/or thrombocytopenia that do not meet the definition of a 
DLT are observed in a patient receiving combination treatment, the patient may continue 
to receive treatment, provided the neutropenia and/or thrombocytopenia has resolved to 
Grade ≤ 2 (or ≥ 80% of the baseline value, whichever is lower) within the time frame 
described above.  Guidelines for dose reduction of R-CHOP or G-CHOP are provided in 
Section 4.3.3.3. 
3.1.3 
Phase II:  Expansion 
The Phase II portion of the study will consist of one cohort for each study arm (R-CHOP 
and G-CHOP) with the use of the established venetoclax dosing schedule identified 
during the dose-finding stage for that arm in patients with previously untreated DLBCL.  
If both arms are open to Phase II enrollment, patients will be assigned to Arm A 


 
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(venetoclax + R-CHOP) or Arm B (venetoclax + G-CHOP) through randomization.  If only 
one arm is open to Phase II enrollment at a given time, then patients will be directly 
assigned to the open arm.  The Phase II portion will enroll only patients with previously 
untreated DLBCL.  Because effects of Bcl-2 inhibition may differ depending on both the 
level of Bcl-2 expression and the molecular milieu (see Section 1.3), activity of the 
combination will be explored in specific molecular subsets, including Bcl-2 high, Bcl-2 
low, Bcl-2- overexpression and c-Myc overexpression (DE), and GCB and ABC subtypes 
of DLBCL. 
Enrollment into the R-CHOP cohort of patients with both Bcl-2 high and Bcl-2 low 
DLBCL will continue until approximately 50 patients with DE-DLBCL (approximately 
160−200 patients total; see Section 4.10.6.  Bcl-2 and c-Myc expression analysis results 
will not be required prior to enrolling patients in the Phase II cohorts.  It is estimated that 
approximately 50% of patients with DLBCL will have high expression of Bcl-2, and that 
approximately 20%−30% of patients with DLBCL will have high expression of both Bcl-2 
and c-Myc (DE). 
Patients will be monitored for safety and tolerability during the study, including ability to 
maintain relative dose intensity of the chemotherapy (CHOP) backbone.  After 
20 patients on Arm A of the Phase II portion of the study have completed the first 
two cycles of study treatment, an interim safety analysis of all patients treated to date on 
both the Phase Ib and Phase II portions of the study will be conducted in order to 
confirm the safety and tolerability of the venetoclax Phase II dose in the combination.  
Enrollment will continue while the interim safety analysis is being conducted.  
If there are concerns about the tolerability of the Phase II dose at any time during the 
Phase II study, a lower dose or an alternative dosing schedule for venetoclax + R-CHOP 
or G-CHOP may be explored on a case by case basis based on the guideline provided 
in Section 4.3. 
Disease assessments will be performed 15−21 days after completion of Cycle 4 dosing 
(interim response assessment) and 6−8 weeks after Day 1 of the last cycle received 
(end-of-treatment response).  Thereafter, patients will be followed in the clinic every 
3 months for safety and disease assessments for up to 2 years after the last patient has 
completed treatment or until death or study termination, whichever occurs first. 
3.1.4 
Discontinuation of Venetoclax plus R-CHOP or G-CHOP 
Patients who discontinue venetoclax plus R-CHOP or venetoclax plus G-CHOP for 
reasons other than PD should have a documented response assessment and continue to 
be followed until disease progression even after institution of alternative therapy.  These 
patients should continue with follow-up visits every 3 months to collect information on 
disease progression and /or initiation of an alternative lymphoma therapy.  After PD, 
patients will also continue to be followed for OS (see Section 4.5.5). 


 
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3.2 
RATIONALE FOR STUDY DESIGN 
3.2.1 
Benefit/Risk Assessment 
This study combines treatments that have demonstrated clinical activity against B-cell 
NHL in general and DLBCL in particular:  R-CHOP chemoimmunotherapy is one of the 
standard treatment regimens for B-cell NHL, and the experimental agent venetoclax is a 
specific inhibitor of the Bcl-2 anti-apoptotic protein expressed in many NHL cells.  
Bcl-2 overexpression is likely to play a role in resistance to the pro-apoptotic activities of 
chemoimmunotherapeutic regimens such as R-CHOP.  In parallel, the substitution of 
obinutuzumab⎯a novel anti-CD20 monoclonal antibody that has shown significant 
promise in B-cell malignancies⎯for rituximab will be tested in this regimen.  
Obinutuzumab is currently being compared with rituximab in combination with CHOP in 
a Phase III study in patients with previously untreated DLBCL and if results of this study 
demonstrate superiority of obinutuzumab, the G-CHOP regimen will be used in future 
studies of the combination.  The addition of a Bcl-2 inhibitor to R-CHOP or G-CHOP has 
the potential to significantly enhance the anti-lymphoma activity of the regimen and to 
result in improved clinical outcomes. 
Nonclinical data support the rationale for improved efficacy and for tolerability, 
respectively, of the combination of R-CHOP and the Bcl-2/Bcl-xL dual inhibitor navitoclax 
(see Section 1.3).  Because venetoclax is a specific inhibitor of Bcl-2 and does not 
appreciably inhibit Bcl-xL, it is predicted that dose-limiting thrombocytopenia may be 
avoided or reduced relative to navitoclax, allowing for a potentially greater therapeutic 
index and increased clinical efficacy compared with either R-CHOP alone or the 
combination with navitoclax. 
Principal risks identified for the combination regimen of R-CHOP or G-CHOP with 
venetoclax include:  TLS, infusion reactions to rituximab or obinutuzumab, cytopenias, 
(i.e., neutropenia, thrombocytopenia, or lymphopenia), infections, other malignancies, 
and drug interactions with CYP3A4 inhibitors or inducers (venetoclax).  In addition, there 
is a theoretical concern for potentiation of anthracycline-induced cardiotoxicity.  The 
protocol includes the following features to address these risks: 
• 
Measures to prevent TLS include use of prophylactic hydration and medication prior 
to initial dosing with careful monitoring during the first 24 hours after dosing for 
metabolic or clinical signs of impending TLS (see Section 4.4.1.5).  In addition, 
dosing of venetoclax will be staggered; venetoclax dosing will be initiated 3 days 
after the first CHOP dose (see Section 3.1.2.1) during the first cycle of 
chemoimmunotherapy in all cohorts for both R-CHOP and G-CHOP arms.  If 
clinically significant TLS is not observed in this study in the initial cohorts then 
venetoclax dosing starting at Cycle 1 Day 1 or Day 2 may be explored.  Guidelines 
for TLS prophylaxis were modified for high-risk TLS patients to consider starting at a 
lower dose of venetoclax and reaching the specified dose in a step-wise fashion in 
discussion with the Medical Monitor to prevent or promptly treat TLS 
(see Section 4.4.1.5) 


 
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• 
Prophylactic medication (see Section 4.3.3) will be administered and careful 
monitoring guidelines will be used to manage infusion reactions for rituximab or 
obinutuzumab. 
• 
Frequent blood testing throughout the treatment period will monitor for cytopenias.  
Dose delays or dose reductions are mandated for severe cytopenias.  In addition, all 
supportive measures including transfusion, antibiotics, and the use of growth factors 
are allowed.  Guidelines for venetoclax dose modification due to thrombocytopenia 
are listed in Section 4.3.6 (see Table 3). 
• 
Anti-infection prophylaxis is not mandated for all patients because of the potential 
risks of adding additional concomitant medications but may be prescribed by the 
investigator in specific cases where patients are at especially high risk.  Patients 
with preexisting infections are excluded from the study to avoid reactivation.  
Neutropenia will be closely monitored and may be treated with growth factors, and 
any signs of infection will be treated with appropriate medication. 
• 
Guidelines for concomitant medications to avoid or use with caution are provided in 
view of the possible drug-drug interactions (see Appendix 5). 
 
The venetoclax + R-CHOP or G-CHOP treatment combinations are expected to be 
associated with toxicities that can largely be managed (e.g., first-dose TLS and infusion 
reactions) or that are commonly encountered with the treatment of NHL and that can be 
mitigated with the measures outlined in this protocol.  In particular, infection and 
cytopenias are common during the treatment of NHL with chemoimmunotherapy as a 
result of myelosuppressive effects of the treatment.  The potential advantage of this 
regimen is that the addition of a Bcl-2 inhibitor may facilitate targeted cell killing of 
high-Bcl-2 expressing NHL cells without the need to further increase myelosuppression 
over what is observed with R-CHOP. 
As discussed in Section 1.1.2, although DLBCL is curable in many patients, those who 
are not cured have extremely poor outcomes, arguing for urgent incorporation of novel 
therapies.  Because the likelihood of curing DLBCL is known to be impacted by 
maintenance of dose intensity of standard chemotherapy, dose intensity will be 
monitored on a regular basis by the IMC/SOC (see Section 4.10.4.2), and evidence of 
excessive dose delays or reductions would prompt modification of the trial. 
Because many patients with B-cell NHL are not cured with standard therapy, the benefit 
of a novel therapy with the potential to evade chemotherapy resistance through the 
incorporation of the Bcl-2 inhibitor outweighs the risks expected from this combination 
regimen and supports initiation of this Phase Ib/II study. 
3.2.2 
Rationale for Venetoclax Dose Selection in the Phase I Portion 
of the Study 
Venetoclax dosing for this study was determined on the basis of the experience from the 
Phase I study (Study M12-175) with single-agent venetoclax in relapsed/refractory 
patients with NHL.  This study explored a step-up dosing schedule in order to safely 


 
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administer venetoclax by reducing the risk for TLS showing safety of initial doses of up 
to 400 mg without clinically significant TLS in NHL.  Final target doses of up to 800 mg 
have been shown to be tolerable in patients with CLL.  Patients with NHL have received 
final target doses of 1200 mg without DLTs.  The starting dose will be 200 mg.  
Subsequent dose cohorts will explore progressively higher starting and target doses up 
to a final dose of 800 mg, if tolerated.  Given that venetoclax will be administered in 
conjunction with R-CHOP or G-CHOP chemoimmunotherapy, which on its own has a 
degree of myelosuppression, venetoclax dosed up to the MTD achieved as monotherapy 
may not be tolerable in this combination.  The number of cycles of dosing (eight 3-week 
cycles) is designed to provide treatment duration consistent with other therapies for NHL 
that have been shown to be sufficient to provide durable responses. 
3.2.3 
Rationale for Venetoclax Dose Selection in the Phase II Portion 
of the Study 
As per study design description (see Section 3.1), the MTD and dosing schedule for 
venetoclax for each arm will be used in the Phase II stage for that arm, unless safety or 
tolerability signals suggest a lower dose would be more appropriate when combined with 
R-CHOP and G-CHOP.   
In the Phase Ib dose-escalation portion of the study, none of the dose levels studied 
exceeded the MTD on the non-continuous dosing schedule.  Since no MTD could be 
identified at any dose-level tested, and since it was considered unlikely that higher doses 
of venetoclax would provide an improved benefit/risk profile, on the basis of the data 
from the other clinical studies of venetoclax in NHL, the 800-mg dose was selected for 
the R-CHOP arm.   
Overall, the combination of R-CHOP with venetoclax administered on the 
non-continuous schedule was well tolerated.  However, two adverse events were noted 
to occur at increased frequency than would be expected with R-CHOP alone and were 
likely because of the combination therapy:  diarrhea and thrombocytopenia.  These 
toxicities were adequately managed with medical intervention and dose interruptions, but 
following review by the IMC/SOC, further dose escalation was not felt to be indicated.  
Guidelines for management of these events are provided in Table 3 and Section 4.4.1.8.  
Therefore, on the basis of safety and tolerability observed in patients treated in the 
dose-escalation portion of the study, the Phase II venetoclax dose for Arm A 
(venetoclax + R-CHOP) is 800 mg on a non-continuous dosing schedule of Cycle 1 
Days 4−10 and Cycles 2−8 Days 1−10.  In M12-175 (singe agent venetoclax) study 
responses were observed in DLBCL with single agent venetoclax doses that range from 
600 mg to 1200 mg with no evidence of improved responses at doses higher than 
600 mg.   
In order to confirm that the Phase II dose is safe and tolerable, a safety interim analysis 
will be performed after 20 patients enrolled in Phase II Arm A have completed two cycles 


 
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of combination therapy.  During this analysis, data will be reviewed for all patients in both 
arms enrolled in the study in order to assess safety and tolerability of the combination in 
a larger number of patients.  In addition, review of data from patients treated on the 
Phase Ib portion of the study will allow assessment of longer-term tolerability of the 
combination throughout the planned treatment course, including incidence of dose 
delays or dose reductions in later cycles.  Enrollment will continue while the interim 
safety analysis is being conducted.   
An IMC and SOC (see Section 3.1.1) will meet to review safety data for all patients 
treated in both the Phase Ib and Phase II portions of the study in order to confirm the 
safety and tolerability of the combination therapy at the Phase II dose.  Given the results 
from this analysis, the Sponsor may decide to decrease the dose or the dosing schedule 
of the Phase II part of the study. 
In addition, the SOC and the IMC will conduct periodic interim reviews of safety data 
during Phase II (see Section 3.1.1).  Given the results from these reviews, the Sponsor 
may decide to decrease the dose or dosing schedule of the Phase II part of the study. 
On 17 July 2016, Roche/Genentech as the sponsor of Study BO21005 (Goya study), a 
Phase III study that evaluated G CHOP versus R-CHOP in 1L DLBCL, informed 
through a press release that the primary endpoint of investigator-assessed PFS was not 
met.  Given these results, Arm B (venetoclax + G-CHOP) will not be expanded in Phase 
II in patients who are first-line with DLBCL. 
3.2.4 
Rationale for R-CHOP Dosing 
R-CHOP will be administered at standard dose on a standard 21-day cycle schedule.  
CHOP chemotherapy will be given for six cycles, with eight total cycles of rituximab 
(Pfreundschuh et al. 2008).  Six cycles of CHOP chemotherapy have been chosen for 
this study on the basis of National Comprehensive Cancer Network guidelines for the 
United States.  However, because global standards of care differ when a 21-day 
schedule for R-CHOP is used and because no comparative data regarding number of 
cycles are available using R-CHOP−21, patients who experience ongoing response 
without excessive toxicity may receive up to eight cycles of CHOP following discussion 
between the investigator and the Medical Monitor. 
3.2.5 
Rationale for G-CHOP Dosing 
G-CHOP is being studied in two ongoing clinical studies in patients with DLBCL.  In both 
studies, CHOP is administered at standard doses and schedule.  The dose and 
schedule for obinutuzumab in this regimen is 1000 mg on Days 1, 8, and 15 of Cycle 1 
and Day 1 of each cycle thereafter for a total of eight cycles of obinutuzumab.  This dose 
and schedule were chosen for the following reasons: 
• 
In Study BO20999, patients were randomized to two different obinutuzumab dose 
cohorts.  In the low-dose (LD) cohort, patients received eight cycles of 400 mg of 


 
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obinutuzumab, with an additional 400-mg dose given on Day 8 of the first cycle.  In 
the HD cohort, obinutuzumab was given at 1600 mg on Days 1 and 8 of the 
first cycle, followed by 800 mg at Cycles 2−8.  No DLTs were observed between the 
two doses and, although there was a slight increase of IRRs and neutropenia rates 
in the HD cohort, obinutuzumab was generally very well tolerated.  As expected, PK 
variability was lower at the higher dose.  Importantly, an increased overall response 
rate was observed in the HD cohort compared with the LD cohort (55% vs. 13%, 
respectively) in the subset of patients with indolent lymphoma and a trend toward 
better response rates in the HD cohort was observed in patients with aggressive 
lymphomas, arguing that a higher dose is more effective and not significantly more 
toxic. 
• 
In the HD cohort of Study BO20999, the first two doses of obinutuzumab were set at 
1600 mg.  Although well tolerated by patients, the dose administration scheme 
resulted in dose administration times of ≥ 5 hours.  With the goal of maintaining the 
loading dose concept and to provide a significant amount of antibody early in the 
treatment course, it was decided to split the obinutuzumab dose administration and 
to change the schedule and dose during the first 2 weeks of any future studies from 
1600 mg administered on Days 1 and 8 to 1000 mg administered on Days 1, 8, 
and 15.  This dosing regimen may provide comparably fast rising PK exposure and 
early target saturation, while avoiding the practical challenges of delivering 1600 mg 
of drug in a single day together with chemotherapy.  The dose administered for 
subsequent cycles is also set at 1000 mg.  This dose and schedule will result in an 
obinutuzumab exposure of 3000 mg during the first 2 weeks for a cumulative 
exposure of 10,000 mg and is therefore very close to the regimen that has delivered 
the best results thus far for obinutuzumab in both indolent and aggressive 
lymphoma.  There is no indication that the additional obinutuzumab doses 
administered on Days 8 and 15 in the first cycle would negatively affect the safety of 
patients. 
 
Results reported to date in these ongoing studies suggest that this dose administration 
schedule is tolerable.  In order to maintain consistency with these studies, the same 
dosing schedule will be administered in the current study. 
3.2.6 
Rationale for Dosing Schedule 
Both venetoclax plus R-CHOP/G-CHOP demonstrate rapid response of malignant and 
normal peripheral B lymphocytes after initial administration.  TLS has been observed 
following initiation of both R-CHOP and venetoclax in both FL and DLBCL, but the 
frequency and severity of TLS related to venetoclax is expected to be less than that 
seen with CLL.  Staggered dosing of venetoclax will be administered, as described in 
Section 3.1.2.2.  If clinically significant TLS is not observed in this study in the initial 
cohorts then venetoclax dosing starting at Cycle 1 Day 1 or Day 2 may be explored. 
Patients will receive TLS prophylaxis with hydration and a uric acid-lowering agent at 
least 72 hours prior to the first dose of venetoclax.  The venetoclax dose administration 
schedule was changed to administering venetoclax in Cycle 1 on Days 4−10 and 


 
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Cycles 2−8 on Days 1−10 due to as a result of toxicities observed in the first cohort of 
200 mg of venetoclax under continual daily dosing.   
3.2.7 
Rationale for Treatment of Patients with Previously Untreated 
DLBCL 
DLBCL is potentially curable, with approximately 60% of patients having long-term 
remissions following standard treatment with R-CHOP.  Patients with intermediate to 
high risk by the IPI have a lower chance of cure with R-CHOP therapy than those with 
low IPI, and patients who relapse or are refractory to R-CHOP have very poor outcomes, 
with most dying within 2 years (Gisselbrecht et al. 2010).  Better treatments are urgently 
needed for these patients.  Bcl-2 is overexpressed in most DLBCL and likely plays a role 
in resistance.  Therefore, exploring this combination in first-line DLBCL is compelling.  
Given the potential for cure of these patients with standard therapy and the importance 
of maintaining dose and schedule of R-CHOP, a critical issue in exploring the 
combination with venetoclax is to minimize the chance for dose delays or reductions.  It 
is critical to explore the tolerability of this combination in the proposed Phase II cohorts 
in order to demonstrate the feasibility of dose maintenance before embarking on a large 
Phase III study in the future. 
3.2.8 
Rationale for Pharmacokinetic Assessments 
The risk of clinically significant PK drug interaction between venetoclax, rituximab, or 
obinutuzumab and CHOP is expected to be low on the basis of their metabolic pathways.  
Venetoclax is primarily metabolized by CYP3A4 and is a reversible inhibitor of CYP2C8 
and CYP2C9.  Rituximab and obinutuzumab are biologics administered intravenously 
and are not expected to modulate CYP3A4 activity and affect venetoclax metabolism.  
Prednisone has been implicated as potential weak CYP3A4 inducer and/or an inducer of 
P-gp, which could result in reduced venetoclax concentrations depending on the 
prednisone dose and timing relative to venetoclax administration and the duration of the 
induction effect after prednisone dosing is stopped. 
Rituximab and obinutuzumab have decreased clearance with time that may be related to 
CD20 target expression and tumor burden.  Venetoclax may affect the clearance of 
rituximab and obinutuzumab because it has the potential to decrease tumor burden.  PK 
samples for rituximab and obinutuzumab will be collected to assess whether drug levels 
differ from the combination compared with historical data to check for potential drug-drug 
interactions. 
Drug-drug interaction potential between venetoclax and prednisone will also be explored 
in this study.  PK samples for prednisone will be collected on Cycle 1 Day 1 (before 
administration of venetoclax) and Cycle 2 Day 1 (when administered with venetoclax). 
PK samples to assess the plasma/serum levels of venetoclax, rituximab, obinutuzumab, 
and CHOP components will be collected according to the schedule in Appendix 3.  


 
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Alternative PK assessments may be explored if there is substantial difficulty in obtaining 
the time points listed in Appendix 3. 
3.2.9 
Rationale for Collecting Tumor Biopsies and Peripheral Blood 
for Biomarker Studies 
DE-DLBCL, defined as Bcl-2 high and c-Myc high protein, are associated with poor 
outcomes in DLBCL.  Identifying these DE patients is a primary objective of this study.  It 
is estimated that approximately 50% of patients with DLBCL will have high expression of 
Bcl-2, and that approximately 20%−30% of patients with DLBCL will have high 
expression of both Bcl-2 and c-Myc (DE).  Bcl-2 is also associated with poor prognosis 
(Iqbal et al. 2011).  The t(14;18) translocation, which places the BCL2 gene under the 
control of the immunoglobulin heavy chain enhancer, is found in the GCB subtype of 
DLBCL; amplification of the 18q21 locus where the BCL2 gene resides are found in the 
ABC subtype.  Together, somatic genetic aberrations are found in 30%−40% of patients 
with DLBCL, and whereas, both result in overexpression of Bcl-2 at the mRNA and 
protein levels, Bcl-2 expression is associated with a poorer prognosis in the GCB 
subtype.  Therefore, the efficacy of therapy in high Bcl-2 (Bcl-2 positive) and in different 
prognostic subgroups, including ABC/GCB, will be important to help identify the target 
population for Phase III that will most likely benefit from venetoclax in combination with 
R-CHOP or G-CHOP. 
Venetoclax inhibits the ability of cancer cells to evade cell death, or apoptosis, by 
blocking the activity of the anti-apoptotic protein Bcl-2.  Nonclinical studies have 
demonstrated a pattern of response to venetoclax on the basis of genetic aberrations in 
Bcl-2, Bcl-2 protein levels, and the levels of Bcl-2 family proteins (Souers et al. 2013).  
High levels of Bcl-2 and low levels of Mcl-1 are generally predictive of response to 
Bcl-2 inhibitors in vitro (Mérino et al. 2012), and loss of expression of proteins involved in 
mitochondrial apoptosis and/or upregulation of Mcl-1 is associated with resistance.  
In addition, high levels of at least one pro-apoptotic “sensor,” such as Noxa or Bim, is 
required.  The following relevant DNA, RNA, and proteins (including Bcl-2 and 
prognostic subgroups) will be measured at baseline to identify biomarkers that predict 
efficacy and, when available, also at relapse to understand mechanisms of resistance: 
• 
Bcl-2 and c-Myc protein expression by IHC 
• 
Bcl-2 and Bcl-2 family protein expression by IHC 
• 
BCL2 and c-MYC copy number gain by FISH and translocation t(14;18) by FISH 
• 
Expression of transcripts for BCL2 family members, other apoptotic genes, and 
genes associated with the ABC or GCB subtypes of DLBCL 
• 
Subgroups relevant to DLBCL biology that are defined genetically or by poor 
prognosis including CD79b, Myd88, CARD11, TNFAIP3, epigenetic markers, and 
MYC translocation 
MRD may have prognostic value in DLBCL.  In patients with an identifiable IgH 
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the Phase II portion of this study, peripheral blood samples will be collected for MRD 
at baseline, Cycle 4 Day 1, 6−8 weeks following Cycle 8 Day 1, and every 3 months 
during follow-up for 1 year.   
 
The following samples will be collected to enable the evaluation of the parameters listed 
above: 
• 
A tumor biopsy sample (either archival or fresh) must be collected from all patients.  
The tumor specimen must contain adequate evaluable tumor cells to enable Bcl-2 
IHC and other relevant biomarker analysis.  Samples can be in a tissue block 
(preferred) or prepared as 20 unstained serial slides, and should be accompanied 
by an associated pathology report.  The specimen must be a formalin-fixed, 
paraffin-embedded tumor specimen, or another appropriate fixative must be used 
(notation of the type of fixative should be included).  Cytological or fine-needle 
aspiration as well as bone marrow samples are not acceptable. 
• 
In the Phase II portion of this study, a tissue punch sample must be collected from 
the tissue block in patients who have an excisional biopsy sample available. 
• 
The tissue punch must be submitted to the pathology central laboratory for 
construction of tissue microarrays (TMAs).  Instructions for tissue punch will be 
provided in the laboratory manual. 
• 
An FFPE tumor biopsy sample must be collected at disease progression and sent to 
the central laboratory to evaluate venetoclax resistance mechanisms.  The sample 
must be a tissue block or 20 unstained serial slides. 
• 
Blood collection to evaluate blood-based approaches to classification of ABC/GCB 
and other DLBCL subgroups 
• 
Plasma collection at Baseline, Cycle 5, and at relapse to evaluate circulating tumor 
markers that could be associated with response/resistance including but not limited 
to mutations in BCL2 
 
3.3 
OUTCOME MEASURES 
3.3.1 
Safety Outcome Measures 
The safety and tolerability of the combination of venetoclax plus R-CHOP or G-CHOP 
will be assessed using the following primary safety outcome measure: 
• 
Incidence and nature of combination DLTs 
 
In addition, safety will be assessed using the following secondary safety outcome 
measures: 
• 
Incidence, nature, and severity of adverse events and serious adverse events 
graded according to NCI CTCAE v4.0.  Adverse events of special interest include 
Grade 4 neutropenic fever, Grade ≥ 3 IRRs to rituximab or obinutuzumab, and 
Grade ≥ 4 TLS. 
• 
Change in clinical laboratory results (including hematology and chemistry) and vital 
signs 


 
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• 
Maintenance of relative dose intensity of CHOP chemotherapy 
 
3.3.2 
Pharmacokinetic Outcome Measures 
The following PK parameters will be derived from the plasma concentration-time profile 
of prednisone, venetoclax, and relevant metabolites following administration when 
appropriate, as data allow: 
• 
Total plasma exposure (AUC) 
• 
Time to maximum observed plasma concentration (tmax) 
• 
Cmax in plasma 
• 
Minimum plasma concentration under steady-state conditions within a dosing 
interval (Cmin) in plasma 
 
The following PK parameters will be determined from the concentration-time profiles of 
rituximab, obinutuzumab, and CHO components, as applicable: 
• 
Cmax in serum or plasma, as appropriate 
• 
Cmin in serum or plasma, as appropriate 
 
Other PK parameters such as clearance, volume of distribution (V), and half-life may 
also be calculated as data allow. 
3.3.3 
Efficacy Outcome Measures 
The following activity outcome measures will be assessed: 
• 
Primary outcome measures: 
CR, as defined by PET-CT scan as well as bone marrow examination when 
applicable (see Appendix 2) 
• 
Secondary outcome measures: 
CR, as defined by CT scan and bone marrow examination, when applicable 
OR, defined as a PR or CR 
DOR, defined as the first occurrence of a documented response until the time of 
relapse or death from any cause 
PFS, defined as the time from date of first dose of study drug to the first 
occurrence of progression, relapse, or death while in the study, where death 
while in the study is defined as death from any cause within 12 weeks of the last 
tumor assessment  
PFS at 12 months 
Relative dose intensity 
OS, defined as the time from date of first dose of study drug until the date of 
death from any cause.  For patients who have not died, survival data will be 
censored at the date of last contact. 
 


 
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OR and disease progression will be determined with use of the modified Lugano 
Classification:  Revised Criteria for Response Assessment (Cheson et al. 2014; 
see Appendix 2).  
3.3.4 
Exploratory Assessments 
The following correlative biology measures will be assessed: 
• 
Bcl-2 high (Bcl-2 positive) as defined by IHC and Bcl-2 family protein expression 
by IHC 
• 
BCL2 and c-MYC copy number gain by FISH and translocation t(14;18) by FISH 
• 
Expression of transcripts for Bcl-2 family members, other apoptotic genes, and 
genes associated with the ABC or GCB subtypes of DLBCL 
• 
Subgroups relevant to DLBCL biology, including CD79b, Myd88, CARD11, 
TNFAIP3, epigenetic markers, and MYC translocation 
 
3.4 
SAFETY PLAN 
Patients who are enrolled in this study will be carefully monitored during the entire study, 
and any new information from this and other studies will be communicated to sites and 
will result in protocol modifications as necessary to ensure appropriate risk-mitigation 
procedures.  Safety evaluations will consist of medical interviews, collection of adverse 
event information, physical examinations, vital sign assessments, and laboratory tests, 
including hematologic, biochemical, and immunologic assessments.  Patients will be 
evaluated for adverse events at each study visit through 30 days after the last dose of 
venetoclax study treatment or the last dose of CHOP or 90 days after the last rituximab 
or obinutuzumab study treatment, whichever is later. 
During the dose-finding stage, F. Hoffmann-La Roche Ltd (Sponsor) will hold 
teleconferences with investigators for evaluation of each dose level to review toxicities.  
Additional ad hoc teleconferences will be held as necessary to discuss any ongoing 
issues regarding toxicity or study conduct.  In addition, an IMC and SOC will be 
established to review all safety data and make recommendations regarding dose 
selection of venetoclax.  Access to safety data will be available to the Medical Monitor 
via the electronic data capture (EDC) system.  All serious adverse events will be 
reviewed by the Medical Monitor within 24−48 hours after reporting, and serious, 
unexpected, related adverse events will be reviewed for regulatory reporting purposes.  
Regular teleconferences will be held with investigators, study sites, and the Medical 
Monitor to review toxicities observed in patients in the study and to discuss decisions 
regarding dose and schedule modifications. 
During the Phase II portion of the study, all patients will continue to be monitored for 
safety and tolerability.  Precautionary safety measures and regular monitoring of safety 
by an IMC and the Sponsor enable early identification of safety signals in the study and 
minimize the risk to patient enrolled.  An IMC/SOC Agreement will be developed to 
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See Section 5 for complete details of the safety evaluation for this study. 
3.4.1 
Risks Associated with Venetoclax and Their Management 
The clinical safety profile of venetoclax based on clinical data obtained in the ongoing 
Phase I studies is summarized in Section 1.2.2.3.  On the basis of clinical data to date, 
the known and suspected risks are described below.  Guidelines around the 
management of these risks through dose and schedule modifications are described in 
Section 4.3.6.  See the ABT-199/GDC-0199 Investigator’s Brochure for complete and 
updated details. 
3.4.1.1 
Tumor Lysis Syndrome 
The principal DLT associated with venetoclax in the ongoing Phase I Study M12-175 to 
date has been TLS (in patients with CLL/SLL), primarily, but not exclusively related to 
the first dose. 
Experience from the Phase I study has suggested that clinically significant TLS is less 
common in NHL than in CLL; however, laboratory TLS has been observed in some 
patients with NHL.  The combination of venetoclax with effective chemotherapy and a 
monoclonal antibody, which may also cause TLS in patients with NHL, raises the 
possibility of more significant occurrences of TLS.  All patients must receive hydration 
and an agent to reduce uric acid as TLS prophylaxis at least 72 hours prior to starting 
venetoclax treatment.  Laboratory testing is required after initial dosing to monitor for 
metabolic changes and will be used to assess the need for closer monitoring and 
hospitalization for IV hydration and treatment of metabolic abnormalities caused by rapid 
cell lysis.  Hospitalization will be required at initial venetoclax dosing for patients who are 
determined to be at high risk of TLS as a result of bulky disease (i.e., any lymphoma 
mass ≥ 10 cm and/or evidence of circulating lymphoma cells).  See Section 4.4.1.5 for 
details of the TLS prophylaxis and monitoring schedule to be used for initial dosing. 
3.4.1.2 
Cytopenias 
Lymphopenia, neutropenia, thrombocytopenia, and anemia have been reported in the 
Phase I study conducted in heavily pretreated patients with CLL and NHL.  In certain 
cases, the condition was preexisting.  In this study, blood counts will be monitored 
closely throughout treatment.  Growth factors are permitted according to local practice, 
and patients will be monitored and treated promptly in case of infections (see 
Section 4.4.1.3).  Blood counts that meet DLT requirements will result in dose changes.  
It is recommended that blood counts be checked within 24-72 hours for patients with 
cytopenias that result in dose delays to see if the counts have recovered. 
3.4.1.3 
Infections 
Infections of various types have occurred in patients in the Phase I study.  NHL can be 
associated with impaired immune function and increased infections, and it is unclear 
whether or how much the incidence could be increased as a result of 
venetoclax treatment.  Patients in this study will be closely monitored for infections, and 


 
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prompt therapy will be instituted, as necessary.  Patients are allowed to receive 
concomitant prophylactic anti-infective therapy at the investigator’s discretion (see 
Section 4.4.1.6). 
3.4.1.4 
Decreased Spermatogenesis 
There is a potential for decreased spermatogenesis without recovery with the use of 
venetoclax.  Male patients considering preservation of fertility should bank sperm before 
treatment. 
3.4.1.5 
Drug-Drug Interaction 
Co-administration of venetoclax with strong and moderate CYP3A inhibitors (see 
Appendix 5 for examples) is not recommended.  Consider alternative medications.  If the 
patient requires use of these medications, use with caution and reduce the venetoclax 
dose by 2-fold for moderate inhibitors and 4-fold for strong inhibitors during 
co-administration. 
If the patient requires use of strong or moderate CYP3A inducers (see Appendix 5 for 
examples), use with caution and contact the Medical Monitor for guidance. 
3.4.2 
Risks Associated with Rituximab Therapy and Their 
Management 
3.4.2.1 
Infusion-Related Reactions 
In single-agent clinical studies of rituximab and in post-marketing surveillance studies, 
mild to moderate IRRs consisting of fever and chills/rigors occurred in the majority of 
patients during the first rituximab infusion.  Other frequent IRR signs and symptoms 
included nausea, pruritus, angioedema, asthenia, hypotension, headache, 
bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, dizziness, and 
hypertension.  These reactions generally occurred within 30−120 minutes of beginning 
the first infusion, and they resolved with slowing or interruption of the rituximab infusion 
and with supportive care (diphenhydramine, acetaminophen, IV saline, meperidine, and 
vasopressors).  The incidence of IRRs was highest during the first infusion and 
decreased with each subsequent infusion. 
Rituximab has caused severe IRRs.  In some cases, these reactions were fatal.  These 
severe reactions typically occurred during the first infusion with time to onset of 
30-120 minutes.  Signs and symptoms of severe IRRs may include urticaria, 
hypotension, angioedema, hypoxia, or bronchospasm and may require interruption of 
rituximab administration.  The most severe manifestations and sequelae include 
pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events 
(see Appendix 4).  Approximately 80% of fatal IRRs occurred in association with the first 
infusion of rituximab. 


 
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3.4.2.1.1 
Management of Severe Infusion-Related Reactions 
Administration of rituximab will occur in a setting with emergency equipment and staff 
who are trained to monitor for and respond to medical emergencies.  The rituximab 
infusion should be interrupted for severe reactions.  Medications and supportive care 
measures including but not limited to epinephrine, antihistamines, glucocorticoids, 
IV fluids, vasopressors, oxygen, bronchodilators, and acetaminophen should be 
available for immediate use and instituted as medically indicated for use in the event of a 
reaction during administration.  In most cases, the infusion can be resumed at a 
50% reduction in rate (e.g., from 100 mg/hr to 50 mg/hr) when symptoms have 
completely resolved.  Patients who require close monitoring during the first and all 
subsequent infusions include patients with preexisting cardiac and pulmonary conditions, 
patients with prior clinically significant cardiopulmonary adverse events, and patients 
with high numbers of circulating malignant cells (≥ 25,000 cells/μL) with or without 
evidence of high tumor burden. 
3.4.2.2 
Tumor Lysis Syndrome 
Rapid reductions in tumor volume followed by acute renal failure, hyperkalemia, 
hypocalcemia, hyperuricemia, or hyperphosphatemia have been reported within 
12-24 hours after the first infusion of rituximab.  Rare instances of a fatal outcome have 
been reported in the setting of TLS following treatment with rituximab.  The risks of TLS 
appear to be greater in patients with high numbers of circulating malignant cells 
(≥ 25,000 cells/μL) or high tumor burden.  Prophylaxis for TLS including hydration and 
administration of a uric acid−lowering agent is required in this study for all patients.  A 
lower starting dose of venetoclax may be used in high-risk TLS patients (see 
Section 4.4.1.5).  Patients deemed to be at high risk for TLS complications may, at the 
investigator’s discretion, receive their initial dose of rituximab over 2 consecutive days 
(see Section 4.3.2.3).  Correction of electrolyte abnormalities, monitoring of renal 
function and fluid balance, and administration of supportive care, including dialysis, 
should be initiated as indicated.  Following complete resolution of the complications of 
TLS, rituximab has been tolerated when re-administered in conjunction with prophylactic 
therapy for TLS in a limited number of cases. 
3.4.2.3 
Hepatitis B Reactivation with Related Fulminant Hepatitis and 
Other Viral Infections 
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death 
has been reported for some patients with hematologic malignancies treated with 
rituximab.  The majority of these patients received rituximab in combination with 
chemotherapy (Yeo et al. 2009). 
All patients will be screened for HBV infection by measuring hepatitis B surface antigen 
(HBsAg), total anti-hepatitis B core antibodies (anti-HBc), and total anti-hepatitis B 
surface antibodies before initiating treatment with rituximab or obinutuzumab.  For 
patients who show evidence of prior hepatitis B infection (i.e., with positive total hepatitis 
B core antibody [HBcAb], negative HBsAg and undetectable HBV DNA), a consult is 


 
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required with a physician who has expertise in managing hepatitis B regarding 
monitoring and consideration for HBV antiviral therapy.  These patients will be monitored 
for clinical and laboratory signs of hepatitis or HBV reactivation during and for several 
months following rituximab therapy (see Section 4.4.1.7).  HBV reactivation has been 
reported up to 24 months following completion of therapy.  In patients who develop 
reactivation of HBV while on rituximab, immediately discontinue rituximab and any 
concomitant chemotherapy and institute appropriate treatment (see Table 3).  
Insufficient data exist regarding the safety of resuming rituximab or obinutuzumab in 
patients who develop HBV reactivation. 
Additional serious viral infections, either new, reactivated, or exacerbated 
(e.g., infections caused by cytomegalovirus, varicella zoster virus, herpes simplex virus, 
West Nile virus, parvovirus B19, John Cunningham [JC] virus, and hepatitis C virus) 
have been reported with rituximab, mainly in patients who had received rituximab in 
combination with chemotherapy or as part of a hematopoietic stem cell transplant.  The 
risk of such infections with rituximab in combination with chemotherapy and venetoclax 
is unknown.  Particular attention should be given to patients who have had significant 
prior immunosuppressive treatment such as HD chemotherapy and stem cell transplant.  
JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and 
death has been observed in rituximab-treated patients with hematologic malignancies or 
with autoimmune diseases.  Most cases of PML were diagnosed within 12 months 
following the patient’s last infusion of rituximab.  Physicians should consider the 
diagnosis of PML in any patient presenting with new-onset neurologic manifestations.  
Evaluation of PML includes but is not limited to consultation with a neurologist, brain 
magnetic resonance imaging (MRI), and lumbar puncture.  Physicians should 
discontinue rituximab or obinutuzumab (and chemotherapy and venetoclax) and 
consider discontinuation or reduction of any immunosuppressive therapy in patients who 
develop PML. 
3.4.2.4 
Cardiovascular Events 
Infusions should be discontinued in the event of serious or life-threatening cardiac 
arrhythmias.  Patients who develop clinically significant arrhythmias should undergo 
cardiac monitoring during and after subsequent infusions of rituximab.  Patients with 
preexisting cardiac conditions including arrhythmias and angina have had recurrences of 
these events during rituximab therapy and should be monitored throughout the infusion 
and during the immediate post-infusion period. 
3.4.2.5 
Bowel Obstruction and Perforation 
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, 
were observed in patients who received rituximab in combination with chemotherapy for 
DLBCL.  In post-marketing reports, which include patients with low-grade or follicular 
NHL and patients with DLBCL, the mean time to onset of symptoms was 6 days 
(range, 1−77 days) in patients with documented gastrointestinal perforation.  Complaints 


 
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of abdominal pain, especially early in the course of treatment, should prompt a thorough 
diagnostic evaluation and appropriate treatment. 
3.4.2.6 
Immunization 
The safety of immunization with live viral vaccines following rituximab therapy has not 
been studied.  Patients who participate in this study may not receive either primary or 
booster vaccination with live virus vaccines for at least 6 months prior to initiation of 
rituximab or at any time during study treatment.  Investigators should review the 
vaccination status of potential study patients being considered for this study and follow 
the U.S. Centers for Disease Control and Prevention guidelines for adult vaccination with 
non-live vaccines intended to prevent infectious diseases prior to study therapy. 
Refer to the Rituxan®/MabThera® Package Insert/Summary of Package Characteristics 
for additional safety information.  
3.4.3 
Risks Associated with Obinutuzumab Therapy 
There may be additional potential health risks, including hitherto unknown risks, derived 
from exposure to obinutuzumab. 
3.4.3.1 
Infusion-Related Reactions and Hypersensitivity Reactions 
(Including Anaphylaxis) 
The commonly experienced IRRs associated with obinutuzumab are characterized by 
hypotension, fever, chills, flushing, nausea, vomiting, hypertension, and fatigue, among 
other symptoms.  IRRs may be clinically indistinguishable from IgE-mediated allergic 
reactions (e.g., anaphylaxis).  IRRs generally appear early during the infusion or shortly 
after, or in some cases, up to 24 hours after the completion of obinutuzumab infusion.  
Some patients have developed severe IRRs resulting in permanent discontinuation of 
obinutuzumab.  In some instances, concurrent signs of TLS are observed. 
In the majority of patients, IRRs were mild or moderate and could be managed by the 
slowing or temporary halting of the first infusion, but severe and life-threatening IRRs 
that required symptomatic treatment have also been reported. 
Respiratory infusion-related symptoms such as hypoxia, dyspnea, bronchospasm, larynx 
and throat irritation, and laryngeal edema have also been reported.  These IRRs were 
mostly mild or moderate (NCI CTCAE v4.0, Grade 1 and 2 events), and < 10% of the 
events were severe (Grade 3 events), occurring predominantly during the first hour of 
the infusion or shortly after the first infusion had finished; the events resolved with 
slowing or interruption of the infusion and supportive care.  The incidence and severity of 
IRRs decreased with subsequent infusions.  Extensive tumor burden predominantly 
localized in the blood circulation (e.g., high peripheral lymphocyte count in patients with 
CLL) may be a predisposing factor for the development of IRRs. 


 
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Hypersensitivity may be difficult to distinguish from IRRs; however, anaphylaxis has 
been reported in patients treated with obinutuzumab.  If a hypersensitivity reaction is 
suspected during infusion (e.g., symptoms typically occurring after previous exposure 
and very rarely with the first infusion), the infusion should be stopped and treatment 
permanently discontinued.  Patients with known IgE-mediated hypersensitivity to 
obinutuzumab should not be treated. 
3.4.3.2 
Tumor Lysis Syndrome 
Cases of TLS have been reported with obinutuzumab administration.  To date, no 
patient has required hemodialysis for renal failure.  Patients with a high tumor burden, 
including patients with a lymphocyte count of ≥ 25 × 109/L (particularly, patients with 
B-cell CLL and MCL), are at increased risk for TLS and severe IRRs. 
3.4.3.3 
Thrombocytopenia and Neutropenia 
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia, 
(occurring within 24 hours after the infusion) has been observed during treatment with 
obinutuzumab.  Fatal hemorrhagic events have also been reported in patients treated 
with obinutuzumab.  The greatest risk of hemorrhage in obinutuzumab-treated patients 
seems to be during the first cycle, although a clear relationship between 
thrombocytopenia and hemorrhagic events has not been established.  Patients treated 
with concomitant medication that could possibly worsen thrombocytopenia-related 
events, such as platelet inhibitors and anticoagulants, may be at greater risk of bleeding.  
Patients should be closely monitored for thrombocytopenia, especially during the first 
cycle.  If an event of thrombocytopenia occurs, regular laboratory tests should be 
performed until the event resolves, and dose delays should be considered in case of 
severe or life-threatening thrombocytopenia.  Transfusion of blood products (i.e., platelet 
transfusion) may be performed at the discretion of the treating physician according to 
institutional practice. 
Cases of Grade 3 or 4 neutropenia, including febrile neutropenia, have been reported 
with obinutuzumab administration.  Grade 3 or 4 neutropenia has been observed 
predominantly in patients with CLL.  Patients who experience Grade 3 or 4 neutropenia 
should be monitored until neutrophil values return to at least Grade 2 or baseline.  Use 
of granulocyte-colony stimulating factor (G-CSF) has been found to result in a rapid 
normalization of neutrophils, similar to what has been observed in patients treated with 
rituximab (see Section 4.4.1.3). 
3.4.3.4 
Anti-Therapeutic Antibody 
Although obinutuzumab is a fully humanized antibody, there is a risk that anti-therapeutic 
antibodies could develop, thus reducing efficacy and/or resulting in symptomatic 
hypersensitivity reactions.  Experience with similar humanized antibodies 
(e.g., trastuzumab) suggests that the incidence and titer of such antibodies will be 
low and will be unlikely to affect efficacy or cause unwanted immunological reactions 
(Genentech data on file). 


 
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3.4.3.5 
Infection 
On the basis of its anticipated mode of action that results in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections.  Infections have 
been reported in patients who received obinutuzumab.  Therefore, obinutuzumab should 
not be administered to patients with active severe infections. 
Serious infections, including fatal bacterial, fungal, and new or reactivated viral infections 
(e.g., cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West 
Nile virus, and hepatitis B or C) have been reported with the B cell−depleting antibody 
rituximab, mainly in patients who had received the drug in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant.  The risk of such 
infections with obinutuzumab is unknown.  Physicians should be aware of symptoms 
suggestive of PML and consider the diagnosis of PML in any patient presenting with 
new-onset neurologic manifestations.  Evaluation of PML includes but is not limited to 
consultation with a neurologist, brain MRI, and lumbar puncture. 
3.4.3.6 
Gastrointestinal Perforation 
Gastrointestinal (GI) perforation has been reported in patients treated with obinutuzumab 
including fatal events.  Patients with GI involvement should be monitored for signs of GI 
perforation. 
3.4.4 
Risks Associated with CHOP Chemotherapy 
Refer to prescribing information for doxorubicin, cyclophosphamide, vincristine, and 
prednisone or prednisolone for risks related to CHOP chemotherapy. 
Common side effects of CHOP include fever, infection, hair loss, nausea and/or vomiting, 
constipation, and potential neurologic, lung, liver, and cardiac toxicity.  Patients treated 
with doxorubicin, an anthracycline-based chemotherapy, are at risk for cardiotoxicity.  
Although the risk increases with cumulative dose, irreversible cardiotoxicity may occur at 
any dose level.  Patients with preexisting heart disease, hypertension, concurrent 
administration of other anti-neoplastic agents, prior or concurrent chest irradiation, and 
advanced age are at increased risk. 
3.4.5 
Risks Associated with the Combination of Venetoclax plus 
R-CHOP or G-CHOP 
This Phase Ib/II study will assess the toxicities associated with the combination of 
venetoclax plus R-CHOP or G-CHOP.  Given their mechanisms of action and 
single-agent safety profiles, additive or overlapping acute toxicities for the combination of 
venetoclax plus R-CHOP or G-CHOP could potentially include neutropenia and TLS.  
The risk of TLS will be mitigated by starting treatment with one agent before the other, to 
allow some reduction of disease burden before the second agent is added.  In addition, 
patients will receive hydration and TLS prophylaxis prior to initial dosing 
(see Section 4.4.1.5). 


 
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In terms of chronic toxicity, it is theoretically possible that inhibition of Bcl-2 could 
enhance and/or prolong neutropenia and lymphopenia following completion of R-CHOP 
or G-CHOP treatment.  These effects, if they occur, could likely manifest as an 
increased incidence of infections.  All patients will be monitored closely for infection and 
treated aggressively according to institutional guidelines.  WBC growth factor support will 
be used for all patients. 
If clinically indicated, anti-infective prophylaxis should be implemented at the 
investigator's discretion, including appropriate prophylaxis for viral, fungal, bacterial, or 
pneumocystis infections.  The Medical Monitor should be notified if these infections are 
observed.  Potential for drug-drug interactions should be considered (e.g., azoles for 
fungal prophylaxis).  See Appendix 5 for a list of excluded and cautionary medications. 
In addition, there has been some indication of mild decrease in cardiac contractility 
following treatment with venetoclax in animal models, though not at this time in humans.  
Myocardial toxicity is a recognized dose-related toxicity of anthracyclines such as 
doxorubicin.  The combination could theoretically, therefore, potentiate cardiotoxicity.  
Since no cardiotoxicity was noted in the Phase I part of the study, only a baseline 
cardiac evaluation with multiple-gated acquisition (MUGA) scan or echocardiogram will 
be performed, unless additional studies are clinically indicated during treatment. 
Potential for drug-drug interactions should be considered (e.g., azoles for fungal 
prophylaxis).  Drug interactions may occur with CYP3A4 inhibitors or inducers 
(venetoclax).  The risk of clinically significant PK drug interaction between venetoclax, 
rituximab, obinutuzumab, and CHOP is expected to be low on the basis of their 
metabolic pathways.  Rituximab has decreased clearance with time that may be related 
to CD20 target expression and tumor burden.  Venetoclax may affect the clearance of 
rituximab because it has the potential to decrease tumor burden.  Similar considerations 
may be relevant for obinutuzumab clearance.  Because the agents in this study have not 
been administered before in combination in patients with NHL, PK samples will be 
collected to assess whether drug levels differ from the combination compared with 
historical data to check for potential drug-drug interactions.  See Appendix 5 for a list of 
excluded and cautionary medications. 
See Section 5 for complete details of the safety evaluation for this study. 
3.5 
ETHICAL CONSIDERATIONS 
Any information obtained from this research will be treated as confidential.  
The information collected will not be provided to any third parties, such as insurers or 
employers (other than those required by law), but will be provided to health authorities 
(e.g., the European Medicine Authority or U.S. Food and Drug Administration [FDA]), 
Roche, AbbVie, and their collaborators. 


 
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This clinical research involves the procurement of samples of blood and lymph node 
samples for evaluation of Bcl-2 and other relevant biomarkers that help to understand 
how the patient’s DLBCL behaves or responds to treatment.  DNA samples will not be 
identified with patients’ names, pictures, or any government-issued identification 
numbers (e.g., Social Security Number).  Samples will be identified using the patient’s 
year of birth and a unique sample identification number only (these are considered 
patient identifiers under the U.S. Health Insurance Portability and Accountability Act 
[HIPAA]).  Samples will be linked with clinical data from the Sponsor’s clinical study 
database (including outcome data) by the patient’s year of birth and study identification 
number. 
3.6 
ADMINISTRATIVE STRUCTURE 
In the U.S., this trial will be sponsored and managed by Genentech.  
F. Hoffmann-La Roche Ltd will sponsor this trial outside of the U.S. with management 
responsibilities being shared by Genentech and Roche.  Genentech and Roche have 
authorized Roche Registrations, a company formed under the laws of England, to act as 
their legally authorized representative for the purposes of Article 19 of Directive 
2001/20/EC relating to the implementation of Good Clinical Practice (GCP) in the 
conduct of clinical trials on medicinal products for human use.  Reference to “Sponsor” in 
this protocol will mean Genentech for the United States and F. Hoffmann−La Roche Ltd 
for all countries outside of the United States. 
Approximately 69 sites in North America, the European Union, and Asia Pacific will 
participate in this study to enroll approximately 290 patients.  Data will be recorded via 
an EDC system from Medidata Solutions (New York, NY) with use of electronic Case 
Report Forms (eCRFs; see Section 6.6).  Central laboratories will be used for the 
analyses of and/or management of PK, pharmacodynamic, genotyping, and tissue 
samples.  An interactive voice/Web response system (IxRS) will be used for patient 
registration, patient number, and dose assignment. 
3.7 
INDEPENDENT REVIEW COMMITTEE 
An IRC composed of board-certified radiologists and oncologists with experience in 
malignant lymphoma will assess all patients for response and progression on the basis 
of imaging results, bone marrow biopsy results, and relevant clinical data and will be 
guided by a charter specific to the independent review. 
3.8 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the International Conference on 
Harmonisation (ICH) E6 guideline for GCP and the principles of the Declaration of 
Helsinki, or the laws and regulations of the country in which the research is conducted, 
whichever affords the greater protection to the individual.  The study will comply with the 
requirements of the ICH E2A guideline (Clinical Safety Data Management:  Definitions 
and Standards for Expedited Reporting).  Studies conducted in the Unites States or 


 
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under a U.S. Investigational New Drug (IND) application will comply with U.S. FDA 
regulations and applicable local, state, and federal laws.  Studies conducted in the 
European Union or European Economic Area will comply with the E.U. Clinical Trial 
Directive (2001/20/EC). 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
Patient Selection 
Patients who are in conformance with the following eligibility requirements may enroll in 
this study. 
4.1.2 
Inclusion Criteria 
4.1.2.1 
Patients Enrolled in the Dose-Finding Portion of the Study 
Patients must have histologically confirmed B-cell NHL (and have never received 
R-CHOP treatment), except MCL or SLL, in order to enroll in this portion of the study. 
Any relapsed/refractory patients who are enrolled during the dose escalation should 
have received only a single previous treatment regimen. 
4.1.2.2 
Patients Enrolled in the Phase II Portion of the Study 
Patients must have previously untreated CD20-positive DLBCL and IPI score must be 
2−5 in order to enroll in this portion of the study. 
4.1.2.3 
All Patients 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form(s) 
• 
At least one bi-dimensionally measurable lymphoma lesion on CT scan defined as 
> 1.5 cm in its longest dimension, which is also FDG avid by screening PET scan. 
• 
Ability and willingness to comply with the study protocol procedures 
• 
Age ≥ 18 years 
• 
Confirmed availability of archival or freshly biopsied tumor tissue meeting 
protocol-defined-specifications prior to study enrollment (see Section 4.1.4)  
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 
• 
Adequate hematologic function (unless caused by underlying disease, as 
established by extensive bone marrow involvement or as a result of hypersplenism 
secondary to the involvement of the spleen by lymphoma per the investigator) 
defined as follows: 
Hemoglobin ≥ 9 g/dL 
ANC ≥ 1.5 × 109/L 
Platelet count ≥ 75 × 109/L 


 
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• 
For women who are not postmenopausal (≥ 12 months of non−therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use single or combined non-hormonal contraceptive methods 
that result in a failure rate of < 1% per year during the treatment period and for at 
least 12 months after the last dose of rituximab or 18 months after the last dose of 
obinutuzumab 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
• 
Non-vasectomized male patients must practice at least one of the following methods 
of birth control throughout the duration of study participation and for at least 
12 months after completing therapy with rituximab or 18 months after completing 
therapy with obinutuzumab. 
A partner who is surgically sterile or postmenopausal (for at least 1 year) or 
who is taking hormonal contraceptives (oral, parenteral, vaginal ring, or 
transdermal) for at least 3 months prior to study drug administration 
Total abstinence from sexual intercourse; double-barrier method 
(condom + diaphragm or cervical cup with spermicidal, contraceptive sponge, 
jellies, or cream) 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
• 
Males must agree to abstain from sperm donation for at least 12 months after the 
last dose of rituximab or 18 months after the last obinutuzumab dose. 
 
4.1.3 
Exclusion Criteria 
4.1.3.1 
Patients Enrolled in the Dose-Finding Portion of the Study 
Patients with MCL or SLL histology will be excluded from study entry. 
4.1.3.2 
Patients Enrolled in the Phase II Portion of the Study 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with transformed lymphoma (patients with discordant bone marrow 
involvement(i.e., low grade histology in bone marrow) may be considered after 
discussion with the Medical Monitor) 
• 
Prior therapy for NHL 
 
4.1.3.3 
All Patients 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies or known sensitivity or allergy to murine products 


 
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• 
Contraindication to receive any of the individual components of CHOP, rituximab, or 
obinutuzumab 
• 
Prior anthracycline therapy 
• 
Ongoing corticosteroid use > 30 mg/day of prednisone or equivalent.  Patients who 
received corticosteroid treatment with ≤ 30 mg/day of prednisone or equivalent must 
be documented to be on a stable dose of at least 4 weeks’ duration prior to Cycle 1 
Day 1.  Patients may have received a brief (< 7 days) course of systemic steroids 
(≤ 100 mg prednisone equivalent per day) prior to initiation of study therapy for 
control of lymphoma-related symptoms (See Section 4.4.1). 
• 
CNS lymphoma or primary mediastinal DLBCL 
• 
Vaccination with live vaccines within 28 days prior to treatment 
• 
Chemotherapy or other investigational therapy within 28 days prior to the start of 
Cycle 1.  
• 
History of other malignancy that could affect compliance with the protocol or 
interpretation of results 
Patients with a history of curatively treated basal or squamous cell carcinoma or 
Stage 1 melanoma of the skin or in situ carcinoma of the cervix are eligible. 
Patients with a malignancy that has been treated with surgery alone with 
curative intent will also be excluded, unless the malignancy has been in 
documented remission without treatment for ≥ 3 years prior to enrollment. 
• 
Evidence of significant, uncontrolled concomitant diseases that could affect 
compliance with the protocol or interpretation of results or that could increase risk to 
the patient, including renal disease that would preclude chemotherapy 
administration or pulmonary disease (including obstructive pulmonary disease and 
history of bronchospasm) 
• 
Significant CV disease (such as New York Heart Association Class III or IV cardiac 
disease, congestive heart failure, myocardial infarction within the past 6 months, 
unstable arrhythmias, or unstable angina) or significant pulmonary disease 
(including obstructive pulmonary disease and history of bronchospasm) 
• 
Left ventricular ejection fraction < 50% as defined by MUGA.  Echocardiogram may 
be used if MUGA is not available. 
• 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment, or any major episode 
of infection requiring treatment with IV antibiotics or hospitalization (relating to the 
completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1 
• 
Received the following agents within 7 days prior to the first dose of venetoclax: 
Steroid therapy for anti-neoplastic intent within 7 days prior to Cycle 1 Day 1.  
See steroid use guidelines in Section 4.4.1 for specific exceptions. 
Strong and moderate CYP3A inhibitors (see Appendix 5 for examples)  
Strong and moderate CYP3A inducers (see Appendix 5 for examples)  


 
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Consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or star fruit within 3 days prior to the 
first dose of venetoclax. 
• 
Clinically significant history of liver disease, including viral or other hepatitis, current 
alcohol abuse, or cirrhosis 
• 
Presence of positive test results for hepatitis B (HBcAb) or hepatitis C (hepatitis C 
virus [HCV]) antibody 
Patients who are positive for HCV antibody must be negative for HCV by 
polymerase chain reaction (PCR) to be eligible for study participation 
Patients with occult or prior HBV infection (defined as positive total HBcAb and 
negative HBsAg) may be included if HBV DNA is undetectable.  These patients 
must be willing to undergo monthly DNA testing. 
• 
Known infection with HIV or human T-cell leukemia virus 1 
• 
Women who are pregnant or lactating 
• 
Recent major surgery (within 6 weeks prior to the start of Cycle 1 Day 1), other than 
for diagnosis 
• 
Any of the following abnormal laboratory values: 
Calculated estimated creatinine clearance (CRCL) < 50 mL/min with the use of 
the 24-hour creatinine clearance or modified Cockcroft-Gault equation (with the 
use of ideal body mass [IBM] instead of mass): 
(140−Age) × IBM (kg) × [0.85 if female] 
CRCL =  
72 • serum creatinine (mg/dL) 
Or, if serum creatinine is in μmol/L: 
 
(140−Age) × IBM (kg) × [1.23 if male, 1.04 if female] 
CRCL =  
serum creatinine (μmol/L) 
 
AST or ALT > 2.5 × ULN (unless due to disease involvement; Medical Monitor 
to be consulted prior to enrollment) 
Total bilirubin ≥ 1.5 × ULN (or > 3 × ULN for patients with documented 
Gilbert syndrome) 
INR > 1.5 × ULN for patients not receiving therapeutic anticoagulation 
PTT or aPTT > 1.5 × ULN 
 
4.1.4 
Criteria for Tumor Biopsy Tissue 
• 
Eligible patients must have a representative formalin-fixed, paraffin-embedded 
tumor specimen to enable the definitive diagnosis of CD20-positive NHL/DLBCL 
available at the study site. 


 
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• 
The specimen must contain adequate evaluable tumor cells to enable Bcl-2 IHC and 
other relevant biomarker analysis. 
Sample can be in a tissue block (preferred) or consist of 20 unstained serial 
slides, accompanied by an associated pathology report.  If fewer than 
20 unstained serial slides (accompanied by an associated pathology report) are 
available, then the study site should consult the Sponsor (or delegate) 
regarding the acceptability of a fewer number of slides.  Cytological or 
fine-needle aspiration as well as bone marrow samples are not acceptable.  In 
countries using a different fixative than formalin, available tissue block will be 
accepted and notation of the type of fixative should be included.  In addition to 
slides in the Phase II portion of the study, a tissue punch for the construction of 
TMAs is required in patients who have an excisional biopsy sample available.  If 
the archival tissue is unavailable or insufficient based on above criteria, the 
patient may still be eligible if the patient is willing to provide tissue from a 
pretreatment core or excisional/incisional biopsy of the tumor.  Cytological or 
fine-needle aspiration samples are not acceptable.  The sample should be 
shipped according to instructions provided in the laboratory manual.  If a tissue 
block is provided, after necessary sections are cut and a core punch sample for 
TMA is taken, the remaining specimen will be returned to site. 
Tissue samples must be sent to the central laboratory within 3 weeks of patient 
randomization. 
  
4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is an open-label study.  Patients will be assigned to dose levels in the order in 
which they are enrolled.  As described in Section 3.1, enrollment in the dose-finding 
portion of the study will be limited to patients with B-cell NHL with no prior R-CHOP 
therapy and who have received only a single prior treatment regimen. 
In the Phase II portion of the study, previously untreated DLBCL with higher-risk clinical 
features as determined by an IPI score of 2−5 will be enrolled.  Allocation to Arm A 
(venetoclax + R-CHOP) or Arm B (venetoclax + G-CHOP) will be by randomization if both 
arms are open to enrollment; allocation will otherwise be via direct assignment to the 
open arm.  Randomization will be performed by an IxRS.  Patients will be assigned in a 
1:1 ratio to one of the two treatment arms until Arm B is filled, at which point all patients 
will be allocated to Arm A. 
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.  After the Sponsor reviews the 
documentation and approves the patient for enrollment, the Sponsor will provide the 
dose group assignment and the patient number will be assigned via the IxRS. 


 
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4.3 
STUDY TREATMENT 
4.3.1 
Venetoclax 
4.3.1.1 
Formulation 
The venetoclax tablets will be packaged in high-density polyethylene plastic bottles to 
accommodate the study design.  Each bottle will be labeled per local regulatory 
requirements.  A desiccant canister may be included in the bottle.  The tablets must be 
stored at 15°C−25°C (59°F−77°F).  If supplied with a desiccant, the desiccant canister 
should be returned to the bottle directly after each tablet removal. 
For further details, see the ABT-199/GDC-0199 Investigator’s Brochure. 
4.3.1.2 
Dosage, Administration, and Storage 
Study patients will self-administer venetoclax tablets by mouth once daily (QD).  Each 
dose of venetoclax will be taken with approximately 240 mL of water within 30 minutes 
after the completion of breakfast or the patient's first meal of the day.  A meal containing 
approximately 30% of the total caloric content from fat is recommended to ensure 
adequate absorption of venetoclax.  On days that pre-dose PK sampling is required, the 
patient’s first meal of the day (e.g., breakfast) will be consumed in the morning at the 
clinic, and venetoclax dosing will occur in the clinic after completion of the to facilitate 
PK sampling.   
The recommended breakfast is as follows:   
1 box cereal (30–40 g) 
Skim milk (240 mL) 
1 boiled egg 
1 slice toast (15 g) 
Margarine (10 g)  
 
Total calories should be approximately 520 Kcal; 30% of the total caloric content of the 
meal is from fat. Total grams of fat should be approximately 17 grams. 
See Section 3.1.2.1 for the venetoclax administration schedule. 
On days when venetoclax plus R-CHOP or G-CHOP are given, the order of study 
treatment administration will be venetoclax prior to rituximab or obinutuzumab, and 
rituximab or obinutuzumab prior to CHOP (with the exception of the first dose of 
prednisone in each cycle; see Section 4.3.4).  On days when both venetoclax and 
prednisone are given, venetoclax will be taken prior to prednisone.  If vomiting occurs 
within 15 minutes after taking venetoclax and all expelled tablets are still intact, another 
dose may be given and the second dose noted in the drug log.  Otherwise, no 
replacement dose is to be given.  In cases where a dose of venetoclax is missed or 
forgotten, the patient should take the dose as soon as possible and ensure that the 
minimal interval between the current dose and the next dose is at least 16 hours in order 


 
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to avoid excessive drug accumulation after the next dose.  Patients will be instructed to 
record the date and time they take their daily dose of venetoclax and prednisone.  
Diaries will be provided by the Sponsor for this purpose.  Venetoclax must be stored 
according to labeled storage conditions. 
All patients must receive prophylaxis for TLS (see Section 4.4.1.2) prior to the initiation 
of venetoclax plus R-CHOP or G-CHOP study treatment. 
4.3.1.3 
Dosage Delays and Modification 
The dose of venetoclax should be withheld for clinically significant toxicity potentially 
related to venetoclax treatment (e.g., clinical TLS, febrile neutropenia) until the toxicity 
has resolved or improved to Grade ≤ 2 or ≥ 80% of baseline.  The dose of venetoclax 
may be reduced for Grade ≥ 3 toxicity or recurrent Grade ≥ 2 toxicity after consultation 
with the Medical Monitor (see Table 2). 
4.3.2 
Rituximab 
4.3.2.1 
Formulation 
Rituximab (Rituxan®/MabThera®) is a sterile, clear, colorless, preservative-free liquid 
concentrate for IV administration.  Rituximab is supplied at a concentration of 10 mg/mL 
in 100-mg (10 mL) and 500-mg (50 mL) single-use vials.  The product is formulated for 
IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 
and 0.7 mg/mL polysorbate 80, after reconstitution with Sterile Water for Injection.  The 
pH is adjusted to 6.5.  Vials are for single use.  Each vial and carton will contain a label 
(either single-panel or booklet) affixed to the vial or carton per individual country 
requirements. 
4.3.2.2 
Dosage, Administration, and Storage 
Rituximab will be administered intravenously once per 21-day cycle in combination with 
CHOP for up to six cycles and as a single agent for two additional cycles.  Patients who 
experience ongoing response without excessive toxicity may receive up to eight cycles 
of CHOP following discussion between the investigator and the Medical Monitor.  The 
infusion of 375 mg/m2 will be based on the patient’s body surface area (BSA) at 
screening and will remain the same throughout the study unless there is a > 10% change 
in body weight.  On a given day, rituximab should be given after venetoclax and prior to 
CHOP (with the exception of the first dose of prednisone in each cycle; see 
Section 4.3.4). 
See Section 3.1.2.1 for administration schedule in combination with CHOP. 
Rituximab should not be administered as an IV push or bolus.  IRRs may occur.  
Premedication consisting of acetaminophen, diphenhydramine (or other suitable 
antihistamine), and a single dose of hydrocortisone (up to 100 mg or an equivalent dose 
of methylprednisolone) may also be administered beginning with the first infusion.  
Premedication may attenuate IRRs.  Because transient hypotension may occur during 


 
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rituximab infusion, consideration should be given to withholding antihypertensive 
medications for 12 hours prior to rituximab infusion. 
4.3.2.2.1 
First Infusion 
The rituximab solution for infusion should be administered intravenously at an initial rate 
of 50 mg/hr.  Rituximab should not be mixed or diluted with other drugs.  If IRRs do not 
occur, the infusion rate should be escalated in 50 mg/hr increments every 30 minutes to 
a maximum of 400 mg/hr.  If an IRR develops, the infusion should be temporarily slowed 
or interrupted.  The infusion can continue at one-half the previous rate upon 
improvement of patient symptoms. 
4.3.2.2.2 
Subsequent Infusions 
If the patient tolerates the first infusion well, subsequent rituximab infusions may be 
administered at an initial rate of 100 mg/hr and increased in 100-mg/hr increments at 
30-minute intervals to a maximum of 400 mg/hr, as tolerated or per an institution’s 
standard of care IV administration procedure.  If the patient does not tolerate the first 
infusion well, the guidelines for the first infusion should be followed. 
Rituximab vials must be stored at 2°C−8°C (36°F−46°F).  Rituximab vials should be 
stored in the outer carton in order to protect them from light.  Rituximab solution for 
infusion may be stored at 2°C−8°C (36°F−46°F) for 24 hours and has been shown to be 
stable for an additional 12 hours at room temperature.  However, because rituximab 
does not contain a preservative, diluted solutions should be stored refrigerated 
(2°C−8°C).  No incompatibilities between rituximab and polyvinylchloride (PVC) or 
polyethylene bags have been observed. 
See the local prescribing information for Rituxan/MabThera for additional information. 
4.3.2.3 
Dosage Modification 
There will be no rituximab dose modification in this study.  Patients who are at high risk 
for IRR or TLS complications (see Section 4.4.1.4) may, at the investigator’s discretion, 
receive their initial dose of rituximab split over 2 consecutive days (e.g., 125 mg/m2 on 
Cycle 1 Day 1, 250 mg/m2 on Cycle 1 Day 2). 
Any NCI CTCAE v4.0 toxicity Grade ≥ 3 in severity that is deemed related to rituximab 
treatment will require interruption of study treatment until resolution to Grade ≤ 1.  
Resumption of rituximab treatment may be considered in patients with resolution of 
toxicities to Grade ≤ 2 within 3 weeks at the discretion of the investigator after 
consultation with the study Medical Monitor.  Failure of such toxicities to resolve after 
3 weeks of suspended study treatment will require permanent discontinuation of 
rituximab. 


 
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Patients who discontinue rituximab because of rituximab-related toxicity may continue to 
receive CHOP and/or venetoclax only after consultation by the investigator with the 
Medical Monitor. 
4.3.3 
Obinutuzumab 
4.3.3.1 
Formulation 
Obinutuzumab is provided as a single-dose, sterile liquid formulation in a 50 mL 
pharmaceutical-grade glass vial containing a nominal 1000 mg of obinutuzumab 
(G3 material).  The formulated drug product consists of 25 mg/mL drug substance 
(G3) formulated in histidine, trehalose, and poloxamer 188.  The vial contains 41 mL 
(with 2.5% overfill). 
For further details, see the Obinutuzumab Investigator’s Brochure. 
4.3.3.2 
Handling and Storage 
The recommended storage conditions for the obinutuzumab drug product are between 
2°C and 8°C and protect from light.  Chemical and physical in-use stability for 
obinutuzumab dilutions in 0.9% sodium chloride (NaCl) has been demonstrated for 
24 hours at 2°C−8°C and at ambient temperature and ambient room lighting.  The 
prepared diluted product should be used immediately.  If not used immediately, in-use 
storage times and conditions prior to use are the responsibility of the user and would 
normally not be longer than 24 hours at 2°C−8°C.  Obinutuzumab should not be frozen 
or shaken.  Mix gently.  All transfer procedures require strict compliance with aseptic 
techniques.  Do not use an additional in-line filter; this will avoid potential adsorption. 
For further details, see the Obinutuzumab Investigator’s Brochure. 
4.3.3.3 
Obinutuzumab Dose and Schedule 
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose of 1000 mg 
in combination with CHOP for up to six cycles and as a single agent for two additional 
cycles.  Patients who experience ongoing response without excessive toxicity may 
receive up to eight cycles of CHOP following discussion between the investigator and 
the Medical Monitor.  On a given day, obinutuzumab should be given after venetoclax 
and prior to CHOP (with the exception of the first dose of prednisone in each cycle; see 
Section 4.3.4), and patients should be observed for 30 minutes prior to starting CHOP.  
Patients at high risk for IRR or TLS complications may, at the investigator’s discretion, 
receive their obinutuzumab dose split over 2 consecutive days (e.g., 100 mg on Day 1, 
900 mg on Day 2).  During Cycle 1, obinutuzumab will also be administered on 
Days 8 and 15. 
4.3.3.4 
Obinutuzumab Preparation 
Obinutuzumab drug product intended for IV infusion is prepared by dilution of the drug 
product into an infusion bag containing 0.9% NaCl to the final drug concentration of 
4 mg/mL.  With the use of a 250 mL infusion bag containing 0.9% NaCl, withdraw and 


 
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discard 40 mL of the sodium chloride.  Withdraw 40 mL of obinutuzumab from a single 
glass vial and inject into the infusion bag (discard any unused portion of obinutuzumab 
left in the vial).  Gently invert the infusion bag to mix the solution; do not shake. 
Administration sets with PVC, polyurethane, or polyethylene as product contact surfaces, 
and IV bags with polyolefin, polypropylene, PVC, or polyethylene as product contact 
surfaces are compatible and may be used. 
4.3.3.5 
Obinutuzumab Administration 
Obinutuzumab should be administered to patients in a clinical setting (inpatient or 
outpatient), where full emergency resuscitation facilities are immediately available and 
patients should be under close supervision of the investigator at all times.  Do not 
administer as an IV push or bolus.  After the end of the first infusion, the IV line or central 
venous catheter should remain in place for ≥ 2 hours in order to be able to administer IV 
drugs if necessary.  If no adverse events occur after 2 hours, the IV line may be 
removed or the central venous catheter may be de-accessed.  For subsequent infusions, 
access (either through an IV line or central venous catheter) should remain in place for 
at least 1 hour from the end of infusion, and if no adverse events occur after 1 hour, 
the IV access may be removed. 
See Section 4.4.1.4 and Section 4.4.1.5 for guidance on the use of premedication and 
prophylaxis of TLS prior to administration of obinutuzumab.  Instructions for the first and 
subsequent infusions of obinutuzumab are presented in Table 1. 


 
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Table 1 
Administration of First and Subsequent Infusions 
of Obinutuzumab 
First Infusion (Day 1) 
Subsequent Infusions 
• Begin infusion at and initial rate of 
50 mg/hr. 
• If no infusion reaction occurs, increase the 
infusion rate in 50 mg/hr increments every 
30 minutes, to a maximum of 400 mg/hr. 
• If an infusion reaction develops, stop or 
slow the infusion.  Administer 
infusion-reaction medications and 
supportive care in accordance with 
institutional protocol.  Resume the infusion 
at a 50% reduction in rate (the rate being 
used at the time that the hypersensitivity 
or infusion-related reaction occurred) if the 
reaction has resolved. 
• If a patient experienced an infusion reaction 
during the prior infusion, start at the same rate 
as the first infusion (50 mg/hr) and follow 
directions as noted. 
• If the patient tolerated the prior infusion well 
(defined as an absence of Grade 2 reactions 
during a final infusion rate of > 100 mg/hr), 
begin the infusion at a rate of 100 mg/hr. 
• If no infusion reaction occurs, increase the 
infusion rate in 100 mg/hr increments every 
30 minutes, to a maximum of 400 mg/hr. 
• If an infusion reaction develops, stop or slow 
the infusion.  Administer infusion-reaction 
medications and supportive care in 
accordance with institutional protocol.  
Resume the infusion at a 50% reduction in 
rate (the rate being used at the time that the 
hypersensitivity or infusion-related reaction 
occurred) if the reaction has resolved. 
 
Obinutuzumab should be given as a slow IV infusion through a dedicated line.  
IV infusion pumps should be used to control the infusion rate of obinutuzumab.  Do not 
administer as an IV push or bolus. 
On days when both obinutuzumab and CHOP are given, obinutuzumab will be 
administered prior to CHOP (except for first dose of prednisone in each cycle; 
see Section 4.3.3.6) and patients should be observed for 30 minutes prior to starting 
CHOP.  CHOP chemotherapy may be administered the next day if it cannot be given on 
the same day as obinutuzumab administration or if the obinutuzumab dose is split 
between 2 days.  Prior to each obinutuzumab infusion that is given in combination with 
CHOP (Day 1 of Cycles 1−6), patients should take the Day 1 dose of oral prednisone 
(100 mg) specified for each cycle of the CHOP regimen.  The prophylactic use of 
corticosteroids (e.g., 100 mg of IV prednisolone or equivalent) may also be considered 
for patients thought to be at high risk for IRRs if deemed appropriate by the investigator 
and should be also administered prior to the obinutuzumab infusion. 
For management of IRRs and anaphylaxis, see Section 4.3.3.8. 
4.3.3.6 
Premedication 
Thirty to 60 minutes prior to all obinutuzumab infusions (following venetoclax dosing, if 
applicable), all of the following premedications will be given (unless contraindicated): 
• 
Oral acetaminophen (650−1000 mg) 


 
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• 
An antihistamine, such as diphenhydramine (50−100 mg) 
• 
Prior to each obinutuzumab infusion that is followed by CHOP chemotherapy, 
patients should take the Day 1 dose of prednisone (100 mg) specified for each cycle 
of the CHOP regimen. 
 
The use of prophylactic corticosteroids (e.g., 100 mg IV prednisolone or equivalent) may 
also be considered for patients thought to be at high risk for IRRs and when deemed 
appropriate by the investigator; they should also be administered prior to the 
obinutuzumab infusion. 
If the dose of obinutuzumab is split, the Day 2 dose of prednisone (100 mg) specified for 
each cycle of the CHOP regimen should be given prior to the infusion of obinutuzumab. 
4.3.3.7 
Management of Tumor Lysis Syndrome 
For patients with evidence of TLS, obinutuzumab should be discontinued and the 
patients treated as clinically indicated.  Following the complete resolution of 
TLS complications, obinutuzumab may be re-administered at the full dose during 
the next infusion in conjunction with prophylactic therapy as indicated 
(see Section 4.4.1.5). 
4.3.3.8 
Management of Infusion-Related Reactions and Anaphylaxis 
Medications (including epinephrine for SC injections, corticosteroids, diphenhydramine 
hydrochloride for IV injection) and resuscitation equipment should be available for 
immediate use at point of infusion.  Management of infusion-related symptoms for 
obinutuzumab is summarized in Table 2.  In the event of a life-threatening IRR (that may 
include pulmonary or cardiac events) or an IgE-mediated anaphylactic reaction, 
obinutuzumab should be discontinued and no additional drug should be administered.  
Patients who experience any of these reactions should receive aggressive symptomatic 
treatment and will be discontinued from study treatment. 
Patients who experience obinutuzumab-associated, infusion-related temperature 
elevations of > 38.5°C or other minor infusion-related symptoms may be treated 
symptomatically with acetaminophen (≥ 500 mg) and/or H1- and H2-histamine−receptor 
antagonists (e.g., diphenhydramine hydrochloride, ranitidine).  Serious infusion-related 
events, manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, 
reduced oxygen saturation, or respiratory distress, should be managed with additional 
supportive therapies (e.g., supplemental oxygen, β2-agonists, epinephrine, and/or 
corticosteroids) as clinically indicated according to standard clinical practice. 


 
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Table 2 
Management of Infusion-Related Symptoms 
Infusion-Related Symptoms a 
Guidance 
Grades 1 and 2 
Slow or withhold infusion. 
Give supportive treatment b. 
Upon symptom resolution, may resume infusion-rate 
escalation. 
Grade 3 
Discontinue infusion. 
Give supportive treatment b. 
Upon symptom resolution, may resume infusion rate 
escalation. 
Grade 4 
Discontinue infusion immediately, treat symptoms aggressively, 
and do not restart drug. 
IV = intravenous. 
a Refer to National Cancer Institute Common Terminology Criteria for Adverse Events, 
(Version 4.0) for the grading of symptoms.  This table does not refer to management of 
IgE-mediated allergic reactions, which should be managed as directed in Section 4.4.1.6. 
b Supportive treatment:  Patients should be treated with acetaminophen and an antihistamine 
such as diphenhydramine hydrochloride if they have not been received in the previous 
4 hours.  IV saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may 
require antihistamines, oxygen, corticosteroids (e.g., 100 mg of IV prednisolone or 
equivalent), and/or bronchodilators.  For hypotension, patients may require vasopressors. 
 
4.3.3.9 
Cardiac or Pulmonary Events 
Patients who have preexisting cardiac or pulmonary conditions should be monitored 
carefully throughout the infusion and the post-infusion period. 
4.3.3.10 
Dosage Modification or Delay 
There will be no obinutuzumab dose modification in this study.  See Section 4.3.6 and 
Table 3 for dose-delay guidelines. 
4.3.4 
CHOP Chemotherapy 
4.3.4.1 
Dosage and Administration 
CHOP chemotherapy consists of IV cyclophosphamide, IV doxorubicin, vincristine 
administered by IV push, and oral prednisone or prednisolone.  Standard CHOP will be 
administered for six 21-day cycles.  Patients who experience ongoing response without 
excessive toxicity may receive up to eight cycles of CHOP following discussion between 
the investigator and the Medical Monitor. 
• 
Cyclophosphamide 750 mg/m2 administered intravenously on Day 1 
• 
Doxorubicin 50 mg/m2 administered intravenously on Day 1 
• 
Vincristine 1.4 mg/m2 administered by IV push on Day 1 with a cap of 2.0 mg 
• 
Prednisone 100 mg/day orally (PO) on Days 1−5 
Note:  The dose of prednisone follows the National Comprehensive Cancer 
Network’s recommendations (2010) based on Czuzman and colleagues (1999) 


 
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and Hiddemann and colleagues (2005).  Prednisone may be replaced with 
prednisolone (1:1 conversion, 100 mg) in countries where prednisone is not 
available or is not the therapy of choice. 
The use of a taper of prednisone (or equivalent) after Day 5 is permitted when 
felt to be appropriate according to the investigator’s standard practice. 
 
CHO(P) will be administered according to the standard preparation and infusion 
procedures at each investigational site and after the rituximab or obinutuzumab infusion.  
Refer to the specific package inserts for preparation, administration, and storage 
guidelines. 
On a given day, CHOP should be given after venetoclax plus rituximab or obinutuzumab, 
with the exception of the first dose of prednisone in each cycle, when prednisone is 
administered prior to the rituximab or obinutuzumab infusion.  On all other days, when 
rituximab or obinutuzumab is not administered, prednisone is given as per institutional 
CHOP administration standard.  Rituximab or obinutuzumab administration should 
be completed at least 30 minutes prior to administration of the CHO (cyclophosphamide, 
vincristine, and doxorubicin) infusions. 
Cyclophosphamide, doxorubicin, and vincristine may be given on Day 2 of Cycle 1 if the 
rituximab or obinutuzumab dose is split or if the extended time of antibody administration 
does not permit dosing of first CHOP on the same day.  If CHOP dosing is performed on 
Day 2 of Cycle 1, the first dose of venetoclax should be administered 3 days after CHOP 
(see Section 3.1.2.1). 
4.3.4.2 
Dosage Modification or Delay 
See Section 4.3.6 and Table 3. 
4.3.5 
Administration of Granulocyte Colony-Stimulating Factor 
All patients must receive G-CSF as primary prophylaxis for neutropenia starting with 
Cycle 1 and continuing through each additional cycle of CHOP therapy received. 
4.3.6 
Dosage Delays and Modifications 
4.3.6.1 
Dosage Delays and Modifications:  Venetoclax, Rituximab, 
Obinutuzumab, and CHOP Chemotherapy 
Guidelines for dose delay and modification of R/G-CHOP and venetoclax are shown in 
Table 3.  These guidelines pertain to dose delays and modifications based on physical 
examination findings, observed toxicities, and laboratory results obtained within 72 hours 
before study treatment administration.  Dose delays and dose modifications as a result 
of adverse events not specified in Table 2 should proceed on the basis of the principle of 
maintaining the dose intensity of R/G-CHOP.  The determination of all dose and 
schedule modifications will be made on the basis of the investigator’s assessment of 
ongoing clinical benefit with continuing study treatment in consultation with and with the 
approval of the Medical Monitor.  It is recommended that blood counts be checked within 


 
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24−72 hours for patients with cytopenias resulting in dose delays to see if the counts 
have recovered. 
No dose modifications of rituximab or obinutuzumab are allowed.  Cyclophosphamide, 
doxorubicin, vincristine, and venetoclax doses may be re-escalated (even to the full dose) 
with the approval of the Medical Monitor. 
If administration of chemotherapy is delayed, the administration of rituximab, 
obinutuzumab, and CHOP should be delayed for the same time frame; for example, 
if CHOP therapy is delayed, administration of rituximab should also be delayed so that 
they are given together beginning on Day 1 of the same cycle. 
For non-hematologic toxicities, dosing of R-CHOP or G-CHOP may be resumed upon 
resolution to Grade ≤ 1 or baseline status.  Resumption of dosing without complete 
resolution of toxicity may only be considered after careful weighing of the benefits and 
risks with the patient and agreement between the investigator and the Sponsor. 
A dose delay of 14 days is permitted for R-CHOP or G-CHOP to allow recovery of 
hematologic toxicities to Grade ≤ 2 or non-hematologic toxicities to Grade ≤ 1 or baseline 
status for the first episode.  Actions for recurrent hematologic adverse events are 
described in Table 3.  If treatment is delayed for more than 2 weeks (except for 
hepatitis B reactivation), the patient should be withdrawn from study treatment, except in 
exceptional circumstances requiring discussion with the Medical Monitor.  (Note that 
lymphopenia is not considered a cytopenic toxicity, because it is an expected outcome of 
therapy)  Patients who discontinue all study treatment for adverse events should remain 
in the study and continue to have disease assessments through progression and 
standard follow-up. 


 
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Table 3 
Guidelines for Dose Delay or Modification of Venetoclax, Rituximab, or Obinutuzumab and CHOP 
Chemotherapy 
Event(s) 
Dose Delay or Modification 
Grade 3 or 4 neutropenia on Cycle Day 1 
with or without infection or fever a 
 
First delay 
• 
Delay doses of all study treatment. 
• 
Administer growth factors; (e.g., G-CSF for neutropenia as indicated and for all subsequent 
cycles). 
• 
If ANC recovers to > 1000/μL by Day 7 of the scheduled date for the next cycle, administer 
full dose of study treatment. 
• 
If ANC recovers to > 1000/μL on or after Day 8 of the scheduled date for the next cycle, 
reduce the dose of venetoclax to the previously tested (lower) dose level (dose will be 
reduced by at least 25%). 
• 
If the primary cause of neutropenia is thought to be lymphoma infiltration into the bone 
marrow, the investigator may elect not to reduce the dose of venetoclax.  Decisions must 
be made in consultation with and with approval of the Medical Monitor. 
Recurrent Grade 3 neutropenia on 
Cycle Day 1 
• 
Delay doses of all study treatment. 
• 
If ANC recovers to > 1000/μL by Day 7 of the scheduled date for the next cycle, administer 
full dose of study treatment. 
• 
If ANC recovers to > 1000/μL on or after Day 8 of the scheduled date for the next cycle, 
then: 
If no prior dose reduction of venetoclax:  Reduce the dose of venetoclax to the 
previously tested (lower) dose level (dose will be reduced by ≥ 25%). 
If there was a prior reduction of venetoclax:  the venetoclax dose reduction should be 
maintained, and the doses of cyclophosphamide and doxorubicin should be reduced to 
75% of the original dose. 
For subsequent episodes, further dose reduction of venetoclax or doxorubicin and 
cyclophosphamide may be considered. 
• 
If Grade 3 neutropenia persists despite growth factor support and following venetoclax, 
cyclophosphamide and doxorubicin dose reductions, in the absence of fever, patient may 
continue with study treatment. 
• 
If patient develops Grade 3 febrile neutropenia or infection despite growth factor support 
and following venetoclax, cyclophosphamide and doxorubicin dose reductions, discontinue 
all study treatment permanently. 


 
 
Table 3 Guidelines for Dose Delay or Modification of Venetoclax, Rituximab, or Obinutuzumab and CHOP 
Chemotherapy (cont.) 
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Event(s) 
Dose Delay or Modification 
Recurrent Grade 4 neutropenia on 
Cycle Day 1 
• 
If patient develops persistent Grade 4 neutropenia requiring dose delay despite growth 
factor support and following venetoclax, cyclophosphamide and doxorubicin dose 
reductions, discontinue all study treatment permanently. 
Febrile neutropenia or neutropenia with 
infection during Cycle 1  
• 
Withhold obinutuzumab dose until it resolves. 
• 
If Cycle 1 Day 8 is delayed to within 2 days of Day 15, then omit the Day 8 dose and 
administer the Day 15 dose as previously scheduled (if infection or neutropenic fever has 
resolved). 
• 
If Cycle 1 Day 15 is delayed to within 2 days of Cycle 2, then omit the Day 15 dose and 
administer the Cycle 2 Day 1 dose of obinutuzumab + CHOP as scheduled (if infection or 
neutropenic fever has resolved). 
• 
Note:  obinutuzumab should not be held for asymptomatic neutropenia. 
Grade 4 thrombocytopenia, first episode 
 
Recurrent Grade 3 thrombocytopenia in 
consecutive cycles 
 
Grade 3 thrombocytopenia on Cycle Day 1, 
first episode 
 
• 
Modify venetoclax dose by reducing to next dose level or decrease dosing schedule to 
7 days 
• 
Modify venetoclax dose by reducing to next dose level or decrease dosing schedule to 
7 days 
• 
Delay doses of all study treatment. 
• 
If platelet count recovers to > 50,000/μL by Day 7 of the scheduled date of the next cycle, 
administer full dose of study treatment. 
• 
If platelet count recovers to > 50,000/μL on or after Day 8 of the scheduled date of the next 
cycle, reduce the dose of venetoclax to the previously tested (lower) dose level (dose will 
be reduced by at least 25%) or decrease dosing schedule to 7 days.  Full dose of R-CHOP 
or G-CHOP may be given. 
• 
If the patient had baseline thrombocytopenia and the primary cause of thrombocytopenia is 
thought to be lymphoma infiltration into the bone marrow, the investigator may elect not to 
reduce the dose of cyclophosphamide and doxorubicin. 


 
 
Table 3 Guidelines for Dose Delay or Modification of Venetoclax, Rituximab, or Obinutuzumab and CHOP 
Chemotherapy (cont.) 
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Event(s) 
Dose Delay or Modification 
Recurrent Grade 3 or 4 thrombocytopenia 
on Cycle Day 1 
• 
Delay doses of all study treatment. 
• 
Reduce the dose of venetoclax to the previously tested (lower) dose level (dose will be 
reduced by at least 25%) or decrease dosing schedule to 7 days. 
• 
If recurrent Grade 3 or 4 thrombocytopenia on Cycle Day 1 after venetoclax dose reduction 
The venetoclax dose reduction should be maintained, and the doses of 
cyclophosphamide and doxorubicin should be reduced to 75% of the original dose. 
For subsequent episodes, further dose reduction of venetoclax or doxorubicin and 
cyclophosphamide may be considered. 
• 
If patient develops Grade 4 thrombocytopenia following venetoclax, cyclophosphamide and 
doxorubicin dose reductions, discontinue all study treatment permanently. 
Severe thrombocytopenia (platelets 
< 10,000/μL) and/or symptomatic bleeding 
in patients who are not receiving 
concomitant anticoagulants or platelet 
inhibitors during Cycle 1 
• 
Withhold obinutuzumab in case of severe thrombocytopenia (platelets < 10,000/μL) or 
symptomatic bleeding (irrespective of platelet count) until it resolves. 
• 
If the Cycle 1 Day 8 dose is delayed, then omit the Day 8 dose and administer the 
Day 15 dose as previously scheduled (if symptomatic bleeding has resolved). 
• 
If the Cycle 1 Day 15 dose is delayed, then omit the Day 15 dose and administer the 
Cycle 2 Day 1 dose of obinutuzumab + CHOP as scheduled (if symptomatic bleeding has 
resolved). 
Thrombocytopenia with platelets 
< 20,000/μL and/or symptomatic bleeding 
in patients who are receiving concomitant 
anticoagulants or platelet inhibitors during 
Cycle 1 b, c 
• 
Withhold obinutuzumab in case of platelets < 20,000/μL or symptomatic bleeding 
(irrespective of platelet count) until it resolves. 
• 
If the Cycle 1 Day 8 dose is delayed, then omit the Day 8 dose and administer the 
Day 15 dose as previously scheduled (if symptomatic bleeding has resolved). 
• 
If the Cycle 1 Day 15 dose is delayed, then omit the Day 15 dose and administer the 
Cycle 2 Day 1 dose of obinutuzumab + CHOP as scheduled (if symptomatic bleeding has 
resolved). 
• 
For patients who are receiving concomitant anticoagulant when thrombocytopenia with 
platelets < 20,000/μL develops, adjust the dose or withhold the drug per investigator 
discretion. 
• 
For patients who are on platelet inhibitors when thrombocytopenia with platelets 
< 20,000/μL develops, consider temporarily withholding their use c. 
Grade 1 or 2 neutropenia and/or 
thrombocytopenia 
• 
No dose reduction or delay 


 
 
Table 3 Guidelines for Dose Delay or Modification of Venetoclax, Rituximab, or Obinutuzumab and CHOP 
Chemotherapy (cont.) 
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Event(s) 
Dose Delay or Modification 
Grade 3 or 4 infection, with or without 
neutropenia 
• 
Withhold rituximab or obinutuzumab. 
Hemorrhagic cystitis 
• 
Patients should be adequately hydrated prior to and after cyclophosphamide administration 
and should be instructed to void frequently.  If gross hematuria develops, 
cyclophosphamide should be withheld until resolution of cystitis.  A dose reduction of 50% 
for cyclophosphamide may be considered at the next cycle.  Re-escalation of 
cyclophosphamide to the initial full dose is recommended if symptoms do not recur. 
Grade 1–4 heart failure or Grade 3 or 4 
LVSD 
• 
Discontinue R-CHOP chemotherapy permanently. 
Bilirubin > 3.0 mg/dL 
• 
Delay treatment with R-CHOP until resolution to Grade ≤ 1 within 14 days.  Evaluate for 
causality 
Bilirubin between 1.5 and 3.0 mg/dL 
• 
Reduce doxorubicin and vincristine dose by 25% of baseline.  With subsequent courses of 
treatment if bilirubin has returned to ≤ 1 mg/dL, full doses may be given.  Give full dose of 
rituximab or obinutuzumab and continue current dose of cyclophosphamide and 
prednisone or prednisolone.  Evaluate for causality. 
Grade 4 neurotoxicity 
• 
Discontinue R-CHOP or G-CHOP chemotherapy permanently. 
Grade 2 or 3 neurotoxicity 
• 
Withhold R- CHOP or G-CHOP chemotherapy. 
• 
If recovered to Grade ≤ 1 value within 14 days, administer full dose rituximab and continue 
current dose of cyclophosphamide and prednisone or prednisolone.  Reduce vincristine 
dose by 50% for current cycle and all subsequent cycles. 
Grade 3 or 4 tumor lysis syndrome 
• 
Withhold all study treatment (venetoclax and R-CHOP).  The patient’s next dose may be 
delayed for up to 14 days.  See Section 4.6 and Appendix 6 for prophylaxis and 
management guidelines. 
• 
Following complete resolution of TLS, obinutuzumab or rituximab may be re-administered 
at the full dose during next scheduled infusion, in conjunction with prophylactic therapy and 
CHOP chemotherapy.  
• 
Venetoclax dosing may be reinitiated at target or reduced dose following discussion with 
the Medical Monitor, in conjunction with prophylactic therapy.   
Anaphylaxis 
• 
Discontinue rituximab or obinutuzumab permanently.  CHOP and venetoclax 
may be continued when recovered if not attributable to CHOP or venetoclax.  Follow 
treatment guidelines in Section 4.3.3.8. 
Grade 4 IRR 
• 
Discontinue rituximab or obinutuzumab permanently.  CHOP and venetoclax 
may be continued when recovered.  Follow treatment guidelines in Section 4.3.3.8.   


 
 
Table 3 Guidelines for Dose Delay or Modification of Venetoclax, Rituximab, or Obinutuzumab and CHOP 
Chemotherapy (cont.) 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
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Event(s) 
Dose Delay or Modification 
Grade 3 IRR, second episode 
• 
Discontinue rituximab or obinutuzumab permanently.  CHOP and venetoclax may be 
continued when recovered.  Follow treatment guidelines in Section 4.3.3.8. 
Grade 1 neurotoxicity (peripheral 
neuropathy) 
• 
Continue treatment at full dose; vincristine may be decreased at the discretion of the 
investigator. 
Grade 3 or 4 non-hematologic toxicity not 
specifically described above 
(excluding alopecia, nausea, and vomiting)
• 
Delay R-CHOP or G-CHOP for a maximum of 2 weeks. 
• 
If improved to Grade ≤ 1 or baseline, continue study therapy at full dose, or reduce dose at 
the discretion of the investigator per site’s standard procedures after discussion with the 
Medical Monitor. 
Grade 1 non-hematologic toxicity 
• 
No dose reduction or delay 
Hepatitis B reactivation (as evidenced by 
new detectable HBV-DNA levels) 
• 
HBV-DNA levels detectable but ≤ 100 IU/mL:  Re-test within 2 weeks.  If still positive, 
withhold R-CHOP or G-CHOP and treat patient with an appropriate nucleoside analogue.  
Immediately refer patient to a gastroenterologist or hepatologist. 
• 
HBV-DNA levels at WHO-recommended cutoff of > 100 IU/mL: withhold R-CHOP or 
G-CHOP and treat the patient with an appropriate nucleoside analogue.  Immediately refer 
patient to a gastroenterologist or hepatologist. 
• 
Rising HBV-DNA viral load while on an appropriate anti-viral therapy:  Discontinue patient 
from rituximab or obinutuzumab and CHOP chemotherapy immediately. 
 CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisolone or prednisone; G-CSF = granulocyte colony−stimulating factor; 
HBV = hepatitis B virus; IRR = infusion-related reaction; LMWH = low−molecular weight heparin; LVSD = left ventricular systolic dysfunction; 
R = rituximab; TLS = tumor lysis syndrome.  
a All on the basis of laboratory results obtained within the time frame listed in the schedule of assessments (see Appendix 1) prior to 
infusion of Day 1 of that cycle  
b If the clinical condition of the patient requires the use of concomitant anticoagulants, the patient is at increased risk of bleeding when 
thrombocytopenia with platelets < 20,000/μL develops.  When possible, replace prior therapy with vitamin K antagonists with LMWH 
before Cycle 1 Day 1. 
c Clinical decision-making may be adjusted depending on the patient-specific assessment of benefit and risk. 
 


 
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4.3.7 
Permanent Treatment Discontinuation Criteria 
Patients who experience toxicity that can be clearly attributed to any particular study 
drug treatment may discontinue treatment with the specific agent.  If toxicity cannot be 
clearly attributed to a single agent and is considered possibly related to the combination 
treatment, treatment with multiple agents should be discontinued.  Patients who 
discontinue treatment for reasons other than PD should remain in the study and continue 
to have disease assessments per protocol. 
4.3.7.1 
Permanent Treatment Discontinuation Criteria for Venetoclax 
A patient should discontinue venetoclax permanently if any of the following occurs: 
• 
Grade ≥ 3 toxicity that has a reasonable possibility of being related to the 
administration of venetoclax and that does not resolve to ≤ Grade 2 within 3 weeks 
• 
Recurrent Grade 4 neutropenia with infection and despite G-CSF support 
• 
Disease progression 
• 
Any dose delay of ≥ 4 weeks after last dose 
 
Patients who discontinue venetoclax for reasons other than PD should remain on the 
study and continue to have disease assessments per the protocol.  Patients may 
continue treatment with R-CHOP or G-CHOP only if it is determined to be in the best 
interests of the patient, after discussion between the investigators and Medical Monitor. 
4.3.7.2 
Permanent Treatment Discontinuation Criteria for Rituximab or 
Obinutuzumab 
A patient should discontinue rituximab or obinutuzumab permanently if any of the 
following occur:  
• 
Grade 4 infusion-related symptom or anaphylaxis:  The patient should be withdrawn 
from study treatment immediately and supportive treatment given. 
• 
Recurrence of Grade 3 infusion-related symptoms at re-challenge, regardless of 
timing (e.g., within same session or at the next session) 
 
4.3.7.3 
R-CHOP or G-CHOP Chemotherapy 
Patients should discontinue protocol therapy for any dosing delay exceeding 14 days for 
the initiation of the next planned cycle of R-CHOP or G-CHOP.  Any exceptions will 
require Sponsor approval. 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES 
4.4.1 
Concomitant Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening through 30 days after the last dose of venetoclax or CHOP, or 
90 days after the last dose of rituximab or obinutuzumab, whichever is later.  All 


 
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concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  
Patients who are receiving oral contraceptives, stable doses of hormone replacement 
therapy, or other maintenance therapy should continue their use. 
Steroid use not otherwise dictated by the protocol CHOP treatment will follow the 
guidelines outlined below: 
• 
Corticosteroid use > 30 mg/day of prednisone or equivalent:  Not allowed within 
7 days prior to Cycle 1 Day 1 except as specified below 
• 
Corticosteroid use 15−30 mg/day of prednisone or equivalent:  Must be documented 
to be on a stable dose of at least 4 weeks’ duration prior to first dose of study drug. 
• 
Corticosteroid use < 15 mg/day of prednisone or equivalent:  Allowed 
 
Exceptions to the above guidelines: 
• 
Corticosteroid used for malignancy-related symptom control (up to 100 mg/day of 
prednisone or equivalent) prior to initiation of study treatment.  Once study treatment 
has been given, corticosteroid use may be tapered down (must be ≤ pre-study 
treatment dose) for no more than 5 days. 
• 
Premedication for rituximab or obinutuzumab infusions, as indicated per protocol 
and/or site local practice (may replace dose of CHOP prednisone) 
• 
Inhaled corticosteroids for the treatment of asthma or chronic obstructive pulmonary 
disease 
• 
Topical steroids 
• 
Replacement corticosteroid therapy for an inherited or acquired deficiency 
• 
Steroid use to treat emergent issues not related to anti-neoplastic intent is allowed 
for no more than 7 days per event.  For steroid treatment > 7 days, the Medical 
Monitor must be consulted to discuss allowing the patient to continue treatment. 
 
4.4.1.1 
CNS Prophylaxis 
CNS prophylaxis with intrathecal chemotherapy may be given according to institutional 
practice and its use documented on the eCRF.  CNS prophylaxis with systemic 
chemotherapy may be given only after completion of the primary response assessment 
(6−8 weeks after Day 1 of Cycle 8). 
4.4.1.2 
Prophylaxis for Hemorrhagic Cystitis 
Patients should be adequately hydrated prior to and after cyclophosphamide 
administration and should be instructed to void frequently.  Mesna may be used as 
prophylaxis according to institutional practice.  
4.4.1.3 
Treatment and Prophylaxis of Neutropenia 
G-CSF should be administered as primary prophylaxis starting with Cycle 1 of therapy 
and continue through each cycle of CHOP therapy received for all patients unless there 


 
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is a medical contraindication or the investigator feels it is not in the patient’s best interest 
to receive G-CSF. 
4.4.1.4 
Premedication before Rituximab or Obinutuzumab Therapy 
Rituximab or obinutuzumab should not be administered as an IV push or bolus because 
IRRs may occur.  Patients should be premedicated with acetaminophen/paracetamol 
and an antihistamine prior to all infusions of obinutuzumab.  A single dose of 
prophylactic corticosteroids (e.g., 100 mg of IV prednisolone or equivalent) may also be 
administered beginning with the first infusion, comprising the prednisone component of 
the CHOP treatment.  Premedication may attenuate IRRs.  Because transient 
hypotension may occur during rituximab or obinutuzumab infusion, consideration should 
be given to withholding antihypertensive medications for 12 hours prior to infusion. 
4.4.1.5 
Prophylaxis for Tumor Lysis Syndrome 
TLS is a risk for patients with NHL who are treated with high cell-killing agents.  The risk 
of TLS is a continuum based on multiple factors that include tumor burden and 
comorbidities.  Risk is highest for those with bulky disease, elevated absolute 
lymphocyte count, elevated pretreatment LDH levels, compromised renal function, and 
dehydration.  All patients should undergo tumor burden assessment and CBC with 
WBC differential, and blood chemistry (potassium, uric acid, phosphorus, calcium, and 
creatinine).  Pre-existing chemistry abnormalities should be corrected prior to 
initiation of treatment with venetoclax.   
Patients who do not present with bulky disease are not considered at higher risk for TLS 
and do not require hospitalization, but may be hospitalized per discussion with the 
investigator and Medical Monitor. 
The risk of TLS in the setting of R-CHOP or G-CHOP should be assessed by the 
investigator and prophylaxis and management undertaken per institutional standard. 
All patients must receive prophylaxis for TLS prior to the initiation of the first dose of 
venetoclax.  Prophylaxis will include the following: 
• 
Appropriate hydration, consisting of a fluid intake of approximately 2−3 L/day 
starting 24−48 hours days prior to the start of venetoclax treatment and continued 
for at least 24 hours after the first dose (for patients for whom volume overload is 
considered a significant risk, hospitalization should be considered) 
• 
Administration of an agent to reduce uric acid, such as allopurinol 300 mg/day, 
orally beginning 72 hours prior to the first venetoclax dose.  Rasburicase IV should 
be administered (unless medically contraindicated) for those patients with elevated 
uric acid levels prior to treatment, which is defined as a value above the local 
laboratory ULN or 476 μmol/L.  Agents should be given until normalization of serum 
uric acid and other laboratory evidence of TLS (e.g., elevated serum LDH levels). 
• 
Laboratory results should be reviewed and electrolyte values should not 
demonstrate any clinically significant abnormalities prior to the first dose of 


 
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venetoclax, if abnormalities are observed, the patient should receive additional 
prophylactic treatment and hydration prior to the initiation of dosing. 
• 
Patients at higher risk of TLS will be hospitalized for the initial venetoclax dose. 
• 
For patients at particularly high risk for TLS, as judged by the investigator, 
consideration may be given to starting at a lower dose of venetoclax and increasing 
venetoclax dose in a stepwise fashion in discussion with the Medical Monitor.   
 
On the day of the initial visit with administration of venetoclax (see Section 3.1.2.1), 
serial vital sign assessments will be performed, and serum chemistry and hematology 
samples will be drawn prior to the dose of venetoclax and at 8 and 24 hours following 
the dose (see Appendix 1).  The serum chemistry and hematology samples will be 
immediately sent to the laboratory, and the investigator or designee must promptly 
review the results.  Laboratory results from pre-dose samples must be reviewed prior to 
venetoclax administration unless laboratory results from within the prior 24 hours have 
already been reviewed.  Laboratory values obtained prior to the dose of venetoclax are 
to be used to determine whether a patient developed a change related to TLS.  
Laboratory results from the 24-hour post-dose assessments must be reviewed prior to 
receiving the dose of venetoclax for that day.  Patients who develop electrolyte changes 
suggestive of TLS should undergo aggressive management and further monitoring per 
Appendix 6. 
4.4.1.5.1 
Hospitalization 
Patients exhibiting specific characteristics at screening or initiation of venetoclax 
treatment are considered to be at high risk for development of TLS and must be 
hospitalized for more intensive prophylaxis and monitored during the initial dose of 
venetoclax.  These patients are identified by the presence of any of the following:   
• 
Any lymph mass ≥ 10 cm on the screening CT scan 
• 
Out-of-range (high) absolute lymphocyte count (ALC) or the presence of abnormal 
cells in the peripheral blood differential signifying circulating lymphoma cells 
 
In addition to characteristics requiring mandatory hospitalization, other patient 
characteristics may suggest an increased risk of TLS.  These include but are not limited 
to the following:   
• 
Overall disease burden (e.g., several enlarged lymph nodes, even if none reaching 
10 cm) 
• 
Elevated LDH levels 
• 
Compromised renal function, as evidenced by low CRCL 
• 
Extensive bone marrow involvement 
• 
Dehydration 
 
Hospitalization is not mandatory for patients who exhibit these characteristics, but these 
and any other factors that are considered relevant to TLS should be considered in the 


 
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overall assessment of the patient’s state and their risk to develop TLS.  Investigators 
should use their judgment in their assessment of the patient’s risk of TLS development 
and may choose to hospitalize any patient they consider to be at risk for the 
development of TLS during the first dose of venetoclax, with approval of the Medical 
Monitor.  
Hospitalization will begin the evening prior to the first dose of venetoclax and continue 
for 24 hours after the first dose.  Upon admission, serum chemistry and hematology 
laboratory samples should be drawn, and IV hydration should be started with a target of 
150−200 mL/hr or as clinically appropriate.  Laboratory results should be reviewed and 
electrolyte values should not demonstrate clinically significant abnormalities prior to the 
first dose of venetoclax, or the patient should receive additional prophylactic treatment 
and hydration prior to the initiation of dosing.  A nephrologist (or acute dialysis service) 
must be consulted/contacted on hospital admission (per institutional standards) to 
ensure emergency dialysis is available and the appropriate staff is aware and prepared 
to handle any necessary intervention for TLS.  Telemetry should also be considered. 
Serial vital sign assessments will be performed, and TLS laboratory samples will be 
drawn (serum chemistry as defined in Section 4.5.1.5) prior to the first dose of 
venetoclax and at 8, 12, and 24 hours post-dose; additionally, hematology samples will 
be drawn at 8 and 24 hours post-dose (see Appendix 1).  These samples are to be 
immediately sent to the laboratory and the investigator or designee must promptly review 
the results.  Laboratory values obtained prior to the dose of venetoclax are to be used to 
determine whether a patient developed a change related to TLS.  Laboratory results 
from the 24-hour post-dose sample must be reviewed prior to receiving the dose of 
venetoclax for that day.  Patients who develop electrolyte changes suggestive of TLS 
should undergo aggressive management and further monitoring per Appendix 6. 
4.4.1.6 
Infection Prophylaxis 
If clinically indicated, anti-infective prophylaxis for viral, fungal, bacterial, or 
pneumocystis infections is permitted.  Although there is a potential for drug-drug 
interactions, there are likely to be limited potential clinical effects, therefore trimethoprim 
sulfamethoxazole can be considered for pneumocystis prophylaxis, with close clinical 
monitoring.  The Medical Monitor should also be consulted regarding any consideration 
of the use of azoles as anti-fungal prophylaxis or therapy because of the potential for 
drug-drug interactions. 
4.4.1.7 
Monitoring and Treatment for Hepatitis B Reactivation 
Patients who are both HBsAg negative and anti-HBc positive may be included in this 
study.  These patients should have HBV-DNA levels obtained monthly during the study 
and for at least 12 months after the last cycle of therapy by means of real-time PCR with 
the use of an assay that has a sensitivity of at least 10 IU/mL  


 
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If the HBV-DNA assay becomes positive and is above the WHO cutoff of 100 IU/mL, 
treatment with R-CHOP or G-CHOP chemotherapy will be held and the patient should 
be treated (for at least 1 year after the last dose of rituximab or obinutuzumab) with an 
appropriate nucleoside analogue and immediately referred to a gastroenterologist or 
hepatologist for management.  Patients may resume R-CHOP or G-CHOP 
chemotherapy once HBV-DNA levels decrease to undetectable levels. 
If the HBV-DNA assay becomes positive and is ≤ 100 IU/mL, the patient should be 
retested within 2 weeks.  If the assay is still positive, treatment with R-CHOP or G-CHOP 
chemotherapy will be held and the patient should be treated with an appropriate 
nucleoside analogue (for at least 1 year after the last dose of rituximab or obinutuzumab) 
and immediately referred to a gastroenterologist or hepatologist for management.  
Patients may resume R-CHOP or G-CHOP chemotherapy once the HBV-DNA levels 
decrease to undetectable levels. 
If a patient’s HBV-DNA level exceeds 100 IU/mL while the patient is receiving anti-viral 
medication, treatment with R-CHOP or G-CHOP will be permanently discontinued (see 
Section 4.3.6, Table 3). 
Patients in countries where prophylactic anti-viral medications for hepatitis B reactivation 
are the standard of care may be treated prophylactically. 
4.4.1.8 
Other Concomitant Medications 
Necessary supportive measures for optimal medical care will be given throughout the 
study according to institutional standards, including the use of growth factors 
(e.g., erythropoietin) if clinically indicated.  G-CSF will be administered as primary 
prophylaxis in each cycle of CHOP therapy (see Section 4.4.1.3). 
Anti-emetic therapy may be instituted for any patient if clinically indicated.  It is 
recommended that CHOP infusions be administered following premedication with a 
serotonin (5-HT3) antagonist (i.e., dolasetron, ondansetron, etc.) or per institutional 
practice. 
Antidiarrheal therapy may be instituted for any patient if clinically indicated per 
institutional practice. 
Live-virus vaccines should not be given within 28 days prior to the initiation of 
study treatment or at any time during study treatment.  Systemic steroid therapy other 
than the prednisone component of CHOP will not be allowed during study treatment with 
the exceptions noted in Section 4.4.1. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 


 
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4.4.2 
Excluded Therapy 
Patients who are discontinued from study treatment will be followed for safety outcomes 
for 30 days following the patient’s last dose of venetoclax or CHOP (or 90 days following 
the patient’s last dose of rituximab or obinutuzumab, whichever is later) or until the 
patient receives another anti-cancer therapy, whichever occurs first. 
Use of the following therapies is prohibited during the study: 
• 
Cytotoxic chemotherapy.  Supplemental systemic therapy for prophylaxis of CNS 
disease is permitted according to institutional practice only after primary response 
assessment and must be recorded in the eCRF. 
• 
Radiotherapy prior to primary response assessment 
• 
Immunotherapy 
• 
Hormone therapy (other than contraceptives, hormone replacement therapy, or 
megestrol acetate) 
• 
Any therapies intended for the treatment of lymphoma/leukemia whether FDA 
approved or experimental (outside of this study) 
• 
Warfarin may be co-administered with venetoclax with caution and with the 
guidance of the Medical Monitor. 
 
The following concomitant medications are not allowed from 7 days prior to the first dose 
of study drug and during venetoclax administration: 
• 
Corticosteroid use > 30 mg/day of prednisone or equivalent (with some exceptions, 
see Section 4.4.1). 
• 
Strong and moderate CYP3A4 inducers (see Appendix 5 for examples) 
 
The following concomitant medications are not allowed from 7 days prior to the 
administration of the first dose of study drug:   
• 
Strong and moderate CYP3A inhibitors (see Appendix 5 for examples) 
• 
Strong and Moderate CYP3A inducers (see Appendix 5 for examples) 
 
Exclude strong and moderate CYP3A inhibitors through the DLT assessment period and 
consider alternative medications.  If a patient requires use of these medications while he 
or she is receiving the target dose of venetoclax, once the DLT assessment period is 
complete, use with caution and reduce the venetoclax dose by 2-fold for moderate 
inhibitors and 4-fold for strong inhibitors during co-administration. 
After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax dose is 
increased back to the initial maintenance/target dose. 
• 
Exclude strong and moderate CYP3A inducers (see Appendix 5 for examples) 
through the DLT assessment period and consider alternative medications.  If a 
patient requires use of these medications while he or she is receiving the target 


 
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dose of venetoclax, once the DLT assessment is complete, use with caution and 
contact the Medical Monitor for guidance. 
 
Table 4 lists categories of excluded and cautionary medications. 
A sample list of excluded medications and cautionary medications that fall into the 
categories within this section can be found in Appendix 5.  It is not possible to produce 
an exhaustive list of medications that fall into these categories, so if in question, refer to 
the appropriate product label. 
Table 4 
Excluded and Cautionary Medications 
Excluded Medications 
Anti-cancer therapies including chemotherapy, radiotherapy, or other investigational therapy, 
including targeted small molecule agents: 
Excluded 28 days prior to first dose and throughout venetoclax administration.  
Biologic agents (e.g., monoclonal antibodies) for anti-neoplastic intent: 
Excluded 8 weeks prior to first dose and throughout venetoclax administration 
Grapefruit, grapefruit products, Seville oranges (including marmalade containing 
Seville oranges) or star fruit: 
Excluded 3 days prior to first dose and throughout venetoclax administration 
Excluded through ramp-up and DLT assessment period (if applicable) and cautionary thereafter: 
Strong and Moderate CYP3A inhibitors: 
Exclude through the DLT assessment period and consider alternative medications.  If 
patient requires use of these medications while they are receiving the target dose of 
venetoclax, once the DLT assessment period is complete use with caution and reduce 
the venetoclax dose by 2-fold for moderate inhibitors and 4-fold for strong inhibitors 
during co-administration. 
After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax dose is 
increased back to the initial maintenance/target dose. 
Strong and Moderate CYP3A inducers: 
Exclude through the DLT assessment period and consider alternative medications.  If 
patient requires use of these medications while they are receiving the target dose of 
venetoclax, use with caution and contact the Medical Monitor for guidance. 
Cautionary Medications 
Warfarin  
Weak CYP3A inducers 
Weak CYP3A inhibitors 
P-gp substrates 
BCRP substrates 
OATP1B1/1B3 substrates 
P-gp inhibitors 
BCRP inhibitors 
OATP1B1/B3 inhibitors 
DLT = dose-limiting toxicity. 
Note:  See Appendix 5 for examples of these medications. 
 


 
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4.5 
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments performed during the study. 
4.5.1 
Definitions of Study Assessments 
4.5.1.1 
Medical History and Demographics 
Medical history includes all clinically significant diseases, smoking history, prior cancer 
history, prior cancer therapies and procedures, and all medications used by the patient 
from 7 days preceding the screening visit to Cycle 1 Day 1. 
4.5.1.2 
Vital Signs 
Vital signs will include measurements of heart rate, systolic and diastolic blood pressure 
while the patient is in a seated position, temperature, weight, and BSA (screening only 
unless > 10% change in weight).  Scheduled vital sign assessments should occur prior to 
drug dosing if applicable unless otherwise specified (see Section 4.4.1.5). 
4.5.1.3 
Physical Examination 
A complete physical examination should include the evaluation of head, eyes, ears, nose, 
and throat and CV, dermatological, musculoskeletal, respiratory, gastrointestinal, and 
neurological systems.  Changes from baseline abnormalities should be recorded at each 
subsequent physical examination.  New or worsened abnormalities should be recorded 
as adverse events if appropriate. 
As part of tumor assessment, physical examinations should also include the evaluation 
of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. 
Targeted physical examinations (including weight) should be limited to systems of 
primary relevance (i.e., CV, respiratory, those associated with symptoms, and those 
associated with tumor assessment [lymph nodes, liver, and spleen]). 
4.5.1.4 
Tumor and Response Evaluation 
All measurable disease must be documented at screening by a combined PET-CT scan 
with a diagnostic quality CT component.  Response assessments will be determined by 
the investigator on the basis of imaging studies and bone marrow examinations (if 
appropriate), with the use of the modified Lugano Classification (Cheson et al. 2014; see 
Appendix 2).  A five-point scale score is required as part of the PET scan response.  
Responses will also be assessed by the IRC (see Section 3.7). 
Clinical response assessment should include evaluation of the presence and degree of 
enlarged lymph nodes, hepatomegaly, and splenomegaly by physical examination. 
Patients will be evaluated for disease response by PET-CT imaging after Cycle 4 and at 
6 to 8 weeks after Day 1 of Cycle 8 or last cycle received.  A bone marrow examination 
must be repeated to confirm a CR if it was previously positive, if it was not performed, 


 
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or if it was indeterminate at screening.  For sites at which PET-CT is not available for 
interim assessment (after Cycle 4), diagnostic CT imaging is an acceptable alternative. 
Diagnostic-quality CT scan with use of oral and IV contrast (unless medically 
contraindicated) must be obtained at baseline, after Cycle 4 and at end of treatment 
evaluation (6 to 8 weeks after Day 1 of Cycle 8 or last cycle received).  If PET-CT with 
diagnostic CT is not obtainable, a separate diagnostic CT scan must be performed at 
these timepoints in addition to the PET scans. 
All patients who have not progressed will then be followed with clinical assessments 
every 3 months until progression or close of study, whichever occurs first.  Assessments 
will be based on full physical examination.  CT scans (with oral and IV contrast, unless 
medically contraindicated) will be performed every 6 months for 2 years and as clinically 
indicated during these follow ups.  If a patient exhibits clinical signs of possible disease 
progression (i.e., increased or de novo enlargement of liver, spleen or lymph nodes on 
physical examination), additional assessments including PET-CT or contrast-enhanced 
CT scan and/or bone marrow must be performed to evaluate for PD. 
CT scans (with contrast) should include chest, abdomen, and pelvis scans; CT scans of 
the neck should be included if clinically indicated (MRIs may be used instead of CT 
scans in patients for whom CT scans are contraindicated).  CT scans for response 
assessment may be limited to areas of prior involvement only if required by local 
regulatory authorities.   
Bone marrow examinations should include biopsy and/or aspirate for morphology and 
flow cytometry and are required at screening. 
4.5.1.5 
Laboratory Assessments 
On days of study drug administration, pre-dose laboratory samples should be drawn 
within 0–4 hours before the start of treatment, unless otherwise specified.  Cycle 1 Day 1 
local laboratory assessments can be performed on Day -1 if this schedule is preferable 
to the site.  Instruction manuals and supply kits will be provided for all central laboratory 
assessments. 
4.5.1.5.1 
Central Laboratory Assessments 
Samples for the following assessments will be sent to one or several laboratories or to 
the Sponsor for analyses. 
• 
Lymphocyte subset counts.  Whole blood samples will be analyzed by flow 
cytometry for B cells (CD19+), T-cell subsets (CD3+, CD4+, CD8+), and NK cells 
(CD16+, CD56+)  
• 
Hepatitis B DNA levels (when appropriate) 
Monitoring of HBV-DNA levels is mandatory for patients who are positive for 
HBcAb and enter the study with negative titers.  For instructions on the 
management of these patients, see Section 4.4.1.7. 


 
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• 
PK assays 
Serum samples will be obtained for measurement of rituximab or 
obinutuzumab concentrations and EDTA-anticoagulated; plasma samples will 
be obtained for measurement of venetoclax or CHOP concentrations at 
timepoints noted in Appendix 3.  The samples will be sent to the central 
laboratory  and then to a Sponsor designated bioanalytical laboratory or to the 
Sponsor or  designee for analysis.  Relevant biotransformation products of 
study treatment may also be analyzed at the discretion of the Sponsor. 
• 
Blood and tumor tissue (tumor biopsy) for BCL2 family expression (by IHC), copy 
number alteration and translocation status (by FISH), DLBCL prognostic markers, 
and other DLBCL disease biology markers including resistance markers. 
• 
Peripheral blood for MRD assessments 
 
4.5.1.5.2 
Local Laboratory Assessments 
Samples for hematology, serum chemistry, liver function, and pregnancy will be 
analyzed at the study site’s local laboratory. 
• 
Hematology:  complete blood count (hemoglobin, hematocrit, RBC count, and WBC 
count), platelet count, ANC, absolute lymphocyte count, and percent or absolute 
differential counts) 
• 
Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine, calcium, magnesium, phosphorus, total bilirubin, total protein, albumin, 
ALT, AST, alkaline phosphatase, LDH, and uric acid 
• 
Viral serology and detection 
Hepatitis B (HBsAg and HBcAb) 
HCV antibody (also HCV RNA by PCR if the patient is HCV antibody positive) 
• 
Serum pregnancy test in females of childbearing potential 
 
4.5.1.6 
Electrocardiogram 
A 12-lead ECG is required at screening and as clinically indicated.  ECGs for each 
patient should be obtained with use of the same machine when possible.  ECGs should 
be obtained in triplicate. 
4.5.1.7 
MUGA/Echocardiogram 
MUGA scans will be obtained prior to treatment (see Appendix 1).  Echocardiogram may 
be used if MUGA is not available.  Any clinically significant changes in cardiac function 
must be reported within 7 days. 
4.5.2 
Screening and Pretreatment Assessments 
All screening evaluations must be completed and reviewed by the Medical Monitor or 
designee to confirm that patients meet eligibility criteria and are approved for enrollment 
before the first dose of study drug.  Written informed consent for participation in the 
study must be obtained before performing any study-specific screening tests or 


 
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evaluations.  Informed Consent Forms for patients who are not subsequently enrolled 
will be maintained at the study site. 
Screening and pretreatment tests and evaluations will be performed within 21 days 
preceding the first dose of study drug (except PET-CT scan, which may be performed up 
to 28 days preceding the first dose of study drug, providing no anti-tumor therapy was 
administered in this period).  Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 21 days prior to first dose of 
study drug may be used (bone marrow examination could have been performed up to 
3 months prior to Cycle 1 Day 1); such tests do not need to be repeated for screening. 
See the Schedule of Assessments provided in Appendix 1 for the schedule of screening 
and pretreatment assessments. 
4.5.3 
Roche Clinical Repository 
4.5.3.1 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities for 
the long-term storage of human biologic specimens including body fluids, solid tissues, 
and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future. 
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.3.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.5.3) will not be 
applicable at that site.   


 
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4.5.3.3 
Sample Collection 
The following samples will be collected for identification of dynamic (non-inherited) 
biomarkers: 
• 
Tissue and blood samples will be collected and sent to the central laboratories as 
part of the planned study assessments.  Any samples at the central laboratories, 
except PK samples, that remain from the planned study assessments may be taken 
and sent to the RCR if the patient consents to the optional RCR sampling. 
 
The following samples will be collected for identification of genetic (inherited) biomarkers: 
• 
One whole blood sample for DNA extraction will be drawn at baseline. 
 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the Sample Handling and Logistics 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). 
The dynamic biomarker specimens for DNA analysis will be subject to the confidentiality 
standards described below. 
4.5.3.4 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
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. 
Patient medical information associated with RCR specimens is confidential and may only 
be disclosed to third parties as permitted by the Informed Consent Form (or separate 


 
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authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
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 regarding 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. 
4.5.3.5 
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 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. 
4.5.3.6 
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 with the use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study GO27878 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 GO27878. 
4.5.3.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with GCP by a quality-controlled, 
auditable, and appropriately validated laboratory information management system, to 
ensure compliance with data confidentiality as well as compliance with authorized use of 
specimens as specified in this protocol and in the Informed Consent Form.  Roche 


 
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monitors and auditors will have direct access to appropriate parts of records relating to 
patient participation in the RCR for the purposes of verifying the data provided to Roche.  
The site will permit monitoring, audits, IRB/EC review, and health authority inspections 
by providing direct access to source data and documents related to the RCR samples. 
4.5.4 
Assessments during Treatment 
All visits must occur within ± 1 day from the scheduled date, unless otherwise noted.  All 
assessments will be performed on the day of the specified visit unless a time window is 
specified.  Assessments scheduled on the day of study drug administration of each cycle 
should be performed prior to study drug infusion, unless otherwise noted.   
See the Schedule of Assessments provided in Appendix 1 for the schedule of treatment 
period assessments. 
4.5.5 
End of Treatment Visit 
Patients who complete the study treatment period (defined as eight cycles) or who 
discontinue early will have an End of Treatment Visit, 6 to 8 weeks from Day 1 of the last 
cycle received.   
The visit at which response assessment shows PD may be used as the End of 
Treatment Visit. 
See the Schedule of Assessments provided in Appendix 1 for assessments to be 
performed. 
4.5.6 
Follow-Up Assessments 
Ongoing adverse events thought to be related to venetoclax, CHOP, rituximab, or 
obinutuzumab will be followed until the event has resolved to baseline grade, the event 
is assessed by the investigator as stable, new anti-tumor treatment is initiated, the 
patient is lost to follow-up, the patient withdraws consent, or when it has been 
determined that the study treatment or participation is not the cause of the adverse event. 
Patients will be followed for response until disease progression, death, or study closure, 
whichever occurs first.   
4.5.7 
Survival Follow-Up Assessments 
Survival follow-up information will be collected via telephone calls, patient medical 
records, and/or clinic visits approximately every 6 months until death, lost to follow-up, 
consent withdrawal, or study termination by Roche, whichever occurs first.  All 
patients will be followed for survival and new anti-lymphoma therapy information 
unless the patient requests to be withdrawn from follow-up (this request must be 
documented in the source documents and signed by the investigator), is lost to follow-
up, dies, or the study is terminated by the Sponsor, whichever occurs first.  If the 
patient withdraws from the study, the study staff may use a public information source 


 
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(e.g., county records) to obtain information about survival status only if permitted per 
local regulations. 
Study closure will occur approximately 2 years after the last patient has completed 
treatment. 
See the Schedule of Assessments provided in Appendix 1 for specified follow-up 
assessments. 
4.6 
PATIENT DISCONTINUATION 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
 
See Section 4.3.7 for treatment discontinuation criteria. 
See Appendix 1 for assessments that are to be performed for patients who prematurely 
withdraw from the study. 
4.7 
STUDY DISCONTINUATION 
Premature termination of this clinical trial may occur because of a regulatory authority 
decision, change in opinion of the IRB/IEC, drug safety problems, or at the discretion of 
F. Hoffmann-La Roche Ltd.  In addition, F. Hoffmann-La Roche Ltd retains the right to 
discontinue development of venetoclax in combination with Rituximab or Obinutuzumab 
and CHOP at any time.  F. Hoffmann-La Roche Ltd reserves the right to discontinue the 
trial prior to inclusion of the intended number of subjects, but intends only to exercise 
this right for valid scientific or administrative reasons.  After such a decision, the 
investigator must contact all participating subjects within 1 week.  As directed by 
F. Hoffmann-La Roche Ltd, all trial materials must be collected and all CRFs completed 
to the greatest extent possible. 
4.8 
POST-STUDY ACCESS TO VENETOCLAX, OBINUTUZUMAB, 
AND RITUXIMAB 
The Sponsor will offer post-study access to the study drug (venetoclax, obinutuzumab, 
and rituximab) free of charge to eligible patients in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, as outlined below. 


 
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A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after completing the study if any of 
the following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for NHL/DLBCL 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for NHL/DLBCL  
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.9 
ASSAY METHODS  
Rituximab and obinutuzumab serum concentrations will be measured using a validated 
ELISA method.  Plasma concentrations of venetoclax will be measured using a validated 
liquid chromatography tandem mass spectrometry method.  The CHO components of 
CHOP may be measured in plasma if needed to confirm exposure for these 
three chemotherapy drugs.  Plasma concentrations of prednisone will be measured if 
needed to test for a potential effect of venetoclax on prednisone pharmacokinetics.  
Bcl-2 and other exploratory markers will be evaluated from lymph node tissue with use of 
validated IHC, FISH, quantitative real-time PCR, and sequencing methodologies. 
4.10 
STATISTICAL METHODS 
The final analysis will be based on patient data collected through study discontinuation.  
Analyses will be based on treated patients (i.e., patients who have received any amount 
of R/G-CHOP or venetoclax).  Analyses will be provided separately for the dose-finding 
and extension cohorts where appropriate.  Data from patients who receive R-CHOP or 
G-CHOP only (i.e., have not received any venetoclax), will be summarized separately. 


 
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4.10.1 
Analysis of the Conduct of the Study 
Enrollment, major protocol violations, and discontinuations from the study will be 
summarized separately for the dose-finding and extension cohorts where appropriate. 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, and type 
and duration of malignancy will be summarized using means, standard deviations, 
medians, and ranges for continuous variables and proportions for categorical variables. 
This study is not designed to detect sex-specific differences.  There is no existing clinical 
data to suggest sex-specific differences regarding efficacy or safety of the investigational 
drugs.  Therefore, a specific male/female distribution is not defined for the study.  Males 
and females are equally eligible to participate if they meet all the inclusion criteria and 
none of the exclusion criteria. 
Study drug administration data will be listed by dose level and line of therapy and any 
dose modifications will be flagged.  The number of doses, treatment cycles, and average 
dose received for venetoclax plus R-CHOP or G-CHOP for the schedule/cohort will be 
summarized by cohort and dose level with the use of means, SDs, medians, and ranges. 
4.10.2 
Safety Analyses 
Safety will be assessed through summaries of adverse events, summaries of changes 
from screening assessments in laboratory test results, ECGs, and changes in vital signs. 
All recorded adverse event data will be listed by line of therapy, study site, patient 
number, and schedule/cohort.  All adverse events occurring on or after first study 
treatment will be summarized by mapped term, appropriate thesaurus levels, and 
NCI CTCAE v4.0 toxicity grade.  All serious adverse events will be listed separately and 
summarized. 
Incidence and nature of DLTs experienced within the combination DLT assessment 
window will be listed by dose cohort and study arm.  Patients who withdraw from study 
treatment prior to completing the DLT assessment window for reasons other than DLT 
will be considered un-evaluable for DLT and MTD assessments and will be replaced. 
Deaths reported during the study treatment period and those reported during follow-up 
after patient discontinuation will be listed. 
Relevant laboratory and vital sign (temperature, heart rate, respiratory rate, and blood 
pressure) data will be displayed by time, with NCI CTCAE v4.0 Grade 3 and 4 values 
identified where appropriate. 
4.10.3 
Pharmacokinetic and Pharmacodynamic Analyses 
Mean serum and plasma concentrations, as appropriate, of venetoclax, rituximab, 
obinutuzumab, and CHOP components versus time will be tabulated and plotted, and 


 
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summary statistics will be computed for each scheduled sampling time after appropriate 
grouping.  Concentration-time data for venetoclax and the other analytes will be 
analyzed using non-compartmental methods, and the PK parameters will be grouped 
and summarized as appropriate. 
Additional analyses, such as population PK/pharmacodynamic analysis, may be 
performed to characterize the pharmacokinetics and potential correlations of exposure 
with dose, demographics, pharmacodynamic, safety, and efficacy outcomes.  The 
results of such additional analyses may be reported separately from the clinical study 
report.  At the discretion of the Sponsor, all analyses may be extended to include 
relevant biotransformation products of study treatment. 
4.10.4 
Activity Analyses 
4.10.4.1 
Tumor Assessment Data 
All patients in the extension cohort who receive any amount of venetoclax or 
R-CHOP/G-CHOP will be included in the activity analysis. 
Response assessment (CR, PR, etc.) as assessed by investigator and central review 
(IRC) by both CT and by combined PET-CT imaging will be summarized.  Summaries 
will be provided across all patients, by Bcl-2 and c-Myc status and molecular subtype.  
Cross-tabulations with IPI score will be provided as exploratory analyses, provided that 
enough patients are available within cells.  DOR and PFS will be summarized.  An 
exploratory analysis of response will be provided on the subset of patients who receive 
six cycles of CHOP. 
Response assessment is determined using the modified Lugano Classification:  Revised 
Criteria for Response Assessment (Cheson et al. 2014) specified in Appendix 2.  Among 
patients with an OR, DOR will be defined as the time from the initial CR or PR to the 
time of disease progression or death.  If a patient does not experience death or disease 
progression before the end of the study, DOR will be censored at the day of the last 
tumor assessment. 
PFS is defined as the time from the first day of study treatment to disease progression or 
death while enrolled in the study (defined as death from any cause within 12 weeks of 
last tumor assessment).  If a patient has not experienced PD or death, PFS will be 
censored at the day of the last tumor assessment. 
4.10.4.2 
Interim Analyses 
Interim analyses will be incorporated into the Phase II portion of the study in order to 
guide potential early stopping of enrollment in the event of lower than expected CR rate.  
Data from completed and ongoing studies using R-CHOP and/or G-CHOP will be used 
as historical controls for comparison.  Currently available data indicates that the 
historical CR rate based on CT is 65% for Bcl-2 high patients and 72% for Bcl-2 low 
patients.  Historical PET-defined CR rates for each of the four biological subgroups are 


 
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expected to be available from ongoing studies for comparison by the time of first interim 
analysis.  An extension of the predictive probability design (Lee and Liu 2008) will be 
used to guide stopping by comparing CR rates in the venetoclax + R-CHOP arm with 
historical controls using R-CHOP.  If at any time, interim analysis suggests that the CR 
rate is lower than expected, the IMC and SOC will review the data and decide whether to 
recommend stopping enrollment.  Interim analysis decision rules will be provided in the 
Statistical Analysis Plan, and will use the most current historical control data available at 
the time of analysis. 
Additional analyses will be incorporated into the Phase II portion of the study in order to 
evaluate the safety and tolerability of the recommended Phase II dose of venetoclax and 
to guide early stopping of enrollment, a decrease of dose or dosing schedule for safety 
reasons on the basis of toxicities observed and ability to maintain chemotherapy dose 
intensity. 
4.10.4.3 
Predictive Diagnostics 
Assay results of additional markers beyond Bcl-2, c-Myc, and molecular subtype may be 
explored and may be reported by response status. 
4.10.5 
Exploratory Analyses 
The effects of demographic and baseline prognostic characteristics, including BCL2 
copy number gain and expression of transcripts for BCL2 and family members, other 
apoptotic genes, and genes associated with the ABC or GCB subtypes of DLBCL 
on efficacy outcomes) will be evaluated using univariate and/or multivariate statistical 
methods such as Cox regression and logistic regression. 
4.10.6 
Determination of Sample Size 
The sample size for the dose-finding stage is based on a modified 3 + 3 design in order 
to guide dose and schedule selection for the Phase II portion on the basis of DLTs.  The 
expected enrollment for the dose-finding stage is 3−6 patients per dose level in each of 
the R-CHOP + venetoclax and G-CHOP + venetoclax arms. 
The sample size for the R-CHOP + venetoclax arm in Phase II is based on obtaining a 
sufficient number for estimation of PET-negative CR rate in patients with DE (Bcl-2 and 
c-Myc co-expressing) DLBCL, overall, for Bcl-2 high patients, and within each of four 
mutually exclusive biological subgroups:  Bcl-2 high and ABC, Bcl-2 high and GCB, 
Bcl-2 low and ABC, and Bcl-2 low and GCB.  The expected enrollment for the 
R-CHOP + venetoclax arm in Phase II is approximately 160−200 patients in order to 
enroll approximately 50 DE-DLBCL patients, approximately 80−100 Bcl-2 high patients, 
and approximately 40−50 patients in each of the two Bcl-2 high subgroups.  With 
50 patients, 95% confidence intervals for estimation of CR would have a margin of error 
not exceeding 16%.  The margin of error would decrease to 9% with 150 patients and to 
8% with 200 patients.  Table 5 shows Clopper and Pearson 95% CIs for expected 
observed rates for sample sizes of 50, 100, 150, and 200.   


 
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Table 5 
95% Confidence Intervals for Expected Observed Rates for 
Sample Sizes 
R-CHOP + 
 
venetoclax 
50 patients 
100 patients 
150 patients 
200 patients 
CR rate 
#CR (CI for rate) 
#CR (CI for rate) 
#CR (CI for rate) 
#CR (CI for rate) 
80% 
40 (66%, 90%) 
80 (71%, 87%) 
120 (73%, 86%) 
160 (73%, 86%) 
75% 
37 (60%, 85%) 
75 (65%, 83%) 
112 (67%, 81%) 
150 (68%, 81%) 
70% 
35 (55%, 82%) 
70 (60%, 79%) 
105 (62%, 77%) 
140 (62%, 77%) 
65% 
32 (49%, 77%) 
65 (55%, 74%) 
 97 (56%, 72%) 
130 (57%, 72%) 
CR = complete response; CI = confidence interval (Clopper and Pearson 95%); 
CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisolone or prednisone; R = rituximab. 
 
4.11 
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 with 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 through use of 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 Sponsor’s standard procedures. 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events including 
serious adverse events and adverse events of special interest, measurement of 
protocol-specified safety laboratory assessments, measurement of protocol-specified 
vital signs, and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor as outlined in 
Section 5.3. 


 
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5.1.1 
Adverse Event 
According to the ICH Guidelines for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product regardless of causal attribution.  Therefore, an adverse event 
can be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.2.5.10 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.1.2 
Serious Adverse Event (Immediately Reportable to the Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
• 
This does not include any adverse event that might have caused death had it 
occurred in a more severe form or was allowed to continue.   
• 
Requires or prolongs inpatient hospitalization (see Section 5.2.5.11) 
• 
Results in persistent or significant disability and/or incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity 
of an adverse event (e.g., rated as mild, moderate, or severe, or according to 
NCI CTCAE v4.0 criteria; see Section 5.2.3); the event itself may be of relatively 
minor medical significance (such as severe headache without any further findings).  


 
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“Serious” is a regulatory definition and is based on patient or event outcome or action 
criteria usually associated with events that pose a threat to a patient’s life or vital 
functions.  Seriousness (not severity) serves as the guide for defining regulatory 
reporting obligations. 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately via the Adverse Event eCRF (i.e., no more than 24 hours after learning of 
the event; see Section 5.3.2 for reporting instructions). 
5.1.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately via the Adverse Event eCRF (i.e., no more than 24 hours after 
learning of the event; see Section 5.3.2 for reporting instructions).  Adverse events of 
special interest for this study include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.2.5.7) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings indicating an infection 
in a patient exposed to a medicinal product.  This term only applies when a 
contamination of the study drug is suspected. 
• 
Grade 4 febrile neutropenia 
• 
Grade ≥ 3 IRRs to rituximab or obinutuzumab 
• 
Grade ≥ 4 TLS 
 
Hepatitis B reactivation will be followed as an adverse event of particular interest. 
5.2 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.1.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.3, Section 5.4, and 
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For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity (see 
Section 5.2.3), and causality (see Section 5.2.4).   
5.2.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.3.2 for instructions for reporting serious adverse events). 
After initiation of study medications (venetoclax, rituximab, obinutuzumab, or CHOP), 
all adverse events, regardless of relationship to study drug, will be reported through 
30 days after the last dose of venetoclax or CHOP, or 90 days after the last dose of 
rituximab or obinutuzumab, whichever is later.  After this period, the investigator should 
report any deaths, serious adverse events or adverse events of special interest that are 
believed to be related to prior study drug treatment (see Section 5.5). 
5.2.2 
Eliciting Adverse Events 
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: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
 
5.2.3 
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 6 will be used for assessing severity for 
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Table 6 
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 one's self, 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 5.3.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.1.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.3.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.1.2. 
 
5.2.4 
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 the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see Table 7): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non−treatment-related factors that are known to be associated with the 
occurrence of the event 
 


 
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Table 7 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse 
event and administration of the study drug, and the adverse event cannot 
be readily explained by the patient’s clinical state, intercurrent illness, or 
concomitant therapies, and/or the adverse event follows a known pattern of 
response to the study drug, and/or the adverse event abates or resolves 
upon discontinuation of the study drug or dose reduction, and if applicable, 
reappears upon rechallenge. 
NO 
Adverse events will be considered related, unless they fulfill the criteria as 
specified below:  
Evidence exists that the adverse event has an etiology other than the study 
drug (e.g., preexisting medical condition, underlying disease, intercurrent 
illness, or concomitant medication) and/or the adverse event has no 
plausible temporal relationship to administration of the study drug 
(e.g., cancer diagnosed 2 days after first dose of study drug). 
 
For patients who receive combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.2.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF; use of colloquialisms and abbreviations should be 
avoided. 
Only one adverse event term should be recorded in the event description field on the 
Adverse Event eCRF. 
5.2.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
that are judged to be related to study drug infusion should be captured as a diagnosis 
(e.g., "infusion-related reaction [IRR]") on the Adverse Event eCRF.  If possible, avoid 
ambiguous terms such as "systemic reaction."  Associated signs and symptoms should 
be recorded on the dedicated IRR eCRF.  If a patient experiences both a local and 
systemic reaction to the same dose of study drug, each reaction should be recorded 
separately on the Adverse Event eCRF, with signs and symptoms also recorded 
separately on the dedicated IRR eCRF. 
5.2.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than IRRs (see Section 5.2.5.1), a diagnosis (if known) should 
be recorded on the Adverse Event eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be 
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individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on of the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.2.5.3 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.2.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity of the event should be recorded at the time the 
event is first reported, and the severity should be updated to reflect the most extreme 
severity any time the event worsens.  If the event becomes serious, the Adverse Event 
eCRF should be updated to reflect this, and the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning that the event became serious; 
see Section 5.3.2 for reporting instructions).  The Adverse Event eCRF should be 
updated by changing the event from "non-serious" to "serious," providing the date that 
the event became serious, and completing all data fields related to serious adverse 
events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 


 
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5.2.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin ≥ 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF along with a 
descriptor indicating if the test result is above or below the normal range (e.g., “elevated 
potassium,” as opposed to “abnormal potassium”).  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens (see Section 5.2.5.4 for 
details on recording persistent adverse events). 
5.2.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  


 
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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens (see Section 5.2.5.4 for 
details on recording persistent adverse events). 
5.2.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(“Hy’s law”).  Therefore, investigators must report the occurrence of either of the 
following as an adverse event: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.2.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.3.2). 
5.2.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.2.1) that are attributed 
by the investigator solely to progression of lymphoma should be recorded only on the 
Study Completion/Early Discontinuation eCRF.  All other deaths on the study, regardless 
of relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.3.2).   
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should only be used for the occurrence of an 
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without preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the 
case of an unwitnessed death, within 24 hours after the patient was last seen alive and 
stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
During survival follow-up, deaths attributed to progression of lymphoma should be 
recorded only on the Study Completion/Early Discontinuation eCRF.  
5.2.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.2.5.10 
Lack of Efficacy or Worsening of Lymphoma 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on the modified Lugano Classification:  Revised Criteria for 
Response Assessment (see Appendix 2).  In rare cases, the determination of clinical 
progression will be on the basis of symptomatic deterioration.  However, every effort 
should be made to document progression with the use of objective criteria.  If there is 
any uncertainty as to whether an event is the result of disease progression, it should be 
reported as an adverse event. 
5.2.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.1.2), except as outlined 
below. 
The following hospitalization scenarios are not considered to be adverse events: 
• 
Planned hospitalization required by the protocol (e.g., to provide TLS prophylaxis 
or monitoring without significant clinical sequelae, or to perform an efficacy 
measurement for the study) 
• 
Hospitalization for respite care 


 
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• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours. 
 
5.2.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event but may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills serious 
criteria, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.3.2). 
5.3 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately via the Adverse Event eCRF; under no 
circumstances should reporting take place more than 24 hours after the investigator 
learns of the event.  The following is a list of events that the investigator must report to 
the Sponsor within 24 hours after learning of the event, regardless of relationship to 
study drug: 
• 
Serious adverse events 
• 
Adverse events of special interest 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately via the Adverse Event eCRF (i.e., no more than 24 hours after 
becoming aware of the information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 


 
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• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.3.1 
Emergency Medical Contacts 
Medical Monitor (Roche Medical Responsible) Contact Information (North 
America) 
Medical Monitor:   
, M.D. 
Telephone Number:   
 
Alternate Telephone Number:   (888) 835-2555 
 Medical Responsible Contact Information (Rest of World) 
Medical Advisor (based in Spain):   
, M.D.   
Telephone Number:   
 
Medical Advisor (based in Singapore):   
, M.D. 
Telephone Number:   
 
Medical Emergency Contact Center:   
 
Alternate Telephone Number:   
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  
5.3.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.3.2.1 
Events Occurring prior to Initiation of Study Drug 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
A paper Serious Adverse Event/Adverse Event of Special Interest Reporting Form and 
fax cover sheet should be completed and faxed to Roche Safety Risk Management or its 
designee immediately (i.e., no more than 24 hours after learning of the event), with use 
of the fax numbers provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators").  The Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form can also be scanned and e-mailed. 
5.3.2.2 
Events Occurring after Initiation of Study Drug 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported through 30 days after the last dose of venetoclax or CHOP or 


 
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90 days after the last dose of rituximab or obinutuzumab, whichever is later.  
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 EDC system.  A report will be generated and sent to Roche Safety Risk 
Management or its designee by the EDC system. 
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form and fax cover sheet should be 
completed and faxed or scanned and emailed to Roche Safety Risk Management or its 
designee immediately (i.e., no more than 24 hours after learning of the event), with use 
of the fax numbers provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators").  After 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 5.5. 
5.3.3 
Reporting Requirements for Pregnancies 
5.3.3.1 
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 12 months after the last 
dose of venetoclax or rituximab or within 18 months after the last dose of obinutuzumab, 
whichever is later.  A Pregnancy eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Roche Safety Risk Management.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue through 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 
update the Pregnancy eCRF when updated information on the course and outcome of 
the pregnancy becomes available. 
In the event that the EDC system is unavailable, a paper Clinical Trial Pregnancy 
Reporting Form and fax cover sheet should be completed and faxed or scanned and 
emailed to Roche Safety Risk Management or its designee immediately (i.e., no more 
than 24 hours after learning of the pregnancy) with use of the fax numbers provided to 
investigators (see "Protocol Administrative and Contact Information & List of 
Investigators").  Once the EDC system is available, all information will need to be 
entered and submitted via the EDC system. 


 
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5.3.3.2 
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 
12 months after the last dose of venetoclax or rituximab or within 18 months after the 
last dose of obinutuzumab, whichever is later.  A Pregnancy eCRF should be completed 
by the investigator immediately (i.e., no more than 24 hours after learning of the 
pregnancy) and submitted via the EDC system.  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 drug.  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 update the 
Pregnancy eCRF with additional information on the course and outcome of the 
pregnancy.  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. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.3.3.1. 
5.3.3.3 
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 5.3.2).   
5.3.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug 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 5.3.2). 
5.4 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.4.1 
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 drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 


 
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verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.3.3.1. 
5.4.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.5 
POST-STUDY ADVERSE EVENTS 
At the time of study treatment completion or study treatment discontinuation, the 
investigator should instruct each patient to report to the investigator any subsequent 
adverse events that the patient’s personal physician believes could be related to prior 
study drug treatment or study procedures.   
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event or adverse event of special interest that occurs after the end of the 
adverse event reporting period (defined as 30 days after the last dose of venetoclax or 
CHOP or 90 days after the last dose of rituximab or obinutuzumab, whichever is later 
[see Section 5.2.1]) if the event is believed to be related to prior study drug treatment.  
The Sponsor should also be notified if the investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a female patient exposed to study drug or the female partner of a male 
patient exposed to study drug. 
The investigator should report these events directly to Roche Safety Risk Management 
via telephone or via fax machine or scanned and emailed with the use the Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form and fax cover sheet 
(see "Protocol Administrative and Contact Information & List of Investigators"). 
5.6 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities on the basis of applicable legislation. 


 
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events with the use of the following reference 
documents: 
• 
ABT-199/GDC-0199 Investigator's Brochure 
• 
Obinutuzumab Investigator’s Brochure 
• 
Local prescribing information for rituximab  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study and any study-related procedures at a specific site, the 
following documents must be on file with the Sponsor or the Sponsor’s representative: 
• 
FDA Form 1572 for each site (for all studies conducted under IND regulations), 
signed by the Principal Investigator 
The names of any subinvestigators must appear on this form.  Investigators 
must also complete all regulatory documentation as required by local and 
national regulations. 
• 
Current curricula vitae and evidence of licensure of the Principal Investigator and all 
subinvestigators 
• 
Complete financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the FDA Form 1572  
• 
Federalwide Assurance number or IRB statement of compliance 
• 
Written documentation of IRB/EC approval of the protocol (identified by protocol 
number or title and date of approval) and Informed Consent Form (identified by 
protocol number or title and date of approval) 
• 
A copy of the IRB/EC-approved Informed Consent Form 
The Sponsor or its designee must review any proposed deviations from the 
sample Informed Consent Form. 
• 
Current laboratory certification of the laboratory performing the analysis (if other 
than a Sponsor-approved central laboratory), and current references ranges for all 
laboratory tests 
• 
A Clinical Research Agreement signed and dated by the study site 
• 
Investigator’s Brochure Receipt signed and dated by the Principal Investigator 


 
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• 
Certified translations of an approved Informed Consent Form, and any other written 
information to be given to the patient (when applicable), IRB/EC approval letters, 
and pertinent correspondence 
• 
A Protocol Acceptance Form signed and dated by the Principal Investigator 
• 
Canada only when applicable:  original Qualified Investigator Undertaking Form, 
signed by each Canadian investigator involved in the study 
 
6.2 
STUDY COMPLETION 
The following data and materials are required by Roche before a study can be 
considered complete or terminated: 
• 
Laboratory findings, clinical data, and all special test results from screening through 
the end of the study follow-up period 
• 
All laboratory certifications for laboratories performing the analysis (i.e., other than 
Sponsor-approved central laboratory) and current normal laboratory ranges for all 
laboratory tests 
• 
eCRFs (including queries) properly completed by appropriate study personnel and 
electronically signed and dated by the investigator 
• 
Completed Drug Accountability Records (Retrieval Record, Drug Inventory Log, and 
Inventory of Returned Clinical Material forms) 
• 
Copies of protocol amendments and IRB/EC approval/notification, if appropriate 
• 
A summary of the study prepared by the Principal Investigator (IRB summary close 
letter is acceptable) 
• 
All essential documents (e.g., curriculum vitae for each Principal Investigator and 
subinvestigator, FDA Form 1572 for each site) 
• 
A signed and dated Protocol Amendment Acceptance Form(s) [if applicable] 
• 
Updated financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the FDA Form 1572 (applicable for 1 year after the last 
patient has completed the study) 
 
6.3 
INFORMED CONSENT FORM 
The Sponsor’s Sample Informed Consent Form will be provided to each site.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sample Informed Consent Form or any alternate consent forms proposed by the site 
(collectively, the “Consent Forms”) before IRB/EC submission.  Patients must be 
re-consented to the most current version of the Consent Forms during their participation 
in the study.  The final IRB/EC-approved Consent Forms must be provided to Sponsor 
for regulatory purposes. 
The Consent Forms must be signed by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history for each 
patient shall document the informed consent process and that written informed consent 


 
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was obtained prior to participation in the study.  A copy of each signed Consent Form 
must be provided to the patient or the patient’s legally authorized representative.  If 
applicable, it will be provided in a certified translation of the local language. 
All signed and dated Consent Forms must remain in each patient’s study file and must 
be available for verification by study monitors at any time. 
The Informed Consent Form should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes available 
that may affect the willingness of the patient to participate. 
For any updated or revised Consent Forms, the case history for each patient shall 
document the informed consent process and that written informed consent was obtained 
for the updated/revised Consent Form for continued participation in the study.  The final 
revised IRB/EC-approved Informed Consent Form must be provided to the Sponsor for 
regulatory purposes. 
If the site utilizes a separate Authorization Form for patient authorization to use and 
disclose personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB/IEC review and approval may 
not be required per study site policies. 
6.3.1 
Optional Research Informed Consent 
If archival tissue and/or plasma/serum collection for optional research described in 
Section 4.5.3 is approved by the IRB/IEC, the Consent Form entitled “Sample Research 
Informed Consent Form” will be provided by the Sponsor to each study site.  This form 
gives patients the option to authorize the collection and use of these samples and 
personal health information for additional research purposes.  Signing of this separate 
consent form is not required for enrollment in the trial but is required prior to any optional 
research sample collection.  All procedures outlined above for review, approval, 
processing, and use of Consent Forms also apply to this optional research form. 
In the United States, each Informed Consent Form may also include authorization 
allowing the institution, investigator, subinvestigator, and the Sponsor(s) to use and 
disclose Personal Health information in compliance with the HIPAA of 1996. 
Signed and dated Informed Consent Forms must remain in each patient’s study file and 
must be available for verification by study monitors at any time. 
6.4 
COMMUNICATION WITH THE 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 


 
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Investigator for review and approval 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 regulatory 
requirements and policies and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol changes or 
amendments and of any unanticipated problems involving risk to human patients 
or others. 
In addition to the requirements to report protocol-defined adverse events to the Sponsor, 
investigators are required to promptly report to their respective IRB/EC all unanticipated 
problems involving risk to human patients.  Some IRBs/ECs may want prompt 
notification of all serious adverse events, whereas others require notification only of 
events that are serious, assessed to be related to study treatment, and are unexpected.  
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 regulatory requirements and 
with the policies and procedures established by their IRB/EC and archived in the site’s 
Study File. 
6.5 
STUDY MONITORING REQUIREMENTS 
Site visits will be conducted by an authorized Sponsor representative to inspect study 
data, patients’ medical records, and eCRFs.  The Principal Investigator will permit 
Sponsor monitors/representatives and collaborators, the FDA, other regulatory agencies, 
IRBs, and the respective national or local health authorities to inspect facilities and 
records relevant to this study. 
6.6 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using 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. 
6.7 
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. 


 
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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 the pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.  
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must never be obliterated or destroyed. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
6.8 
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 (for clinical research purposes) would 
be one that:  1) allows data entry only by authorized individuals, 2) prevents the deletion 
or alteration of previously entered data and provides an audit trail for such data changes 
(e.g., modification of file), 3) protects the database from tampering, and 4) ensures data 
preservation. 
In collaboration with the study monitor, the Sponsor’s Quality Assurance group may 
assist in assessing whether electronic records generated from computerized medical 
record systems used at investigational sites can serve as source documents for the 
purposes of this protocol. 
If a site’s computerized medical record system is not adequately validated for the 
purposes of clinical research (as opposed to general clinical practice), applicable 
hardcopy source documents must be maintained to ensure that critical protocol data 
entered into the eCRFs can be verified. 
6.9 
STUDY MEDICATION ACCOUNTABILITY 
All study drugs required for completion of this study will be provided by the Sponsor.  
The recipient will acknowledge receipt of the drug by returning the appropriate 
documentation form indicating shipment content and condition.  Damaged supplies will 
be replaced. 


 
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Accurate records of all study drugs received at, dispensed from, returned to, and 
disposed of by the study site should be recorded with the use of the Drug Inventory Log. 
Study drugs 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, as determined by the study site.  If the study site chooses to 
destroy the study drug, the method of destruction must be documented. 
The Sponsor must evaluate and approve the study site’s drug destruction standard 
operating procedure prior to the initiation of drug destruction by the study site. 
6.10 
DISCLOSURE OF DATA 
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 to use and disclose personal health information) signed by the patient or 
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 the FDA and other regulatory agencies, national and local health 
authorities, the Sponsor monitors/representatives and collaborators, and the IRB/EC for 
each study site, if appropriate. 
6.11 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
investigational medicinal product, including eCRFs, electronic Patient Reported 
Outcome data (if applicable), Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for at least 
15 years after completion or discontinuation of the study, or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 


 
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7. 
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Appendix 1  
Schedule of Assessments 
Study Period 
Screening 
Period 
Treatment Period 
Follow-Up Period 
Participation 
End 
DLT Observation Period 
(Cycle 1-Cycle 2)
 a 
Cycles of Treatment Period 
Cycle 1 
Cycle 
2 
Cycle 3 
Cycle 4 
Cycles
5-6 
Cycles 
7-8 
End of 
Treatment 
Follow-Up 
Survival 
Follow-
up 
End of 
Study/Early 
Study 
Termination 
Day of Cycle 
Screening
Once 
(-21 to -1) 
1 
4 
5 
8 
(±1)
15 
(±1)
1 
(±2) 10
1 
(±2)
10 
(±2)
1 
(±2) 
10 
(±2) 
once 
(15-
21) 
1 
(±2)
10 
(±2) 1 (±2)
Cycle 8 Day 
1 (or last 
cycle 
received) 
+ 6−8 
weeks 
Every 
3 months 
from End of 
Treatment 
visit (±14) 
Every 
6 months 
(±14) 
 
Informed consent 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Demographic data 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
General medical history & baseline conditions 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Concomitant medications & adverse events 
x 
x 
x 
  
x 
x 
x 
  
x 
  
x 
  
  
x 
  
x 
x 
x
 b 
 
x
 b 
ECOG Performance Status 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
x 
 
  
Complete physical examination 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Targeted physical examination 
  
  
  
  
  
  
x 
  
x 
  
x 
  
  
x 
  
x 
x 
x 
 
x 
Vital signs 
c 
x 
x 
x 
d
x 
d
x 
x 
x 
  
x 
  
x 
  
  
x 
  
x 
x 
x 
 
x 
12-Lead ECG (in triplicate) 
x 
  
 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
MUGA/Echocardiogram
 e 
x 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
 
 
 
Clinical response assessment 
f 
  
  
  
  
  
  
x 
  
x 
  
x 
  
  
x 
  
x 
x 
x 
 
x 
PET-CT scan & Response Assessment 
g, h 
x 
i 
  
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
x 
x 
j 
 
(x) 
k 
Drug administration 
Venetoclax (GDC-0199) 
l 
 
 
x (Cycle 1 Days 4-10, and Cycles 2-8 Days 1-10)  
 
 
 
 


 
 
Appendix 1 
Schedule of Assessments (cont.) 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
155/Protocol GO27878, Version 8 
Study Period 
Screening 
Period 
Treatment Period 
Follow-Up Period 
Participation 
End 
DLT Observation Period 
(Cycle 1-Cycle 2)
 a 
Cycles of Treatment Period 
Cycle 1 
Cycle 
2 
Cycle 3 
Cycle 4 
Cycles
5-6 
Cycles 
7-8 
End of 
Treatment 
Follow-Up 
Survival 
Follow-
up 
End of 
Study/Early 
Study 
Termination 
Day of Cycle 
Screening
Once 
(-21 to -1) 
1 
4 
5 
8 
(±1)
15 
(±1)
1 
(±2) 10
1 
(±2)
10 
(±2)
1 
(±2) 
10 
(±2) 
once 
(15-
21) 
1 
(±2)
10 
(±2) 1 (±2)
Cycle 8 Day 
1 (or last 
cycle 
received) 
+ 6−8 
weeks 
Every 
3 months 
from End of 
Treatment 
visit (±14) 
Every 
6 months 
(±14) 
 
Rituximab 
m 
 
x 
  
  
  
  
x 
  
x 
  
x 
  
  
x 
  
x 
  
  
 
 
Obinutuzumab 
n 
 
x 
  
  
x 
x 
x 
  
x 
  
x 
  
  
x 
  
x 
  
  
 
 
Cyclophosphamide
 o 
 
x 
  
  
  
  
x 
  
x 
  
x 
  
  
x 
  
  
  
  
 
 
Doxorubicin
 o 
 
x 
  
  
  
  
x 
  
x 
  
x 
  
  
x 
  
  
  
  
 
 
Vincristine
 o 
 
x 
  
  
  
  
x 
  
x 
  
x 
  
  
x 
  
  
  
  
 
 
Prednisone 
o, p 
 
x (daily) 
 
 
x 
p 
 
x 
p 
 
x 
p 
 
 
x 
 
 
 
 
 
 
Local laboratory assessments 
Hematology 
q 
x 
x
 d 
x 
d
x 
d
x 
x 
x 
x 
x 
x 
x 
x 
  
x 
x 
x 
x 
x 
 
x 
Serum chemistries 
r 
x 
x
 d 
x 
d
x 
d
x 
x 
x 
x 
x 
x 
x 
x 
  
x 
x 
x 
x 
x 
 
x 
Serum pregnancy test 
s 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
HBV and HCV screening 
t 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Hepatitis B DNA on PCR (as indicated) 
t 
x 
  
  
  
  
  
x 
  
x 
  
x 
  
  
x 
  
x 
x 
x 
 
 
Bone marrow biopsy/aspirate 
u 
x 
i 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
(x) 
u 
(x) 
u   
 
(x)
 u 
Central laboratory assessments 
Blood sample for DLBCL NHL biomarker studies 
 
 x 
v 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 


 
 
Appendix 1 
Schedule of Assessments (cont.) 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
156/Protocol GO27878, Version 8 
Study Period 
Screening 
Period 
Treatment Period 
Follow-Up Period 
Participation 
End 
DLT Observation Period 
(Cycle 1-Cycle 2)
 a 
Cycles of Treatment Period 
Cycle 1 
Cycle 
2 
Cycle 3 
Cycle 4 
Cycles
5-6 
Cycles 
7-8 
End of 
Treatment 
Follow-Up 
Survival 
Follow-
up 
End of 
Study/Early 
Study 
Termination 
Day of Cycle 
Screening
Once 
(-21 to -1) 
1 
4 
5 
8 
(±1)
15 
(±1)
1 
(±2) 10
1 
(±2)
10 
(±2)
1 
(±2)
10 
(±2) 
once 
(15- 
21) 
1 
(±2)
10 
(±2) 1 (±2)
Cycle 8 Day 
1 (or last 
cycle 
received) 
+ 6−8 
weeks 
Every 
3 months 
from End of 
Treatment 
visit (±14) 
Every 
6 months 
(±14) 
 
Tumor biopsy for BCL2 family expression by 
IHC 
x 
i, w 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 x 
x  
 x x  
 
 
Tissue punch for TMAs (in Phase II only) 
x
w 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
PK sample for venetoclax (GDC-0199) 
See Appendix 3 
PK sample for rituximab 
m 
See Appendix 3 
PK sample for obinutuzumab 
n 
See Appendix 3 
PK for CHOP components 
See Appendix 3 
Plasma sample for resistance markers y 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
Blood sample for lymphocyte subsets 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
x z 
 
  
Blood sample for assessment of minimal 
residual disease MRD in Phase II only 
 
x
 v 
  
  
 
  
  
 
  
  
x 
  
  
  
  
 
x 
x aa 
 
 
Optional Roche Clinical Repository 
Sample(s) bb 
 
(x) 
v 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Contacts for Survival Follow-up 
cc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
BSA = body surface area; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; CR = complete response; CT = computed tomography; 
DLBCL = diffuse large B-cell lymphoma; DLT = dose-limiting toxicity; ECOG = Eastern Cooperative Oncology Group; G-CHOP = obinutuzumab + CHOP; 
HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; Hep C Ab = hepatitis C core 
antibody; IHC = immunohistochemistry; MRD = minimal residual disease; MUGA = Multiple-gated acquisition scan; NHL = non-Hodgkin’s lymphoma;  
 


 
 
Appendix 1 
Schedule of Assessments (cont.) 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
157/Protocol GO27878, Version 8 
PCR = polymerase chain reaction; PET = positron emission tomography; PK = pharmacokinetic; R-CHOP = rituximab + CHOP; RCR = Roche Clinical 
Repository; TMA = tissue microarray; (x) = indicates that time point may not apply to all patients, depending on specific requirements or patient 
consent. 
a If venetoclax dosing starts at Cycle 1 Day 1 or 2 then the DLT observation period would be shortened to one cycle. 
b All adverse events and medications to be reported for 30 days after the last dose of venetoclax or CHOP, or 90 days after the last dose of 
rituximab or obinutuzumab, whichever is later.  After this period, serious adverse events or adverse events of special interest that are believed to 
be related to study drug treatment need to be reported. 
c Vital signs to include body temperature, heart rate, blood pressure, and weight.  Height and BSA are only required at screening.  Subsequent 
BSA required if > 10% change in weight. 
d Follow the specific time points described in Section 4.5.1.5. 
e Assessment of cardiac function is to be performed at screening (Day -21 to Day -1) and then as clinically indicated. 
f Clinical response assessment is to include physical examination for the presence and degree of enlarged lymph nodes, hepatomegaly, and 
splenomegaly.  Does not include assessment based on imaging. 
g Imaging should be PET-CT at screening and 6−8 weeks after Cycle 8, Day 1 (or last cycle received.  All others may be CT only. 
h Response assessment will be determined by the investigator on the basis of PET+CT and clinical assessment using the modified Lugano 
Classification (see Appendix 2).  Response assessment should be determined on the basis of the imaging conducted on this day but is not 
required to be done on the same day. 
i All screening assessments to be conducted within 21 days prior to first dose with the exception of the PET-CT scan, tumor biopsy, and bone 
marrow biopsy/aspirate.  See Section 4.5.2. 
j Required every 6 months for 2 years. 
k Assessment does not need to be performed if it has been performed within the last 30 days. 
l Venetoclax dosing on Cycle 1 Day 4 (or 3 days after first CHOP dose) to Cycle 1 Day 10 and then Cycles 2−8 Days 1−10.  Alternative dosing 
regimens are possible based on data from initial cohorts per Protocol Section 3.1.2.2. 
m Arm A (R-CHOP) patients only. 
n Arm B (G-CHOP) patients only. 
o Patients who experience ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the 
investigator and the Medical Monitor. 
p Prednisone days 1−5 of each Cycle 1−6. 
q Hematology to include complete blood count with platelets and WBC count differential. 
r Serum chemistries listed in Section 4.5.1.5. 


 
 
Appendix 1 
Schedule of Assessments (cont.) 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
158/Protocol GO27878, Version 8 
s Required for all women of reproductive potential (see inclusion criteria). 
t HBsAg, anti-HBcAb, and Hep C Ab serology (also HCV and RNA by polymerase chain reaction if the patient is HCV antibody positive) required.  
For hepatitis B core antibody−positive patients, the HBV-DNA titer should be determined using real-time PCR at baseline and monthly until at 
least 12 months after the last treatment cycle. 
u To be performed within 3 months prior to initiating therapy.  If positive, not done or indeterminate at screening, should be repeated at end of 
therapy to document complete remission, if appropriate.  Should be conducted at end of study and/or early termination only if CR was not 
previously confirmed at end of treatment. 
v This baseline sample may be collected at any time before starting treatment.  
w Sample must include 20 unstained, serial slides or a tissue block.  In addition, if slides are sent a tissue punch from excisional biopsies must be 
taken from the tissue block for construction of TMAs in Phase II only.  Tissue samples to be sent to the central laboratory within 3 weeks of 
patient randomization. 
x Only required at disease progression. 
y Plasma sample will be collected for analysis of circulating tumor markers of response/resistance at baseline (pre-dose), between Cycle 4 Day 15 
and Cycle 5 Day 1, and at end of study and/or early termination visit. 
z Required only at months 6 and 12, and every 6 months thereafter until end of study. 
aa Required every 3 months for 1 year. 
bb Optional blood sample is requested at baseline for collection and storage at the RCR.  Any samples at the central laboratories except the PK 
samples that remain from the planned study assessments may be taken and sent to the RCR if the patient consents to the optional RCR 
sampling. 
cc Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 6 
months until death, loss to follow-up, consent withdrawal, or study termination by Roche, whichever occurs first.   
 
 


 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
159/Protocol GO27878, Version 8 
Appendix 2  
The Modified Lugano Classification:  Revised Criteria for 
Response Assessment 
Responses should be determined on the basis of radiographic and clinical evidence of 
disease.  Assessment of positron emission tomography (PET)-computed tomography 
(CT) should follow the Recommendations for Initial Evaluation, Staging, and Response 
Assessment for Hodgkin and Non-Hodgkin’s Lymphoma:  The Lugano Classification 
described by Cheson (2014), is presented in the Revised Criteria for Response 
Assessment table with the following modifications:  (1) For complete response (CR), if 
the bone marrow was involved by lymphoma or indeterminate prior to treatment, the 
infiltrate must have cleared on repeat bone marrow biopsy; (2) For PET-CT-based partial 
response (PR), CT criteria for PR (or CR) must also be met. 
Selection of measured dominant (indicator) lesions:   
• 
Up to six of the largest dominant nodes, nodal masses, and extranodal lesions 
selected to be clearly measurable in two diameters 
A measurable node must have a longest transverse diameter of a 
lesion (LDi) > 1.5 cm. 
A measurable extranodal lesion should have an LDi > 1.0 cm. 
• 
Nodes should preferably be from disparate regions of the body and should include, 
where applicable, mediastinal and retroperitoneal areas. 
• 
Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, and 
lungs), gastrointestinal (GI) involvement, cutaneous lesions, or those noted on 
palpation. 
• 
If possible, they should be from disparate regions of the body 
• 
Should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved 
 
Selection of non-measured (non-indicator) lesions: 
• 
Any disease not selected as measured, dominant disease and truly assessable 
disease should be considered not measured. 
These sites include any nodes, nodal masses, and extranodal sites not 
selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone 
lesions, leptomeningeal disease, abdominal masses, and other lesions that 
cannot be confirmed and followed by imaging. 
 
In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, and bone marrow), 
18F-fleurodeoxyglucose (FDG) uptake may be greater than in the mediastinum with 
complete metabolic response, but should be no higher than surrounding normal 


 
 
Appendix 2  
The Modified Lugano Classification:  Revised Criteria for 
Response Assessment (cont.) 
 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
160/Protocol GO27878, Version 8 
physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid 
growth factors). 


 
 
Appendix 2  
The Modified Lugano Classification:  Revised Criteria for Response Assessment (cont.) 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
161/Protocol GO27878, Version 8 
Response 
Site 
PET-CT−Based Response 
CT-Based Response 
 
Complete metabolic response 
Complete radiologic response (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3 a with or without a residual mass on 5PS b 
It is recognized that in Waldeyer’s ring or extranodal sites 
with high physiologic uptake or with activation within spleen 
or marrow (e.g., with chemotherapy or myeloid 
colony-stimulating factors), uptake may be greater than 
normal mediastinum and/or liver.  In this circumstance, 
complete metabolic response may be inferred if uptake at 
sites of initial involvement is no greater than surrounding 
normal tissue even if the tissue has high physiologic 
uptake. 
Target nodes/nodal masses must regress to ≤ 1.5 cm in LDi. 
No extralymphatic sites of disease. 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Complete 
Bone marrow 
No evidence of FDG-avid disease in marrow. 
If the bone marrow was involved by lymphoma prior to 
treatment, the infiltrate must have cleared on repeat bone 
marrow biopsy.  
If the bone marrow was involved by lymphoma prior to 
treatment, the infiltrate must have cleared on repeat bone 
marrow biopsy. 
 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score of 4 or 5 b with reduced uptake compared with 
baseline and residual mass(es) of any size. 
At interim, these findings suggest responding disease. 
At end of treatment, these findings indicate residual 
disease. 
CT-based response criteria for PR (or CR) must also be 
met. 
≥ 50% decrease in SPD of up to 6 target measureable nodes 
and extranodal sites. 
When a lesion is too small to measure on CT, assign 
5 mm × 5 mm as the default value. 
When no longer visible, 0 × 0 mm. 
For a node > 5 mm × 5 mm, but smaller than normal, use 
actual measurement for calculation. 
Partial 
Nonmeasured lesion 
Not applicable 
Absent/normal, regressed, but no increase. 


 
 
Appendix 2  
The Modified Lugano Classification:  Revised Criteria for Response Assessment (cont.) 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
162/Protocol GO27878, Version 8 
Response 
Site 
PET-CT−Based Response 
CT-Based Response 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% in length beyond 
normal. 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy allowed).  If 
there are persistent focal changes in the marrow in the 
context of a nodal response, consideration should be given 
to further evaluation with MRI or biopsy or an interval scan. 
Not applicable 
 
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 for up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met. 
Nonmeasured lesion 
Not applicable 
No increase consistent with progression. 
Organ enlargement 
Not applicable 
No increase consistent with progression. 
New lesions 
None 
None 
No response 
or stable 
disease 
Bone marrow 
No change from baseline 
Not applicable 
 
Progressive metabolic disease 
Progressive disease (requires at least 1 of the following) 
Progressive 
Disease 
Individual target 
nodes/nodal lesions 
Score 4 or 5 b with an increase in intensity of uptake from 
baseline. 
 
 
 
and/or 
PPD progression:   
An individual node/lesion must be abnormal with:   
• 
LDi > 1.5 cm AND  
• 
Increase by ≥ 50% from PPD nadir AND  
• 
An increase in LDi or SDi from nadir 
• 
0.5 cm for lesions ≤ 2 cm 
• 
1.0 cm for lesions > 2 cm 


 
 
Appendix 2  
The Modified Lugano Classification:  Revised Criteria for Response Assessment (cont.) 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
163/Protocol GO27878, Version 8 
Response 
Site 
PET-CT−Based Response 
CT-Based Response 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at interim or 
end-of-treatment assessment. 
 
Nonmeasured lesion 
None 
New or clear progression of preexisting 
Organ enlargement 
 
 
 
 
and/or 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase beyond 
baseline (e.g., 15 cm spleen must increase to > 16 cm).  If no 
prior splenomegaly, must increase by at least 2 cm from 
baseline. 
New or recurrent splenomegaly. 
New lesions 
New FDG-avid foci consistent with lymphoma rather than 
another etiology (e.g., infection, inflammation).  If uncertain 
regarding etiology of new lesions, biopsy or interval scan 
may be considered. 
 
and/or 
Regrowth of previously resolved lesions. 
A new node > 1.5 cm in any axis. 
A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any 
axis, its presence must be unequivocal and must be 
attributable to lymphoma. 
Assessable disease of any size unequivocally attributable to 
lymphoma. 
Bone marrow 
New or recurrent FDG-avid foci. 
New or recurrent involvement 
5-PS = 5-point scale; CR = complete response; CT = computed tomography; FDG = fluorodeoxyglucose; GI = gastrointestinal; LDi = longest transverse diameter of a 
lesion; MRI = magnetic resonance imaging; PET = positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; PR = partial response; 
SDi = shortest axis perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for multiple lesions. 
a  A score of 3 in many patients indicates a good prognosis with standard treatment, especially if scored at the time of an interim scan.  However, in studies involving 
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). 
b  PET 5-PS:  1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake < mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher 
than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
 


 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
164/Protocol GO27878, Version 8 
Appendix 3  
Pharmacokinetic Samples 
Table 1 
Pharmacokinetic Blood Sampling for Venetoclax + R-CHOP 
(ARM A) in Phase I 
Visit 
Time a 
Event 
Pre-dose 
PK−rituximab 
PK–C, H, O, P 
End of rituximab infusion 
PK–rituximab 
End of C,H, O administration 
PK–C, H, O 
30 minutes after end of P administration 
PK–P 
1 hour after end of P administration 
PK–P 
2 hours after end of P administration 
PK–P 
4 hours after end of P administration 
PK–P 
Cycle 1 Day 1 
6 hours after end of P administration 
PK–P 
Pre-dose 
PK–venetoclax 
2 hours after venetoclax dose 
PK–venetoclax 
4 hours after venetoclax dose 
PK–venetoclax 
6 hours after venetoclax dose 
PK–venetoclax 
Cycle 1 Day 4 (or first day 
of venetoclax dosing) 
8 hours after venetoclax dose 
PK–venetoclax 
Pre-dose 
PK–venetoclax 
Cycle 1 Day 8 
8 hours after venetoclax dose 
PK–venetoclax 
Pre-dose 
PK–rituximab 
PK–C, H, O, P 
End of C, H, O administration 
PK–C, H, O 
30 minutes after end of P administration 
PK–P 
1 hour after end of P administration 
PK–P 
2 hours after end of P administration 
PK–P 
4 hours after end of P administration 
PK–P 
Cycle 2 Day 1 
6 hours after end of P administration 
PK–P 
Cycle 2 Day 10 
Pre-dose 
PK–venetoclax 
Cycles 3−8 Day 1 
Pre-dose 
PK–rituximab 
End of treatment (Cycle 8 
Day 1 + 6−9 weeks) 
Any time during visit 
PK–rituximab 
C = cyclophosphamide; H = doxorubicin; O = vincristine; P = prednisone; PK = pharmacokinetic. 
a Pre-dose samples must be taken within 30 minutes prior to the administration of dose; all other 
samples must be taken within a ± 15 minute window from the scheduled time. 
 


 
 
Appendix 3  
Pharmacokinetic Samples (cont.) 
 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
165/Protocol GO27878, Version 8 
Table 2 
Pharmacokinetic Blood Sampling for Venetoclax + G-CHOP (Arm 
B) in Phase I 
Visit 
Time a 
Event 
Pre-dose 
PK–obinutuzumab 
PK–C, H, O, P 
End of obinutuzumab infusion 
PK–obinutuzumab 
End of C,H, O administration 
PK–C, H, O 
30 minutes after end of P administration 
PK–P 
1 hour after end of P administration 
PK–P 
2 hours after end of P administration 
PK–P 
4 hours after end of P administration 
PK–P 
Cycle 1 Day 1 
6 hours after end of P administration 
PK–P 
Pre-dose 
PK–venetoclax 
2 hours after venetoclax dose 
PK–venetoclax 
4 hours after venetoclax dose 
PK–venetoclax 
6 hours after venetoclax dose 
PK–venetoclax 
Cycle 1 Day 4 (or first day 
of venetoclax dosing) 
8 hours after venetoclax dose 
PK–venetoclax 
Pre-dose 
PK–venetoclax 
Cycle 1 Day 8 
8 hours after venetoclax dose 
PK–venetoclax 
Pre-dose 
PK–obinutuzumab 
PK–C, H, O, P 
End of C, H, O administration 
PK–C, H, O 
30 minutes after end of P administration 
PK–P 
1 hour after end of P administration 
PK–P 
2 hours after end of P administration 
PK–P 
4 hours after end of P administration 
PK–P 
Cycle 2 Day 1 
6 hours after end of P administration 
PK–P 
Cycle 2 Day 10 
Pre-dose 
PK–venetoclax  
Cycles 3−8 Day 1 
Pre-dose 
PK–obinutuzumab 
End of treatment (Cycle 8 
Day 1 + 6−9 weeks) 
Any time during visit 
PK–obinutuzumab 
C = cyclophosphamide; H = doxorubicin; O = vincristine; P = prednisone; PK = pharmacokinetic. 
a Pre-dose samples must be taken within 30 minutes prior to the administration of dose; all other 
samples must be taken within a ± 15 minute window from the scheduled time. 
 


 
 
Appendix 3  
Pharmacokinetic Samples (cont.) 
 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
166/Protocol GO27878, Version 8 
Table 3 
Pharmacokinetic Blood Sampling in Phase II for Approximately 
the First 20 Patients in Arm A  
Visit 
Time a 
Event  
Pre-dose 
PK–venetoclax 
2 hours after venetoclax dose 
PK–venetoclax 
4 hours after venetoclax dose 
PK–venetoclax 
6 hours after venetoclax dose 
PK–venetoclax 
Cycle 1 Day 4 (or first day 
of venetoclax dosing) 
8 hours after venetoclax dose b 
PK–venetoclax 
Pre-dose 
PK–venetoclax 
Cycle 1 Day 8 
8 hours after venetoclax dose b 
PK–venetoclax 
Cycle 2 Day 10 
Pre-dose 
PK-venetoclax 
PK = pharmacokinetic. 
a Pre-dose samples must be taken within 30 minutes prior to the administration of dose; all other 
samples must be taken within a ± 15 minute window from the scheduled time. 
b These samples are not optional, however, due to the complexity of the sample collection and 
processing the Sponsor recognizes that some centers may not have the capability to collect 
these PK samples.  In those instances, these PK samples will not be collected.  These 
samples can be taken within a -1 hr/+20 min window. 
 
Table 4 
Pharmacokinetic Blood Sampling in Remaining Phase II Patients  
Visit 
Time a 
Event 
Cycle 1 Day 8 
Pre-dose 
PK–venetoclax 
Pre-dose 
PK-venetoclax 
Cycle 2 Day 10 b 
4−6 hours after venetoclax dose 
PK-venetoclax 
Cycle 3 Day 10 c 
Pre-dose 
PK-venetoclax 
Cycle 4 Day 10 c 
Pre-dose 
PK-venetoclax 
a Pre-dose samples must be taken within 30 minutes prior to the administration of dose; all other 
samples must be taken within a ± 15 minute window from the scheduled time. 
b Note that there is no window for this visit.  It must occur on Day 10. 
c Note that the window for the participating sites must be adjusted to -2 + 1 day (rather than 
± 2 days) for this visit. 
 


 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
167/Protocol GO27878, Version 8 
Appendix 4  
Anaphylaxis Management 
The following equipment is needed in the event of a suspected anaphylactic 
reaction during study drug infusion: 
• 
Appropriate monitors (ECG, blood pressure, pulse oximetry) 
• 
Oxygen 
• 
Epinephrine for intravenous (IV), intramuscular, and/or endotracheal administration 
in accordance with institutional guidelines  
• 
Antihistamines 
• 
Corticosteroids 
• 
IV infusion solutions, tubing, catheters, and tape 
 
The following are the procedures to follow in the event of a suspected 
anaphylactic reaction during study drug infusion: 
• 
Stop the study drug infusion. 
• 
Call for additional assistance! 
• 
Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
drug.  Do not obstruct arterial flow in the limb. 
• 
Maintain an adequate airway. 
• 
Ensure that appropriate monitoring is in place, with continual ECG and pulse 
oximetry monitoring, if possible. 
• 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
• 
Continue to observe the patient and document observations. 
 


 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
168/Protocol GO27878, Version 8 
Appendix 5  
Sample List of Excluded and Cautionary Medications 
 
Type of Inducer, 
Inhibitor or Substrate 
Medication Name 
Strong CYP3A inducers 
Avasimibe, carbamazepine (Tegretol®), phenobarbital, 
phenytoin (Dilantin®), rifampin (Rifadin®), St. John's wort. 
Moderate CYP3A 
inducers 
Bosentan, efavirenz, etravirine, modafinil, nafcillin. 
Strong CYP3A 
inhibitors 
Boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, 
ketoconazole, mibefradil, lopinavir/ritonavir, nefazodone, 
nelfinavir, ritonavir, posaconazole, saquinavir, telaprevir, 
telithromycin, voriconazole. 
Excluded 
medications during 
Ramp-Up and 
throughout the DLT 
assessment period (if 
applicable) and 
cautionary at the final 
dose of venetoclax, 
once the DLT 
assessment period is 
complete 
Moderate CYP3A 
inhibitors 
Amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib a, 
darunavir/ritonavir, diltiazem, erythromycin, fluconazole, 
fosamprenavir, imatinib a, verapamil. 
 
Warfarin 
Weak CYP3A inducers 
Amprenavir, aprepitant, armodafinil, clobazamechinacea, 
pioglitazone, prednisone, rufinamide, vemurafenib a. 
Weak CYP3A inhibitors 
Alprazolam, amiodarone, amlodipine, atorvastatin, 
bicalutamide a, cilostazol, cimetidine, cyclosporine a, fluoxetine, 
fluvoxamine, ginkgo, goldenseal, isoniazid, nilotinib a, oral 
contraceptives, pazopanib a, ranitidine, ranolazine, 
tipranavir/ritonavir, ticagrelor, zileuton. 
P-gp substrates 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, 
everolimus a, fexofenadine, lapatinib a, loperamide, maraviroc, 
nilotinib a, ranolazine, saxagliptin, sirolimus a, sitagliptin, talinolol, 
tolvaptan, topotecan a. 
BCRP substrates 
Methotrexate a, mitoxantrone a, irrinotecan a, lapatinib a, 
rosuvastatin, sulfasalazine, topotecan a. 
OATP1B1/1B3 
substrates 
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, 
rosuvastatin, simvastatin acid, pitavastatin, pravastatin, 
repaglinide, telmisartan, valsartan, olmesartan. 
P-gp inhibitors 
Amiodarone, azithromycin, captopril, carvedilol, dronedarone, 
felodipine, quercetin, ronalzine, ticagrelor. 
BCRP inhibitors 
Gefitinib a, cyclosporine a. 
Cautionary 
medications 
throughout the study 
OATP1B1/B3 inhibitors 
Gemfibrozil, eltrombopag, cyclosporine a, tipranavir. 
DLT  = dose-limiting toxicity; P-gp  = P-glycoprotein. 
Note(s):  This is not an exhaustive list.  For an updated list, see the following link:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm08
0499.htm  In addition to the medications listed in this table, subjects receiving venetoclax should not consume 
grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruits. 
a These are anti-cancer agents; contact the Genentech Medical Monitor before use.  After discontinuation of the 
strong or moderate CYP3A inhibitor, wait for 3 days before venetoclax dose is increased back to the initial 
maintenance/target dose. 
 


 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
169/Protocol GO27878, Version 8 
Appendix 6  
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome in the 
Setting of Treatment with Venetoclax 
First dose of venetoclax or dose increase: 
• 
Within the first 24 hours after either the first dose or dose increase, if any laboratory 
criteria below are met, the patient should be hospitalized for monitoring and the 
investigator notified.  No additional venetoclax doses should be administered until 
resolution.  A rapidly rising serum potassium level is a medical emergency. 
• 
Nephrology (or acute dialysis service) must be consulted and/or contacted on 
admission (per institutional standards to ensure emergency dialysis is available). 
• 
Intravenous (IV) fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at 
least 1 mL/kg/h rounded to the nearest 10 mL (target 150 to 200 mL/h; not 
< 50 mL/h).  Modification of fluid rate should also be considered for individuals with 
specific medical needs. 
• 
Monitor for symptoms or signs of tumor lysis syndrome (TLS; e.g., fever, chills, 
tachycardia, nausea, vomiting, diarrhea, diaphoresis, hypotension, muscle aches, 
weakness, paresthesias, mental status changes, confusion, and seizures).  If any 
clinical features are observed, recheck potassium, phosphorus, uric acid, calcium, 
and creatinine within 1 hour. 
• 
Vital signs should be taken at time of all blood draws or any intervention. 
• 
The management recommendations below focus on the minimum initial responses 
required.  If a diagnosis of TLS is established, ongoing intensive monitoring and 
multi-disciplinary management will be as per institutional protocols. 
 


 
 
Appendix 6  
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome in the 
Setting of Treatment with Venetoclax (cont.)  
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
170/Protocol GO27878, Version 8 
Abnormality 
Findings 
Management Recommendations 
Potassium ≥ 0.5 
mmol/L increase 
from prior value 
(even if potassium 
WNL) 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour.  If further ≥ 0.2 mmol/L increase in 
potassium, but still < ULN, manage as per potassium ≥ ULN.  
Otherwise recheck in 1 hour. 
• 
Resume per protocol testing if change in potassium 
is < 0.2 mmol/L, and potassium < ULN, and no other evidence of 
tumor lysis. 
• 
At discretion of investigator, may recheck prior to hospitalization. 
If stable or decreased, and still WNL, hospitalization is at the 
discretion of the investigator.  Potassium, phosphorus, uric acid, 
calcium, and creatinine must be rechecked within 24 hours. 
Potassium > ULN 
• 
Perform immediate ECG and commence telemetry. 
• 
Nephrology notification with consideration of initiating dialysis. 
• 
Administer Kayexalate 60 g (or Resonium A 60 g). 
• 
Administer furosemide 20 mg IV × 1. 
• 
Administer calcium gluconate 100 to 200 mg/kg IV slowly if there 
is ECG/telemetry evidence of life-threatening arrhythmias. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour. 
• 
If potassium < ULN 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium, and creatinine 1, 2, and 4 hours later, if no 
other evidence of tumor lysis. 
Hyperkalemia 
(including rapidly 
rising potassium) 
Potassium 
≥ 6.0 mmol/L 
(6.0 mEq/L) and/or 
symptomatic 
(e.g., muscle 
cramps, weakness, 
paresthesias, 
nausea, vomiting, 
diarrhea) 
• 
Perform immediate ECG and commence telemetry. 
• 
Nephrology assessment with consideration of initiating dialysis. 
• 
Administer Kayexalate 60 g (or Resonium A 60 g). 
• 
Administer furosemide 20 mg IV × 1. 
• 
Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV. 
• 
Administer sodium bicarbonate 1 to 2 mEq IV push. 
If sodium bicarbonate is used, rasburicase should not be used 
as this may exacerbate calcium phosphate precipitation. 
• 
Administer calcium gluconate 100 to 200 mg/kg IV slowly if there 
is ECG/telemetry evidence of life-threatening arrhythmias.  Do 
not administer in same IV line as sodium bicarbonate. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine every hour. 
Hyperuricemia 
Uric acid 
≥ 8.0 mg/dL 
(476 μmol/L) 
• 
Consider rasburicase (dose per institutional guidelines). 
If rasburicase is used, sodium bicarbonate should not be used 
as this may exacerbate calcium phosphate precipitation. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour. 


 
 
Appendix 6  
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome in the 
Setting of Treatment with Venetoclax (cont.)  
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
171/Protocol GO27878, Version 8 
Abnormality 
Findings 
Management Recommendations 
Uric acid 
≥ 10 mg/dL 
(595 μmol/L) 
OR 
Uric acid 
≥ 8.0 mg/dL 
(476 μmol/L) with 
25% increase and 
creatinine increase 
≥ 0.3 mg/dL 
(≥ 0.027 mmol/L) 
from pre-dose level
• 
Administer rasburicase (dose per institutional guidelines). 
If rasburicase is used, sodium bicarbonate should not be used 
as this may exacerbate calcium phosphate precipitation. 
• 
Consult nephrology. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour. 
• 
If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium, and creatinine 2 and 4 hours 
later, if no other evidence of tumor lysis. 
Hypocalcemia 
Calcium 
≤ 7.0 mg/dL 
(1.75 mmol/L) 
AND 
Patient 
symptomatic 
(e.g., muscle 
cramps, 
hypotension, 
tetany, cardiac 
arrhythmias) 
• 
Administer calcium gluconate 50 to 100 mg/kg IV slowly with 
ECG monitoring. 
• 
Telemetry. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour. 
• 
If calcium normalized 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium, and creatinine 2 and 4 hours 
later, if no other evidence of tumor lysis. 
• 
Calculate corrected calcium and check ionized calcium if 
albumin low. 
Hyperphosphatemia Phosphorus 
≥ 5.0 mg/dL 
(1.615 mmol/L) 
with ≥ 0.5 mg/dL 
(0.16 mmol/L) 
increase 
• 
Administer a phosphate binder (e.g., aluminum hydroxide, 
calcium carbonate, sevelamer hydroxide, or lanthanum 
carbonate). 
• 
Nephrology notification (dialysis required for phosphorus 
≥ 10 mg/dL). 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 hour. 
• 
If phosphorus < 5.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium, and creatinine 2 and 4 hours 
later, if no other evidence of tumor lysis. 
Creatinine 
Increase ≥ 25% 
from baseline 
• 
Start or increase rate of IV fluids. 
• 
Recheck potassium, phosphorus, uric acid, calcium, and 
creatinine in 1 to 2 hours. 
IV = intravenous; ULN = upper limit of normal; WNL = within normal limits. 
 
 


 
 
Appendix 6  
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome in the 
Setting of Treatment with Venetoclax (cont.)  
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
172/Protocol GO27878, Version 8 
Ongoing dosing of venetoclax:   
Management of electrolyte changes from last value at intervals > 24 hours after either 
the first dose or dose increase (e.g., 48 or 72 hours) are as stated below.  Note:  If the 
patient is hospitalized, no additional venetoclax doses should be administered until 
resolution. 
• 
For potassium, admit patient for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or any level 
> upper limit of normal. 
Refer to the management guidelines for electrolyte changes observed within 
the first 24 hours after either the first dose or dose increase (see table above). 
• 
If a smaller potassium increase is observed that does not meet the criteria for 
admission above, recheck potassium, phosphorus, uric acid, calcium, and creatinine 
in 24 hours and confirm no evidence of tumor lysis prior to further venetoclax dosing. 
• 
For uric acid, calcium, phosphorus, and creatinine, refer to the management 
guidelines for electrolyte changes observed within the first 24 hours after either the 
first dose or dose increase (see table above). 
 


 
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
173/Protocol GO27878, Version 8 
Appendix 7  
International Prognostic Index and Ann Arbor Staging 
Classification 
International Prognostic Index 
The International Prognostic Index for aggressive non-Hodgkin’s lymphoma identifies 
five significant risk factors that are prognostic of overall survival (OS): 
Risk Factors 
Ann-Arbor Stage III or IV 
Age > 60 years 
Elevated LDH 
ECOG performance status ≥ 2 
Extranodal involvement≥ 2 
IPI Risk Group 
Number of IPI Risk Factors 
Low 
0 or 1 
Low-intermediate 
2 
High-intermediate 
3 
High 
4 or 5 
ECOG = Eastern Cooperative Oncology Group; IPI = International Prognostic Index. 
 
Ann Arbor Staging Classification for Hodgkin and Non-Hodgkin’s 
Lymphoma 
Stage I 
Involvement of a single lymph node region (I) or of a single extralymphatic 
organ or site (IE) a 
Stage II 
Involvement of two or more lymph node regions or lymphatic structures on the 
same side of the diaphragm alone (II) or with involvement of limited, contiguous 
extralymphatic organ or tissue (IIE) 
Stage III 
Involvement of lymph node regions on both sides of the diaphragm (III) which 
may include the spleen (IIIS) or limited, contiguous extralymphatic organ or site 
(IIIE), or both (IIIES) 
Stage IV 
Diffuse or disseminated foci of involvement of one or more extralymphatic organs 
or tissues, with or without associated lymphatic involvement 
a The designation “E” generally refers to extranodal contiguous extension (i.e., proximal 
or contiguous extranodal disease) that can be encompassed within an irradiation field 
appropriate for nodal disease of the same anatomic extent.  A single extralymphatic site as 
the only site of disease should be classified as IE, rather than Stage IV. 
 
All cases are subclassified to indicate the absence (A) or presence (B) of the 
systemic (“B”) symptoms of significant unexplained fever (> 38˚C), night sweats, or 
unexplained weight loss exceeding 10% of body weight during the 6 months prior to 
diagnosis.   


 
 
Appendix 7  
International Prognostic Index and Ann Arbor Staging 
Classification (cont.)  
Venetoclax (GDC-0199)—F. Hoffmann-La Roche Ltd 
174/Protocol GO27878, Version 8 
Clinical stage refers to the extent of disease determined by diagnostic tests following a 
single diagnostic biopsy.  If a second biopsy of any kind is obtained, even if negative, 
the term pathologic stage is used. 
Adapted from: 
1. 
Carbone PP, Kaplan HS, Musshoff K, et al. Report of the committee on Hodgkin’s 
disease staging classification. Cancer Res 1971;31:1860–1. 
2. 
Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to 
discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds 
meeting. J Clin Oncol 1989;7:1630–6. 
 

SAP_003.pdf: 
Official Title:  
A Phase IB/II, Open-Label Study Evaluating the Safety and 
Pharmacokinetics of GDC-0199 (ABT-199) in Combination With Rituximab 
(R) or Obinutuzumab (G) Plus Cyclophosphamide, Doxorubicin, 
Vincristine, and Prednisone (CHOP) in Patients with B-cell Non-Hodgkin’s 
Lymphoma (NHL) and DLBCL 
 
NCT Number:   
NCT02055820 
 
Document Dates:  
SAP version 1: 24-Jan-17 




 
TABLE OF CONTENTS 
1.  BACKGROUND ............................................................................................ 7 
2.  STUDY  
DESIGN........................................................................................... 7 
2.1
 Protocol
 
Synopsis..................................................................10 
2.2
 Outcome
 
Measures...............................................................10 
2.2.1
 Primary
 
Efficacy
 
Outcome Measures.................................... 12 
2.2.2
 Secondary
 
Efficacy
 
Outcome Measures................................ 12 
2.2.3
 Exploratory
 
Efficacy Outcome Measures............................... 13 
2.2.4
 Pharmacokinetic
 
Outcome Measures.................................... 14 
2.2.5
 Safety
 
Outcome Measures .................................................... 14 
2.3
 Determination
 
of
 
Sample Size ............................................... 14 
2.4
 Analysis
 
Timing.....................................................................15 
3.  STUDY  
CONDUCT..................................................................................... 16 
3.1
 Method
 
of
 
Treatment Assignment.......................................... 16 
3.2
 Independent
 
Review Committee............................................ 16 
3.3
 Data
 
Monitoring..................................................................... 16 
4.  STATISTICAL  
METHODS.......................................................................... 17 
4.1
 Analysis
 
Populations............................................................. 17 
4.1.1
 Intent-to-Treat Population 
...................................................... 17 
4.1.2
 Safety
 
Population.................................................................. 17 
4.1.3
 Pharmacokinetic
 
Evaluable Population................................. 17 
4.1.4 
Double Expressor Diffuse Large B-Cell 
Lymphoma............................................................................. 18 
4.2  
Analysis of Study Conduct..................................................... 18 
4.3  
Analysis of Demographic and Baseline 
Characteristics....................................................................... 18 
4.4
 Efficacy
 
Analysis.................................................................... 18 
4.4.1
 Primary
 
Analysis.................................................................... 18 
4.4.2
 Sensitivity
 
Analysis of the Primary Analysis........................... 19 
4.4.2.1  
Sensitivity Analysis Using Analysis Method 
Adjusting for Potential Baseline Imbalance............................ 19 
4.4.2.2
 Sensitivity
 
Analysis for Different Populations.........................20 
Venetoclax—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan GO27878, Version 1 


4.4.3
 Secondary
 
Analyses.............................................................. 20 
4.4.4
 Exploratory Analyses 
............................................................. 20 
4.5
 Safety
 
Analyses..................................................................... 21 
4.5.1  
Exposure to Study Medication............................................... 21 
4.5.2
 Dose
 
Modifications
 
and Dose Intensity.................................. 21 
4.5.2.1
 Dose
 
Modifications ................................................................ 21 
4.5.2.2
 Dose
 
Intensity........................................................................ 21 
4.5.3
 Adverse
 
Events .....................................................................23 
4.5.4
 Laboratory Data..................................................................... 23 
4.5.5
 Vital
 
Signs.............................................................................. 24 
4.6
 Pharmacokinetic
 
and
 
Pharmacodynamic
 
Analyses................................................................................ 24 
4.7
 Missing
 
Data..........................................................................25 
4.8
 Interim
 
Analyses.................................................................... 25 
5.  REFERENCES ...........................................................................................26 
 
 
LIST OF TABLES 
Table 1  
Summary of Response Endpoints............................................... 11 
Table 2 
95% CIs for Expected Observed Rates for Sample Sizes ..........15 
Table 3  
Power and Minimum Detectable Difference at Two-Sided 
0.05 Level by Exact Test............................................................. 15 
 
 
LIST OF FIGURES 
Figure 1  
Study Schema............................................................................... 9 
 
 
LIST OF APPENDICES 
Appendix 1  Protocol Synopsis (Study GO27878) ..........................................27 
Appendix 2 
Protocol Synopsis (Study BO21005)........................................... 39 
Appendix 3 
Schedule of Assessments........................................................... 50 
Appendix 4 
The Modified Lugano Classification:  Revised Criteria for 
Response Assessment ............................................................... 56 
Appendix 5  A Bayesian Predictive Probability Design for Phase II 
Studies........................................................................................ 62 
Venetoclax—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan GO27878, Version 1 


Appendix 6  BCL-2 and c-MYC Immunohistochemistry Scoring Algorithm 
..... 63 
Venetoclax—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan GO27878, Version 1 


Venetoclax—F. Hoffmann-La Roche Ltd 
5/Statistical Analysis Plan GO27878, Version 1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
or Term 
Definition 
ABC  
activated B cell 
AUC  
area under the concentration−time curve 
BOR  
best overall response 
Cmax 
maximum concentration observed in serum or plasma, as appropriate 
Cmin 
minimum concentration under steady-state conditions within a dosing interval 
in serum or plasma 
CHO
 cyclophosphamide,
 
vincristine, and doxorubicin 
CHOP
 cyclophosphamide,
 
doxorubicin, vincristine, and prednisone 
CR
 complete
 
response
 
CL/F
 apparent
 
clearance
 
CT
 computed
 
tomography
 
DE
 double
 
expressor
 
DLBCL  
diffuse large B-cell lymphoma 
DLT
 dose-limiting
 
toxicity
 
DOR  
duration of response 
DR
 double
 
robust
 
ECOG  
Eastern Cooperative Oncology Group 
FISH  
fluorescence in situ hybridization 
G
 obinutuzumab
 
(GA101)
 
GCB  
germinal center B cell 
IHC
 immunohistochemistry
 
IMC
 Internal
 
Monitoring
 
Committee
 
IPI 
International Prognostic Index 
IRC 
Independent Review Committee 
IRR
 infusion-related
 
reaction
 
ITT
 intent-to-treat
 
MRD  
minimal residual disease 
MTD  
maximum tolerated dose 
NCI CTCAE  
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL
 non-Hodgkin’s
 
lymphoma
 
OS
 overall
 
survival
 
OR
 objective
 
response
 
PD
 progressive
 
disease
 
PET 
positron emission tomography 
PFS
 progression-free
 
survival
 


Abbreviation 
or Term 
Definition 
PK
 pharmacokinetic
 
PR
 partial
 
response
 
QD
 once
 
daily
 
R
 rituximab
 
SOC 
Scientific Oversight Committee 
T1/2
Half-life 
TLS 
tumor lysis syndrome 
t
max
time to maximum observed plasma concentration 
V 
volume of distribution 
Venetoclax—F. Hoffmann-La Roche Ltd 
6/Statistical Analysis Plan GO27878, Version 1 


 
1. 
BACKGROUND 
Study GO27878 was developed to explore the safety of venetoclax (VENCLEXTA™, 
also known as GDC-0199; ABT-199) in combination with rituximab (R) plus 
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy 
(venetoclax
 +
 R-CHOP) or venetoclax in combination with obinutuzumab (G) plus CHOP 
(venetoclax
 +
 G-CHOP) in patients with B-cell non−Hodgkin’s lymphoma (NHL) who are 
believed to be appropriate candidates for R-CHOP therapy during initial dose-finding 
cohorts, and to further explore safety and efficacy in Phase II in patients with previously 
untreated diffuse large B-cell lymphoma (DLBCL) in order to identify appropriate 
populations for evaluation in a Phase III setting. 
This document is based on the statistical section of the study protocol and provides 
details regarding the planned statistical analyses of the safety and efficacy of 
venetoclax
 +
 R-CHOP and venetoclax +
 G-CHOP in patients with previously untreated 
DLBCL who are enrolled in the Phase II portion of the study.  Key analyses will focus on 
a subset of patients (i.e., patients with double expressor [DE] DLBCL), characterized by 
high expression of both BCL-2 and c-MYC proteins, and has a poor prognosis to 
R-CHOP treatment (Green et al. 2012; Johnson et al. 2012; Hu et al. 2013; 
Valera et al. 2013).  This analysis may support potential registration for 
venetoclax
 +
 R-CHOP in patients with DE DLBCL.  Any analyses that are beyond those 
outlined in the protocol are delineated in this document.  
2. 
STUDY DESIGN 
This is a Phase Ib/II, multicenter, open-label, dose-finding study of venetoclax 
administered orally in combination with rituximab or obinutuzumab plus standard doses 
of CHOP in patients with NHL.  Two parallel treatment arms explored doses of 
venetoclax that had a range of 200−800 mg once daily (QD) administered in combination 
with R-CHOP or G-CHOP (see Figure 1).  Patients were treated for a total of 
eight 21-day cycles (8 cycles of venetoclax
 +
 rituximab or venetoclax
 +
 obinutuzumab 
plus CHOP for the first 6 cycles).  Patients who experienced ongoing responses without 
excessive toxicity may receive up to 8 cycles of CHOP following discussion between the 
investigator and the Medical Monitor. 
The study was designed with two stages:  a Phase Ib dose-finding stage and a Phase II 
expansion stage.  During the Phase Ib stage, the safety profile of venetoclax in 
combination with R-CHOP (Arm A) or with G-CHOP (Arm B) was to be determined 
separately for each arm.  The corresponding determined venetoclax dose level for each 
arm was used in the Phase II stage for that arm, unless safety or tolerability signals 
suggested a lower dose more appropriate, or other evidence showed no need of further 
development.   
No maximum tolerated dose (MTD) could be identified at any dose level tested for Arm A, 
and the safety profile of the combination treatment (up to venetoclax 800 mg) was 
Venetoclax—F. Hoffmann-La Roche Ltd 
7/Statistical Analysis Plan GO27878, Version 1 


 
characterized as safe to go forward based on assessments of dose-limiting toxicities 
(DLTs) and overall tolerability. 
The study enrolled 32 patients during the dose-finding phase for venetoclax +
 G-CHOP 
arm, which contains 4 dose-finding cohorts exploring venetoclax doses and dosing 
schedule ranging from 200 to 800 mg.  As the Study BO21005 that compared R-CHOP 
with G-CHOP for patients with front-line DLBCL did not meet the primary endpoint of 
progression-free survival (PFS), the Internal Monitoring Committee (IMC) and Scientific 
Oversight Committee (SOC) decided not to open Phase II for Arm B for patients with 
DLBCL. 
For the venetoclax +
 R-CHOP Phase II portion of the study, the venetoclax dose selected 
for venetoclax
 +
 R-CHOP arm was 800 mg QD on Days 4−10 of Cycle 1 and Days 1−10 
of Cycles 2−8, as determined by the Phase Ib portion of the study (see Protocol 
Version 8, Section 3.2.3 for justification). 
The study enrolled 211 patients in the Phase II portion for venetoclax +
 R-CHOP arm, in 
order to enroll at least approximately 50 patients with DE DLBCL and approximately 
80−100 patients with high BCL-2 expression (approximately 40−50 patients each for 
germinal center B cell [GCB] and activated B cell [ABC] cell of origin subtypes) at up to 
69 investigative sites in North America, the European Union, and Asia Pacific. 
Patients will be evaluated for safety, tolerability, and pharmacokinetics of study 
treatment.  Assessments for anti-tumor activity are performed following 4 cycles of study 
treatment (i.e., during Cycle 4, between Days 15 and 21) and at the completion of study 
treatment (6−8 weeks from Day 1 of Cycle 8 or last cycle received), and during follow up 
visits post end of treatment assessment until study is terminated. 
Venetoclax—F. Hoffmann-La Roche Ltd 
8/Statistical Analysis Plan GO27878, Version 1 


 
Figure 1  Study Schema 
 
C =
 cycle; D
 =
 day; G
 =
 obinutuzumab; CHOP
 =
 cyclophosphamide, doxorubicin, vincristine, and 
prednisone; R
 =
 rituximab. 
 
If there were concerns about the tolerability of the Phase II dose at any time during the 
Phase II study, a lower dose or an alternative dosing schedule for venetoclax
 +
 R-CHOP 
may be explored based on the guideline provided in Protocol Version 8, Section 4.3. 
After the first 20 patients in the venetoclax +
 R-CHOP arm of the Phase II portion of the 
study have completed Cycles 1 and 2 of study treatment, the IMC and SOC will meet to 
review safety data for all patients treated in both the Phase Ib and II portions of the study 
in order to confirm the safety and tolerability of the combination therapy at the 
venetoclax dose chosen at the end of Phase Ib.  Enrollment will be continued while the 
interim safety analysis is being conducted. 
Based on this review, changes may be made to the dose or the dosing schedule of study 
treatment in Phase II (see Protocol Section 3.2.3). 
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10/Statistical Analysis 
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Plan GO27878, Version 1 
2.1  
PROTOCOL SYNOPSIS 
The protocol synopsis is included in Appendix 1.  For additional details, see the 
Schedule of Assessments in Appendix 3. 
2.2  
OUTCOME MEASURES 
All measurable disease must be documented at screening by a combined positron 
emission tomography and computed tomography (PET-CT) scan and contrast CT, and 
re-assessed at each subsequent tumor evaluation by at least a CT scan except for end 
of treatment assessment (i.e., PET-CT is required for end of treatment assessments, 
whereas CT scan is acceptable for assessments during Cycle 4 and follow-up).  
Response assessments will be determined by the Independent Review Committee (IRC) 
and by the investigator on the basis of imaging studies and bone marrow biopsy sample 
results if applicable, with the use of the following: 
•  The modified Lugano Criteria (see Appendix 4; and Appendix 2 of the 
Study GO27878 Protocol), a modification based on Cheson et al. 2014 
Confirm PET complete response (CR) by cleared bone marrow involvement at 
end of treatment if bone marrow was involved by lymphoma or indeterminate 
prior to treatment. 
Confirm PET partial response (PR) by CT PR (or CR). 
•  Lugano Classification (Cheson et al. 2014) 
 
A summary of response based efficacy endpoints is shown in Table 1. 
 


 
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Table 1  Summary of Response Endpoints 
Response Endpoint 
Definition 
Primary 
Secondary 
PET/CT-CR 
(modified Lugano) 
PET-CR or CT-CR (if PET scan is missing or not evaluable) 
rate, where CR is assessed according to modified 
Lugano 2014 per protocol Appendix 4 for PET and ordinary 
Lugano for CT.  CR is downgraded to PR if there is a positive 
bone marrow biopsy tissue sample result at the time of CR 
assessment, or if the baseline bone marrow biopsy sample 
result is positive and missing at the time of the CR 
assessment. 
IRC at 
end of 
treatment 
Investigator at 
end of treatment 
PET/CT-CR 
(Lugano) 
PET-CR or CT-CR Lugano 2014 (if PET scan is missing or not 
evaluable) rate at end of treatment 
⎯ 
Investigator
 
at
 
end of treatment 
CT-CR 
Lugano 2014 classification with use of CT imaging only 
⎯ 
IRC
 
and/or
 
investigator at 
end of treatment 
OR (PET/CT) 
PET-CR or PR or CT-CR or PR (if PET scan is missing or not 
evaluable) rate at end of treatment 
⎯ 
IRC
 
and/or
 
investigator at 
end of treatment 
DOR (PET/CT-CR) 
Time from the first documented occurrence of CR by PET or 
CT until PET or CT PD or death for the subgroup of patients 
achieving PET/CT-CR (modified Lugano) at end of treatment 
⎯ 
IRC,
 
investigator
 
DOR (BOR) 
Time from the first documented occurrence of CR or PR by 
PET or CT until PET or CT PD or death for the subgroup of 
patients achieving best overall response of CR or PR by PET 
or CT 
⎯ 
IRC,
 
investigator
 
BOR =
 best overall response; CR
 =
 complete response; CT
 =
 computed tomography; DOR
 =
 duration of response; 
IRC
 =
 Independent Review Committee; OR
 =
 objective response; PD
 =
 progressive disease; PET
 =
 positron emission 
tomography; PR
 =
 partial response. 
 


 
2.2.1 
Primary Efficacy Outcome Measures 
The primary efficacy outcome measures for Phase II portion is  
•  Complete response (PET/CT-CR [modified Lugano]) rate at end of treatment by IRC 
assessment using PET/CT, defined as the proportion of patients with either: 
PET-CR when PET is performed, according to the modified Lugano 
Classification:  Revised Criteria for Response Assessment (see Appendix 4; 
Cheson et al. 2014) that incorporates PET assessments according to the 
Deauville criteria (Barrington et al. 2014).  The modification downgrades CR to 
PR if there is a positive bone marrow biopsy sample result at time of the CR 
assessment or if the baseline bone marrow biopsy sample result is positive and 
missing at the time of the CR assessment 
or 
CT-CR when PET assessment is not performed or not evaluable, according to 
Lugano 2014 classification, 
at completion of venetoclax
 +
 R-CHOP treatment (6−8 weeks after Cycle 8 Day 1 for 
patients completing therapy or 6−8 weeks after Day 1 of last cycle visit for patients 
discontinuing treatment early).  This will be assessed for: 
•  Previously untreated patients with DLBCL 
•  Previously untreated patients with DLBCL co-expressing BCL-2 and c-MYC protein 
(i.e., DE DLBCL) as defined through central laboratory testing with use of the 
Ventana immunohistochemistry (IHC) investigational-use-only assay and 
prespecified scoring algorithm (see Appendix 6) by both of the following criteria: 
BCL-2 high (2 +, 3
 +) 
c-MYC positive:  patient samples are considered MYC-positive if ≥
 40% of tumor 
cells demonstrate positive MYC nuclear staining (i.e. ≥
 40% of IHC positive 
nuclear stain [1
 +, 2
 +, or 3
 +]) 
 
2.2.2 
Secondary Efficacy Outcome Measures 
The following secondary efficacy outcome measures will be assessed for all patients 
with DLBCL and DE DLBCL: 
•  PET/CT-CR (modified Lugano) rate at end of treatment by investigator 
•  PET/CT-CR (Lugano) rate at end of treatment by investigator 
•  Overall survival (OS), defined as the time from date of enrollment until the date of 
death from any cause.  For patients who have not died, survival data will be 
censored at the date of last contact.  
 
The below secondary efficacy outcome measures will be assessed both by IRC 
assessment and by investigator assessment for all patients with DLBCL and DE DLBCL: 
• CT-CR rate at end of treatment, as defined by CT scan only imaging assessed by 
Lugano 2014 classification (Cheson et al. 2014). 
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•  Objective response (OR) rate (PET/CT), defined as PR or CR at end of treatment by 
PET according to the modified Lugano 2014 criteria when PET is available and by 
CT according to Lugano 2014 when PET is missing or not evaluable.  All other 
cases are designated non-responders. 
•  Duration of response (DOR; PET/CT-CR), defined as the time from the first 
occurrence of a documented CR by PET or CT, to the date of disease progression 
by PET or CT, relapse, or death from any cause, for the subgroup of patients with 
end of treatment PET/CT-CR (modified Lugano).  For patients achieving an end of 
treatment PET/CT-CR but who have not had disease progression, relapsed, or died 
at the time of analysis, DOR-PET/CT-CR will be censored on the date of last tumor 
assessment. 
•  Duration of overall response and best overall response (BOR), defined as the time 
from the first occurrence of a documented CR or PR by PET or CT, to the date of 
disease progression by PET or CT, relapse, or death from any cause, for the 
subgroup of patients with best overall response of CR or PR by PET or CT.  For 
patients achieving a response but who have not had disease progression, relapsed, 
or died at the time of analysis, DOR will be censored on the date of last tumor 
assessment. 
•  PFS, defined as the time from date of enrollment to the first occurrence of 
progression as assessed by either PET or CT, or death from any cause.  Patients 
who have not had disease progression, relapsed, nor died at the time of analysis will 
be censored on the date of last tumor assessment.  If no tumor assessments were 
performed after the baseline visit, PFS will be censored at the date of enrollment. 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
The exploratory outcome measures of this study are the following: 
•  Minimal residual disease (MRD) negativity rate (% MRD negative) for patients who 
were MRD positive at baseline, at end of treatment and overall. 
•  Assessment of the key biomarkers that might predict disease response or 
resistance to treatment with venetoclax
 +
 R-CHOP, including: 
Patients who are either BCL-2 high or BCL-2 low as defined by central 
laboratory testing with use of the Ventana investigational-use-only IHC assay 
ABC and GCB cell-of-origin subtypes 
In patients who are either BCL-2 positive or BCL-2 negative within cell-of-origin 
subtypes 
In patients who have Double-Hit lymphoma, defined by the double translocation 
of BCL-2 and MYC by fluorescence in situ hybridization (FISH); and in patients 
who are non-Double Hit  
In patients with DE within cell-of-origin subtypes 
In DE patients within non-double hit patients (excluding double-hit) 
In patients with BCL-2 who are FISH positive or FISH negative  
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In patients with MYC who are FISH positive or FISH negative  
In patients with BCL-2 with IHC sub-categories defined by the 4 clinical scores 
(0, 1
 +, 2
 +, 3
 +) 
•  Other biomarkers of potential interest include expression of BCL-2 family members; 
frequently mutated genes in DLBCL; cancer immunotherapy biomarkers 
 
2.2.4 
Pharmacokinetic Outcome Measures 
The following pharmacokinetic (PK) parameters will be derived from the plasma 
concentration−time profile of prednisone, venetoclax, and relevant metabolites following 
administration when appropriate, as data allow: 
•  Total plasma exposure (area under concentration−time curve [AUC]) 
•  Time to maximum observed plasma concentration (t
max) 
•  Maximum observed plasma concentration (C
max) 
•  Minimum plasma concentration under steady-state conditions within a dosing 
interval in (C
min) plasma 
 
The following PK parameters will be determined from the concentration-time profiles of 
rituximab; obinutuzumab; and cyclophosphamide, vincristine, and doxorubicin (CHO) 
components, as applicable: 
• 
C
max in serum or plasma, as appropriate 
• 
C
min in serum or plasma, as appropriate 
 
Other PK parameters such as apparent clearance (CL/F), volume of distribution (V), and 
half-life (T1/2) may also be calculated as data allow. 
2.2.5 
Safety Outcome Measures 
The safety and tolerability of venetoclax +
 R and G-CHOP will be assessed with use of 
the following primary safety outcome measures: 
•  Incidence, nature, and severity of adverse events and serious adverse events 
graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE v4.0).  Adverse events of special interest 
include Grade 4 neutropenic fever, Grade ≥
 3 infusion-related reactions to rituximab 
or obinutuzumab, and Grade ≥
 4 tumor lysis syndrome (by Howard criteria with 
Common Terminology Criteria grade determined by investigator).  Selected adverse 
event analysis includes febrile neutropenia, thrombocytopenia, and infections. 
•  Changes in relevant clinical laboratory test results (including hematology and 
chemistry) and vital signs 
• Maintenance of relative dose intensity of venetoclax
 +
 R-CHOP chemotherapy 
 
2.3  
DETERMINATION OF SAMPLE SIZE 
The expected enrollment for the venetoclax +
 R-CHOP arm in Phase II is approximately 
160−200 patients in order to enroll approximately 50 patients with DE DLBCL, 
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80−100 BCL-2 positive patients, and approximately 40−50 BCL-2 positive patients each 
in the GCB and the ABC subgroups.  With 50 patients, 95% CIs for estimation of 
PET-CR would have a margin of error that would not exceed ±
 16%.  The margin of error 
would decrease to 9% with 150 patients and to 8% with 200 patients.  Table 2 shows 
Clopper and Pearson (1934) 95% CIs for expected observed rates for sample sizes of 
50, 100, 150, and 200 patients. 
Table 2  95% CIs for Expected Observed Rates for Sample Sizes
 
 
Complete Response Rate (CI) 
Venetoclax +
 R-CHOP 
50 Patients 
100 Patients 
150 Patients 
200 Patients 
80% 
40 (66%, 90%) 
80 (71%, 87%) 120 (73%, 86%) 160 (73%, 86%)
75% 
37 (60%, 85%) 
75 (65%, 83%) 112 (67%, 81%) 150 (68%, 81%)
70% 
35 (55%, 82%) 
70 (60%, 79%) 105 (62%, 77%) 140 (62%, 77%)
65% 
32 (49%, 77%) 
65 (55%, 74%) 
97 (56%, 72%) 130 (57%, 72%)
CR =
 complete response; CHOP
 =
 cyclophosphamide, doxorubicin, vincristine, and prednisolone or 
prednisone; R
 =
 rituximab. 
 
Table 3 gives the power of sample size with 50 patients in rejecting a null hypothesis of 
response rate equal to a specified value p
0: 
Table 3  Power and Minimum Detectable Difference at Two-Sided 
0.05 Level by Exact Test 
Power and MDD with two-sided alpha =
 0.05 
(n
 =
 50 patients) 
Exact test 
p
 =
 0.65
 p
 =
 0.7 
Null hypothesis 
Power (%) 
MDD (%) 
Power (%) 
MDD (%)
p0 =
 0.45 
81
 0.60
 95
 0.60
 
p0 =
 0.5 
51
 0.66
 78
 0.66
 
p0 =
 0.55 
28
 0.70
 57
 0.70
 
p0 =
 0.6 
7
 0.76
 22
 0.76
 
MDD =
 minimum detectable difference. 
 
There will be approximately 80% power if the true response is 20% better than as 
assumed in the null hypothesis.  The observed response rate needs to be approximately 
15% larger than control so that a statistically positive result could be obtained. 
2.4  
ANALYSIS TIMING 
The primary analysis will occur after all patients enrolled and dosed in the 
venetoclax
 +
 R-CHOP arm complete the end-of-treatment response assessment or early 
discontinuation assessment.  It is expected that this analysis will occur approximately 
24 months after start of Phase II enrollment.   
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Additionally, interim analyses will be incorporated into the Phase II portion of 
venetoclax
 +
 R-CHOP arm in order to plan for future development.  There are 
three planned interim analyses for safety and efficacy.  A safety interim analysis 
specified per protocol will be performed after 20 patients are enrolled in 
venetoclax
 +
 R-CHOP arm of Phase II and have completed 2 cycles of combination 
therapy.  During this analysis, data will be reviewed by IMC
 +
 SOC in order to assess 
safety and tolerability of the combination in a larger number of patients.  Refer to 
Section 3.3 for more details on IMC and SOC review scope.  The first and second 
efficacy interim analyses will be performed after approximately 40 and 70 patients 
complete end of treatment response assessments, respectively, in the 
venetoclax
 +
 R-CHOP arm of the Phase II portion.  Safety information will be obtained at 
all interim analyses.  Additional interim analyses may be conducted to guide future 
development before or after primary analysis. 
R-CHOP data from completed Study BO21005 (GOYA, see Appendix 2) will be used as 
historical control for venetoclax
 +
 R-CHOP.  Historical PET/CT-CR rates in patients with 
DE DLBCL and in intent-to-treat (ITT) patients whose samples are considered to be 
within stability window are expected to be available from GOYA Study for comparison by 
the time of first interim efficacy analysis. 
3. 
STUDY CONDUCT 
3.1  
METHOD OF TREATMENT ASSIGNMENT 
In the Phase Ib portion of this study, patients will be assigned to dose levels in the order 
in which they are enrolled.  This is an open-label study.  Enrollment in the dose-finding 
portion of the study will be limited to patients with B-cell NHL with no prior R-CHOP 
therapy and who have received only a single prior treatment regimen. 
In the Phase II portion of the study, previously untreated DLBCL with higher-risk clinical 
features as determined by an International Prognostic Index (IPI) score of 2−5 will be 
enrolled.  
3.2  
INDEPENDENT REVIEW COMMITTEE 
An IRC composed of board-certified radiologists and oncologists with experience in 
malignant lymphoma will assess all patients for response and progression on the basis 
of imaging results, bone marrow biopsy sample results, and relevant clinical data, and 
will be guided by a charter specific to the independent review. 
For all investigator-assessed response analyses, including PFS, there will be a 
corresponding analysis of the IRC-determined data.  
3.3  
DATA MONITORING 
An IMC and an SOC has been established to monitor patient safety and to provide a 
recommendation for each treatment arm on the dose to be taken forward into the 
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Phase II portion of the study after completion of the dose-escalation phase.  The IMC 
includes the Genentech Medical Monitor and at least 1 other medical doctor or clinical 
science representative not directly involved in the study, as well as representatives from 
drug safety, biostatistics, and statistical programming and analysis.  The SOC is 
comprised of experts in DLBCL who are investigators for this study in order to provide 
guidance and a review of safety-related events.  Separate IMC and SOC agreements 
outline each committee
's composition, meeting timelines, and members
' roles and 
responsibilities.  The committee members review all potential cases of serious adverse 
events, Grade 3 and 4 adverse events, and deaths as specified in the IMC and SOC 
agreement.  The SOC is kept apprised of all relevant efficacy and safety data from this 
study and other related clinical studies.  Ad hoc meetings may be called in addition to 
scheduled quarterly meetings as necessary to provide recommendations on 
management of any new safety issues. 
4. 
STATISTICAL METHODS 
The analyses outlined in this section are for the Clinical Study Report preparation of 
venetoclax
 +
 R-CHOP arm at end of Phase II of the study.  
Except where otherwise specified, all continuous variables will be summarized with use 
of descriptive statistics (the number of non-missing values, mean, standard deviation, 
median, minimum, and maximum) and all categorical variables will be summarized with 
use of frequency counts and percentages.  Phase Ib results will be presented by 
venetoclax treatment group (venetoclax
 +
 G-CHOP or venetoclax +
 R-CHOP) and dose 
cohort.  Phase II results will be presented separately and as a pooled 800 mg venetoclax 
treatment group by pooling data with patients from cohort 4 of Phase Ib portion for safety 
and for efficacy analysis, unless otherwise specified. 
4.1  
ANALYSIS POPULATIONS 
4.1.1 
Intent-to-Treat Population 
All patients who enrolled in the study will be included in the ITT population used for 
efficacy analyses. 
4.1.2 
Safety Population  
All patients who enrolled in the study and received any amount of venetoclax or 
R-CHOP and/or G-CHOP will be included in the safety population used for safety 
analyses.  Data from patients who receive R-CHOP or G-CHOP will be summarized by 
dose cohort and by phase separately, including a group of those who have not received 
any venetoclax. 
4.1.3 
Pharmacokinetic Evaluable Population 
All patients who enrolled in the study and received any amount of venetoclax or 
R-CHOP/G-CHOP will be included in the PK evaluable population used for PK analyses. 
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4.1.4 
Double Expressor Diffuse Large B-Cell Lymphoma 
DE population is defined for the purpose of the primary efficacy and safety analyses, 
respectively, as 800 mg venetoclax in ITT patients with DLBCL who are co-expressing 
BCL-2 and c-MYC and therefore positive for BCL-2 and c-MYC IHC according to the 
Ventana IHC investigational-use-only assay.  DE will be scored as described in 
Appendix 6 by a central laboratory. 
4.2  
ANALYSIS OF STUDY CONDUCT 
The number of patients who are enrolled will be tabulated by treatment group, center, 
and country.  Major eligibility violations and major protocol deviations will be listed or 
summarized if summary table is deemed appropriate.  Patient disposition and reasons 
for study discontinuation will be summarized by treatment group for all enrolled patients 
(ITT).  Duration of follow-up will also be assessed. 
4.3  
ANALYSIS OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Descriptive summaries will be provided for all baseline characteristics.  Demographic 
and baseline characteristics that will be summarized by treatment group, dose cohort 
and phase for ITT population include but not limited to gender, age at consent 
(continuous and categorical), race, ethnicity, height, weight at baseline, body surface 
area, Eastern Cooperative Oncology Group (ECOG) Performance Status at screening, 
Ann Arbor staging at screening, bone marrow involvement at baseline, tumor bulk at 
baseline (lymph mass ≥
 10 cm), prior lymphoma history (for phase I), prognostic 
biomarkers (e.g., BCL-2 and c-MYC status by IHC and by FISH), DLBCL genotypic 
subtypes (e.g., ABC, GCB), IPI score, confirmed diagnosis to start of treatment, and 
geographic region.  
The number of non-missing observations, mean, median, standard deviations, minimum, 
and maximum values of the continuous variables will be summarized.  Percentages of 
patients within each subgroup of categorical variables will be provided.  
If country policy prohibits the collection of race and/or age information, patients will 
appear in the missing category of summary table. 
4.4  
EFFICACY ANALYSIS 
4.4.1 
Primary Analysis 
The primary efficacy endpoint, PET/CT-CR (modified Lugano) at end of treatment based 
on IRC assessment will be assessed for DE and ITT patients.  Patients who do not have 
available end of treatment PET-CT or CT-CR assessment, or whose PET-CT 
assessment result is not evaluable at end of treatment will be counted as 
non-responders in the primary efficacy analysis.  DE population PET/CT-CR (modified 
Lugano) rate will be defined as the proportion of patients with a PET/CT-CR in the DE 
population.   
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The primary analysis of PET/CT-CR rate will be performed in a frequentist setting with 
use of a one-sample exact test to test the superiority of venetoclax
 +
 R-CHOP over 
R-CHOP historical control response rate in the DE population (i.e., to test H0: ≤ 
versus HA: > , where  is the response rate of venetoclax
 +
 R-CHOP Phase II 
patients with DE DLBCL and  is the response rate of baseline PET evaluable DE 
within stability window, IPI 2−5 patients receiving R-CHOP in GOYA [Study BO21005, 
see Appendix 2]).  95% CIs of response rate for venetoclax
 +
 R-CHOP will be provided  
Efficacy is established if the PET/CT-CR rate in the venetoclax +
 R-CHOP DE population 
is observed to be significantly different from historical control in Phase II DE population.  
Historical control response rates for the ITT population will be also be based on results 
from the GOYA study R-CHOP arm with baseline evaluable PET and IPI score 2−5.  
4.4.2  
Sensitivity Analysis of the Primary Analysis 
4.4.2.1  
Sensitivity Analysis Using Analysis Method Adjusting for 
Potential Baseline Imbalance 
Sensitivity analyses will be conducted with use of propensity score based methods that 
include the double robust (DR) method proposed by Robin (Bang and Robins 2005), to 
adjust for potential baseline imbalance between venetoclax
 +
 R-CHOP and the historical 
control R-CHOP.  The double robust estimator combines inverse weight of propensity 
score as a covariate into the outcome logistic regression model that incorporates the 
important baseline prognostic factors including age, gender, body mass index, lactate 
dehydrogenase, IPI high (4 and 5) versus low, ECOG ≥
 2 versus <
 2, and stage IV 
versus stage I, II, and III. 
Specifically, if 
 is an outcome regression model where  is the 
vector of selected baseline covariates, and 
 is the propensity score (i.e., the 
probability of receiving the treatment given the covariates, estimated from the propensity 
score model), then the DR estimator of mean response rate in venetoclax
 +
 R-CHOP 
treated patients is: 
. 
The DR estimator of mean response rate in historical R-CHOP treated patients is: 
, 
and the response rate difference is simply estimated as: 
. 
Bootstrapped 95% CIs will be provided for the DR estimate of the difference in response 
rate.  


 
Bayesian posterior probability (see Appendix 5) that venetoclax
 +
 R-CHOP has a 15% 
higher response rate than historical control will also be provided.   
4.4.2.2  
Sensitivity Analysis for Different Populations 
The following sensitivity efficacy analyses will also be conducted for PET/CT-CR 
(modified Lugano):  
•  To evaluate the potential impact of missing data on the estimation of PET/CT-CR 
(modified Lugano), a sensitivity analysis will be done in the safety population 
(i.e., Patients who did not start treatment thus do not have available PET and/or CT 
assessment at the end of treatment will be excluded; however, for any reason 
discontinued patients who are treated will be included).  
•  To evaluate the potential impact of missing venetoclax on the estimation of 
PET/CT-CR (modified Lugano), another sensitivity analysis will be done in the 
DLBCL population who received at least one venetoclax dose and who have 
available PET-CT assessment at the end of treatment with protocol allowed 
assessment window. 
 
Response proportions will be presented with 95% Clopper and Person (1934) CIs. 
4.4.3 
Secondary Analyses 
PET/CT-CR (modified Lugano) rate and PET/CT-CR (Lugano) rate as assessed by 
investigator, CT-CR rate and OR (PET) rate as assessed by investigator and by IRC 
(only available for Phase II portion and 5 patients with DLBCL in Phase Ib Arm A 
cohort 4) will be analyzed for ITT patients and patients with DE DLBCL by treatment arm 
and dose cohort.  Proportions will be presented with 95% CIs with use of the method of 
Clopper and Person (1934). 
PFS and OS will be presented using Kaplan-Meier plots separately by treatment group 
and dose cohort for the ITT and the DE DLBCL ITT population.  Median PFS and OS as 
well as 95% CI will be estimated if reached, otherwise, these will be summarized with 
use of the 1-year, 2-year, and if mature enough 3-year rates by Kaplan-Meier method, 
with 95% CIs calculated via Greenwood formula.   
DOR will be analyzed according to the same methods as PFS and OS, for patients who 
are PET/CT CR or OR at end of treatment. 
4.4.4 
Exploratory Analyses 
Key efficacy endpoint analysis will be repeated in biomarker subgroups as listed in 
Section 2.2.3, including BCL-2-high by IHC, c-MYC high by IHC, BCL-2 and c-MYC 
translocation by FISH, GCB, ABC, and others. 
MRD response rate (defined as proportion of patients with negative MRD at the end of 
treatment whose baseline MRD is positive) and other timepoints will be assessed in ITT 
in DE and other relevant biomarker subgroups.  The MRD population will be defined as 
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patients with at least one calibrating clone, and who are MRD positive at baseline.  
Cases where no post-baseline MRD assessment is available will be considered MRD 
non-responders. 
Analysis of biomarker and exploratory endpoints as defined in the protocol will be 
provided in separate reports. 
4.5  
SAFETY ANALYSES 
Safety will be assessed through summaries of adverse events, serious adverse events, 
deaths, and adverse events of special interest (include Grade 4 neutropenic  fever, 
Grade ≥
 3 infusion-related reactions [IRRs] to rituximab, and tumor lysis syndrome [TLS]).  
Summaries of changes include shift tables when appropriate from screening 
assessments in laboratory test results, ECGs, measurement of vital signs, and other 
protocol-specified tests that are deemed critical to the safety evaluation will be included. 
The safety analyses will be performed based on the safety population. 
Safety analysis from Phase Ib will be grouped by treatment arm and venetoclax dose 
cohort (i.e., 200 mg, 400 mg, 600 mg, and 800 mg).  Safety analysis for Phase II will be 
presented separately. 
4.5.1 
Exposure to Study Medication 
Information on each study drug administration will be summarized by treatment duration, 
dose intensity (percentage of the planned dose), and cumulative dose.  Treatment 
exposure will be summarized by each study medication given at each cycle.  Descriptive 
analysis includes number of patients, mean, standard deviation, median, minimum, and 
maximum. 
Listings and summary tables for patients discontinue from study treatment will be 
reported. 
4.5.2 
Dose Modifications and Dose Intensity 
Both Dose Modification and Dose Intensity Evaluations will be performed by venetoclax 
dose groups (200-, 400-, 600-, and 800-mg), and treatment (R, C, H, O, P, R−CHOP, V), 
unless otherwise specified. 
4.5.2.1  
Dose Modifications 
Dose modifications include both dose delays and/or dose reductions. 
Dose delays or reductions for R−CHOP combined will be flagged yes if dose delays or 
reductions occurred to any of R, C, H, O, or P.  
4.5.2.2  
Dose Intensity 
The evaluation of relative dose intensity will be performed at the patient level. 
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Two kinds of dose intensity definition will be explored and calculated:  
∑
∑
dose
planned
dose
actual
_
_
     vs.  
actual dose
∑
total 
timeon 
treatment
planned dose
∑
planned 
timeon 
treatment
 
 
Actual dose:  
•  Overall:  actual cumulative dose until end of treatment or cutoff, whichever occurs 
first. 
 
Planned dose:  
•  Overall:  dose regimen should be per protocol, see details below in italic font.  
Calculation of planned dose depends on the last cycle of that patient until the data 
cutoff date. 
For infusion drugs: 
Rituximab infusion (375 mg/m2) or obinutuzumab (1000 mg) on Day 1 (also 
Day 8 and 15 for Cycle 1) 
Cyclophosphamide 750 mg/m2 administered intravenously on Day 1 
Doxorubicin 50 mg/m2 administered intravenously on Day 1  
Vincristine 1.4 mg/m2 administered by intravenous push on Day 1 with a 
cap of 2.0 mg 
Note:  For planned dose which is based on body surface area, baseline 
body surface area will be used to calculate the planned dose. 
For oral drugs: 
Venetoclax Cycle 1 Days 4−21 or Cycles 2−8 Days 1−21 for Cohort 1 
Venetoclax Cycle 1 Days 4−10 or Cycles 2−8 Days 1−10 for Cohort 2−4 
Prednisone 100 mg/day orally on Days 1−5 
 
Total (actual) time on treatment: 
• Overall:  last treatment date
 −
 first treatment date
 +
 1 
 
Planned time on treatment: 
•  Overall:  based on treatment disposition and patient’s last cycle until the data cutoff 
date.  Planned time is protocol specified cycle length.  In general 21 days per cycle. 
If a patient discontinued treatment, use actual time on treatment 
If a patient completed treatment:  
Use actual time on treatment if actual time on treatment is within 2 day time 
window compared to planned time on treatment. 
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Use calculated planned time on treatment if actual time on treatment 
exceeds 2 day time window. 
If a patient neither discontinued nor completed, calculate planned time until the 
data cutoff date. 
 
Dose intensities will be summarized by the following categories: <
 80%, 80%−84%, 
85%−89%, and ≥
 90% for each formula. 
4.5.3 
Adverse Events 
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  All adverse events and routine laboratory parameters 
will be assessed according to the NCI CTCAE v4.0 grading system.  For the Phase Ib 
portion, incidence and nature of DLTs experienced within the combination DLT 
assessment window will be listed by dose cohort and study arm.   Patients who withdraw 
from study treatment prior to completing the DLT assessment window for reasons other 
than DLT will be considered unevaluable for DLT and MTD assessments and will be 
replaced. 
All recorded adverse events will be listed by treatment arm, study site, patient number, 
and schedule.  The most extreme intensity will be used for reporting.  All adverse events 
occurring on or after the first study treatment will be summarized by body system, 
NCI CTCAE grade, and relation to study treatment.  In tables showing the overall 
incidence of adverse events, patients who experienced the same event on more than 
one occasion are counted only once in the calculation of the event frequency and the 
adverse event with the most extreme severity will be included. 
Selected events of special interest (e.g., Grade 4 neutropenic fever, Grade ≥
 3 IRRs to 
rituximab or obinutuzumab, and Grade ≥
 4 TLS) will be summarized by treatment arm 
and dose cohort and listings will be provided.  Hepatitis B reactivation will be followed 
and summarized as an adverse event of particular interest. 
Adverse events leading to dose interruptions (including dose delay and dose 
modifications), early treatment discontinuation, or early study withdrawal will be 
summarized by treatment arm. 
All serious adverse events will be listed separately and summarized.  Deaths reported 
during the study treatment period and those reported during follow-up after patient 
discontinuation will be listed. 
4.5.4 
Laboratory Data 
Laboratory measurements and change from baseline will be summarized by treatment 
arm, where baseline measurement is defined as the last valid measurement before first 
dose of any study medication.  The summary of TLS-related measurements (including 
uric acid, potassium, inorganic phosphorus, and calcium) and change from baseline will 
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be provided.  In addition, laboratory measurement from individual patients who 
developed TLS by Howard criteria (regardless of TLS adverse event reporting by site) 
during the study will be presented in a listing.  Important hematology parameters, such 
as absolute lymphocyte count, ANC, hemoglobin, hematocrit, and WBC will be 
categorized according to NCI CTCAE version 4.0 grading with values within, above, or 
below the normal range comparing baseline to subsequent assessment by treatment 
arm and overall.  Shift tables will be generated to show the number and percentage of 
patients at baseline versus postbaseline observations.  
The laboratory measurement for hepatitis B DNA polymerase chain reaction, including 
hepatitis B surface antigen, anti-hepatitis B core antibody, and hepatitis C antibody 
serology (also hepatitis C virus and RNA by polymerase chain reaction if the patient is 
hepatitis C virus antibody positive) will be listed. 
4.5.5 
Vital Signs 
Vital signs, including absolute value and change from baseline, will be summarized over 
time by treatment arm without any imputation for missing data.   
ECG data at screening visit will be summarized.  Abnormal physical examination at 
screening visit will be listed. 
4.6  
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Mean serum and plasma concentrations, as appropriate, of venetoclax, rituximab, 
obinutuzumab, and CHOP components versus time will be tabulated and plotted, and 
summary statistics will be computed for each scheduled sampling time after appropriate 
grouping.  Concentration-time data for venetoclax and the other analytes will be 
analyzed with the use of non-compartmental methods, and the following PK parameters 
will be derived from the plasma concentration-time profile of prednisone, venetoclax, and 
relevant metabolites following administration when appropriate, as data allow: 
•  Total plasma exposure (AUC) 
• 
T
max 
• 
C
max 
• 
C
min 
 
The following PK parameters will be determined from the concentration-time profiles of 
rituximab, obinutuzumab, and CHO components, as applicable: 
• 
C
max in serum or plasma, as appropriate 
• 
C
min in serum or plasma, as appropriate 
 
Other PK parameters such as CL/F, V, and T1/2 may also be calculated as data allow. 
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Additional analyses, such as population PK and/or pharmacodynamics analysis, may be 
performed to characterize the pharmacokinetics and potential correlations of exposure 
with dose, demographics, pharmacodynamics, safety, and efficacy outcomes.  The 
results of such additional analyses may be reported separately from the clinical study 
report.  At the discretion of the Sponsor, all analyses may be extended to include 
relevant biotransformed products of venetoclax.  
4.7  
MISSING DATA 
For the response assessments, patients with no end of treatment response assessments 
(for any reason) will be considered non-responders. 
For PFS, patients who do not have documented disease progression and have not died 
will be treated as censored observations on the date of the last tumor assessment.  If no 
tumor assessments were performed after the baseline visit, PFS will be censored at the 
time of enrollment. 
For overall survival, patients who have not died at the time of analysis will be censored 
at the last date of known contact. 
Patients who could not have DE status determined (due to missed sample collection or 
technical failure of assay) will be excluded from efficacy analysis of DE patients. 
4.8  
INTERIM ANALYSES 
The safety interim analysis will occur when 20 patients in Phase II in the 
venetoclax
 +
 R-CHOP arm complete 2 cycles of combination therapy and will enable 
formal safety review of adding venetoclax to R-CHOP.  
Besides the safety interim analysis, an additional two efficacy interim analyses will be 
performed after approximately 40 and 70 patients complete their end of treatment 
response assessments, respectively. Additional interim analyses may be conducted to 
guide future development before or after primary analysis.   
A predictive probability design (an extension to Lee and Liu 2008) will be used to guide 
early decision-making for futility or efficacy by comparison of CR rates in the 
venetoclax
 +
 R-CHOP arm to R-CHOP historical control in the Bayesian setting.  
Predictive probability at interim time points will be estimated to show the chance that 
venetoclax
 +
 R-CHOP is efficacious or futile at the end of the study given evidence from 
ongoing data.  However, there will be no stopping for efficacy as additional safety and 
efficacy data would be required to plan for a Phase III study.   
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5. 
REFERENCES 
Bang H, Robins JM. Doubly robust estimation in missing data and causal inference 
models. Biometrics 2005;61:962−72. 
Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of Imaging in the Staging and 
Response Assessment of Lymphoma: Consensus of the International Conference 
on Malignant Lymphomas Imaging Working Group. J Clin Oncol 2014;32:3048−58. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the 
Lugano classification. J Clin Oncol 2014;32:3059−68. 
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika 1934;26:404−13. 
Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong 
predictor of outcome in patients with diffuse large B-cell lymphoma treated with 
rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. 
J Clin Oncol 2012;30:3460−7. 
Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to 
the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma 
and demonstrates high-risk gene expression signatures: a report from The 
International DLBCL Rituximab-CHOP Consortium Program. Blood 
2013;121:4021−31. 
Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in 
diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, 
doxorubicin, vincristine, and prednisone. J Clin Oncol 2012;30:3452−9. 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clinical 
Trials 2008;5:93−106. 
Valera A, Lopez-Guillermo A, Cardesa-Salzmann T, et al. MYC protein expression and 
genetic alterations have prognostic impact in patients with diffuse large B-cell 
lymphoma treated with immunochemotherapy. Haematologica 2013;98:1554−62. 
 
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Appendix 1   
Protocol Synopsis (Study GO27878) 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IB/II, OPEN-LABEL STUDY EVALUATING THE SAFETY 
AND PHARMACOKINETICS OF VENETOCLAX (GDC-0199; 
ABT-199) IN COMBINATION WITH RITUXIMAB (R) OR 
OBINUTUZUMAB (G) PLUS CYCLOPHOSPHAMIDE, 
DOXORUBICIN, VINCRISTINE, AND PREDNISONE (CHOP) IN 
PATIENTS WITH B-CELL NON-HODGKIN’S LYMPHOMA (NHL) 
AND DLBCL 
PROTOCOL NUMBER: 
GO27878 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2013-003749-40 
IND NUMBER: 
115045 
TEST PRODUCTS: 
Venetoclax (GDC-0199; ABT-199; RO5537382) 
Obinutuzumab (GA101; RO5072759) 
PHASE: 
Ib/II 
INDICATION: 
B-cell non-Hodgkin’s lymphoma 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Primary Efficacy Objectives 
The primary objective of the Phase I portion of the study is the following: 
• To estimate the maximum tolerated dosing schedule for venetoclax given in combination 
with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or 
obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP) to 
patients with B-cell non-Hodgkin’s lymphoma (NHL), either previously untreated or 
relapsed/refractory after a maximum of one prior therapy 
 
The primary objectives of the Phase II portion of the study are the following: 
•  To assess the safety and tolerability of the combination of venetoclax and R-CHOP or 
G-CHOP administered to patients with previously untreated diffuse large B-cell lymphoma 
(DLBCL) 
•  To make a preliminary assessment of efficacy as measured by complete response (CR) 
rate at end of treatment determined by positron emission tomography and/or computed 
tomography (PET-CT) scans of the combination of venetoclax and R-CHOP administered to 
patients with previously untreated DLBCL 
•  To make an assessment of efficacy, as measured by CR rates at end of treatment 
determined by PET-CT scans, of the combination of venetoclax and R-CHOP administered 
to patients with previously untreated DLBCL co-expressing both BCL-2 and c-MYC proteins 
(i.e., double expressor [DE]-DLBCL) 
 
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Appendix 1   
Protocol Synopsis (Study GO27878) (cont.) 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives of this study are the following: 
• To characterize the pharmacokinetics of venetoclax and relevant metabolites when 
administered in combination with R-CHOP or G-CHOP in the relapsed/refractory or 
previously untreated setting in NHL 
•  To characterize the pharmacokinetics of rituximab, obinutuzumab, and prednisone when 
administered in combination with venetoclax in patients with relapsed/refractory or 
previously untreated B-cell NHL 
•  To confirm exposure to cyclophosphamide, doxorubicin, and vincristine when given in 
combination with rituximab, obinutuzumab, and/or venetoclax 
 
Secondary Efficacy Objectives 
The secondary efficacy objectives of this study include the following: 
•  To make a preliminary assessment of efficacy when venetoclax and R-CHOP are 
administered in combination to patients with previously untreated DLBCL, as measured by: 
  
Objective response (OR) rate 
  
CR rate as determined by CT scan 
  
Duration of response (DOR) 
  
Progression-free survival (PFS)  
•  12 month PFS estimate  
•  Overall survival (OS) 
•  To make a preliminary assessment of efficacy when venetoclax and G-CHOP are 
administered in combination, as measured by OR rate, CR rate, and PFS. 
 
Exploratory Objectives 
The exploratory objectives of this study are the following: 
• To make a preliminary assessment of potential biomarkers that might predict disease 
response or resistance to treatment with the venetoclax plus R-CHOP or G-CHOP 
combinations in the relapsed or previously untreated setting: 
BCL-2 and BCL-2 family protein expression, including Bcl-xl and Mcl-1, by 
immunohistochemistry (IHC) 
BCL2 and c-MYC copy number gain by fluorescence in situ hybridization (FISH) and 
translocation t(14;18) by FISH 
Expression of transcripts for BCL-2 family members, other apoptotic genes, and genes 
associated with ABC or GCB subtypes of DLBCL 
Subgroups relevant to DLBCL biology that are defined genetically or by poor prognosis, 
including CD79b, Myd88, CARD11, TNFAIP3, epigenetic markers, and MYC 
translocation 
•  To make a preliminary assessment of the efficacy of venetoclax and R-CHOP in different 
potential prognostic subgroups, including DLBCL genotypic subtypes (e.g., ABC; GCB), 
high BCL-2 (BCL-2-positive) expression, as well as patients displaying BCL2 and MYC 
translocations (Double Hit) 
•  To make a preliminary assessment of minimal residual disease (MRD) as a prognostic 
marker in DLBCL 
•  To evaluate the prognostic significance of interim PET assessment in this setting 
 
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Appendix 1   
Protocol Synopsis (Study GO27878) (cont.) 
Study Design 
Description of Study 
This is a Phase Ib/II, multicenter, open-label, dose-finding study of venetoclax administered 
orally in combination with rituximab or obinutuzumab and standard doses of CHOP in patients 
with NHL.  The study will consist of two stages:  a dose-finding Phase Ib stage and a Phase II 
expansion stage.  In the Phase I portion of the study, two parallel treatment arms will explore 
doses of venetoclax ranging from 200 to 800 mg administered in combination with R-CHOP and 
G-CHOP.  Patients will be treated for a total of eight cycles (six cycles of CHOP and eight 
cycles of venetoclax
 +
 rituximab or venetoclax
 +
 obinutuzumab).  Each cycle will consist 
of 21 days.  Patients who experience ongoing response without excessive toxicity may receive 
up to eight cycles of CHOP following discussion between the investigator and the Medical 
Monitor.  The maximum tolerated dose (MTD) of venetoclax in combination with R-CHOP and 
G-CHOP will be determined separately for each arm during the dose-finding stage.   
The dose and dose schedule for venetoclax for each arm determined in Phase I will be used in 
the Phase II expansion stage for that arm. 
For the Phase II portion of the study, the venetoclax dose for Arm A is 800 mg on a 
non-continuous dosing schedule of Cycle 1 Days 4−10 and Cycles 2−8 Days 1−10, as 
determined by the Phase Ib portion of the study based on safety and tolerability observed in 
patients treated in the dose escalation portion of the study.   
If there are concerns about the tolerability of the Phase II dose at any time during the Phase II 
study, a lower dose or an alternative dosing schedule for venetoclax
 +
 R-CHOP or G-CHOP 
may be explored on a case by case basis based on the guideline.  
For the Phase II R-CHOP arm of the study, after the first 20 patients have completed Cycles 1 
and 2 of study treatment, the Internal Monitoring Committee (IMC) and Scientific Oversight 
Committee (SOC) will meet to review safety data for all patients treated in both the Phase Ib 
and Phase II portions of the study in order to confirm the safety and tolerability of the 
combination therapy at the venetoclax dose chosen at the end of Phase Ib.  Enrollment will 
continue while the interim safety analysis is being conducted.   
On the basis of this review, changes may be made to the dose or the dosing schedule of the 
Phase II.  
Number of Patients 
The study will enroll approximately 24−60 patients during the dose-finding stage and 
approximately 180−200 patients in the Phase II portion at approximately 69 investigative sites in 
North America, the European Union, and Asia Pacific. 
Target Population:  Inclusions Criteria 
Patients must meet the following criteria for study entry: 
Patients enrolled in the Dose Finding Portion of the Study: 
•  Patients must have histologically confirmed B-cell NHL (and have never received previous 
R-CHOP treatment), except mantle cell lymphoma (MCL) or small lymphocytic lymphoma 
(SLL), in order to enroll in this portion of the study 
•  Any relapsed/refractory patients that are enrolled during the dose escalation should have 
received only a single previous treatment regimen 
 
Patients Enrolled in the Phase II Portion of the Study: 
•  Patients must have previously untreated CD20-positive DLBCL and International Prognostic 
Index (IPI) score must be 2−5 in order to enroll in this portion of the study. 
 
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Appendix 1   
Protocol Synopsis (Study GO27878) (cont.) 
All Patients 
•  Signed informed consent form(s) 
•  At least one bi-dimensionally measurable lymphoma lesion on CT scan defined as >
 1.5 cm 
in its longest dimension, which is also F-fleurodeoxyglucose (FDG) avid by screening PET 
scan.
18
 
•  Ability and willingness to comply with the study protocol procedures 
• Age  ≥
 18 years 
•  Confirmed availability of archival or freshly biopsied tumor tissue meeting protocol defined 
specifications prior to study enrollment 
•  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 
•  Adequate hematologic function (unless because of underlying disease, as established by 
extensive bone marrow involvement or as a result of hypersplenism secondary to the 
involvement of the spleen by lymphoma per the investigator) defined as follows: 
 Hemoglobin
 ≥
 9 g/dL 
 
ANC ≥
 1.5
 ×
 109/L 
 Platelet
 
count
 ≥
 75
 ×
 109/L 
•  For women who are not postmenopausal (≥
 12 months of non-therapy−induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use single or combined non-hormonal contraceptive methods that result in a failure rate of 
<
 1% per year during the treatment period and for at least 12 months after the last dose of 
rituximab or 18 months after the last dose of obinutuzumab 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception 
•  Non-vasectomized male patients must practice at least one of the following methods of birth 
control throughout the duration of study participation and for at least 12 months after 
completing therapy with rituximab or 18 months after completing therapy with obinutuzumab: 
A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is 
taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at 
least 3 months prior to study drug administration 
Total abstinence from sexual intercourse; double-barrier method (condom
 +
 diaphragm 
or cervical cup with spermicidal, contraceptive sponge, jellies, or cream) 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Males must agree to abstain from sperm donation for at least 12 months after the last dose 
of rituximab or 18 months after the last obinutuzumab dose. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Patients enrolled in the Dose-Finding Portion of the Study 
• Patients with MCL or SLL histology will be excluded from study entry 
 
Patients Enrolled in the Phase II Portion of the Study 
•  Patients with transformed lymphoma (patients with discordant bone marrow involvement(i.e., 
low grade histology in bone marrow) may be considered after discussion with the Medical 
Monitor) 
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Appendix 1   
Protocol Synopsis (Study GO27878) (cont.) 
•  Prior therapy for NHL 
 
All Patients 
•  History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies or known sensitivity or allergy to murine products 
•  Contraindication to receive any of the individual components of CHOP, rituximab or 
obinutuzumab 
•  Prior anthracycline therapy 
•  Ongoing corticosteroid use >
 30 mg/day of prednisone or equivalent.  Patients who received 
corticosteroid treatment with ≤
 30 mg/day of prednisone or equivalent must be documented 
to be on a stable dose of at least 4 weeks’ duration prior to Cycle 1 Day 1.  Patients may 
have received a brief (<
 7 days) course of systemic steroids (≤
 100 mg prednisone 
equivalent per day) prior to initiation of study therapy for control of lymphoma-related 
symptoms. 
• CNS  
lymphoma  or primary mediastinal DLBCL 
•  Vaccination with live vaccines within 28 days prior to treatment 
•  Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1.  
•  History of other malignancy that could affect compliance with the protocol or interpretation 
of results 
Patients with a history of curatively treated basal or squamous cell carcinoma or Stage 
1 melanoma of the skin or in situ carcinoma of the cervix are eligible. 
Patients with a malignancy that has been treated with surgery alone with curative intent 
will also be excluded, unless the malignancy has been in documented remission 
without treatment for ≥
 3 years prior to enrollment. 
•  Evidence of significant, uncontrolled concomitant diseases that could affect compliance with 
the protocol or interpretation of results or that could increase risk to the patient, including 
renal disease that would preclude chemotherapy administration or pulmonary disease 
(including obstructive pulmonary disease and history of bronchospasm) 
•  Significant cardiovascular disease (such as New York Heart Association Class III or IV 
cardiac disease, congestive heart failure, myocardial infarction within the past 6 months, 
unstable arrhythmias, or unstable angina) or significant pulmonary disease 
(including obstructive pulmonary disease and history of bronchospasm) 
•  Left ventricular ejection fraction <
 50% as defined by multiple-gated acquisition (MUGA).  
Echocardiogram may be used if MUGA is not available. 
•  Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment, or any major episode of infection 
requiring treatment with IV antibiotics or hospitalization (relating to the completion of the 
course of antibiotics) within 4 weeks prior to Cycle 1 Day 1 
•  Received the following agents within 7 days prior to the first dose of venetoclax: 
Steroid therapy for anti-neoplastic intent within 7 days prior to Cycle 1 Day 1.  
Strong and moderate CYP3A inhibitors  
Strong and moderate CYP3A inducers  
Consumed grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or star fruit within 3 days prior to the first dose of 
venetoclax. 
• Clinically significant history of liver disease, including viral or other hepatitis, current alcohol 
abuse, or cirrhosis 
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Appendix 1   
Protocol Synopsis (Study GO27878) (cont.) 
•  Presence of positive test results for hepatitis B (HBcAb) or hepatitis C (hepatitis C virus 
[HCV] antibody  
Patients who are positive for HCV antibody must be negative for HCV by polymerase 
chain reaction (PCR) to be eligible for study participation 
Patients with occult or prior hepatitis B virus (HBV) infection (defined as positive total 
HBcAb and negative hepatitis B surface antigen [HBsAg]) may be included if HBV DNA 
is undetectable.  These patients must be willing to undergo monthly DNA testing. 
•  Known infection with HIV or human T-cell leukemia virus 1 
•  Women who are pregnant or lactating 
•  Recent major surgery (within 6 weeks prior to the start of Cycle 1 Day 1), other than for 
diagnosis 
•  Any of the following abnormal laboratory values: 
Calculated estimated creatinine clearance (CRCL) <
 50 mL/min with the use of the 
24-hour creatinine clearance or modified Cockcroft-Gault equation (with the use of 
ideal body mass [IBM] instead of mass): 
(140−Age) ×
 IBM (kg)
 ×
 [0.85 if female] 
CRCL =
  
72 • serum creatinine (mg/dL) 
Or, if serum creatinine is in μmol/L: 
 
(140−Age) ×
 IBM (kg)
 ×
 [1.23 if male, 1.04 if female] 
CRCL =
  
serum creatinine (μmol/L) 
 
AST or ALT >
 2.5
 ×
 ULN (unless due to disease involvement; Medical Monitor to be 
consulted prior to enrollment)
Total bilirubin ≥
 1.5
 ×
 ULN (or >
 3
 ×
 ULN for patients with documented Gilbert syndrome) 
INR >
 1.5
 ×
 ULN for patients not receiving therapeutic anticoagulation 
PTT or aPTT >
 1.5
 ×
 ULN 
 
Length of Study 
The length of study will be the time from screening of the first patient through 2 years following 
completion of study treatment of the last patients enrolled.  This time is expected to be 
approximately 60 months. 
End of Study 
The end of study will be defined as 2 years following completion of treatment of the last patient 
enrolled. 
Outcome Measures 
Efficacy Outcome Measures  
The following activity outcome measures will be assessed: 
• Primary outcome measures: 
CR, as defined by PET-CT scan as well as bone marrow examination when applicable 
•  Secondary outcome measures: 
  
CR, as defined by CT scan and bone marrow examination, when applicable 
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Appendix 1   
Protocol Synopsis (Study GO27878) (cont.) 
  
OR, defined as a PR or CR 
DOR, defined as the first occurrence of a documented response until the time of 
relapse or death from any cause 
PFS, defined as the time from date of first dose of study drug to the first occurrence of 
progression, relapse, or death while in the study, where death while in the study is 
defined as death from any cause within 12 weeks of the last tumor assessment  
  
PFS at 12 months 
  
Relative dose intensity 
OS, defined as the time from date of first dose of study drug until the date of death 
from any cause.  For patients who have not died, survival data will be censored at the 
date of last contact. 
 
OR and disease progression will be determined with use of the modified Lugano Classification:  
Revised Criteria for Response Assessment. 
Safety Outcome Measures  
The safety and tolerability of the combination of venetoclax plus R-CHOP or G-CHOP will be 
assessed using the following primary safety outcome measure: 
•  Incidence and nature of combination dose-limiting toxicity (DLTs) 
 
In addition, safety will be assessed using the following secondary safety outcome measures: 
•  Incidence, nature, and severity of adverse events and serious adverse events graded 
according to National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0 (NCI CTCAE v4.0).  Adverse events of special interest include Grade 4 
neutropenic fever, Grade ≥
 3 infusion-related reactions (IRR) to rituximab or obinutuzumab, 
and Grade ≥
 4 tumor lysis syndrome (TLS). 
•  Change in clinical laboratory test results (including hematology and chemistry) and vital 
signs 
•  Maintenance of relative dose intensity of CHOP chemotherapy 
 
Pharmacokinetic Outcome Measures  
The following PK parameters will be derived from the plasma concentration-time profile of 
prednisone, venetoclax, and relevant metabolites following administration when appropriate, as 
data allow: 
•  Total plasma exposure (AUC) 
•  Time to maximum observed plasma concentration (t
max) 
•  Maximum plasma concentration observed in plasma (C
max) 
•  Minimum plasma concentration under steady-state conditions within a dosing interval (C
min) 
in plasma 
 
The following PK parameters will be determined from the concentration-time profiles of 
rituximab, obinutuzumab, and cyclophosphamide, vincristine, and doxorubicin (CHO) 
components, as applicable: 
• C
max in serum or plasma, as appropriate 
• C
min in serum or plasma, as appropriate 
 
Other PK parameters such as clearance, volume of distribution (V), and half-life may also be 
calculated as data allow. 
Venetoclax—F. Hoffmann-La Roche Ltd 
33/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 1   
Protocol Synopsis (Study GO27878) (cont.) 
Exploratory Outcome Measures 
The following correlative biology measures will be assessed: 
• BCL-2 high (BCL-2 positive) as defined by IHC and BCL-2 family protein expression by 
immunohistochemistry (IHC) 
• BCL2 and c-MYC copy number gain by FISH and translocation t(14;18) by FISH 
•  Expression of transcripts for BCL-2 family members, other apoptotic genes, and genes 
associated with the activated B cell-like (ABC) or germinal center B cell-like (GCB) subtypes 
of DLBCL 
•  Subgroups relevant to DLBCL biology, including CD79b, Myd88, CARD11, TNFAIP3, 
epigenetic markers, and MYC translocation 
 
Investigational Medicinal Products 
The Investigational Medicinal Products used in this study are venetoclax, rituximab, and 
obinutuzumab (GA101).  
 
Venetoclax 
The venetoclax tablets will be packaged in high-density polyethylene plastic bottles to 
accommodate the study design.  Each bottle will be labeled per local regulatory requirements.  
A desiccant canister may be included in the bottle.  The tablets must be stored at 15°C−25°C 
(59°F−77°F).  If supplied with a desiccant, the desiccant canister should be returned to the 
bottle directly after each tablet removal. 
Study patients will self-administer venetoclax tablets by mouth once daily (QD).  Each dose of 
venetoclax will be taken with approximately 240 mL of water within 30 minutes after the 
completion of breakfast or the patient
's first meal of the day.  A meal containing approximately 
30% of the total caloric content from fat is recommended to ensure adequate absorption of 
venetoclax.  On days that pre-dose PK sampling is required, the patient’s first meal of the day 
(e.g., breakfast) will be consumed in the morning at the clinic, and venetoclax dosing will occur 
in the clinic after completion the meal to facilitate PK sampling. 
On days when venetoclax plus R-CHOP or G-CHOP are given, the order of study treatment 
administration will be venetoclax prior to rituximab or obinutuzumab, and rituximab or 
obinutuzumab prior to CHOP (with the exception of the first dose of prednisone in each cycle).  
On days when both venetoclax and prednisone are given, venetoclax will be taken prior to 
prednisone.  If vomiting occurs within 15 minutes after taking venetoclax and all expelled tablets 
are still intact, another dose may be given and the second dose noted in the drug log.  
Otherwise, no replacement dose is to be given.  In cases where a dose of venetoclax is missed 
or forgotten, the patient should take the dose as soon as possible and ensure that the minimal 
interval between the current dose and the next dose is at least 16 hours in order to avoid 
excessive drug accumulation after the next dose.  Patients will be instructed to record the date 
and time they take their daily dose of venetoclax and prednisone.  Diaries will be provided by 
the Sponsor for this purpose.  Venetoclax must be stored according to labeled storage 
conditions. 
All patients must receive prophylaxis for TLS prior to the initiation of venetoclax plus R-CHOP or 
G-CHOP study treatment. 
Rituximab 
Rituximab (Rituxan®/MabThera
®) is a sterile, clear, colorless, preservative-free liquid 
concentrate for intravenous (IV) administration.  Rituximab is supplied at a concentration of 
10 mg/mL in 100-mg (10 mL) and 500-mg (50 mL) single-use vials.  The product is formulated 
for IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, and 
0.7 mg/mL polysorbate 80, after reconstitution with Sterile Water for Injection.  The pH is 
adjusted to 6.5.  Vials are for single use.  Each vial and carton will contain a label (either 
single-panel or booklet) affixed to the vial or carton per individual country requirements. 
Venetoclax—F. Hoffmann-La Roche Ltd 
34/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 1   
Protocol Synopsis (Study GO27878) (cont.) 
Rituximab will be administered intravenously once per 21-day cycle in combination with CHOP 
for up to six cycles and as a single agent for two additional cycles.  Patients who experience 
ongoing response without excessive toxicity may receive up to eight cycles of CHOP following 
discussion between the investigator and the Medical Monitor.  The infusion of 375 mg/m2 will be 
based on the patient’s body surface area (BSA) at screening and will remain the same 
throughout the study unless there is a >
 10% change in body weight.  On a given day, rituximab 
should be given after venetoclax and prior to CHOP (with the exception of the first dose of 
prednisone in each cycle). 
Rituximab should not be administered as an IV push or bolus.  IRRs may occur.  Premedication 
consisting of acetaminophen, diphenhydramine (or other suitable antihistamine), and a single 
dose of hydrocortisone (up to 100 mg or an equivalent dose of methylprednisolone) may also be 
administered beginning with the first infusion.  Premedication may attenuate IRRs.  Because 
transient hypotension may occur during rituximab infusion, consideration should be given to 
withholding antihypertensive medications for 12 hours prior to rituximab infusion. 
There will be no rituximab dose modification in this study.  Patients who are at high risk for IRR 
or TLS complications may, at the investigator’s discretion, receive their initial dose of rituximab 
split over 2 consecutive days (e.g., 125 mg/m2 on Cycle 1 Day 1, 250 mg/m
2 on Cycle 1 Day 2). 
If the patient tolerates the first infusion well, subsequent rituximab infusions may be 
administered at an initial rate of 100 mg/hr and increased in 100-mg/hr increments at 30-minute 
intervals to a maximum of 400 mg/hr, as tolerated or per an institution’s standard of care IV 
administration procedure. 
Any NCI CTCAE v4.0 toxicity Grade ≥
 3 in severity that is deemed related to rituximab treatment 
will require interruption of study treatment until resolution to Grade ≤
 1.  Resumption of rituximab 
treatment may be considered in patients with resolution of toxicities to Grade ≤
 2 within 3 weeks 
at the discretion of the investigator after consultation with the study Medical Monitor.  Failure of 
such toxicities to resolve after 3 weeks of suspended study treatment will require permanent 
discontinuation of rituximab. 
Patients who discontinue rituximab because of rituximab-related toxicity may continue to receive 
CHOP and/or venetoclax only after consultation by the investigator with the Medical Monitor. 
Obinutuzumab 
Obinutuzumab is provided as a single-dose, sterile liquid formulation in a 50 mL 
pharmaceutical-grade glass vial containing a nominal 1000 mg of obinutuzumab (G3 material).  
The formulated drug product consists of 25 mg/mL drug substance (G3) formulated in histidine, 
trehalose, and poloxamer 188.  The vial contains 41 mL (with 2.5% overfill). 
The recommended storage conditions for the obinutuzumab drug product are between 2°C and 
8°C and protect from light.  Chemical and physical in-use stability for obinutuzumab dilutions in 
0.9% sodium chloride (NaCl) has been demonstrated for 24 hours at 2°C−8°C and at ambient 
temperature and ambient room lighting.  The prepared diluted product should be used 
immediately.  If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user and would normally not be longer than 24 hours at 2°C−8°C.  
Obinutuzumab should not be frozen or shaken.  Mix gently.  All transfer procedures require 
strict compliance with aseptic techniques.  Do not use an additional in-line filter; this will avoid 
potential adsorption. 
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose of 1000 mg in 
combination with CHOP for up to six cycles and as a single agent for two additional cycles.  
Patients who experience ongoing response without excessive toxicity may receive up to 
eight cycles of CHOP following discussion between the investigator and the Medical Monitor.  
On a given day, obinutuzumab should be given after venetoclax and prior to CHOP (with the 
exception of the first dose of prednisone in each cycle), and patients should be observed for 
30 minutes prior to starting CHOP.  Patients at high risk for IRR or TLS complications may, at 
the investigator’s discretion, receive their obinutuzumab dose split over 2 consecutive days 
Venetoclax—F. Hoffmann-La Roche Ltd 
35/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 1   
Protocol Synopsis (Study GO27878) (cont.) 
(e.g., 100 mg on Day 1, 900 mg on Day 2).  During Cycle 1, obinutuzumab will also be 
administered on Days 8 and 15. 
Non-Investigational Medicinal Products 
CHOP Chemotherapy 
CHOP chemotherapy consists of IV cyclophosphamide, IV doxorubicin, vincristine administered 
by IV push, and oral prednisone or prednisolone.  Standard CHOP will be administered for 
six 21-day cycles.  Patients who experience ongoing response without excessive toxicity may 
receive up to eight cycles of CHOP following discussion between the investigator and the 
Medical Monitor. 
•  Cyclophosphamide 750 mg/m
2 administered intravenously on Day 1 
•  Doxorubicin 50 mg/m
2 administered intravenously on Day 1 
•  Vincristine 1.4 mg/m
2 administered by IV push on Day 1 with a cap of 2.0 mg 
•  Prednisone 100 mg/day orally (PO) on Days 1−5 
 
Permitted Concomitant Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by a patient from 7 days prior to 
screening through 30 days after the last dose of venetoclax or CHOP, or 90 days after the last 
dose of rituximab or obinutuzumab, whichever is later.  All concomitant medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.  
Patients who are receiving oral contraceptives, stable doses of hormone replacement therapy, 
or other maintenance therapy should continue their use. 
Steroid use not otherwise dictated by the protocol CHOP treatment will follow the guidelines 
outlined below: 
• Corticosteroid  
use  >
 30 mg/day of prednisone or equivalent:  Not allowed within 7 days prior 
to Cycle 1 Day 1 except as specified below 
•  Corticosteroid use 15−30 mg/day of prednisone or equivalent:  Must be documented to be 
on a stable dose of at least 4 weeks’ duration prior to first dose of study drug. 
• Corticosteroid  
use  <
 15 mg/day of prednisone or equivalent:  Allowed 
 
Exceptions to the above guidelines: 
•  Corticosteroid used for malignancy-related symptom control (up to 100 mg/day of 
prednisone or equivalent) prior to initiation of study treatment.  Once study treatment has 
been given, corticosteroid use may be tapered down (must be ≤ pre-study treatment dose) 
for no more than 5 days. 
•  Premedication for rituximab or obinutuzumab infusions, as indicated per protocol and/or site 
local practice (may replace dose of CHOP prednisone) 
•  Inhaled corticosteroids for the treatment of asthma or chronic obstructive pulmonary 
disease 
• Topical  
ster oids  
•  Replacement corticosteroid therapy for an inherited or acquired deficiency 
•  Steroid use to treat emergent issues not related to anti-neoplastic intent is allowed for no 
more than 7 days per event.  For steroid treatment >
 7 days, the Medical Monitor must be 
consulted to discuss allowing the patient to continue treatment. 
 
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36/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 1   
Protocol Synopsis (Study GO27878) (cont.) 
Excluded Therapy 
Patients who are discontinued from study treatment will be followed for safety outcomes for 
30 days following the patient’s last dose of venetoclax or CHOP (or 90 days following the 
patient’s last dose of rituximab or obinutuzumab, whichever is later) or until the patient receives 
another anti-cancer therapy, whichever occurs first. 
Use of the following therapies is prohibited during the study: 
•  Cytotoxic chemotherapy.  Supplemental systemic therapy for prophylaxis of CNS disease is 
permitted according to institutional practice only after primary response assessment and 
must be recorded in the eCRF. 
•  Radiotherapy prior to primary response assessment 
• Immunotherapy  
• Hormone therapy (other than contraceptives, hormone replacement therapy, or megestrol 
acetate) 
•  Any therapies intended for the treatment of lymphoma/leukemia whether U.S. Food and 
Drug Administration (FDA) approved or experimental (outside of this study) 
•  Warfarin may be co-administered with venetoclax with caution and with the guidance of the 
Medical Monitor. 
 
The following concomitant medications are not allowed from 7 days prior to the first dose of 
study drug and during venetoclax administration: 
• Corticosteroid  
use  >
 30 mg/day of prednisone or equivalent (with some exceptions). 
•  Strong and moderate CYP3A4 inducers 
 
The following concomitant medications are not allowed from 7 days prior to the administration of 
the first dose of study drug:   
•  Strong and moderate CYP3A inhibitors 
•  Strong and Moderate CYP3A inducers  
 
Exclude strong and moderate CYP3A inhibitors through the DLT assessment period and 
consider alternative medications.  If a patient requires use of these medications while he or she 
is receiving the target dose of venetoclax, once the DLT assessment period is complete, use 
with caution and reduce the venetoclax dose by 2-fold for moderate inhibitors and 4-fold for 
strong inhibitors during co-administration. 
After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax dose is increased 
back to the initial maintenance/target dose. 
•  Exclude strong and moderate CYP3A inducers through the DLT assessment period and 
consider alternative medications.  If a patient requires use of these medications while he or 
she is receiving the target dose of venetoclax, once the DLT assessment is complete, use 
with caution and contact the Medical Monitor for guidance. 
 
Statistical Methods 
Primary Analysis 
The final analysis will be based on patient data collected through study discontinuation.  
Analyses will be based on treated patients (i.e., patients who have received any amount of 
R/G-CHOP or venetoclax).  Analyses will be provided separately for the dose-finding and 
extension cohorts where appropriate.  Data from patients who receive R-CHOP or G-CHOP 
only (i.e., have not received any venetoclax), will be summarized separately. 
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37/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 1   
Protocol Synopsis (Study GO27878) (cont.) 
Determination of Sample Size 
The sample size for the dose-finding stage is based on a modified 3 +
 3 design in order to guide 
dose and schedule selection for the Phase II portion on the basis of DLTs.  The expected 
enrollment for the dose-finding stage is 3−6 patients per dose level in each of the 
R-CHOP +
 venetoclax and G-CHOP
 +
 venetoclax arms. 
The sample size for the R-CHOP +
 venetoclax arm in Phase II is based on obtaining a sufficient 
number for estimation of PET-negative CR rate in patients with DE (BCL-2 and c-MYC 
co-expressing) DLBCL, overall, for BCL-2 high patients, and within each of four mutually 
exclusive biological subgroups:  BCL-2 high and ABC, BCL-2 high and GCB, BCL-2 low and 
ABC, and BCL-2 low and GCB.  The expected enrollment for the R-CHOP +
 venetoclax arm in 
Phase II is approximately 160−200 patients in order to enroll approximately 50 DE-DLBCL 
patients, approximately 80−100 BCL-2 high patients, and approximately 40−50 patients in each 
of the two BCL-2 high subgroups.  With 50 patients, 95% confidence intervals for estimation of 
CR would have a margin of error not exceeding 16%.  The margin of error would decrease to 
9% with 150 patients and to 8% with 200 patients. 
 
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Appendix 2   
Protocol Synopsis (Study BO21005) 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, MULTICENTER, OPEN-LABEL, 
RANDOMIZED TRIAL COMPARING THE EFFICACY OF 
GA101 (RO5072759) IN COMBINATION WITH CHOP 
(G-CHOP) VERSUS RITUXIMAB AND CHOP (R-CHOP) IN 
PREVIOUSLY UNTREATED PATIENTS WITH 
CD20-POSITIVE DIFFUSE LARGE B-CELL LYMPHOMA 
(DLBCL) 
PROTOCOL NUMBER: 
BO21005 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2010-024194-39 
STUDY DRUG: 
Obinutuzumab (GA101, RO5072759) 
PHASE: 
III 
INDICATION: 
CD20-Positive Diffuse Large B-Cell Lymphoma 
IND NUMBER: 
104405 
SPONSOR: 
Genentech, Inc. (U.S.) 
F. Hoffmann-La Roche, Ltd (ex-U.S.) 
Objectives 
Primary Objective 
The primary objective of this study is to demonstrate superiority in progression-free survival 
(PFS) with obinutuzumab plus chemotherapy (G-CHOP) compared with rituximab plus 
chemotherapy (R-CHOP) in previously untreated patients with CD20-positive diffuse large B-cell 
lymphoma (DLBCL), based on investigator-assessed PFS. 
Secondary Objectives 
The secondary objectives of this study are as follows: 
• To evaluate and compare overall survival (OS) between the two arms treated with the 
combination of G-CHOP or R-CHOP 
•  To evaluate and compare the overall response rate and complete response (CR) rate after 
the end of treatment between the two arms, as assessed by the investigator, with and 
without 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) 
•  To evaluate and compare PFS between the two arms, as assessed by the Independent 
Review Committee (IRC) 
•  To evaluate and compare the overall response rate and CR rate based on the IRC 
assessment after the end of treatment between the two arms, with and without FDG-PET 
•  To evaluate and compare event-free survival (EFS) between the two arms, as assessed by 
the investigator  
•  To evaluate and compare disease-free survival (DFS), duration of response (DOR), and 
time to next anti-lymphoma treatment (TTNALT) between the two arms 
Venetoclax—F. Hoffmann-La Roche Ltd 
39/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 2   
Protocol Synopsis (Study BO21005) (cont.) 
•  The DFS and DOR will be based on the investigator’s assessment. 
•  To evaluate and compare the safety profiles of patients treated with the combination of 
G-CHOP or R-CHOP 
•  To assess patient-reported outcomes (PROs) in both arms  
•  To evaluate medical resource utilization in both arms  
• For Japanese patients only:  to characterize the pharmacokinetics of obinutuzumab in 
combination with CHOP 
 
Study Design 
This is a Phase III, multicenter, open-label, randomized trial comparing the efficacy of G-CHOP 
versus R-CHOP in previously untreated patients with CD20-positive DLBCL.  Approximately 
1400 patients from approximately 300 centers in 30–40 countries will receive eight 21-day 
cycles of obinutuzumab or rituximab combined with six or eight cycles of standard CHOP 
chemotherapy.  Patients randomized to the obinutuzumab arm will receive an additional two 
doses on Days 8 and 15 of Cycle 1.  This will allow all patients to achieve trough levels of 300–
600 μg/mL. 
Centers must choose prior to study start whether they plan to administer six or eight cycles of 
CHOP chemotherapy.  This will allow for stratification by the number of planned chemotherapy 
cycles. 
Patients will be randomized in a 1:1 ratio to receive G-CHOP or R-CHOP, with patients stratified 
on the basis of the number of planned chemotherapy cycles (6 vs. 8 cycles of CHOP), 
International Prognostic Index (IPI) score (low/low−intermediate [excluding patients with an IPI 
score of 0 without bulky disease], high-intermediate, or high-risk), and region (Western Europe, 
Eastern Europe, South and Central America, North America, Asia, and others).  The control arm 
of the study will receive standard of care treatment with R-CHOP.  No crossover to the 
experimental arm is allowed.  
Patients will be assessed for disease response by the investigator using regular clinical and 
laboratory examinations and computed tomography (CT) scans, according to a modified version 
of the Revised Response Criteria for Malignant Lymphoma.  Best response will be evaluated at 
the end of eight cycles of obinutuzumab or rituximab, or sooner in the event that a patient 
discontinues early.  In patients for whom FDG-PET scans are obtained (FDG-PET scans are 
mandatory at sites where a PET scanner is available), a separate response assessment will 
incorporate FDG-PET scan results.   
After completion of therapy, all patients will be followed at clinic visits conducted every 3 months 
for 2 years, then every 6 months until Month 60, and then annually; after 5 years, patients will 
be followed by telephone contact until the end of the study, which is estimated to be 
approximately 78 months after the first patient is enrolled (for the list of study assessments, see 
Appendices A-1 and A-2).  At each visit up to the Year 5, Month 60 assessment (or until disease 
progression if it occurs before 5 years), assessments will include physical examination, 
standard hematologic and biochemistry assessments, vital signs, weight, liver and spleen size, 
and B-symptoms (e.g., weight loss, night sweats, or fever).  After 5 years, patients will be 
followed only for survival and initiation of a new anti-lymphoma therapy by telephone contact 
until study termination or consent withdrawal by patient.  After disease progression, patients will 
be followed for survival only (by telephone contact) and for applicable adverse event reporting, 
initiation of a new anti-lymphoma therapy, and two PRO assessments. 
Patients who terminate study treatment early without progressive disease (PD) will complete 
their Early Study Treatment Termination visit and then will be followed until disease progression 
and survival as per Appendix A-2 for progression new anti-lymphoma therapy, and overall 
survival. 
Patients who discontinue the protocol-defined treatment and need to start a new anti-lymphoma 
therapy (NALT) in the absence of disease progression (e.g., if wrong diagnosis at screening and 
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40/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 2   
Protocol Synopsis (Study BO21005) (cont.) 
new diagnosis requires a change of treatment) will be followed for disease progression and 
survival. 
Patients who terminate study treatment early because of PD will go into the follow-up per 
Appendix A-2 schedule and will be followed for new anti-lymphoma therapy and overall survival.   
CT scans will be obtained at baseline and after Cycles 4 and 8 of study treatment.  During the 
follow-up period, CT scans will be performed every 3 months (i.e., Months 3, 6, 9, 12, 15, 18, 21, 
and 24) until the end of Year 2 of follow-up (2.5 years after the first dose) in accordance with 
study (clinic) visits and will include the neck (if involved at baseline), chest, abdomen, and pelvis.  
During Years 3 and 4 of follow-up, CT scans will only be obtained of sites with prior involvement 
and will be repeated every 6 months (at Months 30, 36, 42, and 48) and again at Year 5, Month 
60 of follow-up.  If disease in other areas is suspected, additional areas should be imaged.  
FDG-PET scans (which are mandatory at sites where a PET scanner is available) will be 
performed at screening and 6-8 weeks after the last study treatment. 
Safety will be evaluated by monitoring all adverse events, serious adverse events, and 
abnormalities identified through physical examinations, vital signs, and laboratory assessments.  
Such events will be graded using the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE, Version 4.0).  Laboratory safety assessments will include 
routine monitoring of hematology and blood chemistry, and tests of immunologic parameters.  In 
addition, tests for the presence of human anti–human antibodies (HAHAs) will be performed for 
a subset of 100 patients treated in the G-CHOP arm.  
For a subset of Japanese patients only, samples for assessment of serum obinutuzumab 
concentrations will be collected from up to 40 patients enrolled and treated with G-CHOP.  
PK analysis of obinutuzumab will be performed to compare PK profiles between Japanese 
patients and non-Japanese patients on the basis of historical data. 
Outcome Measures 
Primary Efficacy Outcome Measure 
The primary endpoint of this study is investigator-assessed PFS, which is defined as the time 
from randomization to the first occurrence of progression or relapse, using a modified version of 
the Revised Response Criteria for Malignant Lymphoma, or death from any cause.   
While the primary efficacy endpoint is investigator-assessed PFS, PFS based on IRC 
assessment will also be analyzed to support the primary analysis.  In the United States, IRC-
assessed PFS will be the basis for regulatory decisions. 
Secondary Outcome Measures 
Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
•  Overall survival, defined as the time from the date of randomization to the date of death 
from any cause.  Overall survival for patients who are not reported to have died at the time 
of the analysis will be censored at the date at which the patient was last known to be alive, 
as documented by the investigator. 
•  Event-free survival (EFS), defined as the time from randomization to disease progression or 
relapse, death from any cause, as assessed by the investigator, or initiation of any NALT.  If 
the specified event (disease progression or relapse, death, initiation of an NALT) does not 
occur, EFS will be censored at the date of last tumor assessment.  For patients without an 
event who have not had post-baseline tumor assessments, EFS will be censored at the 
time of randomization. 
•  Overall response rate (ORR) at the end of treatment, as assessed by the investigator, with 
and without FDG-PET.  The overall response rate is defined as the percentage of patients 
with CR or partial response (PR) at the end of treatment.  All other cases are designated 
non-responders. 
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Appendix 2   
Protocol Synopsis (Study BO21005) (cont.) 
•  CR rate at the end of treatment, defined as the percentage of patients with CR at the end of 
treatment, as assessed by the investigator, with and without FDG-PET. 
•  Overall response (CR or PR) at the end of the treatment, as assessed by the IRC, with and 
without FDG-PET 
•  CR at the end of the treatment, as assessed by the IRC, with and without FDG-PET 
•  Disease-free survival (DFS), defined as the time from the date of the first occurrence of a 
documented CR to the date of disease progression, relapse or death from any cause (PFS), 
as assessed by the investigator, for the subgroup of patients with a best overall response 
(BOR) of CR.  Patients who have had no documented disease progression, relapse, or 
have not died after CR, will be censored at the last disease assessment date. 
•  Duration of response (DOR), defined as the time from the date of the first occurrence of a 
documented CR or PR to the date of disease progression, relapse or death from any cause 
(PFS), as assessed by the investigator for the subgroup of patients with a BOR of CR or PR.  
For patients achieving a response who have not experienced disease progression, relapse, 
or died prior to the time of the analysis, the duration of response will be censored on the 
date of last disease assessment. 
•  Time to next anti-lymphoma treatment (TTNALT) is defined as the time from the date of 
randomization to the start date of the next anti-lymphoma treatment or death from any 
cause.  For patients who have not received the next anti-lymphoma treatment or have died 
prior to the time of analysis, TTNALT will be censored at the date at which the patient was 
last known to be alive without having received NALT. 
•  Medical resource utilization, including the number of hospitalizations, length of hospital stay, 
types of subsequent drug therapies, and medical and surgical procedures and treatments 
(i.e., blood transfusions, bone marrow transplantation, or stem-cell transplantation) 
 
Safety Outcome Measures 
The safety and tolerability of obinutuzumab in combination with CHOP will be assessed using 
the following primary safety outcome measures: 
•  Incidence, nature, and severity of adverse events and serious adverse events with G-CHOP 
versus R-CHOP administration 
•  Changes in vital signs, physical findings, and clinical laboratory test results during and 
following study treatment administration 
•  Incidence of HAHAs in the first 100 patients treated in the G-CHOP arm 
 
Patient-Reported Outcome Measures 
The quality-of-life measures that will be used to evaluate PROs are as follows: 
•  Change from baseline in health-related PROs to the end of study, as assessed using the 
Functional Assessment of Cancer Therapy–Lymphoma subscale 
•  Descriptive results of the Euro–Quality of Life 5D data during different periods of the study 
•  Change from baseline in each of the 14 domains of the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-
C30) 
 
Pharmacokinetic Outcome Measures (for a Subset of Japanese Patients Only) 
The PK outcome measure for this study is as follows: 
•  PK profile (i.e., plasma concentration−time profiles, pre-dose trough concentrations, and 
clearance rates) of obinutuzumab in the G-CHOP arm 
 
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Appendix 2   
Protocol Synopsis (Study BO21005) (cont.) 
Safety Plan 
This trial is designed to allow for early termination or a modification of the protocol for safety 
concerns, based on the advice of an independent data monitoring committee (IDMC) for safety 
or futility concerns.  The IDMC will be incorporated into the study to review safety data, 
including adverse events of special interest, on a regular basis.  In addition, the dose intensity of 
the CHOP chemotherapy regimen will be included as part of the safety monitoring.  The IDMC 
will meet 1 month after the first patient is enrolled and then approximately every 2 months until 
100 patients have completed two cycles of immunochemotherapy (with approximately 
50 patients in each arm).  Thereafter, the IDMC will meet approximately every 6 months until 
the interim analysis and subsequently at a frequency determined by the IDMC and the Sponsor.  
Both the Sponsor and the IDMC can request ad-hoc meetings for any reason.  Following each 
meeting, the IDMC will recommend to the Sponsor whether the study should continue according 
to the protocol or may suggest changes to the protocol based on the outcome of data review.  In 
exceptional cases, the IDMC may recommend stopping the study for safety reasons.  The 
Sponsor will make the final decision for continuation or discontinuation of the study on the basis 
of the IDMC’s recommendation.   
In addition, the IDMC will meet to review the efficacy and safety data from two formal event-
driven interim futility and efficacy analyses during the study. 
Risks Associated with Obinutuzumab Therapy 
To date, the commonly experienced infusion-related reactions (IRRs) have been characterized 
by fever, chills, flushing, nausea, vomiting, hypotension, hypertension, and fatigue, as well as 
other symptoms. 
Respiratory infusion-related symptoms, such as hypoxia, dyspnea, bronchospasm, larynx and 
throat irritation, and laryngeal edema, have also been reported.  These IRRs were mostly mild 
or moderate (NCI CTCAE, v3.0, Grade 1 and 2 events), and < 10% of the events were severe 
(Grade 3 events), occurring predominantly during the first hour of the infusion or shortly after the 
first infusion had finished; the events resolved with slowing or interruption of the infusion and 
supportive care.  The incidence and severity of IRRs decreased with subsequent infusions.  
Extensive tumor burden predominantly localized in the blood circulation (e.g., high peripheral 
lymphocyte count in patients with chronic lymphocytic leukemia [CLL]) may be a predisposing 
factor for the development of IRRs. 
Cases of tumor lysis syndrome have been reported with obinutuzumab administration.  To date, 
no patient has required hemodialysis for renal failure.  Patients with a high tumor burden, 
including patients with a lymphocyte count ≥ 25 × 109/L (particularly patients with B-cell CLL and 
mantle cell lymphoma), are at increased risk for tumor lysis syndrome and severe IRRs.  
Cases of Grade 3 or 4 neutropenia, including febrile neutropenia, have been reported with 
obinutuzumab administration.  Grade 3 or 4 neutropenia has predominantly been observed in 
patients with CLL.  Patients who experience Grade 3 or 4 neutropenia should be monitored until 
neutrophil values return to at least Grade 2.  Use of granulocyte colony-stimulating factors (G-
CSF) has been found to result in a rapid normalization of neutrophils, similar to what has been 
observed in patients treated with rituximab.  The use of G-CSF is allowed for treatment of 
neutropenia in this study.  Primary prophylaxis with G-CSF is recommended according to the 
American Society of Clinical Oncology (ASCO), EORTC, and European Society for Medical 
Oncology (ESMO) guidelines, namely for patients who are ≥ 60 years old and/or with 
co-morbidities.  The use of G-CSF is strongly recommended in Cycle 1 for all patients treated 
with G-CHOP. 
Severe and life threatening thrombocytopenia including acute thrombocytopenia (occurring 
within 24 hours after the infusion) has been observed during treatment with obinutuzumab.  
Fatal hemorrhagic events have also been reported in patients treated with obinutuzumab.  
Based on the available evidence to date the greatest risk of hemorrhage in 
obinutuzumab-treated patients is observed in the first cycle.  A clear relationship between 
thrombocytopenia and hemorrhagic events has not been established.  Patients treated with 
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43/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 2   
Protocol Synopsis (Study BO21005) (cont.) 
concomitant medication, which could possibly worsen thrombocytopenia-related events such as 
platelet inhibitors and anticoagulants, may be at greater risk of bleeding.  Patients should be 
closely monitored for thrombocytopenia, especially during the first cycle; regular laboratory tests 
should be performed until the event resolves, and dose delays should be considered in case of 
severe or life-threatening thrombocytopenia.  Transfusion of blood products (i.e., platelet 
transfusion) according to institutional practice is at the discretion of the treating physician. 
Based on its anticipated mode of action, resulting in profound B-cell depletion, obinutuzumab 
may be associated with an increased risk of infections.  Infections have been reported in 
patients receiving obinutuzumab.  Therefore, obinutuzumab should not be administered to 
patients with active severe infections.  
Reactivation of hepatitis B as well as other serious viral infections (e.g., infections caused by 
cytomegalovirus, Varicella zoster virus, herpes simplex virus, John Cunningham virus (JCV), 
and hepatitis C virus) that were new, reactivation, or exacerbation, have been reported with the 
B cell−depleting antibody rituximab mainly in patients who had received the drug in combination 
with chemotherapy or as part of a hematopoietic stem-cell transplant.  The risk of such 
infections with obinutuzumab is unknown.  Particular attention should be given to patients who 
have previously received significant immunosuppressive treatment such as high-dose 
chemotherapy and stem-cell transplant.   
Cases (including fatal) of JCV infection that resulted in progressive multifocal 
leukoencephalopathy (PML, destructive infection of oligodendrocytes of the CNS white matter) 
have been reported in patients treated with anti-CD20 therapies, including rituximab and GA101. 
The diagnosis of PML should be considered in any patient presenting with new-onset neurologic 
manifestations.  The symptoms of PML are very unspecific and can vary depending on the 
affected region of the brain.  Motor involvement with corticospinal tract findings, sensory 
involvement, cerebellar deficits, and visual field defects are common.  Some syndromes 
regarded as “cortical” (e.g., aphasia or visual-spatial disorientation) can occur.  
Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain magnetic 
resonance imaging (MRI), and lumbar puncture to quantify DNA of JCV in the cerebrospinal 
fluid. 
There may also be potential health risks, including hitherto unknown risks derived from 
exposure to obinutuzumab.   
Risks Associated with Rituximab Therapy 
Patients treated with rituximab in combination with chemotherapy are at risk for IRRs.  Fatal 
infusion reactions within 24 hours of rituximab infusion can occur; approximately 80% of fatal 
reactions occurred with the first infusion.  Severe reactions to rituximab typically occurred during 
the first infusion with time to onset of 30–120 minutes.  Rituximab-induced infusion reactions 
and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary 
infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, 
cardiogenic shock, anaphylactoid events, or death.  
Patients may be at risk for tumor lysis syndrome.  With rituximab treatment, acute renal failure, 
hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, 
can occur within 12–24 hours after the first infusion of rituximab in patients with non-Hodgkin’s 
lymphoma.  A high number of circulating malignant cells (≥ 25,000/mm3) or high tumor burden 
confers a greater risk of tumor lysis syndrome.  For patients with evidence of tumor lysis 
syndrome, rituximab should be discontinued and the patient treated as clinically indicated.  
Hepatitis B virus reactivation with fulminant hepatitis, hepatic failure, and death can occur in 
patients with hematologic malignancies treated with rituximab.  The median time to the 
diagnosis of hepatitis was approximately 4 months after the initiation of rituximab treatment and 
approximately 1 month after the last dose. 
Patients with chronic hepatitis B (i.e., hepatitis B surface antigen [HbsAg] positive) viral infection 
are at risk for reactivation and will be excluded from the study.  Patients with evidence of prior 
hepatitis B exposure or who are carriers (defined as HBsAg negative and hepatitis B core 
Venetoclax—F. Hoffmann-La Roche Ltd 
44/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 2   
Protocol Synopsis (Study BO21005) (cont.) 
antibody positive) are at a lower risk for reactivation.  In a study of 51 hepatitis B carriers with 
DLBCL who received rituximab, 12% of patients developed evidence of reactivation.   
Rare cases of PML have also been reported in patients treated with rituximab alone or in 
combination with other immunosuppressive medications.  The diagnosis of PML in any patient 
treated with rituximab is extremely rare but should be suspected in any patient who develops 
new-onset neurologic manifestations.  The majority of patients with hematologic malignancies 
diagnosed with PML received rituximab in combination with chemotherapy or as part of a 
hematopoietic stem-cell transplant.  Most cases of PML were diagnosed within 12 months of the 
patients’ last infusion of rituximab.  
Angina and cardiac arrhythmias have occurred with rituximab treatment and can be life 
threatening.  Treatment with CHOP chemotherapy is a known risk factor for cardiotoxicity, and 
to mitigate this risk, patients will be required to undergo assessments of left ventricular ejection 
fraction at baseline, at the end of Cycle 6, and at the end of treatment. 
Serious infections, including fatal bacterial, fungal, and new or reactivated viral infections, can 
occur during and up to 1 year following the completion of rituximab-based therapy.  New or 
reactivated viral infections include cytomegalovirus, herpes simplex virus, parvovirus B19, 
Varicella zoster virus, West Nile virus, and hepatitis B and C. 
Severe reactions, including fatal mucocutaneous reactions, can occur in patients receiving 
rituximab.  These reactions include paraneoplastic pemphigus, Stevens–Johnson syndrome, 
lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.  The onset of 
these reactions in patients treated with rituximab has varied from 1 to 13 weeks following 
rituximab exposure.  
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, can occur 
in patients receiving rituximab in combination with chemotherapy.  In post-marketing reports of 
rituximab, the mean time to documented gastrointestinal perforation was 6 days (range, 1–77) 
in patients with non-Hodgkin’s lymphoma. 
Risks Associated with CHOP Chemotherapy 
Please refer to prescribing information for doxorubicin, cyclophosphamide, vincristine, and 
prednisone or prednisolone for risks related to CHOP chemotherapy. 
Study Treatment 
Patients will receive treatment with one of two immunochemotherapy regimens: 
• G-CHOP (investigational arm):  CHOP chemotherapy combined with obinutuzumab 
•  R-CHOP (control arm):  CHOP chemotherapy combined with rituximab 
 
In the investigational arm, obinutuzumab will be administered by intravenous (IV) infusion at an 
absolute (flat) dose of 1000 mg on Day 1 of each 21-day cycle for 8 cycles.  During Cycle 1, 
obinutuzumab will also be infused on Days 8 and 15.  Administration of obinutuzumab on days 
when both obinutuzumab and CHOP are to be given should be completed for at least 
30 minutes before chemotherapy administration is started.  
CHOP chemotherapy may be given on the next day after obinutuzumab administration if the 
duration of the obinutuzumab infusion necessitates administration of the CHOP infusion the 
next day.  CHOP chemotherapy will be given for a maximum of 6 or 8 cycles, as described in 
Section 4.5.3.a and Table 5.  If only 6 cycles of CHOP chemotherapy are to be administered, 
Cycles 7 and 8 of obinutuzumab will be given as monotherapy on an every-21-day schedule.   
Rituximab will be administered prior to CHOP.  Once the rituximab infusion is completed, 
patients are to be observed for 30 minutes prior to the start of CHOP administration.  For 
patients who experience an adverse event during a rituximab infusion, administration of 
rituximab and CHOP chemotherapy may be continued on the following day if required.  Empiric 
dose adjustment for obese patients (defined as a body mass index ≥
 30, as measured in 
kilograms per meter squared) may be implemented per institutional guidelines.  There will be no 
dose modification for changes in weight unless a patient
's weight increases or decreases by 
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45/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 2   
Protocol Synopsis (Study BO21005) (cont.) 
>
 10% from his or her weight from screening.  The weight that triggered a dose adjustment will 
be taken as the new reference weight for future dose adjustments. 
CHOP chemotherapy may be administered on the next day if administration of rituximab has 
been split or CHOP cannot be administered on the same day.  If CHOP chemotherapy is not 
given at Cycles 7 and 8, rituximab will be administered as monotherapy. 
For dosage and administration instructions for CHOP chemotherapy, see Section 4.3.4. 
Concomitant Therapy and Clinical Practice 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient between the 7 days preceding the study entry evaluation and the end of study 
visits.  All concomitant medications should be reported to the investigator and recorded on the 
appropriate electronic Case Report Form (eCRF).  Patients who are receiving oral 
contraceptives, hormone-replacement therapy, or other maintenance therapy should continue 
their use. 
Central nervous system prophylaxis should be given according to institutional practice and its 
use documented on the eCRF. 
Patients should be adequately hydrated prior to and after cyclophosphamide administration and 
should be instructed to void frequently.  Mesna may be used as prophylaxis according to 
institutional practice.   
The use of G-CSF is allowed for treatment of neutropenia.  Primary prophylaxis with G-CSF is 
recommended according to ASCO, EORTC, and ESMO guidelines for patients who are 
≥ 60 years old and/or with co-morbidities.  The use of G-CSF prophylaxis is strongly 
recommended in Cycle 1 for all patients treated with G-CHOP. 
Patients in countries where prophylactic anti-viral medications for hepatitis B reactivation are the 
standard of care may be treated prophylactically. 
Pre-planned radiotherapy (i.e., radiation that was planned before randomization to be given at 
the end of study treatment) may be administered to initial sites of bulky or extranodal disease 
according to institutional practice.  If indicated, pre-planned radiotherapy should be 
administered within 8 weeks after the last antibody cycle (Day 1 of the last cycle) and radiation 
should start after all “End of treatment assessments” including complete response assessments 
are completed.  Any radiotherapy should be pre-planned by the center and documented prior to 
randomization and then entered in the eCRF once the patient is randomized.  For patients 
receiving pre-planned irradiation, response assessment will be performed prior to the start of 
radiotherapy.  All unplanned radiotherapy administered to patients at the end of treatment will 
be considered as a new anti-lymphoma treatment. 
Treatment with other concomitant anti-tumor agents not defined in this protocol as study 
treatment, radiotherapy, or other concurrent investigational agents of any type will result in 
withdrawal of patients from study treatment; however, patients will be followed as described in 
Section 4.5.4. 
Use of cytotoxic chemotherapy (other than CHOP), immunotherapy, hormone therapy (other 
than contraceptives, hormone-replacement therapy, or megestrol acetate), any therapies (other 
than intrathecal central nervous system prophylaxis) intended for the treatment of lymphoma 
whether European Medicines Agency or Food and Drug Administration approved or 
experimental (outside of this study), radiotherapy, and pre-phase therapy (with the use of 
chemotherapeutic or anti-lymphoma agents) is prohibited.  Use of prednisone alone with 
maximum dose of 100 mg/day (or equivalent dose of other steroids alone), for ≤
 5 days for 
symptom relief after the staging and radiology assessments are completed and before Cycle 1 
Day 1 is allowed. 
Venetoclax—F. Hoffmann-La Roche Ltd 
46/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 2   
Protocol Synopsis (Study BO21005) (cont.) 
Statistical Methods 
Primary Efficacy Analysis 
The primary analysis population for efficacy is the intent-to-treat population, defined as all 
randomized patients.  Patients will be analyzed according to the treatment arm to which they were 
randomized.   
The primary efficacy endpoint is PFS, as determined by the investigator, defined as the time from 
the date of randomization until the first occurrence of disease progression, relapse, or death from 
any cause.  For patients who have not progressed, relapsed, or died at the time of analysis, PFS 
will be censored on the date of last disease assessment.  If no tumor assessments were 
performed after the baseline visit, PFS will be censored at the time of randomization. 
While the primary efficacy endpoint is investigator-assessed PFS, PFS based on IRC 
assessments will also be analyzed to support the primary analysis.  In the United States, IRC-
assessed PFS will be the basis for regulatory decisions. 
The primary analysis of the study will test the equality of PFS distributions in the 
obinutuzumab
 + CHOP (G-CHOP) and rituximab + CHOP alone (R-CHOP) arms:   
H0:  PFS
G-CHOP = PFSR-CHOP versus H1:  PFS
G-CHOP ≠ PFS
R-CHOP
Treatment comparison will be made using a two-sided level 0.05 stratified log-rank test.  While 
randomization is stratified by region, the primary and secondary stratified efficacy analyses will 
omit this factor in order to avoid loss of efficiency.  Therefore, the randomization stratification 
factors to be used in the efficacy analyses are IPI score (low/low−intermediate [excluding 
patients having an IPI score 0 without bulky disease], high−intermediate, or high-risk) and 
planned number of CHOP cycles (8 vs. 6 cycles, see Section 3.1).  The Kaplan–Meier method 
will be used to estimate the PFS distribution for each treatment arm.  The Kaplan–Meier curve 
will provide a visual description of the differences across treatment arms.  Estimates of the 
treatment effect will be expressed as hazard ratios using a stratified Cox proportional-hazards 
analysis, including 95% confidence limits.  Median PFS is not expected to be reached in this 
study at the time of the primary analysis; hence, the 1-year, 2-year, and 3-year PFS rates will be 
used to describe PFS in addition to the hazard ratio. 
Missing Data 
For PFS, patients who do not have documented disease progression or have died will be 
treated as censored observations on the date of the last tumor assessment.  If no tumor 
assessments were performed after the baseline visit, PFS will be censored at the time of 
randomization. 
For OS, data from patients who do not have documented deaths will be censored on the last 
date they were known to be alive. 
For the response endpoints, patients with no response assessments (for any reason) will be 
considered non-responders. 
Determination of Sample Size 
Approximately 1400 patients need to be recruited and randomized in a 1:1 ratio to the two 
treatment arms (R-CHOP and G-CHOP).  The sample size considerations are based on the 
following assumptions: 
•  A two-sided log-rank test 
•  80% power at the 5% significance level 
•  A 25% reduction in the risk of disease progression, relapse, or death (i.e., the PFS hazard 
ratio of G-CHOP over R-CHOP is 0.75) 
Venetoclax—F. Hoffmann-La Roche Ltd 
47/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 2   
Protocol Synopsis (Study BO21005) (cont.) 
•  PFS in the control arm follows a piece-wise exponential distribution, with the hazard rate h(t) 
estimated using historical R-CHOP data as follows:  h(t)
 = 0.0237 for t between 0 and 6 
months; h(t)
 = 0.0414 for t between 6 and 9 months; h(t)
 = 0.0154 for t between 9 and 15 
months;  
h(t)
  = 0.0094 for t between 15 and 21 months; h(t)
 = 0.0066 for t beyond 21 months. 
On the basis of this hazard rate assumption for the control arm and a hazard ratio of 0.75, 
the 3-year PFS rate is expected to improve from 60% to 68%.  One-year, 2-year, and 3-
year PFS rates will be provided as an alternative summary of the magnitude of treatment 
benefit because estimates of median PFS are not expected to be reached in either arm.  
Inference will be based solely upon the log-rank test and power calculations will be based 
on the hazard ratio. 
•  An annual dropout rate of 5% 
•  One planned futility analysis for PFS and one planned efficacy interim analysis for PFS (see 
the interim analysis plan for alpha- and beta-function spending) 
•  In addition, a futility analysis based on the CR rates at the end of treatment will be performed 
for the 200 randomized patients 
 
Based on these assumptions, 405 PFS events are needed for the primary analysis.  There will 
be a staggered recruitment in order to recruit the first 200 patients at a fewer number of sites 
(~80 sites) and then open up recruitment at all 250 sites following the IDMC meeting for the 
futility analysis based on CR rates.  The maximum accrual rate will be approximately 48 patients 
per month, after the IDMC meeting plus 6 months of ramp up.  The 1400 patients enrolled over 
3 years and followed for an additional 7 months will provide 405 PFS events based on 
investigator assessment.  The primary analysis will be performed once 405 
investigator-assessed PFS events have been observed.    
The PK assessment will apply to a subset of up to 40 Japanese patients receiving G-CHOP 
chemotherapy in this study.  Data from 12 Japanese patients enrolled in a Phase I study 
(JO21900) with obinutuzumab are available; therefore, more than 52 patients will be analyzed in 
total.  In addition, to compare the existing NCA parameters from Phase I/II obinutuzumab 
studies, 6 patients will undergo full sampling.  This sample size is believed to be sufficient to 
compare the ethnic difference between Japanese patients and non-Japanese patients. 
Interim Analyses
The IDMC will be used to evaluate efficacy and safety at three formal interim analyses, as well 
as periodic safety reviews, and to recommend if the trial should be stopped early.  All 
summaries and analyses will be prepared by the Independent Data Coordinating Center and 
presented by treatment arm for the IDMC’s review.  Members of the IDMC will be external to the 
Sponsor and the study team and will follow a charter that outlines their roles and responsibilities. 
Three interim analyses, two for futility and one for efficacy, are planned.  The first interim 
analysis will be based on differences in end-of-treatment CR rates in the first 200 randomized 
patients.  This interim analysis will be conducted once 200 patients have completed their end-
of-treatment response assessment or have withdrawn prematurely.  The IDMC may recommend 
that the study be stopped for futility if the observed difference in CR rates is <
 5% in favor of 
G-CHOP (i.e., the CR rate needs to be ≥
 5% higher on G-CHOP compared with R-CHOP). 
The second interim analysis (PFS futility and safety analysis) will be conducted when 
approximately 33% of the required PFS events (134 of 405 total PFS events) have occurred.  
The IDMC may recommend that the study be stopped for futility if the observed PFS hazard 
ratio of obinutuzumab over rituximab is > 1 (futility boundary based on non-binding O’Brien–
Fleming beta-spending function). 
The third interim analysis (PFS efficacy analysis) will be conducted when approximately 70% of 
the required PFS events (284 of 405 total PFS events) have occurred.  PFS will be tested at the 
Venetoclax—F. Hoffmann-La Roche Ltd 
48/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 2   
Protocol Synopsis (Study BO21005) (cont.) 
Venetoclax—F. Hoffmann-La Roche Ltd 
49/Statistical Analysis Plan GO27878, Version 1 
significance level determined using the O’Brien–Fleming alpha-spending function so that the 
overall type I error rate will be maintained at the 0.05 level.  With 70% information, the alpha 
spending is 0.015. 
Additional details of the interim analyses will be provided in the IDMC Charter and Statistical 
Analysis Plan. 
 


 
Appendix 3  Schedule of Assessments 
Study Period 
Screening 
Period 
Treatment Period 
Follow-Up Period 
Participation 
End 
DLT Observation Period 
(Cycle 1-Cycle 2)
 a
Cycles of Treatment Period 
Cycle 1 
Cycle 
2 
Cycle 3 
Cycle 4 
Cycles
5-6 
Cycles 
7-8 
End of 
Treatment 
Follow-Up 
Survival 
Follow-
up 
End of 
Study/Early 
Study 
Termination 
Day of Cycle 
Screening 
Once 
(-21 to -1) 1
 4
 
5
 
8 
(±1)
15 
(±1)
1 
(±2)10
1 
(±2)
10 
(±2)
1 
(±2)
10 
(±2)
once 
(15- 
21) 
1 
(±2) 
10 
(±2) 1 (±2)
Cycle 8 Day 
1 (or last 
cycle 
received)
 
+ 6−8 
weeks 
Every 
3 months 
from End of 
Treatment 
visit (±14) 
Every 
6 months 
(±14) 
 
Informed consent 
x 
  
  
    
  
    
  
  
  
  
  
  
  
  
  
  
 
 
Demographic data 
x 
  
  
    
  
    
  
  
  
  
  
  
  
  
  
  
 
 
General medical history & baseline 
conditions 
x 
  
  
    
  
    
  
  
  
  
  
  
  
  
  
  
 
 
Concomitant medications & adverse 
events 
x 
x 
x 
  x 
x 
x 
  
x 
  
x 
  
  
x 
  
x 
x 
x
 b
 
x
 b
ECOG Performance Status 
x 
  
  
    
  
    
  
  
  
  
  
  
  
  
x 
x 
 
  
Complete physical examination 
x 
  
  
    
  
    
  
  
  
  
  
  
  
  
  
  
 
 
Targeted physical examination 
  
  
  
    
  
x 
  
x 
  
x 
  
  
x 
  
x 
x 
x 
 
x 
Vital signs 
c
x
 x
 
x
 
d x 
d
x 
x 
x 
  
x 
  
x 
  
  
x 
  
x 
x 
x 
 
x 
12-Lead ECG (in triplicate) 
x 
  
 
  
 
  
    
  
  
  
  
  
  
  
  
  
  
 
 
MUGA/Echocardiogram
 e
x 
  
  
    
  
    
  
 
  
  
  
  
  
  
 
 
 
 
Clinical response assessment 
f
  
  
  
    
  
x 
  
x 
  
x 
  
  
x 
  
x 
x 
x 
 
x 
PET-CT scan & Response 
Assessment 
g, h
x 
i
  
  
    
  
    
  
  
  
  
x 
  
  
  
x 
x 
j
 
(x) 
k
Drug administration 
Venetoclax—F. Hoffmann-La Roche Ltd 
50/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 3  Schedule of Assessments (cont.) 
Study Period 
Screening 
Period 
Treatment Period 
Follow-Up Period 
Participation 
End 
DLT Observation Period 
(Cycle 1-Cycle 2)
 a
Cycles of Treatment Period 
Cycle 1 
Cycle 
2 
Cycle 3  
Cycle 4 
Cycles
5-6 
Cycles 
7-8 
End of 
Treatment  Follow-Up  
Survival 
Follow-
up 
End of 
Study/Early 
Study 
Termination 
Day of Cycle 
Screening 
Once 
(-21 to -1) 1
 4
 
5
 
8 
(±1)
15 
(±1)
1 
(±2) 10
1 
(±2)
10 
(±2)
1 
(±2)
10 
(±2)
once 
(15- 
21) 
1 
(±2) 
10 
(±2) 1 (±2)
Cycle 8 Day 
1 (or last 
cycle 
received)
 
+ 6−8 
weeks 
Every 
3 months 
from End of 
Treatment 
visit (±14) 
Every 
6 months 
(±14) 
 
Venetoclax (GDC-0199) 
l
 
 
x (Cycle 1 Days 4-10, and Cycles 2-8 Days 1-10)  
 
 
 
 
Rituximab 
m
 
x 
  
    
  
x 
  
x 
  
x 
  
  
x 
  
x 
  
  
 
 
Obinutuzumab 
n
 
x 
  
  x 
x 
x 
  
x 
  
x 
  
  
x 
  
x 
  
  
 
 
Cyclophosphamide
 o
 
x 
  
    
  
x 
  
x 
  
x 
  
  
x 
  
  
  
  
 
 
Doxorubicin
 o
 
x 
  
    
  
x 
  
x 
  
x 
  
  
x 
  
  
  
  
 
 
Vincristine
 o
 
x 
  
    
  
x 
  
x 
  
x 
  
  
x 
  
  
  
  
 
 
Prednisone 
o, p
 
x
 
(daily)
 
 
 
x
 
p
 x  
p 
 
x
 
p
 
 
x
 
 
 
 
 
 
 
Local laboratory assessments 
Hematology 
q
x
 x
 d
x 
d x 
d
x  x  x  x  x  x  x  x    
x  x  x  
x  
x  
 
x 
Serum chemistries 
r
x
 x
 d
x 
d x 
d
x  x  x  x  x  x  x  x    
x  x  x  
x  
x  
 
x 
Serum pregnancy test 
s
x 
  
  
    
  
    
  
  
  
  
  
  
  
  
  
  
 
 
HBV and HCV screening 
t
x 
  
  
    
  
    
  
  
  
  
  
  
  
  
  
  
 
 
Hepatitis B DNA on PCR 
(as indicated) 
t
x 
  
  
    
  
x 
  
x 
  
x 
  
  
x 
  
x 
x 
x 
 
 
Venetoclax—F. Hoffmann-La Roche Ltd 
51/Statistical Analysis Plan GO27878, Version 1 


 
 
Appendix 3  Schedule of Assessments (cont.) 
Study Period 
Screening 
Period 
Treatment Period 
Follow-Up Period 
Participation 
End 
DLT Observation Period 
(Cycle 1-Cycle 2)
 a
Cycles of Treatment Period 
Cycle 1 
Cycle 
2 
Cycle 3  
Cycle 4 
Cycles
5-6 
Cycles 
7-8 
End of 
Treatment  Follow-Up  
Survival 
Follow-
up 
End of 
Study/Early 
Study 
Termination 
Day of Cycle 
Screening 
Once 
(-21 to -1) 1
 4
 
5
 
8 
(±1)
15 
(±1)
1 
(±2) 10
1 
(±2)
10 
(±2)
1 
(±2)
10 
(±2)
once 
(15- 
21) 
1 
(±2) 
10 
(±2) 1 (±2)
Cycle 8 Day 
1 (or last 
cycle 
received)
 
+ 6−8 
weeks 
Every 
3 months 
from End of 
Treatment 
visit (±14) 
Every 
6 months 
(±14) 
 
Bone marrow biopsy/aspirate 
u
x 
i
  
  
    
  
    
  
  
  
  
  
  
  
  
(x) 
u
(x) 
u   
 
(x)
 u
Central laboratory assessments 
Blood sample for DLBCL NHL 
biomarker studies 
 
 
x
 
v
  
    
  
    
  
  
  
  
  
  
  
  
  
  
 
 
Tumor biopsy for BCL2 family 
expression by IHC 
x 
i, w
  
  
    
  
    
  
  
  
  
  
  
  
  
x
 x
 
 
 
Tissue punch for TMAs (in Phase II 
only) 
x
w
  
  
    
  
    
  
  
  
  
  
  
  
  
  
  
 
 
PK sample for venetoclax 
(GDC-0199) 
See Appendix 3 of protocol 
PK sample for rituximab 
m
See Appendix 3 of protocol 
PK sample for obinutuzumab 
n
See Appendix 3 of protocol 
PK for CHOP components 
See Appendix 3 of protocol 
Plasma sample for resistance 
markers 
y
x
  
 
 
 
 
 
 
 
 
 
 
x
 
 
 
 
 
 
 
x 
Blood sample for lymphocyte 
subsets 
x 
  
  
    
  
    
  
  
  
  
  
  
  
  
x 
x 
z
 
  
Blood sample for assessment of 
minimal residual disease MRD in 
 
x
 v
  
  
 
  
  
 
  
  
x 
  
  
  
  
 
x 
x 
aa
 
 
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Appendix 3  Schedule of Assessments (cont.) 
Study Period 
Screening 
Period 
Treatment Period 
Follow-Up Period 
Participation 
End 
DLT Observation Period 
(Cycle 1-Cycle 2)
 a
Cycles of Treatment Period 
Cycle 1 
Cycle 
2 
Cycle 3  
Cycle 4 
Cycles
5-6 
Cycles 
7-8 
End of 
Treatment  Follow-Up  
Survival 
Follow-
up 
End of 
Study/Early 
Study 
Termination 
Day of Cycle 
Screening 
Once 
(-21 to -1) 1
 4
 
5
 
8 
(±1)
15 
(±1)
1 
(±2) 10
1 
(±2)
10 
(±2)
1 
(±2)
10 
(±2)
once 
(15- 
21) 
1 
(±2) 
10 
(±2) 1 (±2)
Cycle 8 Day 
1 (or last 
cycle 
received)
 
+ 6−8 
weeks 
Every 
3 months 
from End of 
Treatment 
visit (±14) 
Every 
6 months 
(±14) 
 
Phase II only 
Optional Roche Clinical Repository 
Sample(s) 
bb
 
(x)
 
v
  
    
  
    
  
  
  
  
  
  
  
  
  
  
 
 
Contacts for Survival Follow-up 
cc
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x
 
 
 
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Appendix 3  Schedule of Assessments (cont.) 
BSA =
 body surface area; CHOP =
 cyclophosphamide, doxorubicin, vincristine, and prednisone; CR =
 complete response; CT
 =
 computed tomography; DLBCL =
 diffuse large B-cell 
lymphoma; DLT
 =
 dose-limiting toxicity; ECOG =
 Eastern Cooperative Oncology Group; G-CHOP =
 obinutuzumab +
 CHOP; HBcAb =
 hepatitis B core antibody; HBsAg =
 hepatitis B 
surface antigen; HBV =
 hepatitis B virus; HCV =
 hepatitis C virus; Hep C Ab =
 hepatitis C core antibody; IHC =
 immunohistochemistry; MRD
 =
 minimal residual disease; 
MUGA =
 multiple-gated acquisition scan; NHL =
 non-Hodgkin’s lymphoma; PCR =
 polymerase chain reaction; PET =
 positron emission tomography; PK =
 pharmacokinetic; 
R-CHOP =
 rituximab
 +
 CHOP; RCR =
 Roche Clinical Repository; TMA =
 tissue microarray; (x)
  =
 indicates that time point may not apply to all patients, depending on specific 
requirements or patient consent. 
a  If venetoclax dosing starts at Cycle 1 Day 1 or 2 then the DLT observation period would be shortened to one cycle. 
b All adverse events and medications to be reported for 30 days after the last dose of venetoclax or CHOP, or 90 days after the last dose of rituximab or obinutuzumab, whichever is 
later.  After this period, serious adverse events or adverse events of special interest that are believed to be related to study drug treatment need to be reported. 
c Vital signs to include body temperature, heart rate, blood pressure, and weight.  Height and BSA are only required at screening.  Subsequent BSA required if > 10% change in 
weight. 
d Follow the specific time points described in Section 4.5.1.5 of protocol. 
e Assessment of cardiac function is to be performed at screening (Day -21 to Day -1) and then as clinically indicated. 
f Clinical response assessment is to include physical examination for the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.  Does not include 
assessment based on imaging. 
g  Imaging should be PET-CT at screening and 6−8 weeks after Cycle 8, Day 1 or last cycle received.  All others may be CT only. 
h  Response assessment will be determined by the investigator on the basis of PET+CT and clinical assessment using the modified Lugano Classification (see Appendix 4).  
Response assessment should be determined on the basis of the imaging conducted on this day but is not required to be done on the same day. 
i  All screening assessments to be conducted within 21 days prior to first dose with the exception of the PET-CT scan, tumor biopsy, and bone marrow biopsy/aspirate.  See 
Section 4.5.2 of protocol. 
j  Required every 6 months for 2 years. 
k Assessment does not need to be performed if it has been performed within the last 30 days. 
l Venetoclax dosing on Cycle 1 Day 4 (or 3 days after first CHOP dose) to Cycle 1 Day 10 and then Cycles 2−8 Days 1−10.  Alternative dosing regimens are possible based on data 
from initial cohorts per Protocol Section 3.1.2.2 of protocol. 
m  Arm A (R-CHOP) patients only. 
n  Arm B (G-CHOP) patients only. 
o  Patients who experience ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical 
Monitor. 
p Prednisone days 1−5 of each Cycle 1−6.
 
q Hematology to include complete blood count with platelets and WBC count differential. 
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Appendix 3  Schedule of Assessments (cont.) 
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r Serum chemistries listed in Section 4.5.1.5 of protocol. 
s Required for all women of reproductive potential (see inclusion criteria). 
t HBsAg, anti-HBcAb, and Hep C Ab serology (also HCV and RNA by polymerase chain reaction if the patient is HCV antibody positive) required.  For hepatitis B core 
antibody−positive patients, the HBV-DNA titer should be determined using real-time PCR at baseline and monthly until at least 12 months after the last treatment cycle. 
u To be performed within 3 months prior to initiating therapy.  If positive, not done or indeterminate at screening, should be repeated at end of therapy to document complete 
remission, if appropriate.  Should be conducted at end of study and/or early termination only if CR was not previously confirmed at end of treatment. 
v  This baseline sample may be collected at any time before starting treatment.  
w  Sample must include 20 unstained, serial slides or a tissue block.  In addition, if slides are sent a tissue punch from excisional biopsies must be taken from the tissue block for 
construction of TMAs in Phase II only.  Tissue samples to be sent to the central laboratory within 3 weeks of patient randomization. 
x  Only required at disease progression. 
y Plasma sample will be collected for analysis of circulating tumor markers of response/resistance at baseline (pre-dose), between Cycle 4 Day 15 and Cycle 5 Day 1, and at end of 
study and/or early termination visit. 
z Required only at months 6 and 12, and every 6 months thereafter until end of study. 
aa  Required every 3 months for 1 year. 
bb  Optional blood sample is requested at baseline for collection and storage at the RCR.  Any samples at the central laboratories except the PK samples that remain from the planned 
study assessments may be taken and sent to the RCR if the patient consents to the optional RCR sampling. 
cc Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 6 months until death, loss to follow-up, consent 
withdrawal, or study termination by Roche, whichever occurs first.  
 
  


 
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Appendix 4   
The Modified Lugano Classification:  Revised Criteria for 
Response Assessment 
Responses should be determined on the basis of radiographic and clinical evidence of 
disease.  Assessment of positron emission tomography (PET)-computed tomography 
(CT) should follow the Recommendations for Initial Evaluation, Staging, and Response 
Assessment for Hodgkin and Non-Hodgkin’s Lymphoma:  The Lugano Classification 
described by Cheson (2014), 
is presented in the Revised Criteria for Response 
Assessment table with the following modifications:  (1) For complete response (CR), if 
the bone marrow was involved by lymphoma or indeterminate prior to treatment, the 
infiltrate must have cleared on repeat bone marrow biopsy; (2) For PET-CT-based partial 
response (PR), CT criteria for PR (or CR) must also be met. 
Selection of measured dominant (indicator) lesions:   
•  Up to six of the largest dominant nodes, nodal masses, and extranodal lesions 
selected to be clearly measurable in two diameters 
A measurable node must have a longest transverse diameter of a 
lesion (LDi) >
 1.5 cm. 
A measurable extranodal lesion should have an LDi >
 1.0 cm. 
•  Nodes should preferably be from disparate regions of the body and should include, 
where applicable, mediastinal and retroperitoneal areas. 
•  Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, and 
lungs), gastrointestinal (GI) involvement, cutaneous lesions, or those noted on 
palpation. 
•  If possible, they should be from disparate regions of the body 
•  Should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved 
 
Selection of non-measured (non-indicator) lesions: 
•  Any disease not selected as measured, dominant disease and truly assessable 
disease should be considered not measured. 
These sites include any nodes, nodal masses, and extranodal sites not 
selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone 
lesions, leptomeningeal disease, abdominal masses, and other lesions that 
cannot be confirmed and followed by imaging. 
 


 
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Appendix 4   
The Modified Lugano Classification:  Revised Criteria for 
Response Assessment (cont.)   
In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, and bone marrow), 
18F-fleurodeoxyglucose (FDG) uptake may be greater than in the mediastinum with 
complete metabolic response, but should be no higher than surrounding normal 
physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid 
growth factors).


 
 
Appendix 4   
The Modified Lugano Classification: Revised Criteria for Response Assessment (cont.) 
Response
 Site
 
PET-CT−Based Response 
CT-Based Response 
 
Complete
 
metabolic
 
response 
Complete radiologic response (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3 a with or without a residual mass on 5PS
 b 
It is recognized that in Waldeyer’s ring or extranodal sites 
with high physiologic uptake or with activation within spleen 
or marrow (e.g., with chemotherapy or myeloid 
colony-stimulating factors), uptake may be greater than 
normal mediastinum and/or liver.  In this circumstance, 
complete metabolic response may be inferred if uptake at 
sites of initial involvement is no greater than surrounding 
normal tissue even if the tissue has high physiologic 
uptake. 
Target nodes/nodal masses must regress to ≤ 1.5 cm in LDi. 
No extralymphatic sites of disease. 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Complete 
Bone marrow 
No evidence of FDG-avid disease in marrow. 
If the bone marrow was involved by lymphoma prior to 
treatment, the infiltrate must have cleared on repeat bone 
marrow biopsy. 
If the bone marrow was involved by lymphoma prior to 
treatment, the infiltrate must have cleared on repeat bone 
marrow biopsy. 
 
Partial metabolic response 
Partial remission (all of the following) 
Partial 
Lymph nodes and 
extralymphatic sites 
Score of 4 or 5 b with reduced uptake compared with 
baseline and residual mass(es) of any size. 
At interim, these findings suggest responding disease. 
At end of treatment, these findings indicate residual 
disease. 
CT-based response criteria for PR (or CR) must also be 
met. 
≥ 50% decrease in SPD of up to 6 target measureable nodes 
and extranodal sites. 
When a lesion is too small to measure on CT, assign 
5 mm
 ×
 5 mm as the default value. 
When no longer visible, 0 ×
 0 mm. 
For a node >
 5 mm
 ×
 5 mm, but smaller than normal, use 
actual measurement for calculation. 
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Appendix 4   
The Modified Lugano Classification: Revised Criteria for Response Assessment (cont.) 
Response
 Site
 
PET-CT−Based Response 
CT-Based Response 
Nonmeasured lesion 
Not applicable 
Absent/normal, regressed, but no increase. 
Organ enlargement 
Not applicable 
Spleen must have regressed by >
 50% in length beyond 
normal. 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy allowed).  If 
there are persistent focal changes in the marrow in the 
context of a nodal response, consideration should be given 
to further evaluation with MRI or biopsy or an interval scan. 
Not applicable 
 
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 for up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met. 
Nonmeasured lesion 
Not applicable 
No increase consistent with progression. 
Organ enlargement 
Not applicable 
No increase consistent with progression. 
New lesions 
None 
None 
No response 
or stable 
disease 
Bone marrow 
No change from baseline 
Not applicable 
 
Progressive metabolic disease 
Progressive disease (requires at least 1 of the following) 
Progressive 
Disease 
Individual target 
nodes/nodal lesions 
Score 4 or 5 b with an increase in intensity of uptake from 
baseline. 
 
 
PPD progression:   
An individual node/lesion must be abnormal with:   
• LDi
 >
 1.5 cm AND  
• Increase  
by  ≥ 50% from PPD nadir AND  
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Appendix 4   
The Modified Lugano Classification: Revised Criteria for Response Assessment (cont.) 
Response
 Site
 
PET-CT−Based Response 
CT-Based Response 
 
and/or 
•  An increase in LDi or SDi from nadir 
•  0.5 cm for lesions
 ≤
 2 cm 
•  1.0 cm for lesions
 >
 2 cm 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at interim or 
end-of-treatment assessment. 
 
Nonmeasured lesion 
None 
New or clear progression of preexisting 
Organ enlargement 
 
 
 
 
and/or 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase beyond 
baseline (e.g., 15 cm spleen must increase to
 >
 16 cm).  If no 
prior splenomegaly, must increase by at least 2 cm from 
baseline. 
New or recurrent splenomegaly. 
New lesions 
New FDG-avid foci consistent with lymphoma rather than 
another etiology (e.g., infection, inflammation).  If uncertain 
regarding etiology of new lesions, biopsy or interval scan 
may be considered. 
 
and/or 
Regrowth of previously resolved lesions. 
A new node >
 1.5 cm in any axis. 
A new extranodal site >
 1.0 cm in any axis; if <
 1.0 cm in any 
axis, its presence must be unequivocal and must be 
attributable to lymphoma. 
Assessable disease of any size unequivocally attributable to 
lymphoma. 
Bone marrow 
New or recurrent FDG-avid foci. 
New or recurrent involvement 
 
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Appendix 4   
The Modified Lugano Classification: Revised Criteria for Response Assessment (cont.) 
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5-PS
 =
 5-point scale; CR
 =
 complete response; CT
 =
 computed tomography; FDG
 =
 fluorodeoxyglucose; GI
 =
 gastrointestinal; LDi
 =
 longest transverse diameter of a 
lesion; MRI
 =
 magnetic resonance imaging; PET =
 positron emission tomography; PPD
 =
 cross product of the LDi and perpendicular diameter; PR
 =
 partial response; 
SDi =
 shortest axis perpendicular to the LDi; SPD
 =
 sum of the product of the perpendicular diameters for multiple lesions. 
a  A score of 3 in many patients indicates a good prognosis with standard treatment, especially if scored at the time of an interim scan.  However, in studies involving 
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). 
b  PET 5-PS:  1, no uptake above background; 2, uptake ≤
 mediastinum; 3, uptake <
 mediastinum but ≤
 liver; 4, uptake moderately
 >
 liver; 5, uptake markedly higher 
than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
 
 


 
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Appendix 5   
A Bayesian Predictive Probability Design for Phase II Studies 
The Phase II study is designed to test the null hypothesis H0: p ≤ p0 at a level of α and to 
have sufficient power 1−β under the alternative hypothesis H
1: p ≥ p1, where p0 is the 
response rate using standard treatment, p1 is the target response rate of the study 
treatment, and α and β are the type I and type II error rates. 
Bayesian framework starts with a prior π(p) ~ Beta (a0, b0), a0 and b0 essentially 
indicating the number of prior responses and nonresponses.   
The maximum number of patients is Nmax.  In the fixed sample design, the number of 
responses X ~ Binomial (Nmax, p) and the posterior distribution of the response rate is 
P|X =
 x ~ Beta (a0 +
 x, b0 +
 Nmax−x).   
H0 is rejected if the posterior probability Pr(P >
 p0|X =
 x)
 >
 θT, where θT is the threshold for 
the posterior probability that would be used to reject the null hypothesis at the end of the 
study. 
At an interim analysis the number of patients is n ≤ N
max, the number of responses X ~ 
Binomial (n, p) and the posterior distribution of the response rate is P|X =
 x ~ Beta (a0 +
 x, 
b0 +
 n−x).  The distribution of the number of responses in the potential m =
 Nmax−n future 
patients is Y ~ Beta-Binomial (m, a0 +
 x, b0 +
 n−x).  For any given Y =
 i, the probability that 
the response rate is larger than p0 given x
 +
 i responses in n
 +
 m =
 Nmax patients is 
Bi
 =
 Pr(P >
 p0|X =
 x, Y =
 i).  The predictive probability (PP) of concluding a positive result at 
the end of the study based on the current data is given by the weighted sum. 
 
where the posterior probability in the index function is numerically solved in R, since the 
distribution of the response rate difference, i.e., the difference of two beta random 
variables (posterior  of and posterior of ) are not analytically available.  
 


 
Appendix 6   
BCL-2 and c-MYC Immunohistochemistry Scoring Algorithm 
Table 1  Criteria for VENTANA BCL-2 Diagnostic Assessment 
Clinical 
Diagnosis 
Clinical 
Score 
Staining Criteria 
0 
No staining in tumor cells or <
 50% tumor cells with 
cytoplasmic BCL-2 staining of any intensity 
Negative 
1
 + 
≥
 50% of tumor cells with weak or higher cytoplasmic BCL-2 
staining but <
 50% of tumor cells with moderate or strong 
staining intensity 
2
 + 
≥
 50% of tumor cells with moderate or higher cytoplasmic 
BCL-2 staining but <
 50% of tumor cells with strong staining 
intensity 
Positive 
3
 + 
≥
 50% of tumor cells with strong cytoplasmic BCL-2 staining 
 
Table 2  Criteria for VENTANA c-MYC (Y69) Diagnostic Assessment 
Clinical 
Diagnosis 
Staining Criteria 
Negative 
<
 40% of target cells positive for c-MYC at any intensity above background 
staining.  A positive cell is a target cell with staining in the majority of the 
nucleus. 
Positive 
≥
 40% of target cells positive for c-MYC at any intensity above background 
staining.  A positive cell is a target cell with staining in the majority of the 
nucleus.  
 
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